Biodegradable Polymers and Their Bone Applications: A Review

International Journal of Basic & Applied Sciences IJBAS-IJENS Vol: 12 No: 01 31
Biodegradable Polymers and their Bone

Applications: A Review
Saiful Izwan Abd Razak, Noor Fadzliana Ahmad Sharif and Wan Aizan Wan Abdul Rahman*,
Polymer Engineering Department, Faculty of Chemical Engineering, Universiti Teknologi Malaysia,
81310 Skudai, Johor, Malaysia
.
Abstract— Several biodegradable polymers were reviewed in
regard of their properties to be used as bone substitute.
Highlights were made on poly (glycolic acid) (PGA), the
stereoisomers forms of poly (lactic acid) (PLA) and their
copolymer poly (lactic-co-glycolide) (PLGA), poly(ε-caprolactone)
(PCL) including natural biodegradable polymers; chitosan and
collagen. Their composites, forms (scaffold and dense), drawbacks
and potential usage were also discussed in detail.
Index Terms—Synthetic biodegradable polymers, Bone

substitute, Scaffold. Fig. 1. Actual vision inner part of natural bone
There are two types of bone, compact or corical, and

cancellous or trabecular (spongy) bone. The anisotropic
I. INTRODUCTION structure of bone leads to mechanical properties that exhibit
B one is a complex living tissue which has an elegant

structure at a range of different hierarchy scales. It is a
composite comprise of an organic phase (base on collagen) by
directionally. This directionality results from the fact that bone
has evolved to be both tough and stiff, two competing
properties which are optimized in bone but with an inherent
which calcium containing inorganic crystals are embedded loss in isotropy [7]. In fact, bone exhibits extraordinary
(Fig. 1) [1]. Specifically, bone is a natural composite material, mechanical properties, displaying both elastic and semi-brittle
which by weight contains about 60% mineral, 30% matrix and behavior [2, 8]. Compact bone has a compressive strength in
10% water [2]. The matrix bone is primarily consisting of the range of 131 - 224 MPa, and a Young’s modulus ranging
collagen. This organic component of bone is predominantly from 17 - 20 GPa [2, 6], while compressive strength and
responsible for the tensile strength. The mineral component of Young’s modulus for trabecular bones are 5 – 10 MPa and 50
bone is of calcium phosphate, this mineral component gives -100 MPa, respectively [2, 6].
rise to the compressive strength [3]. In the body, bone serves Bone plays an important role in the movement, support and
as number of functions, such as providing the cells found in protection of vital organs. However, it is susceptible to
the marrow, that differentiate into blood cells, and also acting fracture as a result of physiological resorption, dental losses,
as a calcium reservoir [4-6]. Nevertheless, its primary purpose trauma injuries, bone pathology, infection, aging, population
is to provide mechanical support for soft tissues and serve as and bone disease [9-11]. The ways of bone repair improve
an anchor for the muscles that generate motion. year by year, parallel to the development of high technologies.
Traditional biological methods of bone defects management
includes: 1) Autogeneous bone graft which harvested from
different side of the patient’s body, it is considered as the ideal
bone graft substitute [12]. While the use of autograft material
is the preferred technique, there are some limitations such as
donor site morbidity, limited donor bone supply, anatomical
and structural problems and elevated levels of resorption
during healing [13] 2) Allograft bone which is obtain from
The corresponding author can be contacted via e-mail: *[email protected]
123101-8585 IJBAS-IJENS © February 2012 IJENS

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individuals of the same species as the receiver [9]. Allograft partner in reinforcing with ceramic is calcium phosphate,
has the disadvantage of eliciting an immunological response especially hydroxyapatite (HA) since their condition mimic
due to the genetic differences and the risk of inducing natural bone composition [3]. Facing a complex biological and
transmissible disease [14, 15]. This necessities a thorough sensitive system as the human body, the requirement for bone
sterilization procedure that not only damages the graft’s repair using biodegradable polymers are manifold and
biological and mechanical properties, but also expensive [16, challenging. Some of the important properties of
17]. biodegradable polymers can be summarized as follows [33]: 1)
Reconstruction of bone with fully synthetic artificial bone The material should not evoke or toxic response upon
graft is another way to provide and create lost bone mineral. It implantation in the body. 2) The material should have
was started past 30 -40 years, the terms of innovation of acceptable shelf life. 3) The degradation time of the material
ceramic for bone repair and reconstruction become an interest should match the healing or regeneration process. 4) The
in the major advance of medical applications [18]. Calcium polymers should have appropriate mechanical properties for
phosphate is highly promising as a bone substitute in the indicated application and the variation in mechanical
orthopaedics among the other ceramics [19-21]. This group of properties with degradation should be compatible with the
material exhibit high biocompatibility, bioactivity, self setting healing process. 5) The degradation products should be
characteristic, low setting temperature, adequate stiffness and nontoxic, and be able to metabolized and cleared from the
easy shaping in complicated geometries [22, 23]. However, body. 6) The polymers should have appropriate permeability
several drawbacks do exist causing some problems that hinder and processability for the intended application.
clinical use of calcium phosphate. The problem is that calcium Biodegradable polymers offer a number of advantages for
phosphate lack of macropores and low porosity making its developing bone at defect sites [34]. The key advantages
resorbing rate rather slow and mechanically brittle, thus include the ability to tailor mechanical properties and
restricts its utilization in medical applications [24-26]. degradation kinetic. Biodegradable polymers can differ in their
For the last two decades of the twentieth century, a molecular weight (MW), polydispersity, crystallinity, structure
paradigm shift occurred from the biostable materials to and thermal transition, allowing different absorption rates. By
biodegradable materials (hydrolytically and enzymatically means of porosity, biodegradable polymers can be used to
degradable) for the medical and related applications [27-29]. impart macroporosity to the cement as polymers degrade and
Current trend predicts that in the next couple of years, many of expose macropores to bony ingrowth. The strengthening of the
the permanent prosthetic devices used for temporary graft from the bone growth and the deposition of the new bone
therapeutic applications will be replaced by biodegradable should offset the weakening of the graft due to polymer
devices that could help the body to repair and regenerate the degradation [35].
damage bone [30]. A biomaterial can be defined as a material In bone application, biodegradable polymer or its composite
intended to interface with biological system to evaluate, treat, can be prepared in two form, scaffold and dense. Usually,
augment or replace any organ or function of the body [31]. scaffold is used to associate with cell seeded in purpose of cell
The essential prerequisite to qualify a material as a biomaterial growth to form bone. Scaffolds are able to promote cellular
is its biocompatibility, which is the ability of the material to interactions and process uniformly interconnected pores with
perform with an appropriate host response in a specific adequate structural integrity. The interaction between cell and
application. The host response to an implant depends on substrate is related to the osteogenic cells attachment, adhesion
factors ranging from the chemical, physical and biological of and spreading and its quality will influence cell proliferation
the materials to the shape and structure of the implant. and differentiation [36]. Cell can be obtained from calvarine
Biodegradable polymers are materials that fulfill the above [37, 38], trabecular bone [39], human embryonic stem (hES)
requirement. The chemical, physical, mechanical polymers cells and bovine osteoblasts (bOB) [40].
will vary with the time and degradation products produced Dense form of biodegradable polymer can be obtained from
have different level of bony compatibility. Notwithstanding, forging, hot or cold pressing [41]. Formation of bone in this
biodegradable polymers sometimes fall short of achieving particular form is usually by immersing the sample in
satisfactory results in bone fixation [32]. These results should simulated body fluid (SBF). SBF is the most favored model
not necessarily be taken as a negative factor, since they are solution simulating the inorganic part of the blood plasma. The
available to be reinforced with other materials like ceramics, ions concentrations of simulated body fluid are nearly equal to
metals, or clay in order to improve their mechanical properties those of blood plasma (Table 1) by maintaining the pH at 7.25
and meet the promising requirements in bone substitute. for the apatite nucleation [42].
Often, from the medical point of view, biodegradable
polymer with sufficient mechanical strength and optimized
lifetime in the body, which could finally be replaced by bone,
is most desirable. Biodegradable polymers lack in mechanical
properties. It is desirable to reinforce it with other
biocompatible substance to enhance its properties. The best

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TABLE I properties of these polymers allow hydrolytic degradation

COMPARISON OF THE IONIC CONCENTRATION IN BLOOD PLASMA AND SBF
(MM/L) [42]
through de-esterification. Once they degraded, the monomeric
Na
+
K
+
Mg
2+ 2+
Ca Cl
-
HCO3
-
HPO4
2-
SO4
2- components of each polymer are removed by natural pathway
[53, 54]. The human body already contains highly regulated
Blood 142.0 5.0 2.5 1.5 27.0 103.0 1.0 0.5 mechanism for completely removing monomeric components
plasma
SBF 142.0 5.0 2.5 1.5 4.2 148.0 1.0 0.50 of lactic and glycolic acids. Due to these specialty polymers,
such degradable material used in bone substitute have been
approved by the US Food and Drug Administration (USFDA)
Though various studies have been done throughout the [51]. With the exception of PGA, the polymers in this family
scientific community on biodegradable polymers, there is yet a are soluble in many common organic solvents and thus it can
systematic report on the application of biodegradable polymers be processed by a variety of thermal and solvent-based
on bone engineering. The purpose of this review is to observe methods [54, 55].
various parameters (porosity, particle size, molecular weight, Due to several problems, it is advisable not to apply
temperature, crystallinity, filler characteristic and etc) that polyesters alone when dealing with bone substitution, since it
possibly affect the mechanical properties and degradation rates can caused some drawbacks in the implementation in vitro and
of biodegradable polymers, whether in pure or mixing in vivo such as the degradation products reduce the local pH
condition and also observation of bone growth after in vivo value, which in turn, may accelerate the polyesters’
and in vitro implantation. Furthermore, biocompatibilities of degradation rates [56] and induce an inflammatory reaction,
biodegradable polymers in bone engineering were also which are often ascribed to acidosis caused (chemically
investigated unavoidable) by the release of acidic degradation products
(monomeric or oligomeric hydroxycarboxylic acids) [57-59].
II. SYNTHETIC BIODEGRADABLE POLYMERS Another disadvantage is that the mechanical properties of the
highly porous scaffolds made from polyesters are relatively
A. Polyesters / poly (α-hydroxy acids) weak, which limits their use for bone-tissue engineering,
Naturally occurring hydroxyl acids, such as glycolic, lactic especially the in vivo implant site [60].
and ε-caproic acids have been utilized to synthesize an array of
useful biodegradable polymers for a variety of medical product B. Poly (lactic acid)
applications. Especially in the implantable devices (internal
PLA has received the most attention due to its renewable
fixation devices for orthopedic repair) made from these
resource [61], biocompatibility, biodegradation, excellent
polymers are becoming part of standard surgical protocol [43-
thermal and mechanical properties, and superior transparency
45]. It was started 30 years ago where polyesters increased the
of the processed materials [62]. It is a linear aliphatic
popularization of polymers as material for sutures and bone
thermoplastic polyester and is readily biodegradable through
fixation [46] and remain among the widely used synthetic
hydrolytic and enzymatic pathways [61, 63-65]. Since lactic
degradable polymers. Although all polyesters are theoretically
acid is a chiral molecule, it exists in two stereoisomeric forms
degradable through the method of esterification, it is a
that give rise to four morphologically distinct polymers that is
chemically reversible process, only aliphatic chains between
D-PLA, L-PLA, D,L-PLA and meso-PLA. D-PLA and L-PLA are
ester bonds can degrade over the time frame required for most
the two stereoregular polymers, D,L-PLA is the racemic
of the biomedical applications [47].
polymer obtained from a mixture of D- and L- lactic acid, and
Poly (α-hydroxy acids) comprise one of the earliest and
meso-PLA can be obtained from D,L-lactide. Generally, L-PLA
most extensively investigated class of biodegradable polymers.
is more frequently employed than D-PLA, since the hydrolysis
It can be developed from a variety of monomers via ring
of L-PLA yields L(+)-lactic acid, which is the naturally
opening and condensation polymerization routes depending on
occurring stereoisomer of lactic acid. On the other hand, the
the monomeric units. The ester bond of the poly (hydroxyl
semicrystalline solids of L-PLA are preferred in the orthopedic
acids) is cleaved by hydrolysis, which results in a decrease in
surgeries application where high mechanical strength and
the polymer Mw (but not mass) of the implant [47]. The
toughness are required [66-69].
degradation rate of polyester is determined by initial Mw,
In bone tissue engineering, the scaffolds require appropriate
exposed surface area, crystallinity, and (in case of the
material properties, controlled porous architechture, proper
copolymers) ratio of the hydroxyl acid monomers [48].
porosity and appropriate mechanical properties [70]. Poly (L-
Among the class of poly (α-hydroxy acid)s, the most
lactic acid) (PLLA) satisfies many of those material
extensively used polymers are poly (glycolic acid) (PGA), the
requirements and already has been fabricated into scaffolds for
stereoisomers forms of poly (lactic acid) (PLA) and their
bone tissue engineering [71-73]. Typical shaping technologies
copolymer poly (lactic-co-glycolide) (PLGA) [49-52]. These
of those scaffolds include phase separation technology [74,
polymers are candidate in bone tissue engineering since it does
75], salt leaching technology [76] and gas-induced foaming
promote biocompatibility and biodegradability which would
technology [77, 78]. Those technologies can easily form
allow cell growth in human body [30]. The chemical
controlled porous polymers below 200 µm size. But they can

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hardly control the porous from 200-500 µm in size which also produced could not even reached by TIPS method, which was
very important for bone regeneration and vascularization. ranged from 200 µm to 500 µm. This happened due to the well
A thermally induced phase separation technique (TIPS) was prepared column inside the PEM with the additional of
used by Ruiyun and Peter, 1999, in order to create highly compressed air and nozzle. Effectiveness of the porosity
porous composite scaffolds for bone tissue engineering [60]. formed increased the mechanical properties of the PLLA
PLLA was mixed with hydroxyapatite (HA) using dioxane as scaffolds up to 8.32 MPa.
solvent. Freeze drying procedure allows to produce hard and From the observation of Table 2, the compression strength
tough foam with a co-continuous structure of interconnected with the presence of filler was much higher than non-filler,
pores and HA/PLLA composite skeleton. The composite indicating that most of the particles bonded to PLLA matrix
mixture was proved to be in good bone bonding [79, 80]. were on the surfaces of the pores, and it showed good adhesion
Their work showed that foam porosity could be reached as between them [79, 80]. Some molecular interaction and
high as 95% while pore sizes ranging from several microns to chemical bonding which were presented between HA and
few hundred microns were obtained. Mechanical properties of PLLA influenced the interfacial behavior and mechanical
HA/PLLA scaffold was compared to those corresponding pure properties of the composites [83, 84]. It is obvious that among
PLLA and it was found out that the compressive modulus of pure PLLA and composite scaffolds, nano-composite scaffolds
composite (11 MPa) was significantly higher than the pure showed the highest compressive strength because of some
PLLA (6.4 MPa). reasons: 1) Particle sizes may attribute to the large interfacial
Same technique and material was implemented by Nejati area between nano HA and PLLA matrix. 2) More uniform
and co-worker [81], instead of using HA particles, they used distribution of nano HA particles in polymer matrix. Xiong
nano and micro sized HA as filler in scaffolding. Both nano and his co-workers successfully used PEM in order to achieve
and micro composite scaffolds showed some molecular high compression strength and modulus. However, it is still
interactions and chemical linkages between HA particles and inconvenient since there are other alternative methods with
PLLA matrix, affecting the interfacial behavior and reasonable cost [78]. A new artificial structural elastic,
mechanical properties of the HA/PLLA composites. The partially degradable bone graft for supporting weak bone in
porosity of scaffold was up to 85% and the average micropore the proximal femur was presented by Lagoa and co-workers
diameter was in the range of 64-175 µm. The compressive [34]. The implant materials consist of a functionally graded
strength of nano-composite scaffold was up to 14.9 MPa while combination of titanium, PLA, HA and calcium carbonate. The
pure PLLA and micro-HA/PLLA scaffolds were found to be implant has an outer elastic layer in contact with the bone,
1.79 MPa and 13.68 MPa, respectively. This study consisting of D,L-PLA, HA and calcium carbonate, inner layer
demonstrated the positive effect nano-HA and micro-HA on was made by manual dip-coating of the metal into solutions of
improving the mechanical properties of the PLLA matrix, also PLLA with suspended calcium salts. The purpose of D,L-PLA
indicating that the values are comparable to the high end being placed at the outer layer is due to its fast degradation
strength of cancellous bone [82]. Furthermore, Mesenchymal rate which gave an opportunity for bone on and ingrowth when
stem cells (MSCs) for cell culture of scaffolds revealed that it degrades. PLLA has slow degradation rate and provides a
the cell affinity and biocompatibility of nano-HA/PLLA was biocompatible interface between the living tissue and the
found to be higher than the other two scaffolds. bioinert metal while the bone consolidates. The artificial strut
Xiong and co-worker [78] fabricated PLLA scaffold using grafts strengthen its implant by inserting titanium which
precise extrusion manufacturing (PEM). The measured value offered mechanical stability for bone growth.
of scaffold porosity was only 60% but the pore size values

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TABLE 2
COMPARISON MECHANICAL PROPERTIES OF SCAFFOLD COMPOSITES (PLA/FILLER)
Material characteristics Mechanical properties
References Initial Filler Porosity Methods Process condition Compression
PLLA characterist (%)
Mw ics Average
(kDA) pore size
Strength Modulus
[60] n.a. None n.a. Thermally Stirred: 50oC, 2hrs 0.24 6.4
induced Solution: dioxane
phase Immersed in liquid
separation nitrogen.
Freeze Dry:
-5 - -10oC, 4 days
HA, 95.00 0.4 11.0

(50-200
µm)
Stirred: 4hrs*
[81] 140 None 87.37 Thermally Solution: dioxane 1.8 2.2
(0.5g) (64 µm) induced Freeze Dry: -200C,
phase 72 hrs
374 separation
micro-HA 86.56 4.8 14.0
nano-HA 85.06 8.7 14.9

160oC
[78] None 60.30 Precise 8.32 194.96
(200-500 extrusion
µm)

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TABLE 3
COMPARISON MECHANICAL PROPERTIES OF DENSE COMPOSITES (PLA/FILLER)
References Initial PLA Mw Filler Methods Process Tension (MPa) Compression Bending (MPa)
(kDA) characteristics condition (MPa)
strength modulus strength modulus strength modulus

[91] 220 none Hot pressing 103oC 154.10 1300 123.5 4800 258.5 6500
202 HA, 50 wt%, Hot pressing 103oC 103 2400 115 6500 267.5 12,300
0.3-20 µm
[92] 100 HA, 80 wt%, Hot pressing 176oC, 38 2000
0.5-0.7 mm 98.1 MPa
nanoHA, 80 Hot pressing 176oC, 72 3500
wt%, 100 nm 98.1 MPa
430 HA, 80 wt%, Hot pressing 184oC, 50 2500
0.5-0.7 mm 98.1 MPa
nanoHA, 80 Hot pressing 194oC, 139 10,000
wt%, 100 nm 98.1 MPa
[93] 160 none Hot pressing 180oC, 52 3500
40 MPa
HA fibers, Hot pressing 180oC, 40 11,000
70 wt% 40 MPa
[94] 300 none Hot pressing 175oC, 60 1800
10 MPa
Grafted Hot pressing 175oC, 63 2500
nanoHA, 10 MPa
4 wt%
[85] 104 none Hot pressing 160oC, 56
300 MPa
nanoHA, 25 Hot pressing 160oC, 88
wt%, 300 MPa
D=2.1 µm
nanoHA, 50 Hot pressing 160oC, 100
wt%, 300 MPa
D=2.1 µm
[86] n.a none i) mixed i) 25oC, 24h 1200
ii) pressing ii) 200oC
mMMT, 1.5 i) mixed i) 25oC, 24 1400
wt% ii) pressing ii) 200oC
mMMT, 3.0 i) mixed i) 25oC, 24h 2000
wt% ii) press ii) 200oC
mMMT, 6.0 i) mixed i) 25oC, 24h 2400
wt% ii) press ii) 200oC

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Besides using separation technique to produce scaffold filler (%wt) and the initial Mw. Nano-particles obtain better
composite at a range of porosity, there is a way to prepare the results in terms of mechanical strength and moduli. In
mixture of the same composite (nano-HA/PLLA, 0:100, 20:80 addition, composite in the dense form more preferable
and 50:50) by using hot pressing, dense samples were compare to scaffold due to their capability to perform in high
investigated rather than porous scaffolds [85]. In addition, load bearing applications.
annealing treatment was performed with the hope to enhance
the crystallinity of the polymers. However, annealing treatment
C. Poly (glycolic acid)
does not influence the physical properties of the composites
(particle sizes, porosity and mechanical properties, see Table PGA has the simplest structure. It can be considered as one
3) since the polymer has reached its ultimate crystallinity at the of the first biodegradable synthetic polymer investigated for
end of the cooling step, and yet, only remaining chloroform at biomedical implant. PGA is a highly crystalline polymer (45-
the surface of the composites thoroughly eliminated after 50 % crystallinity) and therefore exhibits high tensile modulus
annealing treatment. Dispersion of HA nanoparticles into a with very low solubility in organic solvents. The glass
PLLA matrix was a success whereby compressive strength of transition temperature (Tg) of the polymer ranges from 35 to
over 100 MPa have been achieved, this value expressed that 40oC and the melting point is greater than 200oC. It shows
the developed nano HA/PLLA properties was comparable to excellent mechanical properties, also due to its high
those of cortical bone. Nano-HA/PLLA composites are thus crystallinity. A self reinforced foam composed of PGA is
promising; to be develop as bioresorbable porous bone stiffer than any other degradable polymeric system used
substitutes showing superior mechanical performance. clinically [96] and has been shown to exhibit a modulus
Tzong and Cheng [86] used solution mixing process of PLA approximately 12.5 GPa [97]. Due to its good initial
reinforced with montmorillonite (MMT), the MMT modified mechanical properties, PGA has been investigated as bone
by chitosan function was aimed to improve the chemical internal fixation devices. However, PGA is also known to lose
similarity between PLA and MMT. Polymer/clay composites its strength in 1-2 months when hydrolyzed and losses mass
have received significant attention in academic and industrial within 6-12 months. Thus, this indicates that the degradation
area in recent years due to the excellent enhancement in rate is very high, which in the end would limit the mechanical
physical and/or chemical properties relative to the neat properties and biomedical applications for PGA. Therefore, as
polymer matrix [87-89]. The results showed that the reported by Linhart and his co-workers [37], they used PGA
interaction between PLA and MMT was successful for the reinforced with amorphous carbonate apatite to investigate any
used in biomedical application and the detail is shown in Table potential performance of PGA in bone substitute and found out
3. that the composite could serve only as bone substitution
Mechanical resistance was also evaluated in order to materials for small or non-load bearing indications.
determine the best operating conditions of HA/PLA scaffolds
to produce implants which offers optimized properties for use D. Poly (lactide-co-glycolide)
as bone substitutes [90]. A pore-forming agent (salt) was The combination of lactic and glycolic side formed PLGA
carried out in the forming of scaffolds which restricted to 70 amorphous polymer. Both L- and DL- have been used for co-
wt%, whereby resistance as high as 2.2 MPa could distort the polymerization. In the composition range of 25-75 %, PLGA
composites mechanical properties. It was shown that the forms amorphous polymers. Miller and his co-workers have
addition of 30 % to 40 % of filler allows a satisfactory shown that the 50-50% PLGA is very hydrolytically unstable
dispersion of the mineral within the matrix. A high percentage and the resistance to hydrolytic degradation was found to be
of filler is unfavorable for processing of porous scaffolds, as it more pronounced at either end of the copolymers composition
prevents the matrix from playing its role as a binder. range [98, 99]. PLGA was used in a number of clinical
Table 3 displays several examples of the composite application [100] but few in the orthopedic area. Most of the
according to the initial Mw, the nature of filler and the process PLGA appears in scaffold due to its favorable properties.
conditions. Presence of nano-particles as filler obviously However, the surface chemistry of PLGA does not fully
improves the mechanical strength and stiffness of PLA promote cell adhesion for enhancing the bone ingrowth and
composites. The maximum strength that can be reached was at proliferation due to its hydrophobic nature [101]. The
139 MPa [92]. Nano-particles have gained much recognition mechanical properties and biodegradation rate of PLGA can
as bone dealer not only due to their composition and structural be manipulated to some extent by controlling the molecular
similarity with natural bone but also because of their unique weight of the copolymer and the unit ratio of lactide to
functional properties such as larger surface area and superior glycolide in the copolymer. PLGA used in bone repair or
mechanical strength than those of single or pure constituents substitute applications have shown to be biocompatible, non-
[95]. The effect of micro-fiber demonstrated by Kasuga and toxic and non-inflammatory [102, 103]. However, PLGA
co-workers [93] achieved a very high bending modulus but cannot be utilized as load bearing applications either due to its
showed the vice versa effect on the bending compression. The low mechanical strength, too flexible characteristic or lack of
compressive strength increased by increasing the quantity of osteogenic bioactivity.

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Fei and co-workers created a novel biodegradable PLGA for showed a better achievement after 20 months of post surgery.
bone repair [104]. The moldable, degradable bone substitute Other than that, both composites offered different advantages
with osteogenesis materials composed of PLGA loaded with which make no differences in in vivo implantation where both
bone morphogenetic protein-2 (BMP-2) microspheres showed similar ability to enhance in vivo mineralization and
incorporated with calcium phosphate cement (CPC) for bone allowed rapid mineralization conjugation with neighboring
growth. Lactic to glycolic ratio was 50:50. The scaffolds only bone better than neat PLGA.
appeared when the composites immersed in the phosphate Aligned nanofibrous scaffolds based on PLGA and nano-
buffer saline (PBS) in order to induce degradation towards HA were synthesized by electrospinning for bone engineering
BMP-2 which then formed PLGA/CPC scaffolds. The results [108]. At higher concentration (> 10wt %), a reduction in
showed that the CPC composites compressive strength mechanical properties occurred because of the agglomeration
decreased from 29.48 MPa to 8.26 MPa when PLGA was of HA in the PLGA matrix fiber, whereby the presence of
added during setting. This happened because the structure of nano-HA resulted in fiber breaking (Table 5). In
interlocking CPC crystal needles, which produce the cement electrospinning, the major factors that have a direct effect on
strength, was inhibited when microspheres were added into the fibers diameters (size particles) were solution
CPC [105]. Although the mechanical properties of the concentration and electric field. At higher voltages, needle tip
composites decreased after PLGA was added, better inside the machine produced unstable sources of fibers. The
degradation and stable composite was produce and the results collection of fiber scaffolds on a high speed rotator resulted in
were equivalent to the cancellous bone. a highly oriented fibers. The diameter of the scaffolds from
Another PLGA pellets with a lactide/glycolide ratio of this method can be affected by the choice of the solvent. It was
85:15 with the pore sizes range of 250-450 µm were used by suggested that the used of more polar and hydrophilic solvents
William and his co-workers in their investigation [106]. In this can reduce the degree of aggloromeration of the HA powder
study, the process of mineralization in tooth and bone and can thereby find a good dispersion of particles in the
development was directly mimicked through the use of SBF as polymer matrix [109].
the mineral growth solution. In other words, PLGA was Lee and his co-workers [40] aimed to develop a composite
incubated in SBF at different times to demonstrate the growth scaffold for bone regeneration that would meet criteria by
of a continuous bonelike apatite layer within the pores of the hybridizing bladder submucosa matrix (BSM) as a natural
polymer. In addition, the process was a single step and bioactive material with synthetic PLGA polymers. BSM alone
occurred in the room temperature. It resulted in a growth of a was not suitable for bone graft applications due to its small
continuous layer on much of the inner pore surface, which pore size, poor interconnectivity and inability to maintain
significantly increased the compressive modulus up to 320 ± structural integrity. To overcome these limitations, a design of
60 kPa after 16 days of treatment, without a large decreased in natural-synthetic polymer scaffold that would possess an
total porosity. The mineral grown was a carbonated apatite interconnected network of pores and sufficient mechanical and
mineral layer, similar to the mineral present in bone, and hence chemical properties that would maintain structural integrity,
is expected to have a high degree of bioreactivity. Such a layer thus preventing collapse during the handling and implantation
could be of great importance in the field of bone tissue process. PLGA scaffold with incorporation of BSM did not
engineering, providing the advantages of increased alter structural changes during the fabrication process. From
osteoconductivity and enhanced mechanical properties. Also, Table 5, the compressive strength of hybrid natural-synthetic
it is an efficient and relatively inexpensive mineral growth scaffold was lower than the pure PLGA due to the natural
process. behavior of hydrophilic characteristic by BSM itself. Although
Surface grafted of HA in the PLGA matrix deposition (g- physically weaker than other scaffolds, the result after cell
HA/PLGA) showed excessive improvement on interface seeded in the scaffolds was promising after all. BSM-PLGA
between the polymers and CPC rather than non-grafted allowed 90% cell adhesion, while 30% by pure PLGA.
HA/PLGA [107]. Three dimensional porous scaffolds of
grafted HA/PLGA was fabricated using solvent
casting/particulate leaching method to compare with
conventional HA/PLGA scaffolds and to investigate its
application in bone replacement [107]. In their report, in vivo
mineralization and osteogenesis were investigated by
replacement for repairing radius defects of rabbits. Table 4
analyzes the advantages of g-HA/PLGA and HA-PLGA.
Despite of decreased in calcium exposure when
implantation, surface grafted-HA/PLGA showed some
advantages and good requirements in bone fixation.
Unfortunately, no mechanical properties have been reported
for comparison, but it can be said that non-grafted composites

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TABLE 4
ADVANTAGES OF GRAFTED HA FILLER AND UN-GRAFTED HA FILLER IN PLGA MATRIX [107]
g-HA/PLGA HA/PLGA
More uniform distribution of granules on the pore walls surface. After 20 months post surgery, calcium content that attached to the
composite was 10 wt%, higher than grafted composite (8 wt %).
Improve the microstructure stability of the composite scaffolds Better osteogenesis after implantation
TABLE 5
MECHANICAL PROPERTIES OF SCAFFOLD COMPOSITES (PLGA/FILLER)
Ref. Initial PLGA Mw Filler Lactic:glycolic Porosity (%) Methods Process condition Storage modulus Compressive Young modulus
(kDA) characteristics ratio Average pore size (MPa) strength (MPa)
(MPa)
[40] 110 none 50:50 92.43 Solvent casting/ PLGA: NaCl 1.20 8.33
particulate 1:10,
leaching Air dried 24h,
(134.22 µm) vacuum dried 48h.
100-250 µm
110 Collagen, BSM 50:50 94.79 0.83 5.56
(121.84 µm)
[107] 196 none 80:20 83.6 Solvent casting/ PLGA/HA:sucrose
particulate 1:6
leaching 100-450 µm
HA, 10 wt% 80:20 85.9
Grafted HA, 10 86.6
wt% 80:20
[106] 15 None 94.0 Solvent casting/ PLGA:NaCl 0.32
85:15 particulate
leaching 250-450 µm
63 none 85:15 72.0 electrospinning 13-15 kV, rotating 441.0
HA, 1 wt% 85:15 61.0 speed=6000 rpm, 591.7
HA, 5 wt% 85:15 62.0 solvent=HFP 724.2
HA, 10 wt% 85:15 64.0 557.3
HA, 20 wt% 85:15 72.0 371.4
[104] 24 CPC, 40 wt% 50:50 Molding 8.26

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PLGA scaffolds reinforced with calcium phosphate like HA highly processable as it is soluble in a wide range of organic
as filler showed better mechanical properties compared to pure solvents. The uncommon things of PCL is its high thermal
PLGA, due to the HAs’ more similar characteristics to bone stability, with decomposition temperature (Td) of 350oC,
apatite, its’ ability to promote the attachment of cultured whereas others aliphatic polyesters are between 235oC and
osteoblasts and to improve metabolic activity [110-112]. 255oC [118]. In bone engineering area, PCL can be
Addition of HA in polymer matrix had been approved to categorized as promising biocompatible and biodegradable
increase mineralization in matrices in vitro osteoblasts culture polymers since it is being used to enhance bone ingrowth and
[113]. It provide more favorable surface for cell attachment regeneration in the treatment of bone defects [119, 120],
and the ability of the material to support bone ingrowth [114]. however, PCL is poorly studied due to the slow degradation
In addition, calcium phosphate additives in PLGA matrix [121].
provides surface roughness which enhanced bone attachment One of the work done by Chen and Sun [122] was by
and proliferation [115]. The advantage of PLGA is that the reinforcing PCL with HA by melt blending technique (Table
strength of the composite could be controlled by the amount of 6). This method requires the exact melting temperature of the
PLGA microspheres, which makes it possible for the surgeons biodegradable polymers to ensure that the polymer fully
to modify the material to obtain an adequate strength. The melted and provide fillers with spaces for fine dispersion in the
particles sizes also play a significant role in bone implantation, polymer matrix. Smaller HA particles (3-8 µm) distributed
whereby particle sizes ranging from 50-300 µm have been higher compressive strength than HA (20-80 µm), indicating
found to be optimal for bone ingrowth [116]. However, that size of particle affect the improvement of the composites
previous studies noted that the size of interconnection in the mechanical properties [122]. The smaller the particle diameter
scaffolds is the main limiting factor for bony ingrowth rather the greater the specific surface and interfacial areas within the
than the size of pores themselves [117]. matrix. Their results can simply be plotted as seen in Fig. 2.
Whether the method used are solvent casting, Fig. 2 indicates that the addition of HA increased the
electrospinning or BMP loaded in PLGA matrix and degrade compression of composite towards bone fixation, but, until
when immerse in the PBS solution, the mechanical properties some level, the failure mechanism of the composites changes
produced (shown in Table 5) were all in the range of potential from plastic to brittle (easily rupture) and hence lowering the
in forming cancellous bone, (compression strength, ≤ 10 MPa, mechanical properties of PCL and other biodegradable
modulus, 50-500 MPa). PLGA in the dense form was poorly polymers.
studied and hardly found in the previous work, it could maybe
due to the amorphous characteristics of PLGA whereby
unknown melting temperature renders PLGA unsuitable to be
prepared by melt blending or hot pressing.
E. Poly (ε-caprolactone)
Most research work has been directed at PLA, PGA and
PLGA copolymers. The success of these for pharmaceutical
applications has further led to the evaluation of aliphatic
polyesters such as poly(ε-caprolactone) (PCL). PCL is an
aliphatic polyester that has been intensively investigated as a
biomaterial. It appears as semicrystalline polyester and is Fig. 2. Compression strength versus weight of HA in PCL [122].

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TABLE 6
MECHANICAL PROPERTIES OF COMPOSITES (PCL/FILLER)
Material Mechanical
Characteristics properties
Ref. Initial PCL Mw Filler Composite form Methods Process condition Compressive
(kDA) characteristics strength (MPa)
[122] 80 None dense Melt blending 61.1oC, 10 min, 12.80
Pressing mould 120oC
HA, 3-8 µm, dense 17.90
20 wt%
HA, 3-8 µm, dense 10.50
40 wt%
HA, 3-8 µm, dense 7.60
60 wt%
o
80 None dense Melt blending 62.3 C, 10 min, 12.80
Pressing mould 120oC
HA, 20-80 µm, dense 15.90
20 wt%
HA, 20-80 µm, dense 10.40
40 wt%
HA, 20-80 µm, dense 7.00
60 wt%
[123] 50 None scaffold impregnating 600oC 0.27
HA scaffold 600oC 0.57
TABLE 7
DEGRADATION RATE OF BIODEGRADABLE POLYESTERS
Polymers Glass transition point, Tg (oC) Biodegradable time Ref
(months)
lower upper
DL-PLA 50 60 12-16 [128, 131, 132]
L-PLA 55 65 > 24 [128, 132]
PGA 35 45 6-12 [128, 131, 133]
PLGA 40 55 Adjustable: [52]
1-12
PLGA 1-2 [134]
(50/50)
PLGA 4-5
(75/25)
PLGA 5-6
(85/15)
PCL -60 -65 > 24 [135]
wide range of degradation rates since the ratio of lactic over

F. Biodegradation of polyesters
glycolic varied, the degradation kinetics being governed by
Degradation could be characterized in many ways, like loss both hydrophilic/hydrophobic balance and crystallinity.
of Mw, loss of mass or loss of mechanical strength, chemical Composition of chain (lactic or glycolic units) determines the
composition, configurational structure, stress and strain, degradation rates of PLGA copolymers. Blends that contains
crystallinity, porosity, chain orientation, dispersion of higher amount of PGA have been shown to degrade faster
chemically reactive compounds within the matrix [124, 125]. [124]. PCL degradation proceeds with two stages: random
The polymers degrade by random chain scission [126]. Since hydrolytic ester cleavage and weight loss through the diffusion
only the monomer degradation products are soluble, a very of oligometric species from the bulk. PCL with high Mw could
large reduction in both Mw and mechanical strength typically take several years to degrade in vivo [127-129]. In general, the
occurs before a decrease in the weight of the sample is sequence of polyesters degradation rates decreases in the
observed. In the case of implantation in vivo, the body already following order [54]:
contains highly regulated mechanism for completely removing PGA > PDLLA > PLLA > PCL
monomeric components of lactic and glycolic acids. PGA is The kinetic patterns of polyesters degradation are shown
converted to metabolites or eliminated by other mechanisms, below [130]:
while PLA can be cleared through the tricarboxylic acid cycle. --COOR ···HOOC-- + H2O → 2COOH + ROH
The crystallinity of L-PLA samples has been observed to Table 7 shows the degradation rate of some biopolymers.
increase during degradation and particles of highly crystalline The degradation rate, physical and mechanical properties of
material can be found in vivo long after the bulk of the implant PLA and PGA are adjustable by varying their Mw and
has disintegrated [56]. copolymers. However, from one review of responses towards
Biodegradable polyester degradation occurs by uptake of resorbable pins made from either PGA or copolymer, over 500
water followed by the hydrolysis of ester bonds. PLGA has a

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patients, 7.9 % developed a late noninfectious inflammatory may range from 300 to 1000 kDa. Chitosan is normally
response during healing process. It has been suggested that the insoluble in water and aquoues solutions above pH 7, but, in
consequences occurred due to the release of acidic degradation diluted acid which pH less than 6, the protonated free amino
products (PGA and PLA) [136]. Böstman gave a solution to group on glucosamine facilitate solubility of that molecule
these problems; for orthopaedic applications, it requires the [159-162]. Chitosan has been found to be non-toxic after oral
development of a polymer that is more hydrophobic than PLA administration in humans and has FDA approval.
and PGA and does not release acidic degradation products on Enzymes, such as chitosanase, lysozyme and papain are
hydrolysis [136]. known to degrade chitosan in vitro [163]. The in vivo
New era with new technologies come out with better degradation of chitosan is primarily due to lysozyme and takes
theories and materials. Linhart and his co-workers [37] place through the hydrolysis of the acetylated residues. The
announced that the used of calcium phosphate blended with rate of degradation of chitosan inversely depends on the
polyesters could overcome the drawbacks. These composites degree of acetylation and crystallinity of the polymer [164].
showed good biocompatibility because of: 1. Compensation of The highly deacetylated form exhibits the lowest degradation
acidic release from the polymer through the alkaline calcium rates and may last several months in vivo. Apart from this,
phosphate. 2. Participation of carbonated apatite in the chemical modification of chitosan can significantly affect its
biological remodeling process. Less stability of apatite has solubility and degradation rate [164].
higher solubility under conditions of acidic resorption [137, Chitosan is biocompatible, biodegradable, and can be
138]. 3. Physicochemical and biological transformation of molded into porous structures (allows osteoconduction) [165].
calcium phosphate into biological mineral as present in bone. Several studies have focused on the use of chitosan /calcium
4. Good adhesion of cells on aliphatic polyesters [139]. 5. phosphate composite for this purpose. Chitosan
Better distribution of degradation products through the /nanocrystalline calcium phosphate scaffolds characterized by
microporous structure, thereby avoiding accumulation of a relatively rough surface and approximately 20 times greater
acidic or harmful products. area/unit mass than chitosan scaffold indicate increased
adsorption, improved cell attachment for bone regeneration
[166]. In the development of chitosan/nano-HA scaffold
G. Benzyl ester of hyaluronic acid
conducted by Thein-Han and his co-workers [167], high Mw
Benzyl ester of hyaluronic acid, also known as HYAFF-11, chitosan scaffolds were examined by having superior
has shown good degradation rate and the products of
mechanical properties compared to medium Mw chitosan
degradation are non-toxic and non carcinogenic [140]. It
scaffolds (Table 8). In addition, the significant increased in
undergoes hydrolytic degradation via ester bonds in the
compression modulus of the nano-HA/chitosan composite was
absence of enzymatic activity with degradation times varying
from 1-2 weeks to 2-3 months, depending on the degree of attributed to the good dispersion of nano-HA and strong
esterification. The de-esterified HYAFF-11 is more hydrated, interaction between chitosan and nano-HA to formed a
soluble and resembles native hyarulonic acid [141, 142]. composite. In the nanocomposite scaffold, the organic chitosan
HYAFF-11 has been studied for the use in vascular grafts network uniformly covered the HA nanoparticles, interactions
[143, 144] and for bone tissue engineering [145, 146]. may have occurred similar to those occurring components of
Hyaluronic acid containing fibroblast growth factor is bone. Possible interactions involve Ca2+ and PO43- charged
undergoing clinical trial as a synthetic bone graft to accelerate species of HA with NH3+ of chitosan. However, the
bone fracture healing [30]. Sanginario and co-workers [147] mechanical properties of the composites obtained were
worked on HYAFF-11 reinforced with α-tri calcium phosphate inadequate for bone regeneration.
in the quantity of (14/86 wt%, respectively) in the form of Chitosan with incorporation of collagen (CCS) composite
hydrogel. The highest compression strength was in the range microgranules were fabricated as bone substitutes for the
of 17-12 MPa, compared to pure HYAFF-11 (3.0 MPa). This purpose of obtaining high bone – forming efficacy. The
values are in the range of cancellous bone, thus, HYAFF-11 microgranules have the flexibility to fill various types of defect
can be utilized bone fillers in orthopaedic and dental sites with closer packing. The interconnected pores formed
applications. spaces between the microgranules, which allowed new bone
ingrowth and vascularization [168, 169]. Like any other
biodegradable polymers, mechanical strength of CCS
III. NATURAL BIODEGRADABLE POLYMERS significantly improved after adding HA or any other calcium
A. Chitosan phosphate components (Table 8) [170]. Other than composite
scaffold, chitosan also appeared in the form of membrane
Chitosan derived from chitin, is a natural biopolymer
which was fabricated with silica xerogel [171]. Their potential
originating from crustacean and cell wall of fungi. It is known
applications in guided bone regeneration (GBR) were
as linear polysaccharide, composed of glucosamine and N-
investigated in terms of bone regeneration ability. The in vivo
acetyl glucosamine ratio being referred as the degree of
study in a rat calvarial model demonstrated significantly
deacetylation, which was found in marine environment.
enhanced bone regeneration using the chitosan /xerogel
Depending on the source and the processing method, its Mw

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membrane compared to that of using the pure chitosan one. (structure shown in Fig. 4). The transformation of chitosan into
Histomorphometric analysis performed 3 weeks after N-succinylchitosan incorporated with 50 wt% of hemihydrates
implantation revealed a fully closed defect in the hybrid calcium sulphate resulted in compression strength and Young’s
membrane, whereas there was only 57% defect closure in the Modulus of 0.80 MPa and 14.7 MPa, respectively.
chitosan membrane.
Another scientific studies of modified chitosan structure,
sulfated chitosans with varied sulfate group; the MW and sulfur
content were tailored to investigate the effects on the
bioactivity of BMP-2 [172]. Low dose of synthetic sulfated
chitosan (structure shown in Fig. 3) proved to stimulate
osteoblast differentiation induced by BMP-2 in vitro and
ectopic bone formation in vivo. Another foundation of
chitosan modification is to allow water solubility in chitosan Fig. 4. Succinylation reaction of chitosan [173].
matrix, done by Gomez d’Ayala and co-workers [173]
Fig. 3. Chemical structures of chitosan modified with different sulfate groups.

2-N-Sulfated chitosan, 2SCS; 6-O-Sulfated chitosan, 6SCS; 2-N,6-O-Sulfated
chitosan, 26SCS [172].

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TABLE 8
MECHANICAL PROPERTIES OF SCAFFOLD COMPOSITES (CHITOSAN/FILLER)
Ref. Initial CS Mw Filler Composite Methods Process Tensile Young Compressive
(kDA) characteristics form condition strength modulus modulus
(degree of (MPa) (MPa) (kPa)
deacetylation)
[167] 250 None Scaffold Thermally Solution 4.5
(75%) induce used= acetic
phase acid, 1M
separation Freeze dry = -
20oC, 24 h
nano-HA, 0.5 scaffold 5.5
wt%
(~50 nm)
nano-HA, 1 scaffold 6.8
wt%
(~50 nm)
nano-HA, 2 8.6
wt%
(~50 nm)
400 None Thermally Solution 6.0
(83%) induce used= acetic
phase acid, 1M
separation Freeze dry = -
20oC, 24 h
nano-HA, 1 scaffold 9.4
wt%
(~50 nm)
[170] 100-170 Collagen scaffold Solution 2
(75-85%) used= acetic
acid, 0.5M
Freeze dry = -
20oC, 2h
Collagen & scaffold 10
HA
[171] n.a. None membrane Sol gel Solution 0.9 15
(85%) used=
hydrochloric
acid, HCl,
Methanol.
Rotary pump
and freeze dry
Thickness=
100-250 µm
Silica xerogel, membrane Sol gel 0.52 16.11
10 vol%
Silica xerogel, membrane 0.44 17.47
20 vol%
30 vol%
40 vol%
physico-chemical, mechanical and biological properties,

B. Collagen
collagen have been extensively investigated for biomedical
Approximately 30% of the protein contain in the human applications. Collagen is mostly soluble in acidic aqueous
body, collagen is the most abundant protein being the major solutions and can be processed into different forms such as
component of skin and bone [30, 48]. Collagen is a rod type sheets, tubes, sponges, foams, nanofibrous matrices, powders,
polymer nearly 300nm long with a Mw of 300.000. The injectable viscous solutions and dispersions. The degradation
repeating sequence is responsible for the helical structure and rate of collagen used in biomedical applications can be
the inherent and predictable mechanical strength of collagen significantly altered by enzymatic pre-treatment or cross-
[174]. Collagen undergoes enzymatic degradation within the linking. By increasing the crosslinks, one could: 1) increase
body via enzymes. Due to the enzymatic degradability, the biodegradation time, making collagen less susceptible to

IJENS
enzymatic degradation; 2) decrease the capacity of collagen to hydrophobic and even annealing process could tailor the
absorb water; 3) decrease its solubility, and 4) increase the mechanical properties and degradation rate of the composite.
tensile strength of collagen [175]. And yet, hot pressing is the best method in producing
As a biomaterial, collagen is biocompatible, biodegradable biostable, biodegradable and biocompatible composite because
and osteoconductive [176, 177]. The composition of human the parameters of polymers can be arrange to fulfill the
bone is a well known mineral/organic hybrid consisting of HA mechanical integrity from non-load bearing to compact bone
and organic mainly collagen constituents. Calcium phosphate characteristic, while porous scaffold is only restricted to
/collagen composites are probably the most biomimetic system spongeous bone application. Further research should be
for osseous replacement or regenerative bony [178-182]. embark upon the development of polymeric biomaterials for
When associated with calcium phosphate particles or any other target applications.
filler forming composite, collagen prevents the filler
dispersion in implants, resulting in an easily molded ACKNOWLEDGMENT
biomaterial [183]. In order to investigate the vicinity between The financial support provided by the Universiti Teknologi
collagen and calcium phosphate in bone substitute biomaterial, Malaysia through RUG grant is gratefully acknowledged.
composite constituted of collagen and calcium phosphate
doped by europium were synthesized by a precipitation REFERENCES
method [184]. Interaction checked by Förster resonance [1] F.C.M. Driessens, “The mineral in bone, dentin and tooth enamel,” Bull.
energy transfer (FRET) devices showed a good yield from the Soc. Chim. Belg”, Bull. Soc. Chim. Belg, 89, 1980, 663-689.
composites thus promising to be bone substitute. [2] K.A. Athanasiou, C. Zhu, D.R. Lanctot, “Fundamentals of
biomechanics in tissue engineering of bone”, Tissue Engineering, 6,
Collagen coatings are known to enhance early cell adhesion 2000, 361-381.
and proliferation on calcium phosphate, increasing the in vivo [3] A.M. Rafal, “Polymer-calcium phosphate composites for use as an
osteointegration, osteoconduction and osteoregenerative injectable bone substitute”, Materials Science and Engineering, 2001,
capacity of these materials [39, 185]. For these reasons, 1-42.
[4] A. Guyton, “Textbook of Medical Physiology”, 1991, Saunders,
composite materials containing calcium phosphate and Philadelphia.
collagen have been developed [186] using methods such as [5] S. Weiner, T. Wolfie, H.D. Wagner, “Lamellar bone: structure-function
particle-gel mixing and powder compression [187-189]. relations”, Journal of Structural Biology, 126, 1999, 241-255.
[6] M.J. Yaszemski, R.G. Payne, W.C. Hayes, R. Langer, A.C. Mikos,
One scientific study regarding the effect of collagen/citric “Evolution of bone transplantation: molecular, cellular, and tissue
acid on the setting reaction of brushite found out that collagen strategies to engineer human bone”, Biomaterials, 17, 1996, 175-185.
has the capability in speeding up the cement setting reaction [7] J.D. Currey, “Mechanical properties of vertebrate hard tissues,
Proceedings of the Institution of Mechanical Engineers, Part H”, 212,
and had compressive strength similar to that of spongeous 1998, 399-411.
bone (48.9 MPa) [190]. With the combination of citric acid, it [8] P. Zioupos, “Recent developments in the study of solid biomaterials and
helped to shorten the setting time, increase the injectability, bone: "fracture" and "pre-fracture toughness"”, Materials Science and
Engineering C, 6, 1998, 33-40.
reduce the viscosity and improve the mechanical strength of
[9] S.C.S.X.B. Cavalcanti, C.L. Pereira, R. Mazzonetto, “Histological and
the composite [191]. Citric acid also enable the mixing of a histomorphometric analyses of calcium phosphate cement in rabbit
high collagen content gel (3 wt%) with the cement powder to calvari”, Journal of Cranio-Maxillofacial Surgery, 36, 2008, 354-359.
form brushite-collagen composite that was easy to work with. [10] A.B.M. Rabie, R.M.K. Wong, U. Hägg, “Composite autogenous bone
and demineralized bone matrices used to repair defects in the parietal
The effect of crosslinking on brushite-collagen composites was bone of rabbits”, Br J Oral Maxillofac Surg, 38, 2000, 565-570.
also studied by immersing the composite into 2% [11] P.J. Walsh, F.J., Buchanan, M. Dring, C. Maggs, S. Bell, G.M. Walker,
gluteraldehyde solution in wet condition, neither the addition “ Low-pressure synthesis and characterisation of hydroxyapatite derived
from mineralise red algae”, Chemical Engineering Journal, 137, 2008,
of collagen nor glutaraldehyde crosslinked collagen seemed to 173-179.
increase the compressive strength of the composite after [12] A.B.M. Rabie, S.H. Chay, A.M.K. Wong, “Healing of autogenous
storage in wet condition [190]. intramembranous bone in the presence and absence of homologous
demineralized intramembranous bone”, Am. J. Orthod. Dentofacial
Orthop., 117, 2000, 288-289.
IV. CONCLUSION [13] J. Glowacki, J.B. Mulliken, “Demineralized bone implants”, Clin.
Biodegradable polymers properties do give definite impact Plast. Surg., 12, 1985, 233-241.
[14] I. Binderman, N. Fin, (1990). “Bone substitutes-organic, inorganic, and
on the bone healing, formation, regeneration or substitution for polymeric: cell material interaction”, CRC handbook of bioactive
human body. Without the help of other fillers, biodegradable biomaterials, Yamamuro, T., Hench, L.L., Wilson. J., 45-61, Boca
polymers application is limited to non-bearing bone. Solvent Raton: CRC Press.
[15] B.E. Buck, T.I. Malinin, M.D. Brown, “Bone transplantation and
plays an important role in solubility of polymers. It is also human immunode"ciency virus. An estimate of risk of acquired
important that the initial mechanical strength of the composite immunode"ciency syndrome (AIDS)”, Clin. Orthop., 240, 1989, 129-
significantly higher compared with initially porous materials. 136.
[16] S.C. Gamradt, J.R. Lieberman, Clin. Orthop. Relat. R., 417, 2003,183.
A higher mechanical strength will assure defect stability in the [17] L. Vastel, A. Meunier, H. Siney, L. Sedel, J.P. Courpied, “Effect of
early critical stage when few bones have yet grown onto the different sterilization processing methods on the mechanical properties
defects site. Mw, particle size, porosity, crystallinity, of human cancellous bone allografts”, Biomaterials, 25, 2004, 2105-
2110.
methodology, polymers, fillers concentration, hydrophilic,

IJENS
[18] S.M. Best, A.E. Porter, E.S. Thian, J. Huang, “Bioceramics: Past, [41] Y. Shikinami, M. Okuno, “Bioresorbable devices made of forged
present and for the future”, Journal of the European Ceramic Society, composites of hydroxyapatite (HA) particles and poly-L-lactide (PLLA):
28, 2008, 1319-1327. Part I. Basic characteristics”, Biomaterials, 20, 1999, 859-877.
[19] E.J. Blom, J. Klein-Nulend, J.G. Wolke, M.A., vanWaas, F.C. [42] M. Tanahashi, T. Yao, T. Kokubo, M. Minoda, T. Miyamoto, T.
Driessens, E.H. Burger, “Transforming growth factor-beta1 Nakamura, T. Yamamuro, “Apatite coating on organic polymers by a
incorporation in a calcium phosphate bone cement: material properties biomimetic process”, J. American Ceramic Society, 77, 1994, 2805-
and release characteristics”, J. Biomed. Mater. Res., 59, 2002, 265-272. 2808.
[20] R.H. Li, M.L. Bouxsein, C.A. Blake, D. D'Augusta, H. Kim, X.J. Li, [43] M.N. Helmus, J.A Hubbell, Materials selection, Cardiovasc. Pathol, 2,
J.M. Wozney, H.J. Seeherman, “rhBMP-2 injected in a calcium 1993, 53S-71S.
phosphate paste (α-BSM) accelerates healing in the rabbit ulnar [44] J.A. Hubbell, “Biomaterials in tissue engineering, Biotechnology”, 13,
osteotomy model”, J. Orthop. Res, 21, 2003, 997-1004. 1995, 565-576.
[21] P.Q. Ruhe, H.C. Kroese-Deutman, J.G.C. Wolke, P.H.M. Spauwen, J.A. [45] S.W. Shalaby, R.A. Johnson, (1994). “Synthetic absorbable polyester,
Janse, “Bone inductive properties of rhBMP-2 loaded porous calcium Biomedical Polymers Designed-to-Degrade Systems”, Hanser
phosphate cement implants in cranial defects in rabbits”, Biomaterials, Publishing.
25, 2004, 2123-2132. [46] R.K. Kulkarni, E.G. Moore, A.F. Hegyeli, F. Leonard, “Biodegradable
[22] Fernández, E. (2006). Bioactive bone cements, Wiley encyclopedia of poly (lactic acid) polymers”, J. Biomed. Mater. Res., 5: 1971, 169-181.
biomedical engineering, Metin, A., 1-9, John Wiley & Sons, Inc. [47] M. Vert, S.M. Li, “Bioresorbability and biocompatibility of aliphatic
[23] X.P. Wang, J.D. Ye, Y.J. Wang, L. Chen, “Self-setting properties of a b- polyesters”, J. Mater. Sci. Mater. Med, 3, 1992, 432-446.
dicalcium silicate-reinforced calcium phosphate cement”, J. Biomed. [48] J.M. Pachence, (2007). Biodegradable polymers, in Principles of Tissue
Mater. Res. B, 82, 2007, 93-99. Engineering, 3rd Edition, Academic Press: Burlington.
[24] E.F. Burguera, H.H.K. Xu, S. Takagi, L.C. Chow, “High early strength [49] J. Jagur-Grodzinski, “Biomedical application of functional polymers”,
calcium phosphate bone cement: effects of dicalcium phosphate Reactive Funct. Polym., 39, 1999, 99–138.
dihydrate and absorbable fibers”, J. Biomed. Mater. Res. A, 75, 2005, [50] J.R.L. Kohn (1996). Bioresorbable and bioerodible materials,
966–975. Biomaterials science: an introduction to materials in medicine,
[25] C.D. Friedman, P.D. Constantino, K. Jones, Arch. Otolaryngol Head Hoffman, B.D. and Schoen, A.S., 64-72, New York: Academic Press.
Neck Surg., 117, 1991, 385. [51] J.F. Mano, R.A. Sousa, L.F. Boesel, N.M. Neves, R.L. Reis, “Bioinert,
[26] M.L. Shindo, D.P. Costantino, C.D. Friedman, L.C. Chow, “Facial biodegradable and injectable polymeric matrix composites for hard
Skeletal Augmentation Using Hydroxyapatite Cement”, Arch. tissue replacement: state of the art and recent developments”, Compos.
Otolaryngol. Head Neck Surg., 119, 1993, 185-190. Sci. Technol., 64, 2004, 789-817.
[27] A.J. Domb, D.M. Wiseman, (1998). Handbook of Biodegradable [52] B.L. Seal, T.C. Otero, A. Panitch, “Polymeric biomaterials for tissue and
Polymers, Boca Raton: CRC Press. organ regeneration”, Mater. Sci. Eng.: Rep., 34, 2001, 147-230.
[28] E. Piskin, “Biodegradable polymers as biomaterial”, J. Biomat Sci [53] W.T. Godbey, A. Atala, “In Vitro System Systems for Tissue
Polym Ed, 6, 1995, 775-795. Engineering”, Annals of the New York Academy of Sciences, 961, 2002,
[29] S.W. Shalaby, K.J.L. Burg, (2003). Absorbable and biodegradable 10-26.
polymers (advances in polymeric materials), Boca Raton. CRC press. [54] K. Rezwan, Q.Z. Chen, J.J. Blaker, A.R. Boccaccini, “Biodegradable
[30] L.S. Nair, C.T. Laurencin, “Biodegradable polymers as biomaterials”, and bioactive porous polymer/inorganic composite scaffolds for bone
Prog. Polym. Sci, 32, 2007, 762-798. tissue engineering”, Biomaterials, 27, 2006, 3413-3431.
[31] D.F. Williams, (1999). The Williams dictionary of biomaterials. [55] L.G. Griffith, “Polymeric biomaterials”, Acta. Mater., 48, 2000, 263-
Liverpool University Press. 277.
[32] S. Vainionpaa, E. Laasonen, H. Pätlälä, M. Rusanen, P. Rokkannen, [56] M. Vert, J. Mauduit, S. Li, “Biodegradation of PLA/GA
“Acute dislocation of the patella: Clinical, radiographic and operative polymers:Increasing complexity”, Biomaterials, 15, 1994, 1209-1213.
findings in 64 consecutive cases”, Acta. Orthop. Scand., 57, 1986, 331- [57] C. Martin, H. Winet, J.Y. Bao, “Acidity near eroding polylactide-
333. polyglycolide in vitro and in vivo in rabbit tibial bone chambers”,
[33] A.W. Lloyd, “Interfacial bioengineering to enhance surface Biomaterials, 17, 1996, 2373–2380.
biocompatibility”, Med .Device Technol., 13, 2002, 18-21. [58] C.M. Agrawal, K.A. Athanasiou, “Technique to control pH in vicinity
[34] A.L.C. Lagoa, C. Wedemeyer, M. Knoch, F. Löer, M. Epple, “A strut of biodegrading PLA-PGA implant”, J. Biomed. Mater. Res., 38, 1997,
graft substitute consisting of a metal core and a polymer surface”, J. 105-114.
Mater. Sci.: Mater. Med., 19, 2008, 417–424. [59] H. Winet, J.Y. Bao, “Comparative bone healing near eroding
[35] G.S.J. Carl, C. A. Khatri, S.A. Wight, F.W. Wang, “Preliminary report polylactide-polyglycolide implants of differing crystallinity in rabbit
on the biocompatibility of a moldable, resorbable, composite bone graft tibial bone chambers”, J. Biomater. Sci. Polym. Edn., 8, 1997, 517-532.
consisting of calcium phosphate cement and poly(lactide-co-glycolide) [60] Z. Ruiyun, X.M. Peter, “Poly(alpha-hydroxyl acids)/hydroxyapatite
microspheres”, Journal of Orthopaedic Research, 20, 2002, 473-482. porous composites for bone-tissue engineering. I. Preparation and
[36] K. Anselme, “Osteoblast adhesion on biomaterials”, Biomaterials, 21, morphology”, Journal of Biomedical Materials Research, 44, 1999,
2000, 667-681. 446-455.
[37] W. Linhart, F. Peters, W. Lehmann, K. Schwarz, A. Schilling, M. [61] Y. Tsuji, Y.Ikada, “Blends of aliphatic polyesters. II. Hydrolysis of
Amling, J.M. Rueger, M. Epple, “Biologically and chemically optimized solution-cast blends from poly (L-lactide) and poly(E-caprolactone) in
composites of carbonated apatite and polyglycolide as bone substitution phosphate-buffered solution”, J. Appl. Polym. Sci., 67, 1998, 405-415.
materials”, Journal of Biomedical Materials Research, 54, 2001, 162- [62] H. Urayama, T. Kanamori, Y. Kimura, “Properties and biodegradability
171. of polymer”, Macromol. Mater. Eng., 287, 2002, 116-121.
[38] A.J. Salgado, M.E. Gomes, A. Chou, O.P. Coutinho, R.L. Reis, D.W. [63] T. Iwata, Y. Doi, “Morphology and Enzymatic Degradation of Poly(l-
Hutmacher, “Preliminary study on the adhesion and proliferation of lactic acid) Single Crystals”, Macromolecules, 31, 1998, 2461-2467.
human osteoblasts on starch-based scaffolds”, Materials Science and [64] D. Sawai, K.Takahashi, T. Imamura, K. Nakamura, T. Kanamoto, S.
Engineering, 20, 2002, 27-33. Hyon, “Preparation of oriented β-form poly(L-lactic acid) by solid-state
[39] C.V. Rodrigues, C.V.M. Rodrigues, P. Serricella, , Linhares, A.B.R., extrusion”, J. Polym. Sci. Polym. Phys., 40, 2002, 95-104.
Guerdes, R.M., Borojevic, R., Rossi, M.A., Duarte, M.E.L. and [65] R.G. Sinclair, “The Case for Polylactic Acid as a Commodity Packaging
Farina M. (2003). Characterization of a bovine collagen-hydroxyapatite Plastic”, J. Macromol. Sci. Pure. Appl. Chem., 33, 1996, 585-597.
composite scaffold for bone tissue engineering, Biomaterials, 24: 4987- [66] P. Christel, F. Chabot, J.L. Leray, “Biodegradable composites for
4997. internal fixation”, Biomaterials, 1982, 271-280.
[40] S.J. Lee, G.J. Lim, J. Lee, A. Atala, J.J. Yoo, “In vitro evaluation of a [67] J.W. Leenstag, A.J. Pennings, R.R.M. Bos, F.R. Rozema, G. Boering, “
poly(lactide-co-glycolide)–collagen composite scaffold for bone Resorbable materials of polyl-lactides VI. Plates and screws for internal
regeneration”, Biomaterials, 27, 2006, 3466–3472. fracture fixation”, Biomaterials, 8, 1987, 70-73.

IJENS
[68] S. Vainionpaa, J. Kilpikari, J. Laiho, P. Helevirta, P. Rokkanen, P. [91] Y. Shikinami, M. Okuno, “Bioresorbable devices made of forged
Törmälä, “Strength and strength retention in vitro, of absorbable, self- composites of hydroxyapatite (HA) particles and poly-l-lactide (PLLA):
reinforced polyglycolide (PGA) rodes for fracture fixation”, Part I. Basic characteristics”, Biomaterials, 20, 1999, 859-877.
Biomaterials, 8, 1986, 45-48. [92] N. Ignjatovic, K. Delijic, M. Vukcevic, D.P. Uskokovic,
[69] A.G. Pathiraja, A. Raju, “Biodegradable synthetic polymers for tissue “Microstructure and Mechanical Properties of Hot Pressed
engineering”, European Cells and Materials, 5, 2003, 1-16. Hydroxyapatite/Poly-L-lactide Biomaterials”, Bioceramics, 13, 2001,
[70] Y. Yan, F. Cui, R. Zhang, “Rapid prototyping manufacturing of 737-740.
artificial human bone”, Mater. Rev., 14, 2000, 11-13. [93] T. Kasuga, Y. Ota, M. Nogami, and Y. Abe, “Preparation and
[71] Y.S. Nam, T.G. Park, “Porous biodegradable polymeric scaffolds mechanical properties of polylactic acid composites containing
prepared by thermally induced phase separation”, J. Biomed. Mater. hydroxyapatite fibers”, Biomaterials, 22, 2001, 19-23.
Res., 4, 1999, 8-17. [94] Z.K. Hong, P. Zhang, C. He, X. Qiu, A. Liu, l. Chen, X. Chen, X. Jing,
[72] R.Y. Zhang, P.X. Ma, “Porous PLLA/apatite composites created by “Nano-composite of poly(l-lactide) and surface grafted hydroxyapatite:
biomimetic process”, Biomed. Mater. Res., 45, 1999, 285-293. Mechanical properties and biocompatibility”, Biomaterials, 26, 2005,
[73] M.H. Sheridan, L.D. Shea, M.C. Peters, “Bioabsorbable polymer 6296-6304.
scaffolds for tissue engineering capable of sustained growth factor [95] R. Murugan, S. Ramakrishna, “Development of nanocomposites for
delivery”, J. Controlled Release, 64, 2000, 91-102. bone grafting”, Compos. Sci .Technol., 65, 2005, 2385-2406.
[74] C. Schugens, V. Maquet, C. Grandfils, R. Jerome, P. Teyssie, [96] P. Tormala, “Biodegradable self-reinforced composite materials:
“Polylactide macroporous biodegradable implants for cell Manufacturing structure and mechanical properties”, Clin. Mater., 10,
transplantation. II. Preparation of polylactide foams by liquid-liquid 1992, 29-34.
phase separation”, Journal of Biomedical Materials Research, 30, [97] P.B. Maurus, C.C. Kaeding, “Bioabsorbable implant material review”,
1996, 449-461. Oper. Tech. Sport. Med., 12, 2004, 158–60.
[75] G.B. Wei, P.X. Ma, “Macroporous and nanofibrous polymer scaffolds [98] P. Gunatillake, R. Mayadunne, R. Adhikari, “Recent developments in
and polymer/bone-like apatite composite scaffolds generated by sugar biodegradable synthetic polymers”, Biotechnol .Ann. Rev., 12, 2006,
spheres”, J. Biomed. Mater. Res. A, 78, 2006, 306-315. 301-347.
[76] A.G. Mikos, A.J. Thorsen, L.A. Czerwonka, Y. Bao, R. Langer, D.N. [99] R.A. Miller, J.M. Brady, D.E. Cutright, “Degradation rates of oral
Winslow, J.P. Vacanti, “Preparation and characterization of poly(l-lactic resorbable implants (polylactates and polyglycolates rate modification
acid) foams”, Polymer, 35, 1994, 1068-1077. with changes in PLA/PGA copolymer ratios”, J. Biomed. Mater. Res.,
[77] L.M. Mathieu, T.L. Mueller, P.E. Bourban, D.P. Pioletti, R. Muller, 11, 1977, 711-719.
J.A.E. Manson, “Architecture and properties of anisotropic polymer [100] P.A. Gunatillake, R. Adhikari, “Biodegradable synthetic polymers for
composite scaffolds for bone tissue engineering”, Biomaterials, 27, tissue engineering”, Eur .Cell. Mater., 5,12003-12016.
2006, 905-916. [101] S.J. Lee, K. Gilson, Y.M. Lee, H.B. Lee, “Interaction of human
[78] Z. Xiong, Y.N. Yan, R.J. Zhang, L. Sun, “Fabrication of porous PLLA chondrocytes and NIH/3T3 fibroblasts on chloric acid-treated
scaffolds for bone tissue engineering via precise extrusion”, Scripta biodegradable polymer surfaces”, J. Biomater. Sci. Polym. Ed., 13,
Materialia, 45, 2001, 773-779. 2002, 197-212.
[79] C.M. Flahiff, A.S. Blackwell, J.M. Hollis, D.S. Feldman, “Analysis of a [102] J.F. Nelson, H.G. Stanford, D.E. Cutright, “Evaluation and comparison
biodegradable composite for bone healing”, J. Biomed. Mater. Res., 32, of biodegradable substances as osteogenic agents”, Oral. Surg., 43,
1996, 419-424. 1977, 836-843.
[80] S. Higashi, T. Yamamuro, T. Nakamura, Y. Ikada, “Polymer- [103] J.O. Hollinger, “Preliminary report on osteogenic potential of a
hydroxyapatite composites for biodegradable bone fillers”, biodegradable copolymer of polylactide (PLA) and polyglycolide
Biomaterials, 7, 1986, 183-187. (PGA)”, J. Biomed. Mater. Res., 17, 1983, 71-82.
[81] E. Nejati, H. Mirzadeh, M. Zand, “Synthesis and characterization of [104] Z.Q. Fei, Y. Hu, D. Wu, H. Wu, R. Lu, J. Bai, H. Song, “Preparation
nano-hydroxyapatite rods/poly(L-lactide acid) composite scaffolds for and property of a novel bone graft composite consisting of rhBMP-2
bone tissue engineering”, Composite Part A, 39, 2008, 1589–1596. loaded PLGA microspheres and calcium phosphate cement”, J. Mater.
[82] R.R. Hassna, M. Zhang, “Biphasic calcium phosphate nanocomposite Sci.: Mater. Med., 19, 2008, 1109–1116.
porous scaffolds for load-bearing bone tissue engineering”, [105] B.K. Nicolai, A. Reinstorf, I. Hofinger, K. Flade, R. Wenz, W. Pompe,
Biomaterials, 25, 2004, 5171-5180. “Influence of osteocalcin and collagen I on the mechanical and
[83] W. Jie, L. Yubao, K.T. Lau, “Preparation and characterization of a nano biological properties of Biocement D”, Biomol. Eng., 19, 2002, 227-
apatite/polyamide bioactive composite”, Composites, 38, 2007, 301- 231.
305. [106] L.M. William, H.K. David, J.M. David, “Growth of continuous bonelike
[84] W. Jie, L. Yubao, “Tissue engineering scaffold material of nano-apatite mineral within porous poly(lactide-co-glycolide) scaffolds in vitro”,
crystals and polyamide composite”, Eur. Polym . J., 240, 2004, 509- Journal of Biomedical Materials Research, 50, 2000, 50-58.
515. [107] P.B. Zhang, Z. Hong, T. Yu, X. Chen, and X. Jing, “In vivo
[85] S. Gay, S. Arostegui, J. Lemaitre, “Preparation and characterization of mineralization and osteogenesis of nanocomposite scaffold of poly
dense nanohydroxyapatite/PLLA composites”, Materials Science and (lactide-co-glycolide) and hydroxyapatite surface-grafted with poly(L-
Engineering: C, 29, 2008, 172-177. lactide)”, Biomaterials, 30, 2009, 58-70.
[86] M.W. Tzong, Y.W. Cheng, “Biodegradable poly(lactic acid)/chitosan- [108] M.V. Jose, V. Thomas, K.T. Johnson, D.R. Dean, E. Nyairo, “Aligned
modified montmorillonite nanocomposites: Preparation and PLGA/HA nanofibrous nanocomposite scaffolds for bone tissue
Characterization”, Polymer Degradation and Stability, 91, 2006, 2198- engineering”, Acta Biomaterialia, 5, 2009, 305-315.
2204. [109] H.W. Kim, H.H. Lee, J.C. Knowles, “Electrospinning biomedical
[87] E.P. Giannelis, “Polymer Layered Silicate Nanocomposites”, Adv. nanocomposite fibers of hydroxyapatite/poly(lactic acid) for bone
Mater., 8, 1996, 29-35. regeneration”, J Biomed. Mater. Res., 79A, 2006, 643-649.
[88] M. Ogawa, K. Kuroda, “Preparation of Inorganic–Organic [110] C.D. Friedman, P.D. Costantino, S. Takagi, L.C. Chow, “Bone Source:
Nanocomposites through Intercalation of Organoammonium Ions into hydroxyapatite cement: a novel biomaterial for craniofacial skeletal
Layered Silicates”, Bull. Chem. Soc. Jpn., 70, 1997, 2593-2618. tissue engineering and reconstruction”, J. Biomed. Mater. Res., 43,
[89] A. Okada, A. Usuki, “The chemistry of polymer-clay hybrids”, Mater. 1998, 428-432.
Sci. Eng. C., 3, 1995, 109-115. [111] J. Huang, S.M. Best, W. Bonfield, R.A. Brooks, N. Rushton, S.N.
[90] N.L. Bolay, V. Santran, G. Dechambre, C. Combes, C. Drouet, A. Jayasinghe, “In vitro assessment of the biological response to nano-sized
Lamure, C. Rey, “Production, by co-grinding in a media mill, of porous hydroxyapatite”, J. Mater. Sci. Mater .Med., 15, 2004, 441-445.
biodegradable polylactic acid–apatite composite materials for bone [112] S. Pezzatini, R. Solito, L. Morbidelli, S. Lamponi, “The effect of
tissue engineering”, 190, 2009, 89-94. hydroxyapatite nanocrystals on microvascular endothelial cell viability
and functions”, J. Biomed. Mater. Res. A, 76, 2006, 656-663.

IJENS
[113] B. Zimmermann, H.C. Wachte, C. Noppe, “Patterns of mineralization in [137] Y. Doi, T. Shibutani, Y. Moriwaki, T. Kajimoto, Y. Iwayama, “Sintered
vitro”, Cell. Tissue Res., 263, 1991, 483-493. carbonate apatites as bioresorbable bone substitute”, J. Biomed. Mater.
[114] G. Ciapetti, L. Ambrosio, L. Savarino, D. Granchi, E. Cenni, N. Baldini, Res., 39, 1998, 603-610.
S. Pagani, “Osteoblast growth and function in porous poly 3- [138] R.P. Shellis, A.R. Lee, R.M. Wilson, “Observations on the apparent
caprolactone matrices for bone repair: a preliminary study”, solubility of carbonate-apatites”, J. Coll. Interf. Sci., 218, 1999, 351-
Biomaterials, 24, 2003, 3815-3824. 358.
[115] H. Yuan, K. Kurashina, J.D. de Bruijn, Y. Li, K. de Groot, X. Zhang, [139] S.L. Ishaug, G.M. Crane, M.J. Miller, A.W. Yasko, M.J. Yaszemski,
“A preliminary study on osteoinduction of two kinds of calcium A.G. Mikos, “Bone formation by three-dimensional stromal osteoblast
phosphate ceramics”, Biomaterials, 20, 1999, 1799-1806. culture in biodegradable polymer scaffolds”, J. Biomed. Mater. Res., 36,
[116] Y. Kuboki, Q. Jin, and H. Takita, “Geometry of Carriers Controlling 1997, 17-28.
Phenotypic Expression in BMP-Induced Osteogenesis and [140] L. Benedetti, R. Cortivo, T. Berti, A. Berti, F. Pea, M. Mazzo, M.
Chondrogenesis”, J. Bone J. Surg., 83A, 2001, S105. Moras, G. Abatangelo, “Biocompatibility and biodegradation of
[117] N. Tamai, A. Myoui, M. Hirao, T. Kaito, and T. Ochi, “A new different hyaluronan derivatives (Hyaff) implanted in rats”,
biotechnology for articular cartilage repair: subchondral implantation of Biomaterials, 14, 1993, 1154-1160.
a composite of interconnected porous hydroxyapatite, synthetic polymer [141] M. Mori, M. Yamaguchi, S. Sumitomo, Y. Takai, “Hyaluronan based
(PLA-PEG), and bone morphogenetic protein-2 (rhBMP-2)”, J. Biomed. biomaterials for tissue engineering”, Acta Histochem. Cytochem., 37,
Mater. Res., 59, 2002, 405-417. 2004, 1-5.
[118] I. Engelberg, J. Kohn, “Physico-mechanical properties of degradable [142] C. Giordano, V. Sanginario, L. Ambrosio, L. Di Silvio, M. Santin,
polymers used in medical applications: A comparative study”, “Chemical-physical characterization and in vitro preliminary
Biomaterials, 12, 1991, 292-304. biological assessment of hyaluronic acid benzyl ester-hydroxyapatite
[119] C.G. Pitt, M.M. Gratzel, G.L. Kimmel, “Aliphatic polyesters. 2. The composite”, J. Biomater. Appl, 20, 2006, 237-252.
degradation of poly(DL-lactide), poly(e-caprolactone) and their [143] S. Lepidi, F. Grego, V. Vindigni, “In vivo regeneration of small-
copolymers in vivo”, Biomaterials, 2, 1981, 215-220. diameter (2-mm) articles using a polymer scaffold”, FASEB J., 20,
[120] J.R. Porter, A. Henson, K.C. Popat, “Biodegradable poly(3- 2006, 103-105.
caprolactone) nanowires for bone tissue engineering applications”, [144] N.J. Turner, C.M. Kielty, M.G. Walker, A.E. Canfield, “A novel
Biomaterials, 30, 2009, 780-788. hyaluronan-based biomaterial (Hyaff-11) as a scaffold for endothelial
[121] M.J. Mondrinos, R. Dembzynski, L. Lu, V.K.C. Byrapogu, D.M. cells in tissue engineered vascular graft”, Biomaterials, 25, 2004, 5955-
Wootton, P.I. Lelkes, J. Zhou, “Porogen-based solid freeform 5964.
fabrication of polycaprolactone-calcium phosphate scaffolds for tissue [145] C. Giordano, V. Sanginario, L. Ambrosio, L. Di Silvio, M. Santin,
engineering”, Biomaterials, 27, 2006, 4399-4408. “Chemical-physical characterization and in vitro preliminary
[122] B. Chen, K. Sun, “Poly (3-caprolactone)/hydroxyapatite composites: biological assessment of hyaluronic acid benzyl ester-hydroxyapatite
effects of particle size, molecular weight distribution and irradiation on composite”, J. Biomater. Appl, 20, 2006, 237-252.
interfacial interaction and properties”, Polymer Testing, 24, 2005, 64- [146] V. Sanginario, M.P. Ginebra, K.E. Tanner, J.A. Planell, L. Ambrosio,
70. “Biodegradable and semibiodegradable composite hydrogels as bone
[123] J. Zhao, L.Y. Guo, X.B. Yang, J. Weng, “Preparation of bioactive substitutes: morphology and mechanical characterization”, J. Mater.
porous HA/PCL composite scaffolds”, Applied Surface Science, 255, Sci. Mater. Med, 17, 2006, 447-454.
2001, 2942–2946. [147] V. Sanginario, M.P. Ginebra, K.E. Tanner, J.A. Planell, L. Ambrosio,
[124] S.D. Andrew, G.C. Phil, K.G. Marra, “The influence of polymer blend “Biodegradable and semibiodegradable composite hydrogels as bone
composition on the degradation of polymer/hydroxyapatite biomaterial”, substitutes: morphology and mechanical characterization”, J. Mater.
J. Mater. Sci.: Mater.Med., 12, 2001, 673-677. Sci. Mater. Med, 17, 2006, 447-454.
[125] W. Heidemann, S. Jeschkeit, K. Ruffieux, J.H. Fischer, M. Wagner, G. [148] V.A. Dubok, “Bioceramics-yesterday, today, tomorrow”, Powder
Kruger, E. Wintermantel, K.L. Gerlach, “Degradation of Metallurgy and Metal Ceramics, 39, 2000, 7-8.
poly(D,L)lactide implants with or without additions of calcium [149] K.C. Baker, J. Drelich, “Biomimetic formation of nano-crystalline
phosphate in vivo”, Biomaterials, 22, 2001, 2371-2381. calcium-phosphate films on self-assembled monolayers of alkanethiols:
[126] J.M. Schakenraad, M.J. Hardonk, J. Feijen, I. Molenaas, P. effects of end functionality and deposition methodology”, Functional
Nieuwenhuis, “Enzymatic activity toward poly(lactic acid) Fillers and Nanoscale Minerals, 2006, 199-216.
implants”, J. Biomed. Mater. Aes., 24, 1990, 529-545. [150] K.C. Baker, J. Drelich, R. Israel, H.N. Herkowitz, “Effect of
[127] J. Rich, T. Jaakkola, T. Tirri, T. Närhi, A. Yli-Urpo, J. Seppälä, “In vitro polyethylene pretreatments on the biomimetic deposition and adhesion
evaluation of of poly(var-epsilon)-caprolactone-co-DL-lactide)/bioactive of calcium phosphate films”, Acta Biomater., 3, 2007, 391-401.
glass composite”, Biomaterials, 23, 2002, 2143-2150. [151] M. Yamaguchi, H. Oishi, Y. Suketa, “Stimulatory effect of zinc on bone
[128] S. Yang, K. Leong, Z. Du, C. Chua, “The design of scaffolds for use in formation in tissue culture”, Biochem. Pharmacol., 36, 1987, 4007-
tissue engineering. Part 1: Traditional factor”, Tissue Engineering, 7, 4012.
2001, 679-689. [152] A. Ito, K. Ojima, H. Naito, N. Ichinose, T. Tateishi, “Preparation,
[129] H.L. Gabelnick, (1983). Biodegradable implants: alternative solubility, and cytocompatibility of zinc-releasing calcium phosphate
approaches. In:Mishell DR, editor. Advanced in human fertility and ceramics”, J. Biomed Mater. Res, 50, 2000, 178-183.
reproductive endocrinology: vol. 2: Long acting steroid contraception. [153] M. Ikeuchi, A. Ito, Y. Dohi, H. Ohgushi, H. Shimaoka, K. Yonemasu,
New York: Raven Press, 149-173. T. Tateishi, “Osteogenic differentiation of cultured rat and human bone
[130] V.R. Sinha, K. Bansal, R. Kaushik, R. Kumria, A. Trehan, “Poly-ε- marrow cells on the surface of zinc-releasing calcium phosphate
caprolactone microspheres and nanospheres: an overview”, ceramics”, J. Biomed. Mater. Res., 67, 2003, 1115-1122.
International Journal of Pharmaceutics, 278, 2004, 1-23. [154] J. Charnley, “Anchorage of the femoral head prosthesis to the shaft of
[131] J.C. Middleton, A.J. Tipton, “Synthetic biodegradable polymers as the femur”, Bone J. Surg., 42B, 1960, 28-30.
orthopaedic devices”, Biomaterials. 21, 2000, 2335-2346. [155] J.S. Temenoff, A.G. Mikos, “Injectable biodegradable materials for
[132] L.C. Lu, A.G. Mikos, (1999). Poly (lactic acid), Polymer data orthopedic tissue engineering”, Biomaterials, 21, 2000, 2405-2412.
handbook, Mark J.E., 527-633, Oxford: Oxford Press. [156] Y.W. Li, J.C.Y. Leong, W.W. Lu, K.D.K. Luk, K.M.C. Cheung, K.Y.
[133] S. Ramakrishna, Z.M. Huang, G.V. Kumar, A.W. Batchelor, J. Mayer, Chiu, S.P. Chow, “A novel injectable bioactive bone cement for spinal
(2004). An introduction to biocomposites, Imperial College Press. surgery: a developmental and preclinical study”, Biomedical Materials
[134] J.C. Middleton, A.J. Tipton, “Synthetic biodegradable polymers as Research, 52, 2000, 164-170.
medical devices”, Med. Plast. Biomater., 21, 1998, 2335-2346. [157] S. Saha, S. Pal, “Mechanical properties of bone cement: a review”,
[135] J.O. Iroh, (1999). Poly(epsilon-caprolactone), Polymer data handbook, Biomedical Materials Research, 18, 1984, 435-462.
Mark, J.E., 361, Oxford: Oxford Press. [158] R.N. Stauffer, “10-year follow-up study of total hip replacement: with
[136] O.M. Böstman, “Absorbable implants for the fixation of fractures”, J. particular reference to roentgenographic loosening of the components”,
Bone J. Surg., 73, 1991, 148-153. J. Bone J. Surg., 64A, 1982, 983-90.

IJENS
[159] M. Dornish, D. Kaplan, O. Skaugrud, “Standards and guidelines for [176] A.H. Reddi, “Role of morphogenetic proteins in skeletal tissue
biopolymers in tissue-engineered medical products”, Ann. N. Y. Acad. engineering and regeneration”, Nat. Biotechnol. 16, 1998, 247-252.
Sci., 944, 200, 1388–397. [177] B. Chevallay, D. Herbage, “Collagen-based biomaterials as 3D scaffold
[160] K.A. Athanasiou, A.R. Shah, R.J. Hernandez, R.G. LeBaron, “Basic for cell cultures: applications for tissue engineering and gene therapy”,
science ofarticular cartilage repair”, Clin. Sports. Med., 20, 2001, 223- Med. Biol. Eng. Comput., 38, 2000, 211-218.
47. [178] S.H. Rhee, J.D. Lee, “Nucleation of Hydroxyapatite Crystal through
[161] S.V. Madihally, H.W.T. Matthew, “Porous chitosan scaffolds for tissue Chemical Interaction with Collagen”, J. Am. Ceram. Soc., 83, 2000,
engineering”, Biomaterials, 20, 1999, 1133-1142. 2890-2892.
[162] S.Y. Park, B.I. Lee, S.T. Jung, J.H. Park, “Biopolymer composite films [179] M. Kikuchi, S. Itoh, S. Ichinose, K. Shinomiya, J. Tanaka, “Self-
based on kcarrageenan and chitosan”, Materials Research Bulletin, 36, organization mechanism in a bone-like hydroxyapatite/collagen
2001, 511-519. nanocomposite synthesized in vitro and its biological reaction in vivo”,
[163] R.J. Nordtveit, K.M. Varum, O. Smidstrod, “Degradation of partially N- Biomaterials, 22, 2001, 1705-1711.
acetylated chitosans with hen egg white and human lysozyme”, [180] W. Zhang, S.S. Liao, F.Z. Cui, “Hierarchical self-assembly of nano-
Carbohyd. Polym., 29, 1996, 163-167. fibrils in mineralized collagen”, Chem. Mater., 15, 2003, 3221-3226.
[164] C. Shi, Y. Zhu, X. Ran, M. Wang, Y. Su, and T. Cheng, “Therapeutic [181] N. Roveri, G. Falini, M.C. Sidoti, A. Tamieri, E. Landi, M. Sandri, B.
potential of chitosan and its derivatives in regenerative medicine”, J. Parma, “Biologically inspired growth of hydroxyapatite nanocrystals
Surg. Res., 133, 2006, 185-192. inside self- assembled collagen fibers”, Mater. Sci. Eng. C, 23, 2003,
[165] H. Seeherman R. Li, J. Wozney, “A review of preclinical program 441-446.
development for evaluating injectable carriers for osteogenic factor”, J. [182] Y. Wang, C. Yang, X. Chen, and N. Zhao, “Biomimetic formation of
Bone Jt. Surg. Am.,. 85A, 2003, 96-108. hydroxyapatite/collagen matrix composite”, Adv. Eng. Mater., 8, 2006,
[166] B.M. Chesnutt, A.M. Viano, Y. Yuan, Y. Yang, T. Guda, M.R. 97-100.
Appleford, J.L. Ong, W.O. Haggard, J.D. Bumgardner, “Design and [183] F.Y. Hsu, S.C. Chueh, Y.J. Wang, “Microspheres of
characterization of a novel chitosan/nanocrystalline calcium phosphate hydroxypapatite/reconstituted collagen as supports for osteoblast cell
composite scaffold for bone regeneration”, J. Biomed. Mater. Res. A, growth”, Biomaterials, 20, 1999, 1931-1936.
88A, 2009, 491-502. [184] I. Dos Santos, S. Mazères, M. Freche, J. Lacout, A. Sautereau, “FRET:
[167] W.W. Thein-Han, R.D.K. Misra, “Biomimetic chitosan– A tool to study the interaction between apatite and collagen?”, Materials
nanohydroxyapatite composite scaffolds for bone tissue engineering”, Letters, 62, 2008, 4377–4379.
Acta Biomaterialia, 5, 2009, 1182-1197. [185] J. C. Brodie, E. Goldie, G. Connel, J. Merry, M.H. Grant, “Osteoblast
[168] G.A. Silva, P. Ducheyne, R.L. Reis, “Materials in particulate form for interactions with calcium phosphate ceramics modified by coating with
tissue engineering. 1. Basic concepts”, Journal of Tissue Engineering type I collage”, J Biomed Mater Res, 73, 2005, 409-421.
and Regenerative Medicine, 1, 2007, 4-24. [186] C. Zou, W. Weng, X. Deng, K. Cheng, X. Liu, P. Du, G. Shen, G. Han,
[169] J.Y. Lee, K.H. Kim, S.Y. Shin, I.C. Rhyu, Y.M. Lee, Y.J. Park, C.P. “Preparation and characterization of porous b-tricalcium
Chung, S.J. Lee, “Enhanced bone formation by transforming growth phosphate/collagen composites with an integrated structure”,
factor- β1-releasing collagen/chitosan microgranules”, J Biomed Mater Biomaterials, 26, 2005, 5276-5284.
Res, 7, 2006, 530-539. [187] W.E. Brown, L.C. Chow, (1986). A new calcium phosphate water
[170] H. Zhao, L. Ma, “Fabrication and properties of mineralized collagen- setting cement, Cements Research Progress, Brown, P,W., 352-379,
chitosan/hydroxyapatite scaffold”, Polym. Adv. Technol., 19, 2008, American Ceramic Society.
1590-1596. [188] H.A.Marouf, A.A. Quayle, P. Sloan, “In vitro and in vivo studies with
[171] E.J. Lee, D.S. Shin, H.E. Kim, H.W. Kim, Y.H. Koh, J.H. Jang, “ collagen/hydroxyapatite implants”, Int. J. Oral Maxillofac. Implants, 5,
Membrane of hybrid chitosan–silica xerogel for guided bone 1990, 148-154.
regeneration”, Biomaterials, 30, 2009, 743-750. [189] W. Schneiders, A. Reinstorf, W. Pompe, R. Grass, A. Biewener, M.
[172] H. Zhou, J.Qian, J. Wang, W. Yao, C. Liu, J. Chen, X. Cao, “Enhanced Holch, H. Zwipp, S. Rammelt, “Effect of modification of
bioactivity of bone morphogenetic protein-2 with low dose of 2-N, 6-O- hydroxyapatite/collagen composites with sodium citrate, phosphoserine,
sulfated chitosan in vitro and in vivo”, Biomaterials, 30, 2009, 1715- phosphoserine/RGD-peptide and calcium carbonate on bone
1724. remodeling”, Bone, 40, 2007, 1048-1059.
[173] G. D’Ayala, A. De Rosa, P. Laurienzo, M. Malinconico, “Development [190] F. Tamimi, B. Kumarasami, C. Doillon, U. Gbureck, D. Le Nihouannen,
of a new calcium sulphate-based composite using alginate and E.L. Cabarcos, J.E. Barralet, “Brushite–collagen composites for bone
chemically modified chitosan for bone regeneration”, J. of Biomed. Res., regeneration”, Acta Biomaterialia, 4, 2008, 1315-1321.
81, 2007, 811-820. [191] J.E. Barralet, U. Gbureck, L.M. Grover, “Ionic modification of calcium
[174] G.H. Altman, F. Diaz, C. Jakuba, T. Calabro, R.L. Horan, J. Chen, “Silk phosphate cement viscosity. Part II: hypodermic injection and strength
based biomaterials”, Biomaterials, 24, 2003, 410-416. improvement of brushite cement”, Biomaterials, 25, 2004, 2197-2203.
[175] J.M. Pachence, R.A. Berg, E.H. Silver, “Collagen: Its place in the
medical device industry”, Med. Dev. Diag. Indus., 9, 1987, 49-55.

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Biodegradable Polymers and Their Bone Applications: A Review

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International Journal of Basic & Applied Sciences IJBAS-IJENS Vol: 12 No: 01 31

Biodegradable Polymers and their Bone

Index Terms—Synthetic biodegradable polymers, Bone

There are two types of bone, compact or corical, and

B one is a complex living tissue which has an elegant

The corresponding author can be contacted via e-mail: *[email protected]

123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

TABLE I properties of these polymers allow hydrolytic degradation

123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

HA, 95.00 0.4 11.0

micro-HA 86.56 4.8 14.0

nano-HA 85.06 8.7 14.9

123101-8585 IJBAS-IJENS © February 2012 IJENS

strength modulus strength modulus strength modulus

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123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

wide range of degradation rates since the ratio of lactic over

123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

Fig. 3. Chemical structures of chitosan modified with different sulfate groups.

123101-8585 IJBAS-IJENS © February 2012 IJENS

physico-chemical, mechanical and biological properties,

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123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

123101-8585 IJBAS-IJENS © February 2012 IJENS

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