Surface Modification of Titanium Dental Implants

Karan Gulati Editor
Surface
Modification
of Titanium
Dental Implants
Surface Modification of Titanium Dental Implants
Karan Gulati
Editor
Surface Modification
of Titanium Dental Implants
Editor
Karan Gulati
School of Dentistry
The University of Queensland
Herston, QLD, Australia
ISBN 978-3-031-21564-3 ISBN 978-3-031-21565-0 (eBook)

https://doi.org/10.1007/978-3-031-21565-0
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
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Preface
This book aims to present advances in the surface modification of titanium dental
implants, from the macro and micro to nanoscale surface modifications, focusing on
advanced bioactive and nano-engineered dental implants. Through eight chapters,
the book covers a wide array of topics that provide an improved understanding of
the fabrication, bioactivity, therapy, and stability of modified titanium dental
implants. Overall, the book significantly contributes to the ever-changing field of
dental implants. From the basics of why the surface modification is needed to the
advanced state-of-the-art electrochemically anodized nanostructures fabricated on
implants, the book covers the domain of dental implants from a clinical, materials
science, and nano-engineering perspective.
The first chapter, “Titanium: The Ideal Dental Implant Material Choice”, details
the ideal characteristics of titanium that make it the most popular dental implant
material choice. While modern titanium-based dental implants provide optimum
treatment outcomes in healthy conditions, enhanced bioactivity and therapy are
needed to ensure long-term success in compromised patient conditions. The need to
modify the implant surface (especially in compromised conditions that present a
significant therapeutic challenge) is thoroughly reviewed in the chapter “Titanium
Dental Implants in Compromised Conditions: Need for Enhanced Bioactivity and
Therapy”. Advances in dental implants have evolved from macro- to micro- to
nanoscales. The chapter “Macro to Micro: Surface Modification of Titanium Dental
Implants” is devoted to various macro and microscale modifications performed on
titanium-based dental implants. The next generation of dental implants has con-
trolled nanotopography that augments the bioactivity and therapy toward achieving
timely integration and long-term success.
The fourth chapter, “Nano-scale Surface Modification of Dental Implants:
Fabrication”, compiles various nano-engineering tools and techniques that enable
effective nanoscale surface modification of titanium dental implants, focusing on
easy, scalable and cost-effective electrochemical anodization that fabricates con-
trolled nanotopographies on titanium implants. Titanium dioxide (or titania) nano-
tubes (like nanoscale test tubes) can be fabricated on dental implants via anodization
with excellent control over their dimensions. The nanotube-modified implants offer
v
vi Preface
various functionalities, including enhanced bioactivity and local therapy. The fifth
chapter, “From Micro to Nano: Surface Modification for Enhanced Bioactivity of
Titanium Dental Implants”, and the sixth chapter, “Local Therapy from Nano-
engineered Titanium Dental Implants”, categorically explain the strategies employed
to orchestrate implant integration and achieve tailored local therapy from anodized
nanotubular dental implants, respectively. The seventh chapter, “Mechanical
Stability of Anodized Nano-engineered Titanium Dental Implants”, focuses on the
mechanical stability considerations of anodized dental implants. Finally, the eighth
chapter, “Cytotoxicity, Corrosion and Electrochemical Stability of Titanium Dental
Implants”, presents the advances and challenges associated with the cytotoxicity
and corrosion of modified and nano-engineered dental implants. All chapters pres-
ent clinical translation challenges and recommend future directions to advance the
domain, ensuring long-term success, even in compromised patient conditions.
The book is interdisciplinary and will profoundly interest a broad audience,
including dentists, undergraduate/postgraduate/research students, academics, and
material/biomaterial scientists. Since the book describes cutting-edge nanotechnol-
ogy advances in dental implants, it will be valuable to entrepreneurs aiming to
understand the next generation of nano-engineered implants.
Herston, QLD, Australia Karan Gulati

Contents

Titanium: The Ideal Dental Implant Material Choice �� 1
Himanshu Arora
Titanium Dental Implants in Compromised Conditions:
Need for Enhanced Bioactivity and Therapy�� 23
Necla Asli Kocak-Oztug and Ece Irem Ravali
Macro to Micro: Surface Modification of Titanium Dental Implants �� 61
Yifan Zhang, Shuai Li, Ye Lin, Ping Di, and Yan Liu

Nano-scale Surface Modification of Dental Implants: Fabrication�� 83
Ruben del Olmo, Mateusz Czerwiński, Ana Santos-Coquillat,
Vikas Dubey, Sanjay J. Dhoble, and Marta Michalska-Domańska
From Micro to Nano: Surface Modification for Enhanced
Bioactivity of Titanium Dental Implants �� 117
Tianqi Guo, Sašo Ivanovski, and Karan Gulati

Local Therapy from Nano-engineered Titanium Dental Implants�� 153
Anjana Jayasree, Sašo Ivanovski, and Karan Gulati
Mechanical Stability of Anodized Nano-engineered
Titanium Dental Implants �� 199
Divya Chopra and Karan Gulati
Cytotoxicity, Corrosion and Electrochemical Stability
of Titanium Dental Implants�� 219
Tianqi Guo, Jean-Claude Scimeca, Sašo Ivanovski, Elise Verron,
and Karan Gulati
Index�� 255
vii
Titanium: The Ideal Dental Implant
Material Choice
Himanshu Arora
Abbreviations
Å Angstrom
cpTi Commercially pure titanium
GPa Gigapascal
HA Hydroxyapatite
MPa Megapascal
PEEK Polyether ether ketone
Ti-6Al-4V Titanium aluminium vanadium alloy
TiZr Titanium zirconium alloy
ZrO2 Zirconium oxide
1 Introduction
The relationship between edentulism and dentistry is as long as dentistry itself.

Since then, dentists worldwide have been busy finding novel ways to limit or restore
edentulism. Edentulism, whether partial or complete, has seen an increasing trend
in the last few decades, with reports estimating around 120 million Americans are
missing at least one tooth and approximately 35 million are completely edentulous
(American College of Prosthodontists, 2022). Consequences of partial or complete
edentulism range from functional, esthetic, physical, and psychological limitations
affecting the overall oral health related quality of life. Various treatment options
have evolved to solve this health crisis over the past few centuries with oral
H. Arora (*)
School of Dentistry, The University of Queensland, Herston, QLD, Australia
e-mail: himanshu.arora@uq.edu.au
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 1

K. Gulati (ed.), Surface Modification of Titanium Dental Implants,
https://doi.org/10.1007/978-3-031-21565-0_1
2 H. Arora
implantology the latest addition to this list of options. Till date no treatment option
is complete. Each treatment option must compete with the natural dentition in per-
formance and long-term success. This drives the current research and advances in
oral implantology to find the best performing dental implant.
Dental implant is defined as a prosthetic device made of alloplastic material(s)
implanted into the oral tissues beneath the mucosal and/or periosteal layer and on or
within the bone to provide retention and support for a fixed or removable dental
prosthesis; a substance that is placed into and/or on the jawbone to support a fixed
or removable dental prosthesis (The Glossary of Prosthodontic Terms: Ninth
Edition, 2017). Major advances have occurred over the last few decades in the clini-
cal use of oral and maxillofacial implants. Latest statistics on the use of dental
implants reveal that, in the United States alone, an estimated 5 million implants are
placed annually, and a total of 15–20 million implants are placed worldwide (Misch
& Misch, 2015). Dental implants are currently used to replace missing teeth, rebuild
the craniofacial skeleton, provide anchorage during orthodontic treatments, and
even aid in new bone formation in the process of distraction osteogenesis.
In modern dentistry, the dental implant is the one of the best tooth replacement
options for nearly all situations where a tooth is missing or is failing. The primary
reason for this is the extremely high success rate achieved with dental implants.
Saving teeth at all costs is no longer the norm because of the unpredictability of the
longevity of heroic dentistry. In other words, preserving bone and tissue regenera-
tion are now considered to be more important than trying to prolong tooth retention
(Massa & Von Fraunhofer, 2021).
One of the main reasons for the high success rate of dental implants is their abil-
ity to integrate with bone in the oral environment (Misch, 2008). The goal of place-
ment of endosseous dental implants is to achieve osseointegration of the bone with
the implant in order to support a prosthesis (Brånemark et al., 1983; Branemark
et al., 1977). The physical, chemical, and biological properties of dental implant
materials along with their surface characteristics are key factors in their success
(Binon, 2000; Buser et al., 1991). A wide variety of materials has been used for
these implants, but only a few promote osseointegration and biointegration (Weiss
& Weiss, 2001). Titanium and titanium alloys have been the most widely used of
these materials. This chapter will look into the historical aspect of dental implant
materials, drawing comparisons with the modern-day contemporary materials in an
attempt to arrive to a conclusion ‘why titanium is the most suitable dental implant
material?’.
2 Osseointegration
The godfather of modern implants was a Swedish physician and anatomical and
experimental biologist named Per-Ingvar Branemark. He studied bone healing
response and regeneration in the 1950s and in order to observe the functioning of
bone marrow in vivo, he used titanium to make a chamber that could be inserted into
Titanium: The Ideal Dental Implant Material Choice 3
Fig. 1 Radiographic
image of the original
titanium screw placed in
rabbit
tibial bone by
P. I. Branemark showing
the integration of the
implant with bone that led
to discovery of
osseointegration.
(Albrektsson et al., 2017)
rabbit legs to allow microscopic visualization of vital processes (Fig. 1). After a few
months-long series of investigations, he sought to retrieve the chamber for reuse and
found to his annoyance that it could not be removed from the rabbit bone
(Branemark, 1983).
Branemark reportedly was not struck by the significance of this turn of events
until sometime after 1960, when he accepted a professorship in the Department of
Anatomy at Gothenburg University. There, using an adaptation of the titanium
chamber placed in the upper arms of human volunteers, he and his team investigated
the workings and structure of human blood cells under a number of conditions. This
work yielded a great deal of information about the nature of blood, and it showed
the researchers that the titanium serving as lens casings appeared uniquely compat-
ible with the human soft tissue and skin, provoking no adverse immunological reac-
tions. At this point, Branemark began to contemplate using titanium for medical
applications (Albrektsson et al., 2017).
As this understanding advanced, Branemark believed it necessary to coin a new
term to refer to the in-growth of the bone into the threads and crevices of titanium.
He finally settled upon “osseointegration,” derived from the Latin words os (bone)
and integro (to renew) (Branemark et al., 1977). The first and the most important
event that occurs when an implant is placed in host tissue is surface adsorption of
proteins. The amount, composition, and conformational changes of the adsorbed
proteins influence the entire biological response to the material, including antigenic
response, attachment, and growth of cells.
The host response to implants placed in bone involves a series of cell and matrix
events, ideally culminating in tissue healing that is as normal as possible and that
ultimately leads to intimate apposition of bone to the biomaterial, i.e. an operative
definition of osseointegration. For this intimate contact to occur, gaps that initially
exist between bone and implant at surgery must be filled initially by a blood clot,
and bone damaged during preparation of the implant site must be repaired (Szmukler-
Moncler et al., 1998). The material used to construct oral implants plays a major
role in the host response and has been one of the most researched topics in the field
of oral implantology.
4 H. Arora
3 Materials for Endosseous Dental Implants
Today, the goal of the placement of endosseous implants is to achieve osseointegra-

tion at the surface of the implant. Osseointegration, as defined by Branemark, is the
direct contact of the loaded implant material with living bone (Brånemark et al.,
1983) (Fig. 2). The concept of osseointegration has been developed largely from the
work of Branemark and was introduced in 1982 after several decades of animal
work and at least a decade of work in humans (Fenton, 1992; Albrektsson et al.,
2017). This concept represented a fundamental shift away from the prevailing
dogma of the time.
Previously, implant materials were sought which would act as inert substances,
usually eliciting a fibrous encapsulation around them (Lemons, 1990). However, by
definition, osseointegration demands the absence of a fibrous layer (Meffert et al.,
1992), and implies that the biological response of the bone is not one of inertness
toward a foreign material but rather one of integration of the material with the bone
as if it were part of the body. By today’s standards, the presence of a fibrous layer
between bone and implant indicates failure of the implant (Albrektsson et al., 2017;
Buser et al., 2017). In spite of these definitions, there is still controversy about what
osseointegration really represents. For some, osseointegration does not represent an
Fig. 2 Histological photomicrograph showing a direct contact between a titanium screw/implant

(black) and bone tissue using hematoxylin-eosin staining technique. (Albrektsson et al., 2017)
‘advantageous’ response of the body to the material, but simply the lack of a nega-
tive response (Stanford & Keller, 1991).
One of the key requisites for osseointegration is compatibility between bone tis-
sue and the implantable material/device. Biocompatibility has traditionally been
concerned with implantable devices that have been intended to remain within an
individual for a long time. The selection criteria for implantable biomaterials
involves as a list of events that has to be avoided, on the basis that they would be
non-toxic, non-immunogenic, non-thrombogenic, non-carcinogenic, non-irritant
and so on, such a list of negatives becoming, by default, the definition of biocompat-
ibility (Williams, 2008).
A wide variety of materials has been used for endosseous implants. These could
be divided into:
• Materials of historical interest
• Currently used materials
3.1 Materials of Historical Interest
These include various ceramics, polymers, and metals which have been used clini-
cally in the past but are not being used currently due to their disadvantages/compli-
cations or the advent of new and better materials.
Ceramics
Carbon is a ceramic which was introduced as an endosseous implant in the 1970s
(Lemons, 1990). Most of the vitreous (amorphous) carbons were used as coatings
on stainless steel cores since the bulk form was too brittle (Albrektsson et al., 1986).
To increase the mechanical properties of the carbons, silicon was added to form CSi
ceramics. In addition, forms with isotropic (crystalline) properties, such as low tem-
perature isotropic (LTI) and ultra-low temperature isotropic (ULTI), were devel-
oped and had higher strengths, moduli and better toughness (Kent & Bokros, 1980).
The low corrosion and lack of toxic elements of these implants were viewed as
advantageous initially, but the biological response was far inferior to today’s stan-
dards, and many of these implants were exfoliated. Five-year survival rates for these
implants, even under the best conditions, were 24–65% (Mah, 1990; Albrektsson
et al., 1986).
Other ceramics have also been used as endosseous implants. Alumina, hydroxy-
apatite and tricalcium phosphate were introduced in the 1960s and 1970s (Mah,
1990), although the brittleness of the pure forms was not acceptable for most
implants (Williams, 1981b). The single crystal sapphire is a form of alumina which
has sufficient strength to be used as a bulk material in some clinical situations.
Sapphire dental implants (single crystals of aluminium oxide) have been used since
late 1970s, but there are few well-documented long-term follow-up studies. Such
materials lack the strength and abrasion requirements of an implant material
(Kawahara et al., 1980). The biological response to sapphire can be quite favourable
6 H. Arora
and osseointegration probably occurs. The clinical success rates for sapphire
implants range from 69% to 91% after 5 years (Albrektsson et al., 1986).
Fartash et al. (1990) in their experimental study placed nine single crystal sap-
phire dental implants bilaterally into pre-extracted areas in the lower jaw of two
beagle dogs. Implants were analysed after 180 days in situ. Eight implants were
stable, and radiographs disclosed complete bone healing. The ninth implant was
mobile and surrounded by a non-mineralized connective tissue capsule containing
bundles of collagen. Histometric analysis of the alveolar bone surrounding the sta-
ble implants revealed that the value of the bone contact surface ranged from 37.1%
to 86.9% at the light microscopic level.
Single-crystal alumina, which has good mechanical properties and superb bio-
compatibility, has been used successfully for screw types of implants but cannot
reproduce the physiologic function of natural teeth in the free-standing form.
Therefore, a porous alumina dental implant was fabricated for free-standing appli-
cations such that bone ingrowth would provide additional stability (Mah, 1990;
Williams, 1981b).
Yamagami et al. (1988) placed porous alumina dental implants in free-standing
form and bearing occlusal stress in the jaw of rhesus monkeys for 4, 6, and 8 months.
The porous alumina dental implant was designed with a polished cylindrical core of
single-crystal alumina, an outer porous root layer 1 mm thick, and a smooth apex of
poly-crystalline alumina 3–5 mm. The 20 mm long implant used in this animal
experiment had a porous root portion 4 mm in diameter and 7 mm in length.
Implantations were observed from 4 to 8 months. The implants were free-standing
throughout the examination while bearing occlusal stress. Fourteen of the 15
implants were considered successful. Radiographs showed prolific new calcified
bone growth at the sites of the porous alumina root portions. These data demon-
strated that secure bone fixation had been achieved and that a good biologic seal was
provided at the gingival interface.
Ceramics can make up the entire implant, or they can be applied in the form of a
coating onto a metallic core. Low flexural strength and various degrees of dissolu-
tion/solubility of an all-ceramic implant make coating the application of choice in
the field of implant dentistry (Wataha, 1996; Piconi et al., 2003). Coatings can be
dense or porous, depending on the chemical composition of the parent material and
the coating method employed. The goal is to achieve strong adherence between the
coating and the metallic core that withstands functional loading and avoid
fragmentation.
Hydroxyapatite (Ca10(PO4)6(OH)2), tricalcium phosphate (Ca3(PO4)2), and bio-
glasses are some of the more commonly used bioactive ceramics, which possibly
develop a chemical bond of a cohesive nature with bone (Wataha, 1996; Lacefield,
1998). Hydroxyapatite and tricalcium phosphate are still used today as coatings on
metallic cores with good biological response. Bioglass is a complex glass which has
been researched for used as an implant material. Its bio integration with bone seems
to result from dissolution of the ceramic surface to give a silica-rich gel layer cov-
ered by a layer rich in calcium and phosphorous. These ceramic layers seem to
merge chemically with the bone (Hench & Wilson, 1984).
Some of the concerns associated with HA-coated implants were reviewed by

Biesbrock and Edgerton (Biesbrock & Edgerton, 1995) and included microbial
adhesion, osseous breakdown, and coating failure. However, the authors suggested
that in cases where more rapid and enhanced bone implant contact is needed, such
as in type IV bone (low quality porous bone), grafted bone sites, or when short
implants are indicated, HA-coated implants may be preferable. Caulier and co-
workers (Caulier et al., 1997) found improved performance with threaded calcium
phosphate–coated implants placed in less mineralized trabecular bone, although the
thickness of the coating decreased over time.
While the clinical success of HA-coated implants has been reported to be com-
parable to non-coated implants (Alsabeeha et al., 2012), various concerns have been
reported with their use. The degradation of ceramic coatings has been a point of
controversy (Lozada et al., 1993) and concerns have been expressed about their
long-term stability and success (Zablotsky, 1992). The enhanced bacterial suscepti-
bility of the HA coating due to the surface roughness has been a concern when
compared to titanium implants (Ong & Chan, 2017).
Polymers
A variety of polymers has been used as endosseous implants, but their inferior
mechanical properties or poor biological response have limited their use (Lemons,
1990). The advantage of polymers is their ability to be easily fabricated into the
desired shape. In general, the polymer implants promoted a fibrous response even
when coated with carbon (Williams, 1981b).
Metals
Metals are probably the oldest form of material used for dental implants and are still
by far the most common type of materials used today. A diverse number of metals
and alloys have been used as endosseous implants. The gold-based alloys were
among the first alloys to be used for implants, probably because these alloys were
available in dentistry and the technology existed to cast them (Lemons, 1990). As
endosseous implants, they promoted a fibrous interface with bone, and were there-
fore supplanted by stainless steel and tantalum in the 1940s and 1950s (Mah, 1990).
Cobalt chromium alloys were also developed and used as endosseous implants dur-
ing this time. In hindsight, however, the fundamental problem with all these metals
and alloys was the fibrous response which they promoted with bone. By today’s
standards, none of these materials appropriately osseointegrate, probably because
of their inferior corrosion in the body and release of elements into the tissues. All
these metals have been largely replaced today by titanium or titanium alloys.
3.2 Currently Used Materials
The materials being used, almost exclusively currently, for dental implants are tita-
nium and its alloys which are discussed in detail in the next section. Various other
metal alloy combinations, polymers, and ceramics have been proposed and/or
8 H. Arora
potentially used as dental implant materials. Two of them warrant a discussion:

Polyetheretherketone (PEEK) and Zirconia.
PEEK is an organic synthetic polymeric material which is biocompatible and has
good chemical resistance. Young’s modulus of PEEK material in pure form is
3.6 GPa, carbon-fiber-reinforce PEEK (CFR-PEEK) is around 18 GPa which is very
close to bone (14 GPa) (Mishra & Chowdhary, 2019). When compared to titanium
and other metal alloys, PEEK has been reported to exhibit less stress shielding when
used as an implant in load bearing situations (Lee et al., 2012). Although initial
reports have been promising, there is very limited clinical research available on the
use of PEEK as a dental implant material. More research is needed in this interest-
ing material before it could be used as a potential alternative to titanium dental
implants (Mishra & Chowdhary, 2019).
Zirconia has gained considerable interest in implant dentistry over the last decade
(Chopra et al., 2022). Zirconium dioxide (zirconia) ceramics with improved proper-
ties have been introduced as an alternative material to aluminium oxide implants
which were withdrawn from the market in the early 1990s. Currently, tetragonal
zirconia polycrystal, particularly 3 mol% yttrium oxide (yttria) -stabilized zirconia,
is the ceramic of choice for dental implants (Kelly & Denry, 2008). The white,
opaque color of zirconia, along with early reports of good biocompatibility and low
affinity to bacterial plaque, make it a material of interest in biomedical sciences
(Cionca et al., 2017).
Zirconia also exhibits several promising physical and mechanical properties,
including low thermal conductivity, high flexural strength (900–1200 MPa), favour-
able fracture resistance, as well as wear and corrosion resistance. A phenomenon
termed phase transformation toughening gives zirconia its excellent properties
(Sanon et al., 2015). It stops crack propagation resulting from the transformation of
zirconia from the tetragonal phase into the monoclinic phase and the consequent 4%
volume expansion and induction of compressive stresses. However, one of zirco-
nia’s negative properties is its low-temperature degradation or aging. In the pres-
ence of water or water vapor, slow transformation from the tetragonal phase into the
monoclinic phase leads to slow development of roughness, thus producing progres-
sive deterioration of the material (Kelly & Denry, 2008).
Zirconia implants have several advantages over the gold standard titanium
implants. Their opaque colour is beneficial in the aesthetic regions of the mouth.
They have a reduced affinity to bacterial plaque and have been reported to have
more favourable soft-tissue integration as compared to titanium implants (Roehling
et al., 2019). It has been established that micro-rough ZrO2 implants are equivalent
to the ‘gold standard’ Ti micro-rough implants in terms of osseointegration capacity
(Janner et al., 2018).
Although zirconia implants have been reported to have outcomes comparable to
titanium implants in in-vitro studies, clinical reports have failed to replicate these
findings. A recent systematic review reporting on zirconia implants estimated an
overall survival rate of zirconia one- and two-piece implants was 92% (95% CI:
87–95) after 1 year of function (Hashim et al., 2016). Interestingly, early failure of
one-piece zirconia implants ranged between 1.8% and 100%, with the overall early
failure rate calculated at 77% (95% CI: 56–90). Despite the progress made, signifi-
cant research gaps remain, including mechanical stability and local cytotoxicity
concerns. The next generation of zirconia implants will be nano-engineered with
controlled bioactivity to accelerate implant integration, even in compromised patient
conditions (Chopra et al., 2022).
4 Titanium and Its Alloys
Titanium and its alloys are the most common materials used for endosseous implants
and are the materials of choice according to some researchers (Massa & Von
Fraunhofer, 2021). The two forms of titanium used for endosseous dental implants
are commercially pure titanium (cpTi) and the titanium alloy Ti6A14V. These alloys
are basically dilute alloys of oxygen and titanium, with other elements added.
4.1 Titanium in Its Elemental Form
Titanium (Ti) exists as a pure element listed in the periodic table with an atomic
number of 22 and anatomic weight of 47.9. It is the ninth most abundant element
and the fourth most abundant structural metallic element in the earth’s crust, follow-
ing aluminium, iron, and magnesium. Pure titanium is a rather soft nonmagnetic
material. The principal titanium ore reserves, rutile and ilmenite, are found in abun-
dance in the United States, Canada, and Australia. Though the bulk of titanium ore
is mined for use in the pigment industry, 5–10% of titanium ore is used to produce
cp titanium and titanium alloys (Bannon & Mild, 1983).
The element was discovered by Wilheim Gregor, a clergyman, who found the
metal in a “black magnetic sand” in Cornwall in 1791. Three years later, Klaproth
found a rutile that was the oxide of a new metal he named titanium, after the Greek
Titans. He recognized that this metal was identical to the material Gregor had dis-
covered (Williams, 1981a). The commercial production of titanium was not viable
until the 1930s when the refining process was mastered. In 1925, van Arkel refined
the ore using titanium tetraiodide, producing a metal with acceptable properties and
ductility. In the 1930s, Krol developed commercial extraction procedures that are
still used today (Williams, 1981a).
Titanium is produced by heating titanium ore (rutile, ilmenite) in the presence of
carbon and chlorine and then reducing the resultant TiCl4, with molten sodium to
produce a titanium sponge. This sponge is then fused under vacuum or in an argon
atmosphere into ingots composed of the familiar metal (Cotton & Wilkinson, 1971).
Titanium will burn in air and is the only metal that will burn in the presence of nitro-
gen. Pure titanium undergoes a crystallographic change on heating to 882 °C. This
type of transformation occurs in many materials and produces properties signifi-
cantly different from those of the original state.
10 H. Arora
4.2 Titanium in Alloyed Form
Titanium is a dimorphic alloy with two phases: α and ß phase. α-Titanium is hex-
agonal close-packed (hcp) crystal lattice, and ß-Titanium is body-centered cubic
(bcc) lattice. Titanium alloys of interest to dentistry exist in three forms: alpha, beta,
and alpha-beta. These types originate when pure titanium is heated, mixed with ele-
ments such as aluminium and vanadium in certain concentrations, and then cooled.
This treatment produces true solid solutions. These added elements are said to act as
phase-condition stabilizers (Noort & Barbour, 2013).
Aluminium has been called an alpha-phase condition stabilizer. Aluminium also
serves to increase the strength and decrease the weight of the alloy. Vanadium has
been called a beta-phase stabilizer. As aluminium or vanadium is added to Ti the
temperature at which the alpha-to-beta transformation occurs changes to a range of
temperatures. In these ranges, both the alpha and beta forms may exist. The alloy
form desired is maintained at room temperature by quenching the alloy from the
temperature at which the desired form exists. These combination alloys, especially
alpha-beta, may be heat treated to increase their strength. One of such alloys is
Ti-6Al-4V, also known as Grade V titanium alloy. It is composed of 6% and 4% of
aluminium and vanadium, respectively, together with addition of maximum 0.25%
of iron and 0.2% of oxygen. The remaining of the alloy is titanium (Liu et al., 2017).
Another currently used titanium-based alloy for dental implants is an alloy of
Titanium and Zirconium (Ti-Zr). Zirconium belongs to Group 4 (according to new
IUPAC name) in the periodic table, which is the same as titanium and hafnium, have
similar chemical structure and properties. Thus, they have been recognized as non-
toxic and non-allergic. Zirconium is usually used in dentistry in its ceramic form
(ZrO2). Binary Ti-Zr alloys have been developed to improve bioactivity, biocompat-
ibility, and mechanics of titanium for biomedical application. Currently these alloys
are marketed under the name Roxolid (Straumann, Basel, Switzerland) and have been
shown to significantly improve osteoblast adhesion (Sista et al., 2013). A recent sys-
tematic review reported that TiZr implants exhibited similar soft tissue behaviour
when compared with Titanium and Zirconia implants (Fernandes et al., 2022).
Various currently used materials for dental implants have been summarised in Table 1.
4.3 Physical Properties of Titanium and Its Alloys
The atomic structure of titanium is 1s2, 2s2, 2p6, 3s2, 3p6, 3d2, 4s2. The lightly held
3d2 and 4s2 electrons are highly reactive and rapidly form a tenacious oxide that is
responsible for the metal’s biocompatibility. At temperatures up to 882 °C, pure
titanium exists as a hexagonal close-packed atomic structure (alpha phase). Above
that temperature, the structure is body-centred cubic (beta phase) with the metal
finally melting at l665 °C (Park & Lakes, 1992).
The element titanium dissolves several other elements to form alloys. Among
these are silver, aluminium, arsenic, copper, iron, gallium, uranium, vanadium, and
Table 1 Currently used materials for dental implants and their advantages/disadvantages and clinical uses
Dental Elastic
implant modulus
material Composition (GPa) Advantages Disadvantages Clinical use References
Grade IV Oxygen content (0.4%) 110 Biocompatibility, Aesthetic issues, Commercial Noort and Barbour (2013), Guo
cp-Ti Machinability, Corrosion dental implants et al. (2021a) and Darvell (2018)
Soft tissue Possible
integration hypersensitivity to
released Ti
Ti-6Al-4V Alloy with 6% Aluminium 85–115 Improved strength Tissue toxicity due to Implant Liu et al. (2017)
and 4% Vanadium Al and V leakage abutments
Ti-Zr Titanium 85% 98 Biocompatibility, Aesthetic issues, Dental implants Liu et al. (2017) and Sista et al.
Zirconium 13–15% Improved strength Corrosion, (2013)
Titanium: The Ideal Dental Implant Material Choice
Possible
hypersensitivity to
released Ti
ZrO2 Yttria stabilized tetragonal 200 Biocompatibility, Low temperature Dental implants Chopra et al. (2022), Roehling
zirconia Aesthetics, degradation, and abutments et al. (2019), Kelly and Denry
Reduced affinity to Limited long-term (2008) and Janner et al. (2018)
plaque, clinical data
High flexural
strength
PEEK Polyetheretherketone 3–18 Biocompatibility, Very limited clinical Dental implants Mishra and Chowdhary (2019)
Aesthetics data and abutments
11
12 H. Arora
zinc. The addition of trace amounts of carbon, oxygen, nitrogen, and iron will mark-
edly improve the mechanical properties of pure titanium (Weast & Astle, 1981).
Most commercially or surgically pure titanium products have some of the trace ele-
ments present.
Cp-Ti are categorized into four grades depending on impurity content (e.g., car-
bon and oxygen) under the International Organization for Standardization (ISO)
standards 5832-2. The different grades vary mostly in the oxygen content and have
various corrosion resistance ability, ductility, and strength.
• cp Grade I titanium
• cp Grade II titanium
• cp Grade III titanium
• cp Grade IV titanium
Grade 4 cpTi has the most oxygen at 0.4% (Fig. 3). Nitrogen, carbon, hydrogen and
iron are also present, but do not vary much between grades while iron is added for
corrosion resistance. The mechanical and corrosion properties of these alloys may
change significantly with relatively small changes in the concentrations of the minor
elements. Alloying of titanium helps to enhance some of its properties like strength,
corrosion resistance, machinability, as well as lower the modulus of elasticity (Liu
et al., 2017).
Fig. 3 The strength and oxygen contents variation of various grades of commercially pure tita-
nium. (Darvell, 2018)
4.4 Mechanical Properties of Titanium and Its Alloys
In general, titanium is a good choice for intraosseous applications not only due to
the biocompatibility, but also mechanically. Titanium could be processed and
machined in a rapid manner such that the shapes and sizes could be easily con-
trolled. The elastic modulus of cpTi is 110 GPa, which is half that of stainless steel
or cobalt chromium alloy. Tensile properties of cpTi depend significantly on the
oxygen content and, although the ultimate tensile, proof stress and hardness increase
with increased oxygen concentration, this is at the expense of the ductility.
The alloys most commonly used for dental implants are of the alpha-beta variety.
Of these, the most common contains 6% aluminium and 4% vanadium (Ti-6Al-4V).
After heat treatment these alloys possess many favourable physical and mechanical
properties that make them excellent implant materials. They are light, strong, and
highly resistant to fatigue and corrosion. Although they are stiffer than bone, their
modulus of elasticity (stiffness) is closer to bone than any other important implant
metal; the only exception is cpTi. This property leads to a more even distribution of
stress at the critical bone-implant interface because the bone and implant will flex in
a more similar fashion (Liu et al., 2017). Titanium alloys are largely used in indus-
trial applications such as jet engines, air frames, and the aerospace industry, which
require high strength-to-weight ratios and good corrosion resistance. Other applica-
tions include chemical processing, nuclear waste containment, heat exchange units,
seawater desalinization, marine equipment, deep-well drilling, and food processing
situations that require resistance to corrosion.
When compared with cpTi, Ti-6Al-4V has an excellent yield strength and fatigue
properties, excellent corrosion resistance ability and lower elastic modulus (Liu
et al., 2017). However, Ti-6Al-4V alloy has the disadvantage of low wear resistance
and low shear strength (Kong et al., 2011) that could impair the usage as implant
and as in screw form. Such a phenomenon is termed as ‘stress shielding effect’
(Niinomi & Nakai, 2011), which is a due to the stiffness mismatch between implant
material and surrounding bone. Suitable surface treatments have been recommended
to improve this situation.
4.5 Biological Properties of Titanium and Its Alloys
4.5.1 Oxide Coating
Most metals form oxide layers when exposed to the atmosphere. The nature of this
oxide depends on the metal and the conditions under which it was oxidized.
Anything that comes in contact with the implant surface has the potential to change
it. Assuming that the physiologic conditions of the body remain fairly constant, the
behaviour of a metal in the body depends on the character of the oxide layer.
14 H. Arora
Pure titanium, theoretically, may form several oxides. Among these are TiO,
TiO2, and Ti2O3. Of these, TiO2 is the most stable and therefore the most commonly
used under physiological conditions. These oxides form spontaneously on exposure
of Ti to air. Within a millisecond of exposure to air, a 10 Å oxide layer will be
formed on the surface of pure titanium (Kasemo, 1983). Within a minute, this layer
can become 100 Å thick. The metal may be passivated in this way, although the
U.S. Food and Drug Administration (FDA) requires manufacturers of titanium
implants to passivate their products with a nitric acid bath prior to sale. Theoretically,
breakdown of this oxide layer should not occur under physiological conditions.
Many of the titanium alloys, in which titanium is present in concentrations of
85–95%, maintain the passivity of pure titanium.
When an implant is introduced into the body, complex reactions begin to take
place at the oxide/bioenvironment interface. The oxide film grows as ions diffuse
outward from the metal and inward from the environment. The oxide that forms in
the body may, therefore, be somewhat different than that which forms in air. The
rate of formation and composition of this film is important. Although there is no
universally accepted definition of the term “passivity,” for our purposes, if an
implant metal is oxidized and the oxide does not break down under physiological
conditions, the metal is said to be passive or passivated. Few metals display such a
high degree of passivity under physiologic conditions as does titanium. Titanium,
both as a pure metal and as an alloy, is easily passivated, forming a stable TiO2 (tita-
nia) surface oxide that makes the metal corrosion resistant. This oxide will repair
itself instantaneously on damage such as might occur during insertion of an implant
(Guo et al., 2021a).
In the passive state, the rate of dissolution of TiO2 is extremely low. With time,
little change can be seen on the surface of the metal implant but an accumulation of
titanium in tissue can be observed. The normal level of titanium in human tissue is
50 ppm (Williams, 1981a). Values of 100–300 ppm are frequently observed in soft
tissues surrounding titanium implants. At these levels, tissue discoloration with tita-
nium can be seen. This rate of dissolution is one of the lowest of all passivated
implant metals and seems to be well tolerated by the body. The clinical significance
of this data is substantiated by more than 20 years of clinical experience with cpTi
and Ti-6A1-4V alloys (Mombelli et al., 2018).
The surface properties of implants are increasingly emphasized as important to
the biological response that the materials will elicit from the body (Guo et al.,
2021b). Thus, the surface oxide which forms on the titanium alloys is of paramount
importance to its favourable biological properties (Mombelli et al., 2018). In air, the
oxide begins to form in nanoseconds and reaches 20–100 Å thickness in 1 second.
The thickness of the oxide depends upon factors such as the type of machining
which created the metallic surface, roughness of the surface, coolants used during
the machining, and treatments to passivate or sterilize the surface (Donley &
Gillette, 1991).
The oxide layer can be mechanically disrupted, and such damages can result in
the release of titanium particles. Mechanical wear of implant surfaces can occur at
different instances: during implant placement, during the fitting of a dental
prosthesis, due to mechanical cleaning in the context of prevention and therapy of

peri-implant infections, and as a result of micromovements of parts of the implant
and the suprastructure during function (Mombelli et al., 2018). An in vitro micro-
structural analysis of dental implants subjected to insertion torque and pullout tests
suggested that inserting and removing implants reduced the oxide layer (Valente
et al., 2014). These findings were also confirmed by another in vitro study (Deppe
et al., 2018) reporting that the insertion forces could provoke release of particles
from the implant surfaces by stripping them off.
Some chemical agents like acidic products or fluorides used in dental prophy-
laxis agents could decrease the protection of the oxide layer and initiate a corrosion
process. Different patterns of corrosion were observed when titanium grade II or IV
implants were in contact with saliva containing fluoride ions suggesting that the
fluoride ions were incorporated in the oxide layer decreasing its protective proper-
ties (Souza et al., 2015). Chlorhexidine, a chemical commonly used in mouth-
washes, has also been implicated to affect the oxide layer. Although a 0.12%
concentration of chlorhexidine digluconate did not affect the corrosion resistance
(Faverani et al., 2014), a 0.2% chlorhexidine digluconate might induce pitting
(Quaranta et al., 2010).
Dental implants are different from other implantable devices regarding the way
they interact with environment. Dental implants are permanently exposed to the oral
microflora composed of various bacterial species. Bacteria play a prominent role in
the initiation of corrosion by mainly lowering the pH and release of lipopolysac-
charide (LPS) (Barão et al., 2012). LPS has been reported to negatively affect the
resistance to corrosion and increase the surface roughness of titanium (commer-
cially pure and grade IV) (Mathew et al., 2012). Interestingly, it has also been spec-
ulated that bacterial biofilm might lubricate the implant surface, thereby lowering
the frictional forces and, in turn, decreasing corrosive wear (Souza et al., 2010).
4.5.2 Metal Ion Leakage
The pioneers of cpTi use for implants occasionally noticed blackening in the tissue
surrounding the implant. This reaction is an indication of titanium leakage from the
implant, which has been described by other authors (Emneus, 1967). When titanium
alloys are implanted, higher levels of the component elements can be detected in
tissues locally and systemically.
In a clinical evaluation on patients with peri-implant disease, high contents of
particulate and submicron titanium were present in peri-implantitis tissue. The
authors concluded that these high titanium contents in peri-implant mucosa can
potentially aggravate inflammation, which might reduce the prognosis of treatment
interventions (Pettersson et al., 2019). A systematic review evaluating titanium
release from dental implants reported that titanium particles surrounding peri-
implant tissues are a common finding. Periimplantitis sites presented a higher num-
ber of particles compared to healthy implants. The particles were mostly around the
implants and inside epithelial cells, connective tissue, macrophages, and bone.
16 H. Arora
Various mechanisms were described as causes of titanium release, including friction

during implant insertion, corrosion of the implant surface, friction at the implant–
abutment interface, implantoplasty, and several methods used for implant surface
detoxification (Suárez-López del Amo et al., 2018).
Although Ti-6Al-4V alloy has been widespread in use as an implant biomaterial,
it has been reported that the alloy could release of aluminium and vanadium ions
(Smith et al., 1997). In particular, vanadium exhibits a high cytotoxicity and alumi-
num may even induce senile dementia. This said, these leachable metal ions might
cause various health issues such as allergic, cytotoxic effect and even neurological
disorders.
The released titanium ions from a dental implant could potentially lead to aller-
gic or hypersensitivity reactions. Hypersensitivity reactions to metals may arise in
predisposed patients chronically exposed to metallic materials, including dental
implants made of titanium alloys. Although the evidence is weak, and titanium
allergy is rare, hypersensitivity reactions should not be underestimated (Poli et al.,
2021). This hypersensitivity in susceptible patients could lead to implant failure,
and the need for long-term clinical and radiographic follow-up of all implant
patients who are sensitive to metals has been emphasized in the literature (Siddiqi
et al., 2011).
5 Conclusions and Future Directions
The advent of dental implants has revolutionised the field of oral rehabilitation.
From the variety of materials that have been used for manufacturing dental implants
over the last 50 years, none has been as successful as titanium and its alloys. The
unique physical and biochemical properties of titanium such as the presence of sur-
face oxide layer which is responsible for its inherent inertness and biocompatibility
as well as appropriate physical and mechanical properties like strength and elastic
modulus make it an ideal material choice for dental implants. The fact that titanium
can integrate with bone and its surface can be tailored to enhance the process of
osseointegration, make its use possible for supporting prosthetic restorations in a
challenging oral environment. The favourable soft tissue response around titanium
and its alloys helps in maintaining a healthy peri-implant mucosa, thereby promot-
ing the longevity of implant restorations.
Over the last decade zirconia has been developed and marketed as an alternative
to titanium especially in the anterior region of the mouth where greyish hue of tita-
nium can pose certain aesthetic challenges. Zirconia has the inherent inertness and
biocompatibility, as well as successful osseointegration comparable to titanium
implants. The high elastic modulus and potential for low temperature degradation
can pose challenges with this material in the harsh oral environment.
Future research should explore the possibility of using newer materials with elas-
tic modulus comparable to bone to distribute the stresses more evenly around the
implant. The use of polymeric materials like PEEK seems promising in this regard.
More long-term clinical research is needed to better understand the outcomes and
complications with zirconia implants. Surface modification of titanium has been the
focus of research over the last 2 decades and continues to do so. More research is
needed to tailor the titanium surface to integrate at a cellular level with the soft tis-
sue to help prevent the incidence of peri-implantitis and improve the longevity of
dental implants.
Acknowledgements The author declares no conflicts of interest in relation to this manuscript.
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Titanium Dental Implants in Compromised
Conditions: Need for Enhanced Bioactivity
and Therapy
Necla Asli Kocak-Oztug and Ece Irem Ravali
Abbreviations
5FU Fluorouacil
AIDS Acquired immune deficiency syndrome
AP Antiplatelet
APTT Activated partial thromboplastin time
BMPs Bone morphogenetic proteins
COL1 Collagen 1
CVD Cardiovascular disease
ECT Ecarin clotting time
GNAS1 Guanine nucleotide binding protein 1
HAART Highly active antiretroviral treatment
HbA1c Glycohemoglobin
HIV Human immunodeficiency virus
hs-CRP High-sensitivity C-reactive protein
IHD Ischemic heart disease
INR International normalized ratio
IL-6 Interleukin 6
MRONJ Medication-induced osteonecrosis of the jaw
NSAIDs Non-steroidal anti-inflammatory drugs
PEEK Polyetheretherketone
PRP Platelet-rich plasma
N. A. Kocak-Oztug (*)
Faculty of Dentistry, Department of Periodontology, Istanbul University,
Fatih/Istanbul, Turkey
School of Dentistry, The University of Queensland, Herston/Brisbane, Australia
e-mail: asli.kocak@istanbul.edu.tr; n.kocakoztug@uq.edu.au
E. I. Ravali
Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Istanbul Aydın
University, Kucukcekmece/Istanbul, Turkey
e-mail: eceravali@aydin.edu.tr

https://doi.org/10.1007/978-3-031-21565-0_2
24 N. A. Kocak-Oztug and E. I. Ravali
PT Prothrombin time
RA Rheumatoid arthritis
RANKL Receptor activator of nuclear factor kappa-Β ligand
RUNX2 Runt-related transcription factor 2
SERMs Selective estrogen receptor modulators
SLA Sandblasted, large grit, acid-etched
SLE Systemic lupus erythematosus
SS Sjögren’s Syndrome
TCT Thrombin clotting time
Ti Titanium
TiO2 Titanium oxide
VEGF Vascular endothelial growth factor
WHO World Health Organization
1 Introduction
Brånemark defined the osseointegration as, “the direct functional and structural
adhesion between bone and supporting device surface” (Brånemark et al., 1969).
Today, this term is being used to explain the working mechanism of dental implants.
For a successful osseointegration, the implants must be placed carefully into the
prepared area in the jaw, which is structurally and anatomically sufficient. In fact,
the most important factors for a sustainable osseointegration are biocompatible
materials and a healthy bone (Albrektsson et al., 1981).
Early establishment and long-term maintenance of osseointegration after implant
surgery is the key for a long-term success in implant dentistry. Osseointegration is
prompted through diverse factors, which depend on the host bone and the implant.
This mutual interaction between the host and the implant reveals two important fac-
tors necessary for implant success (Fig. 1). The first factor is patient associated,
including the quality/quantity of the bone in the implant surgery area and the
patient’s immune response. The second factor is dental implant characteristics and
whether it will establish rapid osseointegration in the region (Velasco-Ortega et al.,
2019). While patient factors may require therapeutic intervention, the dental implant
allows for ease of modification to allow for successful implant therapy, even in
compromised conditions (Do et al., 2020). In the literature, failure of the implants
is divided either as early implant failure or late implant failure. The failure prior to
the prosthesis loading is defined as early implant failure whereas late implant failure
represents the unsuccessful implants up to 2 years after prosthesis loading. This
implies that loading protocol is also a vital motive for implant success (DeLuca
et al., 2006).
Numerous titanium (Ti) alloys have been produced and used to reinforce implants
as mentioned in the first chapter. According to literature, Ti alloy dental implants
have been successful compared to their pure Ti ancestors with fewer fracture prob-
lems (Ngeow et al., 2020). In addition to strengthening these implants to resist frac-
tures, many attempts have been made to improve the interface between biomaterials
Titanium Dental Implants in Compromised Conditions: Need for Enhanced Bioactivity… 25
Fig. 1 Factors affecting the long-term success of dental implants. (Modified after Elias et al.
(2012), Ngeow et al. (2020) and Albrektsson et al. (1981))
and bone. In addition to looking for alternative materials for strength and/or aes-
thetic reasons, recent research focuses on improving the interaction between bioma-
terials and bone to achieve faster and improved osseointegration. In the past decade
the trend for the implant surfaces has shifted to rough surfaces (Al-Zubaidi et al.,
2020). Until so far, various types of surface modification have been applied to opti-
mize the roughness and the morphology of the implant surface. Some of these mod-
ifications can be listed as electrochemical anodization, calcium phosphate coating,
acid etching, and various combinations of these processes (Rupp et al., 2018; Gulati
et al., 2021b; Guo et al., 2021b).
In the case of successful osseointegration after implant placement surgery, long-
term success is strongly dependent on the bone remodelling rates (Diz et al., 2013;
Ngeow et al., 2020). Bone remodelling is defined as the bone’s physiological reac-
tion to implant loading in the first year of function (Kocak-Oztug et al., 2022).
Physiological changes in ageing and pathological changes can affect bone health
during this period (Ngeow et al., 2020). Several bone conditions can impair the
healing in alveolar bone such as Paget’s disease, osteoporosis, osteogenesis imper-
fecta, etc. Plus, antiresorptive therapy protocols or corticosteroids used to treat these
conditions also affect the bone quality. Numerous autoimmune diseases, diabetes,
smoking, chronic kidney diseases, radiation therapy, some cardiovascular condi-

tions, oral hygiene, and presence of preoperative periodontal disease are the other
risk factors affecting the outcome of implant surgery (Diz et al., 2013; Anner
et al., 2010).
Except for bone changes caused by antiresorptive drugs and radiation treatment,
the effect of other systemic conditions on bone are still being investigated in the
compromised patient groups. Therefore, recent knowledge about implications of
osseointegration for these risk factors is more hypothetical than evidence based. The
current literature lacks sufficient clinical evidence for comparing the long-term sur-
vival of dental implants in healthy patients and compromised patients (Bornstein
et al., 2009; Dutta et al., 2020; Duttenhoefer et al., 2019).
Only a few conditions that may cause pre- or post-operative medical side effects
and implant failure have been reported as absolute contraindications for implant
application. Until now, recent open-heart surgery or aortic surgery, severe bleeding
disorders, some psychiatric illnesses, drug abuse, active treatment phase for cancer
and intravenous bisphosphonates therapy have been listed as absolute contraindica-
tions for dental implant placement (Diz et al., 2013; Hwang & Wang, 2006). Again,
lack of clinical evidence exists to understand how these contraindications may influ-
ence implant success rates. However, for patients combating serious medical condi-
tions, performing implant surgery can be considered as an important problem in
terms of medical ethics. On the other hand, as improvements are made in the treat-
ment of patients’ general health, focusing on oral health can also benefit the general
health of individuals in the long term (Nickenig et al., 2016). In addition to the view
that implant applications will increase the quality of life of patients in the long term,
it is also an accepted fact that selective treatment should be applied in patients
whose general health has been severely affected. For instance, dental implant place-
ment can always be rescheduled until the patient’s systemic health is in a more sta-
ble condition. Additionally, in such conditions, personalized surgical procedures
should be applied with modified implants with active surface to augment healing
and reduce failure rates (Vissink et al., 2018; Al-Zubaidi et al., 2020).
2 Ageing
With age and requirements, the oral cavity’s characteristics and shape will change.
Likewise dental problems and tooth loss will become more common. Partial or total
edentulism caused by periodontal disease or tooth decay can be treated with tradi-
tional fixed or removable dentures. However, implant-supported dentures can sig-
nificantly improve the comfort of patients at this stage of their life by preventing
further bone loss, providing stability while speaking and eating (Do et al., 2020;
Reissmann et al., 2017; Chan et al., 2021).
Biological ageing alters the immune response, inflammation, regeneration, and
the stages of the wound healing. Further, ageing slows down the immune response
and prolongs the inflammation period by boosting the release of inflammatory bio-
markers. Additionally, ageing affects the regeneration process by reducing the num-
ber of mesenchymal stem cells and altering the angiogenesis (Gündoğar et al.,
2021). The reduced quantity of mesenchymal stem cells also negatively influences
the bone tissue wound healing (Maxson et al., 2012). Attributed to changes in cell
activity, reduced collagen production, decreased matrix metalloproteinase levels
and increased apoptosis, ageing can lead to an imbalance in bone healing. From a
dental implant perspective, ageing might have an adverse effect on osseointegration
after implant surgery (Bartold et al., 2016).
Related studies in the literature represents the cumulative survival rate of dental
implants to be around 94% (Hoeksema et al., 2016). However, considering the
increase in the bone/soft tissue pathology around the implants and the changes in
the marginal bone level by age, it is appropriate to state that more clinical trials are
needed to show how ageing effects the implant survival (Srinivasan et al., 2017).
Oral hygiene practices may also be adversely affected by the slowdown of muscle
activities in old age and the increase in the incidence of diseases such as dementia
and Parkinson’s disease (Chan et al., 2021). These reasons are responsible for the
possibility of increased incidence of implant loss in old age patients (Bartold
et al., 2016).
Detailed clinical and radiological examinations are necessary to track complica-
tions, minimize loss of implants, and identify risk factors, particularly in elderly
patients. In addition, these measures can improve the early acceptance and long
term success of dental implants (Gündoğar et al., 2021).
3 Periodontal Disease
It is known that the human oral cavity is home to over 600 different types of bacteria
(Dewhirst et al., 2010). At least 400 types of bacteria are located in the subgingival
area, making the periodontal pocket a reservoir of periodontal pathogens (Paster
et al., 2001; Taba et al., 2005). Several studies have reported that periodontal patho-
gens spread from the remaining dentition to the implant surface (Lasserre et al.,
2018; Dabdoub et al., 2013; Casado et al., 2011). Therefore, patients who have a
history of periodontal disease with many periodontal pathogens have an increased
potential to contaminate peri-implant area (Casado et al., 2011, 2013; Zhang
et al., 2015).
Various studies have proven that the periodontal pathogens including
Porphyromonas gingivalis, Prevotella intermedia, Aggregatibacter actinomycetem-
comitans, Treponema denticola and Tannerella forsythia can be found in the peri-
implant sulcus (Casado et al., 2011; Cortelli et al., 2013). Around 1 month after the
second stage surgery, these bacteria can be detected in the peri-implant area (Aoki
et al., 2012). Furthermore, it was stated that patients would have the same kind of
periodontal bacteria in their peri-implant sulcus as in their remaining periodontal
pockets (Casado et al., 2011; Zhang et al., 2015). Not only the presence of periodon-
tal pathogens, but also the local immune response driven by the reaction between
bacteria and the host can provide susceptibility to various inflammations and peri-
implant diseases (Lasserre et al., 2018). During periodontal disease, the local
inflammatory response to the bacterial pathogens initiates the host’s immune
response. This response will activate a high volume of biomarkers and spread of the
inflammation through the gingival tissues (Kim & Amar, 2006). In this stage, the
gingival inflammation is reversible, but if this inflammation expands to adjacent
alveolar bone, resorption may occur (Casado et al., 2013). In addition, several risk
factors such as genetic factors, can alter the host’s response. Recent studies have
shown that chronic periodontal disease and peri-implant disease have a genetic
background. Patients who lose their teeth due to periodontal disease are more likely
to develop peri- implant bone loss (Fig. 2) (Zhang & Finkelstein, 2019; Dirschnabel
et al., 2011).
A long-term study showed a significant increase in bone loss around implants, in
patients with a history of periodontitis (Levin et al., 2011). In a review, Schou et al.
analysed studies up to 10-year follow-up (Schou et al., 2006). According to this
review, the number of patients suffering from peri-implantitis increased signifi-
cantly and the number of implants with a bone loss around implants increased for
the patients with a periodontitis history (Schou et al., 2006). Wang et al. stated that
with a precise long-term periodontal follow-up, patients that lost their teeth due to
Fig. 2 Clinical representation of peri-implantitis. (Courtesy of Prof. Dr. Aslan Yasar Gokbuget
from Istanbul University/Turkey)
chronic periodontitis can present relatively high implant survival rate (Wang et al.,
2021). However, bone augmentation with implant surgery, and positioned implants
in the anterior region showed lower implant survivals in patients with chronic peri-
odontitis (Wang et al., 2021). Ong et al. explored bone loss outcomes around the
implants in patients undergoing periodontal disease treatment (Ong et al., 2008).
This review stated that, in comparison to healthy patients, higher amounts of peri-
implant complications and implant loss can be seen in periodontal disease patients
(Ong et al., 2008).
Briefly, short-term survival for dental implants seems acceptable for patients
with a history of periodontitis. On the other hand, there is not enough long-term
clinical trials especially for individuals with a history of aggressive periodontitis
(Theodoridis et al., 2017; Wang et al., 2021). Due to common risk factors such as
diabetes, smoking and different treatment options for periodontitis optimising a ran-
domised clinical trial for those patients are quite challenging (Liddelow &
Klineberg, 2011).
Another problem to identify periodontal disease as a risk factor is the application
of the new classification for periodontal and peri-implant diseases to clinics. Most
of the studies still classify periodontal disease based on the 1999 periodontal dis-
ease classification system. The new classification has been recently started to be in
use to diagnose and classify the periodontal diseases. For example, a recent study by
Adler et al. using the new periodontal disease classification reported in the 2017
World Workshop, showed implant loss related with treated severe periodontitis
(Stage III–IV) (Adler et al., 2020).
4 Smoking
Smoking is still a common habit that affects bone loss and long-term success of
dental implants (Naseri et al., 2020). Several studies stated that smoking has a dose-
dependent negative impact on osseointegration. Smoking disrupts the osseointegra-
tion by inhibiting the growth of progenitor cells that are important for bone healing,
thereby slowing the healing process of healthy bone tissue (D’Haese & De Bruyn,
2013; Naseri et al., 2020; Bazli et al., 2020). According to clinical studies, smokers
are more common than non-smokers with loss of attachment, gingival recession,
and severe periodontal disease, which indicates poor periodontal health for these
individuals (Windael et al., 2020; Ong et al., 2008; Meyle et al., 2019). Kasat and
Ladda reported that heavy smoking will accelerate the loss of marginal bone and
subsequent formation of pockets which will jeopardize the survival rate of implants
(Kasat & Ladda, 2012). According to a systematic review by Strietzel et al., smok-
ing is a significant risk factor for dental implant surgery (Strietzel et al., 2007).
Authors also stated that augmentation procedures for implant treatments in smoking
patients contain increased risks for complications (Strietzel et al., 2007).
Tobacco products consist numerous harmful ingredients, however, nicotine
remains to be the most damaging component. Nicotine is the main chemical com-
ponent leading to tobacco addiction. Moreover, it is stated to be related to negative
prognosis of most diseases (Bazli et al., 2020). Tobacco products also reported to
contain benzene and aldehydes that can impair bone healing (Bezerra Ferreira et al.,
2016; Bazli et al., 2020). In studies observing the very early stages of bone healing
around dental implants, bone healing was found to be severely impaired in smokers,
as compared to non-smokers (Levin & Schwartz-Arad, 2005; Bezerra Ferreira et al.,
2016; Anner et al., 2010).
To sum up, smoking has been shown to impair both osseo- and soft-tissue inte-
gration and healing, and therefore may cause early implant loss (Windael et al.,
2020). The frequency of smoking also plays an important role in the failure of the
implant. In addition, smoking is associated with increased bone loss around implants
and decreased bone density in the jaw, which is related to late implant failure.
Therefore, even after successful osseointegration, smoking may shorten the lifetime
of the implant, and smokers should be aware of the negative effects of smoking on
implant survival before implant surgery (Levin & Schwartz-Arad, 2005; DeLuca
et al., 2006).
5 Diabetes
The WHO states that prevalence of diabetes have increased over the past few
decades (Lin et al., 2020). Diabetes has two types and both types impair the general
well-being of human physiology. First version is Type 1 diabetes named as juvenile
or insulin-dependent diabetes which is a consequence of the autoimmune destruc-
tion of pancreatic beta cells in the earlier periods of life. In all cases of diabetes only
around 10% is Type 1. Second version is Type 2 diabetes named as non-insulin-
dependent or adult diabetes which is more common (King, 2008; Ngeow et al.,
2020). Studies on humans and animals have shown that diabetes changes bone prop-
erties, decreases bone mineral density, and can result in fracture healing disorders
(Romero-Díaz et al., 2021; Yaturu et al., 2007). The leading cause of impaired heal-
ing of bone in diabetes is related to its direct effect on osteoblasts. Diabetes slows
the formation of new bone by inhibiting the development of bone cells. This leads
to a decrease in bone tissue density and for Type 1 diabetes patients it means a risk
of osteoporosis in older ages (Romero-Díaz et al., 2021; Yaturu et al., 2007; Diz
et al., 2013). Diabetes is also a burden for cardiovascular system. Due to microvas-
cular problems and circulatory disturbances, diabetes also has a negative impact on
the healing of soft-tissue, and hence periodontal problems are more common in
these patients (Ngeow et al., 2020).
Some authors stated that in diabetic patients with well-controlled metabolism,
the success rate of routine dental implants is similar to corresponding healthy con-
trol group (Sghaireen et al., 2020). Also in recent studies, implant failure was asso-
ciated with inadequate or non-existent glycaemic control (Dubey et al., 2013).
Attributed to the known impact of hyperglycaemia on recovery before and after the
dental implant therapy; strict blood glucose, HbA1c controls and medical consulta-
tion are recommended (Table 1). Since diabetes, smoking and periodontal disease
Table 1 Dental implant treatment options and precautions in medically compromised patients
Systemic conditions Contraindication Survival rate Precautions/recommendations Dental implant modifications
Ageing No, beware of other Similar Consultation, oral health Prefer implants with osteogenic
systemic conditions maintenance, avoid major surface modifications
surgeries
Periodontal disease No, not enough data for Reduced Oral health maintenance A strict oral care regime, prefer
aggressive periodontitis implants with antimicrobial
surface modifications
Smoking No, beware of other Reduced Early detection of negative A strict recall regime, prefer
systemic risk factors changes in peri-implant tissues implants with osteogenic and
with controls antimicrobial surface
modifications
Diabetes No, it depends on how Reduced Strict blood glucose, HbA1c Frequent control, avoid
controlled the disease is controls and medical consultation immediate implantation
are recommended
Cardiovascular disease Acute MI, recent Similar, high risk of Prophylaxis, consultation, oral Aseptic surgeries minimize the
cardiovascular surgery peri-implant health health maintenance avoid major risk of peri-implant infections
issues surgeries
Bleeding disorders/congenital Consultation required Similar Coagulation tests, factor Frequent control, avoid early
and acquired conditions transfusion, consultation, avoid contacts and mucosal pressure
major surgeries
Bleeding disorders/drug-related No Similar Consultation, coagulation tests, Frequent control, avoid early
avoid major surgeries contacts and mucosal pressure,
avoid immediate implantation
(continued)
Titanium Dental Implants in Compromised Conditions: Need for Enhanced Bioactivity…
31
Table 1 (continued)
32

Head and neck cancer/ Yes (during RT, 9 months Reduced in the Implant placement before or Late loading, prefer rough-
radiotherapy post-RT, if the cumulative irradiated bone, first during ablative surgery or surfaced implants, SLA surfaced
dose of RT is >50 Gy) 9 months after RT, 9 months after RT, consultation, implants avoid mucosal
implantation in the prophylaxis. If RT dose >40 Gy, pressure, prefer implants with
maxilla or hyperbaric oxygen therapy osteogenic and antimicrobial
augmented bone recommended, avoid major surface modifications, PRP
surgeries application may be beneficial
Head and neck cancer/ No (beware of cytotoxic Reduced Consultation, blood tests, oral Late loading, prefer implants
chemotherapy drugs causing bone health maintenance, prophylaxis with osteogenic and
marrow depression and antimicrobial surface
bisphosphonates/ modifications
antiresorptive drugs)
Bone diseases/osteoporosis No (beware of Similar survival, high Minimally invasive, avoid Prefer rough-surfaced implants,
bisphosphonates and marginal bone loss excessive force, implant placement late loading, undersized drilling,
antiresorptive drugs) with osseodensification technique avoid immediate implantation,
prefer implants with osteogenic
Bone diseases/bisphosphonates, Relative (high Reduced Consultation especially if drug use Frequent control, avoid early
antiresorptives accumulation of drugs in >2 years or in the presence of contacts and mucosal pressure,
oncology patients) predisposing factors, avoid prefer implants with osteogenic
excessive force, use antiseptic surface modifications
agents
Bone diseases/Paget’s disease No (beware of Reduced If jaws are not affected by the Prefer high surface energy
bisphosphonates and disease, implant placement with implants, late loading,
antiresorptive drugs) osseodensification technique undersized drilling, avoid
immediate implantation, prefer
implants with osteogenic surface
modifications
N. A. Kocak-Oztug and E. I. Ravali
Bone diseases/fibrous dysplasia No (in the remission Similar If jaws are not affected by the Prefer long implants, late
phase) disease, in the remission phase loading, avoid immediate
implantation
Bone diseases/Cementoosseous Yes (successful implant Reduced If necessary: apply unaffected Avoid excessive surgery
dysplasia cases limited) areas and maxilla
Bone diseases/osteogenesis Yes (in severe cases) Reduced Minimally invasive, avoid using Prefer late loading, avoid
imperfecta force immediate implantation, prefer
implants with osteogenic surface
modifications, anodic oxidation
and, SLA active surface
Immunocompromised patients/ No (if the disease is under Higher risk of Consultation, oral health Frequent control, guided,
SLE, scleroderma, Sjögren’s control and bone peri-implant health maintenance, prophylaxis, use flapless, septic surgeries
syndrome, rheumatoid arthritis, regenerative potential is issues, increased antiseptic agents, minimally minimize the risk of peri-
Crohn’s disease, mucosal adequate) marginal bone invasive surgery implant infections, prefer
diseases resorption implants with antimicrobial
Immunosuppressive therapy/ Yes (if the general health Reduced, high risk of Consultation, oral health Guided, flapless, aseptic
organ transplantation is at risk or total white peri-implant bone maintenance, prophylaxis, use surgeries minimize the risk of
cell count below loss antiseptic agents peri-implant infections, prefer
1500–3000 cells/mm3) rough surface implants, prefer
implants with antimicrobial
HIV and AIDS Yes (in severe cases) Similar Consultation, oral health Prefer implants with
maintenance, prophylaxis, use antimicrobial surface
antiseptic agents, check CD4+ T modifications
lymphocyte level
Ti allergy Yes Reduced Patch testing in patients with a Alternative implant materials
predisposition to allergies or such as zirconia should be
allergies to other metals preferred
Titanium Dental Implants in Compromised Conditions: Need for Enhanced Bioactivity…
Modified after Gündoğar et al. (2021), Levin et al. (2011), Strietzel et al. (2007), Naujokat et al. (2016), Hwang and Wang (2006), Diz et al. (2013), Koudougou
et al. (2020), Shugaa-Addin et al. (2016), Schiegnitz et al. (2021), Granström et al. (1999), Buddula et al. (2011), Heberer et al. (2011), Ocaña et al. (2017), de
33
Medeiros et al. (2018), Wagner et al. (2017), Ngeow et al. (2020), Guo and Yuan (2020) and Vissink et al. (2018)
are common risk factors, it is also recommended that individuals should be informed
about these conditions before the implant application (Strietzel et al., 2007).
Patients with uncontrolled diabetes are generally considered unsuitable for
implant therapy. According to reports, blood glucose levels affect the stability of
early implants and therefore an increase in the implant failure is expected (Naujokat
et al., 2016). In a recent study evaluating type 2 diabetes patients operated with
implants located in the anterior maxillary ridge, the resorption of the alveolar ridges
was proportional with the glycaemic blood levels (Gómez-Moreno et al., 2015).
Compared with other patients, diabetic patients with increased HbA1c levels
showed more marginal bone loss (Gómez-Moreno et al., 2015). Elevated amount of
pro-inflammatory cytokines in the tissue is reported to be another relevant factor
that cause tissue inflammation in diabetic patients. This leads to an increase in
osteoclasts and a decrease in bone mass (King, 2008).
Until now, many studies have focused on judging the success of osseointegration
in various levels of diabetic diseases with different blood sugar levels. Currently
there are limited investigations to determine whether the osseointegration can be
improved with different macro designs, surface coatings and surface modifications
in this compromised population (Dubey et al., 2013; Diz et al., 2013).
6 Cardiovascular Disease
The cardiovascular system is the organ system that transports nutrients and oxygen
through the blood vessels to the tissues and removes carbon dioxide and metabolic
waste. Cardiovascular disease (CVD) is a general term for diseases that affect
organs such as the heart and blood vessels. Risk factors for cardiovascular disease
include obesity, diabetes, high blood pressure, stress, smoking, alcohol and drug
use, inadequate physical activity, and unhealthy diet. At least 70% of patients in the
high-risk group of CVD have more than one risk factor (Khan et al., 2020). Ischemic
heart disease (IHD) manifests as myocardial infarction or ischemic cardiomyopa-
thy. IHD in its non-fatal forms can leave permanent damage to the physical health
and reduces the quality of life of patients. The patient’s suitability for the surgical
procedure can be assessed by the stability of the existing disease and evidence of
recent CVD. However, as mentioned before, CVD such as recent acute myocardial
infarction, stroke and cardiovascular surgery have been reported as absolute contra-
indications for dental implants (Hwang & Wang, 2006).
CVD impairs blood flow and tissue nutrition. Hypercholesterolemia, hypergly-
caemia, and hypertension, which are risk factors for cardiovascular disease, increase
blood viscosity and prolong blood flow time. Since inadequate blood supply causes
chondrogenic differentiation of mesenchymal cells and adequate blood supply is
one of the most important factors for the success of osseointegration, CVD might
affect the further success of the implant by slowing the blood supply to the tissue
(Staedt et al., 2020; Alsaadi et al., 2007).
Apart from the strict contraindications mentioned above, CVD has been reported
not to be a contraindication for dental implants. Preoperative antibiotic prophylaxis
is necessary because CVD increases the risk of infective endocarditis. In addition,
considering factors such as acute cardiovascular conditions and bleeding that may
occur due to stress, medical consultation should be requested following a detailed
anamnesis (Table 1). Also, in the postoperative period, it is recommended to admin-
ister antibiotics and anti-inflammatory drugs approved by the cardiologist to keep
the allotted time short for a fast recovery (Farbod et al., 2009).
CVD and periodontal disease share common risk factors, including diabetes and
smoking. Further, oral pathogens such as Porphyromonas gingivalis, Fusobacterium
nucleatum, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans have
been detected in atheroma plaques due to periodontal inflammation. In the light of
this information, it can be said that periodontal disease and CVD pose a risk for
each other (Figuero et al., 2011). In conclusion, implant success is directly related
to oral hygiene, regular periodontal treatment, informing the patient about the
hazards of smoking, and postoperative care in CVD patients.
7 Bleeding Disorders
Bleeding disorders are conditions that occur because of hereditary diseases, syn-
dromes, or medications and may manifest as epistaxis, postoperative, or spontane-
ous bleeding. Decreased platelet production (e.g., aplastic anemia, myelodysplastic
syndrome, bone marrow suppression due to chemotherapy and radiation therapy,
viral infections such as HIV and rubella, medications) and platelet destruction (e.g.,
idiopathic thrombocytopenic purpura, hemangiomas, vasculitis, hemolytic uremic
syndrome) can lead to uncontrolled bleeding (Dutta et al., 2020). If the platelet
counts in the blood falls below 50,000/mm3, there is a risk of spontaneous bleeding.
Postoperative bleeding can lead to fatal outcomes by obstructing the airway through
the neck fascia (Dutta et al., 2020; Diz et al., 2013).
Use of anticoagulants and thrombolytics, chronic renal failure, liver disease,
vitamin K deficiency, Von Willebrand disease and deficiency of coagulation factors,
multiple myeloma, and hemophilia can cause coagulation disorders. Antiplatelet
(AP) drugs such as aspirin, dipyridamole, and thienopyridines as well as direct
thrombin inhibitors and factor Xa, are direct oral anticoagulants that have been
widely used in recent years because of their clinical benefits. Anticoagulant drugs
such as coumarin, warfarin, and heparin are used to prevent thromboembolic events.
Warfarin is a vitamin K antagonist and is commonly used to prevent thromboembo-
lism. It should be remembered that drugs such as metronidazole, erythromycin, and
clarithromycin, which we use in daily dental practice, enhance the effect of warfa-
rin. Although there are not enough studies showing the success of dental implants in
patients taking anticoagulants, it has been reported that minor surgical procedures
can generally be performed under proper haemostatic measures (Bajkin et al., 2020;
Kalpidis & Setayesh, 2004; Zeevi et al., 2017).
Anemia is defined as a fall in hemoglobin level below normal. It may occur with
blood loss, heavy menstruation, iron deficiency or as a symptom of a disease. While
mild anemia may be asymptomatic, symptoms occur in severe anemia because the
oxygen-carrying capacity of the blood decreases. As mentioned in the previous sec-
tion, inadequate oxygen supply can negatively affect osseointegration and bone
healing. Conditions such as factor deficiency, platelet disorders, and the use of anti-
coagulant medications can lead to uncontrolled bleeding in surgical practice. In
such cases, it is recommended to consult with the appropriate physicians after a
detailed anamnesis. To minimize the risk of uncontrolled bleeding, it is recom-
mended to perform the necessary blood tests before the procedure, to regulate any
medications used, and to use replacement factors in case of factor deficiency. Since
standard blood tests are not sufficient to detect bleeding disorders, it has been found
useful to check renal functions and markers such as coagulation factors, interna-
tional normalized ratio (INR), prothrombin time (PT), activated partial thrombo-
plastin time (APTT), thrombin clotting time (TCT), ecarin clotting time (ECT) and
factor Xa (Diz et al., 2013; Lupi & Rodriguez, 2020).
During surgery, the use of anesthetics containing vasoconstrictors, the use of
local haemostatic and antifibrinolytic agents such as tranexamic acid and desmo-
pressin, the use of antiseptic mouthwashes and oral care to minimize the risk of
local infections, and the preference for minimally invasive surgical methods while
avoiding major surgery are recommended (Table 1). The use of non-steroidal anti-
inflammatory drugs (NSAIDs) should be avoided unless otherwise recommended.
Since oral procedures are usually minor surgeries, they are among the procedures
with a low risk of bleeding. However, more than 3–4 dental implants at a time in a
patient are considered as a risk factor because high number of implants lead to an
increase in the surgical area. Major procedures such as sinus lifts, augmentation,
and regional osteotomies should be avoided as much as possible in these patients
(Lupi & Rodriguez, 2020).
Marković et al. investigated peri-implant bone healing, implant survival, and
success rates on small-diameter implants that can be used in place of augmentation
in patients on anticoagulant therapy (Marković et al., 2017). A 100% survival and
success rate at the end of a one-year follow-up period and a decrease in implant
stability score at 3 months compared to healthy samples were reported, which may
be attributed to the effects of oral anticoagulants on bone healing (Marković
et al., 2017).
In conclusion, although no adverse effects of bleeding disorders on the success
of dental implants have been reported, consultation is required because of the risk
of prolonged haemorrhage and blood loss in this patient population. In cases where
healthy haemostasis cannot be achieved, reducing the risk of major surgical proce-
dures by dividing them into multiple operations is vital (Table 1).
8 Head and Neck Cancer
In cases of malignant tumours of the head and neck, patients often undergo radical
surgical procedures that result in the loss of large amounts of bone, followed by
therapeutic phases such as radiotherapy and chemotherapy. After such radical sur-
geries, it may be necessary to reconstruct the tissues with bone grafts and tissue
flaps to restore aesthetics and function (Koudougou et al., 2020).
Radiotherapy and chemotherapy are used to destroy rapidly proliferating cancer
cells but can also interfere with wound healing and tissue blood supply by suppress-
ing the immune system’s response. As radiation therapy causes a decrease in osteo-
cytes along with the malignant cells, osteoclastic and non-osteoclastic resorption of
bone occurs (Anesi et al., 2020). Dental implant treatments are contraindicated
because the effects of radiotherapy persist for 6 months after treatment. Minimal
trauma and infection can cause osteoradionecrosis, as hypoxic and hypovascular
healing is observed in the injured bone. Further, osteoradionecrosis affects the man-
dible more than the maxilla due to its proximity to the radiation field and less vas-
cularized structure (Hwang & Wang, 2006).
It has been reported that the risk of osteoradionecrosis decreases when the total
radiation dose is less than 66 grays, and the probability of osteointegration increases
when it is less than 50 grays (Diz et al., 2013). It has been also reported that high-
dose radiation (cumulative dose >50 gray) can lead to osseointegration deficiencies
and consequent dental implant failure due to its adverse effects on bone/soft tissue
damage and vascularization (Table 1) (Yu et al., 2021). Successful implant treat-
ment should be performed at least 21 days before the start of radiotherapy or at the
earliest 9 months after the end of treatment (Diz et al., 2013).
According to the current literature review, the success rate of implant-supported
prosthesis in the irradiated area was 67.4%, while the survival rate of implants
placed 1 year after completion of radiotherapy was reported to be 93.1% (Koudougou
et al., 2020). Treatments should be performed under aseptic conditions after pro-
phylactic measures and under appropriate premedication with antibiotics with good
bone penetration, such as clindamycin. Any procedures that compromise osseointe-
gration and increase the risk of osteoradionecrosis, such as early implant loading,
should be avoided (Table 1).
A study by Schiegnitz et al. reported the survival rate of 711 implants in 164
patients with a history of oral cancer up to 10 years, and a significant difference was
found between the survival rates of implants placed immediately after surgical treat-
ment (92.5%) and implants placed after completion of oncological treatment
(89.5%) (Schiegnitz et al., 2021). While no effect of irradiated bone alone on
implant survival was seen, significantly lower survival rates were reported for
implants placed in augmented bone after radiation therapy. During the follow-up
period, a total of 70 implants were lost, including 6 implants due to primary loss,
42 implants due to peri-implant disease, 17 implants due to tumour recurrence, and

3 implants due to osteoradionecrosis (Schiegnitz et al., 2021).
In a study conducted with 1405 implants in 466 oncologic and non-oncologic
patients, the overall implant survival rate was 96.65%, while this rate was 93.02%
in oncologic patients and 97.16% in non-oncologic patients (Silva et al., 2020).
However, the result was limited because the number of implants in oncologic
patients was only 172 (Silva et al., 2020). Also, in a study of 435 implants in 93
patients, implant losses in irradiated bone tissue generally occurred in the short-
term, and long-term implant losses were comparable to those in patients who had
not received radiotherapy [Irradiated (0.81%), Non-irradiated (1.29%)] (Nelson
et al., 2007).
Another study investigated the effects of dental implant manufacturing methods
on survival with 271 implants and a 5-year follow-up in 48 patients with a history
of oral cancer (who received radiation of at least 50 gray to the neck and head
region) (Buddula et al., 2011). In the maxilla, the survival rate was 72.6% for
implants with a turned surface, and 87.5% for implants with a roughened surface.
Whereas in the mandible, 91.7% of implants with a turned surface, and 100% with
a roughened surface survived. Implant loss occurred more frequently in the 2 years
after radiotherapy than in the late phase (Buddula et al., 2011). Heberer et al.
reported that chemically modified and conventional SLA surfaces had a high suc-
cess rate in the irradiated bone (Heberer et al., 2011).
Although there is no study showing clear effects of chemotherapy on dental
implant success, it is suspected that conditions that negatively affect the immune
system may also affect implant success. A 2019 systematic review and meta-analysis
about implants in immunocompromised patients examined four retrospective stud-
ies and two prospective studies, of which only one of the retrospective study was
controlled and found no effect of chemotherapy on implant success rate (Duttenhoefer
et al., 2019). In another retrospective study, 106 mandibular dental implants were
placed in 30 patients with postoperative oral cavity cancer treated with either adju-
vant cisplatin or carboplatin plus fluorouacil (5FU). It was reported that there was
no significant effect on implant survival compared to control groups at 10 years
(Kovács, 2001). However, some cytotoxic anticancer drugs can cause immunosup-
pression by inducing bone marrow depression and making tissues susceptible to
infection and bleeding. Therefore, elective procedures such as implant treatments
are contraindicated in patients taking this group of medication (Hwang &
Wang, 2006).
In summary, bone metabolism and immune response are damaged by the expo-
sure of radiotherapy, chemotherapy, and various cytotoxic anticancer drugs, and
hence it would be advantageous to use implants with osteogenic and antimicrobial
surface modifications (Table 1).
9 Bone Diseases
9.1 Osteoporosis
Osteoporosis is a disease that results from destruction in the bone remodelling

mechanism. Although the bone retains its shape, spontaneous fractures may occur
as it loses its density. Since osteoporosis is a non-localized bone disease, resorption
also occurs in the alveolar bone, mainly in the maxilla and edentulous regions. It
usually occurs in women over 50 years of age and affects 30% of postmenopausal
women and around 200 million people worldwide (Guo & Yuan, 2020). According
to studies, the risk of developing osteoporosis decreases in women who receive
hormone therapy during the postmenopausal period (Rozenberg et al., 2020).
Although hormone therapy has been attributed to have positive effects on the suc-
cess of dental implants, the number of studies on this topic are insufficient, and
there are even studies stating that it increases the risk of implant loss (Wagner et al.,
2017; Rozenberg et al., 2020). In addition to hormone therapy, vitamin D used in the
treatment of osteoporosis has been reported to decrease marginal bone loss, while
bisphosphonates have been reported to have various adverse effects (Wagner
et al., 2017).
A comprehensive meta-analysis conducted in 2018 found that osteoporosis had
no significant effect on implant survival, but marginal bone loss around the implant
was significantly higher in osteoporotic patients than in healthy patients (de
Medeiros et al., 2018). It has also been reported that osteoporosis is not a contrain-
dication for the implant treatment, but some precautions should be taken for suc-
cessful outcomes. In osteoporotic patients, it is recommended to prefer minimally
invasive procedures to avoid excessive force applied to the jaw and to avoid aug-
mentation if possible. Early loading of all implants should be reviewed, as osteopo-
rotic bone tissue may be subject to stress fractures due to masticatory forces
(Guo & Yuan, 2020).
9.2 Paget’s Disease
Paget’s disease, defined by deformity and progressive enlargement of the long

bones, replaces bone with more vascular soft bone. This disease, which is usually
asymptomatic, can manifest itself with malocclusions in the jaws, avulsed teeth,
root resorption, or in some cases, excessive bleeding after an extraction. Removable
dentures are not considered a good treatment option for Paget’s patients, as they
require constant adjustment due to the continuous expansion of the bones. In cases
where bone density is good and the jaws are not compromised according to radio-
logical analysis, dental implant treatments are suitable. Monitoring serum alkaline
phosphatase, calcium and phosphorus activity can provide information on the
course of the disease (Guo & Yuan, 2020). In studies of implant therapy in Paget’s
disease patients, it has been suggested to omit the final drill, use implants with high
surface energy, apply late loading as in osteoporotic patients, and avoid immediate
procedures (Ngeow et al., 2020).
9.3 Cementoosseous Dysplasia
Cementoosseous dysplasia is a non-neoplastic, slow-growing bone disease usually

affecting the mandible in which the normal trabecular structure of the bone is
replaced by dense acellular cementum and osseous tissue. Cementoosseous dyspla-
sia is highly susceptible to infection due to inadequate vascularization. Therefore,
even the most minimally invasive procedures such as elective periodontal scaling
should be avoided in these patients. In mandatory cases, tooth extractions and
implant treatments should be performed under aseptic conditions, especially in the
maxilla and in areas not affected by this disease (Esfahanizadeh & Yousefi, 2018;
Merlini et al., 2016).
9.4 Fibrous Dysplasia
Fibrous dysplasia is a disease characterized by abnormal, non-malignant growths in

long bones. It results from the growth of disorganized fibrous bone due to GNAS1
gene mutation with increased proliferation of osteoblastic cells. It accounts for 10%
of benign bone tumours. Since primary stabilization cannot be achieved in fibrous
bone, it is recommended that dental implants should be used during the remission
phase when bone growth stops. In addition, it is recommended to take measures
such as increasing the surface area by choosing long implants, avoiding immediate
surgery and premature loading (Ngeow et al., 2020).
9.5 Osteogenesis Imperfecta
Osteogenesis imperfecta is a hereditary disease in which brittle bones occur due to

abnormal type I collagen synthesis. It is classified according to the severity of the
disease and can lead to spontaneous fractures of the jaw. In addition, dentinogenesis
imperfecta may also occur along with conditions such as osteopenia, growth and
hearing retardation, blue sclera, lung, and heart malformations in these patients.
Although no significant effect of implant surface characteristics on implant survival
has been found in this group of patients, it has been reported that late loading at the
end of a prolonged osteointegration period may be beneficial, as in other similar
bone diseases (Table 1) (Prabhu et al., 2007, 2018; Wannfors et al., 2009).
9.6 Medication-Induced Osteonecrosis of the Jaw (MRONJ)
Medication-induced osteonecrosis of the jaw (MRONJ) involves exposed and

necrotic areas of bone in the jaw caused by certain drugs that prevent rapid bone
resorption. Osteonecrosis can remain asymptomatic for a long time before reaching
areas of surrounding tissue, such as nerves and soft tissue (Ruggiero et al., 2014).
MRONJ can occur spontaneously but is usually due to tooth extractions and
trauma. Because of the trabecular structure and vascularity, the mandible is more
likely to be affected than the maxilla.
Bisphosphonates cause suppression of bone resorption and are used as a treat-
ment option for osteoporosis, hypercalcemia, Paget’s disease, and malignant bone
disease. Although the mechanisms of action are not fully known, they are thought to
suppress osteoclast precursor cells and promote osteoclast apoptosis (Hwang &
Wang, 2006). Many studies show that the use of bisphosphonates causes
MRONJ. Since their intravenous forms are more effective, they are prescribed more
frequently, but the risk of osteonecrosis increases to the same extent. The half-lives
of bone-bound bisphosphonates range from months to years. Although not as com-
mon as their intravenous forms, studies have reported MRONJ in dental implants
where long-term oral bisphosphonates have been used (Bedogni et al., 2010;
Gelazius et al., 2018; Rawal & Hilal, 2020).
Denosumab is a monoclonal antibody that has been widely used in recent years
to suppress bone resorption in the treatment of osteoporosis, giant cell tumours,
hypercalcemia, and bone metastases. Denosumab does not bind to bone and has a
half-life of 1 month. However, according to a 2020 systematic review and meta-
analysis, denosumab has a higher risk of developing drug-induced osteonecrosis of
the jaw than zoledronic acid (Limones et al., 2020).
The recommended dose of bisphosphonates for osteoporosis patients is much
lower than for cancer patients. A 2018 systematic meta-analysis reported that low-
dose bisphosphonate treatments have no significant effect on marginal bone loss
around implant and implant survival (Stavropoulos et al., 2018). As studies on this
topic are insufficient, it has been reported that minor dentoalveolar surgical proce-
dures such as implants may cause drug-induced osteonecrosis of the jaw, as they are
comparable to tooth extractions in terms of trauma (Ruggiero et al., 2014).
Although there is insufficient evidence to support MRONJ after dental implant
surgery, it would be appropriate to perform elective procedures in high-risk patients
(Table 1).
In cases where bone metabolism is impaired, coating the implant surfaces with
various osteogenic agents has a positive effect on osseointegration. For this purpose,
VEGF, BMPs, extracellular matrix proteins, magnesium, various drugs, graphene,
hydroxyapatite, and various metals have been used in implant surface coatings
(Zhang et al., 2021). Side effects such as MRONJ do not occur with the local appli-
cation of bisphosphonates, as the effect increases at the target site and the toxicity
decreases in the non-target sites. According to studies, coating dental implant sur-
faces with osteoporosis-inhibiting drugs such as RANKL antibodies, selective
estrogen receptor modulators (SERMs), bisphosphonates, parathyroid hormone,

zoledronic acid, ibandronate, and alendronate might promote osseointegration at
the cellular level and suppresses bone destruction (Zhang et al., 2021).
Although bioactive molecules are not very popular due to ethical debates about
their use and high production costs, many studies have been conducted in this field.
Bone morphogenic protein, insulin-like growth factor, platelet-derived growth fac-
tor, fibroblast growth factor and vascular endothelial growth factor, collagen I and
various genes are the most used biomolecules. Studies report that growth factors
promotes angiogenesis, induces osteogenic differentiation of stem cells, and regu-
lates bone regeneration (Zhang et al., 2021; Kocak Oztug et al., 2021).
In addition to the above mentioned methods, the use of inorganic elements on
dental implant surfaces such as silicon, calcium, magnesium, strontium, and zinc,
which are less expensive, promotes osteogenesis when modifying the implant sur-
face (Gulati et al., 2021a; Gulati, 2022). In osteoporotic animal models, studies
report that choosing implants with micro- and nanostructured, hydrophilic and SLA
active surfaces and coating the surfaces with materials such as bisphosphonates,
hydroxyapatite, strontium, collagen I, fibroblast growth factor, simvastatin, and cal-
cium phosphate increase bone-surface contact, bone density, and pull-out force
(Günes et al., 2016; Lin et al., 2019; Lotz et al., 2020; Wermelin et al., 2007).
Another study reported that the use of hydrophilic surfaces plays an important role
in activating BMP signalling (Siqueira et al., 2021).
In 235 osteoporotic female patients treated with bisphosphonates, an implant
survival rate of 98.7% was observed when a plasma-rich growth factor was admin-
istered with the implant (Mozzati et al., 2015). Similarly, growth factors have been
reported to increase implant survival when calcium ion-loaded implant surfaces are
supported with plasma-rich growth factor preparations in osteoporotic patients
(Mozzati et al., 2021). It has been also reported that treatment of PRP on TiO2 sur-
faces promotes early osteogenesis by increasing RUNX2 and COL1 gene expres-
sion and suppresses osteoclastogenesis by increasing OPG expression (Jiang et al.,
2016). When PRP was applied to the nanomodified TiO2 implant surface, an increase
in the bone volume surrounding the implant and implant stability was observed
(Jiang et al., 2016).
When the micro-roughness of dental implant surfaces is increased by methods
such as grit-blasting and acid- etching, bone-implant contact and osseointegration
also increase. Mechanical polishing, abrasive blasting, grinding, polishing, laser
texturing, micro-arc oxidation, hydrothermal treatment, magnetron sputtering,
ultraviolet radiation, and selective laser melting are among the osteogenic surface
roughening techniques commonly used (Stich et al., 2022; Li et al., 2021). Studies
have reported that surface energy can be increased by nanoscale modification of
implant surfaces, and bone cell migration and proliferation increase due to adsorp-
tion of matrix proteins (Alghamdi, 2018). Osteosupportive implant surface modifi-
cations and coatings, such as those mentioned above and others, can be used to
enhance osseointegration. Although there are many in vitro and in vivo studies on
osteogenic modifications, clinical trials are very limited due to ethical discussions.
As more studies are conducted in this area, modified implants could be used more
frequently in medically compromised patients (Table 1).
10 Autoimmune Diseases
Autoimmune diseases are caused by the inflammation of the immune system by the
production of antibodies to its antigens or by the activation of lymphocyte-like cells.
Autoimmune response is responsible for more than 80 diseases (Zeher &
Szegedi, 2007).
10.1 Rheumatoid Arthritis (RA)
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic

inflammation, oedema, and pain in the joints, leading to joint destruction over time.
Anti-inflammatory drugs, corticosteroids and immunosuppressants are used to treat
it. It often occurs in conjunction with osteoporosis and other connective tissue dis-
eases. A 2010 study reported that in the presence of RA with concomitant diseases,
an increase in marginal bone resorption and bleeding should be expected (Krennmair
et al., 2010).
10.2 Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide spec-

trum of symptoms affecting almost all organ systems. Although the aetiology is not
precisely known, the diagnosis is made based on the common occurrence of symp-
toms. The oral mucosa is affected in most SLE patients, with discoid lesions and
ulceration being the most common lesions. Long-term use of corticosteroids is one
of the most used options in the treatment of SLE. In addition, drugs such as cyclo-
phosphamide, mycophenolate mofetil, and azathioprine are also used (Theofilou
et al., 2021).
10.3 Scleroderma
Scleroderma is a connective tissue disease which causes involvement of the internal

organs and the multisystems in its progressive forms, resulting in thickening of the
skin caused by fibrosis. Uncontrolled collagen deposition is one of the main features
Fig. 3 Clinical representation of implant and free gingival graft treatment in a scleroderma patient.
(Courtesy of Prof. Dr. Aslan Yasar Gokbuget and Asst. Prof. Dr. Necla Asli Kocak-Oztug from
Istanbul University/Turkey)
of this disease. The oral symptoms resemble those of the whole body: tense mucous
membranes, shrunken and lost commissures, a hardened tongue (Fig. 3). In cases
where the masticatory muscles are involved, resorptions of the mandible may occur.
In these cases, pathological fractures may also occur during minor surgery and tooth
extraction (Theofilou et al., 2021).
10.4 Sjögren’s Syndrome (SS)
Sjögren’s Syndrome (SS) affects periodontal health by decreasing the quality and
flow of saliva and increasing the susceptibility of teeth to caries. For this reason,
patients often experience tooth loss and the associated need for prosthetic rehabili-
tation. SLE may co-occur with other autoimmune diseases such as scleroderma. A
2017 systematic analysis reviewed 6 studies with a mean follow up period of
3.97 year. This review found high survival and low complication rates for implants
in Sjögren’s patients (Almeida et al., 2017).
10.5 Crohn’s Disease
Crohn’s disease is a chronic inflammatory bowel disease that usually affects the
digestive tract, but the oral mucosa can also be affected. Immunosuppressive and
anti-inflammatory drugs are often used in their treatment. Studies on implant sur-
vival have shown an association between Crohn’s disease and early implant loss
(Alsaadi et al., 2007).
Autoimmune diseases affecting the oral mucosa also include oral lichen planus,
pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa, and systemic
lupus erythema. These diseases are manifested by the formation of painful bullae,
vesicles, erosions, and papules in the mouth, as well as xerostomia in Sjögren’s
syndrome (de Mendonça Invernici et al., 2014; Schifter et al., 2010). Since these are
painful lesions, they interfere with routine activities such as brushing teeth and eat-
ing. As a result, poor oral hygiene leads to loss of periodontal health and teeth over
time. Hence the use of removable dentures is very difficult in these patients, fixed
restorations on teeth or implants are preferred. However, studies report that some
medications used in the treatment of these diseases may affect bone quality and thus
osseointegration of implants (Mustafa et al., 2015).
Autoimmune diseases, except for diseases with joint involvement such as rheu-
matoid arthritis, generally do not affect bone and bone metabolism. Studies report
that implant survival in patients with rheumatoid arthritis who received an abrasive-
blasted, acid-etched surface implant is 94.6% and decreases to 92.3% when connec-
tive tissue disease is concomitant (Krennmair et al., 2010).
When planning dental implant treatment for these patients, the complex disease
symptoms and the effects of the drugs used for treatment on the immune system,
skeletal system, and oral environment should be known. For example, in SLE with
renal involvement, bleeding disorders due to dialysis dependency, susceptibility to
infections, and decreased renal clearance should be considered (Theofilou et al.,
2021). Although very rare, studies have reported that peri-implant carcinomas may
occur in patients with oral lichen planus (Moergel et al., 2014).
11 Organ Transplantation
Organ transplantation is currently a common procedure to restore the functions of

organs. With the knowledge of immune response occurring after these surgeries,
immunosuppressive drugs have been developed to minimize the side effects of
long-term chronic immunosuppression and to prevent organ rejection.
Glucocorticoids and immunosuppressive drugs such as cyclosporine and nife-
dipine impair bone healing (Duarte et al., 2001). Corticosteroids suppress osteo-
blasts and stimulate differentiation of bone marrow cells into adipocytes (Fu et al.,
2012). Although drugs may affect osseointegration by this mechanism, studies on
this topic are inadequate (Ouanounou et al., 2016; Smith et al., 1992). Animal
studies show negative effects of cyclosporine use on osseointegration and peri-

implant bone healing (Sakakura et al., 2007). Immunosuppressive agents have been
reported to cause severe and rapid bone loss in animal models (Movsowitz et al.,
1988). Despite these findings, many studies have reported successful implant and
augmentation procedures under long-term immunosuppressive therapy (Heckmann
et al., 2004; Montebugnoli et al., 2015; Paredes et al., 2018).
Generally, oral surgical procedures should be completed before transplantation
(Duttenhoefer et al., 2019). Considering that this patient group is immunosup-
pressed, all surgical procedures are associated with risks. Elective procedures, such
as dental implants after transplantation, should be performed at times when general
health permits the surgical procedure, in consultation with the appropriate branch
physician and with adherence to a prophylactic medication regimen. Oral surgery is
contraindicated when the total white blood cell counts falls below 1500–3000 cells/
mm3 because of increased susceptibility to infection (Hwang & Wang, 2006).
Patients are susceptible to infections because the host immune response is sup-
pressed by drugs after organ transplantation. In these cases, it may be beneficial to
use implants with antimicrobial surface modifications. In cases where drugs are
used that suppress bone metabolism, the use of modified osteogenic implants may
be considered. Implants embedded in bone tissue without oral mucosal contact with
guided flapless aseptic procedures in transplant patients may minimize the risk of
peri-implant infections (Guo & Yuan, 2020).
12 HIV and AIDS
Human immunodeficiency virus (HIV) is a virus that can be transmitted through

unprotected sexual intercourse, blood contact, and maternal transmission and can
cause Acquired Immune Deficiency Syndrome (AIDS) in humans. According to the
report published by the United Nations and the World Health Organization in 2020,
38 million people are living with HIV, of whom 25.4 million are receiving the nec-
essary treatment (Asfaw & Adamu, 2020). Thanks to antiviral treatment protocols
developed in recent years, the quality of life and the life expectancy of HIV+ patients
is similar to that of healthy people. Highly active antiretroviral treatment (HAART)
is recommended in the presence of AIDS or a CD4+ cell count of <200 cells/mm3
(Durkin et al., 2021).
Apart from the fact that HIV has become a manageable rather than an incurable
disease in recent years, the expected side effects can be quite severe. In the presence
of predisposing factors such as low vitamin D/calcium intake, low testosterone lev-
els, alcohol, smoking and opioid use, depression and low physical activity, altera-
tions in bone metabolism can be observed in patients (Allison et al., 2003). In
addition, there are publications reporting that HAART therapies cause bone disor-
ders, osteopenia, osteonecrosis, and osteoporosis (Annapoorna et al., 2004).
It has been reported that the use of protease inhibitors and corticosteroids in
treatment, hyperlipidaemia, long-term HIV infection or high viral load and low
weight before antiviral therapy predispose to osteoporosis. Agents such as estrogen

hormone therapy, selective estrogen receptor modulators, bisphosphonates, and cal-
citonin may be used in the treatment of secondary osteoporosis that may develop
due to these conditions (Oliveira et al., 2011).
The presence of concomitant factors and diseases, the drug regimen used, the
patient’s CD4+ T lymphocyte count, and general health should be considered when
dental implant treatments are performed in HIV+ patients. Aseptic work is recom-
mended under appropriate prophylactic antiviral and antibiotic therapy in consulta-
tion with the specialist. In the presence of oral lesions accompanying the syndrome,
treatments should be postponed (Allison et al., 2003). Although there are some stud-
ies showing high implant loss in HIV+ patients with small patient groups, there are
also studies reporting short-term implant survival rates up to 100% in larger patient
groups (Stevenson et al., 2007). In this patient group, infections and peri-implantitis
have generally been cited as causes of implant loss however the effects of oral
hygiene and smoking are also quite high. Implants with antimicrobial properties can
be used to reduce peri-implant infections. In cases where medications that suppress
bone metabolism are used, the use of modified osteogenic implants may be consid-
ered (Table 1).
13 Titanium Allergy
Many parts of dental implants are made of Ti or Ti alloys. The percentages of metals
such as aluminium, vanadium, niobium, and zirconium alloyed with Ti are less than
20%. Hypersensitivity reactions have mostly developed against the alloys contained
in dental implants. Allergy cases that developed against commercially pure Ti and
reacted positively to appropriate patch tests are limited (Sicilia et al., 2008; Hosoki
et al., 2016).
Metal allergies are developed against the degradation products of biomaterials.
Since Ti is a metal that resists corrosion by forming a TiO2 layer, it was considered
a non-allergenic material. However, the biofilm layer that forms on implants may
reduce the corrosion resistance of Ti. Ti is known to corrode and cause inflamma-
tory reactions at lower pH levels. Therefore, the development of peri-implantitis
may favour the development of Ti allergy (Guo & Yuan, 2020).
Ti allergy is very rare compared to allergies to other metals. Studies with limited
sample size in the literature have reported that the rate of allergic reaction ranges
from 0.6%/2.7%/6.3%, but this rate increases in patients with a history of allergic
reaction (Hosoki et al., 2018; Kitagawa et al., 2019; Tawil et al., 2020). Ti allergy is
manifested by itching, local redness, swelling, and vesicles. These symptoms
improve when the metal is removed from the environment (Hosoki et al., 2016).
Similarly, studies have reported that Ti allergy plays a critical role in implant loss in
patients with a history of allergy (Siddiqi et al., 2011; Elnayef et al., 2017).
Unlike other metal restorations, implant removal is a difficult procedure and pre-
operative patch allergy testing is required, especially in individuals predisposed to
metal allergies (Siddiqi et al., 2011). In the presence of Ti allergy, the use of Ti-free
implants made of polyetheretherketone (PEEK) and zirconium can be considered
(Rahmitasari et al., 2017; Vissink et al., 2018).
The number of implant applications in the treatment of missing teeth and the aver-
age age of the patients who underwent implant surgery is increasing day by day. As
a result of the improvements made in the macro and micro designs of dental
implants, successful results are obtained in the osseointegration and long-term use
of implants (Al-Zubaidi et al., 2020; Kocak-Oztug et al., 2022). However, the
increase in the age of patients who receive a dental implant also increases the pos-
sibility of encountering systemic diseases and risk factors that will reduce the heal-
ing potential after implant surgery (Bartold et al., 2016). This situation may cause
an increase in the percentage of implant failure. These systemic conditions and risk
factors affecting healing of the implant surgery can be listed as: smoking, diabetes,
head and neck cancer, periodontal disease, radiotherapy applications, bone diseases
and HIV (Duttenhoefer et al., 2019; Secgin-Atar et al., 2021). Also, ageing itself can
have a negative effect on osseointegration (Gündoğar et al., 2021). Some bone dis-
eases, radiotherapy applications to head and neck, and smoking may increase the
dental implant failure risk by increasing the amount of marginal bone resorption
around implants. In addition, impaired wound healing due to smoking can have a
negative impact on osseointegration and remodelling. On the other hand, diabetes
can be a risk factor depending on how well it is controlled (Dutta et al., 2020).
One of the most important factors to be addressed in implant applications with
medically compromised patient is the increase in the probability of multiple risk
factors. Many patients, especially the elderly, have multiple chronic systemic dis-
eases that require multiple drug treatment plus a history of smoking, and periodon-
tal disease. The attending physician and dentist should carefully evaluate the patient,
considering multiple risk factors. Synergic effects of a combination of risk factors
may be seen together (Liddelow & Klineberg, 2011).
For these mentioned reasons, medically compromised patients deserve more
attention and controlled surgical implant intervention in the oral cavity. Furthermore,
improvements in the macro design and surface modifications may enhance the suc-
cess of implant therapy in these individuals (Bazli et al., 2020; Gulati et al., 2021b;
Guo et al., 2021a).
For medically compromised population, dental implants can be the first choice to
solve the problem of edentulism due the requirement to improve the quality of life
(Alsaadi et al., 2007). Therefore, special medical precautions need to be taken for
these patients. Multidisciplinary approach should be followed and according to phy-
sician’s recommendations, use of antibiotic prophylaxis before and after implant
surgery or scheduling implant applications at the beginning of the disease or shortly
after starting the medication can be necessary. Generally, medically compromised

patients should receive a very strict follow-up care, especially those with mucosal
diseases or reduced salivation that are vulnerable to dental problems related to
implants in the long-term. Through well-organized follow-up care, implant-related
problems can be detected early and treated accordingly (Ngeow et al., 2020).
Most of the medically compromised patients with risk factors can be safely
treated with dental implants by following these rules:
1. Paying attention to the patient’s mental ability to cooperate with the physician
and dentist.
2. Working together with the patient’s relevant doctor, identifying the risk factors,
and providing the necessary treatments.
3. Working in sterile conditions with an experienced surgeon and appropriate surgi-
cal protocol (with little trauma, avoiding excessive pressure and bleeding).
4. Long-term follow-up of both for the dental and the systemic conditions.
5. Fast resolution of the problems that may occur in the long term.
6. The patient’s practice of serious oral care.
7. Smoking cessation (Vissink et al., 2018; Bartold et al., 2016; Do et al., 2020).
Although few, a range of contraindications remain for dental implant surgery. Due
to the insufficient amount of prospective clinical trials, the impact of some health
risks on dental implants is still unclear. Moreover, long-term effects of different
macro designs and surface modifications needed to be explored through well
designed clinical studies (Alsaadi et al., 2007; Duttenhoefer et al., 2019). For some
risk factors, the level of disease control can be much more important than the type
of disease/condition itself, and individual medical/dental monitoring should be per-
formed before dental implant surgery. As with any clinical decision in dentistry, the
scope of treatment options and their relative pros and cons must be carefully evalu-
ated according to the needs and wishes of the patient. For medically compromised
patients, careful consideration of cost-benefit analysis is recommended (Diz et al.,
2013; Bornstein et al., 2009).
In conclusion, the ultimate focus of the newest surface alterations on implants is
to promote early osseointegration and long-term bone-to-implant contact while
avoiding significant marginal bone loss. Increased bioactivity and antimicrobial fea-
tures through surface modifications might resolve the implant-related problems in
patients with compromised conditions (Kligman et al., 2021; Yeo, 2019). With more
studies addressing oral rehabilitation demands on implant surface design, the suc-
cess rate of implants will increase, expanding their indications in healthy and com-
promised patients.
Acknowledgements The authors would like to express our very great appreciation to acknowl-
edge Professor Aslan Yasar Gokbuget for their generous help and assistance. No funding was
obtained for this book chapter.
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Macro to Micro: Surface Modification
of Titanium Dental Implants
Yifan Zhang, Shuai Li, Ye Lin, Ping Di, and Yan Liu
Abbreviations
BIC Bone-implant contact

CaP Calcium phosphate
HAp Hydroxyapatite
Sa Estimated average roughness
SLA Sandblasted, large-grit, and acid-etched surface
STI Soft tissue integration
Ti Titanium
TPS Ti plasma sprayed surface
Y. Zhang · S. Li · Y. Lin · P. Di
Department of Oral Implantology, Peking University School and Hospital of Stomatology,
National Clinical Research Centre for Oral Diseases, National Engineering Laboratory for
Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital
Stomatology, Beijing, China
e-mail: yorcklin@263.net
Y. Liu (*)
Laboratory of Biomimetic Nanomaterials, Department of Orthodontics, Peking University
School and Hospital of Stomatology, National Engineering Laboratory for Digital and
Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology,
Beijing, China
e-mail: orthoyan@bjmu.edu.cn

https://doi.org/10.1007/978-3-031-21565-0_3
62 Y. Zhang et al.
1 Roughness of Implant Surfaces: Definition

and Classification
Osseointegration at the bone-implant interface is crucial for stability, loading, and

long-term survival of dental implants (Brnemark, 1983) and biomaterials (Saghiri
et al., 2014). It has been shown that osseointegration is closely related to the chemi-
cal and physical characteristics of titanium-based implants (Sul et al., 2005).
However, in compromised patient conditions, titanium (Ti) and its alloys are not
capable of establishing a reliable bone-to-implant contact, and hence require sur-
face modifications to enhance osseointegration. These modifications mainly include
surface topography and roughness (Cochran et al., 2010), wettability, charge, sur-
face chemistry, metal or nonmetal surface composites, thickness of TiO2 layer and
so on (Anil et al., 2011; Eriksson et al., 2001). Among these characteristics, surface
topography and roughness has the greatest impact on osseointegration (Anil
et al., 2011).
Surface topography of implants can influence proliferation, and functions of
osteoblasts (Shibli et al., 2007). Topography includes the morphological aspects of
the surface in a 3D space, which could be described as the macroscopic and micro-
scopic textures (Gupta et al., 2014). At macroscopic level, implant geometry, thread
design, implant-abutment connection as well as implant surfaces could influence
osseointegration (Rompen et al., 2006; Albrektsson & Wennerberg, 2019). As for
surface roughness, there are several parameters related to the amplitude and spatial
arrangement of surface topographical features, which can be characterized by elec-
tron microscopy images. Among them, the Sa (arithmetic mean height) and Sdr
(developed interfacial area) are the crucial indicators for appropriate 3D assessment
of the average surface roughness (Oliveira et al., 2017; Wennerberg &
Albrektsson, 2010).
According to the dimensions of the surface texture, dental implant surface rough-
ness can be divided into three types of macro-, micro-, and nano-roughness (Anil
et al., 2011). Macro-roughness is referred to the surface features with dimensions
between tens of microns to millimeters. Micro-roughness is defined as being in the
range of 1–10 μm, as shown in Table 1 (Almas et al., 2019; Albrektsson &
Wennerberg, 2004a). Topography in nanoscale range influences protein adsorption,
osteoblastic cell adhesion, and hence the rate of osseointegration (Brett et al., 2004).
2 History of Surface Modifications
The first-generation titanium implants were produced by industrial machining or

turning of the bulk titanium, which leads to a polished or minimally rough surface
with microgrooves. In order to achieve a higher clinical success rate, surface modi-
fications of conventional titanium implants are proposed to increase micro-
roughness by using physical, chemical or mechanical treatments (Guo et al., 2021).
Macro to Micro: Surface Modification of Titanium Dental Implants 63
Table 1 Characteristics of different implant surfaces (Albrektsson & Wennerberg, 2004a)

Roughness (Sa) Applications Advantages Drawbacks
0–0.4 μm Abutments Reduced bacterial Too smooth for proper
(“smooth”) “Machined” adhesion osseointegration and soft
experimental implants tissue integration
0.5–1.0 μm Turned implants, most Long clinical Inferior osseointegration,
(“minimally implants used before documentation of all less forgiving for
rough”) 1995 implants untrained surgeons
1.0–2.0 μm SLActive Stronger bone response, Bacterial plaque adhesion
(“moderately TiUnite® better clinical results
rough”) Most implants of than turned implants
today
>2.0 μm Plasam-sprayed Enhanced micro Severe marginal bone
(“rough”) Hydroxyapatite- retention, increased resorption due to the
coated implants corrosion resistance delamination of layer
Sandblasting and acid etching are the most clinically utilized techniques by manu-
facturers of titanium dental implants (Souza et al., 2019). Compared with a smooth
implant surface, a rough implant surface could not only enhance bone anchorage but
also promote mesenchymal cell differentiation toward osteoblastic phenotype, lead-
ing to the augmented osseointegration (Nagasawa et al., 2016; Khandelwal
et al., 2013).
In the 1980s, the majority of marketed implants had turned or machined surfaces,
with an estimated average roughness (Sa) of 0.5–0.8 μm. Later, a much rougher
surface namely titanium plasma sprayed surface (TPS) and surfaces coated with
hydroxyapatites (HAp) and other calcium phosphates (CaPs) emerged, with the Sa
value >2 μm (Wennerberg et al., 2018). However, these TPS implants coated with
HAp soon disappeared from the market, owing to the delamination of the HAp-
coating, which could cause severe marginal bone resorption, even implant failure.
Next, moderately rough surfaces manufactured via blasting, etching, and oxidation
techniques were introduced to the market during the 1990s and early 2000s. One of
the most successful surfaces in current clinical implant dentistry is the sandblasted,
large-grit, and acid-etched (or SLA) surface. The smooth titanium implant surface
is converted into a roughened surface with cavities of about 200 μm by sand blasting
technology, and then cleaned by acid etching to generate a secondary cavity of
20 μm, resulting in a multi-level rough implant surface that is favorable to bone
bonding.
Another comparable surface is produced by an anodic oxidation (or anodiza-
tion) technique, which uses titanium as anode to form a thickened and roughened
TiO2 layer. This surface is characterized as isotropic with Sa value between 1 and
1.5 μm (Wennerberg & Albrektsson, 2010). Apart from moderate micro-roughness
to increase surface area and oxide thickness, anodized implants could also improve
their surface by increasing OH-groups and adhesion points for proteins and cells,
which enables augmented osseointegration (Karl & Albrektsson, 2017).
64 Y. Zhang et al.
3 Macro-scale Design of Dental Implant Surfaces
Usually, macro-scale alterations provide primary stability and mechanical interlock

between the implants and the tissues, avoiding micro movements that can be delete-
rious to osseointegration (Shalabi et al., 2006; Hyo-Sook et al., 2014). Adopting
geometric design to increase implant surface area and avoid highly focused stress
for bone is critical for osseointegration and survival (Barfeie et al., 2015). Implant
body design (shape, length of implant, outer and inner diameters), thread pattern as
well as pitch distances are mechanical implant features, which are related to implant
macro-design (Dagorne et al., 2015; Abuhussein et al., 2010).
3.1 Implant Body Shape
A number of in vitro and in vivo studies have proven that the implant body shape
plays a vital role not only for the primary stability of an implant, but also for the
long-term success (Kohn, 1992; Steigenga et al., 2003; Kong et al., 2008).
In 1906, Greenfield first implanted the cylindrical hollow circular implants made
of iridium platinum alloy into the jaws, and followed up the clinical results up to
7 years, which was recognized by the American Philadelphia society of Stomatology
(Bell, 1992). This implant body shape is considered to be the predecessor of hollow
cylindrical implants.
In 1937, Müller used iridium platinum alloy to make a mesh implant that can be
placed between the periosteum and the alveolar bone (Bell, 1992). This subperios-
teal implant included four protrusions exposed to the oral cavity, which was intended
to prevent bone structure damage compared to the intraosseous implant. However,
further studies confirmed such implants can be easily infected, leading to severe
bone loss. Attributed to these reasons and a complex manufacturing process resulted
in their elimination from the implant market. In 1938, in a pioneering attempt,
Adams implanted a screw implant with a healing cap for a patient, which is consid-
ered to be the pioneer of modern two-stage implant technology (Bell, 1992). In
1947, Formiggini first introduced the threaded implant made with tantalum wire.
After implantation, good healing and successful repair were achieved (Bell, 1992).
In 1968, in order to increase the contact area between the intraosseous implant
and the bone tissue, Linkow designed a sheet structure on both sides of the implant,
called leaf implant.’ This kind of implant was widely recognized and used in the
1970s. However, a large number of clinical practices had exposed many disadvan-
tages of this body shape design. Due to the lack of standard technology for prepar-
ing implant bone bed (including tools and surgical technology), there was inevitably
a large gap between the implant and the alveolar bone after implantation, which
mostly were fibrous healing, and not osseointegration. In addition, most of these
implants were one-stage implants, which were connected with the oral cavity
directly and hence prone to infection, which can result in implant failure. By the late
Fig. 1 Implants of various shapes and thread types: (a) simple cylindrical, such as IMZ®; (b)
conical thread, such as Camlog® screw line; (c) root thread, such as NobelReplace®; (d) cylindri-
cal thread, such as Straumann®
1980s, the design concept of this leaf implant had been gradually abandoned
(Linkow & Wagner, 1993).
Since Bränemark established the theory of osseointegration, a large number of
clinical practices have confirmed that it is difficult for supra-periosteal and perios-
teal implants to achieve satisfactory osseointegration and long-term favorable out-
comes. The cylindrical and root implant design of pure titanium or titanium alloy
have achieved appropriate bone bonding and long-term stability, and became the
mainstream implant widely used in clinic.
At present, there are more than 200 implant systems registered with the FDA in
the United States and CE certified in Europe. There are a wide variety of different
body shapes, but the basic design is mainly cylindrical and root (Fig. 1).
3.2 Various Geometric Thread Patterns
At present, cylindrical and root shape with special thread patterns have become the
mainstream design, substituting the simple cylindrical one. The implant’s macro
thread structure improves stability and facilitates mounting. At the same time, it
increases the attachment area of bone cells, and provides a favorable environment
for osseointegration in the later stage. It can also optimize the stress distribution,
influence the conduction of bite force and improve the long-term stability of implant.
Common thread shapes include standard V-shape, square shape, sawtooth shape,
anti-sawtooth shape, circular shape, spiral shape, etc. (Fig. 2). An implant may have
66 Y. Zhang et al.
Fig. 2 Threads of different shapes: (a) standard V-shape; (b) square shape; (c) sawtooth shape; (d)
anti-sawtooth shape; (e) spiral shape
only one single thread shape, but also could have different thread shapes at neck,
middle section or root tip with different thread depth, width, pitch, thread angle and
root plane angle. For example, micro thread with small pitch can be designed in the
neck of implant, wide thread or double thread can be designed in the middle, and
self-tapping thread is often designed in the 1/3rd of root tip.
3.3 Different Connection Between the Implant

and the Abutment
The connection between the implant and the abutment has important functions such
as connecting the abutment, transmitting dispersed bite force and anti-rotation,
which are directly related to the long-term performance of the implant. Therefore,
the design of this connection is regarded as one of the major changes in modern
implant.
Implant connection can be divided into the external and the internal type (Fig. 3).
External connection has a certain mechanical structure on the implant shoulder that
is used for abutment connection. For example, the classical Brånemark implant sys-
tem has an outer hexagonal connection structure with a height of 0.7 mm on the
implant shoulder, and the base of the repair abutment is fixed on the outer hexagonal
structure through a central bolt.
By contrast, internal connection has no structure above the implant shoulder, but
extends into the implant body through the extension under the repair abutment for
connection and fixation. Such connection warrants functional anti-rotation, which
helps to resist the clockwise or counterclockwise rotation when the prosthesis faces
Fig. 3 Structure schematic of implant connection (a) External connection; (b) Internal connection
with lateral force. There are several different internal connection structures such as
tube-in-tube connection (e.g., Camlog®), Platform abutment (e.g., NobelSpeedy®),
and Taper connection (e.g., Ankylos®). Most of the tube-in-tube and platform con-
nections have anti-rotation structures. The common anti-rotation designs include
inner triangle and inner hexagon. Taper connection is considered to have good stress
conductivity, but anti-rotation relies on its mechanical embedment.
In 2006, a new internal connection called platform switching emerged, where the
abutment edge ends at the inner side of the implant top platform rather than flush
with the edge. During the last 10–15 years, the internal connection combined with
platform switching design has been widely used in contemporary implant systems
owing to its good mechanical properties, better abutment connection stability, anti-
rotation function and stress conduction. Further, it has been gradually considered to
influence the formation of biological width, preserve and reduce the absorption of
neck bone tissue, and improve the long-term stability of implant neck soft and
hard tissue.
3.4 Surface Modifications on the Neck of Dental Implants
Dental implants, as an open system connected with oral cavity, are different from
implants in other parts of the human body, such as orthopedic implants. The long-
term clinical effect of dental implants depends not only on its appropriate bone
bonding after implantation into the jaw (osseointegration), but also on the sealing
effect of healing soft tissue (soft-tissue integration). Contemporary dental implant
systems can be roughly divided into one-stage and two-stage implants. Because of
their large clinical tolerance and convenience, two-stage implants are the main-
stream design of contemporary implants. The bone implant and abutment of two-
stage implants are two distinct parts that need to be connected with specific
structures. This special neck structure has an important impact on the reconstruction
68 Y. Zhang et al.
of soft and hard tissue around the implant, the generation of stress, the conduction
of bite force and the long-term stability of implant prosthesis.
Within the transmucosal area of implants, epithelial cells proliferate more
quickly on micro-machined roughened surfaces (Sa = 2.972 μm ± 0.126 μm), while
their initial adherence and activation is boosted on polished surfaces
(Sa = 0.012 μm ± 0.002 μm) (Guo et al., 2021; Cao et al., 2018). In the connective
tissue layer, bundles of collagen fibers from periosteum and subepithelial connec-
tive tissue are found to grow parallel to the long axis of the machined implant with-
out surface treatment (Shioya et al., 2009). However, on roughened surfaces with Sa
around 70–100 nm and laser-modified microgroove surfaces, fibroblasts and fibers
are observed inserted into the surfaces with an oblique direction, leading to a more
robust and stable soft tissue integration (STI) (Zhao et al., 2013; Nothdurft et al.,
2015). Embedment of collagen fibers provides the basis for the soft-tissue integra-
tion around the implant that prevents the epithelial tissue in the upper part from
further growing into the root of the implant. However, compared with epithelial
sealing around natural teeth, STI around implants is very fragile due to its fewer
hemi-desmosomes and prolonged establishment time (Ivanovski & Lee, 2018).
The formation of STI is related to the material properties and surface morphol-
ogy of the implant, as well as the position of the micro-gap between implant and
prosthetic suprastructure (Roehling et al., 2019). For better aesthetics, white
coloured zirconia abutments and implants are gaining attention. According to some
studies, soft tissue adherence to zirconia is equivalent to titanium (Hanawa, 2020).
There was no significant difference in the soft tissue response between zirconia and
titanium abutments (van Brakel et al., 2012). In terms of reaction to bacteria, more
remodeling and/or inflammatory phenomena around titanium abutments than those
around zirconia abutments (Nascimento et al., 2014). However, titanium tended to
show a faster initial osseointegration process compared to zirconia (Roehling
et al., 2019).
Macroscopically, the implant neck can be designed as cylindrical, dished or
reverse dished (Fig. 4). Some studies have shown that the design of dish or reverse
dish changes the stress conduction and distribution of the traditional cylindrical
neck, and can reduce the bone resorption at the neck to a certain extent (Messias
et al., 2019; Rokn et al., 2015). Micro threads can also be designed to disperse neck
Fig. 4 Different implant neck morphology

stress and increase the area of bone cell attachment (Bateli et al., 2011; Messias
et al., 2019).
On the micro level, the implant neck surface can be designed as a machined
smooth or rough surface. However, a consensus on a specific surface roughness
value range for enhanced STI is still controversial. Currently, to enhance the longev-
ity of implants, the trans-mucosal regions on commercial implants (either implant
neck or abutment) are mainly fabricated with a smooth surface that is easy to decon-
taminate and inhibits bacterial attachment, which also results in poor STI (Guo
et al., 2021). An ideal implant surface modification strategy would enhance the
function of epithelial and fibroblast cells for improved attachment to the implant
surface, modulate the inflammatory response to promote more rapid healing, while
reducing bacterial attachment and colonization.
4 Micro-scale Design of Dental Implant Surfaces
The classic Brånemark system is a machined surface at the beginning of its design,
with simple processing techniques and low cost. However, it requires a more
extended bone healing period and is less commonly used in the clinic (Buser et al.,
2017). The surface modifications of current micro-rough implant systems have a
variety of improved technologies or biological modifications, which are accom-
plished by different manufacturing techniques, including acid-etching, anodization,
sandblasting, grit-blasting, or other coating procedures, significantly enhancing the
surface area and augmenting osseointegration due to the formation of pits, grooves,
and protrusions (Fig. 5). Next, we introduce several standard techniques to achieve
Sa of 1–10 μm implant surface.
4.1 Strategies of Micro-scale Surface Modifications
4.1.1 Sandblasted, Large-Grit and Acid-Etched (SLA)
This technique involves bombardment of particles (such as silicon, aluminum, tita-

nium dioxide and absorbable bio-ceramic) with 110–500 μm onto the implant sur-
face at high speeds, followed cleaning via acid etching (HCl and H2SO4). Besides,
in order to improve hydrophilicity, Ti implants are immersed in isotonic solution at
low pH to produce a super-hydrophilic titanium surface. This procedure creates a
new hydrophilic and chemically active surface, called SLAactive (Agroya et al.,
2020). Compared with acid-etching surfaces, the super-hydrophilic surface can
increase BIC in 2–4 weeks (Lang et al., 2011). The average BIC on SLA surfaces
showed to be in the range of 67–81% for 6 months (Bornstein et al., 2009).
By utilization of an SLA procedure in isotonic solutions, some spike-like
nanofeatures can be produced on the surface. This moderately rough (Sa of 1–2 μm)
70 Y. Zhang et al.
Fig. 5 Micro-morphology of different implant surfaces by scanning electron microscopy (Jarmar

et al., 2008): (a) machined surface; (b) the hydroxylapatite coating of Ti plasma sprayed surface;
(c) sand blasted and acid etched surface; (d) anodic oxidized surface
surface provides a favorable interface conducive to the generation of bone bonding.

Experimental investigations have shown that SLA treated implants creates a greater
bone contact and stability at early healing phase (Cochran et al., 2010; Taba Júnior
et al., 2003). Moreover, other clinical studies (Nelson et al., 2016; Roccuzzo et al.,
2014) of immediate provisional restorations on implant have reported a clinical suc-
cess rate of about 100% on this super-hydrophilic implant surfaces with positive
aesthetic outcomes. At present, many mainstream implants have adopted SLA tech-
nology to treat the surface, including Straumann®, Ankylos®, Camlog®, Astra®,
Osstem®, etc.
4.1.2 Plasma Spraying Deposition
Plasma spraying deposition can be mainly divided into hydroxyapatite sprayed sur-
face (HAS) such as Zimmer® spline reliance implant and Ti plasma sprayed surface
(TPS) such as early Straumann® implant. In order to increase the surface areas,
TPS, for instance, uses special titanium slurry flame jet coating technology. It adds
titanium particles and hydrides into the pressurized inert gas (argon), which quickly
(3000 m/s) passes through a high-temperature arc (15,000 ~ 20,000 °C). Next, tiny
titanium droplets are sprayed to the implant surface at a distance of 10 ~ 20 cm to
form a 30 ~ 50 μm thick layer, with chemical compatibility and biocompatibility
remaining unchanged (Ong et al., 2004). The ideal film thickness is around 50 μm
(Buser et al., 1991), and the average roughness of the coating is around 7 μm, which
enhances the implant surface area (Buser et al., 1991). This rough surface
(Sa > 2.0 μm) showed comparable, even superior bone responses compared to
machined surface in some animal studies (Ong et al., 2004; Ong et al., 2002).
Studies on the function of HA crystallinity in bone formation and bone bonding
have been conducted, but no consensus on the ideal characteristics has been achieved
thus far (Lo et al., 2000; Mohammadi et al., 2004).
However, it is suspected that the coated titanium particles may fall off during
implant implantation or after implant stress, which can cause severe marginal bone
resorption and even implant failure (Arcos & Vallet-Regi, 2020). Therefore, the
implants with sprayed surface have been gradually replaced by the implants with
medium roughness (1.0–2.0 μm) after being widely used in clinic for more than
20 years.
4.1.3 Anodic Oxidation
The aim of anodic oxidation is to increase the thickness of TiO2 layer in order to
improve the surface characteristics of dental implants (Anil et al., 2011). The anodic
oxide film is generated by the charging of the double electric layer at the metal-
electrolyte interface. The process involves dissolving oxide layer supported by the
electric field and it is accelerated by temperature, including the production of a
soluble salt comprising the metal cation and an anion in the electrolytic bath. This
method enables the growth of 10 nm to 40 μm of TiO2 oxide layer and can also
allow the adsorption and incorporation of ions from the electrolyte. Oxidation dura-
tion, oxidation voltage, electrolyte solution type, electrolyte solution concentration,
and the subsequent heat treatment process are the influencing variables (Wang et al.,
2020). Through anodic oxidation, controlled topographies can be fabricated on
implants, which also offers corrosion resistance and augmented bioactivity.
Alternatively, in electrochemical anodization (EA), fluoride and water in electro-
lytes drive the self-ordering of controlled metal oxide nanostructures when the
implant (anode) and counter electrode (cathode) are immersed, and appropriate cur-
rent/voltage is supplied (Gulati et al., 2015). In comparison to machined surfaces,
anodized surfaces result in a substantial strengthening of the bone response, with
higher results for biomechanical and histomorphometric testing (Rocci et al., 2013).
When compared to turned titanium surfaces of identical forms, anodized titanium
implants had a greater clinical success rate (Jungner et al., 2005). According to a
recently published meta-analysis, in addition to a moderate microroughness that
increases surface area and oxide thickness, anodized implants also provide addi-
tional adhesion points for proteins and cells, which contributes to the augmentation
of osseointegration (Karl & Albrektsson, 2017). There are two mechanisms to
explain the osseointegration: mechanical interlocking and biochemical interaction
found between implant material and bone (Sul et al., 2005).
72 Y. Zhang et al.
4.1.4 Laser Surface Processing
Laser treatment of implants is emerging as a surface modification strategy. It is also

capable to form micro-roughened, as well as uniformly or randomly distributed
grooves/holes on Ti surfaces, which provide various advantages over mechanical
treatments, including precise crafting, accurate controllability, and generating fewer
metal streaks and particles (Chen et al., 2017; Blázquez-Hinarejos et al., 2017). It
can not only control its surface roughness, but also treat it according to a predeter-
mined angle (towards the crown or root or perpendicular to the implant surface).
Besides, different from aforementioned techniques, laser processing focuses more
on improving the integration of dental implants in the surrounding soft tissue. The
neck surface of the implant which has been treated in a laser micromachining stage
could form a pattern of micro- and nanoscale channels. These microchannels have
been postulated to operate as a biologic seal by inducing the adhesion of connective
tissues and bone and limiting epithelial downgrowth (Nevins et al., 2010).
Furthermore, it has been identified that laser modified implants upregulate the
expression of keratinized proteins from junctional epithelial cells and enhance the
formation of collagen fibers, therefore resulting in improved STI in both the epithe-
lium and connective tissue layers (Leong et al., 2018). In a dog model, Nevins et al.
(2010) demonstrated histologically that connective tissue formation around laser-
processing abutments was organized in a perpendicular manner. In a clinical study,
peri- implant soft-tissues were retrieved from patients at 15 months after surgery
and histological staining showed significantly enhanced gingiva-implant contact
area (98.8% ± 3.78%) on the laser modified (Laser-Lok®) Ti implant system as
compared to a smooth surface (24.1% ± 16.63%) (Blázquez-Hinarejos et al., 2017).
4.1.5 Other Modifications
Physical Vapor Deposition (PVD). After thermal oxidation treatment of the

implant in pure oxygen at 800 °C by atmospheric heating method, a dense and thick
oxide film is formed, which increases the corrosion resistance of the implant and
improves the bone bonding ability (Mendonça et al., 2008). Prachar et al. examined
the characteristics of TiN with ZrN on pureTi, Ti-6Al-4V, and Ti35Nb6Ta titanium
alloys. It was proven that TiN had stronger cell colonization than ZrN (Prachar
et al., 2015). Furthermore, their color overcomes the problem of aesthetics in oral
implantology since the color of these coatings prevents Ti visibility through the
gingiva (Prachar et al., 2015). The advantages of this technique include short pro-
cessing time and simple equipment; while the shortcomings are the reduced bond
and wear resistance between surface and deposition coatings (Xue et al., 2020).
Micro-Arc Oxidation (MAO). MAO also known as micro plasma oxidation or

anodic spark deposition. Through this technique, a corrosion and wear resistance
ceramic film can be formed directly on the surface of non-ferrous metals, which is
porous and conducive to the formation of new bone (Yin et al., 2012). As a hot spot
technique for surface modification, MAO was employed in plenty of study schemes,
including the preparation of titanium dioxide and HA layers (He et al., 2018;
Shimabukuro, 2020). The improved surface hydrophilicity of the porous coating
generated by the MAO method may promote the interaction between the implant
and the surrounding biological environment. It also brings excellent antibacterial
capabilities owing to the presence of metal ions. It offers benefits such as a simple
procedure, a compact footprint, high processing capacity, high production efficiency,
suitability for large-scale industrial production, and environmental protection (Xue
et al., 2020).
Chemical Modifications. Chemical modifications mainly promote early bone inte-

gration through hydroxyapatite deposition, an important bone biomimetic material
(Zweymüller, 2012). For instance, the sol-gel method was applied to the implant
surface with the appropriate colloidal calcium and phosphorus ratio, and then heated
to form a solid hydroxyapatite film, which significantly improved the osseointegra-
tion ability of the implant (Abrishamchian et al., 2013). Further, ion beam assisted
deposition technology synthesizes the coating by bombarding the growing surface
with a specific energy, type and current ion beam, during electron beam evaporation
deposition or sputtering deposition (Coelho & Lemons, 2010; Granato et al., 2010).
The hydroxyapatite coating prepared by this method has strong adhesion with tita-
nium matrix and can be combined at low temperature, which overcomes the disad-
vantage of delamination.
4.2 Biological Response to Micro-rough Implant Surfaces:

Cellular Responses, Gene Expression and In Vivo Tests
Over the last few decades, the influence of implant surface characteristics on the
biological response has been extensively investigated. The reactions include induc-
tion of angiogenesis and osteogenesis by cellular responses (cell adhesion, mor-
phology, proliferation and differentiation) (Bosshardt et al., 2016; Liviu et al., 2015).
Compared to macro-rough, the micro-rough surface maximizes interlocking
between the mineralized bone and the implant surface, in addition to enhancing
mechanical stability (Ralf et al., 2016; Junker et al., 2010). One possible way that
topography may impact cellular differentiation is by forced changes in cell shape
(Dike et al., 1999). From a microcosmic point of view, the cytoskeleton senses the
surface texture by actin protuberance of lamellipodia. Interestingly, the micro-
roughness surface presents a strong influence on the lamellipodia direction, which
imposes cytoskeleton mechano-transduction determining cell shape and differentia-
tion fates (Schönichen & Geyer, 2010; Dominguez & Holmes, 2011).
In osteogenesis aspect, one function that microscale surface roughness may play
in better osseointegration is the stabilization of fibrin clots by the implant surface
(Park et al., 2001). The described physical interlocking of fibrin fibers with surface
74 Y. Zhang et al.
features facilitates the directed ongrowth of bone forming cells directly at the
implant/bone contact. Topographic improvement may help in stability of extracel-
lular matrix scaffolds for conduction of cells toward and onto the implant surface
(contact guiding) (Ricci et al., 2008). Several authors have reported surface
topography- specific impacts on titanium-adherent osteoblastic cell activity
(Schneider et al., 2003; Ogawa & Nishimura, 2006). These studies show that the
surface adhesion-mediated modulation of cell activity favours bone formation.
Investigations have established that the micro-level surface topography improves
the adhering osteoblasts’ development and extracellular matrix formation/mineral-
ization (Abron et al., 2001). Micro-roughness induces platelets to secrete biological
mediators that attract differentiated osteogenic cells and promote adhesion, together
with the formation of the fibrin matrix for stabilization of the blood clot (Feller
et al., 2014). Together these experiments have demonstrated that enhanced surface
topography significantly promotes extracellular matrix formation of adherent cells
and produces a quicker and more reliable osseointegration response. The micro-
topography alters the growth, metabolism, and migration of these osteogenic cells.
The alteration allows for the induction and regulation of the expression of specific
osteoblastic integrin subunits that are in contact with the implant. In turn, bone
matrix proteins interact with these integrins-mediating osteoblast activity (Vlacic-
Zischke et al., 2011; Zhao et al., 2007). Besides, the micro-level topography
enhances the secretion of VEGF-A, TGF-β1, FGF-2, osteoprotegerin, and angiopoi-
etin-1 by osteoblast-like MG63 cells (Olivares-Navarrete et al., 2013; Saghiri et al.,
2016); and increases the production of pro-angiogenic factors such as VEGF-A,
fibroblast growth factor (FGF)-2, and epidermal growth factor (EGF) in primary
human osteoblasts (HOB) through α2β1 signaling pathway (Raines et al., 2010).
In immunological aspect, it is demonstrated that the Ti implant surface topogra-
phy and roughness created by SLA treatments stimulated the macrophages to
secrete proinflammatory cytokine including tumor necrosis factor (TNF)-α, as well
as down-regulated the production of chemokines like the monocyte chemoattractant
protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α (Refai et al.,
2004). However, when the macrophages were stimulated by lipopolysaccharide
(LPS), higher level expressions of these cytokines (TNF-α, IL-1β, IL-6) and chemo-
kines (MCP-1, MIP-1α) were observed (Refai et al., 2004).
Additional to cellular responses examined in vitro, the in vivo tests are carried
out providing information on tissue level around surface materials (Ernst et al.,
2014). Parameters related to osseointegration phenomena include: bone-to-implant
contact, bone mineralization, removal torque, histomorphometry and quantification
analysis, all of which can illustrate the osseointegration efficacy of a given implant
material (Bagherzadeh et al., 2013; Ernst et al., 2014). In animal experiments, a
moderately rough surface with a Sa of about 1.5 μm and a Sdr of about 50% leads
to favorable bone remodeling, in contrast the most common implant surfaces pro-
vides a Sa of 1.1 μm and a Sdr of 37% for an anodized surface (TiUnite™, Nobel
Biocare® AB, Gothenburg, Sweden) and a Sa of 1.75 μm and a Sdr of 143% for a
hydrophilic, sandblasted, large grit and acid etched surface (SLActive™,
Straumann® AG, Basel, Switzerland) (Gottlow et al., 2012). Zhang et al.
demonstrated the osteogenic performance of SLA and 3DA (three-dimensional

printing and acid-etching) implants in the femoral condyle of SD rats for 3 and
6 weeks (Zhang et al., 2020). Yet, micron-scale topographic alteration of the cpTi
surface is acceptable in dental implant industry (Albrektsson & Wennerberg, 2004a;
Albrektsson & Wennerberg, 2004b).
5 Contemporary Implant Surface: Clinical Application

and Evidence
Nowadays, surface modification methods (for instance, grit-blasting, acid-etching,

and anodization) have proved clinical efficacy. There is no doubt that osteogenic
cells prefer to recognize and response to the micro-rough Ti surface, compared to
the machined one. In a systematic review which evaluated 7711 implants from well-
documented implant systems, a mean success rate was 89.7% (34.4–100%) over a
mean follow up time of 13.4 years (10–20 years). Cumulative mean values for the
survival rates were 94.6% and marginal bone resorption values were reported to be
1.3 mm (Moraschini et al., 2015). It was concluded that current dental implants are
safe and present a high survival rate with minimal marginal bone resorption in the
long term. The 10-year survival rate of SLA Ti implants was reported to be 95–97%
(Buser et al., 2012; Roccuzzo et al., 2014; Rossi et al., 2018). As one of the main-
stream treatment technologies of implant surface, SLA surface has been tested in
clinics for the longest period.
A recently published meta-analysis comparing 10-year clinical outcome of dif-
ferent dental implant surfaces (machined, blasted, acid-etched, sandblasted and
acid-etched, anodized, Ti-plasma-sprayed, sintered porous and micro-textured)
demonstrated that the anodized implants had the lowest failure rate (1.3%, 0.2–2.4%)
and minor peri-implantitis rate (1–2%) (Wennerberg et al., 2018).
It is well established that osteogenic cells prefer and respond to micro-rough Ti
surfaces, as compared to the machined surfaces (Buser et al., 1991; Klokkevold
et al., 2001). However, additional investigations are needed to find the most opti-
mized implant surface topography (SLA or anodized) that enhances bioactivity and
osteogenesis (Yeo, 2019). Currently, both SLA and anodized implants present a
suitable topography for clinical use. However, SLA surfaces remain the preferred
choice in clinical dentistry, with many manufacturers opting for SLA over anodized
implants. Despite the favorable clinical results, there are still implant-related
mechanical, biological and functional complications (Wennerberg et al., 2018;
Albrektsson et al., 2016). One major complication is peri-implantitis, which can
cause bone loss around the implant, eventually leading to implant failure. Although
there are a great range of surface treatment technologies commercially available for
generating Ti implant surfaces, effect of one surface treatment on the durability and
performance of dental implants over the other has not been fully researched. It’s
worth emphasizing that there are currently no clear rules and recognized standards
for implant surface morphology design (Wang et al., 2020). Besides, the high cost
76 Y. Zhang et al.
is another barrier that causes many difficulties during the clinical validation stage of
implant design. In order to address these problems, the future dental implants should
meet the following characteristics: biocompatibility and antimicrobial properties,
biomimetic and standardized qualities, biological safety and inexpensive cost.
Furthermore, a significant pre-clinical and clinical tests needs to be performed to
assure the security and dependability of implants employing innovative technology.
6 Future Directions
While micro-roughness is regarded as the ‘gold standard’ towards establishment of

appropriate implant-bone bonding, nano-engineering is emerging as a new platform
for further enhancement of the dental implant bioactivity. This new trend in titanium
surface engineering aims to create biologically inspired surfaces that can imitate
natural bone architecture and stimulate osteoblast adhesion, differentiation, prolif-
eration, and migration, resulting in improved bone formation and osseointegration.
To reduce the risk of periimplantitis-induced implant failure, antibacterial and anti-
inflammatory therapeutics can also be physically adsorbed on such nano-scale sur-
faces in order to limit primary bacterial adherence and biofilm formation.
In particularly, synthesis of TiO2 nanotubes using anodization approach on sur-
face of titanium has shown remarkable potential to promote cellular behavior such
as adhesion, proliferation and differentiation (Gulati et al., 2018). In addition,
hydroxyapatite mineralization is enhanced and bacterial adherence is lowered on
nanotubular surfaces compared with normal smooth surfaces (Mei et al., 2014).
Recent attempts have confirmed that nano-engineered implants promote osseointe-
gration, and holds great promise as the next generation of dental implants
(Hamlekhan et al., n.d.; Gulati et al., 2021; Zhang et al., 2021).
Acknowledgements This work was supported by the National Natural Science Foundations of
China 81871492 (Yan Liu), Ten-Thousand Talents Program QNBJ2019-2 (Yan Liu), ITI Research
Grant 1544-2020 (Yan Liu), Key R & D Plan of Ningxia Hui Autonomous Region 2020BCG01001
(Yan Liu), Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-
ZLCX20212402, Yan Liu), Key Research Program of Central Health Commission 2022ZD18
(Ye Lin).
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Nano-scale Surface Modification of Dental
Implants: Fabrication
Ruben del Olmo, Mateusz Czerwiński, Ana Santos-Coquillat, Vikas Dubey,

Sanjay J. Dhoble, and Marta Michalska-Domańska
Abbreviations
A Anatase
AC Alternating current
bFGF Fibroblast growth factor
CAD Computer-assisted design
CaP Calcium phosphate
DC sputtering Direct current sputtering
DCD Discrete crystalline deposition
DDS Drug delivery systems
DLIP Direct laser interface pattering
EA Electrochemical anodization
GO Graphene oxide
HA Hydroxyapatite
LBL Layer-by-layer
LPD Laser pulse deposition
MAPLE Matrix-assisted pulsed laser evaporation
NR Nanorod
R. del Olmo · M. Czerwiński · M. Michalska-Domańska (*)

Institute of Optoelectronics, Military University of Technology, Warszawa, Poland
e-mail: mateusz.czerwinski@wat.edu.pl; marta.michalska@wat.edu.pl
A. Santos-Coquillat
Experimental Medicine and Surgery Unit, Inst. De Investigación Sanitaria Gregorio Marañón,
Madrid, Spain
V. Dubey
Department of Physics, Bhilai Institute of Technology Raipur, Raipur, India
S. J. Dhoble
Department of Physics, R.T.M.Nagpur University, Nagpur, India

https://doi.org/10.1007/978-3-031-21565-0_4
84 R. del Olmo et al.
PDA Polydopamine
PTL Phase transition lysozyme
PVD Physical vapor deposition
PVDMS Physical vapor deposition magnetron sputtering
R Rutile
Ra Profile roughness average
RF sputtering Radio frequency sputtering
RGDC Arginine-glycine-aspartic acid-cysteine
Sa Area roughness average
SA Supramolecular assembly
TA Tannic acid
Ti Titanium
TNT TiO2-based nanotubes
TNWs Titanium nanowires
TPS Ti plasma-sprayed
1 Introduction
1.1 Titanium: The Gold Standard in Dentistry
Metallic biomaterials/implants are widely used in dentistry and dental surgery.

These biomaterials are applied in clinical practice for dental restoration, endodontic
implantations, or orthodontics applications.
Dental implants from commercially pure titanium or titanium alloys have an
extensive and successful history of clinical application of more than 40 years and
can be considered the gold standard in dentistry (Chen & Thouas, 2015; Qu et al.,
2007). Ti CP grade 4 (ASTM F67) is the most common Ti-based alloy investigated
in dentistry. It presents outstanding corrosion resistance, biocompatibility, and
osseointegration. Ti CP has a single-phase alpha microstructure and is available in
four grades where the oxygen (O) content varies between 1.8 and 0.40 wt.%, and the
iron (Fe) content between 0.20 and 0.50 wt.%. Ti CP grade 4 contains up to
0.40 wt.% of oxygen, that influences the physical and mechanical properties (high-
est tensile and yield strengths) (Geetha et al., 2009; Lyndon et al., 2014; Mathieu
et al., 2014).
The main characteristics of Ti are excellent biocompatibility, high strength, stiff-
ness, and relatively low density. More notably, due to surface passivation Ti implants
can osseointegrate with bone tissue (Guo et al., 2012). The passivation process
occurs when pure titanium or its alloys are exposed to the air, producing a ~2–7 nm
thick TiO2 layer in a few seconds. The TiO2 layer provides biocompatibility, chemi-
cal inertness, and high corrosion resistance (Guo et al., 2012; Navarro et al., 2008;
Wang et al., 2016).
Nano-scale Surface Modification of Dental Implants: Fabrication 85
As established in previous chapters, to increase implant bioactivity and improve

the long-term success (especially in compromised patient conditions such as osteo-
penia and diabetes), their surface has been modified in the macro, micro, and
nanoscales. This chapter focuses on the advanced nano-engineering of Ti-based
dental implants.
1.2 Nano-scale Surface Modification of Ti Dental Implants
The long-term success of an implant is dependent on the surface characteristics of

the implant (i.e., the porosity, roughness and chemical composition). The surface
topography of dental implants is crucial for the adhesion and differentiation of
osteoblasts during the initial phase of osseointegration and in the long-term bone
remodeling. However, the implant surface also dictates bacterial adhesion and bio-
film formation.
The usual topographic parameters to describe the surface roughness are the
2-dimensional Ra (profile roughness average) and the 3-dimensional Sa (area
roughness average). Most dental implants on the market have a Ra of 1–2 μm,
because this range provides an optimal degree of roughness to promote osseointe-
gration (Dohan Ehrenfest et al., 2010; Guo et al., 2021a, b). Even though micro-
roughness is considered the gold standard, new nano-engineered implants are being
designed to enhance bioactivity and minimize bacteria adhesion to prevent the loss
of implant due to peri-implantitis (Zhang et al., 2021). This nano-scale surface mod-
ification can help shield implant structures from bacterial attack and biofilm forma-
tion (Navarro et al., 2008; Zhang et al., 2021).
Alternate strategies to promote osseointegration are focused on surface charge
and wettability modulation. After the implantation surgery, proteins are absorbed
onto the implant surface, paving the way for cell-implant interactions. Some cell
types, including osteoblasts and fibroblasts, have a preferential union to the absorbed
proteins rather than the implanted material. The orientation of the adsorbed mole-
cules after implantation can change as a result of the surface energy of the biomate-
rial and after cell adhesion (Guo et al., 2012). Moreover, surface wettability is
highly dependent on surface energy, and enhanced wettability improves the implant
surface biological interaction (Qu et al., 2007). Titanium implant surfaces present
contact angle measurements between 0° (hydrophilic) and 140° (hydrophobic) (Le
Guehennec et al., 2007; Zhao et al., 2005).
Considering these implant surface characteristics, to enable long-term implant
success, current research aims to optimize implant bioactivity to promote early
osseointegration, maintain it in the long-term, and at the same time favor the soft-
tissue integration to prevent bacterial infection (Smeets et al., 2016).
1.3 Current Nanoscale Surface Modification Methods of Ti

Dental Implants
Nowadays, there are more than 1300 implant systems with different shapes, dimen-
sions, bulk and surface material, thread design, implant-abutment connection, surface
topography, surface chemistry, wettability, and surface modifications (Shimizu et al.,
2009). Therefore, numerous surface modifications by different subtractive and addi-
tive methods have been applied to improve implant integration (Table 1). Examples
of conventional subtractive processes include machined, electropolishing, mechani-
cal polishing, sand-blasting, acid-etching, and electrochemical anodic oxidation.
Examples of conventional additive processes are hydroxyapatite (HA) and calcium
phosphate (CaP) coatings, Ti plasma-sprayed (TPS) surfaces, and ion deposition
(Rupp et al., 2018; Wennerberg & Albrektsson, 2009).
For the past few decades, Brånemark Standard implants were considered the
gold standard for implant surfaces (Table 1). These implants were machined with a
turning process, and the imperfections along these machined surfaces allowed
osteogenic cells to adhere and deposit bone, thus creating a bone-implant interface
(Abraham, 2014; Wennerberg & Albrektsson, 2009). These features promoted alter-
native designs to achieve microrough titanium surfaces (e.g., sandblasting and/or
acid etching) with bioactive properties. However, each is associated with pros (aug-
mented bioactivity) and cons (as described next). For example, surface roughening
methods can lead to increased soft tissue growth at the bone-implant interface,
thus reducing the osseointegration between the implant site and the bone
Table 1 Commercial surface treatments on dental implants

Treatment Methodology/composition Product/company
Mechanical Machined Ti Brånemark Standard Implants
(Nobel Biocare), Restore
Machined Implants (Lifecore
Dental)
Surface plasma Welding Ti powder in an inert IMZ TPS (Densply Friadent),
spray atmosphere (e.g., Ar). Plasma Bonefit (Straumann Institute),
spraying of Ti alloy powder onto the Restore TPS (Lifecore Dental),
dental implant. Steri-Oss TPS (Nobel Biocare)
Hydroxyapatite Electrophoretic deposition, sol-gel IMZ HA (Densply Friadent),
(HA) processing, hot isostatic pressing, Restore HA (Lifecore Dental),
flame spraying, plasma spraying, and Steri-Oss HA (Nobel Biocare)
laser pulse deposition.
Double-etched Mixtures of acids (HCl + H2SO4, Osseotite (Zimmer Biomet),
(DE) HF + HNO3) Steri-Oss Etched (Nobel Biocare)
Anodized Electrochemical anodic oxidation Xeal and TiUltra (Nobel Biocare)
Discrete Crystalline Calcium phosphate (CaP) particles Nanotite/T3 (Zimmer Biomet)

Deposition (DCD) are deposited on a double acid-etched
surface by the sol-gel process.
(Santos-Coquillat et al., 2018). For plasma sprayed HA coating, precise control of

the chemical composition, crystallographic structure, and crystallinity of the coat-
ing is not achieved, and the resulting HA layer is mechanically and chemically
unstable (Qu et al., 2007). Therefore, HA tends to disintegrate after the coating
formation, causing cracks in the implant surface.
Surface roughness can determine the fate of the implant as it modulates the
osseointegration and can promote bacteria adhesion and proliferation on the implant.
Commercial implants have been functionalized by different surface treatments in
the past decades (Table 2), obtaining diverse roughness values. Dental implant sur-
faces are classified into different groups considering their surface roughness values
(Ra or Sa). Where smooth implant surfaces present less than 0.5 μm, minimal rough
surfaces are between 0.5 and 1 μm, moderately rough are between 1 and 2 μm, and
rough surfaces are above 2 μm. We can find different smooth surfaces evaluated in
the literature, however with limited or no use in clinical practice (De Bruyn et al.,
2017). Taken together, the use of moderately rough or rough surfaces can promote
bacteria colonization in the implant area, making nano-scale (Ra < 1 μm) modifica-
tions of great interest. Some strategies to avoid this drawback encompass incorpo-
rating antifouling technologies (TiO2-based nanotubes (TNT)) (Gulati, 2021),
bactericidal species (F, Ag, Sr, Cu, Zn, I, Se, Ce, etc.) (Santos-Coquillat et al., 2019,
Table 2 Summary of manufacturers, surface treatments and roughness values for dental implants
Surface name/manufacturer Surface treatment Roughness (Ra, μm)
Brånemark Standard Machined 0.5/Minimal rough
Nobel Biocare
SLA® Large-grit sandblasting + 1.75/Moderately
Straumann Acid-etching Rough
OsseoSpeed® TiO2 sandblasting + 1.5/Moderately rough
Astra Tech Fluoride treatment
Biomimetic® Sandblasting + 2.39–3.63/Rough
Avinent Addition of calcium and
Phosphorous
Osseotite® Double acid-etching 0.68/Minimal rough
Zimmer Biomet
RBM TC® Resorbable particles sandblasting 1.53/Moderately
Mozograu-Ticare + rough
Double acid-etching
TiUnite® TiO2 layer 1.10/Moderately
Nobel Biocare rough
Nanoblast plus® Sandblasting + Triple 1.7/Moderately rough
Galimplant acid-etching
TiOblast TiO2 sandblasting 1.1/Moderately rough
Astra Tech
Dentsply: Ankylos/Friadent/Xive/ Gritblasted+ etched ≥0.2/Rough
Frialit
Adapted from De Bruyn et al. (2017), Jordana et al. (2018) and Nicolas-Silvente et al. (2020)
2021) or antibiotics into the surface (molecules, antibiotics, etc.) (Esteves et al.,
2022; López-Valverde et al., 2021).
Taking into account the previous limitations, nano-engineering strategies such as
physical vapor deposition (PVD), ion implantation, laser patterning, and plasma
treatments, mechanical (micro-machining, polishing/grinding, particle blasting),
the chemical (chemical vapor deposition, sol-gel, etching) and electrochemical
(anodizing) methods, have emerged to fabricate the next generation of dental
implants.
This section is divided into various surface modification methods that are most
effective in rendering the implant surface nano-rough. Further, the current research
gaps and future directions for nano-engineered Ti dental implants are also
summarized.
2 Nanoscale Surface Modification
2.1 Physical
Physical surface modification techniques can be classified as additive techniques,

where another material is added on the surface to achieve desired property, or sub-
tractive methods, where the material is removed from a surface to achieve the
desired property. By contrast, if the material is modified via a chemical or physical
process, the modification can be classified as transformative (Wang et al., 2020;
Zwahr et al., 2019). This section discusses physical strategies for surface modifica-
tion of Ti dental implants to enable nanotopography. Table 3 summarizes the current
trends in physical surface modification techniques.
2.1.1 PVD Magnetron Sputtering
Magnetron sputtering is an additive technique where a thin layer with different com-
positions to the base material enhances specific characteristics such as wettability or
roughness (Oluwatosin Abegunde et al., 2019). Magnetron Sputtering was devel-
oped in the 1850s and was firstly used by Penning et al. in the 1940s (Penning,
1936). These researchers proposed the application of an external magnetic field to
extend the lifetime of electrons escaping from the cathode. In the 1970s, a magneti-
cally enhanced variant of sputtering emerged (magnetron sputtering). Overall, the
main principle of sputtering is the interaction of plasma (ionized gas, usually
Ar + ions) with the cathode surface (Safi et al., 2021). A momentum transfer occurs
between the argon ions and the cathode material due to mutual collisions. The
parameter that determines the ability of the argon ions to transfer energy to the
atoms of the cathode material (sputtering yield) depends on the of the ionized gas,
Table 3 Summary of physical methods of implant surface modification

Method Type Film properties Features
PVD Magnetron Additive Thickness: 0.05–5 μm High deposition rates and uniformity.
Sputtering Easy of sputter metals and nonmetal
layers.
High purity of deposited films.
Highly adhesive films.
Excellent control over the parameters-
coating microstructure.
Laser ablation Subtractive Formation of Enables the creation of nanochannels
controlled with enhanced adhesion between
nanopatterns connective tissue and bone.
Surface property tailoring (i.e.,
roughness, wettability) by the
formation of nanoholes, nanopores,
nanocavities, and nanopillars on the
implant surface.
Laser pulse Additive Thickness: Dense and porous films with
deposition (LPD) 0.05–10 μm controlled Ca/P ratios.
Depending on the process
temperature, amorphous or crystalline
films can be deposited.
Possibility to ablate any kind of
material on the implant surface.
Matrix-assisted Additive Thickness: 10–500 nm Deposition of uniform coatings on
pulsed laser non-planar substrates.
evaporation Optimal control of film thickness and
(MAPLE) topography.
Possibility to obtain multilayer or
composite films.
Compared to LPD, it allows the
deposition on substrates susceptible
to high temperatures.
Direct laser Subtractive Allows the synthesis of Allows surface modification in a
interface pattering periodic porous single step, with ability to control
(DLIP) structures on the topography.
implant surface In comparison to laser ablation, no
photomask is required.
The ability to create periodic
morphologies, controlling the spatial
period of nanochannels.
Ability to change the passive layer
chemistry and microstructure near the
free surface region.
the collision angle, the mass of the colliding atoms, and the type of material on
which the thin deposit layer is obtained (Gudmundsson & Lundin, 2020).
Magnetron sputtering has the following variants:
–– Direct Current Sputtering (DC sputtering), where the ionization of the gas in the
working chamber is achieved by an electrical discharge (Toma et al., 2018);
–– Radio Frequency Sputtering (RF sputtering) uses a high-frequency electric field

at low energy and vacuum-based conditions (radio energy wavelength) (Qadir
et al., 2019).
–– Physical Vapor Deposition Magnetron Sputtering (PVDMS) is a PVD-based sur-
face treatment for polymers, ceramics, and composites (Surmenev, 2012).
For DC sputtering variant, the ionized gas allows a continuous current flow (Toma
et al., 2018), with the target material acting as a cathode and, the substrate and
chamber walls acting as an anode. When the target argon pressure (10−3–10−2 mbar)
is reached inside the chamber, the appropriate DC voltage (500–1000 V) is applied
to ignite the discharge. As a result, the electrons travel towards the anode, while ions
travel towards the cathode and secondary electrons are emitted from the cathode. A
secondary discharge current is created due to the electron acceleration in the electric
field (Calderon et al., 2019). DC sputtering is a relatively fast process, however,
only conducting targets (e.g., metallic substrates) can be deposited.
In RF sputtering, the power source is alternating current (AC), and the high-
frequency generator creates an electromagnetic field in the MHz region (typically at
13.56 MHz). Due to the high charge-to-mass ratio of the electrons, electron-gas
collisions occur in the chamber (Qadir et al., 2019). This low pressure allows an
optimal microstructure control of the deposited layer. With this technique, conduc-
tive materials, as well as insulators, can be deposited. Besides, a superior deposition
rate can be achieved in RF sputtering compared to DC sputtering. However, the
equipment cost is significantly higher. Numerous attempts to modify the classic DC
and RF sputtering methods to extend the lifetime of secondary electrons have been
performed (Jilani et al., 2017; Safavi et al., 2021). The schematic of a RF sputtering
system is shown in Fig. 1.
In PVDMS, the vapour is generated from a target material and deposited on the
substrate surface at a relatively low temperature (250–450 °C), thereby forming a
solid coating. This is the most explored technique as it can create thin layers of
Si-HA, C-HA, Zn-HA, Mg-HA, and Al-HA on different substrates (Qadir et al.,
2021; Safavi et al., 2021; Safi et al., 2021). In the case of Ti dental implants, the
layer thickness control of deposited layer is critical. Namely, the magnetron sputter-
ing allows a thickness control in the range of 0.05–5 μm (Qadir et al., 2021). The
final layer thickness depends on the chemical composition of the sputtered sub-
stance and its adhesion to the substrate. Recently, outstanding results in terms of
adhesion have been reported by PVDMS sputtering ZrO2 on Rutile-based TiO2 films
on Ti dental implants (Chodun et al., 2022; Krýsa et al., 2019).
2.1.2 Laser Patterning
Laser patterning is an effective technique to modify surfaces to fabricate densely

packed 2D nanostructures over a defined area. Each laser is constructed from a
power supply, an optically active medium, and optical coupling (Perveen et al.,
2018). The electromagnetic radiation with the optically active medium excites
Fig. 1 Schematic representation of a typical RF magnetron sputtering configuration used for thin
film deposition. (Adapted and reproduced with permission from Elsevier (Surmenev, 2012))
electrons in the atom to a higher energy state during the interaction. The atom striv-
ing for the lowest possible energy emits radiation spontaneously or due to force by
an initiating photon. When an excited atom interacts with a photon of energy equal
to the transition energy, the atom returns to its basal state, emitting a photon of the
same frequency as the initial one. This process is called stimulated emission and is
the basis of laser operation (Laser: light amplification by stimulated emission of
radiation). The laser light produced by stimulated emission in the laser medium is
coherent, monochromatic, and polarized (Perveen et al., 2018; Zwahr et al., 2017).
In general, laser patterning is used to directly expose or polymerize a base material
to achieve periodic structures with tailored roughness and wettability. This can be
achieved by controlling the incident beam angle, laser wavelength, the phase differ-
ence between the beams, polarization, and intensity (Hindy et al., 2017). Monitoring
and adjusting implant surface roughness and wettability lead to a augmented inte-
gration into the hard and soft tissues.
There are various laser-based surface modification techniques, including laser
ablation, laser pulse deposition (LPD), matrix-assisted pulsed laser evaporation
(MAPLE), and direct laser interference patterning (DLIP), as summarized in Fig. 2
and described below.
Fig. 2 Schematic diagram of different laser ablation setup: (a) LPD, (b) MAPLE and (c)
DLP. (Reproduced from Cristescu et al. (2020), De Bonis and Teghil (2020), Sola et al.
(2021). CC BY)
Laser Ablation
The laser ablation process produces nanochannels on the thread dental implant
surface towards improved integration with the patient’s connective tissue and
bone (Wirth et al., 2017). Laser ablation involves the removal of atoms or ions
from the implant surface by converting the electron or atomic vibrational energy
into kinetic energy. The efficiency of the laser ablation strongly depends on the
process parameters such as laser wavelength, pulse duration, number of pulses,
and material composition (Cunha et al., 2016). For instance, commercial suppli-
ers such as Laser-Lok, Bio Horizons, and Birmingham reported the successful
formation of nanochannels on the Ti surface (Nevins et al., 2010). Additionally,
it was also shown that laser-treated implants exhibit significantly increased
osteointegration and connective tissue adhesion compared to their untreated
counterparts (Subramani et al., 2018). For instance, Farronato et al. (2014)
reported the survival rate of laser-modified Ti dental implants to be 96.1% over
2 years, with enhanced connective tissue integration. Besides, it was demon-
strated that the connective tissue fibre grows perpendicularly to the laser-
fabricated nanostructures. In a recent study, Yeo (2019) reported the Ti implant
survival rate of laser ablated Laser-Lok implant to be 95.6% at 2 years and 94%
at 5 years (Yeo, 2019).
Laser Pulse Deposition (LPD)
Another laser technique, LPD can be utilized to generate a thin layer of material on the
implant surface via a nanosecond pulse laser (Paital & Dahotre, 2009). Briefly, in this
technique, the laser is used to ablate the target material and condense it onto the surface
of the substrate material (Fig. 2). This technique uses an excimer KrF laser (248 nm)
equipped with a pumping system, a high vacuum chamber, a fixed substrate panel, and
a sputtering component (Paital & Dahotre, 2009). LPD technique involves illuminating
the target with a laser and modifying it, for instance, HA incorporation into the implant
surface. The product to be incorporated (e.g. Ca4P2O9, Ca3(PO4)2, CaO, P2O5) can be
deposited as a thin film on the implant surface. In LPD, the substrate temperature
(300–600 °C) controls the crystallinity and roughness of the obtained thin film (Souza
et al., 2019). This technique has been utilized to modify dental implants to enhance
biocompatibility and microbial resistance via modification of Ti implants with Ag-HA,
and F-HA. Also, amorphous and crystalline materials with different porosity and a
fixed Ca/P ratio can be deposited using this technique (Surmenev, 2012). For instance,
Duan et al. (2019), performed LPD (energy 300–420 mJ, frequency 5 Hz) in vacuum
with argon, followed by ablating and depositing a thin HA layer on the surface of the
Ti-based implants (Duan et al., 2019). The study revealed enhanced biocompatibility
and appropriate mechanical stability. Note that the layer thickness can be tailored by
modifying the pulse frequency and laser energy.
Matrix-Assisted Pulsed Laser Evaporation (MAPLE)
MAPLE is used to deposit precise organic thin films such as HA/silk fibroin or HA/
sodium maleate composites on medical implants (Fig. 2) (Miroiu et al., 2010). Briefly,
a frozen solution containing organic particles is used as a target for UV laser ablation.
When the Ti substrate is irradiated with laser light, the frozen liquid is vaporized, and
the dissolved organic material (usually 0.1–4 wt.%) is deposited onto the implant sur-
face. This technique allows control over the thickness (10–500 nm) and topography of
the deposited layer (Rădulescu et al., 2016). Moreover, this technique is highly precise
and permits sequentially deposition of several coatings on the implant surface. Cristescu
et al. (2011) demonstrated the feasibility of the MAPLE to produce a gentamicin-
loaded polymer coating on Ti. The results showed an enhanced bactericidal effect
against E. coli and S. aureus (Cristescu et al., 2011). Further, Popescu et al. utilized
MAPLE to deposit inherently antibacterial bioactive polymer chitosan with hydroxy-
apatite towards improving implant performance (Popescu et al., 2017).
Direct Laser Interference Pattering (DLIP)
DLIP is a relatively new laser-based technique for modifying the topography of

metallic, semiconductor, and polymer surfaces at the micro and nanoscales. DLIP is
used to form highly periodic structures on biomedical surfaces to improve tissue
adhesion (Kuczyńska-Zemła et al., 2021; Kuczyńska et al., 2018). Namely, a pulsed

laser beam (most commonly used Nd: YAG, wavelength 532 nm) is transmitted
through a LENS system and split into two beams (Fig. 2). By acting on the
implant surface with two overlapping beams, periodic distributions of laser power
intensity are achieved (Aguilar-Morales et al., 2018). These beams interact with the
implant surface at a 2α angle and modify the implant surface (Zwahr et al., 2017).
By the laser beam parameters modification, it is possible to control the periodicity
and roughness of the nanoscale structures on the implant surface (Hartjen
et al., 2017).
2.2 Chemical
As can be seen in the previous section, the common factor of surface modification
via physical methods is the expensive equipment and experimental limitations. Over
the last several decades, the scientific community has explored chemical surface
modification methods. There are different routes of chemical modification of Ti
implants, such as the sol-gel route and Discrete Crystalline Deposition (DCD)
(Table 1). However, acid etching is the simpler and easier procedure to modify the
surface of a dental implant at both micro- and nano-scale levels. In a similar way, by
changing the parameters of acid etching (e.g., temperature, treatment time, and acid
concentration), different patterns can be formed.
Overall, the most common procedure consists of immersing Ti implants in an
HF-based solution at high temperatures (60–100 °C) for different treatment times
(5–60 min). Nevertheless, this treatment usually causes pitting corrosion phenom-
ena and heterogeneities on the implant surface. For this reason, Steri-Oss Etched
(Nobel Biocare) developed the chemical treatment using a mixture of acids
(HCl + H2SO4, HF + HNO3) to minimize the surface roughness (Table 1). This treat-
ment produces a more reactive titanium surface, thus favoring the application of
further nano-scale-based surface treatments. Next we discuss the various chemical
surface modification of Ti dental implants.
2.2.1 Supramolecular Modifications
The most recent efforts for surface modification of Ti implants are based on supra-
molecular assembly (SA). This approach is focused on the adsorption of bioactive
molecules on the Ti dental implant surface. The latest technological advances are
listed below.
SA-Based Antimicrobial Peptides and Antibodies
The use of antimicrobial peptides and antibodies that do not promote biofilm forma-
tion is particularly attractive for dental implants (Guo et al., 2021a; Qu et al., 2007).
For instance, lysozyme (Lys) is a microbial enzyme that retains its antibacterial
properties after adsorption onto metal surfaces. So far, the incorporation of chemi-
cal species via adsorption that acts as bonding bridges is needed (e.g., silanes,
acrylic acid, or polydopamine). The main drawback of this strategy is the experi-
mental procedure, since multi-step and time-consuming routes are needed to obtain
a homogeneous coating (Diaz-Gomez et al., 2018; Gulati, 2021).
Recently, phase transition lysozyme (PTL) has been targeted as a cost-effective,
and biocompatible surface method for Ti dental implant surface functionalization.
In recent work (Diaz-Gomez et al., 2018), the use of a PTL film on Ti plates to
induce nucleation and growth of hydroxyapatite (HAp) was reported. The multi-
step functionalization approach included: (i) modification of the Ti surface via the
PTL nanoparticle (containing amyloid-like assembly nanostructures), (ii) surface
Ca2+ binding, and (iii) growth of robust HAp in simulated body fluid (SBF).
Layer-by-Layer (LBL) Assembly
The layer-by-layer (LBL) assembly technique is attracting a great significant atten-

tion due to its simplicity, low-cost equipment, and variety of molecules prone that
can be adsorbed (e.g., Lysozyme, 4-vinylpyridine, Chitosan) (Gulati, 2021). The
main advantages are (i) coating thickness control and (ii) the formation of homoge-
neous coatings on complex-shaped Ti dental implants. The fabrication method of
such systems consists of the adsorption of different films on the Ti surface (Lin
et al., 2022; Yang et al., 2022). A representative example is the work of Li et al.
(2020), where the hybrid layer consist of a tannic acid (TA)-graphene oxide (GO)-
Lysozyme (Lys) was formed by adsorbing these acids in successive steps to form a
multilayer coating. In this study Li et al. reported that the coating thickness is
strongly dependent on pH, following a linear growth model.
2.3 Electrochemical
2.3.1 What is Anodization?
The most recent attempts relating to bioactivity/therapeutic enhancements of

Ti-dental implants have been focused on titania (TiO2) nanotubes (TNT). This is
attributed to its high surface area, biocompatibility, drug loading/release and ability
to post-functionalize with polymeric materials or nanoparticles.
Fig. 3 Timeline of the different experimental methods to fabricate titania nanotubes. (Adapted
and reproduced with permission from Elsevier (Zhang et al., 2012))
In this scenario, numerous synthesis methods such as sol-gel, template-assisted,

hydrothermal, and sonoelectrochemistry have been studied to fabricate TNTs on Ti
implants with controllable and improved surface characteristics (Fig. 3).
However, these methods have disadvantages related to the inherent complexity
of the process (involving complex, multi-step reactions), lack of reproducibility, and
are difficult to scale up. Among them, anodizing or electrochemical anodization has
emerged as an easy, cost-effective, and scalable technique that offers excellent con-
trol over the implant characteristics (Zhang et al., 2012, 2016a).
Anodizing is an electrochemical process that enables the growth of the nano-
structural oxide layer on the metallic surface. The metal (Ti), which serves as the
anode in an electrochemical cell is immersed into the electrolyte, and an external
current is applied by a power supply where an auxiliary electrode serves as a cath-
ode (inert material as Pt) (Fig. 4). Depending on experimental variables, such as
voltage, treatment time, current density, pH, and the dissolving capacity of the elec-
trolyte, the thickness of the oxide formed by anodization can reach a hundred
micrometers or just a few nanometers. In addition, surface topography, roughness,
pore conformation, crystalline structure, and oxide chemistry can be modulated by
adapting these variables according to the desired application (Kim et al., 2018;
Wennerberg & Albrektsson, 2009; Zhao et al., 2005). Various investigations have
established that anodized Ti implants offer enhanced bioactivity (both osseo- and
soft-tissue integration) and the ability to load/release therapeutics (growth factors,
antibiotics, etc.) to achieve maximized therapeutic effect (Pye et al., 2009).
The above-mentioned experimental factors have to be taken into account to
achieve a self-organized morphology. Among them, the choice of electrolyte has
been identified as the key factor for the growth of self-ordered TNT as it is related
to the different viscosity of the electrolytes, i.e., the mobility of the ions present
in the electrolyte solution (e.g., electrical conductivity). Figure 4 shows the
Fig. 4 Experimental setup of anodizing system and summary of the biomedical features of titania
nanotubes (TNT) in dentistry
experimental setup of the anodizing process and the main features for the biomedi-
cal application of TNTs in dental implants.
Among all possible studied electrolytes up to date (Alipal et al., 2021), it is well-
known that F-containing electrolytes are the most suitable to achieve a highly self-
ordered morphology of anodic TNT. Overall, in electrolytes containing fluoride
anions, the anodic TiO2 film will develop a porous/tubular morphology while, in the
absence of F- anions, the TiO2 film will be of barrier type (Macak et al., 2007; Roy
et al., 2011).
Over the last several decades, four generations of electrolytes have been studied.
Namely, the first generation is characterized by use of HF-containing (0.1–5 wt.%)
aqueous electrolytes. Consequently, the TNT morphology is defined as poorly self-
organized, ribbed, and thin (~0.5 μm). Then, considering the dissolving power of
HF, the use of fluoride salts (0.1–0.5 wt.%) in aqueous solutions was widely
extended, thereby forming self-organized and slightly ribbed TNT (second genera-
tion) (Michalska-Domańska et al., 2018, 2020).
Nevertheless, for strictly self-organized morphologies, third and fourth genera-
tions electrolytes were most optimized. These electrolytes are based on organic sol-
vents (i.e., ethylene glycol and to less extent, ethanol) in presence of F-based salts
(0.1–0.5 wt.%). Besides, a small amount of water (0.1–5 wt.%) is used to (i) dis-
solve the F-based salts and (ii) promote the formation of smooth, long (till 100 μm)
and well-ordered TNTs (Alipal et al., 2021; Kim et al., 2018; Macak et al., 2007;
Michalska-Domańska et al., 2018, 2020; Roy et al., 2011).
During the anodizing process, Ti4+ ions are continuously released from the Ti
substrate into the electrolyte (Eq. 1).
Ti Ti 4 4e (1)
Simultaneously, the OH− and O2− species are formed because of the water hydroly-
sis. Note that the ethylene glycol media favors the formation of O2− (Eq. 2) over
OH− (Eq. 3). This is due to the minimal amount of water, thus forming a TiO2-
enriched anodic oxide layer (Eq. 2).
Ti 4 O2 TiO2 (2)
Ti 4 4OH Ti OH 4
(3)
The use of F- containing electrolytes is fundamentally related to the ability of Ti4+
to form stable complexes, such as [TiF6]2− (Eqs. 4–6).
TiO2 6 F 4H TiF6 H 2 O
2
(4)
Ti 4 F TiF6
2
(5)
Ti OH 4 6 F TiF6 4OH
2
(6)
It is well-known that the migration rate of F− through the anodic TiO2 film is almost
twice as fast as that of O2− ions. This is due to the lower ionic ratio of the F- anion
compared to O2− ion. This promotes the formation of an F-rich metal-oxide inter-
face underneath the oxide film, thereby dissolving the formed oxide, preferentially
at the base of the pore/tube, where the electric field is higher (Alipal et al., 2021;
Kim et al., 2018).
Therefore, the F−/H2O relation should be considered. For instance, (Naduvath
et al. (2015) studied the formation of TiO2-based nanotubes in ethylene glycol
media using a minimal amount of NH4F (30 mM) at different concentrations of
water (2–20 vol.%) (Fig. 5a–e). This study proved that the formation of well-
defined, self-ordered nanotubes decreases with increasing H2O content. Further,
ring-like splitting (known also as ribbons or rippled sidewalls) was observed for
water contents of 20 vol.% H2O (Fig. 5d). Instead, for 2 vol.% H2O, the nanotubes
split vertically (Fig. 5a). At an intermediate water content of 5–10 vol.% (Fig. 5b,
c), the splitting is vertical, although the first stages of the ring-like splitting are also
visible (Fig. 5e).
Observed phenomenon was associated with a higher dissolution rate of oxide as
a function of water content in electrolyte. Besides, an increase in the inner diameter
of the nanotubes was reported. More specifically, the inner diameter was reported as
∼100 nm for 2 vol.% H2O and ∼170 nm for 20 vol.% H2O. Regarding F- incorpora-
tion, the TNT prepared in the electrolyte with low water content (2 vol.%), the
F- concentration is higher in the upper part of the nanotubes (Fig. 5f). By contrast,
the difference in F- concentration is negligible for the high-water content electrolyte
(20 vol.%) (Fig. 5g).
The authors explain this phenomenon by the difference in electrolyte viscosity.
Namely, a viscosity of 14.6 mPa was reported for electrolyte with 2 vol.% of water
content and 7.7 mPa for the electrolyte with 20 vol.% of water. The slower ion trans-
port in the higher viscosity electrolyte caused a higher fluorine concentration gradi-
ent along the length of tubes in the low water content-based electrolyte (Fig. 5h)
(Kuczyńska Kwaśniak Pisarek et al.).
Fig. 5 SEM micrographs of the titania nanotube (TNT) layers formed with different H2O
content: (a) 2 vol% (b) 5 vol% (c) 15 vol% (d) 20 vol%, (e) the corresponding schematic image of
nanotube at different water concentration in electrolyte, (f) EDS analysis of TNT anodized at
2 vol% water content (g) EDS analysis of TNT anodized at 20 vol% water content (h) TEM-EDS
of TNT anodized at 20 vol% water content. (Reproduced with permission from Elsevier (Naduvath
et al., 2015))
Despite such developments, the precise mechanism behind self-ordering of

TNTs is still controversial. As a function of the electrolyte composition, several
alternative models have emerged as compared to the traditional theories (i.e., field-
assisted dissolution and field-assisted ejection). These conventional theories imply
the formation of pore channels through the dissolution of the titanium hexafluoride
layer from top to bottom (Jin et al., 2016; Jing et al., 2016; Regonini et al., 2013;
Zhao et al., 2018). In contrast, more recent theories, such as viscous flow and elec-
tron current theories have established that the barrier layer grows around the oxygen
bubbles at the bottom of the pores (Duan et al., 2019; Zhou et al., 2020). Nevertheless,
the validity of these theories has not yet been confirmed. Since it is not within the
scope of the present contribution to review the specific advances in anodizing mech-
anisms of Ti, the reader is referred to published research (Duan et al., 2019; Zhou
et al., 2020).
Overall, the balance between oxide growth and dissolution can be finely tai-
lored by modifying the anodization parameters. The following sections will ana-
lyze the influence of main parameters on the characteristics of the anodized
TNTs layer.
2.3.2 Factors Influencing Anodization
Applied Voltage and Treatment Time
Generally, the applied voltage is the fundamental factor for controlling the TNT
tube diameter, and proportionally influences the surface porosity, thickness, rough-
ness, and crystallinity of the resultant TNT layers. (Hsu et al., 2012; Rupp et al.,
2018; Wennerberg & Albrektsson, 2009).
In non-aqueous electrolytes (third and fourth generation) with 0.1–0.3 M NH4F,
the nanotubes diameter ranges between 24–30 nm for 5 V, 35–53 nm for 10 V, and
60–300 nm for 10–40 V (Indira et al., 2015; Kim & Ramaswamy, 2009). For TNT,
it is possible to estimate the tube diameter, which is described by Eq. 7, where k is
essentially equal to 2 fg (fg being the growth factor for anodic oxides, 2.5 nm V−1
for TiO2) (Alipal et al., 2021).
d kV (7)
Besides higher pore diameter, higher voltages favor the increase in the kinetics of
the electrochemical reactions and the resistance of the oxide layer. As a conse-
quence, its thickness and surface roughness tend to increase proportionally with
voltage.
Regarding the treatment time, Hsu et al. (2012) fabricated TNT at 40 V and stud-
ied their morphology at different times. The results confirmed the formation of
Titanium nanowires (TNWs) at prolonged treatment times. This was associated
with the chemical dissolution of oxide (high concentration of H+) during the growth
of the anodized layer near the top of the nanotubes. On the other hand, the effect of
the ethylene glycol electrolyte limits the ionic diffusion of the electrolyte species in
the electrolyte solution. This influenced the thicknesses of resulted oxide, which
was 10–12 μm for 45 and 60 min and 12 μm for 90 and 120 min of the anodization.
Therefore, the optimum anodizing time depends on many experimental factors
like the electrolyte used (electrical conductivity, dissolution power, pH, and tem-
perature) and the applied voltage. Overall, the use of extended treatment times tends
to increase the thickness of the resultant anodic layer. In the case of organic-based
F-containing electrolytes, the growth rate of the TNT is much slower than in aque-
ous electrolytes, and dissolution phenomena are not as significant as in aqueous
electrolytes (Alipal et al., 2021; Pashchanka, 2021).
Electrolyte Temperature and Annealing
The temperature of the electrolyte affects the dissolution rate of TNT. As a function
of the desired morphological properties, the most suitable temperature range is
0–40 °C (Yetim, 2010). Several studies correlated the increase of the electrolyte
temperature with the diameter of the resultant TNT. This is in line with the viscosity
and mobility of ions during the anodizing process, as low temperature reduces the
dissolution rate of TiO2 (Lazarouk et al., 2012; Traid et al., 2015).
The effect of temperature on the morphological properties of TNT was reported
by Kapusta-Kołodziej et al. (2014). In this study, the formation of regular nanopore
arrays at temperatures below 30 °C was observed. However, for temperatures above
30 °C, a higher oxide growth rate and a complex TNT morphology (due to the pres-
ence of sub-pores) were observed. The authors associated these phenomena with the
precipitation of hydrated TiO2 on the anodic film surface. Besides, the anodizing
temperature affects the oxide growth rate (i.e., the thickness of the oxide layer), the
pore arrangement, and cell size.
Notwithstanding, for dental applications, the formation of bio-active crystalline
phases is not favored, and a thermal post-treatment is necessary (Mazare et al.,
2016; Santos-Coquillat et al., 2019; Yang et al., 2011; Yu et al., 2010). The most
studied method to convert the amorphous TNT into both, crystalline anatase (A) and
rutile (R) phases, is annealing. The anatase phase is formed at 280 °C, anatase/rutile
at temperatures higher than 450 °C, and 750–1200 °C for the rutile phase (Fig. 6)
(Jarosz et al., 2015). The presence of anatase and rutile phases in anodic titanium
oxide often exhibits improved bioactivity than the amorphous TiO2.
Fig. 6 Schematic diagram of the anatase-to-rutile phase transformation of anodic TiO2 nanotubes:
(a) nucleation of anatase crystals and nucleation of rutile crystals at nanotube bottoms; (b, c)
growth in the size of anatase and rutile crystals at nanotube bottoms; (d, e) partial transformation
of anatase crystals in the nanotube walls into rutile crystals; (f) complete transformation of crystal-
lites in the walls and partial oxidation of Ti base to rutile. (Reprinted with permission from Jarosz
et al. (2015). Copyright 2015 American Chemical Society)
Electrolyte Aging
Variables such as electrolyte pH and the chemical composition are constantly

changing during the anodizing process. Nevertheless, it has recently been demon-
strated that these parameters play a fundamental role in the final morphology of the
anodic layers and biocompatibility. This parameter is well-known in the literature as
electrolyte aging (Gulati et al., 2022; Guo et al., 2021c).
Overall, the effect of the electrolyte aging on the TNT morphology can be evalu-
ated by two possible routes: (i) as a function of the number of anodized titanium
specimens (presumably of constant dimensions) by using the constant operating
conditions; and (ii) anodizing of a titanium reference specimen in the studied elec-
trolyte at specific conditions before anodizing the specimens of interest (Guo et al.,
2021c; Sopha et al., 2015; Suhadolnik et al., 2020).
In this scenario, it is well-known that after successive anodizing processes (pre-
sumably in the same electrolyte), the concentration of Ti4+ cations and the [TiF6]2−
complex increases, while the concentration of O2−, F−, H+, OH− decreases (Eqs. 1–6).
Therefore, in fresh electrolytes, the equilibrium is shifted towards the dissolution of
the oxide layer (Eq. 4). Conversely, in aged electrolytes, the amount of H+ and F− is
lower, and the equilibrium shifts towards the formation of a TiO2 (due to the
increased formation of [TiF6]2−) (Eq. 4) (Guo et al., 2021c; Roy et al., 2011;
Suhadolnik et al., 2020).
Another factor to consider is the pH of the electrolyte since due to the decrease
of free H+ species, the pH of the electrolyte will increase proportionally with the
number of successive anodizing processes. According to different studies, the opti-
mal pH for forming self-ordered TNT is between 6 and 8 (Gulati et al., 2022). The
pH of the electrolyte is connected to the ability of the electrolyte to dissolve the
forming oxide layer since, in acidic media, the rate of oxide dissolution tends to be
higher than in the neutral or slightly alkaline electrolytes (Gulati et al., 2022).
Similarly, the role of fluoride ions is to minimize oxide dissolution and ensure the
growth of TNT. In addition, the conductivity of the electrolyte is related to the con-
centration of anions, which can increase (Guo et al., 2021c) or decrease (Suhadolnik
et al., 2020) the electrical conductivity of the electrolyte. Although the one possible
explanation of this finding may be associated with an increase of the water content
in electrolytes aged in open electrochemical cells. This is related to the hygroscopic
character of the ethylene glycol solvent, thus modifying the dielectric constant of
the solvent (Guo et al., 2021c).
In summary, for anodic oxide surfaces produced in the aged electrolytes, more
extensive biocompatibility is reported. This was attributed to the mechanotransduc-
tion from the stable oxide layer with anisotropic nanopores, which promote cell
anchorage (Fig. 7).
Fig. 7 Summary of the biomedical performance of using electrolyte aging in anodizing of tita-
nium for dental implants. HGFs: human gingival fibroblasts. (Reprinted with permission from
Gulati et al. (2015). Copyright 2015 American Chemical Society)
2.3.3 Anodization of Dental Implants: Complex Implant and Geometry
Most of the available studies on TNTs focus on the growth of TNT layers on flat
surfaces, such as CP titanium sheets or their alloys, e.g., Ti-6Al-4V (Jing et al.,
2016; Zhou et al., 2020). However, from a clinical point of view, dental implants
have complex geometries (with curves, edges, and grooves) (Fig. 8).
Recently, several studies explored the fabrication of TNT on wire surfaces.
Nevertheless, these layers showed numerous cracks and delamination phenomena,
thus denoting minimal mechanical stability (Cheng et al., 2018; Lee et al., 2014).
One of the key factors in promoting osseointegration and initial stability from TNT
layers on Ti is the substrate pre-polishing and two-step anodizing. In recent study
published by Li et al. improved mechanical characteristics in single-step
Fig. 8 Electrochemical anodization (EA) of titanium implant screws: (a) top-view SEM image
showing threads of the implant screw, and (b–c) schematic representation of anodized screw with
nanopores, highlighting the areas (yellow arrows) where the stability of the anodic nanostructures
may be compromised leading to delamination and fracture. (Reproduced with permission from Li
et al. (2018))
anodization on micro-roughened Ti in comparison to TNT fabricated on polished

titanium by multi-step anodizing was reported (Cheng et al., 2018; Guo et al.,
2021b; Pashchanka, 2021).
To overcome the gap between research and the clinical implant industry, current
studies are focusing on the optimization of anodizing parameters to obtain highly
ordered TNT layers on curved Ti surfaces. For instance, Gulati et al. (2015) system-
atically investigated the effect of electrolyte aging to obtain ordered TNT layers on
Ti wire. The results showed the formation of mechanically robust and stable anodic
films on wire in electrolyte after aging the electrolyte for 10 h (Fig. 9). Besides, the
authors also ascertained the optimal anodizing conditions (i.e., 1% v/v water-
electrolyte, at 75 V for 10–40 min).
Dual Micro-nanostructures
So far, the formation of nanopatterns to direct cell growth by physical and chemical
techniques has several limitations, as stated previously. Therefore, to overcome this
limitation, a recently studied approach is the one-step generation of TNT on an
underlying micromachined Ti surface (Gulati et al., 2018a, b). The rationale behind
this approach is to preserve the underlying micro-features of the implant substrate
while superimposing the nanotopography. This approach results in a dual micro-
and nanoporous topography. For example, Gulati et al. (2018a) reported that the
double micro(substrate)/nano(TNT) patterns induced fibroblast and osteoblast
alignment on Ti dental implants (Fig. 10). Thus, this novel strategy holds great
promise for achieving desirable cellular function/bioactivity at the Ti implant-tissue
interface. Again, this study shows the influence of electrolyte aging in fabricating
homogeneous and self-ordered anodic surfaces.
Fig. 9 Stability of anodic films for anodization performed in (a, b) fresh and (c, d) aged (10 h)
electrolytes. Anodization was performed at 75 V for 10 min using ethylene glycol/NH4F electro-
lyte with 1% (v/v) water. (Reprinted with permission from Gulati et al. (2015). Copyright 2015
American Chemical Society)
2.3.4 Post-functionalization
TNT have been proven as an excellent platform to promote osseointegration and

present highly desirable characteristics as drug delivery systems (DDS) to deliver
drugs locally at the implant site, bypassing systemic administration. Systemic drug
therapy to treat implant-related conditions such as infection presents limitations
including low efficacy, poor bioavailability and biodistribution, and toxicity
(Micheletti et al., 2021). The incorporation of proteins, growth factors, and antibiot-
ics locally from the surface of the modified implants can achieve maximum local
therapeutic action. Nevertheless, TNTs are like empty test-tube-like structures and
hence have been utilized to deliver therapeutics locally. However, open tops are
prone to quick and uncontrolled release attributed to diffusion gradient. Therefore,
new strategies including post-functionalization of drug-loaded TNTs with a poly-
meric layer to control the release of drugs are emerging.
Polymeric Coatings
Different approaches can be found in the literature where a polymer is incorporated

on the TNT. Among them, Li et al. (2017) proposed hybrid ZnO/polydopamine
(PDA)/arginine-glycine-aspartic acid-cysteine (RGDC) nanorod (NR) arrays to
Fig. 10 Representation of the fabrication of aligned TiO2 nanopores and the parallel cell spread-
ing. (a–b) 1-step anodization of titanium (micro-rough) yields aligned TiO2 nanopores (cross-
sectional view presented) with preserved underlying substrate roughness (dual micro- and
nano-topography), (c–d) top-view schematic of spreading of various cells on bare Ti and aligned
TiO2 nanopores and (e–f) anodized micro-rough surface in a fresh and aged F-containing electro-
lyte. (Reproduced with permission from Elsevier (Gulati et al., 2018b). Reprinted with permission
from Gulati et al. (2018a). EA: electrochemical anodization. Copyright 2018 American Chemical
Society)
improve the osteoconductivity of the implants and kill bacteria by the action of
ZnO. Through the tailoring of the NRs, an accelerated formation of new bone tis-
sues (20.1% higher than pure Ti) and osseointegration, and a high antibacterial effi-
cacy was found (Fig. 11).
Another work used a mussel-inspired (polydopamine, PDA) nano silver/calcium
phosphate (CaP) composite to promote a long-term antibacterial ability (Li et al.,
2015). This coating was achieved through three steps (i) the anodic oxidation to
obtain TNT, (ii) self-polymerization of dopamine on TNT, and (iii) modification
with Ag nanoparticles using polydopamine. Antibacterial effects were found with
S. aureus and biocompatibility was evaluated with human osteosarcoma cells.
Natural polymers stand as excellent alternatives for bone tissue regeneration
applications. Among them, chitosan has been widely investigated as a post-
functionalization polymer for TNT (Chen et al., 2013; Kumeria et al., 2015; Yang
et al., 2016; Zhang et al., 2016b) and stands as an excellent biopolymer for dental
implant applications. Moreover, the combination of gelatin and chitosan has also
been evaluated (Hu et al., 2012; Zhang et al., 2016b). Nevertheless, it is out of
the scope of this chapter to review the drugs and loading strategies from TNT, and
the reader is referred to studies by Krishnakumar and Senthilvelan (2021) and
Makvandi et al. (2020).
Fig. 11 Schematic illustration of the fabrication process of the hybrid ZnO/PDA/RGDC NR

arrays on Ti. (Adapted and reproduced with permission from Reprinted with permission from Li
et al. (2017). Copyright 2017 American Chemical Society)
Nano-particles
The incorporation of nanoparticles into TNTs has proven to be an effective func-

tionalization strategy in soft tissue and bone integration, immunomodulation, and,
especially, anti-biofouling (Priyadarsini et al., 2018; Zhang et al., 2021). In addi-
tion, the functionality of NP-doped TNTs is their controlled release to achieve a
balance between therapy and toxicity.
For this reason, different types of metallic nanoparticles such as Zn (Fadoju
et al., 2019; Lai et al., 2021; Nanthagopal et al., 2017; Wang et al., 2009), Cu (Ingle
et al., 2014; Thukkaram et al., 2021), Zr (Indira et al., 2014; Katunar et al., 2017),
and Ag (Arkusz et al., 2021; Cao et al., 2011; Flores et al., 2013; Gunputh et al.,
2018; Noronha et al., 2017; Perumal et al., 2021) have been widely studied.
However, although all studied NPs have shown positive effects on soft tissue inte-
gration, silver nanoparticles have shown the best bioactivity performance.
Notwithstanding, conventional nanoparticles loading methods include physical
bonding, immersion, sputtering, electrophoresis, and chemical bonding. However,
most have several shortcomings, such as the difficulty of the manufacturing process,
environmental contamination, expensive instruments, and harsh processing condi-
tions (Albashari et al., 2021).
Nowadays, the main goal is to achieve the enhanced stability of silver-loaded
TNT and a controlled release. Overall, in several minutes to hours, a burst release
usually occurs due to the weak interaction between the TNT and the antimicrobial
peptides. In this scenario, a recent and comprehensive study by Albashari et al.
(2021), reported the functionalization of TNT with polydopamine (PDA) and
Ag-bFGF cross-linked with heparin (Fig. 12).
The obtained results showed that such a surface modification could promote the
slow release of bioactive bFGF. Furthermore, the authors demonstrated that the sil-
ver cross-linked and bFGF on the nanoscale modified Ti surface had outstanding
anti-inflammatory and early antibacterial properties.
Fig. 12 Experimental design of the titania nanotube coated with dopamine, and cross-linked with
heparin and basic fibroblast growth factor (bFGF). (Reproduced from Albashari et al. (2021).
CC BY)
In conclusion, active research is undergoing to enable enhanced therapeutic and

bioactivity performance from nano-engineered titanium dental implants, to ensure
the long-term success. In addition, the combination approaches employ varied
materials such as polymers, metallic nanoparticles and therapeutics onto nano-
engineered implants (Gulati et al., 2021; Micheletti et al., 2021; Pashchanka, 2021;
Perumal et al., 2021; Santos-Coquillat et al., 2021; Zhang et al., 2021).
The future directions relating to nano-engineered titanium dental implants are
summarized (Fig. 13):
(i) Optimized fabrication of nano-engineered implants with controlled chemical,
physical and electrochemical methods to fabricate mechanically robust nano-
topographies on complex-shaped and micro-rough Ti dental implants.
(ii) The controlled release of drugs via an internal or external stimulus and its
combination with other bioactive materials (ceramics and polymers) to achieve
maximized and ‘on demand’ local therapy.
(iii) New processing routes, such as additive manufacturing or metal 3D printing.
This technology allows the fabrication of dental implants from computer-assisted
design (CAD) without intermediate production and molding steps, thereby
minimizing environmental impact, production costs, and the ability to manu-
facture custom dental implants. However, the use of 3D-printed implants is
still challenging due to high costs and time requirements. Therefore, this tech-
nology needs to be optimized to obtain biocompatible and bioactive surfaces
for dental implants.
Fig. 13 Schematic representation of the future directions for nano-engineered Ti dental implants.
(Adapted from Yan et al. (2018) CC BY)
Acknowledgments The authors cordially acknowledge the National Centre for Research and
Development (Poland) for financed support made under the program LIDER IX(Nr
LIDER/50/0199/L-9/17/NCBR/2018). A. Santos-Coquillat is grateful for financial support from
Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Spain (Sara Borrell Fellowship
grant CD19/00136).
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From Micro to Nano: Surface Modification
for Enhanced Bioactivity of Titanium
Dental Implants
Tianqi Guo, Sašo Ivanovski, and Karan Gulati
Abbreviations
BIC Bone-to-implant-contact
BMP-7 Bone morphogenetic protein-7
BVD Bone-volume density
CS Chondroitin sulphate
FBR Foreign body reaction
FN Fibronectin
GFs Growth factors
HA Hydroxyapatite
OI Osseointegration
PEA Poly-ethyl acrylate
STI Soft-tissue integration
TNPs Titania nanopores
TNTs Titania nanotubes
1 Introduction
As Albrektsson et al. reported, the long-term (>10 years) survival rates of dental
implants inserted by adequately trained physicians could be up to 98% (Albrektsson
et al., 2017). Under constant load bearing conditions, the long-term survival and
functioning of dental implants is dictated by the integration with the surrounding
tissues, including osseointegration (OI) at the implant screw surface and gingival/
T. Guo · S. Ivanovski · K. Gulati (*)

e-mail: tianqi.guo@uq.net.au; s.ivanovski@uq.edu.au; k.gulati@uq.edu.au
https://doi.org/10.1007/978-3-031-21565-0_5
118 T. Guo et al.
mucosal integration at the transmucosal level (Berglundh et al., 2018). Pioneered by

Branemark et al. in 1969, osseointegration involves the direct contact between liv-
ing bone and the implant at the microscopic level, which is a basis for the success of
a dental implant (Albrektsson & Wennerberg, 2019; Chrcanovic et al., 2014).
Successful OI requires the absence of micro-motion at the bone-implant interface
under constant masticatory loading. Further, a robust and functional OI at the
implant-bone interface is a key determinant of the long-term functioning of the
associated implant prosthodontics (Albrektsson & Wennerberg 2019; Chrcanovic
et al., 2014).
Timely bone healing, intramembranous osteogenesis, limited foreign body reac-
tion (FBR) and absence of chronic inflammation are essential conditions for obtain-
ing successful OI (Berglundh et al., 2003; Trindade et al., 2018). Starting from the
initial angiogenesis induced by the blood clot at the implant-bone interface, micro
vascularisations are observed at the margin of the host bone within 24 h (Berglundh
et al., 2003). The blood clots are then infiltrated by the mesenchymal cells from the
bone marrow, which migrates to the wounded sites with various newly formed
blood vessels (Berglundh et al., 2003; Trindade et al., 2018). The migrated mesen-
chymal cells are modulated by the growth factors (GFs) from the blood to differenti-
ate into osteoblasts, finally establishing osteogenesis around implants (Berglundh
et al., 2003). The earliest new bone formation could be observed at around 5–7 days
post-implantation, which is regarded as the woven bone structures stretched from
the host bone, with calcified tissue and collagen matrix deposited (Berglundh et al.,
2003). Similar to fracture healing in an orthopedic implant setting, continuous bone
remodelling occurs during the bone formation process upon dental implant place-
ment, transforming the initial woven bone into lamellar bone (Wang et al., 2016).
Further, the connection of newly formed bone with the implant surface could be
observed at approximately 4 weeks after implantation (initial OI) (Davies, 2003).
Finally, at approximately 8–12 weeks, the transformation and maturation of lamel-
lar bone is completed, which is regarded as established OI. Under appropriate con-
ditions and maintenance, modern implants should obtain stable osseointegration
with surrounding bones without ongoing bone loss, after the initial bone remodel-
ling within the initial 1 ~ 2 years after implant placement (Albrektsson et al., 2022).
Alongside establishing appropriate OI, obtaining soft-tissue integration (STI) at
the transmucosal region is also critical for the success of dental implants. Appropriate
STI leads to formation of a soft-tissue sealing or barrier that protects the implant
structures from bacteria ingress (Guo et al., 2021a, b). Unlike the OI at the implant-
bone interface, the STI around dental implants is significantly weaker than those
around natural teeth (Atsuta et al., 2016). Such results are attributed to its histologi-
cal characteristics, composed of the superimposed peri-implant epithelial (PIE)
sealing and the connective tissue adaption (Atsuta et al., 2016).
The PIE initiated from the oral epithelium (OE) horizontally migrates to the
surgical site within 3–4 days after implant surgery (Atsuta et al., 2005b). Attachment
structures such as hemidesmosomes (HDs) and internal basal lamina (IBL) are gen-
erated from the epithelial cells and are recruited at the epithelium-implant interface
within 1 week, representing the initial epithelium attachment formation. Such initial
From Micro to Nano: Surface Modification for Enhanced Bioactivity of Titanium… 119
attachment matures until 2–4 weeks when a dense epithelium barrier is established
(Atsuta et al., 2005b). However, compared with the junctional epithelium around
natural teeth, significantly fewer adhesive structures (HDs and IBL) are observed at
the PIE-implant interface, which significantly limits the adhesion strength of PIE
sealing (Atsuta et al., 2005b; Tomasi et al., 2014). Further, such adhesive structures
are only present at the lower 1/3rd of the PIE-implant interface, reducing the adhe-
sion region of PIE sealing and compromising its strength (Atsuta et al., 2005a).
Fibroblasts are responsible for STI in the underlying connective tissue layer,
which induces connective tissue regeneration and wound healing by secreting and
remodelling collagen and extracellular matrix (ECM) (Gulati et al., 2020). Unlike
the epithelium barrier that establishes within 1 week, the formation and maturation
of peri-implant connective tissue is a prolonged process. Typically, the formation of
collagen fibres requires 4–6 weeks and another 2–6 weeks for their maturation
(Ericsson & Lindhe, 1993; Fujii et al., 1998). Thus, the delayed connective tissue
healing and regeneration around dental implants significantly restricts the STI for-
mation. Further, compared to the periodontal ligament that firmly connects a tooth
to alveolar bone, the peri-implant collagens run parallel to the implant surface yield-
ing only a physical “adaption” without biological integration (Fujii et al., 1998).
Immune cells such as polymorphonuclear leukocytes (PMNLs) and macro-
phages also influenced the formation of OI and STI around dental implants.
Immediately after implant placement, a universal FBR will occur within a few sec-
onds, starting from protein adhesion on implant surfaces to forming a transient sur-
face matrix (Brown & Badylak, 2013). Such FBR will initiate acute inflammation
response, with the immediate recruitment of PMNLs that release enzymes and reac-
tive oxygen species (ROS) at the surgical sites (Brown & Badylak, 2013). PNMLs
normally undergo apoptosis within 48 h, followed by the recruitment of macro-
phages, which ends the acute inflammatory responses and initiates chronic inflam-
matory responses. Such acute inflammatory responses should be alleviated and
reduced within 1 week; and any delay beyond 3 weeks will significantly increase
the risk of implant failure (Chen et al., 2016). Chemoattractants and cytokines
released by the PMNLs involve the post-surgical macrophage infiltration at the
implant site, which tailors the inflammation and the host responses (Guihard et al.,
2012). Based on the activation pathway, macrophages could be categorized as clas-
sical (M1) and alternative (M2) activated types (Guihard et al., 2012). Although
M1-activated macrophages were also reported to induce osteogenesis in mesenchy-
mal stem cells (MSCs), the various proinflammatory cytokines may significantly
aggravate the inflammatory response and prolonged the chronic inflammatory pro-
cess after surgery. Driven by interleukin-4 (IL-4) and interleukin-13 (IL-13), mac-
rophages continuously form foreign body giant cells (FBGC), degrading the
surrounding tissue and resulting in implant failure (Freytes et al., 2013). On the
other hand, macrophages with M2-activation promote tissue repair by secreting
osteogenic cytokines such as bone morphogenetic protein-2 (BMP-2) and vascular
endothelial growth factor (VEGF), which regulates excessive inflammatory
responses and finally result in a homeostasis around the implant (Champagne et al.,
2002; Freytes et al., 2013; Ivanovski et al., 2022).
120 T. Guo et al.
The ingress of bacteria and biofilm formation is a critical factor that negatively
influences the OI and STI around dental implants. Some specific pathogens, includ-
ing P. Gingivalis, F. Nucleatum and A. Actinomycetemcomitans are closely related
with inflammation in the peri-implant mucosa and the progressive bone loss (peri-
implantitis) (Shibli et al., 2008). The endotoxin of P. Gingivalis (PgLPS) has been
reported to initiate excessive inflammatory responses, which is the keystone mecha-
nism for aggravated tissue inflammation, swelling and attachment loss (Irshad et al.,
2013). Further, the PgLPS could also induce ECM degradation around implant sites
via upregulating the expression of monocyte chemotactic protein-1 (MCP-1) and
matrix metalloproteinase (MMP), thereby damaging peri-implant tissue and caus-
ing bone resorption (Irshad et al., 2013). F. Nucleatum could promote the superox-
ide anion production from fibroblasts, which are favourable for the proliferation of
P. Gingivalis, thus aggravating the peri-implant tissue damage (Metzger et al.,
2009). Moreover, it has been reported that A. Actinomycetemcomitans damages the
intracellular connections between fibroblasts/osteoblasts, compromising their func-
tions and the related tissue integration (Gutiérrez-Venegas et al., 2007). Apart from
these specific bacteria types, it is accepted that general biofilm is substantially
destructive to peri-implant tissues (Berglundh et al., 1992; Mombelli & Décaillet,
2011). It is noteworthy that biofilm protects the embedded pathogens and impairs
host immunity, resulting in the progressive formation and maturation of pathogenic
biofilms (Mombelli & Décaillet, 2011). Further, the antibiotic resistance gene could
be horizontally transferred into other bacteria within the biofilm, improving their
resistance against antibiotics and yielding uncontrolled biofilm accumulation
(Mombelli & Décaillet, 2011). Hence, maintaining healthy oral conditions, and
periodically disrupting biofilm formation especially against the pathogenic bacteria
is critical for establishing and maintaining tissue integration around the implant
surfaces.
The bio-inertness of non-modified Ti implants also influences tissue integration
and wound healing, especially with respect to limiting STI at the transmucosal
region (Guo et al., 2021b). Typically, 2–5 nm thick TiO2 film readily forms on Ti
upon exposure to air/moisture, which is amorphous and provides biocompatibility
(Lausmaa, 1996). Such a naturally formed oxide layer is responsible for the bio-
inertness of non-modified smooth Ti. Additionally, the native oxide layer could be
corroded within the human body, exposing the underlying Ti to leach ions, which
raises toxicological concerns. Thus to improve the bioactivity of Ti dental implants,
studies have been performed to modify their surfaces, aiming at obtaining improved
OI and STI on the implant-tissue interface, as detailed in the following sections.
In summary, this chapter provides an overview of the formation and characteris-
tics of OI and STI around Ti dental implants. Next, the progress on the various
microscale modifications of Ti implants for enhancing their bioactivity is detailed,
including topographical, chemical and bioactive coatings. Further, the progress
towards novel nano-engineered Ti implants with controlled nanotopographies
towards augmenting implant bioactivity is reviewed. This chapter compares and
contrasts the surface modification of Ti implants towards bioactivity enhancements,
evolving from micro to nano, aimed at ensuring long-term implant success.
2 Microscale Surface Modification
2.1 Enhancing Osseointegration
In 1991, Buser et al. reported that microscale topography and roughness could sig-
nificantly influence osseointegration on a dental implant surface (Buser et al., 1991).
Compared to polished implants, roughened implants demonstrated an increased
bone apposition in vivo, with further enhancements possible via hydroxyapatite
(HA) coatings (Buser et al., 1991). Additionally, acid etched and grit blasted Ti
enhances osteogenesis (Gotfredsen et al., 1990). These observations in the early
1990s led to the evolution of Ti implants from minimally rough microgrooved sur-
faces to moderately rough microscale surfaces (Gulati et al., 2018a). Compared
with the relatively smooth early Ti implants, microscale implants promote prolifera-
tion and migration of osteoblasts/osteoprogenitor cells, which accelerate wound
healing and tissue integration (Albrektsson & Wennerberg, 2019; Buser et al.,
1991). Another critical characteristic for dental implants is surface hydrophilicity,
which significantly affects the protein/plasma adsorption and the adhesion/recruit-
ment of osteoblasts (Devgan & Sidhu, 2019). To date, numerous microscale
approaches have been utilized or studied on Ti implants, targeted at modifying dif-
ferent surface characteristics to enhance osseointegration and bone regeneration on
their surfaces.
2.1.1 Physical and Chemical Modifications
One solution for obtaining microscale rough implants is grit blasting of ceramic
particles such as alumina (Al2O3) and titania (TiO2), driven by compressed air to
collide Ti surfaces (Aparicio et al., 2003). However, the blasted particles can get
embedded on the Ti surface, thus an additional acid-washing is recommended to
remove those embedded particles (Aparicio et al., 2003). The embedded Al2O3 is
resistant to acid-washing and hence the surface chemistry of Ti is significantly
altered. Further, the Al2O3 gritted implants can potentially release Al ions and par-
ticles that can be detrimental to the surrounding bone (Ivanoff et al., 2001). Thus,
less toxic and more acid-soluble TiO2 has been regarded as a preferred option for
blasting Ti implants. It has been reported that 25 μm diameter TiO2 particles could
generate a roughened Ti surface with a consistent roughness value of 1 ~ 2 μm,
which is favourable for the adhesion and proliferation of osteoblasts towards pro-
moting osseointegration (Rasmusson et al., 2001). Compared to the smooth and
machined Ti, a significantly enhanced bone-implant contact (BIC) area was obtained
on the TiO2 blasted Ti implant surface (Ra = 1 ~ 2 μm, gritted by 25 μm diameter
TiO2) (Rasmusson et al., 2001). Further, the clinical reliability of TiO2 blasted
implants was also validated by showing a 96.9% cumulative implant survival rate
over 10 years (Rasmusson et al., 2005). Finally, since washing the embedded par-
ticles is recommended after grit-blasting, the fabrication of commercial implants
122 T. Guo et al.
always combines sandblasting and acid etching (SLA) to obtain a reliable and con-
sistent implant surface.
Implant surface chemistry also influences the performance of adhered cells, and
as a result, numerous chemical modifications have been utilized, including acid-
etching, plasma spraying, sputter deposition, sol-gel coating and electrophoretic
deposition, to either augment osteoblasts activity or promote calcification/mineral-
ization on implant surfaces (Le Guéhennec et al., 2007).
Acid etching via HCl, H2SO4 and HF are practical options for improving the
roughness of Ti implants, which facilitate tiny pits and poles on Ti surface that range
around 0.5 ~ 2 μm in diameter. Cho and Park reported that micro-roughened
implants achieved by acid etching significantly increased removal torque at 3 months
after implantation in rabbit tibia in vivo, indicating their influence on early-stage
osseointegration (Cho & Park, 2003). In addition, acid-etched Ti implants have been
reported with enhanced osteoconductive potential by promoting the attachment of
osteogenic cells (Park & Davies, 2000). Compared with the micromachined or
plasma sprayed Ti, the acid-etched implants could establish a larger bone-implant
contact area with reduced bone resorption, which is both mechanically and biologi-
cally stable (Cochran et al., 2002).
Hydroxyapatite (HA) is extensively utilized on dental implants, attributed to its
similarities with bone minerals in the structural, chemical and mechanical proper-
ties to promote the biological apatite precipitation on the implant surfaces (Davies,
2003). HA precipitation on implant structures upregulates bone healing as the
deposited biological apatite layer serves as a matrix for the osteoblast attachment
and proliferation (Davies, 2003). Further, the release of Ca and P from HA-coated
implants improves the new bone formation during the bone remodelling process
(Ciobanu & Harja, 2019; Ciobanu et al., 2012; Daculsi et al., 2003; Davies, 2003).
Ciobanu and Harja reported significantly accelerated osteogenesis around
HA-coated implants, with enhanced implant stability and wound healing (Ciobanu
& Harja, 2019). It is noteworthy that HA-coated implants not only promote biologi-
cal apatite formation but also enhance osseointegration by directly forming an oste-
oid layer with osteoblasts to improve their proliferation (Goodman et al., 2013).
2.1.2 Incorporation of Bioactive Agents
Numerous biomolecules have been incorporated on Ti implants, including growth

factors, peptides and proteins. Besides, bioactive polymers like chitosan have also
been utilized to modify implants to promote bone healing and osseointegration
(Stadlinger et al., 2008). Stadlinger et al. reported that the coating of Ti implants
with collagen and chondroitin sulphate (CS) resulted in significantly enhanced in
vivo bone-to-implant-contact (BIC) at 5 weeks after implant surgery (Stadlinger
et al., 2008). Similarly, another study reported an increased BIC and bone-volume
density (BVD) after 4 and 8 weeks within the minipigs’ maxilla on the glycosami-
noglycans coated Ti implants (Stadlinger et al., 2012). Functional proteins such as
growth factors effectively modulate the differentiation of osteoblasts and stem cells,
induce angiogenesis, and attract osteoprogenitor cells via chemotaxis effects.

However, loading these biofunctional macromolecules onto implant surfaces is a
complex process that requires incorporating polymeric coatings as the frame to
incorporate those bioactive molecules. For instance, Al-Jarsha et al. spin-coated a
layer of poly-ethyl acrylate (PEA) and fibronectin (FN) complex onto Ti implants to
establish a thin film to load bone morphogenetic protein-7 (BMP-7) (Al-Jarsha
et al., 2018). Compared with the Ti implants directly coated with BMP-7, implants
incorporated with PEA-FN-BMP-7 complex could significantly enhance the adhe-
sion/proliferation of human mesenchymal stem cells (hMSCs) and promote the
expression of osteogenic marker at day 28 (Fig. 1) (Al-Jarsha et al., 2018).
Incorporation of bioactive metal ions is an alternative option to enhance bioactiv-
ity on Ti implants. This could be achieved via immersion in varied ionic solutions
with controlled pH and concentrations. It is known that Sr2+ and Mg2+ ions promote
new bone formation (Song et al., 2018), and soaking Ti implants in a mixture of
50 mM CaCl2 + 50 mM SrCl2 enabled a Sr-containing calcium hydrogen titanate
surface that slowly releases Sr2+ ions (Yamaguchi et al., 2014). Similarly, on the Sr/
Mg loaded Ti implants, the in vitro expression of integrin β1, ALP and β-catenin
were enhanced from MC3T3-E1 osteoprogenitor cells, indicating an enhanced pro-
liferation and osteogenic differentiation potential (Okuzu et al., 2017).
Another modification utilized on Ti implants is coating with bisphosphonates
that promotes the apoptosis of osteoclasts to inhibit bone resorption (Costa & Major,
2009). Biphosphonates modified implants accelerated the bone healing by reducing
the bone resorption around Ti implants during bone remodelling, and reported a
41% enhanced pull-out force after 4 weeks within rats tibiae in vivo (Agholme
et al., 2012). Thus, biophosphonates coated implants may be favourable for patients
Fig. 1 The osteogenic differentiation of human mesenchymal stem cells (hMSCs) on modified Ti
implants. (a) The fluorescence images of hMSCs with osteogenic marker osteocalcin (OCN) and
osteopontin (OPN), which were stained green in both top and bottom column; (b) Significantly
promoted OCN and OPN expression from the hMSCs on the Ti/PEA/FN/BMP-7 implants, show-
ing a promoted osteogenic potential. Ti Ctrl: Non-treated Ti (Control); Ti/BMP-7: Ti coated with
bone morphogenic protein-7 (BMP-7); Ti/PEA/FN: Ti coated with poly ethyl acrylate (PEA) and
fibronectin (FN); Ti/PEA/FN/BMP-7: Ti/PEA/FN infiltrated with an additional BMP-7 layer.
(Reproduced with permission from Al-Jarsha et al. (2018))
124 T. Guo et al.
with compromised bone conditions such as diabetes and osteoporosis, to improve

wound healing and osseointegration (Adler et al., 2016).
In another study, Shim et al. utilized poly(lactide-co-glycolide) particles to load
fibroblast growth factor-2 (FGF-2) onto Ti implants (Shim et al., 2014). FGF-2
loaded particles could be gradually released, promoting the in vitro alkaline phos-
phate activity from osteoblasts. Further, compared with the bare Ti, FGF-2 coated
Ti implants established significant higher BIC percentage and obtained enhanced
new bone formation at 12 weeks within rabbit tibiae (Shim et al., 2014). Another
option to coat bioactive molecules is to apply chemical linkers to immobilize bio-
macromolecules. Zheng et al. reported use of dopamine (DA) and polydopamine
(PDA) to immobilize the chitosan particles with BMP-2 loadings on Ti implants
(Zheng et al., 2013). Further, the layer-by-layer self-assembling technique could
also be utilized for biomacromolecule coatings. For example, BMP-2 encapsulated
BSA (bovine serum albumin) particles were functionalized with chitosan and finally
loaded on Ti implants (Wang et al., 2015), and the modified implants significantly
increased the proliferation and spreading area of BMSCs, and upregulated their in
vitro ALP activity (Wang et al., 2015). In summary, biofunctionalized Ti implants
are a favorable option to augment implant integration via incorporation of potent
proteins and growth factors, however sustained release for months/years of sensitive
proteins still needs further investigation, specially in compromised conditions
in vivo.
2.2 Microscale Approaches to Enhance Soft Tissue

Integration (STI)
Robust STI forms a transmucosal barrier against the ingress of oral microbes;
breach of such barrier results in biological complications such as mucosal inflam-
mation, peri-implant bone loss and implant failure (Guo et al., 2021b). However,
unlike the osseointegration with robust bone anchorage on the implant structure, the
STI at the transmucosal region of the implant is only a ‘physical adaption’ with
significantly weakened sealing strength compared to the soft tissue attachment
formed by inserting collagen fibers at teeth (Guo et al., 2021b). Various attempts
have been made to improve the STI around dental implants by modifying implant
topography, chemistry and utilizing bioactivity coatings (Guo et al., 2021a).
2.2.1 Surface Topography Modification
The topography of dental implants is a critical factor that influences the morphol-
ogy, proliferation and activity of adhered epithelial cells/fibroblasts. Compared with
the irregular roughened surfaces, Ti implants with aligned microgrooves signifi-
cantly improved the function of fibroblasts, including their spreading morphologies,
extracellular matrix (ECM) and collagen secretion (Chou et al., 1995). It has been
reported that the human gingival fibroblasts (hGFs) on wider grooves (width
25 ~ 50 μm) were aligned parallel to the grooves and obtained a dense ECM-like
structure, translating into the peri-implant wound healing (Yoshinari et al., 2003).
Guillem-Marti et al. reported augmented early-stage adhesion and activation of
fibroblasts on microgrooves with width <50 μm, while the wider grooves (>50 μm)
were more effective in maintaining the long-term activity of fibroblasts to secrete
more fibres (Guillem-Marti et al., 2013). Laser treatment has been used to create
microtopography on Ti with precise dimensions (evenly distributed holes/grooves).
For instance, Weiner et al. inserted various Ti implants into dog mandibular for
6 months and found that laser modified Ti implants with microgrooves (width
12 ~ 24 μm) established stable STI around its surface, with significantly reduced
tissue recessions than the smooth counterparts (Weiner et al., 2008). Similarly,
another in vivo study reported augmented adhesion strength of peri-implant epithe-
lium around laser-treated implants with microgrooves within 3 months after implant
placement (Nevins et al., 2010). Moreover, in the connective tissue layer, some
fibres were perpendicularly aligned to the laser-treated implant surfaces, indicating
the direct connection of fibres with implant surfaces (Nevins et al., 2010). To date,
laser-modified dental implants have already been clinically applied (e.g. Laser-
Lok®). Compared with the conventional (smooth) implants, which only acquired a
limited gingiva-implant contact area (24.1% ± 16.63%), the laser-modified Ti
implants enabled significantly enhanced gingiva integration (98.8% ± 3.78%) at
15 months after surgery. Such enhanced STI establishment and maintenance could
be attributed to the augmented junctional epithelium-specific proteins from epithe-
lial layer that enhanced the epithelial attachment, contributing to improved STI
strength and stability (Leong et al., 2018).
To summarize, compared with smooth surfaces, Ti implants with aligned micro-
grooves augments the activity of peri-implant epithelial cells and fibroblasts.
2.2.2 Chemical Approaches
The chemistry of a material surface is also critical in determining the cell behaviour,
including cell adhesion and cytokine expression, which influences the STI forma-
tion around implants. Calcium is a critical element related to cell adhesion and cell-
substrate interaction. As reported in an in vivo study, Ca doped Ti implants (via
hydrothermal treatment) could obtain stable peri-implant epithelium attachment
throughout the implant-epithelium interface at 6 weeks in the transmucosal region
of Wistar rats, significantly surpassing the untreated Ti surface that only presented
PIE attachment at the apical 1/3rd of implant-epithelium interface (Oshiro et al.,
2015). Meanwhile, the adhesion strength of PIE on modified implants was also
enhanced by showing increased resistance against the horseradish peroxidase pen-
etration (Oshiro et al., 2015). Further, phosphate (PO43−) modified Ti implants by
ion beam-assisted deposition (IBAD) promoted connective tissue integration
on Ti implants, enhancing STI formation and stability (Bao Hong et al., 2007;
126 T. Guo et al.
Zhao et al., 2005). Compared with hydroxyapatite (HA) coated Ti implants, a hybrid
coating of tricalcium phosphate/hydroxyapatite (TCP/HA) on Ti significantly
enhanced the fibroblast proliferation and adhesion (Zhao et al., 2005). Moreover,
similar conclusions were obtained by another in vivo study, in which the Ti implants
were coated with calcium phosphate (CaP) and inserted in dog mandibles and
healed for 3 months (Bao Hong et al., 2007). Compared with the uncoated Ti, the
peri-implant connective tissue around CaP-Ti surface obtained more granular tissue
and fibre bundles. Further, some oblique/perpendicular collagen fibres were obtained
around CaP-Ti implant surface, suggesting the direct implant-gingiva connection,
which was absent from uncoated implants (Bao Hong et al., 2007).
2.2.3 Coating with Proteins
Compared with the abovementioned topographical and chemical modifications, the

application of biological coatings on the implant surface can further enhance the
adhesion and proliferation of surrounding cells. Since cells are attached to the
implant surface via adhesive structures, including hemidesmosomes (HDs) and
internal basal lamina (IBL), several studies utilized bioactive coatings to promote
the secretion of these adhesive structures from cells, to enhance STI formation.
As the critical components of HDs and IBL in the epithelial layer, laminin-1 and
laminin-5 and their related proteins have been utilized as coatings on Ti implants.
Initial attempts included physical deposition, however the binding strength of such
coatings on implants was suboptimal (El-Ghannam et al., 1998). Later, chemical
functionalizations were utilized to pretreat the Ti implants to reinforce the binding
strength of the bioactive molecules. Werner et al. chemically cross-linked laminin-5
on Ti implants that enhanced the in vitro proliferation and adhesion of epithelial
cells, translating into enhanced epithelial sealing (Werner et al., 2009). Further, Liu
et al. loaded a bioactive domain of laminin-5 (LNA3G3P protein) via the chimeric
peptide linking onto Ti implants that yielded a stable and firmly adhered PIE layer
within 3 weeks after implantation into the transmucosal region of minipigs (Liu
et al., 2019). Further, facilitating a multilayered porous frame by layer-by-layer
self-assembly also contributed to an effective protein/peptide coating. Briefly, LBL
self-assembly of a multi-layer hydroxyapatite/collagen (HA/Col) was achieved on
Ti implants, which was utilized as a frame to load recombinant adenovirus contain-
ing LAMA3 gene (critical gene for synthesizing laminin) (Zhang et al., 2018).
Compared with the uncoated and HA/Col coated Ti, the HA/Col/LAMA3 coated
implants obtained larger PIE adhesion area, with stronger adhesive structures pre-
sented at the PIE-implant interface at the transmucosal region of Wistar rats at
4 weeks after implant surgery (Fig. 2) (Zhang et al., 2018).
Platelet aggregation on Ti implants also play a crucial role in influencing the
epithelial seal, since adhered platelet could release cytokines and chemotaxis attrac-
tants, which induce cell proliferation and migration. Peptide-activated receptor
4-activating peptides (PAR4-AP, known to influence the initial platelet adsorption),
were incorporated on Ti implants to accelerate the aggregations of platelets (Maeno
Fig. 2 Enhanced epithelium attachments on the Ti implants modified with the LAMA-3 recombi-
nant gene. In vivo immunohistochemical staining of Wistar rats’ periodontal and peri-implant soft
tissue at 4 weeks showed laminin α3 (component of adhesive structures, black arrow) expression
at the tooth/implant-gingiva interface. Compared with non-modified smooth Ti and Ti coated with
chitosan-hydroxyapatite-collagen composite CS/(HA/COL)5, significantly higher laminin α3
expression was present around the Ti implants coated with a combination of LAMA3 gene and
HA/Col film (HA/Col/AdLAMA3). The expression strength of laminin α3 around the HA/Col/
AdLAMA3 implant was comparable to that around natural teeth. (Reproduced with permission
from Zhang et al. (2018))
et al., 2017; Sugawara et al., 2016). Compared with the bare Ti, PAR4-AP modified
implants improved the expression of laminin-5 from epithelial cells, and augmented
their adhesion (Maeno et al., 2017). Further, the expressions of collagen IV, which
is a critical component of IBL, was also upregulated from epithelial cells on
PAR4-AP coated implants (Maeno et al., 2017). In another study, Kihara et al. syn-
thesized a synthetic peptide A10 to coat Ti implants (Kihara et al., 2018), which
enhanced the adhesion of the epithelial cells, and established a dense epithelial bar-
rier layer with pericellular junctions on the surface (Kihara et al., 2018).
3 Nano-engineered Implants for Enhanced Osseointegration
Compared with the microscale modified Ti implants, nano-engineered implants

with customized nanostructures exhibit the following advantages:
• Cell functions are significantly influenced by the nanoscale topography via the
mechanotransduction effect on cell filopodia, thereby influencing cell spreading
and alignment
• Nanoscale roughness promotes extracellular matrix secretion from cells to
enhance their functions (Gulati et al., 2018a, 2020);
128 T. Guo et al.
• Hollow nanostructures (nanotubes/nanopores) could be utilized as drug loading/

releasing reservoirs, to achieve local therapy, including antibacterial and anti-
inflammatory functions leading to enhanced tissue regeneration (Jayasree
et al., 2021)
• Nano-engineering modifications can simultaneously alter different surface char-
acteristics of modified implants (such as surface topography and chemistry),
which enhances the surface bioactivity (Chopra et al., 2021b; Guo et al., 2021d);
• The nanostructured surfaces have increased surface roughness, which enhances
hydrophilicity and cellular adhesion and proliferation (Chopra et al., 2021b; Guo
et al., 2021d).
Various characteristics, including surface roughness, topography, chemistry and
wettability have been reported to influence osseointegration and bone healing (Cho
& Park, 2003; Ivanoff et al., 2001; Mendonça et al., 2008). The commercial
microscale implants require 3 ~ 6 months for complete bone healing and osseointe-
gration, and nanoscale implants targets to achieve osseointegration faster (Mendonça
et al., 2008; Nagasawa et al., 2016; Wennerberg et al., 2014). Mimicking the mor-
phology of natural bone structures, nanoscale surfaces promote bone regeneration
at both cellular and molecular levels (Albrektsson & Wennerberg, 2019; Ivanoff
et al., 2001; Rasmusson et al., 2001; Wang et al., 2013).
3.1 Laser Treatment
Laser modification is an option to create nanostructured surface on Ti implants, that

offers the capability to control the surface texture by adjusting laser parameters
(Ercan et al., 2014). Various laser-related modifications such as laser ablation and
laser-induced periodic surface melting can precisely tailor the geometries of modi-
fied Ti implant surfaces (Cunha et al., 2013; Valle et al., 2015). As reported by
Hallgren et al., a nanopatterned surface with uniformed hemispherical pits can be
fabricated on implants by Nd:YAG laser beam (Hallgren et al., 2003). Further, when
implanted for 12 weeks in rabbits tibiae in vivo, the bone-implant contact (BIC) on
such laser-treated implants was significantly enhanced compared to the non-
modified Ti implants (Hallgren et al., 2003). Similarly, Faeda et al. modified Ti
implants by sequential Nd:YAG laser ablation and hydroxyapatite (HA) coating,
achieving a nanoscale roughened Ti implants that accelerated the bone healing at
4 ~ 12 months with dramatically increased BIC percentages (Faeda et al., 2012).
Further, such laser modified surface not only accelerated the bone healing speed, but
also improved the osseointegration strength by showing increased removal torque at
12 weeks within rabbit tibiae (Faeda et al., 2012). Additionally, the heat generated
by Nd:Yag laser could thicken the TiO2 barrier layer on Ti surface while generating
nanoscale rods, which enhanced the stability of nanostructured TiO2 layer
(Brånemark et al., 2011). The layer with nanorods obtained significantly increased
BIC and showed increased implant removal torque at 8 weeks within rabbit tibiae
(Brånemark et al., 2011). It is noteworthy that laser nano-engineering is mainly

restricted to several hundred nanometers, and mechanotransduction of osteocytes
and osteoblasts (guiding the filopodia extension and stretching) requires smaller
nanostructures (diameter <100 nm).
3.2 Chemical Modification
It has been reported that applying additional chemical treatment on the microscale
roughened implant surface could result in a dual micro-nano scale modified surface,
with potentially enhanced surface bioactivity (Mendonça et al., 2008; Nagasawa
et al., 2016). For example, immersing the conventional sandblasted and acid-etched
(SLA) implants into an acidic isotonic solution could chemically modify their sur-
faces to create super-hydrophilic implants, SLActive (Straumann, Basel,
Switzerland) (Wennerberg et al., 2014). Such isotonic treatments were shown to
create additional nano spikes superimposed on the micropatterned implants, which
significantly enhanced in vivo osseointegration as confirmed by increased pull-out
strength post-implantation into rabbit tibia for 8 weeks (Wennerberg et al., 2014).
Further, the bone healing and regeneration speed were also accelerated on the
hydrophilic surfaces with nanospikes, confirmed by enhanced platelet aggregation
and protein adhesion on their surface to promote bone apposition (Sharon L. Hyzy,
2017). Compared with the micropatterned implants, dual micro-nano acid-treated
surfaces showed significantly upregulated expression of osteogenesis genes from
osteoprogenitor cells, including alkaline phosphate (ALP), bone morphogenetic
protein (BMP) and osteocalcin (Sharon L. Hyzy, 2017). Such high osteogenic
potential on nanostructured SLActive surface significantly increased the in vivo
BIC within rabbit articular femoral condyle at 2 weeks, indicating an improved
early-stage bone regeneration and healing (Offermanns et al., 2018; Scarano
et al., 2017).
Besides acidic isotonic immersion, alternate chemical treatments such as alkali
heating and chemical oxidization also create nanotopographies and expose reactive
groups on Ti, to finally enhance their osteogenic potential. Alkali treatment (usually
by NaOH) can modify Ti implants to produce a nanostructured hydrogen titanate
layer, which augments deposition of hydroxyapatite (Nishiguchi et al., 1999).
However, one disadvantage for alkali-treated nanostructures is the mechanical
weakness of the hydrogen titanate layer, that can easily delaminate. Hence, sequen-
tial heat treatment to stabilize such titanate layer is recommended for the alka-
line fabricated nanostructures (Nishiguchi et al., 1999). Oh et al. reported that on
alkaline heated Ti, the in vitro deposition of hydroxyapatite from simulated body
fluids (SBF) were significantly augmented within 5 days, which established a pre-
ferred microenvironment for the bone regeneration and remodelling (Oh et al.,
2005). Moreover, Krenek et al. reported that the in vitro calcium phosphate (CaP)
deposition on NaOH treated Ti surface was significantly increased, attributed to the
enlarged surface area from nanotopographies and the modified surface titanate layer
130 T. Guo et al.
that promoted Ca-O-Ti bonding (Křenek et al., 2021). Further, the in vitro human
mesenchymal stem cells (hMSCs) spreading area was significantly enlarged on the
alkali-heated Ti at day 5 and showed an improved osteogenic differentiation trend
by expressing more Alizarin Red (Křenek et al., 2021). By adjusting the NaOH
concentration, different nanostructures could be fabricated on Ti, including nano-
flakes and nanowires (Liu et al., 2021). Compared with the non-treated Ti, the alkali
heated Ti with varied nanostructures could induce the formation of lamellipodia and
filopodia from macrophages and promote their M2 (anti-inflammatory) polarization
(Liu et al., 2021). Such M2 polarized macrophages were shown to tailor the inflam-
matory responses and promote the osteogenic differentiation of stem cells, which in
turn promotes osteogenesis (Liu et al., 2021). Further, the in vitro osteogenic poten-
tial of SaOS-2 osteoblasts were significantly promoted on the various alkaline
heated Ti by exhibiting promoted ALP activity and mineralization (Fig. 3) (Liu
et al., 2021).
Fig. 3 The bioactivity of alkali-heat treated (AH) Ti implants with nanostructured surfaces. (a)
The alkaline phosphate (ALP) activity of SaOS-2 osteoblasts was significantly enhanced on
AH-treated Ti implants; (b, c) in vitro collagen secretion and mineralization of SaOS-2 osteoblasts
were significantly improved on AH-treated implants, indicating their enhanced osteogenic poten-
tial. (Reproduced with permission from Liu et al. (2021))
Chemical treatment to facilitate oxidization (via H2O2 and acidic oxidization) is

also utilized to create hollow nanotopographies on Ti implants, including random
nanopores, nanocavities, etc. HF treatment was used to fabricate nanoporous layer
on Ti implants, followed by the treatment with H2O2 and AgNO3 to incorporate Ag
NPs (Ferraris et al., 2014). Such surface modification demonstrated favorable bio-
compatibility (in vitro osteoblasts viability: 95% ~ 96% at 24 h), and significantly
accelerated the in vitro precipitation of hydroxyapatite in simulated body fluid
(SBF) (Ferraris et al., 2014). Further, the modified surfaces showed improved anti-
bacterial capacity against S. aureus (Ferraris et al., 2014). Another study obtained
nanostructured Ti implant surface with densely distributed nanopores via etching in
H2SO4 and H2O2 mixture for 5 h (Greer). Further, the in vitro spreading of hGFs on
these nanostructured surfaces were significantly promoted (Mukaddam et al., 2021).
Additionally, such nanocavities treated by acidic/H2O2 etching enabled inhibition of
proliferation of IC-21 macrophages at 24 h in vitro, and restricted their attachment
and spreading (Ariganello et al., 2018).
3.3 Deposition with Nanoparticles (NPs)
Layer-by-layer deposition/assembly is an alternative approach to fabricate nano-

structures on Ti implants. The sol-gel coating technique can deposit various
nanoparticles such as calcium phosphate (CaP), alumina, titania and zirconia on Ti
implants, altering their topography and chemistry. As Areva et al. reported, the
hybrid TiO2-SiO2 nanoparticles (NPs) coating via sol-gel technique resulted in a
nanostructured layer with nanodots, showing varied influence on the osteoblast
functions dependent on the TiO2/SiO2 ratio. Briefly, the coatings with high TiO2
augmented alkaline phosphate (ALP) expression from osteoblasts, and those with
high SiO2 achieved a sustainable osteoblast activity with enhanced cumulated nod-
ule formation over 21 days (Areva et al., 2007). However, since NPs did not have a
firm bonding with the underlying implants, furnace heating was utilized to enhance
their stability. As Azzawi et al. reported, the coated TiO2-NPs could be effectively
stabilized on Ti implants via furnace heat-treatment (550 °C, 2 h), which was ben-
eficial for the in vivo bone healing and integration within rabbit tibiae model at
2 ~ 4 weeks (Azzawi et al., 2018). Similarly, Greer et al. utilized the sol-gel tech-
nique to fabricate a nanopillar TiO2 film on Ti implants (diameter 40 ~ 100 nm and
height 15 ~ 25 nm), which significantly improved the in vitro expression of osteo-
calcin (OCN) and osteopontin (OPN) from Stro-1 mesenchymal stem cells (Greer
et al., 2020). The modified Ti surfaces were then seeded with Stro-1 cells and sub-
cutaneously implanted into mice, which showed a significantly enhanced in vivo
expression of OPN, OCN, alkaline phosphate (ALP) and collagen I at 28 days
(Greer et al., 2020) (Fig. 4). CaP nanoparticles deposited implant have already been
commercialized (NanoTite surface, BIOMET 3i), which significantly accelerated
the early-stage (2 ~ 3 weeks) bone integration within rabbit tibiae (Östman et al.,
2013). Further, a favourable 1-year implant survival rate was observed for NanoTite
Fig. 4 Bioactivity enhancement of Ti implants with TiO2 nanopillars fabricated by sol-gel deposi-
tion. (a–d) Stromal stem cells (SSCs) were seeded on Ti implants, which were subcutaneously
inserted in mice for 28 days. (e) Bone marker gene expressions from incubated SSCs were signifi-
cantly augmented. (f) The secretion of osteopontin (OPN), collagen-rich matrix deposition (g–i)
were significantly increased at 28 days. (j, k) matured bone was obtained around implant surface
at 12-weeks. (Reproduced with permission from Greer et al. (2020))
implants (99.4%), with a controlled margin bone loss after 1 year functioning
(1.01 mm) (Östman et al., 2013). Sedimending nanoparticles enables a nanorough-
ened Ti surface with nodular nanostructures, which alters their surface bioactivity
by influencing both surface topography and chemistry, but the long-term stability of
such deposited layer should be further evaluated, especially under mechanical
challenges.
3.4 Electrochemically Anodized Implants
Electrochemical anodization (EA) is a scalable and cost-effective nano-engineering

technique, that enables fabrication of self-ordered TiO2 nanostructures (TNPs: tita-
nia nanopores; TNTs: titania nanotubes) on Ti implants (Chopra et al., 2021a, b;
Gulati et al., 2013, 2015a). Briefly, EA involves the electric field-driven oxidation
of Ti surfaces to form TiO2 film, and the fluoride-induced dissolution of TiO2 film to
fabricate hollow nanostructures (TNTs, TNPs) within a fluoride and water contain-
ing organic electrolyte (Gulati et al., 2015b). EA enables great control over the
fabricated nanotopographies by tuning the EA parameters such as voltage and time
and modifying the electrolyte components such as water/fluoride concentration
(Gulati et al., 2016, 2018b). Hence, EA has been regarded as an appropriate technol-
ogy for fabricating nano-engineered Ti implant systems, and various studies have
reported the enhanced osseointegration on anodized nano-engineered Ti implants
(von Wilmowsky et al., 2012).
Anodization enhances implant bioactivity and osseointegration attributed to the
presence of nanoscale tubular/porous structures, that corresponds to the hierarchical
micro/nano bone architecture (Wang et al., 2013; Wennerberg et al., 2014). The
nanoscale rough anodized Ti promotes the attachment, spreading and elongation of
osteoblasts on their surfaces, and enhances the anchorage of collagen fibres into the
pores/tubes for augmented mineralization (Wang et al., 2013; Wennerberg et al.,
2014). Moravec et al. reported that 40 ~ 60 nm diameter nanotubes significantly
promoted the in vitro adhesion of SaOS-2 osteoblasts on modified Ti implants, with
significant increased collagen I and osteocalcin expressions (Moravec et al., 2016).
Additionally, Wang et al. concluded that the proliferation of osteoblasts harvested
from rat calvaria was significantly increased on 30 ~ 50 nm diameter nanotubes at
24 ~ 72 h (Wang et al., 2013). Further, Salou et al. reported that Ti implants modi-
fied with 37 nm-diameter TNPs obtained significantly higher pull-out strength
within rabbit tibiae at 4 weeks after surgery (Salou et al., 2015).
Smaller diameter TNTs/TNPs (40 ~ 60 nm) could augment osteoblasts activity,
while larger nanostructures could also promote bone regeneration by specifically
upregulating the osteogenic gene expression from osteoblasts. As von Wilmowsky
et al. reported, the in vivo secretion of bone morphogenetic protein-2 (BMP-2) from
osteoblasts within pig skulls at 3 months was significantly promoted around 70 nm-
diameter nanotubes, with higher bone-implant-contact (BIC) area (von Wilmowsky
et al., 2012). Similar results were obtained by Shokuhfar et al., that enhanced in
134 T. Guo et al.
vitro attachment and proliferation of MC3T3-E1 osteoprogenitor cells were

observed on 100 nm-diameter TNTs, with the filopodia from the osteoblasts stretch-
ing into the TNTs that aided their anchorage and attachment (Shokuhfar et al.,
2014b). Compared with the microscale modified Ti, nanotubes (~100 nm diameter)
significantly promoted the in vitro proliferation of bone marrow-derived mesenchy-
mal stem cells (BMSCs) at day 1 ~ 7 (Zhang et al., 2021). Further, the osteogenic
related genes (such as RAB27B, SMPD3) expression from BMSCs were also sig-
nificantly improved on such dual micro/nanoscale patterned Ti implants, indicating
their high osteogenic potentials (Zhang et al., 2021). Finally, the in vivo bone forma-
tion around anodized implants was significantly promoted with enhanced exosome
activity, more MSCs infiltration at day 7, and increased BIC percentage at day 28
(Fig. 5) (Zhang et al., 2021). Tailoring the EA conditions in organic electrolytes
could fabricate TNTs/TNPs, meanwhile preserving the underlying microscale
topography of Ti implants (Gulati et al., 2015b, 2018b). As Gulati et al. reported,
tailoring the EA could prevent microtopography dissolution during TNTs/TNPs
fabrication, thereby generating a dual micro/nano-textured TiO2 topography, favour-
able for the proliferation of osteoblasts (Gulati et al., 2018b). In summary, both
Fig. 5 The in vivo osseointegration and related osteogenic-related cytokines secretion on various
Ti implants. (a) The bone-implant interface at day 7. (b–g) The immunohistochemical staining
showed increased CD63 (marker for exosome) and periostin (marker for mesenchymal stem cells)
on bone-implant interface around anodized implants (SAO) at day 7, while CD11b (marker for
macrophages) remain unchanged. (h, i) The bone-implant contact (BIC) ratio was significantly
augmented on SAO implants at day 28. SLM: selective laser melting; SLA: sandblasting and acid
etching; SAH: alkaline-heated SLA implants; SAO: electrically anodized SLA implants.
(Reproduced with permission from Zhang et al. (2021))
small (40 ~ 60 nm) and large (70 ~ 100 nm) diameter TNTs/TNPs have been
reported to enhance osseointegration and bone regeneration, which could be attrib-
uted to the mechanotransduction influences by their distinctive roughness, and mod-
ified surface chemistry and wettability on their surfaces.
Additionally, applying heat treatment on TNTs/TNPs enabled their anatase
transformation, which further enhanced the adhesion and proliferation of osteo-
blasts/MSCs in vitro (Shokuhfar et al., 2014a). Anatase TNTs/TNPs obtained by
hydrothermal treatment exhibited significantly enhanced wettability that promoted
the protein and cellular attachment for an enhanced bioactivity (Butt et al., 2015).
Oh et al. reported that the in vitro proliferation and alkaline phosphate activity of
MC3T3-E1 osteoprogenitor cells were significantly augmented on heat-treated
TNTs within 48 h (Oh et al., 2006). Further, extensive filopodial stretching was
observed from MC3T3-E1 cells, which firmly anchored into the nanotubes at 72 h,
showing an enhanced attachment (Oh et al., 2006). The increased filopodia-
nanotubes interactions significantly aided their early-stage migration and attach-
ment, and promoted the secretion of the extracellular matrix (ECM), which finally
accelerated the new bone healing (Guo et al., 2021c). Further, the hydrophilicity of
hydrothermally treated TNTs/TNPs also promoted the mineral deposition on their
surfaces, which accelerated the mineralization and the new bone formation
(Shokuhfar et al., 2014a).
4 Nano-Engineered Ti Implants for Augmenting

Soft-Tissue Integration
To date, various studies have been performed on the transmucosal region of implant
and abutments to promote soft-tissue integration (STI), which protects the underly-
ing implant structure and promotes long-term functioning, however the quality of
STI on these modified implant surfaces were still suboptimal (Atsuta et al., 2016;
Guo et al., 2021a). The majority of these studies were focused on microscale modi-
fications, including topography (micromaching, grit blasting), chemistry (chemical
coatings, ion implantation) and bioactive coatings (peptides, growth factors) (Atsuta
et al., 2005a, b, 2016; Berglundh et al., 1992; Guo et al., 2021a). Compared with the
microscale approaches, the nanostructured Ti implants and abutments obtained by
nano-engineering significantly influence the cell functions via the mechanotrans-
duction effect. Further, the fabricated nanostructures (nanotubes or nanopores)
alters the topography and the chemistry of Ti implants, meanwhile enhancing their
surface wettability, which contribute to augmented STI at the transmucosal region
(Chen et al., 2016; Guo et al., 2021a).
136 T. Guo et al.
4.1 Influence of Nanoscale Roughness on Epithelial Cells

and Fibroblasts
It has been reported that obtaining a nanoscale roughness could improve the STI on
modified Ti implants by promoting the proliferation and adhesion of epithelial cells.
As Nothdruft et al. showed, the in vitro epithelial cell proliferation was significantly
faster on nanoscale roughened Ti implants (Ra = 69 nm) than the polished counter-
parts (Ra = 10.5 nm) at 24 ~ 72 h (Nothdurft et al., 2015). Similarly, a clinical study
by Glauser et al. reported a stable epithelial sealing around oxidized Ti with a
nanoscale roughened surface, within 8 weeks (Glauser et al., 2005). Compared with
smooth implants, the implants with nanoscale roughness promoted the adhesion of
epithelial cells and fibroblasts by enhancing the secretion of focal adhesions (Puckett
et al., 2010). Based on such criteria, creating nanotubular structures that augment
the nanoscale roughness of smooth Ti has been reported to enhance the prolifera-
tion, and adhesion of epithelial cells significantly (Kloss et al., 2011; Puckett
et al., 2010).
Similarly, fibroblast activity were also favourable on the nanoscale roughened Ti
(Zigterman et al., 2019). As Mustafa et al. reported, the human gingival fibroblasts
(hGFs) proliferation was significantly higher on nanoscale roughened Ti implants
(Ra = 340 and 220 nm) compared to polished counterparts (Ra = 60 nm) (Mustafa
et al., 2005). A similar conclusion was obtained by Kloss et al., that significantly
enhanced fibroblast activity was obtained around the nanocrystalline diamond
(O-NCD) coated Ti implants (Sa = 135 nm) at 4 weeks within the transmucosal
region of Wistar rats, as compared to non-coated counterparts (Sa = 120 nm) (Kloss
et al., 2011). Further, the immunohistochemistry results showed more proliferating
cell nuclear antigen (PCNA) and fibronectin expression (indicating increased fibro-
blast proliferation), but restricted tumour necrosis factor-alpha (TNF-ɑ) expressions
(alleviated inflammation) from the tissues around O-NCD surfaces (Kloss et al.,
2011). To effectively tailor the nanoscale roughness of Ti implants, laser treatment
has been reported to be an appropriate option with precise control over their topog-
raphies. As Gnilitskyi et al. showed, the in vitro human dermal fibroblasts (HDFs)
attachment was promoted on femtosecond laser modified implants with a nanoscale
roughened surface (Ra = 131 nm), as compared to the polished counterparts
(Ra = 6 nm) within 24 h (Gnilitskyi et al., 2019). Further, compared to the non-
modified Ti, laser modified Ti surfaces exhibited higher collagen fibre secre-
tion within 19 days into the surrounding subcutaneous tissue of Wistar rats
(Gnilitskyi et al., 2019). However, over roughened Ti surfaces were suboptimal for
the function of fibroblasts, as Cao et al. showed an inhibited fibroblast proliferation
on SLA treated implants (Ra = 2972 nm) as compared to polished counterparts
(Ra = 12 nm) at day 3 (Cao et al., 2018). To summarize, increasing the nanoscale
roughness could enhance STI on implants by promoting both epithelial cells and
fibroblasts, however, the specific roughness value for optimal STI formation and
maintenance is still under exploration.
4.2 Nanogeometries on Augmenting Soft-Tissue Integration
Nanostructure morphology can modulate STI via mechanical stimulation of cells

that influences the adhesion, spreading and gene expression of fibroblasts and epi-
thelial cells. Xia et al. reported that modifying surface roughness could change the
spreading area and focal adhesion secretion from mesenchymal stem cells (MSCs)
on Ti implants, but with reduced influence on collagen and ECM secretion (Xia
et al., 2020). In comparison, on surfaces with similar roughness but different nano-
pore diameters, the adhesion, spreading of MSCs and their collagen secretions were
all significantly influenced (Xia et al., 2020). Similarly, compared with unmodified
Ti, nanoporous Ti (diameter 20 nm) increased the number of fibroblasts, which
stretched into nanopore walls for an enhanced cell anchorage (Guadarrama Bello
et al., 2017). Additionally, the in vitro expression of adhesive genes such as paxillin,
vinculin, focal adhesion kinase (FAK) and integrins from fibroblasts were also sig-
nificantly augmented on 20 nm-diameter nanopores within 3 days (Guadarrama
Bello et al., 2017).
Further, hierarchical microscale-nanoscale roughened implants mimics the natu-
ral roughness of dentin and hence upregulates proliferation of fibroblasts (Zhou
et al., 2020). Zhou et al. reported that 55 nm-diameter TNTs superimposed on
10 μm-wide microgrooves significantly promoted the viability and proliferation of
fibroblasts (Zhou et al., 2020). Further, Gulati et al. showed that increasing the
nanopore sizes from 50 to 70 nm promoted the proliferation and metabolism of
hGFs and reduced the proliferation of macrophages, finally representing augmented
fibroblast activity with tailored post-surgical immune responses (Guo et al., 2021e).
Further, the spreading morphology of fibroblasts was also influenced by the distri-
bution of nanostructures, by stretching more filopodia extensions into the nanopores
from the cytoskeleton (Gulati et al., 2018c; Guo et al., 2021e). On anisotropic nano-
porous TiO2, hGFs spreaded parallel to the underlying nanopores within 24 h
(Fig. 6). Further, the hGFs functions were significantly augmented on nanoporous
surfaces with increased expressions of collagen I/III and integrin β1, indicating their
enhanced ECM secretion and early-stage adhesion to promote peri-implant soft-
tissue healing (Gulati et al., 2020).
Alkali-heat treatment is one option that enables fabrication of various nanotop-
ographies (nanospikes, nanograss etc.) on Ti implants to tailor the behaviour of
epithelial cells and fibroblasts (Kato et al., 2015). Kato et al. reported that the
expression of type I and III collagen from fibroblasts were significantly augmented
on alkali-heat treated Ti implants with 100 nm-diameter nanotubes at day 7–14
(Kato et al., 2015). The ECM secreted by the fibroblasts was projected into the
nanopores, indicating an enhanced peri-implant connective tissue integration (Kato
et al., 2015). Further, the collagen fibres perpendicularly attached to the alkali-
heated Ti implants at 8 weeks around the rabbits mucosa, indicating a direct metal-
fibre integration at the connective tissue layer (Kato et al., 2015). Similarly, Miao
et al. fabricated nanopillar Ti surface via alkali-heat treatment that augmented the in
vitro proliferation of human gingival epithelial cells (HGECs) on day 1–5 (Miao
138 T. Guo et al.
Fig. 6 Alignment of human gingival fibroblasts (hGFs) on anisotropic titania nanopores (TNPs)
after 24 h. Cells were aligned parallel to the underlying nanopores on all TNPs, with significant
filopodia extensions. TNP-40/60/80: titania nanopores fabricated by anodization at 40 V/60 V/80 V
for 10 min. (Reproduced with permission from Gulati et al. (2020))
et al., 2017). Moreover, the in vitro expression of adhesive genes from epithelial
cells, such as lamimin α3, β3, γ2 and integrin α6 were all significantly improved on
the nanopillar surfaces, which indicated a significant improved epithelial sealing
(Miao et al., 2017).
Electrochemical anodization is an alternative option to modify Ti implants for
enhancing STI, which alters topography (nanotubular/nanoporous surface) and
chemistry (wettability, fluoride incorporation) (Guo et al., 2021e; Puckett et al.,
2010). Although both topography and chemistry could influence the bioactivity of
Ti implants, the functions of epithelial cells and gingival fibroblasts were primarily
dictated by the topographical features (e.g. dimensions, alignment of
nanotubes/nanopores) (Guo et al., 2021e). Puckett et al. reported that the epithelial
cells were influenced by the geometries of the anodized Ti surface, since the filopo-
dia of epithelial cells could be guided by the anodized nanotubes by projecting into
the tubular structures (Puckett et al., 2010). Further, Miyata and Takebe showed that
anodized Ti surface could upregulate the expression of integrin α5 and β4 genes
from epithelial cells within 3 days, which significantly promoted their initial stage
adhesion (Miyata & Takebe, 2013). Moreover, even at day 1, the alignment and
spreading of gingival fibroblasts were stimulated by the anisotropic nanopores
(Gulati et al., 2020).
The modulation of cellular adhesion, spreading and stretching via mechanical
stimulation from the nanopores can easily be achieved by tuning EA parameters
(Gulati et al., 2018b) (Gulati et al., 2020). The diameters of TNTs/TNPs had distinct
influence on different cells, for instance 100 nm-diameter TiO2 nanotubes enhanced
the proliferation and activity of the fibroblasts within the initial 3 days (Tan et al.,
2017). Further, the activated fibroblasts could secrete more TGF-β1 and collagen-IV
into the surrounding peri-implant epithelium layer, which in turn enhanced the
activity of epithelial cells (Tan et al., 2017). Attributed to the secreted growth factors
from fibroblasts, the secretion of laminin-β3 from epithelial cells was significantly
increased at day 7, indicating an improved epithelial attachment for enhanced epi-
thelial sealing (Tan et al., 2017). Finally, the enhanced peri-implant soft-tissue seal-
ing around anodized implants was also supported by the in vivo histological results,
with improved soft tissue attachment (Chen et al., 2009). Briefly, the area of attached
epithelium on anodized Ti implants (90.16%) was significantly higher than the non-
anodized counterparts (3.62%) around the goat subcutaneous tissue at 8 weeks.
Additionally, the insertion of soft tissue into the nanopores was also observed, indi-
cating the formation of a biological integration at the transmucosal region of Ti
implants (Chen et al., 2009) (Fig. 7d).
Further, it has been reported that applying the hydrothermal treatment to TNPs/
TNTs could improve the functions of epithelial cells. Takebe et al. reported that the
anodized Ti (AO-Ti) with nanoscale pillars could mechanically interact with the
filopodia from cells, establishing numerous filopodia-pillar contacts, which signifi-
cantly promoted the epithelial cell adhesion but reduced their proliferation within
1 week (Takebe et al., 2014). However, on hydrothermally treated AO-Ti, both the
adhesion and proliferation of epithelial cells were significantly augmented, which
could be attributed to the enhanced wettability of treated AO-Ti that significantly
augmented the activity of epithelial cells and finally promoted epithelium sealing
(Takebe et al., 2014).
4.3 Tailoring the Immune-Inflammatory Responses
As a heterogeneous material, Ti implants inevitably trigger the foreign body reac-

tion (FBR) when implanted into the human body, initiating immuno-inflammatory
responses that can challenge tissue integration and wound healing (Guo et al.,
2021b). It has been reported that uncontrolled FBR results in chronic inflammation
around implant sites that can cause progressive soft tissue resorption (Guo et al.,
2021b; Lee et al., 2021). Thus modulating the immuno-inflammatory responses to
alleviate FBR in the transmucosal region is extremely important for the long-term
functioning of dental implants (Chen et al., 2016).
It has been reported that nanostructured implants could tailor the macrophage
functions to influence the immune responses by their surface topography and wet-
tability (Hamlet et al., 2019; Lee et al., 2017). Nanoscale crystallines could be
observed on hydrophilic implants that significantly reduced platelet attachment to
decrease the pro-inflammatory cytokines secretion such as TNF-α, IL-1α, IL-1β
140 T. Guo et al.
Fig. 7 The in vivo soft-tissue attachment around smooth (a) and anodized Ti implants (b–e) at
8 weeks at the transcutaneous area of goat tibiae. (a) A crack (absence of soft tissue attachment)
on the non-modified Ti implant surface. (b, c) The intact soft-tissue attachment around anodized Ti
implants. (d, e) the growth of soft tissue into the porous layer of anodized implant surfaces, indi-
cating a biological integration at the connective tissue layer. (Reproduced with permissions from
Chen et al. (2009))
from RAW 264.7 macrophages, yielding a controlled immuno-inflammatory

response (Alfarsi et al., 2014, 2015; Hamlet et al., 2012). Further, Hamlet et al.
reported that Ti implants deposited with CaP nanocrystals significantly reduced
the pro-inflammatory cytokines and chemokines secreted from RAW 264.7
macrophages, without interfering with their proliferation and attachment (Hamlet &
Ivanovski, 2011). Nanoscale roughened Ti with distinct nanoscale protrusions
(Ra = 50 nm) significantly inhibited the early-stage IC-21 macrophage adhesion,
meanwhile reducing the secretion of pro-inflammatory cytokines (Lu & Webster,
2015). Further, the diameter of tubular nanostructures (e.g. nanotubes, nanopores)
was also shown to influence the macrophages functions. Gulati et al. showed that the
70-diameter TNPs could significantly reduce the in vitro proliferation of primary
and RAW macrophages than the 50 nm-diameter counterparts (Gulati et al., 2018c).
Similarly, Lu et al. reported that 60–80 nm diameter TNPs could effectively restrict
the macrophage adhesion and proliferation and inhibit their pro-inflammatory cyto-
kine genes expression (such as TNF-ɑ and MCP-1). Moreover, the LPS-induced
foreign body giant cells (FBGCs) fusion from RAW macrophages was alleviated on
78 nm-diameter TNPs, indicating their capability to alleviate the post-surgical
inflammatory and immune responses (Lü et al., 2015). In summary, the nano-
engineered Ti implants with 60–80 nm diameter nanopores can alleviate inflamma-
tory responses via inhibiting macrophage functions.
Another reason for enhanced soft tissue healing on nanostructured Ti implants
could be attributed to the alleviated reactive oxygen species (ROS) from macro-
phages, which restricted the post-surgical inflammation (Smith et al., 2011; Suzuki
et al., 2003). As reported by Smith et al., compared with unmodified Ti, the nitride
oxide (NO) activity within rat skins was significantly reduced around 70 nm-
diameter TiO2 nanotubes with fewer macrophages infiltrations at 1 week after sur-
gery (Fig. 8), which consequently alleviated the inflammation after surgery (Smith
et al., 2011).
Fig. 8 Significantly reduced nitride oxide (NO) activity from macrophages around anodized Ti
implants with TiO2 nanotubes. The anti-nitrotyrosine staining of peri-implant soft-tissue at the
transmucosal region of implants at 1 week, showing the NO activity of macrophages around (a)
non-modified Ti and (b) TiO2 nanotubes. Significant lower NO-staining signal around nanotubes
indicated their alleviated post-implant inflammation responses. (Reproduced with permission from
Smith et al. (2011))
142 T. Guo et al.
5 Research Gaps and Future Perspectives
Implant-supported prosthodontics is regarded as the preferred treatment option for

partial and complete edentulous area, and augmenting the bioactivity of Ti implants
could improve tissue integration and accelerate wound healing. To address the bio-
inertness of non-modified Ti implants, surface modifications have evolved from
micro to nanoscale. Nevertheless, for the fabrication of next-generation nano-
engineered Ti implants with high bioactivity, some research gaps still remain
unaddressed.
Successful osseointegration involves sufficient mineralized collagen fibrils
around the implant surface at the early stage of bone healing, which is suboptimal
in patients with compromised conditions (e.g. diabetes and osteoporosis) (Shah
et al., 2019). The resorption of parent bone around implants happens within 2 weeks
after implant placement, meanwhile the formation and maturation of newly gener-
ated bone requires minimum 8 weeks, during which the stability of bone-implant
contact is challenged (Albrektsson & Wennerberg, 2019). It has been reported that
the early stage BIC could be enhanced by accelerating the new bone formation via
modifying implants’ wettability, chemistry and bioactivity. However, to date, only
hydrophilic modified implants have been commercially translated, attributed to lack
of biosafety evaluations on alternate nano-engineered osteogenic implants (Azzawi
et al., 2018). Thus more in vivo investigations needs to be performed on nano-
engineered implants to enable its clinical translation. Further, bone resorption is
significantly related with the post-surgical immune responses, thus further investi-
gations are needed to achieve effective immunomodulation at the bone-implant
interface to enable timely wound healing and osteogenesis (Chen et al., 2016).
Moreover, dental implants are subjected to the constant forces during implant sur-
gery and loading, thus both the short-term and long-term mechanical stability of
modified implants (integrity of modified Ti surface and the stability of bioactive
coatings) should be further optimized (Li et al., 2018).
Orchestrating and maintaining appropriate soft-tissue integration (STI) at the
transmucosal region of implant is challenging due to the limited biological integra-
tion at the gingiva-Ti interface (Guo et al., 2021b). Studies on enhancing STI mainly
focused on improving the functions of epithelial cells and fibroblasts, with the
absence of forming direct fibre-implant connection (biological integration of con-
nective tissue), which require further investigations (Guo et al., 2021a). Further, the
transmusocal region of implants are constantly challenged by the changing pH, bac-
teria, and ionic concentrations that can compromise implant coating stability and
leach ions/nanoparticles that can initate toxicity (Guo et al., 2021b). Thus, long-
term corrosion resistance of dental implants, especially mimicking the oral cavity
(presence of bacteria and changing temperature/pH/ions) needs to be evaluated.
Additionally, it has been reported that 6 ~ 8 weeks are required for the STI forma-
tion and maturation, during which the oral pathogens could amplify the post-surgical
inflammations to compromise STI (Ivanovski & Lee, 2018). Thus, the bactericidal
modification of Ti implants that also enable immunomodulation needs further inves-
tigation (Gulati et al., 2018a).
Nano-engineered Ti implants show great promise in augmenting the functions of

epithelial cells, fibroblasts and osteoblasts, attributed to their favorable topography,
chemistry and wettability (Oh et al., 2005, 2006). Systematic evaluation of the influ-
ence of surface topography and chemistry on the bioactivity of nano-engineered Ti
implants is essential towards further bioactivity optimizations (Guo et al., 2021e).
Further, implants are subjected to the continuous forces during the surgery and the
functioning within the oral cavity (mastication), and hence the mechanical perfor-
mance of fabricated nanotopographies on dental implants should be thoroughly
investigated (Li et al., 2018). Ions and nanoparticles from the modified implants can
be released into the surrounding tissue when implanted into the oral cavity site
(Park et al., 2012). Long term in vivo investigations under loading conditions are
needed to ensure stability of implants and their bioactive modifications. Moreover,
TNTs/TNPs could potentially be utilized as drug-eluting reservoirs for customized
local therapy, thus designing a customized drug-loading nano-engineered implant
system might significantly improve wound healing and tissue regeneration (Jayasree
et al., 2021). Finally, current investigations on nano-engineered Ti implants are
mostly restricted to in vitro studies, and long-term in vivo clinical studies are needed
to ensure clinical translation of bioactive nano-engineered dental implants.
6 Conclusions
Aiming at enhancing the bioactivity of Ti dental implants, various investigations

have been performed to enable topographical, chemical and biological modifica-
tions, which have evolved from micro to nanoscale. Compared with microscale
modifications, nano-engineered Ti implants upregulate the functions of osteoblasts,
fibroblasts and epithelial cells. Nano-engineered dental implants with therapeutic
and bioactive functionalities show great promise towards achieving long-term
implant success, especially in compromised patient conditions. However, address-
ing research gaps, such as ensuring the mechanical stability of such bioactive
implants during long-term in vivo function, is needed to achieve clinical translation.
Acknowledgements Tianqi Guo is supported by a UQ Graduate School Scholarship (UQGSS)

funded by the University of Queensland. Karan Gulati is supported by National Health and Medical
Research Council (NHMRC) Early Career Fellowship (APP1140699).
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Local Therapy from Nano-engineered
Titanium Dental Implants
Anjana Jayasree, Sašo Ivanovski, and Karan Gulati
Abbreviations
ALP Alkaline phosphatase

BMP-2 Bone morphogenetic protein
ECM Extra cellular matrix
FGF Fibroblast growth factor
IBR Initial burst release
LbL Layer by layer
LDD Local drug delivery
MSC Mesenchymal stem cell
NP Nanoparticles
PLGA Poly Lactic-co-Glycolic Acid
PTH Parathyroid hormone
RUNX2 Runt-related transcription factor 2
TNT Titania nanotube
TR total release
1 Introduction
The success of a dental implant depends on 3I’s: Integration (both osseo- and
soft-tissue), (control of) Inflammation and (avoidance of) Infection; and these
key biological processes can be modulated using implant surface modification
A. Jayasree · S. Ivanovski (*) · K. Gulati (*)

e-mail: s.ivanovski@uq.edu.au; k.gulati@uq.edu.au
https://doi.org/10.1007/978-3-031-21565-0_6
154 A. Jayasree et al.
(Guo et al., 2021a; Kligman et al., 2021). Upon implantation, dental implants are
highly susceptible to microbial adhesion and biofilm formation as they are under
constant exposure to the oral microbiome (Chopra et al., 2021; Costa et al.,
2021). Several factors like smoking, poor oral hygiene and existing gingivitis can
further aggravate the situation leading to inflammation at the implant site, and
the spreading of infection to the surrounding tissue including underlying bone
(Anil et al., 2015; Barão et al., 2022). Osseointegration depends primarily on the
surface properties of an implant and its interaction with the surrounding tissues
(Gulati et al., 2013). Several attempts have been made to modify the surface of
implants to enhance the response of osteoblasts and promote osseointegration,
discussed in detail in previous chapters (Gulati et al., 2018a; Kurup et al., 2021).
In compromised conditions (poor bone quality or quantity), local elution of
bone-forming proteins or growth factors may be needed to orchestrate osteogen-
esis. As a result, potent proteins/growth factors such as fibroblast growth factor
(FGF), bone morphogenetic protein (BMP-2), and parathyroid hormone (PTH)
have been incorporated inside implant coatings for their local elution (Ma et al.,
2011; Tao et al., 2019).
It is noteworthy that conventional therapeutic administration via oral or intra-
venous routes is limited by poor biodistribution, toxicity, lack of selectivity and
unfavorable pharmacokinetics (Losic et al., 2015; Mainardes & Silva, 2004). For
example, in conventional therapies only <1% of drug reaches the desired site and
hence high doses of the drug are needed to have the desired effect, which can
cause toxicity (Mainardes & Silva, 2004). Delivering sensitive therapeutic agents
like proteins/growth factors via conventional methods risks their denaturation and
elimination by the reticuloendothelial system (Hussain et al., 2021; Ju et al., 2022;
Khan & Akhtar, 2022). Thus the development of localized drug delivery (LDD)
systems to deliver highly sensitive payloads to the target site directly, minimizing
drug wastage and toxicity, and enabling maximized therapeutic action has subse-
quently been a priority (Monahan et al., 2021; Singh et al., 2022). LDD can allow
for the elution of sensitive therapeutic agents at relatively low doses to produce
the desired effect.
Nanoscale modification of implants is an ideal solution to enable LDD (Ahn
et al., 2018; Park et al., 2021; Wang et al., 2016), achieving controlled and tailored
elution of anti-inflammatory drugs, bone-forming proteins, growth factors for soft-
tissue integration and antibiotics (Gulati & Ivanovski, 2017; Kaigler et al., 2006;
Losic et al., 2015). Among the various surface modification techniques, electro-
chemical anodization (EA) to fabricate self-ordered nanotubes or nanopores on the
surface of Ti implants stands out in terms of cost-effectiveness and scalability
(Alipal et al., 2021; Gulati & Ivanovski, 2017; Khaw et al., 2019). While modulat-
ing cellular responses, these tiny ‘test-tube’ like nanostructures have shown great
potential as LDD systems (Jayasree et al., 2021). The ease of tailoring drug release
kinetics by varying the dimensions of the nanotubes makes them widely researched
for LDD applications.
Local Therapy from Nano-engineered Titanium Dental Implants 155
This chapter showcases the various modifications applied to the surface of Ti

dental implants for achieving localized delivery of therapeutics, to cater to the four
therapeutic challenges of a dental implant system: (1) inflammation, (2) osseointe-
gration, (3) soft-tissue integration, and (4) bacterial infection.
2 Local Therapy for Immunomodulation
Though Ti is the most commonly used material for implants due to its ‘inert’
nature, any foreign material placed within the human body will elicit an immune
response, usually referred to as a foreign body reaction (FBR) (Albrektsson
et al., 2018; Anderson et al., 2008; Weber et al., 2022). Adhesion of proteins from
the surrounding biological fluids, acute and chronic inflammation and fibrous
capsule formation are some of the commonly observed FBRs (Klopfleisch &
Jung, 2017). Upon implantation, the infiltration of immune cells is a critical part
of immune response and plays a major role in the long-term stability of an
implant. The early phase in inflammation begins immediately and lasts for
approximately 48–72 h, during which blood coagulates at the implant site induc-
ing the aggregation of polymorphonuclear leukocytes (PMNL) via chemotaxis
(Luttikhuizen et al., 2006; Noskovicova et al., 2021). Degranulation of PMNL
and release of pro-inflammatory cytokines attracts monocyte/macrophages to the
implant site. The level of infiltrated PMNL usually decreases within a week of
implantation as fibroblasts and osteoblasts begin migration towards the implant
surface (Mariani et al., 2019). Increased aggregation of PMNL at the implant site
can exacerbate inflammation while decreased PMNL infiltration can cause
uncontrolled migration of bacteria, thus a balanced PMNL activity is essential
for stability of the implant and tissue integration. Macrophages play a crucial
role in modulating osseointegration, angiogenesis, removal of cellular debris and
regulating the immune-inflammatory cascade (Amengual-Penafiel et al., 2021;
Gulati et al., 2018). Cytokines such as interleukin 1 (IL-1) and tumor necrosis
factor-alpha (TNF-ɑ) secreted by the macrophages activate osteolytic inflamma-
tory processes that can lead to loss of surrounding bone tissue (Trindade et al.,
2016). Macrophages usually demonstrate dual functionality at the implant site in
either an inflammatory (M1 macrophage) or anti-inflammatory (M2 macrophage)
role based on the micro-environment. M1 macrophages secrete an abundance of
inflammatory cytokines that can promote inflammation and accelerate osteolysis
of surrounding bone leading to implant failure. On the contrary, M2 macrophages
secrete growth factors like transforming growth factor-beta 1 (TGF- 1) and bone
morphogenetic protein-2 (BMP-2) that accelerate osseointegration, soft tissue
healing and extracellular matrix formation, thereby enhancing implant stability.
The implant microenvironment is a key determinant of the local immune response
(Fig. 1) (Julier et al., 2017).
Fig. 1 Schematic representation of the influence of implant surface characteristics on immuno-

modulation. (Adapted with permission from Julier et al. (2017))
Besides implant surface topography, roughness and wettability also influence

protein adhesion and immune cell response. Though several approaches have been
made to tailor the surface topography of implants to achieve immunomodulation
(Vishwakarma et al., 2016; Wang et al., 2022), they are beyond the scope of this
chapter, the focus of which is on emerging LDD strategies for delivery of immuno-
modulating or anti-inflammatory agents. Note that administration of nonsteroidal
anti-inflammatory drugs (NSAIDs) via oral or intravenous routes have shown to
cause gastrointestinal and renal toxicity and delayed bone healing (Pei & Yeo,
2016). LDD of such agents at the implant site can help overcome such detrimental
effects.
Doadrio et al. demonstrated the release of the anti-inflammatory ibuprofen
from titania nanotubes (TNTs) (Doadrio et al., 2015). Electrochemical anodiza-
tion (EA) was performed to fabricate three types of TNTs, nanotubes (NT,
100 nm diameter and 300 nm depth), high aspect ratio nanotubes (NT+, 44 nm
diameter and 1250 nm depth), and bottle shape nanotubes (NTb, 47 nm diameter
and 1355 nm depth). The TNTs were immersed in 20 ml of ibuprofen solution for
2 days with stirring and finally dried at 37 °C for 24 h to obtain drug-loaded
TNTs. The release of the drug from the TNTs was analysed using reversed-
phase high-performance liquid chromatography (RP-HPLC) over 48 h. Despite
the differences in the morphology, depth and interpore space of TNTs, the release
profile over the first 180 min was similar for all the three groups. This was due to
the initial bust release (IBR) of the ibuprofen from the pores. However, NTbs
demonstrated a lower rate of drug release after the IBR compared to the other
two TNTs due to their bottle-like morphology where the bottom of the nanotubes
had a larger diameter than the upper region. The release of drug from the three
types of nanotubes was observed to follow zero-order kinetics, indicating that
drug release depends primarily on the electrostatic bond between the drug mol-
ecule and the oxide layer on the TNTs.
Sustained delivery of drugs over a prolonged period ensures a steady dose of
drug over a wider therapeutic window thereby enhancing its efficacy (Alasvand
et al., 2017). To achieve long and sustained release patterns with reduced IBR, coat-
ing of biopolymers onto drug loaded TNTs have been investigated. Gulati et al.
reported the use of poly(lactic-co-glycolic acid) (PLGA) and chitosan coatings on
indomethacin loaded TNTs for prolonged drug release (Gulati et al., 2012). TNTs
of 120 nm diameter and 50 μm length fabricated by EA were loaded with indo-
methacin via drop casting and finally dip coated in PLGA and chitosan. Four groups
were studied based on the thickeness of coating, Chitosan thin (0.2–0.3 μm),
Chitosan thick (2–2.5 μm), PLGA thin (0.3–0.4 μm), and PLGA thick (1.5–2 μm).
The uncoated TNTs showed an IBR of 77% within the first 6 h and 100% of drug
released within 4 days, while prolonged release was observed in coated TNTs. The
thick coatings reduced the IBR and prolonged drug release in both Chitosan
(30 days) and PLGA (31 days) coated TNTs. For thin coatings, PLGA showed a
higher IBR (57%) than chitosan (40%). An opposite pattern was observed for thick
coatings, with Chitosan (32%) having higher IBR than PLGA (12%) as the buffer
takes a longer time to penetrate the thicker hydrophobic PLGA coating. This study
successfully demonstrated that the rate of drug release can be tailored by coating
polymers on drug loaded TNTs.
While polymer coatings ensure a sustained release of bioactive molecules from
implant surfaces, sensitive drug molecules are prone to denaturation and precipita-
tion in the biological environment. Use of polymeric micelles for local therapy of
hydrophobic drugs have shown great promise to locally deliver sensitive drugs
(Zhang et al., 2014). Aw et al. compared the release of indomethacin from three
types of modified Ti surfaces: (1) TNTs loaded with indomethacin (Ind-TNT), (2)
TNTs loaded with indomethacin encapsulated within a Pluronic F127 polymeric
micelle (Ind-Pluronic-TNT), and (3) TNTs loaded with indomethacin and coated
with Chitosan (Ind-Chitosan-TNT) (Aw, 2011). An IBR of 77% was observed
within 6 h from Ind-TNT, whereas a lower IBRs of 58% and 39% were observed in
Ind-Pluronic-TNT and Ind-Chitosan-TNT, respectively. Indomethacin release from
Ind-Pluronic-TNT were 4 days longer than the Ind-TNT because the rate of drug
diffusion was influenced by the large micelle size, prolonging release. Chitosan
coating proved to be an efficient method among the three to enable a sustained
release of drugs for 28 days. The authors further developed a multi-drug delivery
system comprised of a combination of regular polymeric micelles with hydrophobic
cores to encapsulate hydrophobic drugs and inverted polymeric micelles with
hydrophilic cores to encapsulate hydrophilic drugs (Aw et al., 2012b). They
loaded TNTs initially with gentamycin encapsulated in inverted micelles
(1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy (poly ethylene

glycol)-2000] (DGP 2000)) followed by indomethacin and itraconazole encapsu-
lated in a regular micelles (d-α-tocopherol polyethylene glycol 1000 (TPGS)).
Interestingly they observed a sequential drug release where the hydrophobic drugs
(indomethacin and itraconazole, which were loaded at the top) were completely
released within the first 5 days followed by the release of hydrophilic gentamycin
(loaded in the bottom) in the next 5 days. While an IBR of 50% was observed within
6 h, followed by 100% release for indomethacin and itraconazole within 5 days,
gentamycin showed a sustained release from day 5 to 10 without any IBR. The lack
of IBR for gentamycin is attributed to the slow diffusion of gentamycin from the
bottom of the nanotubes.
Coating of polymers on the surface of TNTs, while controlling the drug release,
also masks the nanotubular structure, thereby diminishing the effect of nanotopog-
raphy on cellular functions, especially in the initial phase when the polymer has not
completely degraded to reveal the underlying nanotubes (Gulati et al., 2016a, b). Jia
et al. proposed an interesting concept of ibuprofen-PLGA incorporated TNTs for
prolonged drug release while maintaining the nanotopography (Jia & Kerr, 2013).
TNTs fabricated via anodization were immersed in an ibuprofen-PLGA solution for
3 days at 40 °C and air dried to obtain PLGA infiltrated TNTs. The drug-polymer
solution entered into the nanotubes and formed a thin layer on the walls of the
TNTs. An IBR with 100% of drug release was observed from bare TNTs while the
polymer infiltrated TNTs showed a controlled release. Low molecular weight PLGA
(4000–15,000 Da) incorporated TNTs provided a sustained release for 5 days; while
the higher molecular weight PLGA (24,000–38,000 Da) modified TNTs extended
the release to 9 days. Further, high molecular weight PLGA/TNTs showed lower
IBR (65%) compared to low molecular weight (85%) PLGA/TNTs.
A comprehensive list of various attempts at delivering anti-inflammatory agents
from TNTs modified Ti implants is presented in Table 1. These investigations
focussed mainly on describing the drug release profile and the mechanism of how
drug release is regulated (discussed in Sect. 6); experiments or investigations on
how these release patterns affect immunomodulation especially in cells like macro-
phages have not been investigated.
3 Local Therapy for Osseointegration
Osseointegration at the dental implant surface depends primarily on the osteocon-

ductive nature of the implant biomaterial and follows the basic principle of bone
regeneration (Albrektsson & Johansson, 2001). Histological studies have demon-
strated that the cascade of events for osseointegration at small defect areas like tooth
extraction sockets (Trombelli et al., 2008) and at peri-implant bone defects
(Berglundh et al., 2003) follow a similar pattern and the initial events involve wound
healing cascade (Singer & Clark, 1999). Upon implantation, the surrounding blood
vessels rupture and trigger the formation of a fibrin rich blood clot. The contact of
Table 1 Local delivery of anti-inflammatory drugs from titania nanotubes (TNTs) modified Ti implants
Amount of Evaluation of
Drug incorporated Size of TNTs Drug loading method drug loaded Release observed bioactivity Ref
Ibuprofen NT- [D: 100 nm, L: Immersion in n-pentane/drug 600 mg/ Sustained release for 48 h – Doadrio
300 nm] solution sample observed in all groups et al.
NT + [D: 44 nm, (2015)
L-1250 nm] Bottle
shape nanotube
NTb [D:47 nm, L:
1355 nm]
Indomethacin D:120 nm Drop casting of drug dissolved 20 mg/cm2 Uncoated In vitro analysis using Gulati
L: 50 μm in ethanol followed by PLGA IBR: 77% in 6 h human osteosarcoma et al.
and chitosan dip coating TR: 100% in 4 d cells (HOS). (2012)
Chitosan Thin Increased cell
IBR: 40% in 6 h adhesion observed
TR: 100% in 9 d within 1.5 h on
Chitosan Thick chitosan coated TNTs.
IBR: 35% in 6 h
TR: 100% in 30 d
PLGA Thin
IBR: 57% in 6 h
Local Therapy from Nano-engineered Titanium Dental Implants
TR: 100% in 19 d
PLGA Thick
IBR: 12% in 6 h
TR: 100% in 31 d
(continued)
159
Table 1 (continued)
160
Indomethacin D:140 nm Drop casting of drug dissolved TNTs: TNTs – Gulati
L: 50 μm in ethanol 16.28 μg/ IBR: 77% in 6 h et al.
mm2 TR:100% in 4 d (2015a)
Periodic Periodically modified TNTs:
TNTs: IBR: 50% in 6 h
17.81 μg/ TR: 100% in 17 d
mm2
Indomethacin D:120 nm Drop casting of drug dissolved – Ind-TNT: – Aw
L: 50 μm in ethanol. IBR: 77% in 6 h (2011)
Encapsulation of drug in TR: 90% in 7 d
Pluronic F127 micelle. Ind-Pluronic-TNT:
Encapsulation of bare drug IBR: 58% in 6 h
followed by chitosan coating. TR: 100% in 14 d
Ind-Chitosan-TNT:
IBR: 39% in 6 h
TR: 100% in 28 d
Indomethacin, D: 110 nm Sequential loading of Gen-DGP – IBR: 50% of Ind and Itr – Aw et al.
Itraconazole, L: 40 μm followed by Ind-Itr-TGPS within 6 h (2012b)
Gentamycin TR: 100% of Ind and Itr in
5 days Gen release begins at
day 5 and 100% release by
day 10
A. Jayasree et al.
Ibuprofen and D: 49 nm Sequential loading of drugs into 4.5–7.7 mg Ibu-Gen: – Pawlik
gentamicin TNTs in different order by drop IBR: 70% of Gen and 50% et al.
casting of Ibu in 30 m (2017)
TR: 100% of Gen and 90%
Ibu in 6 d
Gen-Ibu:
IBR: 50% of Gen and 60%
of Ibu in 30 m
TR: 100% of Gen in 20 h
and 90% Ibu in 4 d
Ibu&Gen:
IBR: 90% of Gen and 30%
of Ibu in 30 m
TR: 100% of Gen in 1 h and
90% Ibu in 4 d
Ibuprofen D: 100–120 nm Ibuprofen-PLGA infiltration 6 mg TNT: – Jia and
into TNT by immersion for 3 d IBR: 100% in 30 m Kerr
at 40 °C followed by air drying LMW-PLGA-TNT: (2013)
IBR: 85% in 6 h
TR: 100% in 5 d
HMW-PLGA-TNT:
IBR: 65% in 6 h
TR: 100% in 9 d
(continued)
161
Table 1 (continued)
162
Ibuprofen TNTs P25 (TiO2 nanoparticles) were – TNT: – Wang
D: 200 nm deposited on TNTs via IBR: 90.7% in 5 h et al.
L: 7.2 μm hydrothermal treatment P25-TNT: (2015)
P25-TNT followed by drop casting of IBR: 80.3% in 5 h
D: 100 nm ethanol dissolved ibuprofen Sustained release was
L: 7.2 μm observed till day 15 for both
groups with P25-TNT
having higher amount of
drug released over time
D diameter, L length, PLGA poly(lactic-co-glycolic acid), IBR initial burst release, TR total release, Ind-TNT indomethacine loaded TNT, Ind-Pluronic-TNT
indomethacin encapsulated pluronic micelles loaded TNT, Ind-Chitosan-TNT chitosan coated indomethacin loaded TNT, Gen-DGP gentamycin encapsulated
in DPG 2000, Ind-Itr-TGPS indomethacin and itraconazole encapsulated in TGPS, Gen gentamycin, Ind indomethacin, Itr itraconozole, Ibu-Gen ibuprofen
loaded initially followed by gentamycin, Gen-Ibu gentamycin loaded initially followed by ibuprofen, Ibu&Gen ibuprofen and gentamycin loaded together,
LMW-PLGA-TNT low molecular weight PLGA infiltrated TNT, HMW-PLGA-TNT high molecular weight PLGA infiltrated TNT
A. Jayasree et al.
the implant with this fibrin matrix is crucial for osseointegration, as the matrix acts
as a temporary niche to support the various cell types migrating to the implant site
(Clark, 2001; Guo et al., 2021b). The migration of inflammatory cells and macro-
phages are followed by the secretion of growth factors that promote angiogenesis
and migration of fibroblasts (Brancato & Albina, 2011). The granulation tissue
formed by fibroblasts supports blood vessels and capillaries that play a key role in
metabolite exchange and the migration and osteogenic differentiation of mesenchy-
mal stem cells (MSCs) (Albrektsson & Johansson, 2001). Next, there occurs a rapid
formation of woven bone comprised of random collagen fibers and osteocyte lacu-
nae. The woven bone is formed at rate of 10 μm/day and grows around the blood
vessels (Schenk & Buser, 1998). Woven bone formation always occurs from the
surface of the surrounding bone tissue towards the implant site to bridge the host
bone and the implant surface. However, effective bridging cannot be achieved in
cases where the host bone-implant space exceeds a critical size or if angiogenesis at
implant site is poor, leading to poor osseointegration and ultimately implant failure
(Botticelli et al., 2003). Further, lamellar bone is formed on the woven bone fol-
lowed by remodelling of the bone ECM, after which the bone adapts for functional
loading (Schenk & Buser, 1998). Thus, the cascade of events leads to the formation
of a strong bond between bone tissue and the implant surface with functional load-
ing, referred to as osseointegration. The implant material, geometry, surface topog-
raphy and surface chemistry all play a crucial role in determining the rate and
quality of osseointegration (Jayasree et al., 2022). Nanoscale surface modifications
of implants can not only enhance osseointegration, but also act as a drug delivery
system for delivery of growth factors at implant site to orchestrate osseointegration
and promote bridging in case of critical size defects (Wang et al., 2011; Zhang
et al., 2021a).
Lai et al. developed bone morphogenetic protein 2 (BMP-2) loaded TNTs-based
implant and evaluated its effects on osteogenic differentiation of rat MSCs (Lai
et al., 2011). TNTs fabricated via EA were initially coated with polydopamine and
then immersed in BMP-2 solution overnight at room temperature. Interestingly,
BMP-2 loaded TNTs of diameter 30 and 60 nm showed higher vinculin expression
than the 100 nm diameter TNTs. A similar pattern was observed in both cell prolif-
eration and ALP activity, with BMP-2 loaded TNTs of 30 nm diameter showing
maximum ALP activity, indicating that both BMP-2 and the morphology of the
substrate synergistically enhance osteogenic differentiation of MSCs. Overall, it
was observed that BMP-2 loaded TNTs of 30 nm diameter enhanced osteogenic
potential. However, as the half-life of BMP-2 is very low, further investigation is
needed towards clinical translation of such therapeutic systems.
To prevent denaturation of sensitive growth factors, Hu et al. coated BMP-2
loaded TNTs with multiple layers of gelatin/chitosan (layer by layer-LbL) using
spin assisted layer-by-layer assembly (Hu et al., 2012). Superoxide dismutase
(SOD) was used as a model drug to evaluate the drug release pattern. It was found
that the activity of SOD in coated TNTs were higher even at 96 h, indicating that the
gradual degradation of the multilayer coating enables a sustained release pattern.
Interestingly, they observed that the motogenic response of rat MSCs (in vitro) were
enhanced on BMP-2 loaded LbL-TNTs in comparison to uncoated BMP-2 loaded

TNTs, suggesting that the LbL coating prevented denaturation of BMP-2 and pro-
vided a controlled release pattern.
Besides growth factors, molecules like bisphosphonates have been investigated
as potential therapeutic agents to improve osseointegration. Pamidronic acid (PDA),
a nitrogen rich bisphosphonate, was immobilised on TNTs using a water soluble
carbodiimide (Koo et al., 2013). PDA-TNTs showed favourable biocompatibility
for osteoblasts (MC3T3-E1) and hematopoietic stem cells in vitro, and furthermore
initiated apoptosis in hematopoietic stem cell-differentiated osteoclasts (primary
bone resorption cells), indicating that PDA can prevent bone resorption and thus
enhance osseointegration.
With the development of anti-osteoporotic drug strontium ranelate, Ti implant
researchers investigated the influence of strontium (Sr) incorporation and release
from implants. Zhao et al. developed Sr loaded TNTs (TN-Sr) and evaluated their
effect on rat MSCs in vitro (Zhao et al., 2013). Briefly, TNTs were treated with
strontium hydroxide (Sr(OH)2) at 200 °C for 1 and 3 h to obtain TN-Sr1 and TN-Sr3,
respectively. During the hydrothermal process, the TiO2 layer slowly dissolves and
reacts with Sr(OH)2 to form strontium titanate (SrTiO3). Sr release from the TNTs
was attributed to the dissolution of SrTiO3 and the ion exchange of Sr between
SrTiO3 and hydrogen ions of release buffer. A sustained release of Sr was observed
for 30 days, with TN-Sr3 showing the highest Sr release of 0.053 ppm per day
(Fig. 2c). Further, Sr augmented osteogenic differentiation of rat MSCs by enhanc-
ing the expression of osteogenic markers RUNX2 and ALP. Strontium additionally
altered focal adhesions to promote cell attachment and enhance cell spreading.
Table 2 lists the various local drug delivery approaches to promote osseointegra-
tion using nanoengineered Ti implants (with TNTs) that indicate coupling nanotop-
ography of Ti implants with suitable bioactive molecules can synergistically
enhance osseointegration both in vitro and in vivo.
4 Local Therapy for Soft Tissue Integration
Besides osseointegration, soft tissue integration (STI) at the transmucosal region is

another important factor that determines long-term success of a dental implant (Guo
et al., 2021a). STI at the transmucosal region situated between the dental crown and
the underlying implant attached to the bone serves as a crucial barrier to the ingress
of microbes from the oral cavity to the bone-implant interface (Guo et al., 2021b).
Poor STI and breach of the barrier can lead to severe complications such as inflam-
mation of the peri-implant mucosa, infection of underlying bone leading to bone
resorption, and ultimately implant failure (Guo et al., 2021a). As described in the
previous section, the initial steps occurring at the implant site upon implantation is
very similar to that in osseointegration. Formation of blood clot occurs initially, fol-
lowed by adsorption of proteins on the implant surface leading to infiltration of
immune cells (macrophages and neutrophils) that produce cytokines and growth
Fig. 2 Orchestrating osteogenesis from strontium (Sr) doped titania nanotubes (TNTs). (a)
Schematic representation of Sr-TNTs and the influence on osteoblasts (b) FE-SEM of various
TNTs and Sr-TNTs. [NT10 – TNTs fabricated at 10 V; NT40 – TNT at 40 V; NT10-Sr1 incubated
with Sr(OH)2 for 1 h; NT10-Sr3: NT10 incubated for 3 h; N410-Sr1: NT40 incubated for 1 h;
NT40-Sr3: NT40 incubated for 3 h]. (c) Non-cumulative release of Sr from various substrates. (d)
SEM images of rat MSCs seeded on various substrates after 2 days of culture: (a) Ti, (b) NT10, (c)
NT10-Sr1, (d) NT10-Sr3, (e) NT-40, (f) NT40-Sr1 and (g) NT40-Sr3. (Adapted with permission
from Zhao et al. (2013))
factors triggering the migration of fibroblasts and endothelial cells into the implan-
tation site (Atsuta et al., 2016). Oral epithelial cells start migrating into the wound
site from the mucosa within 3 days of implantation and form a new epithelial layer
(Atsuta et al., 2005, 2016). The oral sulcular epithelium gradually starts generating
internal basal lamina attachments on the implant surface. A strong epithelial barrier
is formed at the implant tissue interface within 2–4 weeks (Atsuta et al., 2005).
Meanwhile, gingival fibroblasts (GF) migrate to the wound site and begin produc-
tion and remodelling of collagen fibre-rich ECM that matures to form a connective
tissue seal in 6–12 weeks (Fujii et al., 1998; Gulati et al., 2020a). However, align-
ment of collagen fibres formed near the implant is parallel to the implant surface, in
contrast to the direct attachment of the periodontal ligament observed in the natural
tooth; this leads to sub-optimal integration of abutments to the surrounding tissue
(Al Rezk et al., 2018; Fujii et al., 1998). In this context, the concept of micro- and
nanoscale modification of the abutment surface for localised drug delivery aimed at
Table 2 Summary of investigations on local elution of growth factors and bioactive agents from
titania nanotubes (TNTs) implants for enhanced osseointegration
Drug Size of Drug loading Release Evaluation of
incorporated TNTs method observed bioactivity Ref
BMP-2 D: 30, 60 Polydopamine – Enhanced Lai
and 100 nm coated TNTs expression of et al.
immersed in osteogenic markers (2011)
BMP-2 solution indicated
osteogenic
differentiation of
rat MSCs, with
TNTs of 30 nm
diameter showing
the highest
expression.
BMP-2/SOD D: 110 nm Drop casting of Without Enhanced Hu
BMP-2/SOD onto coating: osteogenic et al.
TNTs followed by reduced SOD differentiation and (2012)
gelatin/chitosan activity at motogenic response
LbL coating 96 h. of rat MSCs.
With coating:
enhanced SOD
activity at 96
and 120 h
BMP-2 and D: 70 nm BMP-2 drop casted Physiological Enhanced ALP Tao
gentamicin on TNTs followed pH (7.4): activity, ECM et al.
by LbL deposition 100% release mineralization and (2019)
of alginate of BMP-2 expression of
dialdehyde- within 9 d osteogenic markers
gentamicin and Acidic pH by osteoblasts.
chitosan (5.8): 100%
release in 4 d
BMP-2 D: 110 nm Dip coating of Sustained Enhanced bone to Lee
TNTs in BMP-2 in release of implant contact and et al.
a vacuum chamber BMP2 was bone volume in a (2015)
observed for rabbit tibia in vivo
10 days model.
(continued)
Table 2 (continued)
BMP-2 D: 100 nm BMP-2 drop casted Non coated 3% PLGA coated Zhang
on TNTs and then TNTs BMP-2 loaded et al.
lyophilised IBR: 80% in TNTs showed (2021b)
followed by a 1 d. significantly higher
PLGA coating of 1% PLGA proliferation, and
various PLGA coated TNTs gene expression in
concentration (1%, IBR: 30% in MC3T3 cells in
3% and 10%) 1d vitro.
TR: 90% in Enhanced bone
7d regeneration and
3% PLGA increased bone
coated TNTs volume observed in
IBR: 30% in 3% PLGA coated
1d BMP-2 loaded
TR: 60% in TNT implants in a
28 d rabbit tibia in vivo.
10% PLGA
coated TNTs
IBR: <1% in
1d
TR: <5% in
28 d
Parathyroid D: 65 nm Immersion of – Enhanced Gulati
hormone L: 12 μm TNTs in PTH expression of bone et al.
(PTH) solution remodelling (2016b)
markers like SOST
and RANKL in
human osteoblast-
like SaOS2 cells in
vitro.
Pamidronic D: 100 nm Immobilisation of – Enhanced Koo
acid PDA using osteogenic et al.
carbodiimide linker differentiation and (2013)
mineralization of
MC3T3-E1
Ibandronate D: TNTs immersed in – Enhanced new Lee
80–150 nm drug dissolved in bone formation, et al.
DI water for collagen and (2011)
physical absorption osteocalcin
expression was
observed in rat tibia
in vivo model.
(continued)
Table 2 (continued)
Fetal Bovine TNT: Immersion of Ti-FBS: Enhanced Peng
Serum (FBS) D: 150 nm TNTs in FBS IBR: 60% in osteogenic activity et al.
L: 3.5 μm followed by 1d and osteogenic (2015)
TNT-FBS: lyophilisation TR: 100% in gene expression in
D: 70 nm 5d MC3T3-E1 mouse
L: 3.5 μm TNT-FBS: pre-osteoblast cells.
IBR: 55% in
1d
TR: 90% in
5d
Strontium D: 30 and High temperature NT10-Sr1 Enhanced Zhao
80 nm treatment of TNT IBR: 0.2 ppm expression of et al.
with Sr(OH)2 for in 1 d osteogenic markers (2013)
various time points TR: 30 d like RUNX2,
NT10-Sr3 BMP-2, ALP and
IBR: 0.4 ppm osteocalcin
in 1 d indicating
TR: 30 d osteogenic
NT40-Sr1 differentiation of
IBR: 0.6 ppm rat MSCs.
in 1 d
TR: 30 d
NT40-Sr3
IBR: 0.8 ppm
in 1 d
TR: 30 d
BMP-2 bone morphogenetic protein 2, SOD superoxide dismutase, MSC mesenchymal stem cell,
LbL layer by layer, ALP alkaline phosphatase, ECM extracellular matrix, NT10 TNTs fabricated at
10 V, NT40 TNT at 40 V, NT10-Sr1 incubated with Sr(OH)2 for 1 h, NT10-Sr3 NT10 incubated for
3 h, NT40-Sr1 NT40 incubated for 1 h, NT40-Sr3 NT40 incubated for 3 h
increasing bond strength and optimal alignment of collagen fibres is gaining

momentum (Al Rezk et al., 2018).
In 2011, Ma et al. developed a dual delivery system where TNTs were loaded
with Ag NPs via electrodeposition followed by immersion in FGF-2 and lyophilisa-
tion (Ma et al., 2011). Immunofluorescence assay demonstrated a uniform loading
of FGF-2, and with decreasing fluorescence intensity, complete FGF-2 release after
9 days. In vitro studies using human gingival fibroblasts confirmed no cytotoxic
effect of Ag, and showed that the Ag-TNTs and FGF-2 enhanced cell adhesion,
proliferation, and expression of ECM markers such as type 1 collagen, VEGF, fibro-
nectin, integrin β and ICAM-1. The proposed system shows great promise to pro-
mote STI while synergistically aiming to prevent infection. The efficacy of Ag- TNTs
against specific oral pathogens like Porphyromonas gingivalis and Actinobacillus
actinomycetemcomitans was further assessed by the same group in 2014 (Mei et al.,
2014). The study revealed that while Ag-TNTs showed high antibacterial efficacy,
there was mild toxicity towards epithelial cells and fibroblasts. In vivo studies in a
Fig. 3 CNN2 connective tissue growth factor loaded TNTs for enhanced fibroblast activity.
(a) Loading efficiency of CNN2 loaded TNTs, Release profile of CCN2 from (b) TNT of 100 nm
diameter loaded with 50 ng CCN2, (c) TNT of 100 nm diameter loaded with 25 ng CCN2, (d) TNT
of 120 nm diameter loaded with 50 ng CCN2 and (e) Confocal images of actin fibres on Ti sub-
strates at various time points. (Adapted with permission from Wei et al. (2012))
rat intramuscular model demonstrated that the modified surfaces elicited reduced
inflammation and promoted fibrous tissue formation, evidencing the potential for
nano-engineered therapeutic implants in enhancing transmucosal healing.
To improve the functionality of fibroblasts towards promoting formation of a
soft-tissue seal, Wei et al. loaded TNTs with the connective tissue growth factor
fragment CCN2 (Wei et al., 2012). TNTs of diameter 100 nm loaded with 50 ng of
CCN2 via lyophilisation showed a longer sustained release of drug (105 min) in
comparison to 100 nm TNP loaded with 25 ng CCN2 and 120 nm TNP loaded with
50 ng CCN2 (both 90 min) (Fig. 3). Apart from enhanced adhesion and viability of
human skin fibroblasts in vitro, cells showed multiple stress fibres even at earlier
time points (4 h) on the CCN2 loaded TNTs in comparison to other substrates
(Fig. 3e). By day 3, thick stress fibres and well spread morphology of the cells was
observed on the CCN2/TNTs surface, supporting the potential for the proposed sys-
tem to promote formation of a strong soft-tissue seal.
Serum proteins have demonstrated the ability to inhibit bacterial adhesion (An
et al., 1996) and promote mineral deposition thereby enabling osseointegration
(Chakraborty et al., 2009), however, their effect on STI remains unexplored. In a
pioneering attempt, Liu et al. evaluated the influence of serum proteins on STI by
loading bovine serum albumin (BSA) into TNTs via lyophilisation (Liu et al., 2014)
and demonstrated in human gingival fibroblasts enhanced attachment and changes
in morphology leading to a well spread cellular structure, essential at the transmu-
cosal region of the implant.
5 Local Therapy for Antibacterial Efficacy
Immediately post implantation, the ‘race to invade’ the implant surface between
host cells and bacteria begins and the outcome determines the fate of an implant
(Guo et al., 2021b). The implant comes into contact with saliva within minutes of
implantation and gradually forms a protein pellicle. Early colonizers (e.g.,
Streptococcus) begin attaching onto the pellicle within the first 48 h, followed by
secondary colonizers such as Porphyromonas gingivalis and Actinobacillus actino-
mycetemcomitans (Hao et al., 2018; Narendrakumar et al., 2015). These microor-
ganisms adhere strongly to the implant surface using their pili and fimbriae and lead
to formation of multi-layered clusters and biofilm that shields the microbes from the
host immune system (Watnick & Kolter, 2000). Proliferation of microbes continues
within the biofilm resulting in inflammation of the soft tissue. Poor STI can facili-
tate bacterial ingress into the underlying implant structure and result in infection,
bone loss and finally implant failure (Ribeiro et al., 2012; Watnick & Kolter, 2000).
Modifying the implant surface topography and chemistry can influence bacterial
adhesion (Chopra et al., 2021). However, localised delivery of antibiotics at the
implant site is an active and tailorable strategy that may reduce the probability of
implant failure, bypassing systemic antibiotic administration.
The open ‘test- tube’ like structure of TNTs make them ideal reservoirs for bio-
active/therapeutic molecules towards their local elution directly within the dental
micro-environment. In a pioneering study, Popat et al. investigated the loading and
release of gentamicin from TNTs and their effect on Staphylococcus epidermis
activity in vitro (Popat et al., 2007). Increase in the amount of drug loaded led to
sustained release for longer periods of time. While a 70% reduction in bacterial
activity was observed due to the drug loaded TNTs, osteoblast proliferation and
ALP activity were augmented. A similar pattern was observed when vancomycin-
loaded TNTs demonstrated high antibacterial efficacy against Staphylococcus
aureus in vitro and in vivo in an infectious rat femur model (Fig. 4) (Zhang et al.,
2013). Several studies have demonstrated similar therapeutic efficacy via loading/
releasing antibiotics from TNTs (Chopra et al., 2021) (Table 3).
Fig. 4 Vancomycin loaded TNTs to prevent infection at implant surfaces. (a) SEM images of
Staphylococcus aureus attached on various Ti substrates. (b) Planktonic bacterial viability in the
culture medium after incubation with Ti substrates and (c) Microbiological assessment of the
implanted rod and the bone from the site of implantation in infectious rat femur model. (Adapted
with permission from Zhang et al. (2013))
Table 3 Various approaches for localized delivery of antibiotics using titania nanotubes (TNTs) for antibacterial efficacy
Amount
Nanotube Loaded
Loading Dimensions (A: area,
Method/ Additional (Diameter: D LC: loading Initial Burst Total Antibacterial
No. Drug Loaded Substrate Feature Length: L) capacity) Release (IBR) Release Bacterial Cell Studied Functions Other Findings Ref
1 Gentamicin Drop-casting – D: 49 ± 4 nm 4.5–7.7 mg 2 h: >90% 7 days – – Co-delivery of Pawlik et al.
ibuprofen (2017)
(anti-inflammatory)
2 Vancomycin Drop-casting Vancomycin D: 100 nm IBR @ 5 h 30 h S. aureus Only HAP Ionita et al.
release L: 3.5 μm Ti/Van HA: coatings ensure (2017)
compared >75% an excellent
between HAP, Ti/Van antibacterial
HAP-collagen HA-col: activity, but
and TNTs >62% faster release.
Ti/Van TiO2: All coatings
>54% displayed
antibacterial
functions.
3 Vancomycin + Ag Immersion Aqueous L: 6.54 μm – IBR @ 6 h 300 days – – Drug was released Moseke et al.
ions electrolyte D: 160 nm EG-EA8h: faster (aqueous (2012)
38.3 μg electrolyte)
Ethylene (22.9%) Release was
glycol (EG) EG-EA18h: significantly delayed
electrolyte 103.2 μg
(24%)
EG-EA30h:
49.4 μg
(21.4%)
(continued)
Table 3 (continued)
Amount
Nanotube Loaded
Loading Dimensions (A: area,
Method/ Additional (Diameter: D LC: loading Initial Burst Total Antibacterial
No. Drug Loaded Substrate Feature Length: L) capacity) Release (IBR) Release Bacterial Cell Studied Functions Other Findings Ref
4 Cecropin B Hyaluronidase Chitosan D: 70 nm 200 μg/ 6 h: 37% 72 h S. aureus TNT–CecB– Good Shen et al.
sensitive coating implant S. epidermidis LbLc substrates cytocompatibility for (2016)
multilayers of A: had good early osteoblasts, even
chitosan/ 10 × 10 mm. (4 h) and long co-culture with S.
sodium LC:2ug/mm2 term (72 h) aureus
hyaluronic- anti-
cecropin B bactericidal
[(Chi/ capacity against
SH–CecB)5] both bacteria
via LbL
technique
5 Gentamicin BMP2-loaded pH-responsive D: 70 nm 153.2 μg 24 h: 10 days S. aureus TNT-BMP2- Acidic environment Tao et al.
TNTs via LbL multilayer pH 7.4: pH 7.4: E. coli LbLg had could trigger the (2019)
[TNT-BMP2- film: alginate 17.0 μg 44 μg excellent release of Gen from
LbLg] dialdehyde- pH 5.8: pH 5.8: antibacterial the multilayer films
gentamicin 38.1 μg 130.3 μg capacity both in and BMP2 from
(ADA-Gen) early (6 h) and TNTs.
and chitosan in long-term In vitro: TNT-BMP2-
(Chi) (72 h) LbLg promoted
osteoblast functions.
6 Cefuroxime Nano-smooth – L: 300-400 nm 25 mg/mL Maximum 90 min – – Nano-smooth samples Chennell et al.
Nano-rugged D: 70–90 nm and release in released the least (2013)
150 mg/mL 1–2 min cefuroxime, and the
Nano-tubular nano-tubular samples
released the most
7 Cephalothin Mesoporous Circular Ti Ti substrate 3.01 μg IBR@ 9 h 119 h S. aureus Minocycline- Park et al.
thin films substrates with D: 12 mm 1.28 μg/h P. aeruginosa loaded samples (2014)
Minocycline composed of pre- Ti-NPs 5.70 μg IBR@ 9 h 119 h A. showed
TiO2 synthesized ∼20 nm 1.06 μg/h actinomycetemcomitans maximum
nanoparticles TiO2 P. intermedia efficacy
Amoxicillin on anodized Ti nanoparticles 2.90 μg IBR@ 9 h 119 h P. gingivalis Minocycline
for loading (Ti-NPs). 1.12 μg/h combined with
Ag NPs drugs at high 4.4 μg/day 16 days Ag NPs showed
doses. during the effectiveness
first 2 days against all
Ag + Minocycline – – tested bacteria.
8 Vancomycin Immersion – 50V – 50V 24 h: 28 days S. aureus TNTs anodized Most uniform Mansoorianfar
method (I) or L 2.5 ± 0.1 μm >0.1 mg (I); at morphology, et al. (2019)
Electrophoresis D: 78 ± 3 nm 0.2 mg (E) 60–75 V appropriate drug
method (E) 60 V 60 V 24 h: showed release, cell viability
L 3.2 ± 0.3 μm >0.2 mg (I); strong behaviour achieved by
D: 93 ± 3 nm 0.16 mg (E) antibacterial TNTs [60–75 V].
behaviours Drug loading
75 V 75 V 24 h: against S. efficiency increases up
D: 115 ± 5 nm >0.14 mg (I); aureus due to to 60% via
L 3.4 ± 0.1 μm 0.18 mg (E) high IBR electrophoresis
method (for 75 V
TNTs).
9 Vancomycin Simplified – In vitro 500 μg/cm2 In vitro 210 min S. aureus Good Good biocompatibility Zhang et al.
(NT-V) lyophilisation D: 80 nm 15 min: antibacterial (2013)
method L: 800 nm 600 μg/mL effect both in
In vivo In vivo vitro and in
Rod, D: 1 mm Unable to vivo.
H 20 mm measure
Adapted with permission from Chopra et al. (2021)
TNTs titania nanotubes, LbL layer by layer, LC loading capacity, IBR initial burst release, HA/HAP hydroxyapatite
While the localised delivery of antibiotics helps prevent infection at the implant
site, these treatments might not be effective against resistant strains of bacteria like
methicillin-resistant Staphylococcus aureus and polymicrobial systems (Godoy-
Gallardo et al., 2021; Lin et al., 2021). Delivery of metallic ions or NPs like Ag, Cu,
F, Zn have been explored recently to address the shortcomings of localised delivery
of antibiotics. Chen et al. (2013) demonstrated a dual action system (loading of
AgNPs into TNTs followed by immobilisation of quaternary ammonium salt
(QAS)) where high positive charge of QAS attracts negatively charged bacteria and
induces contact killing, while AgNPs released into the surrounding environment
eliminates remaining bacteria. They observed approximately 90% killing efficiency
for TNT-QAS against Escherichia coli over 30 days, while TNT-Ag-QAS showed
an enhanced killing efficiency of 99.9%. Though Ag-loaded TNTs showed minor
cytotoxicity towards osteoblasts, the presence of QAS enhanced osteoblast activity.
Jia et al. proposed a triple action mechanism of preventing infections at implant
surfaces using AgNPs (Jia et al., 2016). Initially a mico-nano surface was fabricated
on Ti using micro-arc oxidation (MAO) followed by coating self-polymerising
polydopamine and immobilization of AgNPs. The release of Ag+ ions repel the
attachment of planktonic bacteria onto the implant surface, although the action is
not 100% effective and some bacteria still make it to the implant surface. However,
upon landing, these bacteria come in contact with the AgNPs present on the surface
and undergo apoptosis. Finally, negatively charged bacteria are attracted to the sur-
face micropores where they undergo ‘trap-killing’ attributed to either collision with
pore walls or Ag NPs-initiated membrane destruction (Fig. 5). Additionally, an
effect of the modified implants to enhance osteoblast adhesion, pseudopodal exten-
sion and ALP activity was demonstrated in vitro, while a minimal immune response
to their subcutaneous implantation in a rabbit model supported clinical applicabil-
ity. Table 4 summarizes the key advances relating the loading and release of metal-
based ions and NPs from TNTs towards local therapy.
Even though the incorporation of metallic nanoparticles and ions have shown
great potential to eliminate infection in in vitro and in vivo studies, detailed investi-
gations regarding their long-term effects on therapeutic efficacy and toxicity are
required (Gulati et al., 2021).
6 Strategies of Regulating Drug Release
To ensure clinical translation of localised therapy from nano-engineered Ti implants

the drug release pattern should be tailorable, matching specific therapeutic require-
ments. The release of drugs from TNTs usually follows Fick’s first law of diffusion
and depends primarily on:
(a) drug- size, molecular weight, charge;
(b) TNT- diameter, length, charge, and surface chemistry;
(c) interaction between drug and implant surface; and
(d) other factors like pH and temperature (Losic et al., 2015).
Fig. 5 Bioinspired AgNPs loaded titanium implants for trap killing of bacteria. (a) Schematic
representation of fabrication of AgNPs immobilized micro-arc oxidation (MAO) system. (b)
Schematic representation showing the three proposed killing mechanisms. (c) SEM images dem-
onstrating ‘trap killing’. The colours represent: Yellow: bacteria, blue: nanosilver and pink:
nanosilver bound to bacteria. (Adapted with permission from Jia et al. (2016))
Soon after implant placement, high concentration of drug is released consequent to

rapid diffusion of the drug present on the surface of the implant (initial burst release
or IBR) (Gulati et al., 2015a,b). Regulating and minimising IBR is critical as these
abrupt high doses of drugs can be toxic to nearby cells thereby affecting osseointe-
gration and STI. Even though the most desirable strategy is to obtain a zero-order
kinetics where the drug is released at uniform rate irrespective of time and concen-
tration, in certain situations a lower or higher dose of drug might be preferred.
Several strategies have been utilized to tailor the release pattern of drugs from the
implant surface and will be discussed in the following sections.
Table 4 Localised delivery of metallic/semi-metallic ions and nanoparticles (NPs) from titania nanotubes (TNTs) and evaluation of their antibacterial efficacy
176
Initial Burst
Amount Release Bioactivity/
Loading Method/ Size of Nanotube Loaded [time + amount Total Bacterial Cell Antibacterial Toxicity Evaluation
No. Metal Loaded Substrate Metal NPs Dimensions (μg) released (%)] Release Studied Efficacy (special features) Ref.
1 Ag NPs Chemical D: D: 3.35– – 24 h S. aureus Ag NPs – Gunputh
reduction using 102 ± 21 nm 116.2 ± 6.4 nm 14.6 ppm exhibited et al. (2018)
δ-gluconolactone antibacterial
(GL) effect in both
micron- and
nano-sized
clusters.
2 Au NPs Visible-light D: 20 nm D: – – 24 h P. gingivalis UV irradiation Immunomodulatory Xu et al.
irradiation 150 ± 10 nm F. nucleatum increased functions from (2019)
L: 1.5 μm antibacterial TNT-Au
functions
3 Ag NPs Spin coating and D: 40 nm D: 110 nm – – 24 h E. coli The dual action Displayed long-term Chen et al.
annealing L: 900 nm antibacterial biocompatibility. (2013)
efficacy achieved
via contact and
release killing.
4 Ag NPs Photo-reduction D: 8 nm D: 100 nm – – 24 h E. coli Bacterial Enhanced TNTs Hajjaji et al.
L: 15 μm inactivation crystallinity leads to (2018)
reduced surface
defects.
5 Ag2O- NT 01.27 Magnetron D: 5–20 nm Length 45 ppb 7 days: 50% 28 days E. coli Antibacterial No cytotoxicity and Gao et al.
Ag2O- NT 04.67 sputtering and decreases with 50 ppb 7 days: 25% S. aureus rates higher than supports cell (2014)
anodization increase of Ag 97% proliferation
Ag2O- NT 07.43 content 42 ppb 7 days: 50%
Ag2O- NT 28 ppb 7 days: 50%
014.63
A. Jayasree et al.
6 Ag-doped Electrophoretic D: 100 nm T: 24.2 μm 1.6 ppm 24 h: >0.3 ppm 14 days S. aureus Ag-HAp-0.05 The passive current Mirzaee
hydroxyapatite Ag-HAp-0 P. aeruginosa showed excellent densities of the et al. (2016)
(Ag-HAp) Electrophoretic antimicrobial HAp -TNTs are
Ag-HAp-0.02 efficacy (> 99% lower than those of
Electrophoretic reduction in Ag-HAp-TNTs,
Ag-HAp-0.05 viable cells) leading to a slightly
Electrophoretic lower corrosion
Ag-HAp-0.08 resistance.
Electrophoretic
Ag-HAp-0.1
7 Cu NPs-0.3 Cu Micro-arc D: 1–5 μm T: 5–10 μm 140 ppt 24 h ~ 115 ppt 14 days S. aureus Excellent 0.3 Cu promotes Zhang et al.
Cu NPs-3.0 Cu oxidation (MAO) antibacterial osteoblast functions. (2018)
24 h ~ 135 ppt activity 3.0 Cu shows
cytotoxicity.
8 Ag NPs Micro-arc D: 50 nm – 8.57 μg/ 6 h: 2.65 μg/ 28 days S. aureus Nearly 70% Antibacterial Jia et al.
oxidation cm2 cm2 decrease of activity is reduced (2016)
viable bacteria by over 64.2%
and 300%
increase of dead
cells
9 Cu-Ti-O NTAs Anodizing – – – – 28 days S. aureus No colony No cytotoxicity of Zong et al.
magnetron- observed on Cu-Ti-O NTAs to (2017)
sputtering Cu- NTAs during endothelial cells
(AMS) the first 21 days. (ECs) and

Cu-Ti-O0.00 Only few colonies upregulated cell
AMS can be seen after proliferation.
Cu-Ti-O2.69 immersion for Enhanced in vitro
28 days. angiogenesis
AMS Antibacterial rate activity of
Cu-Ti-O4.62 remains >90% at endothelial cells.
AMS the end of test
Cu-Ti-O15.14 duration
AMS (permanent
Cu-Ti-O20.47 bactericidal effect).
177
(continued)
Table 4 (continued)
178
Initial Burst
Amount Release Bioactivity/
Loading Method/ Size of Nanotube Loaded [time + amount Total Bacterial Cell Antibacterial Toxicity Evaluation
No. Metal Loaded Substrate Metal NPs Dimensions (μg) released (%)] Release Studied Efficacy (special features) Ref.
10 B, P, Ca Plasma – T: – IBR @ 24 h 28 days S. aureus Boron in B-CaP B incorporation Sopchenski
electrolytic 5.1 ± 1.6 μm CaP coating P. aeruginosa coating prevents does not change et al. (2018)
oxidation (PEO) Ca ~1 ppm biofilm formation coating morphology
CaP coating P ~ 0.6 ppm and crystallinity in
B-CaP coating B-CaP coating comparison with
Ca ~ 1.8 ppm free B coating. B
P ~ 0.6 ppm presence promoted
B ~ 0.4 ppm ADSCs spread after
1 day of culture,
with no cytotoxicity.
11 Fluoride EA with D: 20-40 nm T: 150 nm – – – S. aureus Decrease in the FBL surface Arenas et al.
incorporated fluoride-TiO2 S. bacterial (increased (2013)
Ti–6Al–4V barrier layers epidermidis adhesion as roughness and
(FBL) compared to surface energy)
EA with T: 200 nm fluorine free promotes increased
fluoride-free barrier layers protein adsorption.
TiO2 BL (BL). No change in
surface topography
12 Ti/Van HA Drop-casting D: 200 nm – – IBR @ 5 h 30 h S. aureus TNTs have long – Ionita et al.
(Hydroxyapatite) Ti/Van HA term release. (2017)
: >75% Both coatings
Ti/Van D: 0.5 μm – IBR @ 5 h show
HA-collagen Ti/Van antibacterial
HA-collagen functions.
: >62%
Ti/Van TiO2 D: 100 nm L: 3.5 μm IBR @ 5 h
Ti/Van TiO2
: >54%
A. Jayasree et al.
13 Folic acid Vancomycin ZnO QDs TNTs 100 μL 5h 24 h S. aureus Antibacterial Excellent Xiang et al.
conjugated ZnO loaded TNTs D: 3–5 nm ID:~80 nm ZnO-FA action enhanced biocompatibility of (2018)
quantum dots. capped by solution from pH 7.4 to NTs-Van@ZnO-FA
TNTs-Van@ ZnO-FA QDs of 1 mg/ 5.5: QDs with
ZnO-FA QDs mL NTs-Van@ MC3T3-E1 cells in
ZnO-FA QDs vitro
60.8% to 98.8%
TNTs-Van 85.2%
to 95.1%
14 (poly-DL-lactic Dip coating – D: 146 nm 50 ppm in 1 d 400 S. aureus Ga-doped TNTs Reduced Dong et al.
acid) with L: 7.12 μm ppm in E. coli showed excellent inflammation and (2019)
gallium (III) dip 14 d anti-bacterial favourable
coated on TNTs property compatibility with
(assessed in the osteoblasts
spinal infection
rat model in
vivo)
15 Gallium (III) Drop casting – L: 550 nm 683 μg 30% in 1 d 60% in S. aureus 100% eradication – Maher et al.
loading on 3D 5d P. aeruginosa of both bacteria (2022)
printed nanopiller was observed
Adapted with permission from Chopra et al. (2021)
179
6.1 Altering TNTs Dimensions
Based on Fick’s law of diffusion, the dimensions of TNTs play a major role in deter-
mining the rate of drug release and can be easily tailored by varying the parameters
of anodization. TNTs of fixed diameter (110 nm) but varying lengths (25–100 μm)
were fabricated and indomethacin drug loading and release was analysed to evalu-
ate the effect of TNTs length on drug release kinetics (Aw et al., 2014). An initial
drug loading capacity of 15% and 26%, and overall drug release of 6 days and
23 days, were observed for TNTs with length 25 μm and 100 μm, respectively. A
reduced IBR was observed with an increase in the length of TNTs indicating that
longer tubes ensure deeper loading of higher drug concentration that delays its dif-
fusion and reduces IBR and total release (100% release). Similar experiments with
nanoporous anodized alumina (NAA) studied the effect of varying nanopore diam-
eter (65–160 nm) with constant length and observed that greater the diameter of the
nanostructure, greater the contact with surrounding media leading to higher rate of
diffusion (Aw et al., 2014). Hamlekhan et al. demonstrated that TNTs of diameter
60–80 nm with 1–5 μm length released the entire drug amount within 25–110 min,
and TNTs of diameter 110–170 nm with length of 40–70 μm prolonged the release
for 4–11 days (Hamlekhan et al., 2015). Overall, varying the aspect ratio of the
TNTs can help tune the drug release kinetics.
To evaluate the correlation between the size of the loaded drug molecule and the
dimension of TNTs, Peng et al. studied the release of albumin (large protein mole-
cule), paclitaxel and sirolimus (small molecules) from TNTs of various dimensions
(Peng et al., 2009). TNTs (100 nm diameter) of length 1 μm held less than half the
amount of drug held in 5 μm, confirming that longer the tube, the greater the volume
for drug entrapment. They also observed that TNTs of diameter 100 nm and 5 μm
length could prolong the release of the larger sized albumin to 30 days, while small
molecules were released within 7–14 days. To summarise, longer and wider TNTs
can be loaded with higher drug amounts but can also demonstrate high IBR and
faster release in comparison to short and narrow TNTs (that can be loaded with
lower drug amounts but show lower IBR and prolonged drug release). Further opti-
mization and techniques to effectively alter these parameters to obtain an improved
control over the release pattern need to be developed.
6.2 Polymeric Modifications of TNTs
A thin polymer coat on the open pores of drug-loaded TNTs can act as a barrier
towards the diffusion of drug from the TNTs and thereby achieve controlled
release. Further, polymer encapsulation of sensitive drugs prior to loading inside
the TNTs can also be utilized as a strategy to control drug release. Vasilev et al.
utilised plasma polymerisation (PP) to deposit a layer of poly(allylamine) onto
TNTs to create a thin chemically reactive chemical coating containing amine
functional (Vasilev et al., 2010). The functional groups present in this coating
was utilised to fabricate two types of TNT surfaces; (a) TNTs coated by LbL
assembly of poly(sodium styrenesulfonate) (PSS), and (b) TNTs covalently cou-
pled with poly(ethylene glycol) (PEG). They demonstrated that by altering the
time of plasma deposition the diameter of the nanotubes can be changed from 20
to 140 nm. The proposed system is an interesting proof of concept for incorpora-
tion of polymeric coatings on the surface of nanotubes. However, PP requires
costly equipment and which makes it highly unsuitable for translation purposes.
As an alternative, scientists have developed a much simpler alternative of dip
coating polymers onto surface of TNTs. Gulati et al. dip coated indomethacin
loaded TNTs with chitosan and PLGA and evaluated its influence on the drug
release kinetics (Gulati et al., 2012). Chitosan modified TNT showed a 35% IBR
and PLGA modified TNT a 12% IBR within 6 h in comparison to uncoated sam-
ples which showed an IBR of 77%. While the entire drug in uncoated samples
was released within 4 days, the coated TNTs showed a prolonged release up to
30 days, thereby establishing dip coating as an efficient technique to prolong the
drug release from TNTs. These biopolymeric coatings also demonstrated
enhanced osteoblast cell adhesion at early time points indicating that these sur-
faces have great potential for improving osseointegration and control local ther-
apy synergistically. A similar pattern was observed when BMP-2 loaded TNTs
were coated with gelatin and chitosan (Hu et al., 2012) and LbL deposition of
alginate dialdehyde-gentamicin and chitosan (Tao et al., 2019). Briefly, the
PLGA coating on BMP-2 loaded TNTs prolonged the release of BMP-2 to
28 days in comparison to the 80% IBR observed in non-coated TNTs within
1 day (Zhang et al., 2021b).
In a pioneering attempt, Fathi et al. developed a silk fibroin nanofiber coated
vancomycin loaded TNTs (Fathi et al., 2019). The vancomycin was drop casted on
the TNTs followed by electrospinning of silk fibres onto their surface. They demon-
strated that the amount and duration of drug release can be modulated by altering
the diameter of the silk nanofibers. By decreasing the diameter of nanofibers from
350 to 180 nm, the IBR within 6 h could be reduced from 73% to 30% and the total
release can be prolonged from 1 to 28 days.
6.3 Encapsulation of Drug in Nano-carriers
Ensuring the stability of sensitive therapeutics such as drugs, growth factors and
proteins, and preventing their denaturation and precipitation within the physiologi-
cal environment is one of the major challenges in LDD (Atanase, 2021; Son et al.,
2021). Polymeric micelles with hydrophobic and hydrophilic cores have shown
great potential in localised delivery of sensitive payloads (Ghosh & Biswas, 2021;
Gigmes & Trimaille, 2021). Aw et al. loaded TNPs with five types of polymeric
micelles (i) d-α-tocopheryl polyethylene glycol 1000 (TPGS), (ii) Pluronic
F127, (iii) PEO(260)–PPO(400)–PEO(260), (iv) 1,2-distearoyl-sn-glycero-3-
phosphoethanolamine-N-[methoxy (polyethylene glycol)-5000] (DGP 5000), and
(v) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene

glycol)-2000] (DGP 2000) (Aw, 2011). All groups showed similar IBR pattern for
6 h and sustained release was observed in all micelles for 21 days irrespective of
micelle type. The largest micelle, PEO-PPO-PEO (75 nm), showed a slightly
quicker drug release. To further prolong the drug release the TNP loaded with
micelles were further coated with allylamine using PP and it was observed that a
70 nm thick coating reduced the IBR by 50% and prolonged the drug release to
30 days.
6.4 Triggered Therapy
Various strategies to control and regulate a sustained local release might address
therapeutic demands in most cases, although they fall short in cases when a change
in therapeutic dosage is needed to obtain a desired effect (Jayasree et al., 2021). A
further drawback of sustained release is complete consumption of loaded drugs/
antibiotics that may allow re-infection in later stages. The ability to control drug
release based on the needs of the local microenvironment is ideal. ‘On-demand’
triggered therapy can minimize IBR and achieve maximized therapeutic potential.
Triggered therapy using an external or internal stimulus has been explored to over-
come shortcomings of sustained drug release. TNTs are an ideal candidate for trig-
gered therapy due to their enhanced surface properties and ease of functionalisation.
The chemical/temperature changes in the implant microenvironment (onset of
infection/inflammation) can be utilized as internal stimuli for localised therapy (Liu
et al., 2015). While internal triggers cater to the microenvironment and cannot be
regulated by a clinician/patient, external triggers such as magnetic/electric fields
and electromagnetic waves provide more control as they can be managed externally
(Timko et al., 2010). Some of these triggered therapy systems are discussed in the
following sections (Fig. 6).
6.4.1 Enzyme Trigger
At various stages of implant surface microbial infection, the pathogens secrete

enzymes like hyaluronidase (HAase) and chymotrypsin that can also be utilised as
triggers to initiate drug release from TNTs (Yu et al., 2020). Grafting antibiotics
with polymers like hyaluronic acid that are easily degraded by HAase can be used
to achieve enzyme triggered release. Yu et al. loaded defroxamine (DFO) inside
TNTs followed by spin coating gentamycin-grafted hyaluronic acid (Yu et al.,
2020). Observing a sustained release of DFO from the TNTs in absence of HAase
and a burst release when HAase was added confirmed that the presence of HAase
enzyme triggered drug release. Further, the presence of E. coli and S. aureus resulted
in a release of gentamycin that reduced the microbial load. It is noteworthy that the
Fig. 6 Triggered release of drugs from titania nanotubes (TNTs). Schematic representation:
(a) uncontrolled drug release from TNTs, (b) triggers based on internal factors like pH and enzyme,
(c–f) externally triggers: ultrasound, magnetic field, electrical stimulation and electro-magnetic
radiation. (Adapted with permission from Jayasree et al. (2021))
microbes secrete large amounts of HAase as part of their metabolism, which

degrades the polymers and triggers the release of gentamycin. A similar principle
was employed by Yuan et al., in developing vancomycin-loaded TNTs coated with
dopamine-modified hyaluronic acid and 3,4- dihydroxyhydrocinnamic acid-
modified chitosan via LbL assembly (Yuan et al., 2018). The researchers reported a
sustained release of vancomycin for 6 h followed by a triggered release upon intro-
ducing HAase. They further demonstrated an increase in the amount of drug release
(80% of drug within 6 h) in the presence of S. aureus, compared with only 25%
release in the absence of bacteria, confirming that bacterial load can act as an inter-
nal trigger to facilitate drug release. Further, the antibacterial efficacy of the trigger
system was evaluated in vivo in a rat femur infection model, with significantly lower
microbial load, lower neutrophil infiltration and higher bone formation observed,
demonstrating the antibacterial efficacy of the system while simultaneously improv-
ing osseointegration.
6.4.2 pH Trigger
Bacterial attachment and biofilm formation at an implant site can reduce the local
pH from 7.4 to an acidic 5.5, and this change can be utilized as a trigger to facilitate
an ‘on demand’ release of therapeutics (Dong et al., 2017; Ribeiro et al., 2012).
Dong et al. utilised a pH sensitive acetal linker to immobilise AgNPs on TNTs and
assessed its release pattern with changes in pH (Dong et al., 2017). Though a sus-
tained release of AgNPs was observed at both neutral (7.4) and acidic pH (5.5), the
amount of drug released in pH 5.5 was 2.5 times higher than pH 7.4. Further, a
sustained release was observed for 28 days in pH 7.4, followed by a burst release of
high dose of AgNP when the pH was dropped to 5.5. The proposed system showed
great potential as an implant surface modification that limits drug release at physi-
ological conditions for prolonged periods and provide a burst release upon infec-
tion. Wang et al. used the same principle to develop TNTs loaded with AgNPs and
vancomycin and coated them with a pH sensitive coordination polymer 1,4-bis
(imidazol-1-ylmethyl) benzene (BIX) (Wang et al., 2017). Capping of vancomycin
loaded TNTs with folic acid modified ZnO quantum dots demonstrated a similar
triggered release pattern, with release of 500 μg/mL within 15 days in pH 5.5 com-
pared to the 200 μg/mL observed at pH 7.4 (Xiang et al., 2018).
6.4.3 Electrical Triggers/Electrical Stimulation Therapy (EST)
EST or the modulation of cellular activity by providing an electrical stimuli has

shown to augment differentiation of osteoblasts (De Giglio et al., 2000), fibroblasts
(Shi et al., 2008), neurons (Gomez & Schmidt, 2007), endothelial cells (Garner
et al., 1999) and cardiomyocytes (Nishizawa et al., 2007) through signalling cas-
cade activation. In pioneering studies, Sirivisoot et al. developed Polypyrrole (PPy)
doped TNTs loaded with penicillin, streptomycin and dexamethasone via electrode-
position (Sirivisoot et al., 2011). The continuous redox reactions occurring within
PPy upon electrical stimulation lead to rupture of bonds between the polymer and
drug molecules resulting in an abrupt release of 80% of the drug within 5 cycles of
electrical stimulation. Cyclic voltammetry measurements by applying voltages of
−1 to 1 V showed an ON-OFF release pattern for drug release corresponding to
electrical stimulation. Further, Shi et al. (2013) demonstrated that while chitosan
coated vancomycin loaded TNTs showed sustained release of drug in the absence of
trigger, application of a voltage of 3 V triggered an abrupt release of 50% of drug
within 10 min. Upon application of voltage, a reduction in pH caused degradation
of the chitosan layer and thereby enabling quick diffusion of vancomycin. Gulati
et al. converted TiO2 nanotubes on Ti wires into Ti nanotubes via magnesiothermic
reaction and demonstrated that such systems can be used to enable simultaneous
EST and LDD (Gulati et al., 2016c). Interestingly, as the nanotubes were not modi-
fied, they reported that drug release was not dependent on the EST.
6.4.4 Magnetic Field
Due to its ease in handling, high tissue penetration and minimal adverse reactions,
magnetic field is the most versatile trigger mechanism widely investigated for tar-
geted therapy and imaging (Bi et al., 2016). The success of magnetic NPs in the field
of targeted drug delivery and imaging has inspired researchers to explore their
potential as a localised triggered therapy mechanism (Bi et al., 2016; Hoare et al.,
2009). In a pilot study, Gulati et al. demonstrated an interesting system of loading
TNTs with magnetic iron oxide nanoparticles followed by indomethacin for trig-
gered therapy (Gulati et al., 2010). The same group later evaluated the release of
indomethacin loaded polymeric micelle from TNTs via magnetic trigger (Aw et al.,
2012a). TNTs were initially loaded with dopamine-conjugated iron oxide NPs fol-
lowed by incorporation of polymeric micelles loaded with indomethacin. Three
types of micelles, d-a-tocopheryl polyethylene glycol 1000 (TPGS), Pluronic F127
and PEO–PPO–PEO were used, and a sustained release pattern was observed in the
absence of a magnetic field, with an IBR of 50% within 5 h. However, upon intro-
duction of a magnetic field an abrupt drug release of 95–100% was observed
within 1.5 h.
6.4.5 Radiofrequency (RF)
Increased skin permeation of electromagnetic waves in the range of 3 kHz–300 GHz

makes RF highly suitable for non-invasive imaging and drug delivery applications.
Bariana et al. used a solenoid copper coil and a variable frequency generator to
evaluate RF triggered release of indomethacin from gold nanoparticles (AuNPs)-
loaded TNTs upon application of a 1 GHz RF field (Bariana et al., 2014). TNTs
were initially loaded with AuNPs followed by either bare indomethacin (Ind-TNT)
or indomethacin preloaded in TPGS micelle (Ind-TPGS-TNT). Ind-TNT and Ind-
TPGS-TNT demonstrated a burst release of 100% of drug within 5 min when RF
was applied, while in the absence of RF trigger a release of 25–30% was observed
within 3 h. The release was attributed to the application of RF that generated eddy
currents causing friction amidst the vibrating AuNPs, leading to temperature
increase and a convective displacement of indomethacin from the TNPs. The study
also showed that drug release can be further tailored by varying the time of RF
exposure, for example, 2–5 min RF exposure corresponded with 70–90% of drug
released, respectively.
6.4.6 Near Infra-Red (NIR)
NIR waves in the range 650–900 nm can penetrate tissues and bone with minimal
phototoxicity and minimal attenuation of blood and soft tissues (Cho et al., 2015).
Several NIR based therapeutic drug delivery systems utilise the photolytic cleavage
mechanism, where the NIR waves causes cleavage of polymeric chains and release
payloads (Cao et al., 2013; Wu et al., 2008). Recently, upconversion nanoparticles
(UCNPs) were investigated for triggered therapy due to their ability to convert NIR
into different wavelengths such as visible and UV (Carling et al., 2010; Chen et al.,
2014). Zhao et al. combined UCNP and photolytic cleavage potential of NIR to
develop amphiphilic TNTs with AuNP grafted hydrophobic cap and an ampicillin
loaded hydrophilic bottom for triggered therapy (Zhao et al., 2020). Upon applica-
tion of NIR, the UCNPs absorbed the photons and emitted waves of lower wave-
length that generated reactive oxygen species (ROS) resulting in cleavage of the link
between ampicillin and TNT, and thus its release. Upon triggering with NIR, a burst
release of 75% of drug was observed within 120 min, compared to 20% release
observed without the trigger. A sustained release of only 10% was observed for
10 days, with a subsequent burst release at day 10 upon NIR illumination. Further,
bioactivity evaluation with human keratinocyte cell line (HaCaT) in vitro showed
that NIR stimulation can cause production of ROS leading to minor cytotoxicity.
6.4.7 Visible Light
Visible light of wavelength 380–700 nm has been used extensively for phototherapy
in medicine since 1960. The photothermal, photocatalytic and photodynamic proper-
ties of light on interaction with polymeric and metallic surfaces make them highly
suited for triggered therapy applications (Yun & Kwok, 2017). An amphiphilic TNTs-
based LDD system has recently been developed where TNTs are loaded with ampicil-
lin via a silane linker (3-glycidozypropyl) trimethoxysilane (GPMS) (hydrophilic
part) and an AuNP-octadecylphosphonic acid (ODPA) hydrophobic cap as shown in
Fig. 7 (Xu et al., 2016). Upon illumination, surface plasmon resonance of AuNPs trig-
gers incision of the hydrophobic cap (followed by the cleavage of ODPA) resulting in
ampicillin release. In this system, bare drug-loaded TNTs exhibited an IBR of 80%
within 10 min, while the amphiphilic TNTs produced <1% IBR in the absence of
light. However, upon illumination, 80% of the drug was released within 2 h. The study
also reported stimuli responsive antibacterial efficacy against E coli (Fig. 7c, d).
6.4.8 Ultrasound Waves (USW)
Non-ionizing high frequency sound waves have been studied towards achieving
local triggered release and targeted delivery of therapeutic agents by using poly-
meric micelles and microbubbles as carriers (Huang & Macdonald, 2004; Rapoport,
2012; Unger et al., 2004). In a pioneering attempt, Aw et al. utilised USW to trigger
the release of indomethacin-loaded TPGS polymeric micelles from TNTs using a
sonotrode (Aw & Losic, 2013). Application of USW caused cavitation within the
release media resulting in triggered drug release. Further, the release of drugs was
shown to depend upon the duration of USW applied. For example, short pulses trig-
gered 100% of drug released within 5 min, while long pulses prolonged the release
to 1 h. A sustained release over 2 weeks was observed in the absence of the trigger.
Carrier sequestration of drugs is a major concern with USW trigger therapy
(Husseini et al., 2002), however, the use of small size drug micelle complex (20 nm)
Fig. 7 Near infra-red (NIR) responsive titania nanotubes for triggered therapy and antibac-
terial efficacy. (a) Schematic representation of fabrication of light responsive TNTs. (b) Release
of AMP. (c) Antibacterial efficacy of modified TNT; (A) comparison between the various groups,
(B) antibacterial efficacy as a function of time upon illumination, (C) antibacterial efficacy against
E. coli in the presence of light showing lower bacterial count in comparison to (D) absence of light.
(Adapted with permission from Xu et al. (2016))
and mechanically stable TNTs help preserve the integrity of the drugs. A similar
principle was utilised to trigger the release of tetracyclin from superhydrophobic
TNTs via USW application (Zhou et al., 2018).
In summary, triggered therapy using internal and external triggers from TNTs/Ti
implants shows great potential as demonstrated in proof-of-concept studies.
However, these approaches come with limitations that require consideration in
terms of clinical application. While internal triggers such as enzymes may respond
to the microbial load at the implant site, the cascade of cellular activities in the
microenvironment can stimulate alternate enzymes that may accidently trigger drug
release. Magnetic triggered therapy can be easily administrated and regulated exter-
nally by a clinician, however, there is the possibility for magnetic fields around us
to cause premature or unwanted triggering. Moreover, potential phototoxicity and
ROS production from electromagnetic waves (RF and NIR) requires further
investigation (Sabella et al., 2014), while trigger-induced tissue/implant heating due

to vibrations from USW can potentially lead to denaturation of proteins, membrane
dysfunction and apoptosis (Shankar & Pagel, 2011).
7 Research Challenges and Future Directions
Despite the several advances made in the surface modification and nano-engineering
of titanium implants to improve their bioactivity and local therapy, several research
gaps remain unaddressed that need to be thoroughly investigated towards clinical
translation.
• Dental implants are exposed to a complex biological environment that not only
involves the host cell response but also microbes (Martinez-Marquez et al.,
2020). Dental implant therapeutic modification must be able to withstand masti-
catory loading and physiological conditions including bacterial infection and
frequent pH changes. Very few studies have demonstrated successful fabrication
of nano engineered surfaces on clinically relevant implant morphologies with
appropriate mechanical stability (Li et al., 2018a, b). While, localised drug deliv-
ery using nanostructures have shown great potential in vitro with some optimiza-
tions performed ex vivo (Aw et al., 2012c; Rahman et al., 2016), their stability
and therapeutic performance under such complex and mechanically loaded con-
ditions needs to be thoroughly investigated in long-term in vivo studies.
• A major concern with LDD systems is cytotoxicity due to local release of high
drug concentrations that might hinder cellular maturation and proliferation
(Chang et al., 2006). Further, the ions and degradation products arising
from various polymeric coatings and metal dopings upon bioaccumulation can
elevate ROS levels leading to DNA damage and cellular apoptosis (Johnston
et al., 2010).
• To ensure successful clinical translation of nano engineered therapeutic implants,
they must meet regulatory parameters (sterilization, packaging, handling) and
the impact of implantation upon nano-modification stability needs to be assessed.
The shelf-life and stability of drug-incorporated nano-engineered implants, espe-
cially those loaded with sensitive bioactive molecules (drug/growth factor), is
crucial and requires validation.
8 Conclusion
Titania nanotubes-modified titanium dental implants have shown great potential

towards achieving local drug delivery for optimal therapeutic efficacy targeting
integration, inflammation and infection. Various strategies to reduce initial burst
release of drugs involve the use of biopolymers, drug encapsulation and enabling
triggered release upon internal/external stimulation. Clearly, current investigations
demonstrate the proof-of-concept of these novel therapeutic approaches in vitro.

Evaluation of their long-term efficacy under in vivo settings with infection/inflam-
mation and under mechanical loading will aid in their clinical translation.
Acknowledgements Anjana Jayasree is supported by a UQ Graduate School Scholarship

(UQGSS) funded by the University of Queensland. Karan Gulati is supported by the National
Health and Medical Research Council (NHMRC) Early Career Fellowship (APP1140699).
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msec.2016.09.077
Mechanical Stability of Anodized
Nano-engineered Titanium Dental
Implants
Divya Chopra and Karan Gulati
1 Introduction
Titanium and its alloys are the favorable material choice for dental implants and
have been extensively researched and modified to achieve early stability and long-
term success. Various investigations have established that Ti implants possess
appropriate mechanics with the human bone to ensure osseointegration without
causing any micro-motion. However, critical considerations concerning implant
success involve mechanical stability in ever-evolving and mechanical loading con-
ditions. Overall, implant material’s corrosion resistance, biocompatibility and
mechanical strength are key considerations towards ensuring implant success.
However, most research (mainly encompassing surface modification) has been
restricted to bioactivity enhancements (Ivlev et al., 2015).
In the presence of oxygen, Ti readily forms a thin oxide (TiO2) layer responsible
for biocompatibility and corrosion resistance (Elias et al., 2008). Known to form the
stable oxide layer, the commercially pure titanium (cpTi) is considered the best
biocompatible material. Depending on the impurities present in cpTi, the American
society for testing and materials (ASTM F-67) has classified the cpTi into four
grades. For medical applications, especially dental implants, the cp Ti and its alloys
are extensively used in fabricating crowns, bridges, dentures, implants, prostheses,
abutments, screws, etc. Specifically, cp Ti is widely used for endosseous dental
implants. It is noteworthy that Ti alloys (Ti–6Al–4V) are still preferred for orthope-
dic implants due to higher mechanical resistance than commercially pure Ti.
Ti–6Al–4V is considered the Ti grade 5 according to the technical standard
ASTM-136, which covers the mechanical and chemical composition of the alloy to
D. Chopra · K. Gulati (*)

e-mail: k.gulati@uq.edu.au
https://doi.org/10.1007/978-3-031-21565-0_7
200 D. Chopra and K. Gulati
be used in surgical implants (Elias et al., 2008). Each grade of unalloyed cpTi has
specific mechanical characteristics. For example, G-1 has the highest purity with the
lowest strength and excellent durability at room temperature; G-2 is used exten-
sively in dental implant applications; G-3 has maximum iron content, and G-4 pos-
sesses the highest strength. However, Ti-G2 and G4 have poor wear resistance, and
it is not easy to enhance their mechanical performance without affecting biocompat-
ibility (Niinomi, 2008).
The mechanical compatibility between a material and biological tissue where it
will be implanted is crucial in implant material selection. The natural bone’s
mechanical stability depends on the bone tissue’s ultrastructure, such as on mineral
crystals, dimensions, collagen fibres, etc. These considerations change with age or
ailment. For instance, premature bone has compact bone tissue with high elasticity
and plasticity, while adult bone has more strength and hardness. However, with
time/age, the bone reduces its strength and elasticity (Milovanovic et al., 2012).
Overall, Ti and Ti-based alloys have proven to match the mechanical requirements
of the dental implant setting (Gulati et al., 2017).
While optimum treatment outcomes are observed when Ti dental implants are
placed in healthy patients, in compromised patient conditions (aged, diabetic or
smokers), long-term success is challenged (Guo et al., 2021b). To achieve favorable
long-term integrated implants, surface modification of Ti dental implants to enable
topographical, chemical, biological or therapeutic enhancements to augment cellu-
lar functions (translating into enhanced implant-bone/soft-tissue integration) is
emerging as a promising strategy (Gulati et al., 2016b; Guo et al., 2021a). This can
be achieved via polymer coating, surface roughening, bioinspired surface engineer-
ing, and coating ceramics or synthetic coatings (Zhang et al., 2021; Chopra et al.,
2021c), as presented in Fig. 1. Further, surface modification of Ti-based dental
implants in the various scales (macro, micro and nano) has established that nano-
scale surface modification surpasses microscale features in augmenting implant
bioactivity, corrosion resistance and achieving local therapy (Chopra et al., 2021b).
Interestingly, mechanical stability and survival of such nano-engineered coatings
remains unexplored, especially considering that a dental implant micro-environment
is mechanically challenging attributed to high masticatory loading cycles. Other
mechanical considerations include: packaging, handling and surgical placement,
which are often not considered while proposing novel nano-engineered coatings in
proof-of-concept investigations.
Among the various nano-engineering strategies optimized for dental implant
modification, electrochemical anodization (EA) stands out as a cost-effective and
scalable strategy that permits excellent control over the characteristics of the modi-
fied implant (Jayasree et al., 2021). Briefly, EA involves immersion of a Ti-based
dental implant as an anode and a cathode (Ti or Pt) in an appropriate electrolyte
(containing fluoride and water) and supply of constant current or voltage using a DC
power supply (Gulati et al., 2022). Under optimized conditions and dependent on
EA parameters, including time, voltage, current, water/fluoride content, etc.,
Mechanical Stability of Anodized Nano-engineered Titanium Dental Implants 201
Fig. 1 Schematic representation of various surface modification strategies to enhance bioactivity,

therapeutic and corrosion-resistance performance of Ti-based dental implants
self-ordering of titania (TiO2) nanotubes (TNTs) or nanopores (TNPs) occurs on the

surface of the implant (Guo et al., 2021c). Further, using the abovementioned
parameters, the dimensions of the nanostructures can be controlled. Briefly, TNTs
are like tiny test tubes, open at the top and closed at the bottom; TNPs are TNTs
fused at the top. Various investigations in in vitro, ex vivo and in vivo settings have
established that TNTs or TNPs modified dental implants hold great promise in alle-
viating challenges associated with long-term success of dental implants in compro-
mised conditions, including poor integration (both osseo- and soft-tissue) and
bacterial infection (Guo et al., 2021a).
Interestingly, the mechanical performance of anodized nano-engineered Ti den-
tal implants is poorly understood and optimized. Especially considering that nano-
scale modifications on implants must endure and survive the mechanical challenges
experienced by the implant, any delamination or release of nanoparticles can initiate
both local and systemic cytotoxicity and result in implant failure; the mechanical
performance of anodized implants represents a critical research gap. This chapter
focuses on the mechanical stability of electrochemically anodized Ti-based dental
implants modified with nanotubes or nanopores and strategies to augment their sta-
bility to ensure long-term success, bridging the gap between research and clinical
translation. Various clinical translation challenges of anodized Ti-based implants
are presented in Fig. 2 (Gulati et al., 2021b).
Fig. 2 Clinical translation challenges associated with the success of electrochemically anodized
Ti implants (modified with nanotubes). (Adapted with permission from Gulati et al. (2021b))
2 Enhancing Stability of Anodized Ti Dental Implants
The following present critical strategies employed to augment the mechanical sta-
bility of anodized Ti dental implants modified with nanotubes or nanopores.
2.1 Fabrication Optimization
As established in previous chapters, numerous investigations support the fabrication

of TNTs and TNPs on Ti dental implants to augment implant-tissue integration or
local drug release to prevent bacterial infection. Most investigations are performed
on ‘easy to manage’ polished and planar flat Ti foils; however, clinical dental
implants are curved, micro-rough and with sharp edges, representing additional
challenges. Figure 3 presents the top-view SEM images of clinical dental implant
abutments and screws that show micro-machining lines and sharp edges in screws
(Li et al., 2018a). Micro-roughness or micro-machining of dental implants is
regarded as the ‘gold standard’ to ensure timely integration (Guo et al., 2021b).
Often Ti foils (or other substrates) are polished via various mechanical, chemical
and electro-polishing treatments (Lu et al., 2011) that improve the self-ordering of
TNTs upon anodization, but do not represent clinically-relevant implant surfaces.
For dental implants, any reduction or loss of microscale features can not only reduce
implant dimensions (hence poor fitting upon placement) but can eventually result in
inferior osseointegration (Du et al., 2016). It is noteworthy that anodization and the
self-ordering of TNTs or TNPs is influenced by the substrate geometry, shape and
presence of roughened or micro-structured topography (Li et al., 2018a).
Further, to ensure the formation of well-ordered TNTs, a two-step EA is per-
formed, whereby the first anodic layer is removed and a second EA is performed
(Xing et al., 2014). The two-step EA removes underlying substrate micro-features
and may be unsuitable for dental implant application. Hence, implant micro-
roughness is often compromised to fabricate ordered TNTs/TNPs. The fabrication
of TNTs or TNPs on micro-rough implants to yield dual micro-nano structures is
essential. To better understand the interface between the anodic film (TNTs or
TNPs) and the underlying Ti substrate the readers are directed to the extensive
mechanical stability focused review on TNTs by Li et al. (2018b).
Fig. 3 Clinical dental implants represent a difficult surface to achieve mechanically stable and
well-ordered nanostructures via anodization. SEM images showing (a, c) Ti dental implant abut-
ment and (b, d) screw. (Adapted with permission from Li et al. (2018a))
Advances in anodization optimizations have improved our understanding of the

self-ordering of TNTs or TNPs on complex implant surfaces and have permitted the
fabrication of stable, ordered, and reproducible nanostructures on implants, as
described below:
Altering Anodization Parameters
The simplest way to assure stable anodic films are formed on implants is reduced
electrolyte water content, use of low voltage/current or reduced time of anodization
(Zhu et al., 2011). Using one or combining such strategies reduces the growth rate
of nanostructures and yields reduced diameters and lengths of TNTs or TNPs. It is
generally accepted that the lower length and diameter of TNTs/TNPs are robust. It
is noteworthy that TNTs dimensions influence both the bioactivity and the local
drug release. For instance, tube/pore diameter influences the activity of cells and the
length dictates the amount of drug loaded/released (Brammer et al., 2012; Alipal
et al., 2021; Oliveira et al., 2017). Hence, fabricating reduced dimensions of nano-
structures can significantly impact bioactivity and drug release kinetics.
Use of Micro-patterned Substrates
While initial attempts at anodizing Ti and most optimization attempts are restricted
to polished substrates, various mechanical treatments have been performed on as-
received rough or polished substrates to yield controlled micro-topographies. These
include mechanical preparation (micro-machining), photolithography, laser treat-
ment, and 3D printed micro-rough substrates, followed by anodization that results
in preserved micro-patterns and superimposition of nanotubes/nanopores (dual
micro-nano) (Gulati et al., 2017, 2018; Peng et al., 2013; Wang et al., 2009). Further,
as-received and micro-rough Ti rods and wires have also been used to demonstrate
the fabrication of nanostructures using anodization (Shivaram et al., 2016; von
Wilmowsky et al., 2009; Rahman et al., 2016).
Electrolyte Aging
Repeated use of the same ethylene glycol-based electrolyte (with F and water) to
anodize non-target Ti, before anodizing target Ti is referred to as electrolyte aging
(Gulati et al., 2022). Aging conditions the electrolyte and results in increase in pH
and TiF6 concentration and reduction in electrolyte conductivity and free F ions, that
yields TNTs or TNPs with superior mechanical stability (Guo et al., 2022). More
recently, we have shown that electrolyte aging improves the ordering of nanopores,
mechanical stability and bioactivity of the anodized micro-rough Ti (Guo et al.,
2021c). The nanoindentation data revealed that at the same indentation depth, TNPs
fabricated by aged electrolytes had enhanced Young’s modulus and hardness com-
pared to TNPs fabricated by the fresh (unused) electrolyte. Our group has widely
utilized and optimized electrolyte aging to enable the fabrication of titania nano-
structures (nanotubes and nanopores) on curved Ti wires and rods, dental abutments
and screws and micro-rough flat substrates (Gulati et al., 2022).
Single-Step Anodization
Contrary to two-step anodization, single-step anodization of micro-rough/micro-
machined substrates using aged electrolyte permits the fabrication of dual micro-
nanostructures, especially nanopores (top-nanoporous layer and nanotubes
underneath) (Chopra et al., 2023). Preserving the implant micro-roughness and fab-
rication of nanopores yields a dual micro-nano surface that offers superior mechani-
cal performance compared to conventional nanotubes (Gulati et al., 2018).
Nanoindentation testing was performed to evaluate the elastic modulus and hard-
ness values of the TNPs with 50 and 70 nm diameters. For TNP-70, modulus and
hardness reduced with indentation depth; for TNP-50, only hardness reduced with
depth. This was attributed to the compact and dense nature of TNPs, which were
less prone to collapse under indentation. In contrast, nanotubes have inter-tube gaps
between them which can be prone to strain and failure. It is worth noting that the
study reported the fabrication of robust TNPs that outperformed conventional TNTs
(typical modulus of 36–43 GPa) by several orders of magnitude.
Further, for micro-machined surfaces, the nanopores fabricated via single-step
EA in the aged electrolyte results in anisotropic nanopores that mechanically stimu-
late osteoblasts and gingival fibroblasts to align parallel (Gulati et al., 2018).
Interestingly, two-step EA has also been used to fabricate nanopitted surfaces with
enhanced integrity and tensile strength (Weszl et al., 2017). Compared to nanotubes,
the formation of nanopits did not show any signs of corrosion or exfoliation upon
scratch resistance testing. Also, the nanopits were fabricated with high reproduc-
ibility on the surface of dental implant screws.
Use of Clinical Implants
While most studies described above use implant-relevant geometries or surface
topography, few studies have utilized clinical implants to demonstrate the success-
ful fabrication of stable TNTs or TNPs via anodization (Choi et al., 2012; Li et al.,
2018a). Choi et al. used machined orthodontic miniscrews and performed anodiza-
tion to fabricate nanotubular/porous implants, followed by implantation in the man-
dible of beagle dogs in vivo (Choi et al., 2012). Further, Li et al. utilized clinical
dental implant abutments and screws and performed anodization using aged electro-
lyte to fabricate aligned nanopores (single-step EA), nanotemplate (removal of the
anodic film) and random nanopores (second EA on nanotemplate) (Fig. 4) (Li et al.,
2018a). To evaluate mechanical characteristics, TNPs fabricated on micro-rough Ti
wires (model implant surface) via fresh or aged electrolyte were tested via nanoin-
dentation. The study reported significantly enhanced elastic modulus for TNPs
(fresh and aged electrolyte anodized) compared to conventional nanotubes.
2.2 Physical Treatments
Annealing of TNTs is routinely practiced to convert as-fabricated amorphous TiO2

into crystalline TiO2. Annealing above 280 °C yields the anatase phase, while
500–600 °C yields the rutile phase. It is also established that the rearrangement of
Fig. 4 Controlled nanotopographies fabricated via anodization on Ti dental implants. SEM

images showing various nanostructures formed on implant abutment and screws. (Adapted with
permission from Li et al. (2018a))
TiO6 octahedra during crystallization improves mechanical stability without impact-

ing structural morphology (Yu et al., 2010). Further, rutile TiO2 is more mechani-
cally stable than the anatase.
To augment mechanical and chemical stability of TNTs, Zazpe et al. utilized
atomic layer deposition (ALD) to deposit thin alumina (Al2O3) films of varied thick-
ness on TNTs (Zazpe et al., 2017). The modified TNTs survived high-temperature
annealing (870 °C), showing that alumina coating imparts thermal stability. Next,
nanoindentation measurements confirmed significantly enhanced hardness as com-
pared to bare TNTs. Further, exceptional chemical stability of modified TNTs was
confirmed upon exposure to concentrated H3PO4 solutions.
The annealing of amorphous TNTs has also been used as a strategy to improve
mechanical characteristics (Munirathinam & Neelakantan, 2016). For instance,
Chang et al. reported that Young’s modulus increased with annealing temperature
for TNTs (Chang et al., 2011).
Xiong et al. investigated the interfacial chemistry and adhesion between TNTs
and Ti substrates and reported that the adhesion (evaluated by the Rockwell C
indentation test) improved with the extension of annealing time (Xiong et al., 2011).
The presence of additional Ti-O bonds in the TNTs-Ti interface post-annealing
resulted in improved adhesion of TNTs.
In an interesting study, Shokuhfar et al. reported the use of an integrated trans-
mission electron microscope (TEM) and atomic force microscope (AFM) for direct
measurements of the compressive mechanical characteristics of individual TNTs
(Shokuhfar et al., 2009). Upon applying compressive loading to annealed (450 °C
3 h) individual TNTs, it was found that the Young’s modulus (range 23–44 GPa)
depended on the TNTs diameter and wall thickness. Wang et al. fabricated micro-
patterned TNTs via anodization of laser micro-machined Ti and reported that laser
treatment augmented the adhesive strength of TNTs to Ti substrate during an exter-
nal solvent attack attributed to the expanded interfacial area (Wang et al., 2009).
Deposition of secondary material on anodic film can also serve the purpose of
shielding against mechanical challenges and hence improving implant performance.
For example, bioactive hydroxyapatite was coated onto TNTs to augment the bond
strength, and further annealing improved the strength attributed to hydroxyapatite
crystallization and diffusion of Ca and Ti ions into the TNTs/Ti interface (Kar et al.,
2006). While these strategies augment the mechanical characteristics of TNTs, the
additional coatings on TNTs can influence both cell bioactivity and drug loading/
releasing ability, requiring further investigation.
2.3 Chemical Treatments
The incorporation of particular chemical species inside TNTs can alter their
mechanical characteristics. For instance, carbon incorporation inside TNTs can act
as a crystal phase transition inhibitor (Enache et al., 2006), and this has been utilized
to improve mechanical characteristics of carbo-thermally (acetylene treatment)
treated TNTs (Schmidt-Stein et al., 2010). Briefly, as-fabricated TNTs were con-
verted into semi-metallic oxycarbides and TiC and the increased number of carbide
species augmented the stability of TNTs. To test stability, bare and carbonized TNTs
were bent at 180°, and bare TNTs showed cracks and delamination, whereas modi-
fied TNTs showed only a few cracks (Fig. 5). The carbon treatment enhanced the
tensile strength, friction behavior and hardness of the TNTs. Further, the hardness
of carbonized TNTs increased with temperature in the presence of acetylene, from
0.5 GPa (300 °C) to 2.5GPa (800 °C). It is noteworthy that TiC and its sub-oxides
are biocompatible; hence, this mechanical enhancement of TNTs should not impact
their bioactivity performance (Van Raay et al., 1995).
Fig. 5 Augmented
stability of TNTs upon
carbon-thermal treatment.
Top-view and cross-
sectional SEM images
showing (a) as-fabricated
TNTs; (b) TNTs
carbonized at 900 °C in
acetylene/N2 atmosphere.
(c) Photos of bent TNTs
showing anodic film
cracking on untreated
TNTs. (Adapted with
permission from Schmidt-
Stein et al. (2010))
In an interesting study, adding specific chemicals in the anodization electrolyte

yielded TNTs with enhanced adhesion strength. Zhang et al. added magnesium
acetate into the electrolyte to enable sedimentation of F ions in the ultra-thin F-rich
layer at the TNTs/Ti interface (Zhang et al., 2015). The modified anodization
yielded TNTs that were shown to have an F-free amorphous TiO2 layer at the TiO2/
Ti interface. The study also reported that variation in magnesium acetate concentra-
tion and sedimentation voltage/time influences the adhesion strength between TiO2
(TNTs) and Ti. In summary, the investigation presented an optimized protocol to
fabricate robust TNTs: normal anodization using ethylene glycol electrolyte (with
2% H2O + 0.08 M NH4F) at 60 V 60 m, and the second anodization by adding
0.06 M Mg2+ in the same electrolyte at 80 V 70 m.
3 Testing Mechanical Stability of Anodized Dental Implants
Various mechanical characteristics (modulus of elasticity, hardness and fracture

strength) of anodic films on Ti proposed as implant modification are critical consid-
erations to ensure long-term success in load-bearing dental implants. Survival of
anodized implant modification throughout the lifetime of a dental implant, from
sterilization, packaging, and placement to functioning for many years, represents
clinical translation challenges and remains poorly researched. It is also noteworthy
that the consistent presence of corrosive agents, pathogens and pH variation can
also compromise implant surface stability in the oral cavity. Mechanical stability
via the absence of any cracks or delamination is often confirmed visually via SEM
imaging, which may be inappropriate and only shows that the fabrication was suc-
cessful. Alternatively, testing via implant retrieval from the bone in vivo or ex vivo,
and nanoindentation, scratch tests, tensile tests and Vickers hardness are also uti-
lized to gauge the mechanical robustness of anodized implants (Li et al., 2018b).
3.1 Electrochemical Stability in Saliva
The formation of a native oxide film on Ti renders it corrosion-resistant, which is

one of the key reasons for its suitability as a dental implant material choice. Several
conditions in the oral cavity, including mechanical loading friction (fretting), pH
changes (crevice formation), cracking, galvanization, and oral pathogens, can result
in damage to the protective oxide, thereby exposing underlying Ti to corrosive
agents (Prasad et al., 2015). Besides, using toothpaste, mouthwash, and acidic
foods/drinks causes variation in F concentrations and pH and hydrogen embrittle-
ment, which the implant must withstand (Kaneko et al., 2003). The anodic film must
be stable against such mechanical and electrochemical stresses for anodised
implants with oxide nanostructures. Any mechanical failure in the anodic film can
leach out nano-scale debris that can cause immuno-toxic reactions locally and upon
ingestion systemically (Gulati et al., 2021a; Vasconcelos et al., 2016).
To ensure that the anodized implants survive the complex oral micro-environment,
several investigations tested the mechanical performance of modified implants in
artificial saliva (Alves et al., 2017, 2018; Demetrescu et al., 2010). In 2010,
Demetrescu et al. investigated the electrochemical stability of 120 nm diameter
TNTs and, via electrochemical testing, reported that structures were stable in artifi-
cial saliva (Demetrescu et al., 2010).
Comparing native oxide film on conventional implants with anodized implants in
Fusayama artificial saliva, Man et al. reported that TNTs were more stable (Man
et al., 2008). Next, Liu et al. tested various diameters of TNTs in artificial saliva and
reported that 22–59 nm diameter TNTs showed enhanced stability, whereas for
TNTs with a diameter >60 nm, reduced stability was observed (Liu et al., 2011).
Further attempts at augmenting corrosion/electrochemical stability involve the
treatment of TNTs via thermal oxidation (Grotberg et al., 2016) and Ca/P/Zn bio-
functionalization using reverse polarization (Alves et al., 2018). For biofunctional-
ized TNTs, the segmented tribo-electrochemical resistance was attributed to forming
a thin oxide film at the interface between TNTs and Ti and forming a P-rich tribo-
film (Alves et al., 2018). Chapter 8 focuses on understanding and augmenting the
corrosion and electrochemical stability of modified and nano-engineered Ti dental
implants.
3.2 Stability During Sterilization
Effective cleaning and sterilization post-fabrication are essential steps for implants
and their surface modifications. Interestingly, for anodized Ti-based dental implants
with TNTs or TNPs, only a few studies have explored and optimized this aspect.
Zhao et al. reported, for the first time, the influence of varied sterilization tech-
niques, including autoclaving, UV irradiation and ethanol treatment, on the bioac-
tivity of TNTs (Zhao et al., 2010). The study reported that UV irradiation was the
most favorable sterilization option attributed to observing higher proliferation and
mineralization of osteoblasts in vitro and effective removal of organic impurities on
UV-treated TNTs. Further investigations evaluated wet autoclaving (TNTs in water)
and dried autoclaving (TNTs sealed, no water) and found that dry autoclaving was
favorable towards osteoblast proliferation in vitro (Oh et al., 2011). Next, compar-
ing various sterilizations, Kummer et al. reported that UV and ethanol treatment
reduced bacterial growth while autoclaving enhanced the bacteria on TNTs
(Kummer et al., 2013). While the abovementioned studies investigated the influence
of various sterilization methods on TNTs bioactivity, the mechanical stability of the
sterilized TNTs was not examined.
Junkar et al. performed mechanical testing during sterilization and reported that
among autoclaving, UV, H2O2 plasma and O2 plasma, autoclaving was unsuitable as
it caused delamination and mechanical failure of the TNTs anodic film (especially
Fig. 6 Autoclaving of TNTs damages the nanostructures and alters surface morphology. AFM
images of 100 nm TNTs sterilized using (a) autoclaving, (b) UV irradiation, and (c) plasma treat-
ment. (Adapted with permission from Junkar et al. (2016))
for large diameter TNTs, confirmed via SEM and AFM imaging) (Junkar et al.,
2016). The damage to TNTs during autoclaving is a combined influence of moisture
and high temperature/pressure, which induced TNTs crystallization and changed
the surface morphology of TNTs. Figure 6 presents the AFM images of the various
sterilized TNTs and clearly shows that autoclaving resulted in TNTs destruction and
change in surface morphology.
To perform disinfection of TNTs, Beltrán-Partida et al. used superoxide water
(SOW with H2O2 and oxidizing radicals) to clean TNTs, which resulted in signifi-
cantly enhanced osteoblast (pig periosteal osteoblasts) functions while reducing
bacterial viability (Staphylococcus aureus) in vitro on cleaned TNTs (Beltrán-
Partida et al., 2016). In another study, Radtke et al. reported that the structure and
morphology of TNTs (amorphous, fabricated at low voltages) were not influenced
by autoclaving (Radtke et al., 2019). The authors also found that TNTs fabricated at
higher voltages must have absorbed water adequately removed prior to autoclaving
to prevent structural damage. More recently, Guo et al. thoroughly investigated the
influence of various sterilization techniques on topography, chemistry, bioactivity
and stability of the titania nanopores (TNPs) (Guo et al., 2021d). Briefly, using
appropriately aged electrolyte, micro-rough Ti substrates were anodized to fabricate
anisotropic TNPs, followed by sterilization using autoclaving (wet and dry), ethanol
immersion, gamma irradiation and UV irradiation (various times). The findings
revealed that autoclaving compromised the mechanical stability of the anodic film.
Among other techniques, UV irradiation (irrespective of the time of exposure)
resulted in favorable hydrophilicity, protein adhesion capacity and proliferation of
gingival fibroblasts in vitro. Next, nanoindentation testing revealed that ethanol
immersion reduced the TNP elasticity, while UV and gamma irradiation showed
similar modulus and hardness values as the non-sterilized TNPs.
4 Testing Stability Post-implantation
Ti substrates and implants modified with TNTs and TNPs have been inserted in
bones ex vivo and in vivo to observe integration, therapy and mechanical stability.
While most attempts have been made on bones, they lack the use of a masticatory
simulator to mimic an oral cavity.
Ex Vivo Implantation
4.1
As discussed previously, the oral cavity represents a complex environment, and the
implant micro-environment is further challenged with implantation surgery. Ex vivo
models allow for mock clinical surgery and can be used to investigate if the implant
can survive the handling and surgical placement. To assess the mechanical stability
of bare and silver nanoparticles (Ag NPs) modified TNTs on Ti rods, Shivaram et al.
implanted the TNTs into equine cadaver bone ex vivo (Shivaram et al., 2016).
Briefly, the implant placement involved drilling holes and hammered insertion, and
the implants were retrieved after 14 days and analyzed using SEM. Both bare and
Ag-TNTs showed no visible damage or delamination, and the implantation did not
impact the release profile of therapeutic Ag NPs.
To ease bone ex vivo maintenance and manipulation for complex experimental
conditions, three-dimensional (3D) bone reactor-Zetos™ was used to investigate
the therapeutic release and stability of TNTs modified Ti wires (Aw et al., 2012).
The Zetos™ system maintains the bone viable for up to 3 weeks ex vivo via continu-
ous media perfusion and can also exert load cycles to evaluate mechanical charac-
teristics of the bone/implants (David et al., 2008). Rahman et al. inserted rhodamine
B dye-loaded TNTs/Ti wires into bovine trabecular bone cores (three types: marrow
removed; marrow intact: coagulated; and marrow intact: coagulation prevented via
heparin) ex vivo using Zetos™ system (Rahman et al., 2016). Upon retrieval of the
TNTs/Ti wire implants after 11 days, the implants were analyzed via SEM, and the
data confirmed that the TNTs retained their structures without any visible deforma-
tion or delamination.
It is known that anodization of curved substrates like wires, abutments or
implants can result in surface cracks, which are a result of substrate curvature and
roughness, internal and mechanical stresses in the anodic film, weak spots and col-
lapse of nanotubes (Chopra et al., 2021a; Gulati et al., 2015). At the same time,
these cracks may be reduced by tuning anodization voltage/time, water content and
electrolyte aging, the cracking of anodic film on curved substrates must be tested for
mechanical stability. To achieve this, TNTs on Ti wires with micro-scale cracks
were inserted into bovine trabecular bone cores ex vivo using Zetos™ for 5 days,
followed by retrieval and surface morphology analysis via SEM that confirmed the
stability of the TNTs (Gulati et al., 2016a). Additionally, ex vivo 3D cell culture
models have also been used to investigate bioactivity and local drug release
functions of drug/protein loaded TNTs (with micro-cracks on anodic film) on Ti

wires, and the examination of TNTs confirmed that their surface integrity was main-
tained (Gulati et al., 2016a; Kaur et al., 2016).
In Vivo Implantation
4.2
In one of the pioneering attempts relating to in vivo placement of TNTs, von

Wilmowsky et al. inserted TNTs on Ti rods into the front skull of domestic pigs in
vivo for up to 90 days and found that retrieved implants had intact TNTs (von
Wilmowsky et al., 2009). Next, Bjursten et al. performed the pull-out testing of
heat-treated TNTs on Ti implants via placement in rabbit tibia in vivo (Bjursten
et al., 2010). The findings confirmed that a fracture force of up to 10.8 N was insuf-
ficient to compromise adhesion strength between TNTs and Ti. Advancing the
domain and testing the anodized Ti implants in vivo, Choi et al. implanted bare and
anodized orthodontic miniscrews in the mandible of beagle dogs in vivo for
12 weeks (Choi et al., 2012). Upon retrieval, SEM confirmed that the thread edge
(close to tip) of the anodized screw was smoothened via smearing, and the thread
edge (close to the top) of the machined implant became rough, as compared to the
unused respective implants. This observation was attributed to the stress concentra-
tion in the tip area that made it prone to mechanical damage. Next, AFM measure-
ments of the implants were performed, and the roughness of the anodized screws
was significantly reduced compared to the unused anodized screws. It is noteworthy
that while the roughness of the anodized screw was reduced due to the implantation
procedure, their values were higher compared to non-anodized bare screws. Overall,
the damage to the anodic film was attributed to the insertion shearing force or orth-
odontic tension, which are important parameters to consider while placing anodized
nano-engineered implants.
Although not directly applicable to a dental implant setting, the mechanical sta-
bility of TNTs modified Ti wires have also been confirmed in a mice tumour model
in vivo (Kaur et al., 2016). Briefly, anti-cancer drug-loaded TNTs were implanted
into mice tumour sites and retrieved after 6 days, and SEM imaging confirmed the
stability of the structures. The abovementioned ex vivo and in vivo studies demon-
strate that TNTs are a favorable bioactive and therapeutic modification for implant-
able applications and maintain their structural integrity while implanted; however,
more dental implant-focused in vivo investigations are needed, specially under
mechanical loading conditions.
5 Future Directions and Conclusions
Optimizing electrochemical anodization (EA) has enabled the fabrication of con-

trolled and stable nanostructures, including nanotubes and nanopores on dental
implants, to achieve superior bioactivity and mechanical stability. Various
investigations have evaluated the mechanical characteristics of nano-engineered

implants in corrosive environments, sterilization techniques and ex vivo and in vivo
implantations. The stability of nano-engineered titanium dental implants is crucial
to ensure ease of clinical translation; however, various research gap remains unad-
dressed, as described below:
Dimensions vs Stability
The mechanical investigations on anodized implants often reveal that nanotube
dimensions dictate stability. For physically/chemically enhanced nanotubes, dimen-
sions decide the mechanical performance and need for further modification. At the
same time, it is well established that wettability, protein adhesion capacity, cell
adhesion/proliferation, drug loading capacity and drug release kinetics are all influ-
enced by nanotube dimensions. This means one or more functions must be sacri-
ficed to accommodate appropriate mechanical performance. For example, very high
drug loading amounts and prolonged release require longer and wider tubes/pores,
which may not be as robust as a thin anodic film with smaller/shorter tubes.
Cytotoxicity
While titania nanoparticle cytotoxicity has been investigated, the findings cannot be
adequately translated for anodized implants with nanotubes and nanopores. This is
because anodic film is attached to the underlying substrate (implant), and if any
mechanical failure happens, the anodic film may break in the form of aggregations
of nanotubes or loose nanotubes. These will behave significantly differently com-
pared to nanoparticles’ geometry and size. Further, the anodic film contains organic
electrolyte and fluoride ions, and only limited studies have explored its complete
removal. Hence, a thorough cytotoxic evaluation of nanotubular or nanoporous
implants is needed.
Stability Enhancements Alters Topography
Various physical (crystallization, deposition of secondary material and heat-
treatment) and chemical (carbonization and F sedimentation) strategies have shown
promising outcomes towards achieving augmented mechanical performance of
anodized Ti with TNTs or TNPs. However, such modifications can change surface
chemistry, topography or the dimensions of the nanostructures. These alterations
can further influence implant bioactivity and the ability to load and release
therapeutics.
Long-Term In Vivo Testing
Anodization performed on clinical implants has been placed inside bones ex vivo,
and in vivo. However, these investigations only partially achieve the dental implant-
relevant physiological conditions. For instance, long-term in vivo investigations in
the oral cavity with mechanical loading is needed to ensure the implant experiences
physiological conditions with appropriate mechanics, chemical/saliva environment
and possible implant placement trauma. Such investigations must be carried out for
months to ensure the anodic film survives the implantation.
Acknowledgements Divya Chopra is supported by a UQ Graduate School Scholarship (UQGSS)

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Cytotoxicity, Corrosion
and Electrochemical Stability of Titanium
Dental Implants
Tianqi Guo, Jean-Claude Scimeca, Sašo Ivanovski, Elise Verron,

and Karan Gulati
Abbreviations
ASTM American Society for Testing and Materials

BL Barrier layer
BMSCs Bone marrow mesenchymal stem cells
COF Coefficient of friction
EA Electrochemical anodisation
EDXS Energy dispersive X-ray spectroscopy
EIS Electrochemical impedance spectroscopy
FBGC Foreign body giant cell
GNPs Graphene nanoplatelets
HA Hydroxyapatite
ICPMS Inductively coupled plasma mass spectroscopy
MAO Micro-arc oxidisation
NPs Nanoparticles
OCP Open circuit potential
PIII Plasma immersion ion implantation
PVD Physical vapour deposition
PVP Polyvinylpyrrolidone
ROS Reactive oxygen species
T. Guo · S. Ivanovski (*) · K. Gulati (*)

e-mail: s.ivanovski@uq.edu.au; k.gulati@uq.edu.au
J.-C. Scimeca
Université Côte d’Azur, CNRS, Inserm, iBV, Nice, France
E. Verron (*)
Nantes Université, CNRS, CEISAM, UMR 6230, 44000, Nantes, France
e-mail: elise.verron@univ-nantes.fr
https://doi.org/10.1007/978-3-031-21565-0_8
220 T. Guo et al.
SBF Simulated body fluids

SLA Sandblasted and acid-etched
SLM Selective laser melting
SMAT Surface mechanical attrition treatment
TiN Titanium nitride
TNPs Titania nanopores
TNTs Titania nanotubes
UMCA Ultrasonic mechanical coating and armouring
1 Corrosion of Ti Implants
According to the American Society for Testing and Materials (ASTM), five grades
of Ti are used for implant biomaterials. Grades I–IV differ according to the purity
grade, and the amount of various interstitial elements (carbon, oxygen, nitrogen,
hydrogen, and iron), while Grade V refers to the Ti alloy Ti-6Al-4V, the most com-
monly used in the medical implant industry. Regardless of the grade, Ti dental
implants have been widely used due to their favorable biocompatibility and mechan-
ical properties such as high fatigue strength (140–1160 MPa) and fracture tough-
ness (Guo et al., 2021a). It is estimated that around 5 million implants are placed in
the USA per year, and 15–20 million worldwide (Pettersson et al., 2019). Despite
this huge success, increasing reports of implant instability related to peri-implantitis,
a multifactorial disease caused by several factors impacting implant/bone tissue
interactions, is a growing concern (Guo et al., 2021b).
Dental implant surface characteristics, its composition and mechanical proper-
ties and especially the Ti oxide layer, are critical for osteointegration. A variety of
nanomaterials (NM) can be used for the surface treatment of Ti-based dental
implants (Zhang et al., 2021). For example, NM of titanium nitride (TiN) has
been shown to improve the chemical and wear resistance of Ti implants (Xuereb
et al., 2015). Unfortunately, changes in chemical and topographic structures occur
over time in response to mechanical stimuli and oral cavity environment, leading
to the release of particles and ions from the coating layer or from the implant
itself. All these changes, mostly irreversible, dramatically compromise implant
osteointegration.
1.1 Reasons for Ti Implant Degradation
Identifying the underlying mechanisms governing implant alterations could help (i)
engineers to improve the design of implants, and (ii) clinicians to adapt their prac-
tices for optimizing long-term survival of implants. To this end, Romanos et al. have
analyzed the processes leading to the release and distribution of Ti particles and ions
Cytotoxicity, Corrosion and Electrochemical Stability of Titanium Dental Implants 221
within peri-implant hard and soft tissues (Romanos et al., 2021). They have high-
lighted that implant wear mechanisms occur at different stages including implant
bed preparation, insertion step, and implant decontamination/maintenance.
1.1.1 Mechanical Corrosion
Mechanical corrosion first appears during the implant bed preparation, which
requires bone-cutting instruments that cause the release of Ti particles due to metal
attrition, wear, and corrosion. Indeed, Ti particles and ions have been observed in
irrigation liquid collected from the implant bed preparation by piezosurgery or drill
procedures (Rashad et al., 2013). In fact, drills induce abrasive wear, coating dam-
age and blunting (especially at the tip and flanks), and plastic deformation of the
cutting point (Mishra & Chowdhary, 2014). In addition, substance loss and the con-
densation of particles detached from the tool is correlated to the number of drills
used, suggesting that single-use drill may be an optimum choice. Moreover, steril-
ization of the cutting tools can generate particles by initiating corrosion (Allsobrook
et al., 2011). Consequently, the number of sterilization procedures should be con-
trolled, although there is no consensus on this point.
During the insertion procedure, friction between the implant and bone tissue
generate Ti particles of various size concomitantly with implant insertion in the
mandible and maxilla, as observed by Romanos et al. in periprosthetic tissues
(Romanos et al., 2014). Abundant irrigation may prevent this accumulation of rem-
nant particles within the surgery site.
Implant-abutment fit strongly impacts on implant longevity, and as described by
Stimmelmayr et al. (2012), material characteristics influence wear of the implant-
abutment connection. Indeed, the association of an implant with an abutment gener-
ates the release of particles. These particles can remain inside the connection area,
resulting in frictional wear, or can migrate to adjacent tissues and contribute to a
foreign body reaction (Delgado-Ruiz & Romanos, 2018). The gap (i.e., the mis-
match) between abutment and implant can grow in the presence of micromotion
resulting from functional loading. During mastication, a larger gap favors micro-
movements and fretting at the interface which amplifies implant destabilization in a
vicious cycle (Schwarz, 2000). Moreover, high loading forces observed during oste-
otomy and manual bone condensation promote microcracks and particles release at
the implant-bone interface (Romanos, 2015). Regardless of their origin, micro-
movement of the abutment is deleterious through inducing Ti particles release and
further metal corrosion (i.e. fretting). Notably, the gap can be colonized by microor-
ganisms, glycoproteins, and fluids that can easily accumulate and form a stable
biofilm responsible for implants microbiological corrosion (Apaza-Bedoya et al.,
2017), although, as compared to butt-joint implant-abutment connections, conical
implant-abutment connections have been shown to minimize the micro gap at the
connection, and to reduce bacterial accumulation (Zipprich et al., 2018).
222 T. Guo et al.
1.1.2 Chemical and Electrochemical Degradations
In addition to production of metal particles through mechanical degradation, the

implant surface can undergo chemical and electrochemical degradations resulting in
the release of soluble ions. A stable Ti oxide layer (1.5–10 nm thickness) due to the
high affinity of Ti for oxygen is spontaneously formed at the surface of implant.
This thin film provides sufficient protection of the bulk material from corrosion
(i.e., electrochemical phenomenon) and the formation of reactive oxygen species
(ROS) (Abey et al., 2014). Although this film can be reformed through a re-
passivation phenomena, it is exposed to functional stimuli (i.e., micromotions,
micromovement of the implant-abutment interface) and various environmental con-
ditions such as acidic pH and electrolytes that can degrade this protective layer over
time and expose the bulk material to the oral environment (Delgado-Ruiz &
Romanos, 2018). A wet corrosion of dental implants is predominantly observed
given that oral cavity is a humid environment. Depending on its composition, pH,
buffering capacity and surface tension, saliva can play the role of an electrolyte and
contribute to the dissolution of the oxide layer. In addition, acidic metabolites (citric
acid and lactic acid) are produced by biofilm microorganisms such as Streptococcus
mutans and Candida albicans (Noronha Oliveira et al., 2018). The resulting low pH
can block the re-passivation phenomena and favor corrosion of the thin oxide layer
and implant instability/failure (Siddiqui et al., 2019; Souza et al., 2015). Moreover,
very low levels (or absence) of oxygen below the gingival margin around dental
implants stimulate the proliferation of anaerobic microbes (Porphyromonas gingi-
valis, Actinomyces) generating lactic acid (Noronha Oliveira et al., 2018).
1.1.3 Tribocorrosion
Oral environment and mechanical constraints (loading or velocity) impact dental

implant integrity. Considering the different mechanisms involved in Ti implants
degradation, the term “tribocorrosion” has been defined as a combination of tribo-
logical (i.e., wear and fretting) and corrosive (i.e., chemical or electrochemical reac-
tions) phenomena (Apaza-Bedoya et al., 2017; Revathi et al., 2017). Among
different types of corrosion characterized by Noumbissi et al., crevice, galvanic and
pitting corrosions are mostly observed in patients (Noumbissi et al., 2019) (see
Table 1).
Implant maintenance (cleaning, disinfection) constitutes a risk of tribocorrosion.
Despite this risk, these procedures are essential to prevent the formation of biofilm
involved in the pathogenesis of dental caries, gingivitis and peri-implantitis. Saliva
contains multiple proteins and electrolytes that can adsorb onto the implant surface.
The resulting organic layer favors adhesion of cells and bacteria through specific
membrane protein- or glucan-binding sites (Busscher et al., 2010; Song et al., 2015).
These interactions are also influenced by implant surface characteristics such as
surface tension (Banas & Vickerman, 2003). Various bacteria populations progres-
sively accumulate and grow, and the composition and the thickness of the resulting
Table 1 The three main forms of corrosion observed in patients with dental implants
Crevice Corrosion – Occurs within constricted spaces where there is no exchange of oxygen
(e.g., at the implant-abutment interface) and is favored by an acidic environment due to chloride
ion concentration increase.
Galvanic Corrosion – Takes place when dissimilar alloys are in direct contact within the oral
cavity. In such cases, the implant plays the role of an anode, and metal ions are released because
of the resulting galvanic activity (i.e., ion exchange between implant and its prosthetic
components).
Pitting Corrosion – A localized form of corrosion arising on openly exposed metal surfaces in
the absence of any apparent crevices. This occurs usually along with fluoride based solutions
used during dental procedures and daily care.
biofilm can evolve in response to the continuous introduction and removal of micro-
organisms and nutrients within the oral cavity (Chin et al., 2006). In addition, hard
structures such as teeth and implants provide non-shedding surfaces favorable to the
formation of a stable biofilm, whereas soft tissues (including oral epithelia) com-
promise this stability due to rapid tissue turnover (Sanz-Martín et al., 2018).
Excessive accumulation of bacteria produces favorable conditions for the develop-
ment of dental caries, gingivitis and peri-implantitis. Hence, to prevent these delete-
rious events and despite the risk of damage, decontamination of the implant surface
is required. While no consensus has been reached in terms of the method, soft pro-
cedures are strongly recommended (Khan & Sharma, 2020; Sato et al., 2021;
Schwarz et al., 2011). Delgado-Ruiz and Romanos extensively analyzed the causes
of particle and ion release during the maintenance phase (Delgado-Ruiz & Romanos,
2018). Among the different procedures, they mentioned that chemical decontamina-
tion methods can damage the Ti layer and induce corrosion because of the pH. This
release can be amplified by friction leaving the bulk surface of implant exposed.
Minimal degradations have been observed with saline, chlorhexidine, hydrogen per-
oxide and citric acid, while there is no information regarding the impact of tetracy-
cline and doxycycline use (Noronha Oliveira et al., 2018; Souza et al., 2019).
Mechanical methods using lasers can be used in combination with chemical meth-
ods to improve the efficiency of decontamination. However, surface alterations fol-
lowing laser treatment have been reported, depending on the delivered energy, the
irradiation duration, and surface characteristics of the treated area (i.e., roughness)
(Vayssette et al., 2018). Upon irradiation, temperature increase at the irradiated spot
can induce surface modification. Thus, it is recommended to use pulsed modes to
reduce the intensity/duration of irradiations, and to cool the area using devices
implementing air-water flux delivery with proper ratios (Giannelli et al., 2015).
1.2 Factors Influencing Ti Corrosion/Degradation
As described above, tribocorrosion can result in release of metal particles and ions
results. The amount of released Ti is dependent on many factors, including the type
of implant. Joseph et al. (2009) evaluated the tribocorrosion of Ti implants in
224 T. Guo et al.
simulated biological fluids in vitro, and showed the rate was 23 to 448 μg/L/week
for commercially pure Ti. The release rate of soluble Ti from Ti6Al7Nb alloy was
lower and ranged from 17 to 50 μg/L/week. These amounts seem to be relatively
small, but considering that implants are present for many years, Ti can gradually
accumulate in the body (Golasik et al., 2016).
Tribocorrosion depends also on the oral cavity environment, which it is known to
fluctuate in terms of pH, salt concentrations, oral flora, temperature, oxygen con-
tent, food, beverages, tobacco consumption, and toothpaste use. All conditions that
can lower the pH under 6 favor the corrosion process. These constant aggressions
lead to the degradation of the Ti oxide thin layer, and the removal of metallic debris
and ions from the surface (Mouhyi et al., 2012; Peixoto & Almas, 2016).
Most toothpastes or gels contain fluoride at concentrations 0.1–2 wt% that can
induce the dissolution of the thin oxide layer (Perinetti et al., 2012; Schiff et al.,
2002). Addressing this issue, Kaneko et al. characterized compounds formed at the
implant surface and documented the presence of Ti fluoride, Ti oxide fluoride and
sodium Ti fluoride (Kaneko et al., 2003). By replacing the original Ti oxide layer,
these Ti/fluoride compounds form a more soluble layer which undergoes chemical
events leading to accelerated dissolution.
Lastly, inflammatory episodes occurring within surrounding tissues can also
alter the corrosion resistance of implants. Notably, the presence of bacteria-derived
lipopolysaccharides (LPS) exacerbates peri-implant tissues inflammation (Yu
et al., 2015).
1.3 Importance of Augmenting Anti-corrosion Capacity of Ti

Implants (Cytotoxicity Concerns)
1.3.1 Molecular Interactions
As previously mentioned, Ti displays a high reactivity when exposed to oxygen.

After conversion into Ti dioxide/titania (TiO2), the resulting layer may interact and
bind calcium, hydroxyapatite and organic compounds including serum proteins.
This binding process leads to the formation of a dynamic protein corona, and its
composition depends not only on the environment at a given time (i.e., nature and
concentration of proteins present in the environment) but also on material character-
istics (shape, structure, size) (Gulati et al., 2021). The presence of the corona enables
the cellular internalization of TiO2 particles through a “Trojan horse”-like mecha-
nism. Once inside the cytoplasm, particles can interact with various proteins, lipids
and genetic materials. These interactions may alter cell homeostasis, create intracel-
lular lesions and result in toxic effects (Mano et al., 2013; Ribeiro et al., 2016).
Particles may be exposed to an acidic environment mediated by endosomes (pH
6.0) or lysosomes (pH 4.5), thus generating free metal ions. These metal ions can
potentially affect cellular homeostasis and functions by influencing gene/protein

expression (Sabella et al., 2014). Moreover, by disrupting electron transport in the
mitochondria inner membrane, they may interfere with energy production and gen-
erate endogenous ROS. Low levels of ROS can activate transcription factors, lead-
ing to enhanced expression of inflammation-associated genes. Furthermore, a high
and sustained production of ROS that are not detoxified by endogenous antioxidant
defenses affects cellular membranes (lipid peroxidation, structural proteins altera-
tions) as well as enzymes, ion pumps, or nuclear DNA (Bressan et al., 2019).
Ti (ions, NPs, oxide) and ROS may diffuse via nuclear pores and translocate into
the nucleus. TiO2 can act as a DNA intercalator and generate severe DNA damage
(Pogribna et al., 2020). Additionally, interactions between nano-scale Ti particles
and plasmatic/cellular proteins affect protein structure and/or functions. Interactions
with the cytoskeleton may also induce conformational changes in tubulin and dis-
rupt its polymerization, as shown with TiO2 NPs that considerably alter intracellular
transport, cell division and cell migration (Hou et al., 2019).
1.3.2 Cellular Interactions
Immune Cells
Ti particles generate a pro-inflammatory response via interaction with immune cells

(e.g., macrophages and T lymphocytes) and stimulating the release of multiple
inflammatory cytokines such as IL-1β, IL-6, TNF-α and prostaglandins (Noronha
Oliveira et al., 2018). Among the interactions with inflammatory cytokines, TiO2-NP
seems to preferentially adsorb CXCL8 and INF-α, thus resulting in the disruption of
neutrophil chemotaxis. This adsorption impacts local concentration of inflamma-
tory mediators that can hamper physiological inflammatory responses (Batt
et al., 2018).
Pettersson et al. also described a pro-inflammatory response in macrophages
(Pettersson et al., 2017). Nevertheless, they demonstrated that Ti particles alone
displayed a limited impact on cytokines secretion, strongly increased only in the
presence of bacteria. This suggests that Ti particles act as a secondary stimulus
enhancing the production by macrophages of cytokines such as IL-1β.
As expected, the presence of Ti nanoparticles (NPs) exacerbates this feature as
compared to Ti microparticles (MPs). Indeed, compared to MPs, NPs offer a greater
potential of reactivity and interaction with various biological macromolecules and
cells (Gulati et al., 2021). However, it is worthwhile to note that NPs can agglomer-
ate and increase their size, thus lowering their reactive surface area. Accordingly,
NPs agglomeration may reduce the severity of the NP toxic effect, as explored by
Bruno et al. (2014).
226 T. Guo et al.
Bone Cells
Osteointegration of implants is crucial and strongly dependent on the activity of

osteoblasts and bone marrow mesenchymal stem cells (BMSCs) (Takeda et al.,
2012). Unfortunately, Ti particles can disturb the cytoskeleton of BMSCs, thus
affecting their migration and differentiation capabilities. These particles can also
display cytotoxicity toward BMSCs (Meng et al., 2009), and change in osteoblastic
viability has been demonstrated at high concentration of Ti particles (0.15–1%)
(Pioletti et al., 1999). Similarly, Mine et al. demonstrated that the viability of murine
osteoblastic cells (MC3T3-E1) was lowered by high Ti concentrations (e.g.
20 mg/L), while concentrations in the range of 1–9 mg/L were ineffective in altering
cell viability (Mine et al., 2010).
Saldaña et al. reported that osteoblast proliferation was reduced by more than
50% when cells were exposed to 48 mg/L of Ti during 3 days, or to 24 mg/L of Ti
for 7 days (Saldaña et al., 2006). Further, the metabolic activity of osteoblasts was
reduced by 20% for a 7 day exposure to 24 mg/L of Ti, and to very low levels when
a 48 mg/L concentration was used.
Other studies have shown that Ti in the form of powder is cytotoxic towards
human osteoblast-like cells (SAOS-2) in a time and dose-dependent manner (at con-
centrations above 15.5 μg/L), while Ti in bulk form (disc made from metal powder)
displayed no cytotoxicity (Li et al., 2010). Viability of MC3T3 cell line was less
than 10% after 5–7 days incubation with Ti particles (5 and 10 g/L), with caspase-3
activity and apoptosis increased after 48 h of incubation with Ti particles at 2.5 g/L
(Qiu et al., 2015).
Ti particles can inhibit osteoblastic cell viability through the stimulation of
excessive interleukin secretion (Il-6 and Il-8) by abnormally recruited neutrophils
(Chen et al., 2020; Happe et al., 2019; Schulze et al., 2013). Expression of osteo-
blastic proteins such as matrix metalloproteinase-2 (MMP-2), membrane type 1
MMP (MT1-MMP), and p38 protein is also upregulated in the presence of Ti par-
ticles (0.1 g/L). Consequently, Ti particles are involved in periprosthetic osteolysis
(Chen et al., 2014). Similarly, Ti particles inhibit the activity of periodontal liga-
ment cells, and the osteogenic differentiation of alveolar bone cells (Zhou
et al., 2021).
Regarding bone resorbing cells, Ti particles tend to enhance the differentiation
and resorption activity of osteoclasts by promoting the release of RANKL and pro-
inflammatory cytokines (Il-1 and TNFβ) by macrophages and lymphocytes (Wachi
et al., 2015). Osteoclasts are involved in the process of Ti surface corrosion, and a
subsequent accumulation of metal ions in their cytoplasm and nuclear heterochro-
matin has been observed. Cadosch et al. showed that in over 20% of 22 healthy
donors, monocytes differentiated into mature osteoclasts after 10 days’ exposure to
Ti at a concentration of 48 μg/L (Cadosch et al., 2010). They also demonstrated
increased expression of specific osteoclastic biomarkers such as cathepsin K and
TRAP in monocytes after 10 days incubation with Ti at 48 μg/L, a level measured
in blood and tissue from patients with loosened implants. A great concentration of
mature osteoclasts surrounding Ti implants leads to a large resorption area.
Consequently, the osteolysis generated around implants progressively contributes to

the aseptic loosening (Zhou et al., 2021), and is exacerbated by an alteration of
osteoblastic cell viability (Park et al., 2013).
Other Cells
Ti particles also interact with peri-implant tissues including gingival epithelium.

High concentrations of Ti (>13 ppm) can alter gingival epithelial cell viability, and
induce cell necrosis (Makihira et al., 2010). This damage can be amplified when Ti
particles surface contains phosphate-enriched TiO2 or fluoride-modified species
(Wei et al., 2005). Furthermore, low particle concentrations (0.001%) reduce the
proteolytic and collagenolytic activities of fibroblasts, while their proliferation
remains unaffected. By contrast, higher contents of particles are toxic for fibroblasts
in terms of both viability and proliferation (Kheder et al., 2021). These deleterious
effects impact the epithelial barrier integrity, which in turn favors bacterial coloni-
zation (Dini et al., 2020). It has been observed that Ti can stimulate the expression
of Toll-like receptor-4 by fibroblasts, and also that the sensitivity of these cells to
oral bacteria is modified (Wachi et al., 2015). With oral infection, Ti particles exac-
erbate the inflammatory response caused by oral biofilm (Berryman et al., 2020)
resulting in chronic inflammation of peri-implant tissues (Wilson Jr. et al., 2015).
In summary, inflammation of peri-implant tissues associated with an excessive
osteoclastic activity contribute strongly to implants loss, and oral infections worsen
this situation. As identified in chapter “Titanium Dental Implants in Compromised
Conditions: Need for Enhanced Bioactivity and Therapy”, several risk factors such
as smoking, premature loading and diabetes have been associated with weak osseo-
integration or excessive bone resorption (Berryman et al., 2020; Dini et al., 2020;
Ferreira et al., 2018; Lee et al., 2017; Mombelli et al., 2018; Stacchi et al., 2016;
Wilson Jr. et al., 2015).
1.3.3 Tissue Interactions
Dental implants are considered a source of Ti particles in both intra-oral and extra-
oral tissues. In fact, Ti particles have been observed in tissues surrounding Ti
implants such as the submucosal plaque, peri-implant soft tissues and bone, but also
in distant locations such as lymph nodes (Frisken et al., 2002). Various investiga-
tions have evaluated Ti levels in the peri-implant mucosa in patients with pure or
alloy Ti implants (Frisken et al., 2002; He et al., 2016; Mercan et al., 2013). In
comparison with samples collected from patients with stainless steel brackets and
tubes, Ti level in oral mucosa cells increased by a factor of 3 after a 30 days orth-
odontic treatment. Similarly, when compared with patients with healthy peri-
implant tissues, submucosal biofilm of implants with peri-implantitis displayed
high concentrations of dissolved Ti (He et al., 2016). Consequently, serious con-
cerns regarding the long term safety of Ti implants have been raised.
228 T. Guo et al.
Mercan et al. investigated Ti release from cover screws of endosteal implants to

adjacent gingival tissues (Mercan et al., 2013). A 1.4-fold increase in gingiva Ti
content was found after 3 months. It was also observed that metallic debris could
migrate throughout the different layers of peri-implant soft tissues, and then be
involved in inflammatory responses (Paknejad et al., 2015). Moreover, the inflam-
matory status was correlated with particle size.
Histological analysis of tissues adjacent to dental implants harvested from
patients (e.g., oral mucosa in contact with Ti implant, mucosa of overlying Ti cover
screws during submerged healing of 2-piece implants, gingiva) revealed peri-
implantitis lesions as well as mucosa displaying various grades of inflammation
(Mombelli et al., 2018). Ti particles have been detected in tissue, and a gradual
decrease in their density observed between connective tissue and epithelium
6 months-post Ti implant placement (Flatebø et al., 2006). Further, an inflammatory
infiltrate was evidenced within the connective tissue facing the cover screw, and it
was shown that the inflammatory infiltrate/fibroblast ratio decreased with time.
Based on energy dispersive X-ray spectroscopy (EDXS) and inductively coupled
plasma mass spectroscopy (ICPMS) analysis, Ti particles have been localized and
quantified in tissues surrounding dental implants in patients (Table 2). For example,
Ti particles phagocytosed by macrophages in soft tissue has been reported and tis-
sue inflammation intensity was generally correlated with the presence of the parti-
cles (Olmedo et al., 2013). Paknejad et al. noted that particles were not exclusively
observed close to tissues adjacent to Ti implants (Paknejad et al., 2015), and it
seemed that keratinocytes might transport particles to more superficial tissue layers.
Table 2 Distribution and quantification of Ti particles in tissues surrounding dental implants

in human
Type of the biopsy Distribution of
analyzed particles Quantification of Ti level Ref
Diseased implants Submucosal peri- 0.07 ± 0.2 ng/μL Safioti et al.
(N = 20) implant plaque (2017)
Control: healthy
implants (N = 20)
Diseased implants Peri-implant tissue – High concentrations (7.53 × 10 5 Fretwurst
(N = 12) mainly in soft tissue count) et al. (2016)
Control: ceramic
implants (N = 1)
Diseased implants Upper half of bone 1940 ± 469 μL/kg bone weight He et al.
(N = 7) crest Presence confirmed (but not (2016)
Control: healthy Bone marrow quantified)
jawbones without (60–700 nm from the
implants (N = 6) implant surface)
Diseased implants Peri-implant tissue 2–2.44 ppb Olmedo
(N = 15) Presence of particles (individual et al. (2013)
Control: healthy or clusters) in epithelial cells and
implants (N = 15) macrophages
Based on Suárez-López del Amo et al. (2018)
Due to the ability of TiO2 to bind biomacromolecules such as proteins, new anti-
genic determinants can be exposed and lead to hypersensitivity reactions in vulner-
able patients (Gulati et al., 2021). Various signs and symptoms of Ti allergy have
been described including swelling, redness, rash, vesicular lesions of the skin, and
facial eczema reactions (Fage et al., 2016). Fortunately, removing Ti implants
relieves these clinical symptoms, thus supporting the causal relationship between
tissue exposure to Ti and the incidence of these reactions. In addition to temporal
association, this causal relationship is strongly suggested in several cases by the
proximity between implants and oral lesions (Mombelli et al., 2018). For example,
one patient developed facial eczema following the placement of a Ti implant for a
mandibular overdenture (Egusa et al., 2008), and reactive lesions of the peri-implant
mucosa (i.e., pyogenic granuloma and peripheral giant cell granuloma) have been
observed (Olmedo et al., 2010). During a clinical study, a patient displayed a chronic
inflammatory response (with concomitant fibrosis around all implants) associated
with a foreign body giant cell (FBGC) reaction (du Preez et al., 2007). In addition,
persistent proliferation of the peri-implant soft tissue has been described after a
mandibular vestibuloplasty and the placement of a split-thickness skin graft
(Mitchell et al., 1990). In other cases, patch or blood tests performed in patients
with Ti implants evidenced an allergy/hypersensitivity to Ti (Müller & Valentine-
Thon, 2006; Sicilia et al., 2008).
To complete the analysis of hypersensitivity reactions to Ti, Mombelli et al. com-
pared alleged cases of Ti hypersensitivity in dental and non-dental implants, and
reported few differences (Mombelli et al., 2018). For example, all dental implants
were contaminated by bacteria during surgery, whereas it was not the case for
indwelling devices. Moreover, clinical symptoms in the non-dental field are not
restricted to tissues surrounding the implant. By contrast, clinical signs are pre-
dominantly observed in tissues in direct contact with dental implants. However,
given the few reported cases in the literature, there are still controversies around the
existence of Ti allergy/hypersensitivity in patients receiving Ti implants.
Finally, a “yellow nail syndrome” has been described in patients with Ti implants
(Kim et al., 2019). This syndrome results in a high content of Ti in the nails of
patients. It is characterized by a change in nails, postnasal drip, cough-associated
sinusitis, and bronchial obstruction (Berglund & Carlmark, 2011). Lymphedema
can also be associated in chronic pathologies. Pleural effusion was the most com-
mon lung change, and chronic sinusitis with an early onset was reported to occur.
Several studies have established a correlation between Ti and this yellow nail syn-
drome (Cheslock & Harrington, 2022; D’Alessandro et al., 2001; David-Vaudey
et al., 2004; Decker et al., 2015). Ti ions could be released by galvanic corrosion due
to electro-chemical coupling between Ti implants and gold elements present in the
teeth. Indeed, in few patients, disease symptoms disappeared after several months
when gold elements were removed. Pathogenesis is still under investigation.
230 T. Guo et al.
2 Physical Modification and Utilizing Ti Alloys
Chemical and corrosion resistance are important criteria for the success of Ti dental
implants, as they regularly interact with fluids having various pH and temperature.
Suboptimal corrosion resistance may leach Ti ions and cause toxicity, while the cor-
rosion can challenge mechanical stability. To augment the corrosion resistance of
Ti-based dental implants, as described below, physical modifications with altered
topography and alloying Ti have been explored.
2.1 SLA Implants and Corrosion
Sandblasting involves the collision of compressed air-driven alumina (Al2O3) or

titania (TiO2) particles on Ti implants, enabling the fabrication of micro-roughened
Ti implants and augmented osseointegration (Burnat et al., 2013; Jiang et al., 2006;
Li et al., 2001; Wang et al., 2017). Sandblasted implants possess varied corrosion
resistance as compared with bare Ti. Jiang et al. reported blasting of Ti implants
with 200 ~ 300 μm diameter TiO2 particles to achieve a surface with an average
roughness of 1.1 μm (Jiang et al., 2006). Regardless of the microscale cracks by
blasting, blasted Ti achieved lower corrosion current density (Icorr) within 3.5%
NaCl solution compared to non-modified counterparts, indicating a decreased pas-
sive corrosion rate (Jiang et al., 2006). Such enhanced anti-corrosion capacity could
be attributed to the newly generated layer with microscale pits and peaks with thick-
ened oxide layer, which reduces chemical reactivity (Jiang et al., 2006). Interestingly,
alternate studies revealed increased corrosion of Ti implants post-sandblasting.
Burnat et al. blasted Ti6Al4V and Ti6Al7Nb alloys with 110 μm diameter Al2O3
grains at a pressure of 4.5 bar at an angle of 45°, resulting in microscale pits and
holes (Burnat et al., 2013). Blasted alloy surfaces showed increased corrosion rates
within PBS, attributed to the enlarged surface area and the embedded Al2O3 grits
(Burnat et al., 2013). Similarly, Li et al. reported increased Ti ion release (soaking
in simulated body fluids (SBF) for 3 months) from the Al2O3 blasted Ti
(0.65 ± 0.014 μg/mL) compared to non-blasted polished Ti (0.23 ± 0.020 μg/mL)
(Li et al., 2001). Also reported were the significantly reduced open circuit potential
(OCP) on blasted substrates, indicating their aggravated passive corrosion (Wang
et al., 2017). It is noteworthy that the sharp edges and contours on blasted Ti implant
surfaces can increase the tribocorrosion and the contact area, making them prone to
corrosion.
Alternatively, some studies utilised the acid etching of blasted surfaces to reduce
surface protrusions to augment corrosion resistance of blasted implants (sandblast-
ing and acid-etching, SLA). Li et al. reported utilising 40% nitric acid for 30 min on
sandblasted Ti substrates to significantly reduce the Ti ion release within SBF (Li
et al., 2001). Acid etching reduced the sharp protrusions from the blasted surface
and dissolved the embedded sand particles. A similar conclusion was drawn by
Ogawa et al., demonstrating that HCl treatment significantly improved the corrosion
resistance of sandblasted implants by showing a marked decreased corrosion cur-
rent (Icorr) value (Ogawa et al., 2016). Interestingly, some studies reported that the
chemical resistance of Ti implants was not significantly improved after SLA treat-
ment, as Xu et al. indicated, the Icorr values of SLA implants were comparable to
smooth-Ti within SBF solution (Xu et al., 2020). Further, it is noteworthy that SLA-
treated implants with micro-rough surface could inevitably increase bacteria aggre-
gation and proliferation, among which the S. mutans (generates lactic acids) and
P. gingivalis can compromise TiO2 layer leading to chemical corrosions (Guo
et al., 2021b).
2.2 Cryogenic Treatment
Cryogenic treatment involves freezing Ti at approximately −185 °C with liquid

nitrogen to significantly reduce the residual stress within the implant structures to
improve resistance against wear. As reported by Bhaskar et al., cryogenic treatment
could refine the grain size of Ti implants significantly (from around 5 μm to 17 nm)
to reduces its dislocation density (number of dislocations within a specific volume
of a crystalline material) and augment wear resistance (Bhaskar et al., 2014).
Similarly, it was shown that the grain refinement by cryogenic treatment reduced the
composition of β-phased Ti, contributing to enhanced wear resistance (Revathi
et al., 2017). The scalability and cost-effectiveness of cryogenic treatment has seen
its application to treat and increase mechanical strength in other prosthodontic
materials such as cobalt-chromium.
Compared with non-treated or annealed Ti, the significantly improved corrosion
resistance of cryogenic treated Ti is attributed to the thickened oxide film on the
treated surface (Bhaskar et al., 2014). This is supported by Zhu et al., who observed
a significantly reduced passive corrosion current value for cryogenic Ti (0.536 μA/
cm2) compared to non-treated pure Ti (0.917 μA/cm2) (Zhu et al., 2014). Additionally,
increasing the cryogenic treatment time could increase corrosion resistance.
Compared with the untreated Ti alloys with a corrosion current density (Icorr) of
153.1 nA/cm2, reductions in values up to 86.3 nA/cm2 and 43.3 nA/cm2 were
obtained after immersion in liquid nitrogen for 24 and 48 h, respectively (Fig. 1)
(Gu et al., 2018). Such enhancements are attributed to the resistance value changes
of the outer porous layer (Rp) on Ti surfaces (Gu et al., 2018). Compared with
implants at room temperature, the cryogenic-treated implants showed significantly
reduced surface roughness due to the dislocation of grain size and increased corro-
sion resistance (Tang et al., 2017). Further, the cryogenic treatment divides and
separates the grains on Ti, releasing internal strains and yielding a submicron-scale
crystalline structure, thereby enhancing the mechanical resistance of the implant
(Tang et al., 2017). The refined grain size could reduce the Gibbs free energy
between the boundary of grains (anodic area) and their interior region (cathodic
area), which in turn increases corrosion resistance (Tang et al., 2017). The rapid
232 T. Guo et al.
Fig. 1 Electrochemical potential dynamic polarisation curves demonstrating augmentation of the

chemical resistance of Ti implants with cryogenic treatment. Cryogenic treatment of Ti-6Al-4V
implants over 24 (DCT-24) and 48 (DCT-48) hours exhibited lower corrosion current values than
untreated implants (UT) within Hanks solution. (Reproduced with permission from Gu et al. (2018))
establishment of passive film over the refined nanocrystalline surface with more
boundaries further increases its corrosion resistance (Tang et al., 2017).
In summary, cryogenic treatment remodels the crystalline structure of Ti implants
by separating grains and refining their size. The grain refining process significantly
reduces internal strain to improve chemical corrosion resistance and wear of Ti
implants.
2.3 Alloying of Ti
Apart from pure titanium (cp-Ti), Ti alloys such as Ti-Zr and Ti-Nb are suitable for
fabricating dental implants (Chopra et al., 2022). Studies to date have reported that
these alloys are substantially more resistant to chemical corrosions than cp-Ti
(Akimoto et al., 2018; Han et al., 2014). This may be attributed to the composition
of passive oxide films on Ti alloy surfaces, composed of ZrO2, Nb2O5 and NbO2
with TiO2, which are more electrochemically stable and compact than the thin,
amorphous TiO2 from cpTi surface (Akimoto et al., 2018; Han et al., 2014).
One example of such alloy is the Ti-Zr, with a dual surface oxide layer of TiO2
and ZrO2 that is more chemically stable and resistant to acid challenges than the
TiO2 film on pure Ti (Akimoto et al., 2018). The composition of Zr within the Ti-Zr
alloys was shown to influence their corrosion resistance (Akimoto et al., 2018). As
reported by Akimoto et al., Ti-Zr alloys containing 30–50 wt% Zr showed signifi-
cantly reduced pitting corrosions in artificial saliva (pH 4.9) than pure Ti
Fig. 2 Galvanic passivation curves showing TiZr alloy with 5 ~ 15% Zr presents appropriate elec-
trochemical stability. The data indicates that electrons flows from pure Ti (cp-Ti) to Ti-5/10/15Zr
(TiZr with 5 ~ 15% Zr), but the direction is reversed from Ti-20Zr (TiZr with 20% Zr) to cpTi.
(Reproduced with permission from Han et al. (2014))
counterparts, attributed to the stable Zr-rich protective layer on those Ti-Zr alloy
surfaces (Akimoto et al., 2018). Another study investigating the chemical resistance
of Ti-Zr revealed that corrosion potential (Ecorr) values increases with the Zr compo-
sition (Zr ranged 5 ~ 15 wt%) (Han et al., 2014). The further galvanic passivation
experiment revealed that such changes attributed to the electron flow from cp-Ti to
the Ti-Zr alloy when Zr composition ranged at 5 ~ 15 wt%, but reversed from Ti-Zr
to cp-Ti when Zr composition increased to 20 wt% (Fig. 2) (Han et al., 2014). With
constant oral cavity pH changes and fluorine incorporation by toothpaste, the opti-
mised Zr concentration of Ti-Zr implants ranges between 10 ~ 15%, as the clinically
utilized Zr concentration within the Straumann® Roxolid implant system (15% Zr).
Niobium (Nb) incorporation can also influence the stability of the Ti implants.
Ti-Nb alloys are fabricated using an arc melting furnace. Han et al. reported that the
corrosion resistance of Ti-Nb alloys increased with an Nb content of 5–10 wt%,
although continuously increasing Nb composition to 20 wt% reduced the resistance
(Han et al., 2015). This effect could be attributed to the phase of Ti-Nb alloys, main-
taining the α phase until 10 wt%, followed by a shift to the less stable β and ω phases
with the increase in Nb content (Han et al., 2015). Similarly, Caha et al. reported an
enhanced corrosion resistance of Ti with 15 wt% Nb (combination of α + β phase)
compared to 40 wt% Nb (mainly β phase) (Çaha et al., 2020). An additional disad-
vantage for the Ti-40Nb (40 wt% Nb) alloy is its low resistance to the tribocorro-
sion, with higher weight loss and a higher coefficient of friction (COF) value (Çaha
et al., 2020). While Ti-40Nb showed favourable Young’s modulus (51 Gpa) that is
closer to natural bone, the optimal Nb content for fabricating Ti-Nb implants should
be 10–15 wt%, which yields favourable resistance to chemical corrosion and tribo-
corrosion, towards long-term stability (Çaha et al., 2020).
234 T. Guo et al.
In summary, incorporating metal elements such as Zr or Nb could significantly

improve the corrosion resistance of conventional Ti implants. It is noteworthy that
the Ti-Zr implants are already commercially utilised.
3 Surface Chemical Modification to Augment

Corrosion Resistance
It has been reported that the surface TiO2 layer of conventional Ti implants is thin,
amorphous and inconsistent, which is insufficient against chemical and electro-
chemical corrosion. Chemical modification of the TiO2 layer using nitriding, plasma
spraying, coating and micro-arc oxidisation can enable the protection of the Ti
implants against chemical corrosions.
3.1 Nitriding
Nitriding diffuses nitrogen onto the metal surface via a hydrothermal process to
fabricate a hardened surface shielding layer. Since the metal-nitrides such as TiN
and TiAlN are ceramic coatings with exceptional chemical stability in corrosive
medium, nitriding treatment could effectively improve the corrosion resistance of
the modified Ti implants (Chung et al., 2004). It has been reported that the TiN layer
possess favourable mechanical hardness and chemical stability, attributed to the
covalent bonding between Ti and N; hence, TiN-coated Ti has been utilized across
various industries, such as anoxic casting metals, precursor for wear-resistant and
biomedical implants (Kazemi et al., 2020). Compared with non-treated Ti, TiN-
coated implants showed significantly reduced corrosion current within simulated
body fluids, indicating their decreased degradation speed within the human body
(Fig. 3) (Kazemi et al., 2020). Additionally, traditional physical vapour deposition
(PVD) could enable TiN and other ceramic coatings on Ti substrates, although cor-
rosion may occur through defects in the coating layer such as delamination, indicat-
ing the need for improvements in layer consistency and mechanical stability. The
isothermal exposure technique involves gradually heating Ti in N2 (10−3Pa to 850 °С
for 12 h) followed by cooling in N2 (0.028 °С/s till 500°С) in vacuum. This method
results in TiN coating with improved stability and adherence, demonstrating aug-
mented corrosion resistance in Ringer’s solution at both 36 and 40 °С (Pohrelyuk
et al., 2013). Alternatively, selective laser melting (SLM) with acid etching
(HF + HNO3) has been used to fabricate firmly adhered TiN coating on Ti with
evenly distributed spherical TiN particles (Zhou et al., 2020). Such TiN composite
is composed of a combination of δ-TiN and ε-Ti2N that is strongly incorporated
with the underlying hexagonal-Ti, reducing the passivation current density and cor-
rosion current density (Icorr) of Ti in acidic solution (Zhou et al., 2020).
Fig. 3 Polarisation curves of bare and coated Ti-6Al-4V alloys within the SBF solution. Results
confirm reduced corrosion density values on TiN and hydroxyapatite (HA)-coated implants as
compared to non-coated counterparts, indicating that both TiN and HA coatings could protect Ti
implants against chemical corrosion. (Adapted with permission from Kazemi et al. (2020))
Magnetron sputtering and glow discharge have also been used to perform nitrid-
ing of Ti. Ananthakumar et al. deposited a 2 μm thick TiN coating via DC magne-
tron sputtering that significantly reduced the degradation speed of Ti as shown by
the reduced corrosion current density (Icorr) within 3.5% NaCl solution
(Ananthakumar et al., 2012). Glow-discharge ion nitriding also resulted in a consis-
tent TiN coating layer on Ti implants, which showed exceptional corrosion resis-
tance in 5 wt% HCl, with the corrosion potentials significantly increased from
−150 mV (non-coated Ti alloy) to 300 mV (TiN coated alloy) (Rossi et al., 2003).
While TiN coated Ti exhibits exceptional corrosion resistance, the main application
focus was fabricating aeroplane/marine equipment and electrochemical cells (e.g.
EV batteries), and not dental implants. Thus biocompatibility and bioactivity stud-
ies are needed for TiN application in dental implants.
3.2 Coating with Calcium Phosphate (CaP)
CaP is a bioceramic with desirable corrosion resistance that could be utilised as a

coating to protect Ti implants from the electrochemical corrosion and damage. It
has been reported that the CaP coated Ti has significantly reduced corrosion current
value and increased polarisation resistance in vitro, indicating corrosion resistance
(Qadir et al., 2019). Similarly, Coelho et al. reported that CaP coating on Ti alloys
236 T. Guo et al.
Fig. 4 Potentiodynamic polarisation curves for non-modified Ti and hydroxyapatite (HA)-coated

Ti implants via ultrasonic mechanical coating and armouring (UMCA). Results show that the cor-
rosion density values (Icorr) of UMCA-Ti was significantly lower than non-modified counterparts,
indicating a reduced corrosion speed of HA-coated implant surfaces. (Adapted with permission
from Lin et al. (2022))
via sputtering significantly increased the polarisation potential of alloys within a

PBS solution, demonstrating its enhanced corrosion protection (Coelho et al., 2009).
Hydroxyapatite (HA), one of the most applied forms of CaP, is similar to human
bones in both morphology and composition and has been coated on Ti implants to
improve osseointegration (Gulati et al. 2022a). Lin et al. fabricated a porous HA
coating on Ti by ultrasonic mechanical coating and armouring (UMCA) (Fig. 4)
(Lin et al., 2022). Compared with the unmodified Ti, UMCA-modified Ti signifi-
cantly reduced the corrosion current density (Icorr) within Hank’s solution. This
could be attributed to the HA coating layer behaving as a resistant barrier between
Ti implants and corrosive solution (Lin et al., 2022). Saeed et al. also utilised micro-
arc oxidisation (MAO) on Ti alloys to fabricate a porous and roughened HA coating
that significantly increased the corrosion potential and reduced the corrosion current
of Ti alloy, improving corrosion resistance (Saeed et al., 2021). Incorporating the
MAO treatment, a composite HA/TiO2 coating could be fabricated on Ti, with dual
microscale texture (microgrooves) and superimposed nanorods (Khalid Naji et al.,
2021). Such modification not only increased the corrosion resistance of Ti signifi-
cantly, but also enhanced its hydrophilicity due to the generated nanoscale rods
(Khalid Naji et al., 2021). Compared with CaP with similar chemical compositions,
HA-coated implants were more resistant against chemical corrosion by presenting
increased corrosion potential (Ecorr) and reduced corrosion current (Icorr) values
within SBF (Liu et al., 2021). Moreover, as the main inorganic component of human
bones, HA coatings can also accelerate bone regeneration on implant surfaces, thus
the utilisation of HA-coated implants could potentially benefit both the osseointe-
gration and long-term functioning of dental implants.
3.3 Micro-arc Oxidisation (MAO)
Modifying the surface chemistry via MAO to induce ions on Ti implant surface is
an alternative approach to improve corrosion resistance (Prando et al., 2018). Such
ion implantation is achieved at high voltages, where the high current density initi-
ates a dielectric breakdown of TiO2 surface to expose the underlying Ti to the elec-
trolyte containing different ions (Prando et al., 2018). Next, the various ions and
functional groups (i.e., -OH, Ca ions, P ions) could be implanted onto Ti from the
electrolyte to modify the chemistry of the passive TiO2 layer (Prando et al., 2018).
Compared with the non-treated Ti that only enables a thin and amorphous oxide
layer (2 ~ 5 nm), MAO establishes a porous structure on Ti via crystallisation of
surrounding electrolytes. Deposition of Ca ions enabled a uniformed Ca-Ti layer
that promoted cellular adhesion and migration to improve surface bioactivity (Krupa
et al., 2004). However, several defects on Ca implanted Ti were observed after
immersion in SBF (Krupa et al., 2004). Thus, Krupa et al. incorporated phosphorus
(P) on Ca-induced implants by MAO, which resulted in significantly reduced pits
and defects after SBF immersion (Krupa et al., 2004). Besides incorporation of
ions, another benefit of P-doped Ti implants by MAO against chemical corrosion is
increase in thickness and modified topography of the implant surface. It has been
reported that doping P on Ti implants generates TiP-containing crystalline struc-
tures on the TiO2 oxide layer which significantly increases the stability of amor-
phous TiO2 and fills the cracks to reduce defects (Prando et al., 2018). Further, the
TiP-crystalline is more resistant against chemical corrosion than the native TiO2
film. This observation is supported by electrochemical impedance spectroscopy
(EIS) results, where the resistance value against the polarisation of P-incorporated
Ti implants was 2.5-fold higher than the non-treated counterparts (Diamanti
et al., 2013).
In summary, MAO enables the implantation of P onto the TiO2 surface and alters
the chemistry of Ti implants, yielding a corrosion-resistance surface.
3.4 Plasma Spraying
Plasma spraying is a scalable surface modification approach that sprays the plasma
of melted metal under high-temperature to cover the material surface, with the
thickness of deposited coatings controlled from microscale to nanoscale (Geetha
et al., 2009). The deposited nanoscale particles/crystals from plasma spraying could
238 T. Guo et al.
improve the resistance against mechanical friction and chemical corrosion (Geetha
et al., 2009). Hydroxyapatite (HA) coating could also be achieved on Ti surfaces via
plasma spraying, exhibiting increased corrosion potential and reduced corrosion
current during electrochemical corrosion tests (Kwok et al., 2009). However, some
gaps inevitably existed between the deposited HA crystals/particles, which was
inefficient to shield the underlying Ti. To address this, Singh et al. mixed 1 ~ 2 wt%
graphene nanoplatelets (GNPs) in HA powder to form a composite HA-GNP coat-
ing. Such HA-GNP coated Ti implants showed higher corrosion resistance (Rcorr)
values than the HA-coated Ti (Singh et al., 2020). This is attributed to the embed-
ding of the wrinkled GNPs into the defects of HA matrix, which blocks the electro-
lyte from penetrating the HA matrix and causing Ti corrosion (Singh et al., 2020).
Alternatively, a composite of Al2O3-TiO2 (AT) nanoparticles was coated on Ti
implants via plasma spraying (Palanivelu et al., 2014). Both AT and AT-HA sprayed
Ti implants had nanoscale roughened surfaces with numerous nanoparticles, with
significantly decreased corrosion current density (Icorr) compared to non-modified
implants (Palanivelu et al., 2014). Moreover, the wear-resistance of such AT-HA
coated Ti implant was significantly increased (with reduced weight loss and cracks
formation throughout the wear experiment). Such results supported the long-term
mechanical and chemical stability of dual AT-HA sprayed implants, indicating their
favourable stability for clinical application as endosseous implants (Palanivelu &
Ruban Kumar, 2014). Similar results were reported by Richard et al., where AT
could be agglomerated into nanoscale dots onto Ti via plasma spraying (diame-
ter 30 ~ 50 nm) (Richard et al., 2010). Such AT-nanodots were shown to signifi-
cantly reduce the friction coefficient and the weight loss from modified surface
during the tribocorrosion tests (Richard et al., 2010). Further, SEM images indi-
cated that the AT-sprayed Ti was intact, dense and significantly reduced the corro-
sion current density (Icorr) throughout electrochemical corrosion tests by shielding
the underlying Ti (Richard et al., 2010).
In summary, plasma spraying could effectively melt and spray the coating mate-
rials onto Ti implant, modifying the implant surface with a nanoscale layer contain-
ing nanorods/nanoparticles. Such technique alters both the topography and the
chemistry of implant surface, contributing to their mechanical, chemical and elec-
trochemical stability. Moreover, such modified implants exhibits enhanced bioactiv-
ity and osseointegration attributed to HA incorporation within the surface layer
(Palanivelu & Ruban Kumar, 2014; Richard et al., 2010).
3.5 Plasma Immersion Ion Implantation (PIII)
PIII enables superimposition of metallic/non-metallic ions in a nanoscale film on Ti

that thickens the TiO2 layer and alters the chemistry. Metal ions such as Ca or Ag
implanted on Ti via PIII can result in a thin composite coating with numerous nano-
structured dots/peaks (Cao et al., 2016; Harrasser et al., 2015). It has been reported
that the Ag-implanted Ti alloys have significantly reduced friction coefficient values
(reduced from 0.78 to 0.20) indicating their enhanced protection against tribological
corrosions (Hongxi et al., 2012). However, most studies on metal ions implanted Ti
mainly showed their bioactivity and antibacterial enhancements.
The incorporation of non-metal ions (e.g., N, O, C) via PIII can enhance corro-
sion resistance of Ti implants significantly (Cao et al., 2016; Harrasser et al., 2015).
3.5.1 Nitrogen Treatment
Silva et al. treated Ti-6Al-4V alloy by PIII with different combinations of H2 and N2
gases for varied times, which resulted in N-enriched layer on Ti alloys (da Silva
et al., 2007). After 90 min N2/H2 treatment, an 88 nm-thickened N-enriched layer
could be obtained on Ti alloys with approximately 33% N concentration.
Interestingly, the thickness of the N-enriched layer was significantly higher on the
N2/H2 treated alloys, compared with the pure N2 treated counterparts. Thicker
N layer on N2/H2 treated alloys is attributed to H2 plasma that removes the protective
oxide layer from metal surface, thereby augmenting the nitrogen penetration for a
thicker metal-nitride layer (da Silva et al., 2007). Further, N2/H2-coated alloy
showed a larger passive region in the potentiodynamic polarisation curve, indicating
their improved resistance against passive surface dissolution due to the superim-
posed N layer that shielded the alloy surface (da Silva et al., 2007).
3.5.2 Oxygen Treatment
Yang et al. utilised oxygen plasma with a dose of 1 ~ 4*1016/cm2 on Ti discs to aug-
ment corrosion resistance (Yang et al., 2011). Unlike N2 implantation, oxygen
plasma implantation does not change the topography of modified Ti implants, and
only alters the surface chemistry by thickening the native TiO2 layer via forming
Ti2+(TiO) and Ti3+(Ti2O3) (Yang et al., 2011). Compared with the non-treated Ti, the
corrosion rate (Icorr) and passive current (Ipass) of oxygen modified Ti implants were
significantly reduced (Fig. 5) (Yang et al., 2011). Further, fewer etching holes were
observed on the oxygen implanted Ti after the electrochemical corrosion tests,
attributed to the thickened and compact TiO2 layer of oxygen implanted Ti (Mohan
& Anandan, 2013). This compact TiO2 layer behaves as a protective shield against
the release of Ti ions from the underlying implant surfaces, ensuring their stability
under the potential chemical challenges within the oral cavity (Mohan &
Anandan, 2013).
3.5.3 Carbon Treatment
PIII technique has also been utilized to modify Ti-based implants to deposit a
nanoscale diamond-like carbon-rich layer. Shanaghi and Chu reported the fabrica-
tion of a 50 nm-thick carbon-rich layer after C-PIII for 2 h (Shanaghi & Chu, 2019).
240 T. Guo et al.
Fig. 5 Oxygen plasma modified Ti implants demonstrate superior corrosion resistance by the
potentiodynamic polarisation curves. The corrosion rate (Icorr) and passive current (Ipass) of oxygen
treated Ti implants (b & c, concentrations of implanted oxygen: b = 1*1016/cm2, c = 4*1016/cm2)
were significantly lower than non-treated counterparts (a). (Reproduced with permission from
Yang et al. (2011))
Compared with the non-treated Ti alloys, C-PIII modified surfaces showed signifi-
cantly increased corrosion potentials (Shanaghi & Chu, 2019). Further, the Icorr and
Ipass values of Ti alloys were reduced after the C-PIII treatment. This is attributed to
the formation of chemically inert carbide bonds between Ti and carbon, which pre-
vented the penetration of corrosive ions during the electrochemical corrosion tests
(Shanaghi & Chu, 2019). Similarly, utilising C2H2 to enable C-PIII on Ti alloys also
established a C-rich coating layer that improved both the chemical corrosion and the
mechanical properties of Ti (Young’s modulus and hardness), attributed to the tita-
nium carbide layer (Poon et al., 2005).
In summary, PIII treatment is a scalable and tailorable technique that can implant
numerous ions on Ti implants, aiming at specific enhancements, including mechani-
cal stability and corrosion resistance. Doping Ti implants with N, C and O can
improve the corrosion resistance via formation of a nanoscale chemically inert pro-
tective layer. However, whether such modifications influence the bioactivity of the
Ti implants needs further investigations.
4 Ti Implant Nano-engineering
To date, numerous modification techniques have been utilised to fabricate nanotop-

ography on Ti implants, including physical (e.g., laser-texturing, deposition), chem-
ical (e.g., chemical etching, plasma spraying) and electrochemical approaches (e.g.,
electrochemical anodisation) (Guo et al., 2021a; Martinez-Marquez et al., 2022).

Nano-engineering techniques (especially via the electrochemical approaches) can
create TiO2 nanostructures and thicken the TiO2 layer on Ti implants, thereby form-
ing a protective shield against the chemical corrosion.
4.1 Nano-crystallinzation
Nanocrystal layers are defined as a layer of nanoscale grains in different shapes that
can be obtained on Ti implants by refining the grain size via surface mechanical
attrition treatment (SMAT), a typical severe plastic deformation (SPD) technique
(Gleiter, 1989). Grain refinement by SMAT significantly reduces the residual com-
pressive stress within the implant surface, thereby augmenting its mechanical
strength (Lin et al., 2006). Attributed to the distortions and strain during treatment
that splits the initial grains into smaller nanoscale grains, SMAT reduces the grain
size from 10 μm to 50 nm (Jelliti et al., 2013). The chemical stability of SMAT-
treated Ti implants was significantly enhanced, as evident by the reduced corrosion
density and increased potential values from electrochemical impedance spectros-
copy (EIS) tests (Jelliti et al., 2013). Besides the EIS results, the wear rate of SMAT-
treated Ti was reduced 3- to 10-fold than that of the non-treated surfaces (Jelliti
et al., 2013). Further, surface cracks and delamination were significantly reduced on
SMAT-Ti after the wearing tests (attributed to the thickened passive layer) (Lin
et al., 2006). As reported by Huang and Han, the passive film resistance (Rp) of Ti
alloys (7.5*105 Ω.cm2) was significantly augmented after the SMAT treatment
(20.5*105 Ω.cm2), indicating a compact and thicker passive film formed on the
SMAT-treated Ti alloys with refined grains (Fig. 6) (Huang & Han, 2013). The
SMAT treatment was more significant on rough Ti for corrosion resistance enhance-
ments, for which their grain size changed dramatically and yielded a thickened TiO2
protective layer (Skowron et al., 2021).
In summary, by refining the grain size of Ti to nanoscale, nanocrystallinity
achieved via SMAT could significantly increase the chemical stability and the cor-
rosion resistance of Ti implants. SMAT enhances the mechanical strength of Ti
implants by refining the grain size to release their internal stresses. Additionally,
SMAT treatment does not alter the chemistry of Ti implants, preserving their favour-
able biocompatibility.
4.2 Nanowires
Fabrication of nanowires via alkali-heat treatment or electrospinning can establish a

mesh structure with a distinctive surface roughness on Ti implants (Alali et al.,
2021) to promote surface bioactivity (Stevens & George, 2005). Ti implants with
nanowires/nanofibres exhibit enhanced corrosion resistance (Manole et al., 2018;
242 T. Guo et al.
Fig. 6 Enhanced corrosion resistance of SMAT-treated Ti implants as shown by the electrochemi-

cal impedance spectroscopy (EIS). The Nyquist plots indicate an increase in the passive film resis-
tance (Rp) of SMAT-treated Ti implants in both (a) physiological saline (PS) and (b) simulated
body fluids (SBF). (Reproduced with permission from Huang and Han (2013))
Zhu et al., 2019). For example, Zhu et al. fabricated interconnected nanowires via
hydrofluoric acid etching and alkali-heat treatment on Ti implants that generated a
mesh structure that shielded the implant against the chemical corrosion (Zhu et al.,
2019). It is noteworthy that nanowires-interconnected mesh structures could be
mechanically delaminated and require further optimization (Zhu et al., 2019).
Alternatively, electrospinning can be utilised to obtain interconnected nanowires.
Manole et al. mixed titanium butoxide with polyvinylpyrrolidone (PVP) and spun
them on Ti implants to distribute nanowires and form an interconnected mesh struc-
ture (Manole et al., 2018). Compared with the untreated Ti, PVP-TiO2 nanowires on
Ti implants exhibited significantly reduced corrosion current and increased corro-
sion potential within artificial saliva (Manole et al., 2018). Bioactivity assessments
revealed that PVP-TiO2 nanowires could significantly enhance fibroblast viability
and inhibit their secretion of inflammatory cytokines. Together, these observations
suggest PVP-TiO2 nanowires, in promoting both corrosion-resistance and bioactiv-
ity, are suited as dental implant surface modification (Manole et al., 2018).
4.3 Anodised Nanostructures
Electrochemical anodisation (EA) is a scalable and cost-effective strategy to fabri-

cate hollow TiO2 nanostructures (nanotubes or nanopores) on Ti implants (Chopra
et al., 2023). Several studies have evaluated the influence of nanotubes/nanopores
on enhancing the corrosion resistance of Ti implants (Demetrescu et al., 2010; Liu
et al., 2011; Man et al., 2008). Man et al. reported that TiO2 nanotubes (TNTs) could
significantly reduce the corrosion current density (ICorr) and increase the polariza-
tion resistance of modified Ti implants (Man et al., 2008). Similarly, Demetrescu
et al. reported a significant higher polarisation resistance of 120 nm-diameter TNTs
(20 nm thickened wall) than the non-treated Ti implants (Demetrescu et al., 2010).
The data from electrochemical impedance spectroscopy (EIS) showed that the
corrosion rate of TNTs (0.0076 mm/year) was significantly lower than bare Ti
(0.27 mm/year) (Demetrescu et al., 2010).
To evaluate the corrosion resistance of varied dimensions of nanotubes, Liu et al.
anodised Ti foils at 5, 10, 15 and 20 V for 30 min to fabricate TNTs with the diam-
eter of 22 nm, 39 nm, 59 nm and 86 nm, respectively (Liu et al., 2011). Interestingly,
the testing revealed that the corrosion resistance of TNTs increased with the nano-
tube diameter until 59 nm, but then significantly reduced for the 86 nm-diameter
TNTs (Fig. 7) (Liu et al., 2011). This observation is attributed to the underlying
barrier layer of 5 ~ 15 V fabricated TNTs (diameter 22 ~ 59 nm) that increased with
voltage (and hence increased the corrosion resistance). However, the TNTs fabri-
cated at 20 V had a significantly larger diameter, which increased the surface area
for contact with electrolytes and hence reduced their corrosion-resistantance (Liu
et al., 2011). Alternatively, Saji and Choe reported that TNTs anodised by H3PO4-
based electrolyte had reduced corrosion resistance than the non-anodised counter-
parts, since the acidic electrolytes significantly reduced the thickness of TiO2 BL
beneath the nanostructures to reduce its corrosion resistance (Saji & Choe, 2009).
Apart from the TNTs diameter, length, and thickness of the barrier layer, the crystal-
line phase also influences their corrosion resistance. Compared with the amorphous
TNTs, the corrosion resistance of anatase TNTs was reduced at the BL but increased
at the nanotubes (Fatichi et al., 2022). Heat treatment during anatase transformation
244 T. Guo et al.
Fig. 7 The anodisation polarisation curves of the polished Ti (MPT) and various anodised TNTs
(5 V = NT05, 10 V = NT10, 15 V = NT15, 20 V = NT20) in artificial saliva. It is notable that the
corrosion resistance could be described as NT15 > NT10 > NT05 > NT20 > MPT. (Reduced with
permission from Liu et al. (2011))
compromises BL integrity, reducing the corrosion resistance. Further, the annealing

treatment collapses (closes the tops) the anatase nanotubes and reduces the
electrolyte-nanotube contact, thereby increasing the corrosion resistance (Fatichi
et al., 2022). Increasing the annealing temperature to 650 °C to create dual anatase-
rutile phase TNTs exhibited an increased corrosion resistance value at the underly-
ing BL, mainly attributed to the increased thickness during rutile transformation
(Fatichi et al., 2022).
To further enhance the resistance against tribocorrosion, an additional reverse-
polarisation was evaluated by Alves et al., which formed a protective P-rich layer
with Ca and Zn deposition on the fabricated TNTs (Alves et al., 2018). Such protec-
tive film could significantly increase the open circuit potential (OCP) values of
TNTs and reduce the formation of the crack during the tribocorrosion tests (Alves
et al., 2018). Further, the reverse polarisation thickened the nanoscale oxide film at
the Ti-TNTs interface, improving the adhesion of the TNTs layer and their mechani-
cal stability (Alves et al., 2017).
In summary, electrochemically anodised Ti implants with nanotubes demon-
strate enhanced corrosion resistance attributed to the thickened TiO2 BL and the
superimposed nanostructures. Rutile phase nanotubes, with a thickened barrier
layer, smaller tube/pore diameters, and longer tube length, are optimal against
chemical corrosions.
5 Research Gaps and Future Directions
Dental implants are subjected to the chemical challenges from the ever-changing
oral microenvironment at the site of implantation. Modifying implant surfaces from
micro- to nanoscale to enhance their surface corrosion resistance can contribute to
long-term implant success. However, there remains unanswered questions with
respect to the role of surface modification in limiting corrosion of Ti dental implants
that will inform future research in this field:
• Sandblasting and acid-etching (SLA) is widely utilised for fabricating commer-
cial dental implants, however there are conflicting reports on their corrosion
resistance. Additional research is needed to thoroughly evaluate the corrosion
resistance of SLA implants by incorporating other anti-corrosion modifications
(Guo et al., 2021b; Li et al., 2001; Ogawa et al., 2016).
• While refining the grain size of Ti implants by cryogenic treatment could signifi-
cantly release their internal strains and enhance their wear/corrosion resistance,
investigations into bioactivity performance are needed (Gu et al., 2018; Tang
et al., 2017). It is noteworthy that corrosion protection modifications can alter
surface topography and chemistry, which can influence surface bioactivity (Guo
et al., 2021). For instance, nitriding forms a protective TiN layer on Ti implants
(Rossi et al., 2003), however the effect on bioactivity performance remains
underexplored.
• Utilising sputtering and plasma spraying to create CaP and HA coating could
generate a protective layer on Ti implants against chemical corrosions, while
simultaneously enhancing their bioactivity. However, the mechanical stability of
such coatings needs thorough testing, for instance in a long-term in vivo study
under loading (Khalid Naji et al., 2021; Richard et al., 2010). Ideally, all corro-
sion protection modifications should survive the constant mechanical forces
encountered in an oral setting. For example, bioactive and corrosion protecting
nanowire coatings can mechanically delaminate under loading and require fur-
ther optimization (Manole et al., 2018).
• The next generation of anodised nano-engineered Ti implants with nanotubes
offer multiple functionalities including corrosion protection, ease of further
modification, enhanced bioactivity and tailored drug release; however, their per-
formance must be investigated in vivo for long term functionality (Gulati et al.,
2022b). Whether nanotubes will survive mechanical handling associated with
surgical insertion into the oral cavity needs examination.
6 Conclusions
Physical/chemical treatments (SLA, plasma, nitriding), alloying (Zr and Nb) and
nano-engineering (nanowires, nanocrystals and nanotubes) have been employed to
modify Ti dental implants to augment their long-term implant survival in a corrosive
246 T. Guo et al.
oral environment. However, corrosion protection coating alters the topography,

chemistry, mechanical stability and bioactivity performance of the implants, which
to-date remains underexplored. Clearly, the next generation of dental implants will
employ advanced nanotechnology that offers exceptional corrosion protection,
while maintaining favorable stability and bioactivity, tested in a long-term and
‘under load’ in vivo setting.
Acknowledgements Tianqi Guo is supported by a UQ Graduate School Scholarship (UQGSS)

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Index
A E
Alloplastic materials, 2 Electrochemical methods, 108
Anodization, 25, 69, 71, 75, 76, 96, 99–106, Electrochemical stability, 211–212,
133, 138, 154, 156, 158, 176, 180, 202, 222–248
205–209, 211, 214–216
L
B Limitations, 1, 88, 94, 104, 105, 187
Bacterial infections, 85, 155, 188, 203, 204 Local drug delivery, 164, 188
Bioactivity, 9, 10, 24–49, 71, 75, 76, 85, 86,
95, 96, 104, 117–143, 159, 166, 176,
186, 188, 201–203, 206, 209, 212–216, M
237, 239–243, 245, 247, 248 Mechanical stability, 9, 73, 93, 103, 142,
Biocompatibility, 5, 6, 8, 10, 11, 13, 16, 70, 143, 188, 201–216, 232, 236,
76, 84, 93, 95, 102, 106, 120, 131, 164, 242, 246–248
173, 176, 179, 201, 202, 222, 237, 243
N
C Nano-engineering, 76, 85, 88, 128, 129, 133,
Chemical corrosion, 233–240, 242–244, 246, 247 135, 188, 202, 242–247
Chemical methods, 225 Nanopores, 89, 101, 102, 104, 106, 128,
Corrosion, 5, 7, 8, 11–16, 47, 63, 71, 72, 84, 94, 129, 131, 133, 135, 137–139, 141,
142, 177, 201, 202, 207, 212, 222–248 154, 180, 203, 204, 206, 207, 213,
Cytotoxicity, 9, 16, 174, 176–178, 186, 188, 215, 216, 245
203, 216, 228 Nanoscale surface modification, 86–107, 163
Nanotopography, 88, 104, 108, 120, 129, 131,
133, 137, 143, 158, 164, 208, 242
D Nanotubes, 76, 87, 95, 98–101, 128, 133–135,
Dental implants, 1–17, 24–49, 62–76, 84–109, 137–139, 141, 154, 156–159, 171, 176,
117–143, 153–189, 201–216, 222–248 181, 184, 203, 204, 206, 207,
Diabetes, 25, 29–35, 48, 85, 124, 142, 229 214–216, 245–247
© The Editor(s) (if applicable) and The Author(s), under exclusive license to 255
Springer Nature Switzerland AG 2023
https://doi.org/10.1007/978-3-031-21565-0
256 Index
O S
Osseointegration, 2–6, 8, 16, 24–27, 29, 30, Sand-blasted and acid-etched surface, 86, 122,
34, 36, 37, 41, 42, 45, 46, 48, 49, 129, 134, 232, 247
62–65, 67–69, 71, 73, 74, 76, 84–87, Smoking, 26, 29–31, 34, 35, 46–49,
103, 105, 106, 117, 118, 121–124, 154, 229
127–135, 142, 154, 155, 158–164, Surface modification, 17, 25, 31–34, 38, 42,
166–169, 175, 181, 183, 201, 205, 229, 46, 48, 49, 62–76, 84–108, 117–143,
232, 238–240 153, 154, 184, 188, 201–203, 212, 225,
Oxide layer, 13–16, 71, 96, 97, 100–102, 120, 239, 245, 247
157, 201, 222, 224, 226, 232, 234, Systemic diseases, 48
239, 241
T
P Therapy, 15, 24–49, 105, 107, 128, 143,
Physical methods, 89, 94 153–189, 202, 214
Titania nanotubes, 96, 133, 156, 159–162,
165–168, 173, 176–179, 183, 187
R Titanium, 1–17, 24–49, 62–76, 84–86, 94,
Roughness, 7, 8, 14, 15, 25, 62, 63, 69, 71–74, 99–104, 106, 117–143, 153–189,
85, 87–89, 91, 93, 94, 96, 100, 106, 201–216, 222–248
121, 122, 127, 128, 135–137, 156, 178, Titanium alloys, 2, 7, 9, 10, 13–16, 65,
214, 215, 232, 233, 243 72, 84, 234

Surface Modification of Titanium Dental Implants

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Herston, QLD, Australia Karan Gulati

The relationship between edentulism and dentistry is as long as dentistry itself.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 1

3 Materials for Endosseous Dental Implants

Today, the goal of the placement of endosseous implants is to achieve osseointegra-

Fig. 2 Histological photomicrograph showing a direct contact between a titanium screw/implant

3.1 Materials of Historical Interest

Some of the concerns associated with HA-coated implants were reviewed by

3.2 Currently Used Materials

potentially used as dental implant materials. Two of them warrant a discussion:

4 Titanium and Its Alloys

4.1 Titanium in Its Elemental Form

4.2 Titanium in Alloyed Form

4.3 Physical Properties of Titanium and Its Alloys

4.4 Mechanical Properties of Titanium and Its Alloys

4.5 Biological Properties of Titanium and Its Alloys

prosthesis, due to mechanical cleaning in the context of prevention and therapy of

4.5.2 Metal Ion Leakage

Various mechanisms were described as causes of titanium release, including friction

5 Conclusions and Future Directions

Acknowledgements The author declares no conflicts of interest in relation to this manuscript.

Necla Asli Kocak-Oztug and Ece Irem Ravali

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 23

smoking, chronic kidney diseases, radiation therapy, some cardiovascular condi-

Systemic conditions Contraindication Survival rate Precautions/recommendations Dental implant modifications

8 Head and Neck Cancer

42 implants due to peri-implant disease, 17 implants due to tumour recurrence, and

Osteoporosis is a disease that results from destruction in the bone remodelling

Paget’s disease, defined by deformity and progressive enlargement of the long

Cementoosseous dysplasia is a non-neoplastic, slow-growing bone disease usually

Fibrous dysplasia is a disease characterized by abnormal, non-malignant growths in

Osteogenesis imperfecta is a hereditary disease in which brittle bones occur due to

9.6 Medication-Induced Osteonecrosis of the Jaw (MRONJ)

Medication-induced osteonecrosis of the jaw (MRONJ) involves exposed and

estrogen receptor modulators (SERMs), bisphosphonates, parathyroid hormone,

10.1 Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic

10.2 Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide spec-

Scleroderma is a connective tissue disease which causes involvement of the internal

10.4 Sjögren’s Syndrome (SS)

Organ transplantation is currently a common procedure to restore the functions of

studies show negative effects of cyclosporine use on osseointegration and peri-

12 HIV and AIDS

Human immunodeficiency virus (HIV) is a virus that can be transmitted through

weight before antiviral therapy predispose to osteoporosis. Agents such as estrogen

14 Conclusions and Future Directions

after starting the medication can be necessary. Generally, medically compromised

Journal of Oral and Maxillofacial Surgery, 68(7), 1662–1666. https://doi.org/10.1016/j.

medication-­related osteonecrosis of the jaw--2014 update. Journal of Oral and Maxillofacial

BIC Bone-implant contact

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 61

1 Roughness of Implant Surfaces: Definition

Osseointegration at the bone-implant interface is crucial for stability, loading, and

2 History of Surface Modifications

The first-generation titanium implants were produced by industrial machining or

Table 1 Characteristics of different implant surfaces (Albrektsson & Wennerberg, 2004a)

3 Macro-scale Design of Dental Implant Surfaces

Usually, macro-scale alterations provide primary stability and mechanical interlock

3.1 Implant Body Shape

3.2 Various Geometric Thread Patterns

3.3 Different Connection Between the Implant

Herston, QLD, Australia Karan Gulati

3 Materials for Endosseous Dental Implants

3.1 Materials of Historical Interest

3.2 Currently Used Materials

4 Titanium and Its Alloys

4.1 Titanium in Its Elemental Form

4.2 Titanium in Alloyed Form

4.3 Physical Properties of Titanium and Its Alloys

4.4 Mechanical Properties of Titanium and Its Alloys

4.5 Biological Properties of Titanium and Its Alloys

4.5.2 Metal Ion Leakage

5 Conclusions and Future Directions

8 Head and Neck Cancer

9.6 Medication-Induced Osteonecrosis of the Jaw (MRONJ)

10.1 Rheumatoid Arthritis (RA)

10.2 Systemic Lupus Erythematosus (SLE)

10.4 Sjögren’s Syndrome (SS)

12 HIV and AIDS

14 Conclusions and Future Directions

medication-related osteonecrosis of the jaw--2014 update. Journal of Oral and Maxillofacial

1 Roughness of Implant Surfaces: Definition

2 History of Surface Modifications

3 Macro-scale Design of Dental Implant Surfaces

3.1 Implant Body Shape

3.2 Various Geometric Thread Patterns

3.3 Different Connection Between the Implant

3.4 Surface Modifications on the Neck of Dental Implants

4 Micro-scale Design of Dental Implant Surfaces

4.1 Strategies of Micro-scale Surface Modifications

4.1.1 Sandblasted, Large-Grit and Acid-Etched (SLA)

4.1.2 Plasma Spraying Deposition

4.1.4 Laser Surface Processing

4.2 Biological Response to Micro-rough Implant Surfaces:

5 Contemporary Implant Surface: Clinical Application

1.1 Titanium: The Gold Standard in Dentistry

1.2 Nano-scale Surface Modification of Ti Dental Implants

1.3 Current Nanoscale Surface Modification Methods of Ti

(Santos-Coquillat et al., 2018). For plasma sprayed HA coating, precise control of

2 Nanoscale Surface Modification

2.1.1 PVD Magnetron Sputtering

2.3.2 Factors Influencing Anodization

2.3.3 Anodization of Dental Implants: Complex Implant and Geometry

3 Conclusions and Future Directions

2 Microscale Surface Modification

2.1.1 Physical and Chemical Modifications

2.1.2 Incorporation of Bioactive Agents