biocybernetics and biomedical engineering 40 (2020) 596–610

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journal homepage: www.elsevier.com/locate/bbe

Review Article

Biodegradable bone implants in orthopedic

applications: a review

Girish Chandra *, Ajay Pandey

Department of Mechanical Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh
462003, India

article info abstract

Article history: A biologically - validated biodegradable material must comfortably stay in the physiological
Received 20 August 2019 environment it is placed in, before finally disappearing over the intended period of time with
Received in revised form adequate rates of degradation. The primary objective and utility of such a material is to
30 January 2020 eliminate the requirement of secondary surgery in applications involving bone implants. In
Accepted 1 February 2020 recent decades, biodegradable alloys have exhibited enhanced biocompatibility, and im-
Available online 20 February 2020 proved mechanical and biodegradation properties. This has generated renewed interest in
the design of bone implants made up of such materials that can successfully support
Keywords: fractured bone till the culmination of the healing process. However, striking a balance
Bone implant between two seemingly conflicting requirements, namely - sustaining the strength of the
Biodegradable implant till the bone acquires the desired strength of its own, and allowing the implant to
Healing keep losing strength with its gradual degradation – may be rather complex. To manage this,
Mechanobiology different healing phases and the associated bone - biodegradable implant interface mechan-
obiology needs to be focused upon. An adequate and/or optimal design of the implant is
based on mechanical properties, degradation rates of implant and bone-biodegradable
implant interface interactivity. This review mainly focuses on bone - biodegradable implant
interface with due consideration accorded to the mechanical properties, degradation rates
and healing process in a standard duration.
© 2020 Nalecz Institute of Biocybernetics and Biomedical Engineering of the Polish
Academy of Sciences. Published by Elsevier B.V. All rights reserved.

reflective of micro damage to bones due to cyclic loads [1].

1. Introduction
Bone fracture is the most common structural breakage.
Termed as injury, it involves both biological and mechanical
aspects that are mainly produced by accidental load, cyclic
loads, or constant loads acting over prolonged periods of time
beyond the physiological range. Some of the cases are indeed
Fatigue failure is essentially because of the accumulation of
microscopic damage as a consequence of repeated loading.
Naturally occurring materials can display exceptional me-
chanical performance and serve as useful models for design-
ing the microarchitectured materials. However, it is also
reported that stress concentrations within the microstructure
of microarchitectured materials can result in flaw intolerance

* Corresponding author.
E-mail address: girishcd.3003@gmail.com (G. Chandra).
https://doi.org/10.1016/j.bbe.2020.02.003
0208-5216/© 2020 Nalecz Institute of Biocybernetics and Biomedical Engineering of the Polish Academy of Sciences. Published by Elsevier
B.V. All rights reserved.
 biocybernetics and biomedical engineering 40 (2020) 596–610
under cyclic loading, thereby limiting the fatigue life. Bone is a
biological material with high stiffness and strength relative to
density. In humans, most bones survive more than 50 years of
habitual loading without failure [2]. In human bone fracture
cases, the implant needs to provide support till complete
recovery of the original bone to its pre –fracture state [3]. Some
types of fracture can be supported from outside using plaster
but some critical fractures require an inside support using
implant [4].
An implant made up of a biomaterial must be biocompati-
ble and provide support to the biological, fractured structure.
Implants are essentially of two types: Non-biodegradable (like
stainless steel, titanium alloy, etc.) that need to be removed
after healing process or replaced during healing process by a
secondary operation/surgery, and Biodegradable which might
not require a removal after healing [4,5]. Designing biodegrad-
able orthopedic implants made up of biodegradable metallic
materials is a complex area in biomechanics [6].
Non-biodegradable implants have been used for more than
100 years for internal fixation of bone fractures but the use of
biodegradable materials for orthopedic applications has been a
true game changer. Initial shortcomings encountered due to
some biodegradable implant material (like pure magnesium)
exhibiting fast degradation rates and insufficient strength
have been significantly taken care of, though the design can't
be termed as flawless even now. Further research is needed to
understand the interface mechanobiology for developing an
orthopedic implant that improves fracture healing without
interfering with bone physiology [7]. Biocompatibility is the
ability of the material to conform to the host response, cell
response, and living systems [8]. Cytocompatibility and
hemocompatibility are well - known tests to indicate the
compatibility of an implant device with the surrounding
physiological atmosphere throughout the healing process [9].
During bone fracture healing process, with an anabolic
phase, hematoma formation and local tissue volume starts
just after the bleeding at fracture site in the initial inflamma-
tion stage with an anabolic phase. To regenerate new bone
formation, specific mesenchymal stem cells (MSCs) proliferate
and separate into osteogenic cells in the form of soft callus.
Further regeneration progress takes place with soft cartilagi-
nous callus which needs to be reabsorbed and converted to
hard callus. The hard bone callus improves biomechanical
stability simultaneously to form a rigid structure. The
fractured bone starts working as a normal bone with gradual
increase in mechanical stability within 3–6 months [10].
Traditional biomaterials (non-biodegradable), used as
orthopedic implants for the regeneration of damaged/frac-
tured tissue, are often removed/replaced by secondary
surgery. This results in painful and pestilent effects on the
patient due to increase in weal and infections [11,12]. The
biodegradable implant has a temporary stay only for support-
ing the fractured/failed bone and not allowing it to be
misaligned after competition of the healing process. It also
gets gradually dissolved or absorbed (as nutrients) to promote
the healing process [6,13].
Some metals play a potentially important role in develop-
ment of biodegradable materials and are the preferred options
over ceramics and polymers due to their excellent mechanical,
biological and degradation properties. Generally, degradable
597
metallic biomaterials should provide adequate mechanical
strength until the affected part of body heals. Nutrients
required for bone regeneration process go a long way in
improving the healing process. Some of the biodegradable
metals like Magnesium (Mg), Calcium (Ca), Zirconium (Zr), Zinc
(Zn), Strontium (Sr), Silicon (Si), Manganese (Mn), Yttrium (Y)
etc. provide very good biocompatibility, nutrients, biodegra-
dation and required mechanical properties for human body
during healing process [14–17].
Design of implant plays a very important role to success-
fully support the affected bone. The dimensions of the bone,
the behavior of the contacting surface with tissues, and
contacted surface area to volume of implant, etc., determine
the life span of the implant. Design of implants and arriving at
suitable dimensions depends mainly on mechanical proper-
ties, degradation behavior, etc. [18].
It is important to ensure that the behavior of biological
activity in healing process matches the mechanical and
degradation behavior of the biodegradable implant. The
process itself is quite involved as it includes two sub -
processes going on simultaneously, namely – the healing
process and the implant - degradation phenomenon. These
two need to be optimally balanced across the entire service
span. Other influencing variables like fracture type and its
location, target age group, desired mechanical properties
including strength, etc., add further complexity to this design
task. This review is an attempt to understand the mentioned
associated challenges and timeline of bone healing - biode-
gradable implant life, with adequate consideration for me-
chanical properties, biodegradation behavior, healing
processes and mechanobiological regulation.
2. Biocompatibility and nutrients
Biocompatibility of any medical device can be defined as the
satisfactory performance of material used for biological
application with an appropriate host response in living systems
[8]. A biodegradable implant has to be biocompatible to become
suitable for biomedical applications. There are some metals,
ceramics and polymers that have been identified and analyzed
as biocompatible elements, e. g. calcium phosphate coatings
have an ability to improve biocompatibility and corrosion
resistance in Mg - alloys [19]. They can be used for biodegrad-
able implants. Most of the biodegradable metals listed in
Table 1 with their biological properties and significance are
found in bone and blood as well [20]. Metals and their alloys
must be negligible to cause low infection as per a standard,
prescribed limit. The cytocompatibility test and hemocompat-
ibility tests can be used for validation in various physiological
environments inside the human body. According to ISO 10993-
5:2009, the reduction of cell viability must be more than 30% to
consider it as cytotoxic [21]. If the cell viability is more than 70%,
it will be considered as more nontoxic or biocompatible. Its
values for any samples with surface stabilization must be
higher at all time intervals. Some of the pre-described alloys are
listed in Fig. 1 for cell viability for confirmation of biocompati-
bility using cytocompatibility test.
Cell viability and adhesion can be observed using a live/
dead assay for 4–7 culture day tests with some of the cell lines
598 biocybernetics and biomedical engineering 40 (2020) 596–610

Table 1 – Details of some common essential elements [6,38–44].

Element Amount present Blood serum Daily Part in Pathophysiology and Part in
in human beings level allowance human blood toxicology human bone
Mg 25 g 0.73–1.06 mM 0.7 g 900 mmol/L Improves bone quality, 1.7 mg/g
activates the enzymes,
economizes the DNA and RNA;
excess Mg leads to nausea.
Fe 4–5 g 5.0–17.6 g/l 10–20 mg 45–50 mg/cm 3 Some metalloproteins 91 mg/Kg
components, contributes in
biochemical activities; its
toxicity can fester liver and
gastrointestinal tract.
Si 1–2 g 9.5 mmol/L <204 mg <44 mg/g Cross-linking agent of –
connective tissue, bone
calcification; silica and silicate
cause lung diseases.
Ca 1100 g 0.919–0.993 mM 0.8 g 1300 mmol/l Major function in skeleton, key 353.3 mg/g
signal functions including
muscle contraction, blood
clotting, cell function, etc.;
inhibits the intestinal
absorption of other essential
minerals.
Zn 2g 12.4–17.4 mM 15 mg 6.42 mg/L Incompetence during growth 67 mg/Kg
reduces peak bone density,
cofactor for many
metalloproteins, clues found in
enzyme classes but mainly in
muscle; neurotoxic and hinders
bone development at higher
concentration.
Sr 0.3 g 0.17 mg 2 mg 3 mmol/l Mostly found in bone, low 0.287 mg/g
doses stimulate new bone
formation and mass; high dose
induces skeletal dissimilarity.
Mn 12 mg <0.8 mg/l 4 mg 5.67 mg/l Involvement in bone –
metabolism, clues as activator
of enzyme; lack of Mn causes
osteoporosis, diabetes mellitus,
atherosclerosis and excessive
contents causes neurotoxicity.
Sn 30 mg – 10.6 mg – Deficiency indicates chances of –
hearing and bilateral hair loss;
some organic compounds are
poisons.
Zr <250 mg – 3.5 mg – Probably excreted in feces, no –
absorption when passes
through digestive system; very
low toxicity in animals, high
concentration in liver and gall
bladder.
Li – 2–4 ng/g – 0.004 mmol/l 2–4 ng/g level of blood serum –
used in the treatment of
depressive disorders; overdose
causes impaired kidney
function and respiratory
disorders.
Y – <4.7 mg – – Probably excreted in feces, very –
low toxicity in animals,
compound of drugs used for
treatment of cancer; high
concentration in liver and gall
bladder,
REE – – – – Anti-carcinogenic properties, –
used in cancer treatment;
accumulates in liver and bone.
 biocybernetics and biomedical engineering 40 (2020) 596–610 599

Fig. 1 – Cell viability analysis [16,22,24–30].

Fig. 2 – Hemocompatibility analysis [17,23,33–37].

being L929, MC3T3-E1, MG63, etc. [22]. The cell relative growth
rate (RGR) can be calculated from the following equation:
RGRð%Þ ¼ ðODt ODn Þ  100%;
where ODt is the optical density value of the tested groups, and
ODn is the optical density value of the negative groups [23].
Another common reason for implant incompatibility is
the surface bacterial effect which may be tough to treat. It
needs to be an antibacterial effect also for the implant that
can be evaluated using various type of bacteria like for vitro
test, Escherichia coli (E. coli) (gram-negative) and staphylococcus
aureus (S. aureus), staphylococcus epidermidis (S. epidermidis)
(gram-positive), although for in - vivo test S. aureus can be
used [25]. In-vivo biocompatibility must be determined and
ensured by resorting to both shorter and longer period -
implantation tests, so as to examine the cellular section of
the bone and associated tissue compatibility in the process
of osteogenesis with implanted biomedical implant. ISO
10993:2017 has also listed many In - vivo tests for local
effects after implantation; tests for irritation and sensiti-
zation, etc. [31,32].
Since blood flows in physiological environment inside the
human body, the compatibility with blood also becomes
important. According to ISO 10993-4:2017, the criterion can be
fulfilled by testing for interaction with blood. A biodegradable
material can be termed as 'hemolytic' if the hemolysis rate
(HR) would be greater than 5%. Some of the pre-described pure
metals or alloys are listed in Fig. 2 as per the hemolytic rate.
The optical density value of the negative control groups should
be less than 0.03 and the optical density value of the positive
control groups should be 0.8  0.3. Hemolysis rate can be
calculated from the equation mentioned below:
HR ¼ ðODt  ODn Þ=ðODp  ODn Þ  100%
600 biocybernetics and biomedical engineering 40 (2020) 596–610
Table 2 – Determination of corrosion rates [57].
Mass loss Volume Loss Hydrogen Evaluation
CR = 8.76  104DW/ CR = 8.76  104DV/At PV = nRT
Atr where where
where DV = Volume loss P = Atmospheric pressure
DW = Weight loss A = Original surface (Pa)
A = Original surface area V = volume of H2
area t = exposure time n = Substance amount of
t = exposure time the gas(mol)
r = standard T = Temperature(K)
density of the R = Universal gas constant
material (J/mol.K)
where ODt is the optical density value for the tested group. ODn
and ODp are the optical density values for negative and posi-
tive control groups respectively [23].
Nutrients also play a vital role in the healing process for
bone, thereby resulting in formation of a healthy, new bone.
For bone fracture healing, some nutrients like minerals,
collagen, proteins and vitamins, can contribute to the growth
and strength of the bone. It is common knowledge that
micronutrients and metals like calcium, magnesium, zinc,
manganese, etc., enhance the growth rate of the bone healing
process [14,45–47]. Some biodegradable metals and hydroxy-
apatite promote bone growth and reduce the degradation rate
of the substrate [48]. Biodegradable metallic alloys (Mg - alloys)
using nutrients and mineral alloying elements like Zn, Ca, etc.
have an ability to control the biodegradation rate by reducing
hydrogen evolution while also improving the growth of
damaged bone by adequate selection of manufacturing
technique. Hydroxyapatite is used as an alloying element
and surface coating. It also promotes bone growth by acting
like a mineral. The existing research findings can be compared
with recent clinical trials for selection of the biodegradable
element (metals, ceramics, etc.) and study of the associated
aspects like biocompatibility, nutrient addition, etc., to fulfill
the intended design objectives [6,49–52].
3. Biodegradation process of biodegradable
metals
Biodegradability refers to the property of some biocompatible
metals that makes them corrode in vivo within the physiolog-
ical environment over a period of time. Trending biodegrad-
able metals like Mg, Zn, etc., show very good biocompatibility
and biodegradability. Most biodegradable metals work at a
negative electrochemical potential of 2.37 V and are quite
susceptible to corrosion. The free ions from their surfaces
migrate into the surrounding fluid environment (body fluids)
that is composed of water, dissolved oxygen, proteins, and
electrolytic ions such as chlorides and hydroxides [53].
Biological corrosion is an important property of the oxide
layer in biodegradable metals because if the oxide layer
ruptures during mechanical loading it exposes the form
substrate to body fluids which results in further corrosion.
The clinical repercussion of the corrosion process shows the
loss of mechanical strength corresponding to ultimate failure
Ion Release Potentio-dynamic
Polarization
CR = cV/St CR = K (Icorr/r)me
where where
c = ion release K = 3.273  103 mm g/(mAcm
concentration a) Icorr = Current Density
V = volume of me = Equivalent mass
immersion solution
S = original surface
area exposed to
corrosive media
t = exposure time
of the implant across the healing period and up to complete
healing [54,55,6]. There are mainly two approaches to deter-
mine the corrosion rates: in vivo (in living cells), and in vitro (in
glass) [56]. It is observed that not only the in vivo and in vitro
corrosion rates are different but there is no definitive
correlation between them either. There is a clear requirement
of improving the in - vitro test models so that the commonly
used models (like mimic) provide correlation in the two and
predict the factors influencing the corrosion rate in in - vitro to
identify the in - vivo degradation behavior and corrosion
mechanisms. It is quite difficult to digitally monitor the
degradation behaviors corresponding to physiological param-
eters in in vivo [57]. In case of in vivo, the implantation site is
surrounded by blood and tissues can affect the corrosion rate
due to their contacting areas and their biochemical environ-
ments [57]. There are many methods for finding biodegrada-
tion/corrosion rates as listed in Table 2. These methods can be
used for in vivo or in vitro modes to have a fair idea about the
capability to degrade within the physiological environment.
To evaluate the degradation rates in the in vivo mode, the
commonly used methods are weight loss and volume loss w.r.
t. time (few days to one year). For better resolution, it needs to
remove from implantation site, and scanned in 3-D micro CT
images which can be modified into an equivalent corrosion
rate [57]. Degradation rates observed for some materials for
in vivo tests are listed in Table 3.
For determining in - vitro degradation rates, the time (10 h
to 18 weeks) and solution (SBF, Hank's etc.) are crucial
parameters. Table 4 provides in vitro degradations rates based
on different solutions.
The relations between the degradation time and environ-
ments indicate that corrosion rates usually vary over a period
of time. This time - dependent study also shows that
degradation rate is not a linear function. The degradation
rate can predict the reasons behind the dissimilarities on
surfaces, protective corrosion layer formation, microstructure,
post treatments during manufacturing, etc.. The slower
degradation rate pertaining to the biodegradable alloys is
attributed to the wrapping by the tissue when the material gets
implanted into the dorsal muscle. Homogenization and aging
treatments have significant effects on the mechanical and
corrosion properties of the material. Different mechanical
processing operations like rolling, extrusion, heat treatment,
etc., have the potential to greatly influence surface and
microstructural properties, thereby affecting the performance
 biocybernetics and biomedical engineering 40 (2020) 596–610 601

Table 3 – Degradation rates for In vivo tests.

In vivo

Material Surface Method Animal model Evaluation times Average Ref.

coating degradation rate
Pure Mg – Weight loss Rat 7, 14, 21 days 0.33 (mm/year) [58]
AZ91 – Weight loss Rabbit 2 Months 25 mg/cm 2 [59]
MAO 16 mg/cm 2
FHA/MAO 4 mg/cm 2
Zn-0.05 Mg (Extruded) – Weight loss Rabbit 4, 12, 24 weeks 0.15 mm/year [60]
Mg-Nd-Zn-Zr alloys (JDBM) – Weight loss Rat 3, 14, 28 days 0.092 mm/year [25]
Mg-3.2Zn-0.8Zr – Volume loss Rabbit 1 month 0.826 mm/year [61]
MgF2 0.155 mm/year
– 6 months 0.861 mm/year
MgF2 0.516 mm/year
ZEK100 – Volume loss Rabbit 2 and 6 months 0.1105 mm/year [62]
Mg-1.5Nd-0.5Y-0.5Zr – Volume loss Rat 6 and 12 weeks 0.15 mm/year [63]
Mg-1.5Nd-0.5Y-0.5Zr-0.4Ca – 0.195 mm/year
ZX50 – Volume loss Rat 12 months 1.58 mm/year [64]
Zn-1Mg – Weight loss Rat 0, 1, 2, 3, 4, 6, 8 weeks 0.17 mm/year [52]
Zn-1Ca – 0.19 mm/year
Zn-1Sr – 0.22 mm/year
Mg-30Sc – Volume loss Rat 24 weeks 0.06 mm/year [26]

Table 4 – Degradation rates for In vitro tests.

In vitro

Material Surface Test Solution Evaluation time Average corrosion Ref.

coating/ others rate (mm/year)
Pure Mg – Immersion SBF 3 days 1.3 [23]
Pure Mg – Electrochemical SBF – 1.39 [24]
Pure Mg – Immersion Hank's 5 days 1.52 [65]
Pure Mg – Electrochemical Hank's – 0.36 [66]
Mg-HA – Electrochemical Artificial Sea water 72 hours 1.25  0.16 [67]
Mg-HA – Immersion Artificial Sea water 24, 72 hours 2.0–3.2 [67]
Mg-30Sc – Immersion Hank's 10 days 2.9  0.1 mm/year [26]
GZKM-1 – Immersion Hank's 240 hours 0.46  0.19 mm/year [68]
GZKM-1 – Electrochemical Hank's – 0.34  0.09 mm/year
NZK – Immersion SBF 30 days 0.34  0.05 mm/ year [23]
Mg-Sr alloy PED Coated & Electrochemical Hank's 24 hours 0.09 mm/year [69]
extruded
Mg-2.0Zn-0.5Zr-3.0Gd – Immersion SBF 120h 0.417 mm/year [70]
Mg-2.0Zn-0.5Zr-3.0Gd – Electrochemical SBF – 0.116  0.002 mm/year
ZK60 – Electrochemical SBF – 0.247 mm/year [71]
ZK60 T5 Treated Electrochemical SBF – 0.12 mm/year
Mg-1.2Zn-0.5Ca 2h Aged Immersion SBF 0,3,7,14,21,28 days 4.4 mm/year [72]
Electrochemical SBF – 8.9 mm/year
Mg-Zn-Sr – Immersion SBF 15 days 4.07  0.71 mm/year [73]
Mg-Zn-Zr – Immersion SBF 15 days 6.92  0.3 mm/year
Mg-Zn-Zr-Sr – Immersion SBF 15 days 5.357  0.75 mm/year

of Mg-alloy. The strength, ductility and corrosion resistance of
Mg-alloys is significantly improved by rolling and extrusion
processes, reduced grain size and definite grain orientation.
Surface roughness plays a truly critical role in cell attachment
and affects the corrosion rate of Mg and its alloys considerably.
The morphology and hierarchical structure of bone should
always be taken into account in implant design for achieving
bone and implant integrity [6,11,65,74–76]. The electrochemical
method is also a qualitative method for evaluation of corrosion
behavior. Potentio-dynamic polarization is the most frequently
used electrochemical technique for studying in - vitro corrosion
test of biodegradable materials. Electrochemical Impedance
Spectroscopy is another technique that has been widely used
for evaluating corrosion behavior of biodegradable biomaterials
[34,77–79].
3.1. Causative factors of biodegradation of different
materials
Biodegradation is an electrochemical reaction (under physio-
logical environment) with electrolyte that results in genera-
tion of oxides, hydroxides, hydrogen gas, or other compounds.
The process is accompanied by anodic dissolution of the metal
and the cathodic reaction. Causative factors of biodegradation
602 biocybernetics and biomedical engineering 40 (2020) 596–610

Table 5 – Mechanical properties of some biodegradable alloys.

Elements (Alloys) Yield stress (MPa) Ultimate stress (MPa) Elongation (%) Ref.
Mg-Zn-Sr 187.324  4.015(T) 278.002  5.352(T) 19.8  3.6(T) [73]
Mg-Zn-Zr 227.509  5.009(T) 306.052  4.588(T) 20  2(T)
Mg-Zn-Zr-Sr 322.363  4.547(T) 376.400  7.526(T) 16  1(T)
Mg-5.5Zn 115.6  3.9(C) 303.2  5.6(C) – [85]
Mg-5.5Zn/5HA 154.7  4.2 (C) 351.6  5.2(C) –
Mg-5.5Zn/10HA 165.3  3.7(C) 379.7  4.1(C) –
Mg-Zn-Mn- 198(T) 220(T) 4.5(T) [86]
Ca
ZK60(Extruded) 210  10.80(T) 300  0.42(T) 19.6  0.73(T) [71]
ZK60(T5) 274  5.83(T) 324  1.57(T) 17.9  1.07(T)
ZK60(T6) 202  2.50(T) 289  0.42(T) 23.2  1.05(T)
Mg-1.2Zn-0.5Ca(as-cast) 64.5  10.5(C), 60.3  3.1(T) 255.2  7.6 (C), 121.3  5.2(T) 17.4  0.43(C), 3.2  0.13(T) [72]
Mg-1.2Zn-0.5Ca (Heat treated) 124.4  6.9 (C), 84.3  7.1(T) 309  17.3(C), 150.7  8.5(T) 18.9  0.3(C), 4.9  0.24(T)
GZKM-1(as-cast) 149.1(T) 220.8(T) 18.7(T) [87]
GZKM-1(Heat treated) 157.9(T) 260.2(T) 18.1(T)
GZKM-1(Hot Extrusion) 315.2(T) 341.5(T) 21.3(T)
Mg-5Zn 120(T) 212(T) 10(T) [88]
Mg-5Zn-0.2Sr 117(T) 233(T) 15(T)
Mg-5Zn-0.6Sr 115(T) 215(T) 13(T)
Mg-5Zn-1.0Sr 107(T) 194(T) 9(T)
Zn–1Mg–0.1Sr (Hot rolled) 196.84  13.20(T) 300.08  6.09(T) 22.49  2.52(T) [36]

for many biodegradable materials mainly depend on inorganic Some of the biodegradable alloys are listed with their
ions, buffering system, organic molecules, dissolved oxygen mechanical properties in Table 5. In this table, T and C indicate
and interrupted stress [6]. tension and compression respectively.

4. Mechanical properties of biodegradable 5. Fractured bone healing process and

materials mechanobiology

For internal fixation of fractured bone as a fixture device, the
implant needs appropriate mechanical properties. The prima-
ry application of any implant is to hold the fractured bone.
From a mechanical engineering point of view, moduli of
elasticity of implant material and bone material should be as
close as possible, e. g. – modulus of elasticity for Mg - based
alloys ( 40 GPa) is not significantly higher than that for the
bone material (18 GPa) [6]. This will help in uniform
distribution of stress throughout and can minimize possible
stress concentration effects at the joint interface between
bone and implant. The material of the implant should have
higher yield strengths (both tensile and compressive) to avoid
development of cracks or fracture of implant, although this
also depends on manufacturing techniques. To enhance the
functional stability and proper stress transfer from implant to
bone at the successfully constrained assembly, the interfacial
shear strength needs to go up which can decrease the stress
occurring in the implant [80,81]. To avoid fluctuations in
dynamic loading (cyclic loading) conditions, an implant
material should have high fatigue strength that can prevent
the occurrence of brittle fracture [82]. Ductility shows the
highest strain (more than 5%) that an implant can bear without
the assembly, during deformation (elongation/compaction)
under the existing loads. The contouring and shaping of an
implant are also an important consideration. Toughness
shows the capability to store maximum energy up to the
breaking of implant whereas ultimate stress indicates the
maximum stress that occurs before the implant breaks [83,84].
Bone is one of the few tissue whose fracture can heal without
fibrous cicatrix formation in a physiologically complex
involving both mechanical and biological aspects [1,10].
Fracture occurs due to exceeded limits of strain and deforma-
tion. New bone formation in fracture healing process is based
on the gap size in fractured site. At times, new bone formation
may be similar and comparable to children's bone growth. The
corresponding healing process management may be carried
out by bone age assessments [89]. It can mainly be classified in
two ways; primary and secondary healing [90]. Primary healing
process starts formation directly due to small voids without
intermediate tissue formation. In secondary healing process,
void space is surrounded by outer adjacent callus and tissue
differentiation. It is a complicated biological process around
the fracture site involving interfragmentary movement be-
tween the fracture ends [91,92]. Once a fracture has healed
which may take few months to a year, the structure may
return back to its pre-damage state [93,94].
Healing process has a close linkage with cell activities,
growth factor production, angiogenesis and transmission of
oxygen. Understanding the timeline of biological and bio-
mechanical aspects of the healing process is specific for
orthopedic surgeons to create the optimal healing arrange-
ment to give appropriate alignment for a fractured bone
[95,96]. Secondary healing process is characterized by three
distinct phases: (1) Inflammation phase, (2) Repairing (soft and
hard callus) phase, and (3) Remodeling phase. In the first
phase, various cells and hematoma prepare the fracture area
biocybernetics and biomedical engineering 40 (2020) 596–610 603

Fig. 3 – Healing process stages in fractured bone [95,118,100].

604 biocybernetics and biomedical engineering 40 (2020) 596–610
for healing. In the second phase, formation of soft callus in the
form of cartilage and hard callus in the form of cartilage get
converted to woven bone which generates around the fracture
area. In the final phase, woven bone (WB) changes to lamellar
bone (LB). After the end of this last phase, the bone is expected
to come back to its original biomechanical state [10,95–100].
The three phases and their mechanobiology have been
elaborated below and healing process stages of fractured
bone also shown in Fig. 3.
5.1. Inflammation phase
This phase starts just after the bone ruptures which takes
approximately 4 days in rats, 3 days in mice, and about a week
in humans [101]. The hemorrhage charges a hematoma to
form in the fracture region and brings many related biological
factors like bone marrow cells, and cells from both the acentric
and intramedullary blood supply [102,103]. Hematoma is
characterized by hypoxia and low pH which acts as a
temporary protective part of inflammation for MSCs that
migrate towards the fracture region to form a loose granula-
tion tissue. Through circulation, MSCs emerge from the broken
periosteum and soft tissues near the fracture region also arrive
at the periosteum and the initial callus status [104]. The
connective tissue consists of fibrin and is produced by platelets
and thrombotic factors although some growth factors, such as
- interleukin-1, interleukin - 6, insulin, transforming growth
factors - betas, platelet - derived growth factors and bone
morphogenetic proteins, also occur [91,98,105]. These cells
divides (proliferate) into later differentiate and change their
cell constitution to tissue - specific cells that can generate
fibrous tissue, cartilage, respectively [10,98,103,106]. The
biomechanical (stiffness and strength) activity starts at the
end of this phase. Some of the medical devices are inventing
which can evaluated the biomechanical improvement in in-
vivo during overall healing stages [107].
5.2. Repair phase (Soft and hard callus)
This phase requires the deposition of new extracellular matrix
that forms during soft cartilage deposited by chondrocytes
[95]. The soft callus consists of fibrous and/or cartilaginous
connective tissues, which have developed from the MSCs
tissue. Then the MSCs starts differentiating into individual
specific cells at different regions in the formed callus according
to conditions such as the related growth factors, restoration
condition of vascular network, and oxygen conditions
[101,108]. The soft callus formation provides partial mechani-
cal support in the intermediate phase and also forms an
outline for hard callus after mineralization [109].
In this intermediate phase, biomechanical activity is not at
a saturation state. This is followed by the beginning of WB
several distance( mm) away from the fracture gap [110]. WB,
though mechanically deficient to mature LB, can be rapidly
deposited and mineralized and provides mechanical stagna-
tion to the fractured bone by providing a large regenerated
frame type surrounding to the fracture. The mineralized
cartilage is resorbed by osteoclasts and replaced with WB by
osteoblasts, thus forming a hard callus that provides rigidity to
the fracture site [101,108]. The amount of cartilage that is
formed is dependent on the amount of mechanical influences
[111,112]. Intermediate moderate axial interfragmentary
movement is used to enhance fracture repair rate by
stimulating formation of periosteal callus. When the fracture
gap is filled with bony callus, a clinical union is reached and
the remodeling phase begins [113].
5.3. Remodeling phase
The last phase is characterized by fracture repair through
replacement of WB that bridges the cortical fracture gap by LB
to form the secondary osteons [114]. The less organized WB is
gradually supersede and reshaped by more organized and
stiffer LB, and remodeling of the generated bone tissue and of
the fracture ends restores the regenerated shape (before
fractured) and lamellar structure of the bone [10,110].
Periosteal and medullary calluses are being absorbed by
osteoclasts that leads to a remodeling of diaphyseal bone,
which can take about years in humans [98,110]. Then the
established misalign bone is resorbed with the activity of
osteoclasts and regeneration of new bone along lines of stress
with the activity of the osteoblasts. As the WB gets gradually
replaced by LB, bone starts matching the original one in all
aspects [115,116]. Some examples of transverse movements at
the fracture site indicate decrease in adjacent callus forma-
tion, delay in the bone creation in the fracture gap, and
deficient mechanical stability, as compared to healing with
longitudinal movement [117]. For bone remodeling to be
prosperous, appropriate blood supply and gradual improve-
ment in mechanical stagnation is conclusive which can be
provided only by the internal fixation implant.
6. Biodegradable implant design for fractured
bone
The consistent evolution of implant design owes a lot to the
use of biodegradable materials and the study and analysis of
their degradation behavior. Some research has been done
based on biological validation of biodegradable implant [4].
The use of orthopedic implant for internal fracture fixation
began more than 100 years ago, although metal plating began
in 1895 [119]. In1912, different versions of the internal fracture
fixation plate were introduced which were truly the first
generation implants [120]. Due to improvements in the
metallurgical formulation, there were efforts to improve the
corrosion resistance of the plate. The next generation of
implants appeared in 1948 with due focus on improving the
design of the plate. The plates now had two long slots that
could allow sliding of the screw heads to compensate for
resorption of the fragment ends [121].
An orthopedic implant device must provide stability, fully
constrained design with bone and maintain the appropriate
alignment of bone fragments at the time of implantation and
regular checkup of healing process. It must be sufficiently
strong, stiff and tough to allow early mobilization of damaged
part of bone up to remodeling and provide relief to the patient.
Another very important part of the implant device pertains to
the screws that are mainly used for inter-fragmental attach-
ment of plates. These screws are expected to prevent
 biocybernetics and biomedical engineering 40 (2020) 596–610
Fig. 4 – Fractured femur bone supported with biodegradable implant (Plate) tightened with screws.
displacement of implant w. r. t. the bone location and support
the fragments up to healing [122]. The dimensions of the screw
should ideally be based on the lowest possible pitch length,
highest possible diameter, and trapezoidal threads for better
performance against failure – causing agents like bending
loads, etc. [123]. An implant, where the plate and screws are
supporting the fractured femur bone, is shown in Fig. 4. Pins
and wires are also used for internal fixation of micro fractures
in small size bones [124].
The fracture bone needs support during healing process
due to insufficient load bearing capacity, even the human body
weight cannot bear the fractured bone [125]. Generally, non-
biodegradable (permanent) implants need to be removed by a
secondary operation/surgery. However, during this operation,
there are chances of failure of the regenerated bone due to
cortical porosis, delayed bridging, and refractures. There are
many detrimental effects at the bone – permanent plate
interfaces, one major issue being bone loss caused by stress-
shielding (SS) [126]. Stress - shielding occurs due to mismatch
of elastic moduli between bone and implant during the healing
process. Adequate biodegradation rate can go a long way in
avoiding stress – shielding effects by giving some balancing
loads to both partially - healed bone and partially - degraded
biodegradable implant [13]. Some non-biodegradable materi-
als like cobalt chromium (CoCr) shield the peri -implant bone
stress, contributing to premature loosening of the implants. To
reduce the need for secondary surgeries, light weight implants
with tailored functionalities need to be developed. For stress –
sharing orthopedic applications, incorporating the axially
graded cellular structure in femoral prosthesis may improve
the load distribution in adjacent bones [127]. Micromotions of
broken bone parts in longitudinal plane promote healing
during their joining phase. The decrease in SS along with
gradual degradation during the remodeling phase can only be
possible with a biodegradable implant. To acquire strength,
bone must have a dynamic fixture that can provide support in
accordance with the healing stages. Initial bone healing
process, under a rigid internal fixation, is a slow process
where the only possible solution to improve fracture healing is
to allow micromotion throughout the fracture site [7]. In
biodegradable implant applications, the standardization of
mechanical characterization must be based on different
testing configurations, sample dimensions, reference config-
urations, deformation and degradation rates, physiological
conditions, human body nutrients absorption rates, and
605
selection of relevant parameters for benchmarking of results
obtained through different studies.
7. Timeline of bone - biodegradable implant
interface and discussion
The interphase between the permanent or non - biodegradable
implant and bone healing is largely dependent on controlling
the biochemical, biomechanical and biological activity. The
interface between bone and biodegradable implant presents a
rather complex scenario where biochemical, biomechanical
and biological activities interact to influence the biodegrada-
tion behavior. The corresponding loss of mechanical integrity
can follow an unpredictable timeline up to about 6 months of
the remodeling phase [128,129].
A bone - biodegradable implant interface prediction model
provides an effective approach to understand the timeline as
shown in Fig. 5. It shows the biodegradable implant v/s bone
strength which needs to fulfill the load carrying capacity gap
up to the 100% strength requirement. As the implant degrades,
the mechanical strength also decreases simultaneously.
Similarly, bone strength increases with increase the healing
stages (phases) as shown in Fig. 3, [130,131]. It is expected that
the implant does not degrade completely across the three
phases before complete healing of the fracture. The combined
percentage strength (partially healed bone and partially
degraded implant) must be higher than 100% to meet the
strength requirement. The implant must be completely
degraded within six months from the completion of healing
to avoid detrimental complications and damages [18,90]. It
may be inferred that maximum possible strength to support
fractured bone with minimum possible remaining volume/
mass due to degradation of biodegradable implant is desirable
at successive ascending stages of healing. This makes it
imperative to opt for adequate processes and properties all
through [6,132]. More investigation is needed for integrating
the parameters involved and arriving at a definite conclusion
regarding the bone – implant interaction.
To optimize all relevant parameters of interest, the three
stages from raw materials to the final product need to be
regulated. The first stage requiring attention is the
manufacturing process, which mainly depends on biodegrad-
able material selection, characterization of its microstructure
in accordance with the fabrication technique, post hot/cold
606 biocybernetics and biomedical engineering 40 (2020) 596–610

Fig. 5 – Bone - implant interface with strengthening and degradation percentage.

Fig. 6 – Overview of inter – dependency and linkage between different processes.

working operations, etc. [15]. The biological, mechanical and
biodegradation behavior are to be controlled in this stage.
Surface modification is another important aspect where the
degradation, mechanical and biological behavior can be
controlled at the outer surface of the implant and the
degradation rate can be reduced [133]. The second stage of
control involves the design of implant which has a connection
with the first stage and depends on the mechanical properties,
biodegradation rates and bone - biodegradable interface
behavioral patterns. Implant design focuses on structural
dimensions and transfer of loads from bone to implant and
vice - versa [18,56,134]. The third stage of control emphasizes
on the production process that reflects the accuracy with
which the designed implant transforms into the product that
can be used directly for implantation and fulfills the objectives
envisaged in first and second stages [135]. The inter –
dependency of these stages and processes is shown in Fig. 6.
Current state of the article: This manuscript makes an
attempt to highlight the challenges in identifying and
understanding the complexities associated with the interface
between bone and biodegradable biomaterials in the physio-
logical environment existing during the process of healing.
Biocompatibility, biodegradation rate and mechanical proper-
ties of any biodegradable implant material are the major
implant design influencers that have a close connection with
the efficacy of the healing process and healing time for
different patients. Many researches have indicated that Mg -
alloys have the potential to achieve all implant design
objectives due to their predictable and controllable corrosion
behaviour [54,136]. There has been significant amount of work
in the area of biodegradable materials. However, design and
manufacturing of biodegradable material - based implants for
orthopaedic applications and the commercialization of such
medico devices with the ultimate objective of avoiding
secondary surgeries is still a work in progress [6,51,109,137].
This is an exciting cross-disciplinary area that needs material
scientists, design engineers and medical professionals to come
together and develop a new template for implant manufactur-
ing industries.
8. Conclusion
Biodegradable material implants are playing a vital role in
eliminating painful and cumbersome secondary surgery
operations that are aimed at removal / replacement of the
implant. To successfully heal different types of damages,
cracks or fractures of any bone using biodegradable implant, a
careful insight needs to be developed covering all stages right
from the choice of raw material to the manufacturing of
 biocybernetics and biomedical engineering 40 (2020) 596–610
implant, compatible design of implant before the implantation
phase to the remodeling stage, and eventual degradation of
the implant after culmination of the healing process. Study
and prediction of bone - biodegradable implant interface
behavior shows how a combination of mechanical; degrada-
tion and biological behavior needs to be analyzed so as to
arrive at an effective and optimal design for the biodegradable
implant, keeping in mind the healing phases and degradation
after complete healing. An appropriate biodegradable implant
must fulfill the twin requirements of adequate support
strength and loss of mechanical integrity at the bone -
biodegradable implant interface across the period of recovery.
Funding
None.
Ethical approval
Not required.
Conflict of interest
The authors declare that the current research work does not
involve any conflict of interest in any manner whatsoever.
They are thankful to Maulana Azad National Institute of
Technology (MANIT), Bhopal (INDIA), for the facilities
extended.
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