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1 s2.0 S0142961206001232 Main PDF
1 s2.0 S0142961206001232 Main PDF
Review
Department of Materials, Imperial College London, Prince Consort Road, London SW7 2BP, UK
Centre for Tissue Engineering and Regenerative Medicine, Imperial College London, London SW7 2AZ, UK
Abstract
Biodegradable polymers and bioactive ceramics are being combined in a variety of composite materials for tissue engineering scaffolds.
Materials and fabrication routes for three-dimensional (3D) scaffolds with interconnected high porosities suitable for bone tissue
engineering are reviewed. Different polymer and ceramic compositions applied and their impact on biodegradability and bioactivity of
the scaffolds are discussed, including in vitro and in vivo assessments. The mechanical properties of todays available porous scaffolds are
analyzed in detail, revealing insufcient elastic stiffness and compressive strength compared to human bone. Further challenges in
scaffold fabrication for tissue engineering such as biomolecules incorporation, surface functionalization and 3D scaffold characterization
are discussed, giving possible solution strategies. Stem cell incorporation into scaffolds as a future trend is addressed shortly, highlighting
the immense potential for creating next-generation synthetic/living composite biomaterials that feature high adaptiveness to the
biological environment.
r 2006 Elsevier Ltd. All rights reserved.
Keywords: Scaffolds; Bioactivity; Bone tissue engineering; Composites; Porosity; Biodegradability
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biodegradable polymer matrices . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Saturated aliphatic polyesters (PLA, PGA and PCL). . . . . . . .
2.2. Polypropylene fumarate (PPF). . . . . . . . . . . . . . . . . . . . . . . .
2.3. Polyhydroxyalkanoates (PHB, PHBV, P4HB, PHBHHx, PHO)
2.4. Surface bioeroding polymers . . . . . . . . . . . . . . . . . . . . . . . . .
Bioactive ceramic phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Bioactive glasses and glass-ceramics . . . . . . . . . . . . . . . . . . . .
3.1.1. Composition and bioactivity . . . . . . . . . . . . . . . . . . .
3.1.2. Mechanical properties. . . . . . . . . . . . . . . . . . . . . . . .
3.2. Calcium phosphates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1. Composition and bioactivity . . . . . . . . . . . . . . . . . . .
3.2.2. Mechanical properties. . . . . . . . . . . . . . . . . . . . . . . .
3.3. Other bioactive ceramics . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Corresponding author. Department of Materials, Imperial College London, Prince Consort Road, London SW7 2BP, UK. Tel.: +44 207 594 6731;
fax: +44 207 594 6757.
E-mail address: a.boccaccini@imperial.ac.uk (A.R. Boccaccini).
0142-9612/$ - see front matter r 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2006.01.039
ARTICLE IN PRESS
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4.
1. Introduction
Tissue engineering applies methods from materials
engineering and life sciences to create articial constructs
for regeneration of new tissue [1]. One common approach
is to isolate specic cells through a small biopsy from a
patient to grow them on a three-dimensional (3D) scaffold
under controlled culture conditions. Subsequently, the
construct is delivered to the desired site in the patients
body with the aim to direct new tissue formation into the
scaffold that can be degraded over time [13]. An
alternative approach is to implant scaffolds for tissue
ingrowth directly in vivo with the purpose to stimulate and
to direct tissue formation in situ [2,4,5]. The advantage of
this approach is the reduced number of operations needed,
resulting in a shorter recovery time for the patient.
Facing a complex biological and sensitive system as the
human body, the requirements of scaffold materials for
tissue engineering are manifold and extremely challenging.
First, biocompatibility of the substrate materials is
imperative; that is the material must not elicit an
unresolved inammatory response nor demonstrate immunogenicity or cytotoxicity. In addition, the mechanical
properties of the scaffold must be sufcient and not
collapse during handling and during the patients normal
activities. As with all materials in contact with the human
body, tissue scaffolds must be easily sterilizable to prevent
infection [6]. This applies notably for bulk degradable
scaffolds, where both the surface and the bulk material
must be sterile. A further requirement for a scaffold
particularly in bone engineering is a controllable interconnected porosity to direct the cells to grow into the
desired physical form and to support vascularization of the
ingrown tissue. A typical porosity of 90% as well as a pore
diameter of at least 100 mm is known to be compulsory for
cell penetration and a proper vascularization of the
ingrown tissue [710]. Other highly desirable features
concerning the scaffold processing are near-net-shape
fabrication and scalability for cost-effective industrial
production.
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3420
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3415
Table 1
Physical properties of synthetic, biocompatible, and biodegradable polymers used as scaffold materials
Melting point Tm (1C)
Biodegradation time
(months)
Compressive* or
tensile strength (MPa)
Modulus (GPa)
5560
1216
PLLA [36,38]
173178
6065
424
PGA [3739]
PLGA [31]
PPF [31,40]
PCL [41]
PHA and blends [62]
225230
Amorphous
3540
4555
58
120177
72
2 to 4
612
Adjustable: 112
Bulk
424
Bulk
Pellet: 35150*
Film or disk: 2935
Pellet: 40120*
Film or disk: 2850
Fibre: 8702300
Fibre: 340920
41.455.2
230*
Polymer
Surface
Surface
242
2043
2527
3040*
416*
0.141.4
2.54.4
Surface
tration [2]. PLA and PGA can be processed easily and their
degradation rates, physical and mechanical properties are
adjustable over a wide range by using various molecular
weights and copolymers. However, these polymers undergo
a bulk erosion process such that they can cause scaffolds to
fail prematurely. In addition, abrupt release of these acidic
degradation products can cause a strong inammatory
response [47,48].
In general, PGA degrades faster than PLA, as found in
Table 1. Their degradation rates decrease in the following
order:
The most often utilized biodegradable synthetic polymers for 3D scaffolds in tissue engineering are saturated
poly-a-hydroxy esters, including poly(lactic acid) (PLA)
and poly(glycolic acid) (PGA), as well as poly(lactic-coglycolide) (PLGA) copolymers [2,31,45,46]. PLA exists in
three forms: L-PLA (PLLA), D-PLA (PDLA), and racemic
mixture of D,L-PLA (PDLLA).
The chemical properties of these polymers allow hydrolytic degradation through de-esterication. Once degraded,
the monomeric components of each polymer are removed
by natural pathways. The body already contains highly
regulated mechanisms for completely removing monomeric
components of lactic and glycolic acids. PGA is converted
to metabolites or eliminated by other mechanisms, and
PLA can be cleared through the tricarboxylic acid cycle.
Due to these properties PLA and PGA have been used in
products and devices, such as degradable sutures which
have been approved by the US Food and Drug Adminis-
PGA4PDLLA4PLLA4PCL:
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K. Rezwan et al. / Biomaterials 27 (2006) 34133431
3417
Fig. 1. SEM micrographs illustrating the typical cauliower morphology of hydroxyapatite formed on the surface of a 45S5 Bioglasss-based
foam after immersion in simulated body uid (SBF) for 28 days. The foam
was sintered at 1000 1C for 1 h. The magnication of the framed area
shown in the inlet picture reveals rod-shaped crystals of hydroxyapatite
(adapted from Ref. [69]).
Table 2
Mechanical properties of dense and highly porous hydroxyapatite, 45S5 Bioglasss, A/W glass-ceramic, and human cortical bone
Ceramics
Compressive strength
(MPa)
Tensile strength
(MPa)
Fracture toughness
p
(Mpa m)
References
Hydroxyapatite (HA)
45S5 Bioglasss
Glass-ceramicA/W
Porous bioactive glass70S30C
(82%)
Porous Bioglasss-derived glassceramic (490%)
Porous HA (8286%)
Cortical bone
Cancellous bone
4400
500
1080
2.25
40
42
215
100
35
118
1.0
0.51
2.0
[70,71]
[71,72,76]
[73]
[105]
0.2-0.4
[69]
0.210.41
130180
412
50151
0.831.6 103
1218
0.10.5
68
[106]
[31,74,75]
[107,108]
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3419
ARTICLE IN PRESS
3420
higher bioactivity, hence in some applications the incorporation of bers instead of particles is favored [27,138].
Addition of bioactive phases to bioresorbable polymers
can also alter the polymer degradation behavior, by
allowing rapid exchange of protons in water for alkali in
the glass or ceramic. This mechanism is suggested to
provide a pH buffering effect at the polymer surface,
modifying the acidic polymer degradation [24,52,139].
Inclusion of bioactive glasses has been shown to modify
surface and bulk properties of composite scaffolds by
increasing the hydrophilicity and water absorption of the
hydrophobic polymer matrix, thus altering the scaffold
degradation kinetics. In particular, the inclusion of 45S5
Bioglasss particles was found to increase water absorption
compared to pure polymer foams of PDLLA [133] and
PLGA [24,52]. In related research, it has been reported that
polymer composites lled with HA particles hydrolyzed
homogeneously due to water penetrating the interfacial
regions [140]. Ideally, the degradation and resorption
kinetics of composite scaffolds are designed to allow cells
to proliferate and secrete their own extracellular matrix
while the scaffolds gradually vanish, leaving space for
new cell and tissue growth. The physical support provided
by the 3D scaffold should be maintained until the
engineered tissue has sufcient mechanical integrity to
support itself.
There are numerous foaming techniques including solgel
routes to obtain highly porous structures [141,142]. However, only relevant fabrication techniques leading to 3D
composite scaffolds with highly interconnected pores are
discussed in the following paragraphs and compared in
Table 3, compiled with data available from the literature
[133,135,143148]. A selection of dense and porous scaffold
composites including their physical properties is given in
Table 3
Fabrication routes for 3D composite scaffolds with high pore interconnectivity and their advantages and disadvantages
Fabrication route
Advantages
Disadvantages
Controlled porosity
Controlled interconnectivity (if particles are
sintered)
Interconnectivity is an issue
Use of organic solvents
ARTICLE IN PRESS
K. Rezwan et al. / Biomaterials 27 (2006) 34133431
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Table 4
Selection of scaffold composites designed for bone tissue engineering and their properties
Scaffold composite
Ceramic
1. Dense composites
HA bre
HA
b-TCP
A/W
Cortical bone
2. Porous composites
Amorphous CaP
HA
Bioglasss
Percentage of
ceramic (%)
Porosity (%)
Compressive (C),
tensile (T), exural
(F) strength (MPa)
Modulus (MPa)
Reference
PDLLA
PLLA
PLGA
PLLA-co-PEH
PPF
PE
210.5 (vol.)
1070 (wt.)
4085 (vol.)
75 (wt.)
25 (wt.)
1050 (vol.)
45 (F)
5060 (F)
22 (F)
51 (F)
7.57.7 (C)
1828 (B)
50150(T)
130180 (C)
1.752.47 103
6.412.8 103
1.1 103
5.18 103
191134
0.95.7 103
1218 103
[149]
[150]
[29,151]
[152,153]
PLGA
PLLA
PLGA
PLGA
PLGA
PLLA
2875 (wt.)
50 (wt.)
6075 (wt.)
75 (wt.)
2050 (wt.)
75
8596
8191
3040
43
7780
0.42 (C)
1.53.9 (T)
65
1014
27.5
3371459
51
137260
[28,155]
[127]
[156]
[157]
[93,148,158]
[17]
PLGA
PDLLA
0.11 (wt.)
529 (wt.)
94
4100
100 300
8001800
110150
89
100 (macro)
10 (micro)
50300
100 (macro)
1050 (micro)
0.070.08
0.651.2
[15,148]
[132,134,136]
PLA-PDLLA
PDLLA
40 (wt.)
2040 (wt.)
9397
85.595.2
0.0170.020 (C)
412 (C)
0.0750.12
100500
[159,25]
[107,108]
Polymer
Cancellous Bone
98154
0.39 (C)
0.070.22 (C)
[154]
[31,74,75]
ARTICLE IN PRESS
3422
Fig. 2. Typical morphologies of porous polymer foams produced by different techniques and structure of cancellous bone. (a) Thermal induced phase
separation (TIPS, adapted from Ref. [160]), (b) solvent casting and particle leaching [161], (c) solid freeform fabrication technique [147], (d) microspheresintering [148], (e) cancellous bone [162]. (Micrographs (b), (c) and (e) reprinted with permission of Elsevier Ltd. Micrograph (d) reprinted with permission
of John Wiley & Sons, Inc.)
It is well documented [52,163,165] that due to autocatalysis non-porous biodegradable polylactides undergo
degradation more rapidly than the porous counterparts.
The reason for this effect lies in the fact that porous
materials are able to facilitate dissolving and spreading of
degradation products throughout the aqueous medium,
thereby preventing autocatalysis. PDLLA/Bioglasss composites exhibit high bioactivity, assessed by the formation
of HA on the composite surfaces upon immersion in SBF
[133,134]. It has also been shown that the foams support
the migration, adhesion, spreading and viability of MG-63
cells (osteosarcoma cell line) [134].
The potential of these scaffolds in bone and soft-tissue
engineering has been demonstrated in vitro with optimized
concentrations of 45S5 Bioglasss added to PDLLA or
ARTICLE IN PRESS
K. Rezwan et al. / Biomaterials 27 (2006) 34133431
nanoparticles and Bioglasss additions have been synthesized by TIPS. These foams demonstrate enhanced
bioactivity and surface nanotopography [131].
4.2. Solvent casting and particle leaching
Solvent casting of biocomposite scaffolds involves the
dissolution of the polymer in an organic solvent, mixing
with ceramic granules, and casting the solution into a
predened 3D mould. The solvent is subsequently allowed
to evaporate. The main advantage of this processing
technique is the ease of fabrication without the need of
specialized equipment. The primary disadvantages of
solvent casting are: (1) the limitation in the shapes
(typically at sheets and tubes are the only shapes that
can be formed); (2) the possible retention of toxic solvent
within the polymer; and (3) the denaturation of the
proteins and other molecules incorporated into the
polymer by the use of solvents. The use of organic solvents
to cast the polymer may decrease the activity of bioinductive molecules (e.g. protein). The detailed processing steps
have been described in the literature [93].
Polymer-ceramic constructs can also be fabricated by the
solvent aggregation method. The polymer microspheres are
rst formed from traditional water oil/water emulsions.
Solvent-aggregated polymer-ceramic scaffolds can then be
constructed by mixing solvent, salt or sugar particles, ceramic
granules, and pre-hardened microspheres [131]. A 3D structure
of controlled porosity is formed based on this method
combined with particle leaching and microsphere packing.
Fig. 2b illustrates a typical pore morphology obtained by this
technique. The method shares similar advantages and
disadvantages with the solvent casting technique [93].
There has been little work done on producing bioactive
polymer-ceramic scaffolds using particle leaching. Certainly, a drawback of this technique is achieving pore
interconnectivity at low porogen (salt/sucrose) loadings, as
many of the porogen particles may remain trapped.
Nevertheless, composites based on calcium phosphate
inclusions with variable and graded porosity have been
produced using this route [168].
4.3. Solid freeform fabrication techniques (SFFT)
SFFT, such as fused deposition modeling, have been
employed to fabricate highly reproducible scaffolds with
fully interconnected porous networks [147,169] as shown in
Fig. 2c. Using digital data produced by an imaging source
such as computer tomography or magnetic resonance
imaging enables accurate design of the scaffold structure
[169]. Solid freeform (SFF) manufacturing coupled with
conventional foam scaffold fabrication procedures (phase
separation, emulsion-solvent diffusion or porogen leaching) may be used to develop scaffolds with controlled
micro- and macroporous structures. Such biomimetic
internal architectures may prove valuable for multi-tissue
and structural tissue interface engineering.
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3425
Table 5
Overview of in vitro investigated biodegradable polymer/inorganic phase composites available in the literature
Composite
PLGA/45S5 Bioglasss
PDLLA/45S5 Bioglasss
PLGA/HA
PCL/HA
Cell culture
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reviewed here, will play a vital role and perhaps they will
be the scaffolds of choice in combination with stem cell
seeding.
Acknowledgment
Stimulating discussions with Prof. L.L. Hench, Prof. J.
Polak and Dr. A. Bishop (TERM-Centre, Imperial College
London) and with Dr. F. Filser (ETH Zurich) are
acknowledged.
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