Materials Science and Engineering C 71 (2017) 1175–1191

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Materials Science and Engineering C

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

Review

Biodegradable ceramic-polymer composites for biomedical applications:

A review
Michal Dziadek a,⁎, Ewa Stodolak-Zych b,⁎, Katarzyna Cholewa-Kowalska a,⁎
a
AGH University of Science and Technology, Faculty of Materials Science and Ceramics, Department of Glass Technology and Amorphous Coatings, 30 Mickiewicza Ave., 30-059 Krakow, Poland
b
AGH University of Science and Technology, Faculty of Materials Science and Ceramics, Department of Biomaterials, 30 Mickiewicza Ave., 30-059 Krakow, Poland

a r t i c l e i n f o a b s t r a c t

Article history: The present work focuses on the state-of-the-art of biodegradable ceramic-polymer composites with particular
Received 2 August 2016 emphasis on influence of various types of ceramic fillers on properties of the composites. First, the general
Received in revised form 18 September 2016 needs to create composite materials for medical applications are briefly introduced. Second, various types of
Accepted 13 October 2016
polymeric materials used as matrices of ceramic-containing composites and their properties are reviewed.
Available online 14 October 2016
Third, silica nanocomposites and their material as well as biological characteristics are presented. Fourth, differ-
Keywords:
ent types of glass fillers including silicate, borate and phosphate glasses and their effect on a number of properties
Silica of the composites are described. Fifth, wollastonite as a composite modifier and its effect on composite character-
Bioglasses istics are discussed. Sixth, composites containing calcium phosphate ceramics, namely hydroxyapatite, tricalcium
Wollastonite phosphate and biphasic calcium phosphate are presented. Finally, general possibilities for control of properties of
Calcium phosphate ceramics composite materials are highlighted.
© 2016 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176
2. Biodegradable polymer matrices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176
3. Silica based composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176
4. Bioglass based composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178
4.1. Silicate bioactive glasses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178
4.2. Borate and borosilicate bioactive glasses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
4.3. Phosphate glasses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
5. Wollastonite based composites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181
6. Calcium phosphate ceramics based composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185

Abbreviations: ABTS•+, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation; ACP, amorphous calcium phosphate; ALP, alkaline phosphatase; BBG, borate-based glass;
BCP, biphasic calcium phosphate; BET SSA, Brunauer-Emmett-Teller specific surface area; BG, bioactive glass/bioglass; BMP-2, bone morphogenetic protein 2; BSP, bone sialoprotein; CAM,
cylinder chorioallantoic membrane; CaP, calcium phosphate; CBF-alpha-1, core-binding factor alpha-1; CMC, carboxymethylcellulose; CS, chitosan; DEX, dexamethasone; DPPH•, 2,2-
diphenyl-1-picrylhydrazyl radical; DSC, differential scanning calorimetry; ECM, extracellular matrix; EDX, energy dispersive X-ray spectroscopy; FN, fibronectin; FTIR, Fourier
transform infrared spectroscopy; FTIR-ATR, attenuated total reflectance Fourier transform infrared spectroscopy; gHAp, grafted hydroxyapatite; HAp, hydroxyapatite; hAT-MSCs,
human adipose tissue-derived mesenchymal stem cells; hBMSCs, human bone marrow mesenchymal stem cells; HCA, carbonated hydroxyapatite; HOC, human osteoblastic cells;
MSCs, mesenchymal stem cells; MSNs, mesoporous silica nanoparticles; mWS, mesoporous wollastonite particles; nHAp, nano-sized hydroxyapatite; NMR, nuclear magnetic
resonance; OC, osteocalcin; ON, osteonectin; OPN, osteopontin; Osx, osteoblast-specific transcription factor Osterix; PBG, phosphate glass; PBS, phosphate buffer saline; PBSu,
poly(butylene succinate); PCL, poly(ε-caprolactone); PDGF, platelet-derived growth factor; PDLLA, poly(D,L-lactide); PEG, polyethylene glycol; PEI, polyethylenimine; PEO,
poly(ethylene oxide); PGA, poly(glycolic acid); PHB, poly(3-hydroxybutyrate); PHBV, poly(3-hydroxybutyrate-co-3-hydroxyvalerate); PIXE, proton-induced X-ray emission; PLA,
poly(lactic acid); PLDLA, poly(L-lactide-co-D,L-lactide); PLGA, poly(lactic-co-glycolic acid); PLLA, poly(L-lactide); PRP, platelet-rich plasma; rBMSCs, rat bone marrow mesenchymal
stem cells; RT-PCR, reverse transcription polymerase chain reaction; RUNX2, runt related transcription factor 2; SBF, simulated body fluid; SBG, silicate bioactive glass; SCPL, solvent-
casting particulate leaching; SF, silk fibroin; TCP, tricalcium phosphate; TGF, transforming growth factor; TIPS, thermally induced phase separation; VEGF, vascular endothelial growth
factor; WAXS, wide-angle X-ray scattering; wHAp, hydroxyapatite whiskers; WS, wollastonite; XRD, X-ray diffraction.
⁎ Corresponding authors.
E-mail addresses: dziadek@agh.edu.pl (M. Dziadek), stodolak@agh.edu.pl (E. Stodolak-Zych), cholewa@agh.edu.pl (K. Cholewa-Kowalska).

http://dx.doi.org/10.1016/j.msec.2016.10.014
0928-4931/© 2016 Elsevier B.V. All rights reserved.
1176 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191

6.1. Hydroxyapatite based composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186

6.2. Tricalcium phosphate based composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
6.3. Biphasic calcium phosphate based composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187
7. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1188
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1188

1. Introduction and overall hydrophilicity [1]. Synthetic polymers possess relatively

On account of rapid development of novel biomedical technologies,
including tissue engineering, regenerative medicine, gene therapy and
controlled drug delivery, new materials are being developed to meet
specific requirements of these fields. Conventional single-component
ceramic or polymer materials cannot satisfy them. In addition, in order
to fully meet the basic requirements such as biocompatibility, biode-
gradability, appropriate mechanical properties, there is a need to obtain
materials fulfilling several advanced functions at once. For example, a
multifunctional material for bone tissue regeneration should induce for-
mation of new bone tissue without an addition of organic bone growth
factors (e.g. BMP-2), degrade progressively at a rate matching the re-
generation of new bone, induce new blood vessels formation and exhib-
it antibacterial and anti-inflammatory activity. Therefore, key material
and biological features can be achieved by design and development of
multi-component materials, including selection of matrix and modifier
materials, their parameters (e.g. shape, distribution, content), as well
as fabrication techniques of composites. In particular, this work deals
with the introduction of ceramic modifiers into biodegradable polymer
matrices to obtain composites with specific properties for biomedical
applications, especially tissue engineering and regenerative medicine.
The most widely used ceramic modifiers including bioactive glasses
and calcium phosphates, as well as less widespread silica and wollas-
tonite, with focus on their beneficial effects on material and biological
properties of the composites will be discussed.
A table placed at the end of the review (Table 3) provides an over-
view of polymer matrices, ceramic modifiers, methods of fabrication
and forms of composites discussed in this work, as well as their physical
properties.
2. Biodegradable polymer matrices
Many types of biodegradable polymeric materials have already been
used as matrices of ceramic-modified composites for tissue engineering
applications. These materials can be classified into two major groups
based on their origin, namely natural-based polymers, including pro-
teins (soy, collagen, fibrin gels, silk) or polysaccharides (starch, alginate,
chitin/chitosan, hyaluronic acid derivatives) and synthetic polymers,
such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(ε-
caprolactone) (PCL), poly(3-hydroxybutyrate) (PHB) [1–2].
Generally, biodegradation of polymeric biomaterials involves cleav-
age of enzymatically (natural polymers) or hydrolytically (synthetic
polymers) sensitive bonds in the polymer structure leading to the poly-
mer erosion [3]. Naturally-derived polymers possess the ability to bio-
logical recognition, including presentation of receptor-binding ligands,
that may support cell adhesion, migration, differentiation and prolifera-
tion. However, the rate of their in vivo degradation depends on avail-
ability and concentration of the enzymes at the site of implantation,
therefore it is difficult to predict. The use of natural polymers alone is
often restricted because of potential immunogenic reactions, possibility
of disease transmission and relatively poor mechanical properties [1–3].
Synthetic polymers have more predictable properties including degra-
dation kinetics that can be controlled by chemical composition and con-
figurational structure, molecular weight, polydispersity, crystallinity,
material morphology (e.g. porosity, surface area), chain orientation
good mechanical strength and their properties (e.g. porosity, shape)
can be tailored for specific applications. However, the surfaces of syn-
thetic polymers are hydrophobic and lacking in cell-recognition se-
quences [1–2].
In addition to the biodegradability, the composites take advantage of
high formability of polymer matrices. Many methods have been devel-
oped to fabricate composite materials for biomedical applications, in-
cluding solvent casting [4–6], tape casting [7], particulate leaching [8],
freeze drying [9], phase separation [10], thermal processing [11−12],
gas foaming [13], electrospinning [14] and rapid prototyping [15].
These methods allow obtaining the required properties, especially the
form and microstructure of the composites.
3. Silica based composites
Reports on silica (silicon dioxide, SiO2) as a filler or a nanofiller of
polymer matrix composites showed many advantages of composite or
nanocomposite materials based on biodegradable polymers [16–55].
Silica particles, incorporated into polymer matrices, cause higher bio-
compatibility and bioactivity of the materials and/or implants. These
compositions stimulate biological properties interesting for bone tissue
applications, such as given bioresorption rate and porosity, as well as
the ability to induce formation of calcium phosphate similar to the
one present in bone on biomaterials surfaces, and the introduction of bi-
ologically active agents [16–18]. Since silica reinforcements are fre-
quently used in the form of nanoparticles, understanding of
mechanisms of dissolution and metabolism of these particles in the or-
ganisms have also deserved considerable attention [17]. Nanometric
particles of SiO2 in polyesters provide many advantages compared to
other nanofillers and exhibit many properties associated with an ideal
material for grafting and scaffolding [19]. Due to silanol groups (Si-
OH) present on the surface of silica, covalent bonds can be formed be-
tween macromolecular chains and the fillers [20]. During the process
of nanocomposite synthesis, silane coupling agents play important
roles in connecting the interfaces of organic (polymer chain) and inor-
ganic phases (nanofillers, SiO2 particles). It is because they can be func-
tionalized at the interface to create a chemical bridge between the
reinforcement and the polymer matrix, and thus improve the stability,
adhesion and mechanical properties such as strength, Young's modulus
or wear resistance of the nanocomposites [21–24].
Some investigations on nuclear magnetic resonance spectra (13C
NMR) of nanocomposite materials i.e.; PBSu/SiO2 (poly(butylene succi-
nate)/SiO2) confirmed a reaction between the surface silanol groups
from SiO2 nanoparticles with hydroxyl end groups of the polymer
(PBSu) leading to formation of covalent bonds [20]. These covalent
bonds resulted in a substantial improvement of mechanical properties
of PBSu, even in cases where amounts of SiO2 lower than 2.5 wt.%
were used [20,25]. Nano-SiO2 in different forms i.e.; nanotubes, nano-
particles present in the polymer matrix changes also physicochemical
properties of the nanocomposite surface e.g.; some of the hydroxyl
groups are exposed on the surface and increase hydrophilic character
of the surface of materials. This phenomenon can explain a higher hy-
drolysis rate of nanocomposites based on biodegradable polymers
[26]. A similar accelerating effect of SiO2 nanoparticles on a PLA
hydrolysis rate was reported by many authors [27–30]. They found
 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
Fig. 1. Durability of poly(L-lactide-co-D,L-lactide)/SiO2 (PLDLA/SiO2) membrane after 8-week incubation in H2O/37 °C/PBS.
that PLA/SiO2 nanocomposites degrade faster than the pure PLA, which
indicate that incorporation of silica enhances biodegradation of PLA in
the nanocomposites. The addition of silica may lead to facilitated attack
of water and enzyme molecules on ester groups of the PLA chains, be-
cause of high hydrophilicity of silica. The effect of degradation was
much more visible (Fig. 1) in case of porous nanocomposite membrane
after 8-week in vitro degradation [30]. This experiment also showed a
decreasing molecular weight of the polymer and disintegration of the
materials.
The incorporation of silica nanoparticles into the polymer matrix
stimulated osteoblast-like cells interaction with natural tissue after con-
tact with the surface of material i.e. cell viability increased since silicon
(at critical concentrations) is able to stimulate proliferation of osteo-
blast-like MG-63 cells [31]. Silicon can also be involved in bone forma-
tion and mineralization [32], whereas orthosilicate acid (Si(OH)4) at
physiological concentration of 10 μmol was shown to stimulate forma-
tion of type I collagen in human osteoblastic cells (HOC) and to stimu-
late cell differentiation [33]. Even though no significant effects of SiO2
inclusion on cells behavior could be detected, the results were in agree-
ment with reports from the literature showing silica materials used for
bone regeneration. Si-OH groups can induce apatite formation and thus
strong bone bonding [34]. Furthermore, silica nanotube meshes were
shown to support the adhesion of murine osteoblast-like MC3T3-E1
cells and expression of alkaline phosphatase (ALP), even without
BMP-2 supplements [35].
Mesoporous silica characterized with regular, parallel pores of 2 to
50 nm diameter, high specific surface area, low density, high biocom-
patibility shows capacity for encapsulation of drugs and biological
agents [36]. These particles are widely used in pharmaceutical applica-
tions, in most cases in drug delivery systems. In order to control drug re-
lease from the mesoporous silica, it was mainly mixed with
biodegradable polymers such as; poly(lactic-co-glycolic acid) (PLGA),
polyethylene glycol (PEG), PCL, chitosan (CS), alginate, gelatin,
polyethylenimine (PEI) etc. [37–40]. Drugs such as vancomicine,
gentamicine, fluoxetine, lidocaine, morphine, nifedipine, paracetamol,
tetracyclin, ibuprofen etc. were used in these applications [41–43]. The
drug could be incorporated in the silica xerogel during the sol–gel pro-
cess instead of a adsorption method. In some cases the drug can be in-
corporated into the polymer matrix as well, which may have an effect
on the release properties of the composite [39]. Ahola et al. showed
that increase of an initial drug loading increased an amount of
toremifene citrate released from PCL matrix [40]. The release rate was
found to be directly proportional to the load of toremifene citrate. The
drug release kinetics was controlled by the slowest process i.e. the re-
lease from the polymer matrix which was a diffusion controlled process
[44–45]. Deviations from linearity were observed after 70% of the drug
had been released. This may be due to a large amount of toremifene
1177
citrate used, which enhanced degradation of the matrix, thus leading
to an increased release rate. A new method of carrying drugs into a dam-
aged tissue is an application of core-shell structures. Formation of firm
bonds between silica and polymer (PEG, PEI, PLGA) on the silica core
improves controlled release of a drug or other molecules i.e. molecules
that can regulate biological behavior of osteoblasts/osteoclasts [46–47].
Silica nanoparticles with a drug incorporated inside their pores
could be used as fillers of a polymeric matrix used to prepare a scaffold
or a membrane, which provided an additional degree of control of drug
release, independent from the polymer material itself [48]. Additionally,
scaffolds based on mesoporous silica characterized by macro-, meso- as
well as micropores were identified as important contributors to bone
formation. The micropores may serve as nucleation sites for mineraliza-
tion, causing local supersaturation and subsequent nucleation of apatite
forms, the mesopores can be used as reservoirs of nutrients and growth
factors or carry therapeutic agents, and macropores can promote cells
infiltration. Such implants could by fabricated by traditional techniques
such as; salt leaching, freeze drying or new methods like
electrospinning or rapid prototyping. Polymer scaffolds modified by
mesoporous silica nanoparticles (MSNs) were often called multifunc-
tional scaffolds [48–50]. Porous 2D or 3D structures fabricated from a
polymer modified with nanometric silica using the electrospinning
technique can be used to obtain a superhydrophobic layer on the im-
plant surface [51]. This method enables control of nanoroughness of
the surface by the presence of polymer fibers with nanometric or
submicrometric diameters containing silica nanoparticles which in
turn influence wettability and surface free energy (Table 1).
CS fibers were successfully electrospun with poly(ethylene
oxide) (PEO) as a co-blending polymer and with nanometric silica
(CS(PEO)/SiO2) by Suzuki and Mizusima [52]. These organic-inor-
ganic hybrid biomaterials earlier proved to increase oxygen perme-
ability, biocompatibility and biodegradability. Other works showed
how to control a process of manufacturing of CS(PEO)/SiO2 nanofi-
bers and the ability of these hybrid nanofibers to favor cell attach-
ment of murine osteoblast-like 7F2 cells. A hybrid fibrous mesh has
a capability to be modified by incorporation of calcium ions resulting
in formation of bioactive carbonated hydroxyapatite (HCA) crystals
Table 1
Diameters of the PCL and the PCL/SiO2 nanocomposite fibers with physicochemical prop-
erties of the layer.
Material Fiber diameter Water contact angle Surface free energy
(nm) (°) [mN/mm]
PCL 152 ± 19 151 44.8
PCL/SiO2 178 ± 53 113 34.7
1178 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
[53]. The incorporation of silica particles into natural hydrogels such
as CS or alginate creates another possibilities for cells e.g.; bone-like
cells such as human osteoblast-like Saos-2 cells and RAW 264.7
mouse macrophage cells differentiated into osteoclast-like cells
were embedded in silica-containing Na-alginate-based hydrogel.
During the test biocompatible hydrogels with Saos-2 cells retained
their capacity to synthesize the hydroxyapatite (HAp) crystals [54]
and increasingly express the gene encoding for osteoprotegrin [55].
In another study when CS was used as a matrix a significantly in-
creased protein adsorption and improved apatite deposition were
observed by the addition of nano-silica into the composite scaffold
[54].
To conclude, nanosilica present in the polymer matrix composite
works not only as a filler enhancing its biological properties and
guaranteeing increase of its biomineralization capability but it also in-
creases stiffness of the polymer composite without decreasing its me-
chanical strength.
4. Bioglass based composites
Bioactive glasses (BGs, bioglasses) are very attractive materials for
modifying a polymer matrix of composites dedicated for tissue engi-
neering applications. One of the key reason that makes these materials
relevant composite modifiers is the possibility of controlling a wide
range of biological and chemical properties. The structure and chemistry
of glasses can be tailored at a molecular level by varying composition, a
preparation method (melt-quenching or sol-gel), and manufacturing
conditions [1,56–57]. It provides a simple way to control properties of
glass-containing composites.
BGs are commonly produced by a melt-quench route or a sol-gel
method [56,58]. Gel-derived BGs usually exhibit improved bioactivity
and cellular response related to a larger volume fraction of mesopores
[59–61], a larger concentration of silanols on the surface [59–60] and
also larger specific surface area [58,60–61] than the melt-derived
glasses. Furthermore, an advantage of the sol-gel process is the
ability to control the phase composition, structure, texture, micro-
structure and surface chemistry of the glasses by the synthesis condi-
tions (e.g. type of a catalyst) and thermal treatment [61–62]. The sol–
gel process allows obtaining mesoporous micro- and nanoparticles,
simply by changing pH of the process, which can be directly used
as composite modifiers [61]. To improve or induce desired biological
response and adjust the surface reactivity, as well as solubility in
biological environment, BGs can be doped with trace elements and
other therapeutic oxides [17,58,63,64]. The research works mainly
focus on developing silicate and borate/borosilicate BGs, as well as
Fig. 2. In vitro bioactivity of PCL/SBG films after 7-day incubation in simulated body fluid (SBF). No morphological changes on pure PCL film (a) after immersion in SBF are observed. On the
surface of a composite film containing silica-rich bioglass (S2 (mol%): 80SiO2–16CaO–4P2O5) (b) clusters of calcium phosphate precipitates occur, while the surface of a film with calcium-
rich glass (A2 (mol%): 40SiO2–54CaO–6P2O5) (c) is fully covered with a thick, continuous layer of HAp.
resorbable phosphate glasses and their application in tissue
engineering.
4.1. Silicate bioactive glasses
Silicate bioactive glasses (SBGs) are the most extensively researched
glasses for biomedical applications and also the most frequently consid-
ered as fillers of polymer-based composites for bone tissue engineering.
The first melt-derived silicate SBG of the quaternary SiO2–Na2O–CaO–
P2O5 system – Bioglass® 45S5, synthesized by Hench et al., is widely
reported as a modifier of biodegradable synthetic polymers and copoly-
mers: PLA [65–66], PGA [67], PCL [4,8,10,68], PHB [69], PLGA [65,70–71],
as well as natural polymers: collagen [72] and CS [73]. Moreover, other
SBGs based on both binary SiO2–CaO [74] and ternary SiO2–CaO–P2O5
[4–6,8,71,75] systems are also used for modifying a polymer matrix.
Bioglass® 45S5 and other SBGs exhibit an ability to bond to soft and
hard tissues which is attributed to the formation of a HCA layer on the
glass surface in contact with the body fluids [57–58]. Apart from the bio-
activity, it was observed that ionic dissolution products (e.g. Si, Ca, P)
from some of BGs stimulate expression of several genes of osteoblastic
[76] and stem cells [71,77] involved in bone growth, show ability to
stimulate angiogenesis [78], while possibly exhibit antibacterial [79]
and anti-inflammatory actions [80]. Furthermore, release of calcium
(Clotting factor IV) being considered a reason for SBG haemostatic prop-
erties [81]. All these specific properties and advantages of BGs can be
conferred to a polymer matrix by the glass filler incorporation.
Probably the most important reason for developing polymer-glass
composites for bone tissue engineering is the possibility of achieving a
bioactive properties of the polymer matrix [1]. The degree of bioactivity
of a composite can be controlled mainly by the chemical composition [8,
71,82], volume fraction [9–11,65–66,83], size [5,11,68–69,73] and dis-
tribution [5,68–69] of a bioactive phase. It was shown that the rate
and intensity of apatite-like layer formation on the surface of PCL and
PLGA-based composites containing SBG particles increased with an in-
creasing CaO:SiO2 molar ratio of the glass [8,71] (Fig. 2.). Other results
indicated that lower P2O5 content in SiO2–CaO–P2O5 SBG nanoparticles
enhanced the bioactivity of (poly(L-lactide)-based (PLLA) scaffolds [82].
Furthermore, an increased volume fraction [9–11,65–66,83] and higher
surface area to volume ratio of the glass modifiers (e.g. the incorpora-
tion of nano-sized particles instead of microparticles) [5,11,68–69,73]
improved the composite bioactivity.
The incorporation of SBG particles in a biodegradable polymer ma-
trix can be advantageous as it imparts osteoinductivity to the composite.
It was demonstrated that the addition of gel-derived SBG particles into a
PLGA matrix promoted the expression of early osteogenesis-related
transcription factors (runt related transcription factor 2 (RUNX2) and
 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
Fig. 3. The real-time reverse transcription polymerase chain reaction (RT-PCR) analyses of RUNX2 and Osx mRNA levels in; (a) hBMSCs cultured for two days on PLGA, PLGA/S2 and PLGA/
A2 without osteogenic inducers and BMP-2, osteopontin and collagen I mRNA levels (b-d) in hBMSCs cultured for ten days without osteogenic inducers (NONE) or in the presence of
recombinant human BMP-2 or dexamethasone (DEX). Fold changes in mRNA levels (mean ± SD) are expressed relative to PLGA [77]. © IOP Publishing.
Reproduced with permission. All rights reserved.
osteoblast-specific transcription factor Osterix (Osx)) and osteogenic
genes (BMP-2, osteopontin (OPN), osteocalcin (OC) and collagen I) in
human bone marrow mesenchymal stem cells (hBMSCs). As with bioac-
tive properties, osteogenic potential depends on chemical composition
of glass modifiers [77] (Fig. 3.) and their content in composites [71].
The experiment during which rat mesenchymal stem cells (MSCs)
were cultured in the presence of PLGA/SBG porous scaffolds (but phys-
ically separated from them) showed that the dissolution products from
the materials stimulated osteogenesis alone [84]. Apart from the effect
of solution-mediated factors, a three-dimensional structure and surface
properties of the scaffolds also strongly influenced the osteogenic re-
sponse [8,84]. A recent trend is the incorporation of different elements
into the composition of SBGs to enhance their biological benefits, espe-
cially osteogenic and angiogenic potential [63]. Therefore, Ren et al. [14]
and Poh et al. [15] demonstrated that the addition of strontium-
substituted SBG into a PCL matrix enhance osteoblast differentiation,
collagen deposition and also matrix mineralisation compared to pure
PCL scaffolds. In turn, Oh et al. showed that PLDLA-based membranes
with zinc-substituted SBG possessed significantly improved osteogenic
and matrix mineralization potential of the rat bone marrow mesenchy-
mal stem cells (rBMSCs) comparing to zinc-free glass-containing mem-
branes and pure polymer membranes [85].
The addition of 45S5 SBG particles into poly(D,L-lactide) (PDLLA) and
PLGA matrices, as well as a PGA mesh significantly enhanced vascular
endothelial growth factor (VEGF) in vitro secretion of fibroblasts [67,
86–87] and also in vivo blood vessel formation [67,86]. These results in-
dicated a beneficial effect of bioglass inclusion into a polymer matrix on
induction of neo-vascularisation and rapid vascular ingrowth necessary
for delivery of nutrients and oxygen into the developing tissues, and
thus the possibility of using glass-containing composites, not only for
hard tissue regeneration, but also for the soft one [67], and soft-hard tis-
sue interfaces [86]. Other experimental study showed that the addition
of a limited concentration (10 wt.%) of 45S5 SBGs nanoparticles to col-
lagen films induced an early angiogenic response evaluated using the
cylinder chorioallantoic membrane (CAM) model [72]. Quinlan et al. de-
veloped collagen-glycosaminoglycan-based porous scaffolds containing
cobalt-substituted SBG which show ability to stimulate both angiogen-
esis and vascularisation through the release of Co2 + ions which are
known for their potential to mimic hypoxia [88].
SBGs present in a bioresorbable polymer matrix can also affect the
polymer degradation behavior by modification of its surface and bulk
properties. On one hand, the degradation process of the composite can
be accelerated because hydrophilic SBG particles improve surface wet-
tability of the composite, allowing the scaffold to absorb more water
[9,12,83,89] and also increase the surface area of a hydrolytic attack
[4]. Furthermore, water can more easily diffuse through the interface
between the two phases by capillarity and microcrack transport mech-
anisms [12]. In particular, the greater amount and the smaller particle
1179
size of SBG are, the more rapid degradation rate of the poly(ε-
caprolactone-co-D,L-lactide)/SBG [12] and the higher water absorption
of the PHB/SBG composites are [69]. On the other hand, a delayed deg-
radation rate in the composite can be achieved by the dissolution of al-
kaline ions (e.g. Ca2+, Na+) from the bioactive glass structure. It results
in neutralisation of the released acidic by-products of the polymer deg-
radation and thus prevents its autocatalytic degradation process [83].
Furthermore, a buffering effect of the glass modifiers can be considered
as an advantage, because it helps to avoid a possible inflammatory re-
sponse, due to acidic degradation of the polymer [4,8–9]. It was
shown that the degradation behavior of PLGA, PLLA and PCL composites
can be controlled not only by tailoring the concentration of BG [9,70–71]
but also SBG composition, namely the amount of alkaline glass network
modifiers (e.g. CaO) [4,8,71].
The introduction of SBG particles into a polymer matrix contributed
to increase stiffness of the composites [4,10,71,75,86]. In particular,
nano-sized SBG particles had a significant enhancing effect on the
Young's modulus of CS/SBG [73], PHB/SBG [69] and PCL/SBG [68] com-
posites when compared with SBG microparticles. Mechanical properties
of a composite can be controlled mainly by the amount [4,10,70–71,75,
86] textural properties [4,90], and phase composition [4,68] of glass
fillers. It was shown that porous microstructure of gel-derived 58S
SBG particles compared to dense melt-derived 45S5 glass [90] and
also larger mesopores of gel-derived calcium-rich SBG (~ 13.3 nm)
with respect to smaller pores of silica-rich BG (~3.0 nm) [4–5] resulted
in an improvement of mechanical strength of PDLLA and PCL-based
films, respectively. In turn, partially crystallized SBG particles could
have different interfacial bonding strength with PCL as compared with
the fully amorphous particles, which would affect strength of the com-
posites [4–5,68]. The presence of SBG particles in a polymer porous scaf-
folds generally induces an increase of their compressive strength [10,77,
86]. On the other hand, decrease of tensile strength is a frequent effect of
modification of polymer films with SBG fillers [4,71,75]. In order to im-
prove the interface compatibility between SBG particles and a polymer
matrix, surface modification of the SBG particles is used. The modifica-
tion would make the particles disperse within the matrix more homo-
geneously [91]. Furthermore, molecules grafted onto the particles
could interact with the polymer matrix, thus the final mechanical prop-
erties could be improved. It was shown that surface modification of SBG
particles by esterification reaction [90] or surface-grafting with
diisocyanate [91] improved the tensile strength of PDLLA and PLLA-
based composites, respectively.
In case of composites consisting of semicrystalline polymers (e.g.
PCL, PLLA), their properties strongly depends on crystallinity of the
polymer matrix. It is well known that a degree of crystallinity, size and
distribution of crystallites in semicrystalline polymers have a large ef-
fect on their mechanical properties [92]. Furthermore, amorphous re-
gions of a semicrystalline polymer degrade prior to crystalline
1180 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
Table 2
Degree of crystallinity (χc), melting temperature (Tm) (mean ± SD) and crystallite size (L110 and L200) of pure PCL and SBG-PCL composite films. The composite materials contained 12 and
21 vol.% of gel-derived silica-based bioglass microparticles with different compositions - S2 and A2.
PCL 12S2-PCL
χc (%)a 42.69 ± 1.16 36.22 ± 0.68
Tm (°C)a 62.33 ± 0.09 60.17 ± 0.14
L110 (nm)b 30.4 26.5
L200 (nm)b 23.6 19.1
a
Evaluated by the differential scanning calorimetry (DSC).
b
Evaluated by the wide-angle X-ray scattering (WAXS).
domains, thus initial crystallinity of the polymer determines its degra-
dation behavior [89]. Recent studies showed that different polymer
crystallinity strongly influences adhesion and proliferation of osteo-
blasts and fibroblasts [93]. Some studies indicated a possibility of mod-
ulation of crystalline properties of a polymer matrix by the addition of
glass particles. On one hand, microparticles of SBG introduced into PCL
and PLLA matrix caused a reduction of the polymer crystallinity, melting
temperature [4–5,8] and crystallite size [4,94], which were affected by
the filler amount (Table 2.). On the other hand, the incorporation of
nano-sized SBG into PLLA resulted in an increase of a nucleation rate
and crystallinity of the polymer. In addition, PLLA grafting onto the sur-
face of the nanoparticles with diisocyanate enhanced this effect [91].
Microstructure and porosity of a material play a critical role in tissue
engineering because they determine cell migration, cell-cell interac-
tions and molecular transport of nutrients, wastes, and biological medi-
ators within a scaffold. There are various methods for controlling
porosity and pore architecture of polymer and composite scaffolds. In
particular, it is possible by varying the amount and size of porogen par-
ticles in the solvent-casting particulate leaching (SCPL) method [8] or by
using various solvents [10], polymer concentrations [10,65] and cooling
temperatures [65] in the thermally induced phase separation (TIPS)
process. It turned out that when TIPS method was used to obtain com-
posite scaffolds based on PCL [10], PDLLA [65–66,83], PLGA [65,70]
and PLLA [9], porosity of the materials decreased and the pores became
irregular in shape with increasing content of SBG particles. According to
the authors, the probable reason for these phenomena is a hindering ef-
fect of randomly distributed solid inorganic fillers in the polymer/sol-
vent solution on the growth of solvent crystals during the phase
separation process. On the other hand, the enlargement of pore size in
PLLA-based scaffold upon the addition of SBG particles can be attributed
to the effect of released ions from the glass surface on the TIPS thermo-
dynamics [94].
Surface properties of biomaterials, such as wettability, roughness,
surface energy, surface charge determine cell adhesion, proliferation
and differentiation [95], protein adsorption, bioactivity [69], as well as
degradation behavior. It was shown that SBG particles, as a hydrophilic
material, remarkably improve hydrophilicity of PCL [4,68,75] and PHB
[69] matrices. Furthermore, the decrease in water contact angle was
more visible for PHB-based composites containing SBG nanoparticles
than for microparticles due to the fact that more of the nano-sized
SBG particles were exposed on the surface [69]. Some authors observed
that the excess over the certain content of BG in a composite did not re-
sult in a further reduction of the contact angle. It can be attributed to the
notable increase of surface roughness [4,69,75].
Our recent study indicated that PCL/SBG composite films are capable
of serving as a carrier of natural polyphenols extracted from sage (Salvia
officinalis L.) [6]. Polyphenols-loaded composites showed potential anti-
oxidant activity against the ABTS•+ and DPPH• radicals, and antiprolifer-
ative activity against human malignant melanoma WM266–4 cells. In
contrast to PCL film, composites containing gel-derived and melt-de-
rived SBG particles exhibited a reduced initial burst release of drug in
the first day and also excellent in vitro bioactivity. Reduction in the
initial fast release was particularly pronounced for a film with gel-
derived fillers which can be attributed to much larger specific surface
area of these particles (BET SSA 101.6 m2 g− 1 ) compared to the
21S2-PCL 12A2-PCL 21A2-PCL
20.79 ± 0.79 37.25 ± 0.72 20.84 ± 0.85
59.00 ± 0.14 60.67 ± 0.13 59.20 ± 0.10
22.1 24.7 19.1
17.2 20.5 15.5
melted ones (BET SSA 0.3 m2 g− 1) and also to the presence of –OH
groups on the surface of the gel-derived glass that can bind polyphe-
nol molecules.
4.2. Borate and borosilicate bioactive glasses
Borate-based glasses (BBGs) are known for their high reactivity and
bioactivity, however their biocompatibility still remains debatable [58,
96]. It is due to cytotoxicity of high concentration of boron released
into the solution as borate ions (BO3)3− related to high solubility of bo-
rate glasses [97–99]. Probably for this reason, borate-based glasses are
not as common choice for tissue engineering applications as the silicate
ones. Under static in vitro culture conditions, some BBGs showed signif-
icant reduction in cell proliferation, in turn, the cytotoxicity was
inhibited under dynamic culture conditions [100]. In vitro response
study of scaffolds consisting of borate glass 13-93B3 (B2O3–CaO–K2O–
Na2O–MgO–P2O5 system) exhibited a cytotoxic effect, whereas the
same scaffolds showed the ability to support in vivo tissue infiltration
[101]. The conversion mechanism of BBG to HAp is similar to that of sil-
icate glass, with the formation of a borate-rich layer, similar to the silica-
rich layer of the SBGs [58]. Partial replacement of B2O3 in BBG with
Al2O3 [102] or SrO [96] was shown to reduce the dissolution rate of
the glass. Furthermore, the presence of strontium oxide induce the ad-
hesion of osteoblast-like cells, thus significantly increasing biocompati-
bility [96,102].
Based on the available literature, there are only a few reports on the
use of borate-based glasses as polymer matrix modifiers [7,103–105].
Because of high degradation rate, BBGs are considered as modifiers of
a biodegradable polymer matrix to obtain bioactive and drug-releasing
scaffolds. Zhang and Jia et al. developed teicoplanin-loaded CS/BBG
composites for the chronic osteomyelitis (bone infection) treatment.
The materials did not cause any toxic injury to local or systemic tissues,
while they showed ability to cure chronic bone infection within
12 weeks of implantation in a rabbit tibia osteomyelitis model. Further-
more, the composites exhibited a multifunctional role including an
antibiotic release function, sufficient load-bearing capacity, biodegrad-
ability and the ability to support bone regeneration [103–105].
A significantly higher degradation rate of borate-based glasses com-
pared to the silicate ones makes them more suitable for soft tissue appli-
cations. Furthermore, by altering composition of the glass fillers, namely
SiO2 and B2O3 content, physical and chemical properties of a polymer-
based composite can be easily tailored to meet tissue regenerative re-
quirements. Mohammadkhah et al. showed that composites containing
50 wt.% PCL and (1) 50 wt.% 13-93B3 BBG or (2) 50 wt.% 45S5 SBG or (3)
a blend of 25 wt.% 13-93B3 and 25 wt.% 45S5 glass particles showed a
modified degradation rate. It was also demonstrated that faster conver-
sion of 13–93B3 fillers to HAp may improve the effectiveness of the PCL-
based material as a nerve guide conduit when compared to silicate
glass-containing material [7].
4.3. Phosphate glasses
Phosphate glasses (PBGs), containing P2O5 as a network-forming
oxide, have a wide range of solubility which can be controlled by mod-
ifying their composition [106]. In the basic P2O5-CaO-Na2O system, a
 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
lower CaO content causes higher dissolution rate [107]. Furthermore,
the dissolution rate of PBGs can be tailored by the addition of several ox-
ides such as; Al2O3, B2O3, Fe2O3, Ga2O3, TiO2, ZnO, MgO, SrO, NiO, MnO
and CuO [17,58,106,108]. Therefore, PBGs may be used as an inorganic
filler of a bioresorbable polymer matrix (e.g. PCL, PLA) to obtain fully re-
sorbable composite materials with a controlled resorption profile [106,
109]. Moreover, PBGs are considered as materials for bone tissue engi-
neering due to their chemical similarity to the inorganic phase of
human bone [17]. It was also observed that dissolution products of
PBGs from P2O5-CaO-Na2O system with a lower dissolution rate (28
and 40 mol% CaO) enhanced proliferation of osteoblastic cells and also
expression of the bone-associated proteins (bone sialoprotein (BSP),
osteonectin (ON) and fibronectin (FN)) in contrast to highly soluble
glasses (8 and 16 mol% CaO) which showed inhibitory action [107]. An-
other work showed that the incorporation of TiO2 (5 mol%) alone, as
well as a mixture of TiO 2 (5 mol%) and ZnO (1, 3 and 5 mol%) in
PBG of the basic system enhanced proliferation of osteoblastic cells
compared with the basic glass and PBG containing ZnO only, which
can be attributed to the significant reduction in a degradation rate
of these glasses and also beneficial effect of Zn2 + ions. Moreover,
the transcription level of osteogenesis-related genes (ALP, ON and
core-binding factor alpha-1 (CBF-alpha-1)) of osteoblastic cells
seeding on glasses containing a mixture of TiO2 and 1, 3 mol% ZnO
was comparable or even significantly higher compared to a positive
control (Thermanox®) [108]. The presented studies showed that,
by tailoring composition of PBGs, it is possible to modulate their bio-
logical properties.
Most of the works concerning the modification of a polymer ma-
trix with phosphate bioglass are devoted to degradation studies. It
was shown that the dissolution of glass fillers directly influences
the degradation behavior of the polymer-based composites, as with
pure phosphate glasses, the degradation rate of the composites in-
creased with decreasing CaO content in PBG fillers [110−111].
Mohammadi et al. obtained two kinds of PCL-based composites con-
taining PBGs modified with SiO2 and/or Fe2O3: (1) composite films
containing PBG fibers of the (mol%) 50P 2O 5 –40CaO– (10-x)SiO 2 –
xFe2O3 system, where x = 0, 5 and 10 [109], as well as (2) composite
films containing 40 vol.% glass particles of the (mol%) 50P2O 5 –
40CaO–10SiO 2 or 50P2O 5 –40CaO–10Fe2 O 3 systems or blends of
these glasses (0/40, 10/30, 20/20, 30/10, 40/0) [106]. The authors
showed that the increasing SiO2 content enhanced the degradation
rate of the composites. It was manifested by higher weight loss, in-
crease in the release of PO4 3 − , Ca2 +, Fe3 + and Si4 + ions, formation
of pores, decrease in mechanical properties and more rapid reduc-
tion in pH during the degradation test [106,109]. In turn, Georgiou
et al. showed that the degradation behavior of PLLA-based compos-
ites can be also controlled by tailoring the concentration of glass par-
ticles: the higher content of the (mol%) 46CaO– 4Na2O–50P2O5 PBG
particles in the composite is, the higher is the degradation rate of
the materials [13].
Polymer-based composites containing phosphate glasses are consid-
ered as drug delivery systems. It was shown that the higher the CaO
content in glass is, the lower a vancomycin release from the PCL-based
composites is. Furthermore, the addition of glass with higher CaO con-
tent into PCL matrix reduced the initial burst effect and prolongs release
of a drug. It is probably related to high affinity of hydrophilic drugs to
the hydrophilic surface of glass particles and lower solubility of high-
CaO glasses. These results indicated that it is possible to control degra-
dation rate and drug release of the PCL/PBG composites depending on
the glass composition while maintaining excellent biocompatibility
[110].
Navarro et al. showed that the incorporation of PBG particles from
the (mol%) 44.5P2O5–44.5CaO–6Na2O–5TiO2 system in a PLA matrix in-
duced formation of calcium phosphate precipitates at the composite
surface after immersion in SBF. The X-ray diffraction (XRD) and Fourier
transform infrared spectroscopy (FTIR) of the CaP precipitation showed
1181
the presence of an amorphous phase. The Ca/P ratio obtained from the
energy dispersive X-ray spectroscopy (EDX) confirmed the presence
of amorphous calcium phosphate (ACP) [112].
To conclude, besides calcium phosphate ceramics, bioactive and re-
sorbable glasses are the most widely used and researched materials
for modifying biodegradable polymer matrices. It is due to the possibil-
ity of modulating a wide range of BG properties and thus, by its incorpo-
ration into a polymer matrix, possibility of imparting and controlling,
not only physicochemical or mechanical properties, but also a number
of biological effects of the obtained composites.
5. Wollastonite based composites
Wollastonite (WS, CaO-SiO2, CaSiO3) is a typical example of calcium-
silicate-based ceramics. WS is a naturally occurring calcium silicate,
which has been widely used as a filler in polymers and cements to fab-
ricate composites with improved mechanical properties [113–115]. Be-
cause of its excellent bioactivity and degradability, WS has been
proposed as a potential material for bone tissue regeneration [116–
118] with the same or better possibilities than classic ceramic particles
such as TCP or HAp. Nevertheless, the extensive use of WS, TCP, HAp
or BG is still limited by their brittle nature. Most of literature positions
showed composite materials based on synthetic or natural polymers
in which WS was used as a filler to produce composites with improved
mechanical and bioactive properties [1,119–120]. Synthetic biodegrad-
able matrices such as; PLGA, PLDLA, PCL or poly(3-hydroxybutyrate-co-
3-hydroxyvalerate (PHBV) guarantee also short-term durability
under in vitro/in vivo conditions, this property of materials can be
controlled by modification with WS. Results of studies of Li and Chang
[121−122] showed influence of WS particles on PHBV matrix. Thermo-
plastic polyester such as PHBV gains bioactivity in similar way as poly-
mer composites modified with BG particles (with CaO-SiO2 formula).
According to this mechanism, silicate ions released from WS particles
are attached to Si–OH groups inducing nucleation of apatite on the sur-
face. At the same time, release of calcium ions from WS particles in-
creases the ionic activity product of SBF with respect to apatite and
accelerates the apatite nucleation. Finally, the apatite nuclei formed on
the surface grow spontaneously by consuming Ca and P ions from the
fluid [123–124]. A layer formed by apatite crystals was observed on
the surface of PHBV/20 or 40 wt.% WS composite after soaking in SBF
for 14 days. Additionally, pH of the immersion medium (SBF) was stable
until 21 days of soaking which means that the WS incorporated into the
PHBV could neutralize acidic by-products and stabilize pH of the SBF so-
lution [121–122]. It suggested that WS/PHBV composites could gradual-
ly release Ca and Si ions, and the release rate depended on content of WS
in the composites (20 wt.% or 40 wt.%). The released Ca and Si ions were
able to form basic hydrates and this can possibly explain the ability of
pH-stabilization showed by WS. A rapid degradation process of WS par-
ticles was confirmed in long-term observations and in the other immer-
sion medium i.e.; phosphate buffer saline (PBS) where pH was also
stable after 14 days of incubation [122]. The alkaline ions neutralized
acidic products of degradation of PHBV and had a buffering effect on
the acidification caused by degradation of PHBV. This effect could also
be identified in the other aliphatic polyesters matrices such as PGLA or
PLLA [125–126]. Both properties i.e.; bioactivity and biodegradability
of composite materials based on WS are results of high hydrophilicity
of WS particles. The suitable amount of inorganic material i.e. N
20 wt.% reduces hydrophobic character of polymers surface and facili-
tates local supersaturation, which are necessary for apatite nucleation,
and hydrolysis of a polymer chain, which is a beginning of its degrada-
tion process. A good example of possibility of the water-uptake capacity
was characterized by a composite scaffold based on silk fibroin (SF)
formed by the freeze-drying technique [124]. The first reason of high
water absorption is high porosity (80–90%) and then wettability of
composite materials e.g. water contact angle decreases from 65o to
40o with an increasing amount of WS.
1182 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191

Fig. 4. The dispersion of WS in the PCL/nanoWS composite determined with the PIXE technique. Pure PCL – reference sample. FTIR-ATR confirming chemical interaction between a
polymer chain and nanofillers; a) nano-WS, b) pure PCL, c), d), e) the nanocomposite with different contents of nano-WS particles; 1%, 4%, 6%wt.

Another aspect of modification of a biodegradable polymer matrix
by WS is its influence on mechanical properties of composite materials
i.e.; porous scaffolds. The addition of WS to the SF matrix resulted in a
structure with higher compressive strength than the pure SF e.g. com-
pressive strength of SF/40 wt.% WS composite was two times higher
than strength of the pure SF [124]. Compressive strength of PHBV/WS
composite scaffolds was higher and reached 0.28 MPa when weight
ratio of WS in the composite was 40% [122]. The same effect was ob-
served in the case of collagen/WS composites; where tensile strength
and bioactivity of the composite scaffolds were improved by increasing
WS content [126].
The same author showed that composite systems based on polymer
and wollastonite (PGLA/WS, PBVH/WS) might be used as bioactive drug
delivery systems which were not only able to enhance bone growth, but
also could release antibiotics to minimize infection problems [123–124].
The most popular model of this study is gentamicin – an antibiotic
used in inflammatory therapeutic. It was proved that WS in poly-
mer-based composites such as PGLA/WS/gentamicin or PBVH/WS/
gentamicin retarded release of gentamicin and this might be due to
formation of an apatite layer on the surface of the composite. This ef-
fect strongly depends on composition of an ions-reached immersion
medium such as SBF or PBS which could stimulate bioactivity process
[127–128].
Mesoporous particles of wollastonite (mWS), similarly to the meso-
porous silica, possess high specific surface area and high pore volume.
These properties significantly improve the kinetics of process of apatite
formation on their surface thereby exhibiting better bioactivity and pos-
sibility of being a drug carrier [129–130]. Wie et al. confirmed that an

Fig. 5. Morphology of the nanocomposite fibers; PLA modified with 1% wt. TCP nanoparticles (a), morphology of the PLA/TCP nanocomposite fibers after 7 days of incubation in SBF and
EDX analysis confirming apatite composition (b). Republished with permission of Trans Tech Publications Inc., from [184]; permission conveyed through Copyright Clearance Center, Inc.
Table 3
Review of biodegradable ceramic-polymer composites, their form, preparation method, potential application and mechanical properties.

Polymer matrix Ceramic modifier Composite form Composite preparation Potential Compressive Young's Reference
method application (C), modulus
Type Form/preparation
tensile (T) (MPa)
method/size/amount
flexural
(F) strength
(MPa)

PCL SBG Particles/sol-gel/b50 μm/21 vol.% Scaffold (porosity Solvent casting particulate Bone tissue [8]
80SiO2–16CaO–4P2O5 55–92%, pore size b leaching; Solid-liquid phase engineering
40SiO2–54CaO–6P2O5 (mol%) 300 μm) separation; Phase inversion
SBG Particles/sol-gel/b40 μm/12, 21 Film (thickness ~ Solvent casting Bone tissue 10.5–14.5 (T) 0.6–1.3·103 [4]
80SiO2–16CaO–4P2O5 vol.% 90 μm) engineering
40SiO2–54CaO–6P2O5 (mol%)
45S5 Bioglasss® Particles/melting/b45 μm/25, 50 Scaffold (porosity Solid–liquid phase Bone tissue 92–214·10−3 132–251·10−3 [10]
wt.% 87–92%, pore size separation engineering (C)

M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191

10- some hundreds
μm)
Sr-SBG Particles/melting/b38 μm/10 wt.% Scaffold (fiber Melt-electrospinning Bone graft [14]
46SiO2-26Na2O–17SrO–6CaO–5P2O5 (mol%) diameter 46.1 μm, substitutes
fiber spacing
222.1 μm)
45S5 Bioglasss® Particles/ b38 μm/10 wt.% Scaffold (porosity 3D printing, melt Bone tissue 48–59 [15]
Sr-SBG ~75%, pore size b extrusion-based additive engineering
46SiO2-24Na2O–20SrO–7CaO–3P2O5 (mol%) 2.05 mm) manufacturing technology
SBG Particles/sol-gel template Film (thickness Solvent casting Bone tissue 15–19 (T) 200–383 [75]
60SiO2–63CaO–4P2O5 (mol%) method/50–150 nm/10, 20, 30 wt.% 65 μm) engineering
BBG Particles/b20 μm/50 wt.% Film (thickness Tape casting Neural tissue 40–50 (T) 150–190 [7]
53B2O3–20CaO–12K2O–6Na2O–5MgO–4P2O5 60 μm) engineering
(wt.%)
45S5 Bioglasss®
PBG Particles/melting/10 wt.% Film Solvent extraction Tissue [110]
45P2O5–xCaO–(55-x)Na2O, x = 20, 30, 40, and thermal pressing regeneration
50 and
wound-healing
PBG Fibers/melt–draw Film (thickness ~ Thermal pressing Bone fracture 35–45 (F) ~1.8·103 [109]
50P2O5–40CaO–(10- x)SiO2–xFe2O3, x = 0, spinning/diameter 10–20 μm/~18 200 μm) fixation
5, 10 vol.% devices
(mol%)
BCP Particles/microwave-hydrothermal Scaffold (porosity Solvent casting particulate Bone tissue 1.0–2.2 (C) 6.5–20.5·103 [189]
method/80-100 nm/50–70 wt.% 71–82%, pore size leaching engineering
100–500 μm,)
SiO2 Particles/ 2.3–2.7 nm/10, 30 wt.% Scaffolds (porosity Supercritical carbon dioxide Hard tissue 10–175 [48]
11–55%, pore size (scCO2)-assisted engineering
4.1 nm-39.5 μm) foaming/mixing
WS Particles/sol-gel/20, 40, 50 wt.% Scaffold (porosity Solvent casting particulate Hard tissue 5–12 (C) [129]
57–74%, pore size leaching repair
1–500 μm)
PLGA SBG Particles/sol-gel/b50 μm/12, 21, 33 Film (thickness ~ Solvent casting /solvent Bone tissue 24–55 (T) - 2–4·103 - [71,77]
80SiO2–16CaO–4P2O5 vol.% 110 μm /scaffolds casting particulate leaching engineering films films
40SiO2–54CaO–6P2O5 (mol%) (porosity 88–95%,
pore size
90–300 μm)
45S5 Bioglasss® Particles/melting/b5 μm/10, 25, 50 Scaffold (porosity Thermal induced phase Hard and soft 22–27 [65,70]
wt.% N90%, pore size separation tissue
10–100 μm) engineering

1183
(continued on next page)
 1184
Table 3 (continued)

Polymer matrix Ceramic modifier Composite form Composite preparation Potential Compressive Young's Reference
method application (C), modulus
Type Form/preparation
tensile (T) (MPa)
method/size/amount
flexural
(F) strength
(MPa)

BCP Particles/ heating bovine Scaffold (porosity Thermal induced phase Bone tissue 0.16–0.55 3.2–15.0 [192]
63/37 HAp/β-TCP bone/b100 nm/ 10–50 wt.% N89%, pore size separation engineering (yield
60–150 μm) strength) (C)
HAp Particles/~100 nm/50 wt.% Scaffold (porosity Gas foaming, Particulate Bone tissue 2.3–4.5 [146]
86–91%) leaching engineering
PLLA SBG Particles/sol-gel template Scaffold (pore size Thermal induced phase Bone tissue [82]
55SiO2–40CaO–5P2O5 method/20 nm/25 wt.% 10–300 μm) separation engineering
30SiO2–60CaO–10P2O5
68SiO2–28CaO–4P2O5 (mol%)

M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191

45S5 Bioglasss® Particles/melting/50–63 μm/25, 50 Scaffold (porosity Solid–liquid phase Bone tissue [9]
wt.% 48–52%, pore size b separation/freeze-extraction engineering
40 μm)
SBG Particles/melting/10 μm/10, 30, 50 Scaffold (pore size Thermal induced phase Bone tissue 0.62–0.75 (C) 6.61–10.88 [94]
33CaO–28P2O5–16MgO–23SiO2 (wt.%) wt.% 27–150 μm) separation engineering
PBG Particles/melting/32–1000 μm/5, Scaffold (porosity Melt extrusion and Bone tissue 80.0–116.5 [13]
46CaO–4Na2O–50P2O5 (mol%) 10, 20 wt.% ~81%, pore size supercritical CO2-foaming engineering
200–400 μm)
HAp Particles/0–50 μm, 5 μm, b200 Cylindrical profile Melt extrusion Various 100–136 (F) 3.3–4.3·103 [151]
nm/10, 20, 30 wt.% medical
application
β-TCP Particles/microwave accelerated Scaffold (porosity Particulate leaching Bone tissue 1–5 (C) [168]
wet method/100–300 nm/60 vol.% 50%, pore size engineering
200–450 μm)
β-TCP Particles/in the presence of Scaffold (porosity Thermal induced phase Bone tissue 0.3–0.8 [171]
PEG/290 nm/10–30 wt.% N93%, pore size separation + particulate engineering
0.5–300 μm, fiber leaching
diameter 70–300
nm)
PDLLA 45S5 Bioglasss® Particles/melting/b5 μm/5, 10, 25, Scaffold (porosity Thermal induced phase Hard and soft 21 [65–66,83]
40, 50 wt.% N90%, pore size separation tissue
10–100 μm) engineering
45S5 Bioglasss® Particles/melting/0.1–25 μm/5, 10, Film (thickness Solvent casting/solvent Regeneration 0.38–1.59 (C) 0.36–1.80 [86]
20 wt.% - films, 20 wt.%- scaffolds 25–40 μm)/scaffolds casting particulate leaching of hard-soft
Particles/flame spray (porosity 85–93%, tissue defects
synthesis/35–40 nm/5, 10, 20 wt.%
- films, 20 wt.%- scaffolds
PLDLA SBG Particles/sol-gel/b45 μm/30 wt.% Membrane Solvent casting Guided bone 54.2–56.3 (T) [85]
70SiO2–30CaO (thickness ~ regeneration
Zn-SBG 150 μm)
70SiO2–25CaO–5ZnO
PBG Particles/melting/b80 μm/50 wt.% Disk (thickness ~ Solvent casting Bone tissue [112]
44.5P2O5–44.5CaO–6Na2O–5TiO2 (mol%) 1.5 mm) and thermal pressing engineering
Poly(e-caprolactone-co-DL-lactide) SBG Particles/b45 μm, 90–315 μm/40, Disk (thickness 2 Compression moulding Bone [11–12]
53SiO2-23Na2O–20CaO–4P2O5 (wt.%) 60, 70 wt.% mm) substitution
PHB 45S5 Bioglasss® Particles/melting/b5 μm/10, 20, 30 Film (thickness Solvent casting Bone tissue 0.8–1.6·103 [69]
wt.% 120–140 μm) engineering
Particles/flame spray synthesis/29
nm/10, 20, 30 wt.%
PHBV WS Particles/chemical Scaffold (porosity Compression moulding Bone tissue 0.20–0.28 [121]
coprecipitation/98–154 μm/20, 40 73–78%, pore size particulate leaching engineering
wt.% 30–300 μm)
 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191 1185

[103–105]
apatite layer on the surface of a composite with mWS was observed
after 7-days soaking in the SBF medium. In the case of a composite

[141]

[124]
[73]

[72]

[88]
with the same amount of classic WS it took 14 days [129,131].
Higher specific surface area provided by mWS particles present in a
polymer matrix promotes cells interaction (osteoblast, chondrocyte)
5.5–9·10−3

4–6·10−3
modulus)

[76,132–133]. Further studies on the application of mWS showed that

(Storage
17–20

1.6–2
even 0.5% concentration of mWS in chitosan/carboxymethylcellulose
(CS/CMC) scaffolds significantly improves their physicochemical and bi-
ological properties [131]. Inclusion of mWS particles had no effect on al-

0.15–0.2 (C)
tering the porous architecture of the CS/CMC scaffolds but influenced
23–33 (C)

protein adsorption and biomineralization ability. The CS/CMC/mWS

scaffolds were biocompatible and enhanced differentiation of MSCs to
osteoblasts [132].
Hard and soft
osteomyelitis

A small amount of additives present in a degradable polymer matrix

Treatment of
engineering

engineering

engineering

engineering

engineering
Bone tissue

Bone tissue

Bone tissue

Bone tissue

characterizes nanocomposite materials. When PCL was used as a matrix

chronic

with nanometric WS (0.5–1 wt.%.) as a filler a homogenous dispersion

tissue

was obtained. A result of a good distribution of the nanofiller within

the polymer matrix was better mechanical properties (Young's modu-
lus, tensile strength and work-of-break) [134]. It suggests that there is
Thermal induced phase

Thermal induced phase

Compression moulding

some interaction between WS nanoparticles and the polymer matrix

(hydrogen bonding, van der Waals interaction) indicating that the ce-
ramic filler contributes to the overall elastic properties of the composite
Solvent casting

Solvent casting

Freeze-drying

samples. Enhancement of the modulus of nanocomposites at such a low

separation

separation

concentration of ceramic particles cannot be attributed to the introduc-

tion of a ceramic filler with higher modulus, which is observed in tradi-
tional composite materials i.e. with 40 wt.% of WS. The same interaction
between a polymer chain and nanometric WS could be confirmed by
Scaffold (porosity N

81–85%, pore size ~

Scaffold (pore size

Scaffold (porosity
Film (thickness ~

Film (thickness ~

spectroscopic studies such as FTIR in the transmission mode, the FTIR-

ATR technique and the proton-induced X-ray emission (PIXE) method
60–125 μm)

[135]. Dispersion of WS nanoadditives is well visible in PIXE where an-

100 μm)
50 μm)

40 μm)
Particles/melting/b50 μm/~70 wt.% Pellet

alytical elements for WS (i.e. Ca and Si) could be observed (Fig. 4).
98%)

To conclude, the biodegradable polymer/WS composite possess

many interesting properties (biocompatibility, bioactivity, biodegrad-
ability and combining with them carrying therapeutic agents) which
Particles/20–30 nm/10, 20 wt.%
Particles/~50 nm/0.5, 1, 2 wt.%

Particles/melting/38, 100 μm/

synthesis/30–50 nm/30 wt.%

were guaranteed by WS particles. Some authors pointed out that

precipitation/10, 20 wt.%

these materials can be used as an alternative for conventional bioactive

available/5 μm/30 wt.%
Particles/commercially

ceramic fillers such as HAp, TCP, BCP and BG used to modify the polymer
Particles/flame spray

Particles/chemical

matrix.

6. Calcium phosphate ceramics based composites

Over the past few decades, calcium phosphate (CaP) ceramics alone
have been widely used as bone graft substitutes, especially because of
49SiO2-26Na2O–19CaO–1P2O5-4CoO (mol%)
6Na2O–8K2O–8MgO–22CaO–54B2O3–2P2O5

similarity of their chemical composition to the mineral phase of bone

[136–137]. Due to their nature, calcium phosphate ceramics show also
46SiO2-23Na2O–27CaO–4P2O5 (wt.%)

high biocompatibility and ability to bond with bone tissue under certain
conditions, however, because of their brittleness, their clinical applica-
49SiO2-26Na2O–23CaO–1P2O5

tions have been limited to the non- or low-load bearing parts of the
skeleton.
Many types of calcium phosphates have been considered as bioma-
terials for bone reconstruction in dental, orthopaedics and maxillofacial
45S5 Bioglasss®

45S5 Bioglasss®

application due to different behavior in the living organism, including

bioactivity, biodegradability and biological response. Bioactivity, degra-
Co-SBG
(mol%)

dation behavior and osteoconductivity/osteoinductivity of CaP ceramics

HAp
BBG

SBG

WS

generally depend on the Ca/P ratio, crystallinity and phase composition

[138–139]. Synthetic HAp (Ca10(PO4)6(OH)2) shows good stability in
the body, while tricalcium phosphates (α-TCP, β-TCP, Ca3(PO4)2) are
more soluble, whereas biphasic calcium phosphate (BCP; an intimate
Collagen-glycosaminoglycan

mixture of HAp and β-TCP) exhibits intermediate properties depending

on the weight ratio of stable/degradable phases. Thus, the dissolution
rate decreases in the following order: α-TCP N β-TCP N BCP N HAp [1,
138]. Because the natural bone hydroxyapatite is nonstoichiometric
and contains, beside the main components i.e.; Ca, (PO4)3 −, (OH)−,
Collagen

−
some other groups and trace elements (e.g. CO2– 3 , F , Mg
2+
, Na+, K+,
2+ 2+
Sr , Zn ), new trends in calcium phosphates preparation, especially
CS

SF

HAp, consist in obtaining substituted CaP ceramics. They do not only

1186 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
have a different solubility and bioactivity than the parent materials, but
also cause modified biological response due to the release of biologically
active ions during dissolution [136]. CaP ceramics exhibit different bio-
logical effects in vivo, while most of them are osteoconductive, only cer-
tain types are osteoinductive. Samavedi et al. proposed that a range of
osteoinductive potentials of CaPs decrease in the following order
BCP N TCP N HAp [138].
Currently HAp, TCP and BCP ceramics are quite common types of
materials used for various biomedical applications and they are avail-
able on the market. In the past few years, many efforts have been direct-
ed to develop calcium phosphate-containing composite materials,
especially polymer-matrix composites.
6.1. Hydroxyapatite based composites
Stoichiometric HAp (Ca/P molar ratio of 1.67) is considered to be
osteoconductive but not osteoinductive. Furthermore, because HAp is
the most stable among CaP ceramics, its surfaces provide highly effec-
tive nucleating sites for the precipitation of an apatite crystal in contact
with culture medium and body fluids [138]. Solubility, bioactivity and
biological response of HAp can be modified by anionic and cationic sub-
stitution [136]. Mainly for these reasons, HAp is widely used to prepare
polymer-ceramic composite materials usually with the aim to impart
the bioactivity and osteoconductivity and also improve mechanical
properties [140–147].
It is believed that one of the most promising bone graft material is
collagen/nano-sized HAp (nHAp) composite because of its ability to
mimic structure and composition of natural bone. New technics such
as self-assembly and biomineralization have been recently used to ob-
tain collagen/nHAp composites with oriented and hierarchical structure
considering the spatial relationship between organic and inorganic
phases [148–149]. Using the self-assembling method, a highly oriented
and with morphology similar to compact bones, collagen/nHAp com-
posite was obtained [148]. A pre-crystallization method allowed
obtaining a composite in which HAp nanocrystals were situated
among the collagen fibers creating a suitable structure for bone defect
repair [149].
Several studies were conducted on the use another natural polymer,
namely CS, as a component of HAp-containing composites. The pres-
ence of nHAp in a CS matrix increased compressive strength [140] and
Young's modulus of composites [141]. It can be related to hydrogen-
bonding interactions between NH2 and OH groups of nHAp and chela-
tion between NH2 and Ca2+ when the co-precipitation method of com-
posite preparation was used [140]. The incorporation of nHAp affected a
degradation rate of composites [140,141], induced bioactivity [140] and
favored murine osteoblast-like MC3T3-E1 cells attachment and prolifer-
ation [141].
In the literature, HAp fillers have also been shown to modify numer-
ous properties of synthetic polymer matrices, especially poly(α-hy-
droxy esters). The comparison of hydroxyapatite with different
morphologies, namely nanoparticles (nHAp) and whiskers (wHAp), as
PLGA matrix modifiers, showed that composites with nHAp had higher
bending strength in comparison with wHAp-containing materials. It can
be attributed to a more homogeneous distribution of nHAp in the poly-
mer matrix and also enhanced crystallization of the PLGA matrix. It was
also shown that morphology of HAp fillers influenced in vitro degrada-
tion behavior of the composites [150]. In turn, the use of various con-
tents (0–30 wt.%) and also sizes (0–50 μm, 5 μm and N 200 nm) of
HAp particles led to changes in thermal properties and/or crystallinity,
as well as the mechanical strength of the PLLA and PLGA-based compos-
ites [151].
In order to improve the adhesive strength between HAp nanoparti-
cles and PLLA and PLGA matrix, the hydroxyl groups on the surface of
the ceramic nanoparticles were grafted with PLLA by chemical bonding
[142–143]. It was shown, that composites containing grafted HAp
(gHAp) exhibited significantly improved tensile strength, bending
strength, and impact energy. Furthermore, a composite with a low con-
tent (4 wt.%) of gHAp possessed higher mechanical properties than the
pure PLLA. The implantation study of repairing critical-sized defects in
the radius of a rabbit forelimb showed that the gHAp/PLGA scaffold ex-
hibited rapid and strong mineralization and osteoconductivity [143].
Degradation studies showed that the incorporation of HAp [144] and
nHAp particles [145] into PCL and PLGA matrix, respectively, accelerat-
ed degradation of the composites. Furthermore, a degradation rate of
composites can be adjusted by varying the HAp content [144–145].
Kim et al. obtained nHAp/PLGA composite scaffolds using the gas
forming particulate leaching method. The scaffolds exhibited signifi-
cantly higher rat calvarial osteoblast growth, alkaline phosphatase ac-
tivity, and extracellular matrix (ECM) mineralization in vitro
compared to the pure PLGA material. Furthermore, the presence of
nHAp fillers enhanced hydrophilicity and in vivo osteoconductivity
(higher bone formation area and more extensive calcium deposition)
of the material [146–147].
Another study showed that incorporation of Ag-doped HAp into
PHBV nanofibers imparted antibacterial activity against E. coli and S. au-
reus bacteria and enhanced in vitro bioactivity when compared to the
material containing unmodified HAp, while did not show any cytotoxic
effect [152].
6.2. Tricalcium phosphate based composites
Tricalcium phosphate (β-TCP, TCP) is a well-known CaP-based
bioceramics. β-tricalcium phosphate has been widely investigated and
successfully used in clinical application as a biomaterial for bone repair
applications due to its remarkable biocompatibility, in vivo
resorbability, bioactivity and good osteoconductivity [153–183]. More-
over, some results indicated that TCP is considered to be osteoinductive
[138]. For many years TCP has been combined with other ceramic mate-
rials such as; HAp, Al2O3, ZrO2 to produce small dental or orthopedic im-
plants [154–156] in the form of composites or composite layers on the
implants [156–159]. Last decades showed that the most perspective
form of TCP is small particles or nanoparticles which modify a biode-
gradable polymer matrix [157,160–162]. Incorporation of the ceramic
particles into polymer-based composite materials presented significant
osteogenic benefits and encouraged formation of a new bone on im-
plant surfaces [163–164]. In addition, during degradation process of
composite implants/scaffolds based on biodegradable aliphatic polyes-
ters, particles of TCP which modified the polymer matrix, improved
not only osteoconductivity but also neutralized acidic pH of the environ-
ment typical for degradation of a polymer matrix [163–165]. These phe-
nomena decrease the risk of local complications (inflammatory
reactions) and increase the degradation rate comparing to pure poly-
mer implants [166]. Moreover, employment of a room temperature
preparation technique of such composites may allow incorporating of
thermally unstable antibiotics, as well as growth factors e.g.; BMP-2 as
stimulants of bone formation. Osteoconductive composite materials
such as; PLLA/β-TCP, PCL/β-TCP comprising a large volume fraction of
β-TCP (≥ 60 vol.%) and a smaller amount of polymer (PLLA, PCL) were
studied as degradable antibiotic carrier materials for the orthopedic
treatment [166–167]. A study on PCL/TCP beads loaded with vancomy-
cin (1–4 wt.%) showed that a gradual drug release observed over the pe-
riod of 4–11 weeks had diffusional character and depended on the
composite matrix homogeneity and porosity [167].
Methods of fabrication of PLA/β-TCP and PCL/β-TCP composites i.e.;
cold sintering and/or salt leaching allowed obtaining materials suitable
for load-bearing bone scaffolds [167–169]. These materials were charac-
terized by high strength and Young's modulus required as biomechani-
cal properties of such implants. It is, therefore, believed that the first
resorbable and a strong bone graft substitute will consist of a poly-
mer-calcium phosphate composite and will contain a large ceramic frac-
tion [170]. A small fraction (≤40 vol.%) of the particulate ceramic phase
decreased mechanical properties of composite implants and scaffolds
 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
but they were still osteoconductive and promoted osteoblasts adhesion,
proliferation, penetration, and ECM deposition and influenced their
degradation rate [171]. Kobayashi et al. showed that small amount of
TCP (contents of 5–15 wt.%) in PLLA agglomerated and these regions
acted as water diffusion paths and started hydrolytic degradation of
the polymer matrix near the TCP-PLLA interfaces [172].
Results of some investigations pointed out that nanometric par-
ticles of β-TCP with high specific surface area and chemical groups
capable of interaction with a polymer chain can affect both bioactiv-
ity/osteoconductivity and mechanical properties [173]. The fibrous
PLA/TCP (1 wt.%) nanocomposites produced by the electrospinning
method belong to a group of biomimetic materials because they
chemically and structurally mimic a natural bone tissue. The nano-
composite fibers with nanometric or submicrometric diameters
have particle size and composition similar to the natural collagen fi-
bers present in a bone. A three dimensional (3D) form of the mate-
rial facilitates settling and adhering of bone cells and inducting
apatite formation on the surface of nanofibers (Fig. 5) [184].
Despite of this, implants/scaffolds made of PLGA and nanometric
particles of β-TCP would not induce stronger osteointegration than im-
plants made of PLGA and micrometric-size β-TCP particles e.g. a push
out test showed similar results in both materials.
To overcome these limitations, the reinforcement of a polymer ma-
trix by TCP nanoparticles was proved when crosslinking CS was used
as the matrix polymer [174–176]. As a crosslinking agent could be
used; genipine, gluatre aldehyd or tripolyphosphate. It was shown
that a composite scaffold obtained with genipine-crosslinked CS and
nanometric β-TCP improved mechanical, bioactivity and cell supportive
properties such as viability and osteogenic differentiation of human
MSCs [177–178]. Such scaffolds had slightly higher extent of mineraliza-
tion after 21 days of incubation in an osteogenic medium. By changing
the crosslinking agent e.g. to tripolyphosphate it was possible to reduce
its degradation rate without harmful side effects [179–180], pores size
and wettability, swelling and compressive strength of scaffolds [176–
177].
In order to enhance osteoconductive process supported by a
polymer composite with TCP a new strategy was proposed. To im-
prove and accelerate healing of bone grafts for orthopedic and dental
use a platelet-rich plasma (PRP) was applied on 3D scaffolds made of
PCL/TCP composite materials. The PRP is an autologous source of
concentrated platelets that contains several prepackaged growth
factors including transforming growth factor (TGF), platelet-derived
growth factor (PDGF), and vascular endothelial growth factor
(VEGF). Immersion of a PCL/TCP scaffold in PRP fluid and its
implanting into a critical-size femoral defects of a rat led after 3
months of the implantation to neovascularization and bone bridging
[181–182]. In another study, when PCL/TCP scaffolds in combination
with PRP were used in critical-sized defects healing of a canine man-
dible the results were confirmed in long-term observations: a bone
volume fraction after both control times i.e. 6 and 9 months was bet-
ter than in the control group. The regular deposition of osteoid with
alveolar bone trabeculae was shown for all treated defects [183].
6.3. Biphasic calcium phosphate based composites
Biphasic calcium phosphate ceramics are a family of two-phase ma-
terials that combine the low solubility and osteoconductive character of
HAp with the osteoinductivity of a more soluble phase, namely β-TCP.
The main advantage is the possibility of controlling bioactivity, resorp-
tion rate and also mechanical properties of CaP ceramic by manipulating
the HAp/β-TCP ratio [138,185–186]. BCP properties, especially biologi-
cal effects, can be modified also by ion substitution. Kim et al. showed
that that Sr incorporation into CaP ceramics increased a proliferation
rate and differentiation (ALP activity) of the MG63 and HOS osteo-
blast-like cells. Such behaviours can be attributed to the combined ef-
fects, that is, not only to the Sr ions release but also to higher
1187
concentration of β-TCP phase in the BCP [187]. In turn, Mg substitution
of BCP ceramics enhanced their biodegradation and bioactivity, and also
improved biocompatibility, as well as in vitro and in vivo
osteoconductivity tested with human adipose tissue-derived mesen-
chymal stem cells (hAT-MSCs) [188]. Above-mentioned features make
BCP ceramics useful as a modifier of biodegradable synthetic polymers
and copolymers; PCL [189], PLLA [190], PLGA [191–192] as well as nat-
ural polymers and their blends; collagen [193–194], gelatin-pectin
[195].
Ebrahimian-Hosseinabadi et al. demonstrated that the modification
of PLGA with various amounts (10–50 wt.%) of BCP nanoparticles affects
in vitro degradation behavior of the composite scaffolds. On one hand,
with increasing amount of BCP nanoparticles in the composites, reduc-
tion of Young's modulus increased as a result of higher weight loss of the
scaffolds. It could be related to an increase in hydrophilicity and the
water uptake of the composite scaffolds. On the other hand, a buffering
effect of basic degradation products of BCP on a degradation process of
PLGA was observed. Namely, more pronounced decrease in the molec-
ular weight of the polymer with reducing amount of BCP in the matrix
occurred during the degradation process [192].
Another work showed that BCP particles, homogeneously dispersed
in PLGA nanofibers, enhanced expression of osteogenic differentiation
markers (ALP and BSP) and also ECM mineralisation as a function of in-
creasing content of the ceramic particles in the composites. These find-
ings demonstrated a beneficial effect of BCP inclusion in PLGA
nanofibers on the osteogenic differentiation of osteoblast-like MC3T3-
E1 cells and confirmed osteoinductive character of the composites
[191]. The incorporation of BCP nanoparticles in another polymer ma-
trix, namely PCL, resulted in an increase in ALP activity of human
MSCs and also significantly improved compressive strength and Young's
modulus of the materials [189]. In order to enhance mechanical proper-
ties of PLLA-based composites, the surface of BCP microparticles was
modified by direct grafting with L-lactide. The results showed improved
interfacial interaction between the BCP filler and the polymer matrix,
and thus higher compressive strength in comparison to composites con-
taining the unmodified particles [190]. It was also shown that when TIPS
[192] and SCPL [189] methods were used to obtain PLGA and PCL-based
composite scaffolds the porosity of the materials decreased with in-
creasing BCP nanoparticles content.
A commercially available collagen/BCP composite (Osteon™ II colla-
gen, Genoss. Co. Ltd) was studied using a rabbit calvarial defect model
by Lee et al. [193–194]. The composite material showed good
osteoconductive properties and also relatively slow resorption and
thus, in contrast to collagen sponge, it maintained the space needed
for bone tissue regeneration [193]. It was also shown, that the colla-
gen/BCP composite is a promising candidate for a carrier of recombinant
human BMP-2 providing a constant release profile [194]. In turn, a gel-
atin-pectin/BCP nanocomposite scaffold was fabricated for delivering
growth factors (BMP-2 and VEGF). The release studies exhibited that
the scaffold had constant release properties. Furthermore, in vitro and
in vivo tests conducted with osteoblast-like MC3T3-E1 and rat models,
respectively, showed that the composites enhanced cell proliferation
and new bone formation [195].
To conclude, calcium phosphates, due to their wide range of solubil-
ity, bioactivity, osteoconductivity/osteoinductivity and various mechan-
ical behaviours, can be successfully applied as fillers of biodegradable
polymer matrices to modulate composite properties.
7. Summary
As pointed out above, ceramic materials discussed in this work,
namely silica, bioactive and resorbable glasses, wollastonite and calcium
phosphate ceramics have a number of unique and beneficial properties
for medical applications, especially for tissue engineering and regenera-
tive medicine. Depending on the type of ceramics, these properties in-
clude; bioactivity, osteoconductivity, osteoinductivity, resorbability,
1188 M. Dziadek et al. / Materials Science and Engineering C 71 (2017) 1175–1191
antibacterial and anti-inflammatory activity, ability to induce vascular-
isation and many others. As it has been shown in this review, the cur-
rent biomaterials age belongs to composite materials which are
classified as the fourth generation of biomaterials. They combine not
less than two different phases i.e.; polymer and ceramic particles or
nanoparticles. These new materials are mostly characterized by many
advantageous physicochemical, mechanical and biological properties
and what is even more important, they give scientists the opportunity
of a better control of such properties as; mechanical behavior, degrada-
tion rate, surface topography, surface charge and wettability and inter-
action with cells. Many of the new composite materials modified with
the ceramic fillers gain unique futures as antibacterial properties or in-
duct specific cells reactions e.g.; differentiation or activation of secretion
of growth factors. Apart from the ceramic filler amount, other parame-
ters such as its size (nanometric or micrometric), its shape (particles,
whiskers, nanotubes, fibers), distribution and a type of surface function-
al groups influence final properties of the composites. Type of matrix
polymer and its parameters, such as the molecular weight, polydispersi-
ty, crystallinity, chain orientation, functional groups and overall hydro-
philicity also strongly affect the composites properties. Of a great
importance and impact for applications in the medicine is that natural
and synthetic polymers have good formability. As presented in Table
3, numerous methods of fabrication of polymer-based composites com-
bined with many types of ceramic fillers allow obtaining the composites
in various forms (porous scaffolds, films, membranes, fibers) and with
different morphology and mechanical properties. Moreover, as de-
scribed in the subsequent sections of this work, these composites also
vary in terms of biological effects and other relevant properties. The
present work shows that through the selection of materials of the ce-
ramic filler and the matrix, their properties and relationships, it is pos-
sible to design and obtain materials with a wide range of properties
for various applications in the medicine, especially in the bone defects
treatment.
To conclude, the composite materials provide a multistage design
approach and therefore greater possibilities to control their material
and biological properties than the ceramics and the polymers alone.
Acknowledgments
The authors would like to acknowledge the financial support from
the National Science Centre, Poland Grant Nos. 2015/17/N/ST8/00226
(MD), 2014/13/B/ST8/02973 (KCK), 2012/07/B/ST8/03378 (ESZ) and
from the Polish Ministry of Science and Higher Education Grant No. N
N507 401 939 (ESZ).
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