Advances in Colloid and Interface Science: Historical Perspective

Advances in Colloid and Interface Science 298 (2021) 102551
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Advances in Colloid and Interface Science

journal homepage: www.elsevier.com/locate/cis
Historical Perspective
Fitting pieces into the puzzle: The impact of titanium-based dental implant
surface modifications on bacterial accumulation and
polymicrobial infections
Raphael C. Costa a, Bruna E. Nagay a, Martinna Bertolini b, Bárbara E. Costa-Oliveira a, c,
Aline A. Sampaio d, Belén Retamal-Valdes e, Jamil A. Shibli e, Magda Feres e, Valentim A.
R. Barão a, 1, *, Joāo Gabriel S. Souza a, e, f, 1, *
a
Department of Prosthodontics and Periodontology, Piracicaba Dental School, University of Campinas (UNICAMP), 901 Limeira Ave, Piracicaba, São Paulo 13414-903,
Brazil
b
Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030, USA
c
Graduate Program in Dentistry, University Ceuma (UNICEUMA), 01 Josué Montello St, Renascença II, São Luis, Maranhão 65075-120, Brazil
d
Department of Clinic, Pathology and Dental Surgery, Federal University of Minas Gerais (UFMG), 6627 Antônio Carlos Ave, Belo Horizonte, Minas Gerais 31270-901,
Brazil
e
Dental Research Division, Guarulhos University, Guarulhos, Sāo Paulo 07023-070, Brazil
f
Dental Science School (Faculdade de Ciências Odontológicas - FCO), 20 Waldomiro Marcondes Oliveira Ave, Montes Claros, Minas Gerais 39401-303, Brazil
A R T I C L E I N F O A B S T R A C T
Keywords: Polymicrobial infection is the main cause of dental implant failure. Although numerous studies have reported the
Dental implant ability of titanium (Ti) surface modifications to inhibit microbial adhesion and biofilm accumulation, the ma
Titanium jority of solutions for the utilization of Ti antibacterial surfaces have been testedin in vitro and animal models,
Surface modification
with only a few developed surfaces progressing into clinical research. Motivated by this huge gap, we critically
Biofilm
Microbial infection
reviewed the scientific literature on the existing antibacterial Ti surfaces to help understand these surfaces’
impact on the “puzzle” of undesirable dental implant-related infections. This manuscript comprises three main
sections: (i) a narrative review on topics related to oral biofilm formation, bacterial-implant surface interactions,
and on how implant-surface modifications can influence microbial accumulation; (ii) a critical evidence-based
review to summarize pre-clinical and clinical studies in an attempt to “fit pieces into the puzzle” to unveil the
best way to reduce microbial loads and control polymicrobial infection around dental implants showed by the
current in vivo evidence; and (iii) discussion and recommendations for future research testing emerging anti
bacterial implant surfaces, connecting basic science and the requirements for future clinical translation. The
findings of the present review suggest no consensus regarding the best available Ti surface to reduce bacterial
colonization on dental implants. Smart release or on-demand activation surface coatings are a “new piece of the
puzzle”, which may be the most effective alternative for reducing microbial colonization on Ti surfaces, and
future studies should focus on these technologies.
1. Introduction bacterial-surface interactions and microbial accumulation over time

[2–4]. Once a microbial biofilm forms on the Ti surface, the host
Titanium (Ti) and its alloys are the main biomedical materials used immune-mediated responses and inflammatory processes are activated,
for the manufacturing of dental implants due to their good biocompat and the environmental conditions surrounding the implant may change
ibility, suitable mechanical properties, and adequate corrosion resis [5]. If a deleterious shift in the balance of the healthy-associated
tance [1]. Nevertheless, Ti biomaterial is a substrate that allows for endogenous microbiome occurs, an overgrowth of pathogenic species
* Corresponding authors at: Department of Prosthodontics and Periodontology, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901,
Piracicaba, São Paulo 13414-903, Brazil and Dental Research Division, Guarulhos University, Guarulhos, Sāo Paulo 07023-070, Brazil.
E-mail addresses: vbarao@unicamp.br (V.A.R. Barão), jgabriel.ssouza@yahoo.com.br (J.G.S. Souza).
1
Valentim Adelino R. Barão and João Gabriel S. Souza should be considered joint senior author.
https://doi.org/10.1016/j.cis.2021.102551
Received in revised form 9 October 2021;
Available online 20 October 2021
0001-8686/© 2021 Elsevier B.V. All rights reserved.
R.C. Costa et al. Advances in Colloid and Interface Science 298 (2021) 102551
within the biofilm leads to progressive destruction of the peri-implant 2.1.1. Mechanism of biofilm formation on implant surfaces
bone [6]. Thus, biofilm-related infections can lead to the failure of the Biofilms consist of highly organized microbial communities
implant and its associated prosthetic devices, which may require embedded in a self-produced extracellular polymer matrix adhered on
implant removal, generating severe problems to the patients’ oral health the surface [22–24], which contribute to the unique attributes of biofilm
and quality of life [7,8]. lifestyle and virulence [25], forming a protected community on implant
Implant surface modifications designed to fight microbial infections surface [26]. In fact, oral biofilms are complex systems that have high
and enhance implant survival rates have been a major focus of microbial cell densities and typically represent 5–35% of the biofilm
biomedical research in the last 30 years [9,10]. In this context, many volume, while the remaining volume is composed of the biofilm matrix
surface modification techniques have been proposed, with countless [27]. The biofilm matrix is formed by biomolecules such as exopoly
variations in Ti surfaces in terms of bioactivity, functionalization, and saccharides (EPS), nucleic acids (eDNA and eRNA), proteins, lipids, and
antibacterial activity [11–13]. For instance, the application of coatings other biomolecules responsible for the structural and biochemical
that contain bioactive elements, anti-infective agents, therapeutic properties of biofilms [25]. This complex architecture of biofilms is a
nanoparticles, or antimicrobial drugs became popular for the prevention survival mechanism that provides a protected mode of growth, allowing
of microbial colonization of implants, but these lacked long-term effect cells to survive in hostile environments and providing growth conditions
options [14]. Recently, a new generation of antibacterial surfaces, better than those of planktonic cells [28]. The classic model of microbial
combining methods to create on-demand activation antimicrobial biofilm formation includes several stages: protein adsorption, microbial
coatings, has been proposed to solve the increasing burden of peri- adhesion, biofilm formation, maturation, and dispersal [3,16], which
implant infections [1,15]. However, the influence of clinically avail can be modulated by different factors (i.e., carbohydrate exposure)
able Ti-surface modifications and these emerging coatings on bacterial promoting or suppressing microbial growth (Fig. 1).
accumulation remains clinically relevant. Microbial biofilm formation relies on the interaction among bacterial
Despite numerous literature reviews on implant surface topography cells, adhesion to substrates, and the availability of nutrients [22,29].
and biofilm control [9,11,12,14,16], there are still “missing pieces of the Cell-surface interactions allow for the accumulation of certain microbial
puzzle” that would explain why the in vitro options proven to create species on exposed surfaces, and they pave the way for the colonization
antibacterial Ti surfaces have not yet entered clinical use. Furthermore, of the implant surface [30]. Biofilms can show microbial composition in
the antibacterial potential of these surfaces has only been partially a symbiotic state related to health; however, different factors can trigger
portrayed on those reviews, and the assessment of microbial contami the microbiological shift increasing the levels of putative pathogens
nation for all developed implant surfaces has not been systematically [31]. Despite the considerable progress that has been made over the past
reviewed. Importantly, the focus on antibacterial surfaces is an ever- few decades in attempts to understand the etiology of biofilm formation
prevalent issue, especially when considering the current rise in anti and maturation on dental implants, it is important to appreciate that this
biotic resistance, widely considered to be the next global pandemic [17], field is still an area of ongoing research. Targeted approaches to biofilm
and the need for alternative solutions. eradication can be applied to different steps of biofilm formation, which
This review aims to provide a critical appraisal of the existing liter should be considered a ‘chronic process’ of formation onto implant
ature assessing the effects of antibacterial Ti surfaces for controlling surfaces. Therefore, therapeutic strategies that reduce initial microbial
bacterial accumulation. This manuscript was divided into three main adhesion may do not control the chronic microbial accumulation and
sessions. (i) In order to create a background on the important topics to be disease progression.
considered, we first generated a narrative review to detail topics related
to biofilm formation, bacterial-implant-surface interactions, and how 2.1.2. Bacteria-surface interactions and peri-implant tissue damage
implant-surface modifications can influence oral biofilm formation on Ti Bacteria-surface interactions may be influenced by several factors,
biomaterial. (ii) Next, will systematically summarize pre-clinical and such as implant characteristics, peri-implant environment, site-specific
clinical studies in an attempt to “fit pieces into the puzzle” to unveil the microbiota, nutrient availability, and host response [6]. Indigenous
best way to reduce microbial loads and control polymicrobial infection microbial species can reach all implant surfaces via saliva or blood
around dental implants. (iii) Finally, a perspective on the current liter plasma, but peri-implant environmental factors determine which species
ature regarding expanding the applicability of Ti surfaces as antibacte are able to remain and colonize successfully [31]. Transmucosal surfaces
rial materials will be discussed. support a distinctive oral microbiota (supragingival biofilm) dominated
by facultative Gram-positive cocci, rods, and bacilli, while implant
2. Biofilm formation vs. surface modifications: a narrative screws harbor a submucosal microbiota, with an abundance of anaer
review obic Gram-negative species (subgingival biofilm) [29]. Nonetheless, the
factors that influence the transition from a health-associated to a
2.1. Dental implant-related infections: a disease of the century disease-associated oral microbiome are still not fully understood. Until
now, it was believed that the inflammatory process [29], poor oral hy
Since their introduction in the 1960s, dental implants have revolu giene [32], lack of regular dental implant maintenance [33], frequency
tionized dental medicine allowing the replacement of missing teeth by of sucrose consumption [34], products released by implant degradation
using Ti screws directly osseointegrated into patients’ bone [18]. [35], and nature of the EPS-enriched environment [36] are conditions
Notably, the use of dental implants has grown rapidly in recent decades, indicated as potential players in the microbiological shift of oral biofilms
accompanied, unfortunately, by a steady increase in implant failures inducing overgrowth of putative species with pathogenic potential.
caused by polymicrobial infections [8]. Such infections may also have Likewise, each individual displays unique biological factors that influ
harmful consequences to general health, causing significant morbidity ence disease initiation, activity, and progression [37].
and considerably increasing healthcare costs [19]. In this regard, more In health, the soft tissues surrounding dental implants are charac
than 40% of dental implants can be affected by infection when affecting terized by the absence of erythema, bleeding on probing, swelling, and
soft tissues, and over 22% can also affect anchoring bone within 5–10 suppuration, with stable bone levels around the implant platform
years after placement [20]. Thus, microbial accumulation control is [38,39]. In contrast, if patient compliance is not fully obtained and
essential for the long-term survival of implants [21]. These facts proper oral hygiene is not performed, microbial accumulation will
emphasize the need for discussion of topics critical to the understanding certainly induce inflammatory changes in the peri-implant sites [6].
of microbial accumulation on dental implant devices and how surface Peri-implant mucositis is characterized by inflammation in the mucosa
changes can affect this process and control or prevent the infection. around dental implants, with local bleeding and/or suppuration, but its
progression and the subsequent progressive loss of supporting bone are
2
Fig. 1. An overview of the temporal sequence of polymicrobial biofilm formation on a dental implant. Immediately after implant insertion, the titanium surface is
coated by proteins from saliva (supra-mucosal segment) and plasma (sub-mucosal segment). Stable anchorage of initial bacterial colonizers is generally followed by
the formation of an early biofilm. Subsequently, intercellular interactions mediated by proteins on the surface and cell-wall proteins lead bacteria to cluster together,
forming microcolonies, and this interaction also promotes bacterial co-aggregation and biofilm accumulation. These microbial communities are gradually embedded
into the extracellular matrix as part of the oral biofilm maturation process. Environmental conditions such as pH, oxygen level, nutrients, metabolites, and mass
transport mechanisms can lead to microbial dysbiosis. Consequently, the transition process from health to disease occurs. Finally, proteases and nucleases are
involved in biofilm dispersal, whereby cells leave the biofilm to re-enter the planktonic phase. Overall, this biofilm environment (structure) provides the emergent
properties of biofilms, including surface adhesion, spatial and chemical heterogeneities, synergistic/competitive polymicrobial interactions, antimicrobial recalci
trance, and biofilm virulence. Created with BioRender.com (Licence number: FH22YOWKFD).
Fig. 2. Schematic representation of the “ecological plaque hypothesis” in relation to peri-implant disease, adapted from Souza et al. (2021) [16]. Increased biofilm
accumulation on the implant surface triggers an inflammatory process that changes the environment, leading to a microbiological shift and disease progression (red
boxes). Other host and environmental factors can also favor the microbiological shift on biofilms growing on titanium surfaces. However, some factors can control
biofilm accumulation and inflammatory responses (blue boxes), such as surgical and antimicrobial intervention and host responses. Consequently, the clinical
transition from peri-implant mucositis to peri-implantitis occurs (please see the clinical photographs).
3
known as peri-implantitis [7]. Both conditions are considered “biofilm- about biofilm formation on oral surfaces cannot be simply transferred to
associated pathological conditions”, strengthening the evidence that implant surfaces [16]. Therefore, to control and prevent biofilm accu
biofilm is the etiological factor in dental implant-related infections [38]. mulation on implant devices, we must first understand these chronic
As suggested for dental caries and periodontal disease [3,31], an processes and the factors that modulate them and use this information to
adaptation of the “ecological plaque hypothesis” on tooth surfaces may develop suitable therapeutic strategies [40]. Unfortunately, there is no
be applied to describe a transition from a healthy state to a disease state consensus regarding the best therapeutic protocol to treat dental
in the peri-implant mucosa and bone structures (Fig. 2). In this adapted implant-related infections [41], and this may be due to the lack of
hypothesis, suggested by Souza et al. (2021) [16], increased biofilm knowledge regarding biofilm accumulation, pathogenesis process, and
accumulation acts as a “stress” factor triggering an inflammatory process irregular implant topography, which hamper biofilm removal.
that leads to changes in the local microenvironment, favoring proteo
lytic and anaerobic Gram-negative bacterial overgrowth [16]. This 2.2. Microbial responses to implant surfaces: design and engineering
microbiological shift favors disease progression, which can be affected concepts for dental implants
by different factors that either lead to tissue damage or reverse the
process [31]. Although oral biofilm formation and factors affecting this One way to interfere with microbial adhesion and biofilm formation
accumulation have been widely explored in the literature, research has is by modifying the characteristics of implant surfaces [40]. Notably, a
focused mainly on dental surfaces, but the knowledge we have gained plethora of surface modification techniques has been investigated,
Fig. 3. Schematic diagram of surface treat

ments applied to a Ti substrate divided into
surface modifications (macro-, micro-, and
nanostructured) and multifunctional coat
ings (bioactive and antimicrobial) and
possible antimicrobial surface mechanisms,
adapted from Linklater et al. (2021) [15].
For micro- and nanostructured surfaces (top
panel), there is a relationship between the
length scale of the bacteria (green) and the
characteristic dimensions of the surface
topography (gray), which may impart anti
fouling or antimicrobial capabilities. Nano
structured surfaces have been demonstrated
to be more efficient at reducing bacterial
attachment and preventing biofilm accumu
lation than surfaces exhibiting modifications
in only macro or micro scale. For the Ti
coating developed (middle panel), the
incorporation of antimicrobial agents (red)
can be in both molecular and particle forms,
including one- or two-step with bottom-up
(direct antimicrobial incorporation during
the deposition process) or up-down (sec
ondary antimicrobial deposition after sur
face treatment) approaches to functionalize
the surface. In general, bioactive, antimi
crobial, and release-based antimicrobial
coatings have been investigated to control
microbial biofilms. In terms of antimicrobial
mechanisms (bottom panel), antifouling,
contact-killing, and smart release with on-
demand activation have been proposed as
promising surface mechanisms. Created with
BioRender.com (Licence number:
WL22YP56T8).
4
aimed at altering the interfacial properties of implanted devices without be used in implant dentistry and, therefore, could be considered from a
disrupting the bulk properties of the Ti biomaterial [1,11]. For the dental implant standpoint in future studies.
purposes of this review, it is worth dividing surface treatments into two
broad categories: surface modifications and multifunctional coatings 3. Evidence-based review findings
(Fig. 3). Conceptually, it is often quite difficult to categorize some of
these novel techniques, since most are still in the preliminary stage of 3.1. Systematic search outcomes: state-of-the-art in surface science
development and some fall into both categories. Depending on how they
are applied, a method could be used to coat Ti with biocompatible ele To summarize the current in vivo evidence of Ti surfaces developed to
ments, and, equally, the same method may be used to develop an anti prevent or control microbial accumulation on implant surfaces, we
microbial coating. Here, we summarize the arsenal of strategies that conducted a systematic search. For complete details about the searching
have been deployed to overcome the harmful effects resulting from method, see Supplementary Methods (Supplemental materials and
microbial accumulation on Ti surfaces. methods; Table S1). From an initial pool of 4155 relevant search titles
collected from all databases, 2793 were included after the elimination of
2.2.1. Ti surface modifications duplicate studies (Supplemental results; Fig. S1). From a total of 128
Surface modification implies that the micro- or nanostructure of Ti is articles thoroughly assessed in full text, 59 were considered not eligible
modified [42,43]. This can be performed at the atomic, molecular, or according to the inclusion/exclusion criteria (Supplemental results;
textural level to determine the overall topography of the surface [9]. In Table S2). Consequently, 69 studies were included in this critical
terms of dental implants, the vast majority of commercial surface evidence-based review, comprising 61 pre-clinical studies (51 animal
treatments focus on changes in the surface layer of titanium’s roughness, models; 10 in situ models) and 8 human clinical studies.
mostly focused on improving the osseointegration process [1]. None Although Ti implants have progressively evolved and completely
theless, the remarkable properties of micro- and nanostructured mate revolutionized the biomedical field, with several attempts to reduce
rials go far beyond this. Based on current evidence, the topographical biofilm formation on Ti surfaces, thus far, no evidence-based review has
modification of the material may also include bioactive, antifouling, or comprehensively covered this engaging research area. Here, we noted
antimicrobial capabilities [15]. In addition to the micro-nanostructuring that in the first 20 years following initial publications about Ti surface
of Ti biomaterial, changes in the physicochemical properties of the modifications (1990–2010), only 13 articles were published, for a mean
substrate can also be achieved to promote anti-biofilm effects by killing of 1.6 articles per year. These studies were initiated by research groups
bacteria upon direct contact [15,44]. Moreover, the bactericidal and/or in the USA, with a focus on hydroxyapatite-coated implant assessment in
bacteriostatic effect does not lead to the eradication of biofilms, since animals [50] and humans [51]. Within the past five years (2015–2020),
dead cells still attached to the substrate can act as binding sites for other the field grew rapidly, with 56 published articles dominated by research
microorganisms, promoting colonization by live pathogens [45]. groups in China and in the USA, testing surface modifications and
emerging coatings on Ti implants (Supplemental results; Fig. S2).
2.2.2. Ti coatings developed
Antimicrobial/bioactive coatings are formed by the apposition or 3.2. Current pre-clinical and clinical models to test antimicrobial effects
spreading of an antimicrobial agent or bioactive element onto a sub of implant surfaces
strate, or by changes on physical-chemical surface properties focusing
on aspects that reduce microbial adhesion, such as wettability [1]. To explore differences between and among the study designs, data
Hence, an additional layer is formed on the existing surface to enhance from animal model (Table 1), in situ model (Table 2), and human clinical
biomechanical behavior or even to reduce bacterial adherence to the Ti studies (Table 3) were outlined. Regarding animal models, the vast
biomaterial [9]. A critical issue in the development of new coatings is majority of the 51 studies were conducted with rodents (rats, n = 32;
how the coating will be applied to and stabilized on the biomaterial to be mice, n = 5) or in small animals (rabbits, n = 13; dogs, n = 1). For
stable over time or possibly recharged, mainly considering that proteins biomaterials research, these rodent and small-animal models have pre
and even microorganisms will immediately cover the surface after the dominated, since they are cost-effective in the majority of research
insertion [46]. This can be achieved by various techniques, which may laboratories around the world, allow for ideal sample size, standardized
be physical, chemical, mechanical, or a combination of these [47]. age, diet, and behavior, as well as requiring limited implant samples that
Additionally, to avoid introducing an external coating, Ti-based alloys can be fabricated or processed to a size appropriate for small surgical
containing heavy metal elements can also endow the implants with self- sites [52]. Meanwhile, large animals like sheep, goats, pigs, and dogs
antibacterial ability [42]. Ti coatings involve the incorporation of an have extra housing requirements with a high cost of feeding, surgery,
timicrobials, such as metallic ions, antibiotics, drugs, antimicrobial and post-operative care, and raise complex ethical issues [53].
peptides (AMP), and biopolymers, which can be incorporated in bulk or In terms of surgical site, implants were commonly located in the
by the coating of a Ti biomaterial based on chemical compatibility femoral shaft (n = 22), tibial shaft (n = 15), or subcutaneous sites (n =
[1,9,14]. They are incorporated onto the surfaces by many different 12), which do not ideally represent the environmental conditions and
techniques, such as immersion in Ti substrate, covalent binding to healing processes that occur in the oral cavity. Moreover, this different
functionalized polymeric coatings, and incorporation into self- environment may modulate microbiological accumulation and compo
assembling mono/multilayer organic coatings [47]. The incorporation sition and the results found may not be applied for oral conditions, but it
can be in either molecular or particle forms, including one- or two-step, may suggest promising results to be further tested by models resembling
with bottom-up or up-down approaches for surface functionalization the oral environment. The antimicrobial activity and infection rate were
[9]. In this framework, because coating synthesis methods allow for the evaluated in a broad range of follow-up times, varying from 2 h [54] up
incorporation of a broad range of compounds, researchers have under to 8 weeks [55,56] after implant insertion at different time points. In the
taken the development of biomedical coatings that do not rely solely on current review, the long-term effects of antimicrobial coatings were
one target property, but instead seek to couple multiple approaches that analyzed based on the longest follow-up time reported in each study.
likely present antimicrobial mechanisms with no additive cytotoxicity to For in situ models, 10 eligible articles were fully reviewed. This study
surrounding tissues [48,49]. This opens up a broader array of promising design has been commonly used in dental research to evaluate poly
approaches and deposition techniques for designing coatings with microbial biofilm formation on Ti surfaces [36] and dental surfaces [57]
controlled multifunctional capabilities that can remain on biomaterial inserted in the oral environment. For this, samples are positioned in
surfaces for long periods. Although most experimental antimicrobial intra-oral appliances that are maintained in the volunteer’s mouth
coatings are designed for non-dental systems, some have the potential to throughout the experimental period. As a result, biofilm grows in the
5
R.C. Costa et al.
Table 1
Summary of implant surface, animal model, and microbiobiological data from included experimental studies (study ID, type of method; implant surface: surface treatment, deposition technology and antimicrobial; animal:
type and infection model; microbiological assessments: quantitative test, bacterial load, p-value, infection rate, and reference).
Study Type of Implant surface Animal model Microbiological assessments Reference
ID method
Deposition Surface Antimicrobial Type Microbial infection Quantitative Bacterial load p-value Infection rate
technology treatment (concentration) test
Control Experimental
F1 = 4.6 (±0.4)
C1 = 3.0 (±0.3) × 105
Machined CaP- Fluoride – F (0.05 × 105 F6 = 0.7 (±0.5)
1 Physical Plasma treatment Rab S. aureus (ATCC6538) CFU/implant <0.01 NR [56]
coated to 0.30 M) C2 = 4.3 (±0.3) × 105
× 105 F9 = 0.7 (±0.2)
× 105
T1 = 1.4 ×
Zn (8.79; 16.98; 108(±1.2)
2 Physical Plasma treatment PEO coating 34.08 wt% - for R S. aureus (ATCC 25923) CFU/cm2 1.8 × 108(±1.0) T2 = 4.4 × <0.01 NR [72]
each group) 107(±0.5)
T3 = 0
24 h: Ti = 5.6 (±
2.1) × 103 Ti-O
= 8.4 (± 2.4) ×
103 24 h: Ti-I = 1.2
48 h: Ti = 6.4 (± (± 0.7) × 103
24 h: <0.05
Anodic oxide Iodine (10–12 μg/ 2.1) × 104 48 h: Ti-I = 8.6
3 Physical Plasma treatment R S. aureus (ATCC 25923) CFU/implant 48 h: <0.05 NR [117]
film cm2) Ti-O = 7.9 (± (± 2.6) × 103
72 h: <0.05
2.3) × 104 72 h: Ti-I = 5.0
72 h:Ti = 2.0 (± (± 2.1) × 104
0.6) × 105
6
Ti-O = 2.9 (±
0.6) × 105
Ti = 6.1 (±0.5) TiO2 = 5.5
4 Physical Plasma treatment Machined TiO2 (NR) Rab MRSA (ATCC 43300) Log CFU Ti-UV = 4.1 (±0.5) TiO2-UV <0.05 NR [118]
(±1.1) = 1.8 (±1.4)
C: 37,5% (6/
Grit-blasted Rolled out on
5 Physical Plasma treatment HA (NR) Rab S. aureus (ATCC 10832) NR NR NR 16) T: 56,2% [119]
surface agar plates test
(9/16)
1w: C1 = 7.530
(± 788) C2 = 1w: 5.999 (±
Acid-etched
7.485 (± 761) 788)
6 Physical Plasma treatment surface Gallium (NR) Rab S. aureus (ATCC2592) CFU/mL NR NR [120]

2w: C1 = 7.560 2w: 7.469 (±
Anodic coating
(± 625) C2 = 734)
7.487 (± 788)
F0 = 3.9 (±0.3)
× 105
F1 = 3.7 (±0.3)
× 105
Plasma and
Fluoride – F (0.05 F2 = 1.9 (±0.2)
7 Physical hydrothermal Machined Rab S. aureus (ATCC43300) CFU/implant 3.0 (±0.2) x 105 <0.01 NR [55]
to 0.45 M) × 105
treatment
F5 = 0.2 (±0.1)
× 105
F7 = 0.1 (±0.2)
× 105
Bi2S3 =
Hydrothermal Machined + NIR Ag (20 days: 35 μg/ Antibacterial
8 Physical R S. aureus (ATCC 25923) 0 94.3% <0.01 NR [66]
method Light L) efficiency (%)
Ag3PO4 = Stepwise
(continued on next page)
R.C. Costa et al.
Table 1 (continued )
ID method
electrostatic
adsorption
9 Physical Hydrothermal Machined + NIR NR (only report R S. aureus (NR) Antibacterial 1d: NIR-: 0% 1d: NIR-: 60.75% 1d: <0.001 NR [85]
method (MoS2) + light concentration ratio (%) (±6.14) (±4.91) 3d: <0.001
vacuum drying during process: NIR+: 0.92% NIR+: 99.15% (NIR +)
process MoS2 = 0.04 g; (±7.32) (±1.83) <0.05 (NIR
(gentamicin) + gentamicin = 1 mg/ 3d: NIR-: 70% 3d: NIR-: 88.59% -)
spin-assisted mL) (±4.91) (±2.45) 7d: <0.05
chitosan NIR+:82.42% NIR+: 99.67% (NIR +)
(±2.75) (±0.91) <0.01 (NIR
7d: NIR-: 7d: NIR-: 99.42% -)
81.05% (±3.68) (±1.23)
NIR+:88.22% NIR+: 99.97%
(±4.58) (±0.91)
1.7 × 105
10 Physical Hidrothermal TiO2 nanotubes MoS2 (10 mg) Rab S. aureus (ATCC 25923) Log CFU 5.5 × 103 (±11) NR NR [68]
(±27.9)
24 h: 5.3 (±2.5) 24 h: 3.5 (±2.2)
x 104 x 103
24 h:0.002
Flame Spraying HA-coated Ag2O (0.21 wt% 48 h: 1.2 (±0.5) 48 h: 2.1 (±3.0)
11 Physical R MRSA (UOEH6) CFU/implant 48 h:0.008 NR [76]
System Ag-HA-coated after spraying) x 105 x 104
72 h:0.041
72 h: 4.4 (±3.0) 72 h: 4.0 (±3.5)
x105 x104
Flame Spraying
12 Physical Al-sandblasted Ag2O (3 wt%) R MRSA (UOEH6) CFU/implant 1.5 (± 0.5) x 105 1.1 (± 0.4) x 104 <0.001 NR [121]
System
7
1) 40% (2/5)
3) CH1mMAg: 6 2) 100% (8/
× 106 4) 8) 3) 100%
Additively 1) AsM = 5 × CH50mMAg: 6 (8/8). 4)
Electrophoretic Ag (1.69 up to
13 Physical manufactured R S. aureus (ATCC 49230) CFU/implant 106 2) Ch = 6 × × 106 5) >0.05 100% (8/8) [122]
deposition 10.95 at.%)
highly porous 106 CH100mMAg 6 5) 100% (8/
× 106 6) CHVan: 8) 6) 40% (2/
5.5 × 106 5) p = .035 (2
vs 6)
2) Ti-Nd = 1727
(±246) 3) Ti-Nd-

PDA = 1060
(±67) 4) Ti-Nd-
Dopamine
1) Ti = 1954 PDA + NIR = <0.05 (6 vs
14 Physical Oxidation process TiO2 nanotubes hydrochloride (2 R MRSA (NR) CFU/implant NR [74]
(±221) 435 (±147) all group)
mg/mL)
5) Ti-Nd-PDA-Fc
= 484 (±42) 6)
Ti-Nd-PDA-Fc +
NIR = 79 (±12)
TiO2 coating + Sublimed sulfur Antibacterial
15 Physical Tube furnace R S. aureus (ATCC 29213) 0% 99.43% <0.001 NR [82]
NIR light + US (NR) efficiency (%)
Pg: HA = 138.1
Pg: 257.6
(±223.9) x 103
Porphyromonas gingivalis; (±274.1) x 103
TPS = 285.5
P. intermedia; Pi: 21.2 (±21.0)
16 Physical Plasma-sprayed HA-coated HA (NR) D DNA counts (±303.9) x 103 NR NR [50]
A. actinomycetemcomitans x 103
Pi: HA = 12.8
(clinical strain) Aa: 1.0 (±2.4) x
(±10.6) x 103
103
TPS = 31.5
R.C. Costa et al.
ID method
(±54.1) x 103
Aa: HA = 1.1
(±2.6) x 103 TPS
= 1.0 (±2.4) x
103
17 Physical Surface-induced Machined Selenium NP (NR; R MRSA (ATCC 43300) Log CFU MRSA = 5.9 MRSA = 2.2 <0.05 NR [73]
nucleation- only report MRSE (ATCC 35984) (±1.2) x 106 (±0.4) x 106
deposition concentration MRSE = 5.3 MRSE = 1.0
during process = (±0.3) x 106 (±0.5) x 106
10 mM)
102 = 1.3
102 = 1.6 (±1.6)
(±1.3) 103 =
Vacuum plasma- 103 = 2.0 (±2.0)
18 Physical Machined HA (NR) Rab S. aureus (ATCC 10832) Log CFU 2.1 (±1.2) 104 <0.05 NR [123]
spray 104 = 5.6 (±1.9)
= 3.7 (±1.5)
105 = 6.3 (±0.7)
105 = NR
Ti = 6.7 × 105
(±7.5 × 104)
1.5 × 104 (±2.0
19 Physical Vacuum-drying Nanotubes - NT Gentamicin (NR) R S. aureus (ATCC 25923) CFU/implant Ti-NT = 4.6 × <0.01 NR [69]
× 103)
105 (±6.2 ×
104)
Ta-I: S. aureus:
4.28 (NR)
E. coli: 2.88 (NR)
TaO(at.%) Ta-I = S. aureus: 5.63
Luminescent S. aureus Ta-II: S. aureus:
8
Magnetron 5.52(±0.43) Ta-II (NR)

20 Physical Acid-etched Mic (ST1792-Lux) Log CFU 3.44 (NR) <0.01 NR [80]
sputtering = 8.14(±0.04) Ta- E. coli: 3.88
E. coli (ST1) E. coli: 2.23 (NR)
III = 6.40(±0.97) (NR)
Ta-III: S. aureus:
2.82 (NR)
E. coli: 1.47 (NR)
Machined + Vancomycin (25.0
21 Chemical Manual application Rab S. aureus (UAMS-1 strain) CFU/implant 600,000 (NR) 20 (±21) NR <0.001 [88]
Acid etched at.%)
C1: 67% (12/
C1 = 3.29 (C1 Vs T) p
Machined or 18)
Tobramycin (2.4 (±0.88) = .004
22 Chemical Manual application PeriApatite Rab S. aureus (ATCC 10832) Log CFU 0.05 (± 0) C2: 53% (9/ [124]
mg) C2 = 2.98 (C2 Vs T) p
coated 17)

(±1.28) = .045
T: 6% (1/18)
(3-aminopropyl)
Hydroxide
23 Chemical Immersion triethoxysilane R S. aureus (ATCC 29213) CFU/implant 173.9(±33.7) 12.8(±13.2) <0.05 NR [71]
coated
(NR)
CZ-01127 polymer
24 Chemical Immersion Si-based coating S MRSA (clinical strain) CFU/g 2.6 × 104 (±NR) 3.0 × 102 (±NR) 0.035 NR [125]
(15.9 ± 1.5 mg)
191.30
25 Chemical Immersion Machined Ag (8.19 wt%) R S. aureus (ATCC 25923) CFU/implant 8.69 (± 4.35) <0.05 NR [126]
(±17.39)
ε-poly-L-lysine
(EPL; 30 mM)
26 Chemical Immersion Machined R MRSA (ATCCBAA40) CFU/implant 5.48 (±0.41) 4.35 (±0.24) <0.01 NR [127]
Catechol (C; 15
mM)
NR (only report
concentration Not bacterial Not bacterial
Machined + NIR Rolled out on
27 Chemical Immersion during process: Red R No infection counted (only counted (only NR NR [98]
light agar plates test
phosphorus = 0.15 photograph) photograph)
g/mL; IR780 =
R.C. Costa et al.
ID method
0.02 mg/mL; RGDC

peptide = 2 mg/
mL)
Vitamin E (5 mg/
28 Chemical Immersion Machined R S. aureus (UAMS-1Xen40) Log CFU 3.8 (±0.4) 3.2 (±0.5) <0.001 NR [128]
cm2)
TiO2 nanospike Cationic
29 Chemical Immobilization R S. aureus (ATCC 6538) CFU/implant ~3.26 × 108 ~28 <0.001 NR [129]
coating polypeptide (NR)
MPDA (0.09 mg)
Machined + NIR Antibacterial
30 Chemical Immobilization RGD peptide (5 R S. aureus (ATCC 29213) 0% (NR) 95.4% (NR) <0.01 NR [49]
light efficiency (%)
mg/mL)
<0.05
C - NIR: 192.5
T - NIR: 82.5 (compared
Machined + NIR Daptomycin (634.6 (±12.5) C +
31 Chemical Immobilization R S. aureus (ATCC 25923) CFU/implant (±10.0) T + NIR: to control NR [78]
light μg) NIR: 182.5
5.00 (±2.5) groups and
(±22.5)
NIR-)
C: 100% (6/
6)
Impregnated on Tobramycin (4 mg 3
32 Chemical PDLLA-coated Rab S. aureus (ATCC 25923) CFU/implant >104 <10 NR T: 16.7% (1/ [130]
PDLLA coating wt%)
6)
p < .05
Machined:
1.181.000 <0.05 (NO
Machined Nitric Oxide - NO NO: 170.000
33 Chemical Dip-coating R No infection CFU/implant (±2.717.000) vs machined NR [97]
Xerogel film (NR) (±181,000)
XG: 677.000 and XG)
9
(±675.000)
1d: Ti: 80%
(16/18)
CHX10%: (4/
1d: CHX10% 17)
CHX (4.9–9.5 - 1d: Ti (86)
34 Chemical Dip-coating Machined Mic S. aureus (ATCC 49230) Log CFU (24) ≤0.05 1d: Ti: (5/18) [70]
10.0 wt%) 4d: Ti (28)
4d: CHX10% (0) CHX10% (0/
18) (p > .05
for 1 and 4
days)
Gentamicin (NR;

C: 100% (9/
only report
9)
35 Chemical Dip-coating CaP-coated concentration R S. aureus (JAR060131) Log CFU 1.76 (NR) x 106 6.43 (NR) x 101 <0.01 [131]
T: 12.5% (1/
during process =
9)
40 mg/mL)
2) DDDEEK-G4-
2) S. aureus: 0
(DOPA)4 (5 mg/
E. coli: 0
mL)
S. aureus: 2.7 × 3) S. aureus: 2.8
3) WRWRWR-G4-
E. coli (ATCC 8739) 104 (±1.0) × 104 (±1.4)
36 Chemical Dip -coating Machined (DOPA)4 (5 mg/ R CFU/implant <0.05 NR [75]
S. aureus (ATCC 6538) E. coli: 3.2 × 104 E. coli: 3.2 × 104
mL)
(±0.5) (±0.5)
4) DGD + WGD
4) S. aureus:
(2.5 mg/mL for
0 E. coli: 0
each component)
5 d: (107 5 d: (107 <0.05
Cys-melimine
Mic inoculum) = inoculum) = 2.1 (Control Vs
37 Chemical Silanization Machined peptide (3.1 × 109 S. aureus (strain 38) Log CFU NR [132]
R 4.0 × 106 (105 × 105 (105 Tests; 105
mol/cm2)
inoculum) = inoculum) = 4.8 and 107)
R.C. Costa et al.
ID method
5
8.0 × 10 × 103
7 d: (105 7 d: (105
inoculum) = inoculum) = 6.1
9.1 × 104 × 103
Polyelectrolyte
TiO2 (1 g; wt%) Median: 5.3 Median: 3.1
38 Chemical Silanization multi-layers R S. aureus (ATCC 29213) CFU/implant <0.05 NR [133]
CHX (10 mg/mL) (±14.6) × 105 (±8.5) × 105
coating
Vancomycin (90 Bioluminesce
39 Chemical Covalently bond Machined Mic S. aureus (Xen29) 520 (±40) 0 <0.01 NR [99]
μg/mm3) intensity
104 CFU:
33.3% (1/3)
Tobramycin (NR; 104 inoculum:
104 inoculum: test; 100.0%
only report 3.4(± 2.0) ×
Anodized 1.35 × 105 (only control (3/3)
40 Chemical Soaking method concentration in Rab S. aureus (ATCC 6538) CFU/implant 105 NR [83]
surface 1 implant) 105 CFU: 0%
the stock solution 105 inoculum:
105 inoculum: 0 test (0/2)
used for loading) 2.8(±1.4) × 105
100.0%
control (2/2)
Ti: 100% (4/
4) NTATi:
Machined + TiG = 73.75 <0.05
Ti = >1.000 100% (4/4)
nanotubular Gentamicin – G (10 Rolled out on (±10.69) NTATi- NTATi-G Vs
41 Chemical Soaking method Rab S. aureus (ATCC 25923) NTATi = Ti-G: 100% [134]
anodized surface mg/mL) agar plates test G = 40.5 NTATi and
>1.000 (4/4) NTATi-
(NTATi) (±12.36) Ti groups.
G: 100% (4/
4)
10
Machined or % reduction
Mg (7.6 ± 0.7 wt%) AT: 3.16% (±
42 Chemical Soaking method Alkali-heat R S. aureus (ATCC 29213) related to 95.99% (± 4.53) <0.01 NR [77]
Zn (1.8 ± 0.1 wt%) 7.58)
treatment (AT) machined Ti
Loading of the drug
on nanotubes layer
via immersion Vancomycin (200
followed by μg/cm2)
43 Chemical Machined R S. aureus (ATCC 25923) Log10 CFU 3.4 (±0.1) 0.9 (±0.4) <0.01 NR [135]
catechol- Chitosan-catechol
functionalized (0.01 g/mL)
multilayer films
(spin coating)

1w: 100.56 1w: 26.47
(±28.4) (±4.67)
Layered double
Ciprofloxacin (1.2 P. aeruginosa (PAO1 CTX:: Bioluminesce 2w: 99.40 2w: 68.45
44 Chemical hydroxides Porous Mic NR NR [81]
± 0.2 mg/cm2) lux) intensity (±37.64) (±28.03)
suspension
3w: 289.88 3w: 276.19
(±21.30) (±47.43)
HACC (Na = TC-CH: 8.37
TC <0.05
0.14–0.25; Si = 8.65 (±0.66) x (±0.59) x 104
45 Chemical Layer-by-layer TC-CH R MRSA (ATCC 43300) CFU/implant (Control vs NR [84]
0.44–0.84; Cl = 105 TC-CHH: 3.6
TC-CHH TC-CHH)
1.07 at.%) (±0.95) x 104
C: 80% (16/
Rolled out on
20)
46 Chemical Sol-gel method Machined Ag (NR) R S. aureus (NR) agar plates test NR NR NR [136]
T: 0% (0/20)
(%reduction)
p < .001
Lyophilization Ti = 4.7 × 105
Physical Ti-NT-C = 1.0 ×
47 method + vacuum Nanotubes- NT CS (2 mg) R MRSA (ATCC4330) CFU/implant (± 8.0 × 104) <0.01 NR [137]
Chemical 104 (± 1.6 × 103)
drying Ti-NT = 2.8 ×
R.C. Costa et al.
ID method
105 (± 3.0 ×
104)
48 Physical MoS2 = Magnetron Machined + NIR Mo (11.22 at.%) R S. aureus (ATCC 29213) Antibacterial NIR -: 0% (± NIR -: 4.62% (± <0.01 (NIR NIR -: 0% [79]
Chemical sputtering light S (23.87 at.%) ratio (%) 4.61) 1.53) +) NIR +:
IR780 = dropping I (0.02 at.%) NIR +: 6.15% NIR +: 98.99% ~92.84%
PDA + RGDC = (± 2.31) (± 0.42)
immersion
HA-VCM: 1.2
Thermal spraying Ag (3 wt%) (±1.3) × 106 <0.05 (all
Physical (HA and Ag) Vancomycin - VCM HA: 4.2(±3.5) × HA-Ag: 1.9 tested
49 HA-coated R MRSA (UOEH6) CFU/implant NR [54]
Chemical Immersion (20 μg/mL – 106 (±2.0) × 106 groups vs
(Vancomycin) topically applied) HA-Ag-VCM: 1.2 Control)
(±3.4) × 105
11
2756.25 1829.62
50 NR NR Machined TiO2 (NR) R S. aureus (ATCC 29213) Log CFU >0.05 NR [138]
(±1622.35) (±2939.75)
8.42 (±0.6) x 4
51 Unclear Unclear Machined Vancomycin (NR) Rab MRSA (ATCC 43300) CFU/implant 4.04 (±0.8) x 10 NR NR [139]
105
Notes: Surface treatment (HA – Hydroxyapatite; TC – titanium-coated by plasma vacuum plasma spraying; TC-CH – Collagen I/Hyaluronic acid modified Titanium Coatings; TC-CHH – Collagen I/Hyaluronic acid/
Quaternized Chitosan multilayer modified Titanium Coatings; RGDC = Red Phosphorus/IR780/Arginine-Glycine-Aspartic Acid-Cysteine coating; NIR – Near-infrared light; PEG – Polyethylene glycol; CS – Chitosan; PEO –
Plasma Electrolytic Oxidation; PDLLA – Poly(D,L-lactide), Deposition technology (NR – Not reported), Antimicrobial (HACC –Hydroxypropyltrimethyl Ammonium Chloride Chitosan; NR– Not reported; MoS2 – Mo
lybdenum disulfide; CHX – Chlorhexidine; NP – nanoparticles; CS – Chitosan; MPDA – mesoporous polydopamine nanoparticles); Animal type (Rat – Rats; Mic – Mice; Rab – Rabbit; S –Subcutaneous; D – Dog); Infection
model (MRSA – methicillin-resistant Staphylococcus aureus); Microbial load (C – Control; T – Test; h – Hour; d – Day; w – Week; NR – Not reported).

R.C. Costa et al.
Table 2
Summary of subjects (study ID, number of male and female, and mean age), intraoral appliance (material and location), sample (shape, location, number/group, and surface treatment), microbiological assessment
(quantitative test, microbial species, time points, microbial load, p-value and qualitative tests), and reference from included in situ studies.
Study Subjects Intraoral Sample Microbiological assessment Reference
ID appliance
N (M/F) Mean Material Shape Material Surface Quantitative Microbial species Time Microbial load p-value Qualitative
age (location) (location, treatment test points tests
(years) N)
2)
Median: 2) Median:
30 9.16 × 2.75 × 105
p < .05 FISH and CLSM
min 104 (± (± 2.33 ×
analysis
1) Anodized 2.75 × 105)
23 to Cylindrical (Streptococcus
Acrylic (upper (TiUnite®) DAPI staining 103)
1 6 (NR) 54 (buccal, 6/ cpTi Total oral bacteria spp. represent [58]
jaw) 2) Machined (Ti- (cells/cm2)§ 3)
(range) group) the largest
m) Median: 2) Median:
proportion on
120 1.41 × 2.49 × 105
p < .05 all materials)
min 105 (± 3.74 ×
(±1.16 × 105)
105)
NC: Noncoated S.m.: UVNC
UVNC: UV = 0.25
treated NC (±0.4)
HT = 0.07
(±0.2)
UVHT = 0.16
S.m.: NC
(±0.3)
= 0.35
N-m:
12
(±0.4)
UVNC = 6.06
N-m: NC
101,000 NA - directly Cylindrical HT: S. mutans (±0.6)
Ti-6Al- Log = 6.16 (±
2 10 (6/4 39.7 attached on the (buccal, hydrothermally Non-mutans streptococci 24 h HT = 6.14 p > .05 [140]
4V CFU/mL 0.5)
(N (6/4) tooth (upper jaw) 10/group) induced TiO2 Total facultative bacteria (±0.6)
Facult.:
coating UVHT = 5.97
NC =
UVHT: UV (±0.5)
6.26
treated HT Facult.:
(±0.5)
UVNC = 6.24
(±0.6)
HT = 6.16
(±0.6)

UVHT = 6.09
(±0.4)
Surface
Surface
covered
covered total
total p=
bacteria (%)
bacteria .00478
= 11.2
(%) = 3 (total
(median;
Machined (median; bacteria)
8.7/13.7)
Cylindrical (control) 1.7/3.6) p=
Acrylic (upper CLSM (live/ Vital bacteria
3 6 (3/3) 28 (buccal, 2/ cpTi Sandblasted and Total oral bacteria 12 h Vital .00215 NA [21]
jaw) dead) § (%) = 10.7
group) acid-etched bacteria (vital
(8.3/13.2)
(Promote®) (%) = 2.7 cells) p
Ratio dead to
(1.5/3.2) = .0332
total bacteria
Ratio (dead
(%) = 3.7
dead to cells)
(median;
total
3.5/4.3)
bacteria
R.C. Costa et al.
ID appliance
(years) N)
(%) =
11.4
(median;
10.8/
12.9)
1) Machined
(control)
2) SiB-Na (ASD)
3) SiB-Na +
AgNPs (ASD)
2) 1.6 × 106
4) SiB-Na +
Cylindrical 3) 1.2 × 106 p < .05
Polyvinylchloride AgCis (ASD) Log 1) 1.8 ×
4 7 (4/3) 24 (buccal, 3/ cpTi Total oral bacteria 24 h 4) 1.3 × 106 (1 vs 5 NA [141]
(NR) 5) SiB-Na + CFU/mm2 106
group) 5)1.0 × 106 and 6)
GaCiss + L-
6) 1.1 × 106
cysteine (ASD)
6) SiB-Na +
Gaoss + oxalic
acid dehydrate
(ASD)
SEM (No
1) Machined Mean difference in
(control) percentages of 2) 14.91% (± terms of plaque
Cylindrical p > .05
13
Acrylic (upper 2) RBM surface plaque 1) 8.10% 11.00) accumulation

5 3 (NR) NR (buccal, 6/ Ti Total oral bacteria 48 h (tests vs [142]
jaw) (Megagen®) accumulated (± 6.03) 3) 9.40% can be seen
group) control)
3) Xspeed determined by (±7.45) among the 3
(Megagen®) Image J different
surfaces)
Actinomyces naeslundii An = 6 Al-blasted/
A. actinomycetemcomitans Aa = 1 HA: An = 5/4
A. viscosus Av = 5 Aa = 0/2
Bacteroides forsythus Bf = 4 Av = 6/6
Capnocytophaga gingivalis Cg = 2 Bf = 1/3
C. rectus Cr = 2 Cg = 0/1

Eikenella corrodens Ec = 1 Cr = 1/4
Eubacterium nodatum En = 3 Ec = 2/2
Fusobacterium nucleatum Fn = 4 En = 3/4
Gemella morbillorum Gm = 1 Fn = 3/4
Machined N. mucosa Nm = 0 Gm = 2/1
Sheet Checkerboard p > .05
Al-blasted P. micros Pm = 3 Nm = 0/0
6 6 (5/1) 32 Acrylic (unclear) (lingual, 6/ cpTi DNA-DNA 21 d* (All NA [59]
HA-coating P. intermedia Pf = 4 Pm = 4/3
group) Hybridization species)
(electrophoresis) Porphyromonas gingivalis Pg = 3 Pf = 4/5
P. nigrescens Pn = 5 Pg = 2/5
Propionibacterium acnes Pa = 4 Pn = 3/3
P.melaninogenica Pml = 0 Pa = 4/3
S. sanguis SS = 6 Pml = 0/0
Streptococcus oralis So = 4 SS = 6/6
Streptococcus gordonii Sg = 4 So = 6/5
S. intermedius Si = 3 Sg = 6/4
Selenomonas noxia Sn = 1 Si = 4/3
V. parvula Vp = 0 Sn = 2/1
T. denticola Td = 2 Vp = 0/2
R.C. Costa et al.
ID appliance
(years) N)
1) Polished
Mean number
(control)
24 to Cylindrical of bands p > .05
Acrylic (upper 2) ZrN (PVD) 1) 4.5 (± 2) 3.2 (± 3.4)
7 5 (3/2) 31 (buccal, cpTi (richness) of Total oral bacteria 24 h (all NA [143]
jaw) 3) 800-grit 4.8) 3) 6.3 (± 5.5)
(range) 45/group) SSCP-gels tests)
polishing
(rDNA)
(slightly rough)
2) MTT assay
= 0.14
(±0.08)
RT-PCR
MTT
(total
assay =
bacteria) =
1) Machined 0.19 (±
5.4 (±0.3)
(control) 0.05) RT-
RT-PCR
2) Acid etched PCR SEM (the vast
MTT assay (S. oralis) =
Cylindrical (Master (total majority of
Acrylic (upper (OD) RT-PCR Total oral bacteria 3.8 (±0.4)
8 10 (NR) NR (buccal, cpTi Porous®) 24 h bacteria) p > .05 surfaces were [144]
jaw) (log bacterial S. oralis 3)
17/group) 3) Anodized and = 5.5 (± colonized by
cell/disc) MTT assay =
laser irradiated 0.2) cocci)
0.12 (±0.07)
(Vulcano RT-PCR
RT-PCR
active®) (S oralis)
(total
= 3.7 (±
bacteria) =
0.3)
14
5.4 (±0.3)
RT-PCR
(S. oralis) =
3.6 (±0.6)
Microscopic
analysis
Implant 4 Uncoated (percentage of
21 to
× 13 mm (control) surface 21.3 (±
9 6 (NR) 25 Acrylic (unclear) cpTi Total oral bacteria 24 h 13.1 (± 2.01) p < .05 SEM [145]
(buccal, TiN-coated covered by 1.9)
(range)
12/group) (PVD) bacteria using
Image-Pro Plus
4.5)

1) Machined
(control)
2) 1.21
2) Acid-etched SEM (similar
(±0.46)
Cylindrical TiZr 3) Sandblasted Biofilm mass p < .05 patterns and
16 (5/ Acrylic (upper and 1) 0.61 3) 1.17
10 25.5 (palate, 64/ Ti-6Al- (corundum) and by safranin Total oral bacteria 24 h (1 vs all; amounts of [89]
11) lower jaw) (± 0.38) (±0.40)
group) 4V acid-etched staining (OD) § 3 vs 4) biofilm among
4) 0.87
4) Micro- all groups)
(±0.48)
grooved (laser
process)
Notes: Subjects (M – Male; F – Female; NR – Not reported), Intraoral appliance (NA – Not applicaple; NR – Not reported), Sample (N – number of samples; Ti – Titanium; Zr – Zirconium; Ti-6Al-4 V – Titanium-6Aluminum-4
Vanadium; ASD – Anodic Spark Deposition; ZrN – Zirconium nitride; PVD – Physical Vapour Deposition; TiN – Titanium nitride), Microbiological assessment (CFU – Colony Forming Units; CLSM – Confocal Laser Scanning
Microscopy; MTT - 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide; RT-PCR - Reverse Transcription–Polymerase Chain Reaction; SEM – Scanning Electron Microscopy; OD – Optical Density; § - values
reported as median; min – minutes; h – hours; d – days; * - the study evaluated 5 time points; FISH - Fluorescence in situ hybridization; SSCP – Single-strand conformation polymorphism; NA – Not Analyzed).
Table 3
R.C. Costa et al.

Summary of study ID, study design, implant (surface treatment, brand and sample), microbiological assessment (quantitative test, microbial species, microbial load and p-value), peri-implant data (quantitative test; peri-
implant outcome and p-value) and reference from included human studies.
Study Study Patients Mean Implant Microbiological assessment Follow- Reference
ID design (sex) age up
Surface Brand Sample Quantitative test Microbial species Microbial load p-value
(±y)
treatment (N)
S. sanguis
S. mitis
S. mutans
Strep. spp
Staph. spp
Enterococcus faecalis
Enterococcus faecium
Enterococcus avium
P. micros
P. prevotti
S. constellatus
8.6 × 106 CFU/mL 4.8 × 106 CFU/mL
9 (M = 53–69 C = machined Tri-stage (San CFU (% positive Streptococcus morbillorum
1 N-RCT 40 (Total bacteria (Total bacteria >0.05 10 m [51]
5/F = 4) (NR) T = HA-coated Diego, USA) culture) Actinomyces naeslundii
count) count)
A. viscosus
E. spp
V. parvula
A.actinomycetemcomitans
Klebsiella pneumoniae
Enterobacter cloacae
Enterobacter aerogenes, P.
aeruginosa
Pseudomonas stutzeri
15
W. recta
F. spp.
Supragengival: T1
C = machined
= 47.4(±32.4)%
T1 =
T2 = 18.6 Supragingival:
Sandblasted Coverage surface
Supragengival: 5.7 (±31.4)% <0.05 (T1 vs C,
(Al2O3) Nobel Biocare (%) of supra and
11 (M = 52 (± (±14.4)% T3 = 15.6 T2 and T3)
2 N-RCT T2 = Ground (Goteborg, 15 subgingival Total oral bacteria counts 14 d [60]
7/ F = 4) 21.2) Subgengival: 0.6 (±18.7)% Subgingival:
(diamond bur) Sweden) biofilms (Image J
(±1.2)% Subgengival: T1 = >0.05 (all
T3 = Acid- software)
1.3(±1.2)% groups)
etched (HF
T2 = 0.6(±0.8)%
acid)

T3 = 0.6(±1.3)%
A.actinomycetemcomitans 2w: 43.8% 2w: 40.6%
Keystone RT-PCR (number
18 (M = C = Machined Porphyromonas gingivalis 3w: 46.9% 3w: 40.6% 2, 3, 4
62.4 dental group of positive >0.05 (all time-
3 N-RCT 11/F = T = Anatase- 32 T.denticola 4w: 40.6% 4w: 31.3% w [94]
(NR) (Burlington, implant points)
7) coated collar T.forsythia 1y: 18.8% (Total 1y: 25.0% (Total 12 m
USA) colonization)
P. intermedia bacteria count) bacteria count)
Coverage surface
17 (M = C = Machined Pikkasshu
64.6 (%) of biofilms
4 N-RCT 6 /F = T = nano-Ag (Kumamoto, 34 Total bacteria 44.3% (±12.67) 33.6% (±8.35) 0.0079 4w [93]
(NR) (Photo-editing
11) coating Japan)
software)
Aerobic bacteria Aerobic bacteria (5
(5.5 log 10) log 10) Anaerobic
C = Turned Aerobic bacteria,
14 (M = Nobel Biocare Anaerobic bacteria bacteria (6 log 10)
62.1 surface Anaerobic bacteria, >0.05 (All
5 RCT 10/F = (Goteborg, 75 qPCR (6 log 10) P. gingivalis (0 log 3y [90]
(NR) T = TiUnite P. gingivalis, P. intermedia, species)
4) Sweden) P. gingivalis (2 log 10)
surface T. forsythia
10) P. intermedia (0 log
P. intermedia (0 log 10)
R.C. Costa et al.
Study Study Patients Mean Implant Microbiological assessment Follow- Reference
ID design (sex) age up
Surface Brand Sample Quantitative test Microbial species Microbial load p-value
(±y)
treatment (N)
10) T. forsythia (1 log

T. forsythia (0 log 10)
10)
F. nucleatum F. nucleatum
C = Machined
410 (±393) 81 (±79)
T = PIXIT Total bacteria (TB)
15 (M = 53 Edierre srl C. rectus C. rectus Fn = 0.000 Cr =
6 RCT (CHX 1% - 52 RT-PCR Fusobacterium nucleatum 4m [92]
6/F = 9) (NR) (Genova, Italy) 914(±758) 59 (±66) 0.006 TB = 0.001
internal C. rectus
Total bacteria 90.0 Total bacteria 81.0
coating)
(±53.7) (±45.1)
Study Study Patients Mean Implant Peri-implant outcomes Follow-up* Reference

ID design (sex) age
Surface treatment Brand Sample Quantitative test# Control Experimental p-value
(±y)
(N)
Lower anterior
region: GI = 2.4
Lower anterior
(±0.1)
region: GI = 2.2
16
PD = 2.0
(±0.1)
(±0.1)
PD = 2.0 (±0.2)
PI = 57.5%
PI = 59.8%
Lower posterior
Lower posterior
region: GI = 2.2
1) Gingival index (GI) region: GI = 2.0
62.9 C = machined Paragon Company (±0.2) >0.05 (All
1 N-RCT NR 2900 2) Silness and Löe plaque index (PI) (±0.1) 36 m [91]
(NR) T = HA-coated (Encino, CA). PD = 2.3 indexes)
3) Probing depth (PD) PD = 2.3 (±0.1)
(±0.1)
PI = 60.0%
PI = 57.2%
Upper anterior
Upper anterior
region: GI = 1.1
region: GI = 0.9
(±0.1)

(±0.1)
PD = 3.0(±0.1)
PD = 2.9
PI = 70.6%
(±0.1)
PI = 76.0%
1) 0.53 (±0.7) 12y (PI, AB
Astra Tech 1) Plaque index (PI) 2) Angulated 1) 0.5 (±0.64)
C = Turned T = 2) 0.37(±0.3) and PD
20 (M = 7/ (Dentsply Sirona, bleeding index (AB) 3) Probing pocket 2) 0.44 (±0.33)
2 RCT 53 (NR) Tioblasted 80 3) 2.57(±1.13) NR analysis) [61]
F = 13) AB, Molndal, depth (PD; mm) 4) Marginal bone 3) 2.68 (±1.18)
(moderately rough) 4) − 0.11 5 y (MB
Sweden) changes (MB; mm) 4) − 0.06 (±0.41)
(±0.34) analysis)
Notes: NR– Not reported; C – Control; T – Test; h – Hour; d – Day; w – Week; # – Gingival index evaluated by Löe and Silness index and plaque index evaluated by Silness and Löe; * – End-point for each analysis.
Fig. 4. Overview of available titanium surface modifications. The physical, chemical, and physical-chemical methods were used to produce Ti surface modifications,
as follows: porous surface (1 [72] and 2 [55]), particles-containing surface (3 [73] and 4 [49]), pillars-type surface (5 [74] and 6 [56]), nanotubes surface (7 [69]),
slice-type surface (8 [75] and 9 [76]), pitting-like surface (10 [71], 11 [77] and 12 [78]), spike-like surface (13 [66]), column-type surface (14 [79]), granular-like
surface (15 [80] and 16 [81]), spear-type surface (17 [82]), wires-like surface (18 [83] and 19 [68]). Each number (black square) represents the study and its
respective micrograph of the surface. Different scale bars were considered based on study’s description, showing μm- and nano-scale surfaces changes. Reprinted
(adapted) with permission from Elsevier (Licence Numbers: 5155910020417; 515,591,036,048; 5,155,910,766,325; 5,155,911,132,061; 5,155,920,044,862;
5,155,920,350,790; 5,155,920,489,184; 5,158,220,465,489; 5,158,220,682,404; 5,158,220,945,204; 5,158,230,390,889), Springer Nature, American Chemical
Society, and John Wiley and Sons in terms of Creative Commons CC BY licence.
mouth, mimicking real conditions that allow biofilm to form, with the samples are in contact not with oral mucosa, but with acrylic appliances
expected oral bacterial interactions. In this case, in situ studies can mimic only, which can not mimic sub-gingival environment.
the in vivo biofilm formation when the implant is placed in a patient’s Different from pre-clinical studies, only 8 human studies met the
mouth, but with better control of outcomes. All 75 volunteers described inclusion and exclusion criteria for assessment of the effects of available
in the selected articles wore intra-oral appliances containing Ti samples implant coatings on microbial accumulation. Importantly, many human
to allow for biofilm accumulation. The follow-up times in the included studies were excluded, since they did not evaluate the antimicrobial
articles ranged from 30 min [58] up to 21 days [59] after early biofilm effect of the Ti surface by any microbiological method. This represents a
formation. Although in situ models represent an interesting and ethically significant scientific barrier to be overcome in the implant dentistry
acceptable research approach, the extrapolation of results to dental field. Altogether, approximately 104 participants of both genders and a
implant conditions should be carefully done. The host–bacterial in range of ages were treated with 300 dental implants for tooth replace
teractions cannot be fully reproduced with this model, because the Ti ment. Prosthetic and patient factors could not be summarized due to the
17
Fig. 5. The spider-web-like graph presents the network of antimicrobial subgroups functionalized on a Ti surface by different deposition methods. Green nodes
represent the chemical deposition methods and purple nodes the physical deposition methods. The size of the node is proportional to the number of animal studies
included. Gray lines represent the direct comparisons of each antimicrobial deposition method, and the line thickness is directly proportional to the number of
incorporations. The antibacterial polymers, biological peptides, silver ions, and vancomycin were the agents most functionalized in implant surfaces. Abbreviations:
AMP = antimicrobial peptides; BP = biopolymers; VitE = Vitamin E; DTM = Daptomycin; CHX = Chlorhexidine; NO = nitric oxide; CT = catechol; CFX = Cip
rofloxacin; CHT = Chitosan; F = Fluoride ion; Ga = Gallium ion; HA = Hydroxyapatite; MoS2 = Molybdenum disulfide; Bi2S3 = Bismuth sulfide; Se = Sellenium ion;
GTM = Gentamycin; TBM = Tobramycin; TaO = Tantalum oxide; P = Red Phosphorus; VCM = Vancomycin; Zn = Zinc ion; I = Iodine ion; Ag = Silver ion; and TiO2
= Titanium dioxide. Of note, biopolymer (BP) and antimicrobial peptide (AMP) classes were created to match biological agents with similar biocompatible behavior.
(Created by Cytoscape®).
lack of information. For the included studies, the minimum and to limit microbial adhesion [16]. Clearly, the combination of suitable
maximum follow-up periods were 14 days [60] and 12 years [61], rough topography (Ra = 0.51–1.36 μm; Sa = 0.66–2.91 μm) [63] and
respectively. higher surface energy/hydrophilicity [64] may synergistically induce a
suitable microenvironment to modulate macrophage polarization and
host-cell migration and proliferation, thus reducing healing time and
3.3. Outlining deposition technologies applied to promote surface
accelerating osseointegration [47]. This principle is used in sandblasted
modifications and antimicrobial agents’ functionalization
and acid-etched (SLA) surfaces, which are commonly available surface
treatments in dental implants [65]. Although SLA surfaces have a strong
The implant materials used in all eligible studies were medical-grade
track record of clinical success in dentistry, they lack antibacterial ca
pure titanium, titanium‑aluminum‑vanadium (Ti-Al-V), and titaniu
pabilities, and their effects against biofilm infections are limited. In line
m‑aluminum‑niobium (TiAlNb) alloys. Only in the animal model studies
with clinical demands, several antibacterial Ti surfaces modifications
were the most common anchoring implant designs screw-type (threa
have frequently been proposed over the years (Fig. 4). The mechano-
ded), cylindrical (without thread), and wires (rod-shaped). Screw-type
bactericidal mechanisms have been well-defined in material science
implants have been most used because of their excellent initial stabil
and surface engineering in recent decades, including the creation of
ity, whereas the stability of cylindrical and wire implants depends on an
biomimetic surfaces bioinspired in nature [66–68], which offers various
exact fit within the bone [62]. Conversely, Ti discs (various shapes and
physical ways to reduce microbial adhesion [15]. In addition to the
diameters) were commonly tested in in situ models, while human studies
micro-nanostructuring of Ti biomaterial, changes in the physicochem
have used real dental implants with different macrogeometric shapes/
ical properties of the substrate can also be achieved to promote anti-
designs. In terms of microbiological assessment, both surface topog
biofilm effects by killing bacteria upon direct contact [69–71].
raphy and design of implants can influence biofilm accumulation
Regarding surface treatment applied in bulk Ti material, the majority
[10,59], and these factors should also be considered in pre-clinical
of the studies used machined (n = 30), titanium dioxide (TiO2) nano
studies for translation of these findings into clinical situations.
tubes (n = 7), hydroxyapatite-coated (n = 6), or porous-coated (n = 3)
Since the implant surface is involved, surface properties and chem
implant surfaces. Mostly, these surfaces were evaluated either isolated
ical composition play a crucial role in the predictability of the implant-
or associated with antimicrobial components incorporated into the
to-bone response [12]. Among the physical-chemical modifications that
coatings. For the development of emerging antimicrobial coatings,
have been proposed so far to alter Ti surface properties, the most
plasma treatment (n = 13) and the immersion method (n = 10) were the
important are surface-free energy, wettability, charge, and topography,
18
most used coating technologies (Fig. 5). The antimicrobial agents were
functionalized directly into the material surface (one-step reaction) or
under pre-formed surface treatment (two-step reactions), by either
several physical and chemical methods or both. Generally, a one-step
reaction was directly applied to implant surfaces to change their
topography (μm and nm scales), while two-step reactions under pre-
formed surface treatments were used as cross-linker substrates to func
tionalize therapeutic nanoparticles [49,66] or drug immobilization
[84,85].
Based on antimicrobial incorporation, biopolymers (n = 7), AMP (n
= 7), silver ions (n = 7), and vancomycin (n = 7) were the agents most
functionalized on implant surfaces. Also, it was possible to observe that
the same agent could be incorporated into the substrate either alone or
in combination with others, by physical or chemical methods. Interest
ingly, chemical methods were more often applied to immobilize organic
elements, because long-term adsorption may not be successful due to
possible detachment when physical methods are used [9]. Meanwhile,
physical and physical-chemical methods have been widely used to dope
metallic ions onto Ti surfaces by a one-step reaction. Each deposition
method has pros and cons as a route to synthesis Ti modifications, as
previously revised [9]. Physical methods (e.g., plasma treatment, hy
drothermal method, magnetron sputtering, thermal spraying, tube
furnace, spin-assisted, electrostatic adsorption, vacuum-drying, plasma-
sprayed, and flame spraying system) are cheaper and generally per
formed in a shorter time, while chemical methods (e.g., immersion,
soaking method, manual application, impregnation, sol-gel method,
covalently bond, layer-by-layer, dipping method, silanization, dropping
method, and immobilization) are more expensive and often involve
several steps for coating synthesis [12]. Conceptually, the ideal method
should be low-cost, structurally reliable, reproducible, and environ
mentally friendly, thus being a critical industrial challenge [86]. Obvi
ously, it was not possible to strictly delimit physical from chemical
coatings for the current study analysis since some techniques combined
multiple physical and chemical processes. However, we relied mostly on
the main idea behind each process. The main features of surface modi
fications and deposition methods were described individually for direct
comparison among the studies (Tables 1, 2 and 3).
Another relevant point is that antimicrobial concentrations on the
surfaces should be suitable to promote the dose-response effect without
affecting biocompatibility or creating a lower dose that could allow for Fig. 6. Bacterial species assessment in each study design. The bacterial abun
the selection and overgrowth of bacteria-resistant strains. Moreover, it is dance (%) was calculated based on the main pathogen used in the infection
essential that the drug delivery system release the antimicrobial agent in model for all included studies. Total oral bacteria, anaerobic bacteria, and
a minimum concentration for a long period to achieve the antimicrobial aerobic bacteria were generally reported as described by the authors. Alto
gether, 45 bacterial species were used, with different frequencies among the
effect for a chronic process, such as dental implant-related infections.
studies. The in situ model and the N-RCT showed more extensive diversity of the
We found a wide range in the antimicrobial concentrations tested among
bacterial species evaluated.
the animal studies, in which either concentrations were standardized
based on in vitro screening tests or this information was not reported.
clinical trial (RCT; n = 1; ~ 30%). As expected, almost all current
Furthermore, only a few studies (n = 11) evaluated sustained drug
clinical studies in implant dentistry have used commercial implant
release in long-term follow-ups (e.g., weeks or months). Overall, drug-
surfaces such as SLA® [21,60,89], TiUnite® [58,90], Turned® / Bio
release methods were observed in almost half of the experiments (n =
blast® [61,90], and PerioApatite® [51,91]. This can be partially
21), with antibacterial effects reported in only early biofilm develop
attributed to the fact that all papers retrieved in our literature search
ment (Supplemental results; Table S3). Importantly, drug-release ki
were focused on the interrelationship between surface treatments and
netics is dependent on the type of deposition method applied [87], and
osseointegration, and, therefore, microbiological outcomes were not
the same drugs [54,88] can show different chemical and release
their main purpose. Surprisingly, a small number of clinical research
behavior when immobilized on the surface by physical or chemical
papers (n = 8) addressed relevant oral microorganisms and conducted
methods. Thus, the choice of deposition method, the drug type, and
biofilm characterizations.
establishment of the desired concentration to be released are essential
Among the antibacterial coatings tested in humans, only chlorhexi
steps toward the production of a sustainable drug delivery system in the
dine [92], silver [93], and titanium dioxide (anatase phase) [94] were
physiological environment.
compared with either machined or commercial surfaces. To date, no Ti
Based on the available scientific literature, we have confirmed that
surface modifications or antimicrobial coatings have shown a good
there is a huge discrepancy in the surfaces investigated between pre-
clinical effect in controlling dental implant-related infections. Another
clinical and clinical studies. In animal studies, many experimental
current limitation is that some studies [60,93,94] used the screw-type
antimicrobial coatings have been tested (n = 50; ~ 98%). However, even
implant component known as the healing abutment (located in the
when promising laboratory results were demonstrated, these surfaces
transmucosal area, not in contact with the bone) as a clinical substrate
have barely progressed to be tested in in situ models (n = 4; ~ 40%), non-
for testing the impact of antibacterial coatings on microbial
randomized clinical trials (N-RCTs; n = 2; ~ 40%), and a randomized
19
accumulation. This research approach can be interesting for evaluation

of the treatment for the abutment itself but not for coatings proposed to
be applied to the implant screw body. Moreover, distinct oral micro
biomes, expected on different implant sites (supragingival and sub
gingival environments) [95] are not considered in this experimental
design, thereby demonstrating the need for careful evaluation of the
microbiological effect found and the experimental design used.
3.4. From animals to humans: bacterial profiles and microbial

assessments on titanium-based implants
Aside from the previous findings, the evaluation of bacterial profiles

also differed between pre-clinical and clinical studies (Fig. 6). Staphy
lococcus aureus, the main bacterium related to bone infection in ortho
pedic implants [96], is the preferred pathogen used in animal models
(where tested implants are usually in extra-oral sites) (n = 47). Impor
tantly, since dental implant-related infections feature polymicrobial
communities [29], it is necessary to consider infection models with
relevant bacteria for peri-implant diseases and the microbial diversity of
oral biofilms. In this way, a single study [50] used bacterial strains from Fig. 7. Percentage of reduction in the bacterial load on different titanium
clinical isolates, including Porphyromonas gingivalis, Prevotella inter implant modifications and developed coatings (compared with their control
media, and Aggregatibacter actinomycetemcomitans. From animal data, it groups) according to the study results included in this systematic review. For
is possible to observe that a majority of experimental coatings were this analysis, only studies with the same end-point follow-up were considered
from the total number of studies. The animal model showed a higher % of
developed exclusively for orthopedic applications. Consequently, these
biofilm reduction at all periods of follow-up. In situ models had a large range of
results should be interpreted with caution, since the antibacterial effects
antibacterial effects between 1 and 2 days. There were no clinically relevant
in clinically important oral bacterial strains were not investigated. A effects of the Ti implant surface in preventing bacterial accumulation over
more diverse pool of bacteria has been considered in in situ and clinical long periods.
studies (n = 45); however, only 5 in situ and 3 human studies investi
gated the total load of polymicrobial communities formed over anti
pathogenic biofilms [36], and their morphology, biovolume, and dis
microbially treated Ti surfaces. Therefore, these findings are also
tribution in implants remain to be investigated. Understanding the
limited, due to the different bacterial species and surface treatments
biofilm morphology and 3D arrangement can guide new mechanical
evaluated in each study, not allowing for direct comparison among all
approaches to disrupt pathogenic biofilms, including the use of sonic
studies. Furthermore, it is relevant to highlight the need for a study
instruments [82] and a dual strategy whereby biofilm matrix is first
model that reproduces mature biofilm, since implant-related infections
degraded followed by antimicrobial use, as recently described for Ti
are chronic diseases.
surfaces [36]. Only microbial accumulation on healing abutments has
Nearly all included animal studies reported contamination of the
been measured by photographs used to determine the percentage of
surgical site immediately after implant insertion by a wide range of
biofilm area coverage [60,93]. Thus, information about the spatial or
bacterial inoculum sizes (ranging from 102 up to 109 CFU [colony-
ganization of naturally grown biofilm associated with a human peri-
forming units]). Conversely, only 2 studies [97,98] did not induce
implant disease is currently unavailable.
infection exogenously. It is important to mention that for an implant
Another methodological issue is that several analytical methods have
infection model to be established, a sublethal microbial infection is
been used to determine implant contamination. Generally, in pre-
required — that is, the bacterial concentration must be high enough to
clinical and clinical studies, microbial load has been determined by
generate a self-sustaining infection but low enough to maintain the
CFU counts. For the animal model, an infected implant sample is har
localized condition, not resulting in systemic disease or sepsis in the
vested, and microorganisms are removed, placed in a medium (often by
animal [53]. For this purpose, optimal bacterial inoculum concentra
homogenization or sonication), and plated after serial dilution [96].
tions and vehicles (media or pre-formed biofilm) must be evaluated in a
Interestingly, two studies with mice [81,99] used in vivo imaging of
pilot study for better standardization of microbial concentrations
bacteria with a bioluminescence-labeled strain to track the progression
[52,96], not reported in most of the included studies. To check the ef
of microbial infection in real-time. Since rodents are small, it is some
fects of Ti-surface modifications on the underlying mechanisms of
what less challenging, since light penetration depth is shorter than in
infection, some animal studies (n = 42) have evaluated hard and soft
larger animals, thus being a relevant strategy for the evaluation of
tissues surrounding the implants by radiologic, histologic, immunohis
release-based antimicrobial coatings [100]. Additionally, in some
tochemical, and biomechanical tests (Supplemental results; Table S4).
studies (n = 4), contaminated implants were rolled out on agar plates
Overall, the bacterial reduction on Ti surfaces had a direct impact on
only, for the determination of infection rates. As a result, the infection
better control of implant-related infections.
rates in the experimental groups were lower (close to 0%) compared
In biofilm analyses, bacterial load was measured by destructive
with those on control surfaces (Table 1).
methods leading to disorganization of the three-dimensional biofilm
Polymicrobial biofilms have been exclusively evaluated in human
structure, not allowing for qualitative and architecture biofilm analyses
studies (in situ and clinical) by the Checkerboard DNA-DNA Hybridiza
in animal models. Some studies (n = 11) evaluated biofilm morphology
tion technique and/or PCR analysis to determine individual or total
by scanning electron microscopy (SEM) and confocal images. In transi
bacterial levels, or both (Tables 2 and 3). Biofilm composition is a crucial
tion from the laboratory to the clinic, the techniques most performed for
factor for further studies, since a high bacterial load with an unknown
biofilm harvesting included the use of paper-point instruments in the
profile does not represent a microbiological composition related to
peri-implant sulcus or microbiota removal with a curette. In contrast to
infection. Classic animal studies have used biofilm-retaining ligatures
animal models, no microscopy analyses for the evaluation of biofilm
around the implant to initiate tissue damage and lead to biofilm accu
morphology have been conducted in humans, which would be expected
mulation [101]. Nevertheless, alveolar bone loss in the ligature model is
since samples cannot be removed. As previously mentioned, the extra
dependent on pathogenic bacterial abundance on the ligature, not
cellular biofilm matrix, which is an important virulence factor of
20
Fig. 8. The risk-of-bias graphs review the

authors’ overall judgments about each risk-
of-bias item as a percentage of the total
number of studies. (A) Quality assessment
for animal studies based on the Systematic
Review Centre for Laboratory Animal
Experimentation (SYRCLE). (B) Quality
assessment for non-randomized studies
based on the ROBINS-I tool (Risk Of Bias In
Non-randomized Studies - of Interventions).
(C) Quality assessment for randomized
studies based on the Revised Cochrane risk-
of-bias tool for randomized trials (RoB 2).
Overall, some methodological problems
were found in each study design.
21
necessarily on the implant surface [6,29]. Additionally, some aspects of methodological principles for biomedical research, especially for animal
the animal model — such as dietary habits, oral microbiota, stability of models. Furthermore, animal studies must provide more comprehensive
immune responses, and specific dento-alveolar anatomy — are also and complete reports for an adequate risk-of-bias assessment, since the
significantly different from those of humans [102]. With those limita prevalence of “unclear” judgment was noted, which is not surprising,
tions, these models cannot fully address specific questions related to the since numerous unclear risk-of-bias items are often observed in animal
disease-associated human oral microbiome and require further and experiments in the implant field [103]. By careful evaluation and
detailed investigation for findings to be determined appropriately. reporting of these unclear issues, an optimization of the design and
Tables 1, 2, and 3 summarize the bacterial loads (control and test conduct of animal studies may be achieved [103]. Thus, since animals
groups) based on the microbiological test used, taking into account the are vulnerable, models should be carefully planned, and sample sizes
longest follow-up time for each study. To facilitate reporting, included clearly justified. Clinically, well-designed randomized clinical studies
studies were also ‘lumped’ into each study design, and then the per comparing emerging antimicrobial coatings and control surfaces (i.e.,
centages (%) of biofilm reduction were calculated (Fig. 7). Although commercial or without the incorporation of antimicrobial factors) with
various Ti implant-surface modifications and experimental coatings well-defined inclusion and exclusion criteria, adequate sample size,
have been considered, it is essential to highlight the considerable gap experienced and blinded surgeons, standardization of implant and
between pre-clinical and clinical findings. Regardless of the study prosthesis types, sites of implant placement, and suitable microbiolog
design, there is a highly variable % of biofilm reduction, ranging from ical assessments are required to validate current laboratory findings.
− 25% to >95%. In terms of study design, the animal model shows % of
biofilm reduction higher than that of other study designs in all follow-up 4. Discussion and suggestions for future research in surface
periods (~ 3-fold increase), which may be due to greater control of the science
experimental models and conditions. Indeed, we also found a trend to
ward reduced antibacterial effects in long-term periods (~ 28% of The pursuit of Ti surface modifications is a research area that has
reduction). Importantly, in situ models were used only in short-term received substantial attention in recent years due to the possibility of
periods, showing a more extensive range of effects between 1 and 2 preventing microbial infections. In this regard, we conducted this
days (from 65% to 5% reduction). In a clinical scenario, the effects of Ti narrative and critical evidence-based review about the potential of
implant surfaces in long-term periods were limited (< 25% of reduc various available surface-modification methods as well as emerging
tion), also showing an absence of effect (from − 10% to − 25% of coatings to combat oral bacterial accumulation investigated in pre-
reduction) at some time points. From a careful evaluation of all these clinical and clinical studies. Our main strength was in showing, sys
contrasting studies, it seems that the anti-biofilm effects of these tematically, that there is no current consensus regarding the optimal Ti
experimental surfaces are often transient or subject to “species bias”. surface modifications and coatings for reducing oral microbial accu
mulation and preventing dental implant-related infections. There is a
3.5. Methodological weaknesses and strategies to enhance the weight of huge gap between animal and human studies related to the limitations of
evidence in antimicrobial implant surfaces research methodological issues and clinical expectations. Thus, because dental
implant-related infection remains a major clinical challenge, new smart-
To provide a better critical appraisal of the pre-clinical and clinical release approaches to improve current surfaces have been strongly
studies included in this critical evidence-based review, we performed a recommended to control and treat pathogenic biofilms and allow for the
risk-of-bias assessment in animal, N-RCT, and RCT studies (Fig. 8). For re-establishment of a health-associated microbiome.
this analysis, in situ studies were not considered because of the current According to the regulatory requirements of the ISO (International
lack of availability of quality assessment methods. For animal models Organization for Standardization) and the FDA (U.S. Food & Drug
(Fig. 8A), we have demonstrated that all studies failed to report whether Administration), animal experimentation in dental research is an
caregivers and outcome assessors were blinded to knowledge regarding essential step toward the conduct of clinical trials [104]. The animal
the intervention to which each animal was assigned, as well as sample studies in our review varied in methodological quality and sample sizes
size calculation to determine the numbers of samples and animals rather than providing a single, definitive high-quality experiment for
required to achieve statistical significance without alpha or beta errors, each emerging Ti implant modification and coating tested. Furthermore,
and other bias. Consequently, most animal studies were classified as there are many critical variables to be considered in selection of a model
having unclear risk-of-bias. We have provided a full list of risk-of-bias of dental implant-related infections. Pathogen species (type of inoc
assessments for each included animal study (Supplemental results; ulum), amount of pathogen (concentration of inoculum), inoculation
Fig. S3). vehicle, and the course of infection/inflammation should be monitored
Regarding the quality assessment of N-RCTs (Fig. 8B), the included and validated [53,96]. These issues need to be taken into consideration
articles exhibited a serious or moderate overall risk-of-bias. Generally, for future research to improve quality and reduce heterogeneity among
problems were related to confounders in either the participant selection studies [103]. In general, the goal should not be to define the most
process or inequality among participants. In addition, potential biases similar model to humans, but rather to investigate how various models
associated with the measured outcomes arose for all clinical trials, since can be used to provide insights into the mechanisms of dental implant-
blinding of outcome assessors was not possible, and the inclusion of an related infections [101]. It is well-established that the etiology of peri-
examiner outside the trial context was not done. Overall, risk-of-bias in implant diseases is multifactorial, more specifically polymicrobial, and
RCTs (Fig. 8C) revealed some concerns as a final classification, mainly host-specific. However, the pathogenesis of peri-implant disease is in
because of insufficient information about randomization, selection of flammatory [38]. Thus, we are now in a position to deepen and improve
patients, and measurement outcomes domains. In cases where partici the classic animal models with a focus on the expression of virulence
pants were selected into studies by a randomization process, these were factors and host responses. In this way, the aim is to induce deleterious
biased by the selection of participants based on characteristics observed microbial shift and hence the inflammation process to establish a cause-
after the start of intervention and the absence of accordance between effect inference by using different implant surfaces.
methodology and reported results. Individually, the included human From the implant surface standpoint, future challenges include the
studies were also fully described (Supplemental results; Figs. S4 and S5). newly proposed biomimetic surfaces inspired by nature, with micro- or
From the risk-of-bias assessments, it is not surprising, therefore, why nanoscale modifications, which could constitute a dynamic behavior
several antimicrobial implant coatings have been developed over time pattern for the prevention of bacterial re-colonization [11]. Although
with promising laboratory results but have not progressed to clinical nanopattern topography can lead to bacterial killing by bacteria-surface
use. This creates the need to revisit the basic science models and interactions (without drug incorporation), the increased accumulation
22
Fig. 9. Fitting pieces into the puzzle: Overview of emergent smart surfaces and their mechanisms to improve implant-related infection management. Created with BioR
ender.com (Licence number: KS22ZBDZ12).
of dead bacteria over time might also promote new attachment of live biomaterials, there are three main barriers to the design of these sur
bacteria and development of a multi-structured biofilm [15]. To over faces: (i) long-term and sustained antibacterial effects; (ii) ability to
come this current limitation, flexible nanopatterns (bioinspired in the reload the surface; and, primarily, (iii) maintenance of an effective local
cilia of epithelial cells) have been suggested to ensure more effective bacteriostatic or bactericidal effect at the implant surface without
mechano-bactericidal actions regulated by an electromagnetic field affecting the host response, causing cytotoxicity to the implant-
[105]. Additionally, other emergent and promising strategies for biofilm surrounding tissues or allowing increased antimicrobial-resistant
removal on Ti surfaces, such as electron transfer between the bacteria strains at the site [87,100]. Based on the revised scientific literature,
and the implant interface, or electrical modulation of the implant have we show that designing an implant coating to overcome these current
been proposed in recent years [106,107]. Both methods are able to barriers, regardless of deposition technology, is still an unfulfilled
disrupt bacterial viability on implant surface based on electron-transfer- promise. Clinically, until now, only chlorhexidine, silver, and titanium
induced reactive oxygen species mechanism, either by using wave- dioxide antimicrobial coatings for dental implants have been tested in
driven triboelectric nanogenerator and two nanobrush electrodes humans [92–94]. Despite the efforts made by the scientific community
made of Ag-nanoparticles integrated ZnO-nanowires or by using Ti to create and test new antimicrobial coatings, most of them are still
embedded with silver nanoparticles (Ag-NPs@Ti) that after electron under development and, for this reason, have only been tested in vitro;
transfer between the Ag-NPs and Ti substrate produce bursts of reactive thus, with yet unknown long-term clinical benefits. In the near future,
oxygen species leading to bacteria death by inducing intracellular we hope that some of the currently emergent surfaces can show prom
oxidation. As a result, both treatments create strong antibiofilm mech ising results under in vivo conditions. For this, it is imperative that future
anisms, which can facilitate the control of titanium-associated microbial studies use standardized and widely accepted validation methodologies
infections, as also reported by others [15,105]. Another interesting idea for antibacterial coatings in the setting of specifically structured dental
would be to combine these antimicrobial nanostructures with bioactive research that is consistent with its intended oral-clinical applications
compounds, biomolecules, growth factors, and immunomodulators for [16]. Furthermore, investigators undertaking the development of new
future multi-targeting strategies based on the modulation of the local surfaces should consider basic sciences, including the biologic and
immune responses of the host [1,9]. microbiological aspects of the oral environment and factors modulating
In terms of antimicrobial load on and release-based coatings of Ti biofilm formation, which affect bacterial growth. As we showed recently
23
[108], a surface coating may not reduce late biofilm growth, but can Declaration of Competing Interest
affect the process and modulate the microbial composition, driving to
ward an increased level of host-related microorganisms favoring a The authors declare that the research was conducted in the absence
symbiotic state. Since most of the studies evaluated only initial biofilm of any commercial or financial relationships that could be construed as a
formation, it should not be considered to control peri-implantitis in potential conflict of interest.
fections — a chronic disease triggered by mature biofilms [29] — and
the developed surface may act only during the healing process of the Acknowledgments
implant device.
The accumulated knowledge in material and surface engineering for This study was funded by São Paulo Research Foundation (FAPESP)
the last 30 years has facilitated the consolidation of the new generation grant number 2020/10436-4 and Coordenação de Aperfeiçoamento de
of activated biomedical surfaces, denominated as ‘functional self-regu Pessoal de Nível Superior (Grant/Award Number: 001) to R.C.C., and
lating’ or ‘smart’ surfaces (Fig. 9) [109,110]. Although many of these Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
surfaces are still under development in the laboratory, some are grant number 304853/2018-6 and São Paulo Research Foundation
advancing rapidly and certainly represent a powerful and valuable op (FAPESP) grant number 2020/05231-4 to V.A.R.B. Graphical abstract
tion to prevent implant-related infections in the near future [111]. and figures were designed using the web interface BioRender®.
Conceptually, smart surfaces are substrates that respond to distinct
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