Polymer International Polym Int 56:145–157 (2007)

Review
Biodegradable polymers applied in tissue
engineering research: a review
Monique Martina1 and Dietmar W Hutmacher2∗
1 Department of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 10 Kent Ridge Crescent,
Singapore 119260
2 Division of Bioengineering, Faculty of Engineering, Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine,

National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260

Abstract: Typical applications and research areas of polymeric biomaterials include tissue replacement, tissue
augmentation, tissue support, and drug delivery. In many cases the body needs only the temporary presence of
a device/biomaterial, in which instance biodegradable and certain partially biodegradable polymeric materials
are better alternatives than biostable ones. Recent treatment concepts based on scaffold-based tissue engineering
principles differ from standard tissue replacement and drug therapies as the engineered tissue aims not only to
repair but also regenerate the target tissue. Cells have been cultured outside the body for many years; however, it
has only recently become possible for scientists and engineers to grow complex three-dimensional tissue grafts to
meet clinical needs. New generations of scaffolds based on synthetic and natural polymers are being developed and
evaluated at a rapid pace, aimed at mimicking the structural characteristics of natural extracellular matrix. This
review focuses on scaffolds made of more recently developed synthetic polymers for tissue engineering applications.
Currently, the design and fabrication of biodegradable synthetic scaffolds is driven by four material categories:
(i) common clinically established polymers, including polyglycolide, polylactides, polycaprolactone; (ii) novel
di- and tri-block polymers; (iii) newly synthesized or studied polymeric biomaterials, such as polyorthoester,
polyanhydrides, polyhydroxyalkanoate, polypyrroles, poly(ether ester amide)s, elastic shape-memory polymers;
and (iv) biomimetic materials, supramolecular polymers formed by self-assembly, and matrices presenting
distinctive or a variety of biochemical cues. This paper aims to review the latest developments from a scaffold
material perspective, mainly pertaining to categories (ii) and (iii) listed above.
 2006 Society of Chemical Industry

Keywords: scaffolds; biodegradable polymers; tissue engineering; matrices

INTRODUCTION degradation and mechanical property customization;

A great number of current tissue engineering strate-
gies are based on the development of a cell–scaffold
construct whose role is to repair and regenerate tissue
defects (Fig. 1). During the first phase of tissue engi-
neering in the 1990s research utilized either US Food
and Drug Administration (FDA)/CE mark approved
devices or used so-called conventional scaffold fabrica-
tion technologies in combination with FDA/CE mark
approved biomaterials of synthetic and natural origin.
This work has been reviewed in detail elsewhere.1 – 3
Currently, the design and fabrication of syn-
thetic scaffolds is driven by four material categories:
(i) biodegradable and bioresorbable polymers, which
have been effectively used for clinically established
products, including polyglycolide (PGA), polylactides
(PLA), poly-L-lactic acid (PLLA), poly-D,L-lactic
acid (PDLA), polycaprolactone (PCL); (ii) novel di-
and tri-block polymers which predominantly incor-
porate PGA, PLA, and other resorbable polymers
in different chain arrangements which confer both
(iii) polymers that are regulatory approved for spe-
cific applications and/or are in clinical trials, e.g.
polyorthoester (POE), polyanhydrides, polyhydrox-
yalkanoate (PHA), and newly synthesized polymeric
biomaterials, such as polypyrroles (PPy), poly(ether
ester amide)s (PEEA), and elastic shape-memory poly-
mers; and (iv) biomimetic materials, supramolecular
polymers formed by self-assembly, and matrices pre-
senting distinctive or a variety of biochemical cues.
The aim of this review is to capture the latest develop-
ments from a scaffold material point of view covering
the aforementioned categories (ii) and (iii).
DI- AND TRI-BLOCK POLYMERS BASED ON
ALIPHATIC POLYESTERS
In attempts to tune aliphatic polymer properties
to wider applications for scaffold-based tissue engi-
neering, di- and tri-block polymers are seen as
promising alternatives. By modifying the backbone

∗
Correspondence to: Dietmar W Hutmacher, Division of Bioengineering, Faculty of Engineering, Department of Orthopaedic Surgery, Yong Loo Lin School of
Medicine, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260
E-mail: biedwh@nus.edu.sg
(Received 3 October 2005; revised version received 28 February 2006; accepted 21 March 2006)
Published online 13 October 2006; DOI: 10.1002/pi.2108

 2006 Society of Chemical Industry. Polym Int 0959–8103/2006/$30.00

M Martina, DW Hutmacher
Figure 1. Schematic of scaffold-based tissue engineering.
of the polymers, some of the characteristics, such
as degradation properties, mechanical properties, and
even biocompatibility, of the polymers can be changed
to a significant extent.4 – 6
Li et al.4 developed a series of di- and tri-block
polymers based on PCL, PLA, and poly(ethylene gly-
col) (PEG)/poly(ethylene oxide) (PEO). They used a
tri-block made of PLA/PEO/PLA, with PEO as the
hydrophilic and swollen component; and PLA chains
as the nanometric nodes in the gel network. These
physically crosslinked hydrogels possessed interesting
degradation properties. Incorporation of PLA blocks
at the end of the PEO segments decreased the degra-
dation rate when compared to pure PEO. Weight
losses of 49% after 10 days and 77% after 30 days
were observed. A fast initial loss was observed due to
the release of PEO-rich segments. Enzymatic degra-
dation promoted a much faster degradation rate which
reached 59% weight loss after 80 h of immersion, com-
pared to 5% under hydrolytic degradation conditions.
The author of this review and co-workers prepared a
series of scaffolds from these materials using a rapid
prototyping system (Fig. 2) and the scaffolds were
studied in vitro and in vivo.6
PCL/PGA di-block systems5 have certain elastic
properties. Scaffolds with pore sizes of 250 ± 50 µm
and a porosity of 93% were produced using a sol-
vent casting and particulate leaching method. Due
146
to its elasticity (elongation up to 250% and recovery
up to 98% after applied strain of 120%) Lee et al.5
predicted the potential of this di-block in muscle tis-
sue engineering. Preliminary in vitro studies using rat
smooth muscle cells (SMC) displayed growth and tis-
sue formation on the PCL/PGA scaffold. A summary
of the properties of this system is given in Table 1.
PCL-based copolymers for soft tissue engineering
have been investigated by Cohn’s group,7 who
synthesized tri-blocks based on PCL/PEO/PCL (soft
segment with hexamethylene diisocyanate chain
extension as the hard segment). Incorporation of PEO
enhanced water permeability. These tri-blocks have
a water uptake of up to 94%, which also influences
the mechanical properties and biodegradability. The
length of the blocks affect polymer properties: for
example, longer PEO segments lead to a decrease
in the degree of crystallinity, an increase in water
uptake, and an increase in degradation rate. Possible
applications include soft tissue replacement and drug
delivery systems. The cell biocompatibility of this
system was studied by the authors of this review
(Fig. 3(a)–(c)).
One of the current challenges facing polymer
usage in cell therapy is the ability to add bioac-
tive molecules to enhance cytocompatibility. Con-
ventional biodegradable polymers lack this charac-
teristic. A strategy to overcome this limitation is
Polym Int 56:145–157 (2007)
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Table 1. Summary of polymer properties

Mechanical Degradation Biocompatibility Biocompatibility

Polymer Abbreviation properties rate Application in vivo in vitro Reference

Polym Int 56:145–157 (2007)

Poly(glycolide-co- PGCL >250% elongation at 50% mass loss in Smooth muscle tissue Subcutaneous Rat SMC 5
caprolactone) break 6 weeks (PBS, engineering implantation using
37 ◦ C) mouse model,
appropriate SM
tissue formation
after 3 weeks
Poly(ester urethane)urea PEUU 0.97–1.64 MPa tensile 13.37–20.7% mass Soft tissue engineering Rat SMC 23
strength (3D porous loss in 8 weeks (in
scaffold) PBS, 37 ◦ C)
Poly(ether ester PEEUU 0.59–1.68 MPa tensile 25.4–47.3% mass Soft tissue engineering Rat SMC 23
urethane)urea strength (3D porous loss in 8 weeks (in
scaffold) PBS, 37 ◦ C)
Poly(ester urethane)urea PEUU 13 ± 4 MPa tensile Soft tissue engineering Rat SMC 24
strength (nanofibre)
Lysine diisocyanate-glucose LDI-glucose 67.7% mass loss in Bone tissue Subcutaneous Rabbit BMSC 22
60 days (PBS, engineering implantation using
37 ◦ C). Approx. rat model, no tissue
90–100% mass loss necrosis,
in 60 days (in vivo) vascularized, no
giant cells
Poly(propylene fumarate) PPF 354.1–1024.2 MPa 13.6–27.9 ± 1.8% Bone tissue Subcutaneous and Rat osteoblast 26–28
compression modulus mass loss in engineering cranial implantation
12 weeks (in PBS, using rabbit model,
37 ◦ C) 5–15 layers of
fibrous capsule, and
inflammatory cells
are seen

147
Biodegradable polymers in tissue engineering
 148
M Martina, DW Hutmacher

Table 1. Continued

Mechanical Degradation Biocompatibility Biocompatibility

Polymer Abbreviation properties rate Application in vivo in vitro Reference

Poly(ethyl PPHOS/HA 200 MPa compression Less than 5% mass Bone tissue Rabbit tibial model, Osteoblast cell lines 12
glycinate/p-methyl modulus, and remains loss in 12 weeks (in engineering minimal
phenoxy) phosphazene/ after 2 weeks PBS, 37 ◦ C) inflammatory
hydroxyapatite response
Poly(trimethylene Poly(TMC/CL) 1–10 MPa Young’s Approx. 6% after Cardiovascular Subcutaneous 16,17,19
carbonate/ε- modulus 52 weeks’ implantation using
caprolactone) implantation rat model, sterile
inflammation with
normal foreign body
reaction
Poly(glycerol sebacate) PGS 0.282 ± 0.025 MPa 17 ± 6% mass loss in Microvasculature, soft Subcutaneous Fibroblast cell lines 33,34
tensile Young’s 60 days (in vitro). tissue implantation using
modulus Totally absorbed rat model, similar
(in vivo) inflammatory
response to PLGA
Poly(desamino Poly(DTE carbonate) 57 ± 8 MPa ultimate No mass loss after Anterior cruciate Subcutaneous Fibroblast human cell 10
tyrosyl-tyrosine ethyl ester tensile strength 30 weeks (in PBS, ligament implantation using lines and primary
carbonate) 37 ◦ C) rat model, tissue rabbit fibroblast
ingrowth similar to
collagen. Rabbit
model

DOI: 10.1002/pi
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 Biodegradable polymers in tissue engineering

Figure 2. Polyester–polyether block copolymers composed of PCL or PLA and poly(ethylene glycol) (PEG) have attracted much attention as they
offer the possibility of varying the ratio of hydrophobic/hydrophilic constituents to modulate the degradability and hydrophilicity of the polymer
matrix and surface. Scaffolds were fabricated using a rapid prototyping (RP) machine built in-house at the National University of Singapore. System
details are reported elsewhere.7 Briefly, in contrast to traditional RP systems such as fused deposition modelling, three-dimensional printing,
stereolithography, and selective laser sintering, which mainly focus on a single mode of material processing, this system can accommodate a much
larger variety of synthetic and/or natural biomaterials. A lay-down pattern of 0/90 was used to form the honeycomb patterns of square with a single
fill gap (FG) of 1 mm. Porous sheets measuring 40 × 40 × 3 mm were fabricated using the system, with a 0.5 mm diameter nozzle. PCL–PEG
diblock copolymer was synthesised by Li et al.4 The extrusion temperature was set at 110 ◦ C for PCL–PEG. PCL–PEG was dispensed with an air
pressure of 3.5 bar and a speed of 30 mm min−1 in the x/y axis. Scanning electron micrographs (right) of melt extruded PCL–PEG scaffolds display
typical honeycomb morphology (A). Alternate layers of filaments were positioned at right angles to one another creating pore sizes of 600 µm.
Confocal laser microscopy of scaffold/cell constructs was used to study cell attachment and proliferation.

to use polymers containing functional side groups.
Guan and co-workers8 attempted to synthesize an
ABA tri-block polymer that had this particular
property. Fabrication from ABA-type tri-block poly-
mer PLGBG–PEG–PLGBG consisting of PEG and
poly[(lactic acid)-co-(glycolic acid)-alt-(γ -benzyl-L-
glutamic acid)] that had undergone catalytic hydro-
genation resulted in PLGG–PEG–PLGG, which
contained carboxyl pendant groups. These carboxyl
pendant groups may be useful to facilitate the attach-
ment of oligosaccharides, drug molecules, or short
peptides. Due to its amphiphilic nature, the polymer
formed micelles and may find useful applications in
drug delivery systems.
Another new tri-block system are thermogelling
copolymers9 made of PEG/PCL/PEG. At a copolymer
concentration of less than 1% and at a temperature
of 20 ◦ C, micelle aggregates of 10 and 23 nm coex-
isted, but at 25–45 ◦ C micelle aggregates of 23 nm
were dominant. Increasing the copolymer concentra-
tion also increased the micelle aggregation size. Upon
varying the PCL block’s length, sol–gel temperature
decreased due to the hydrophobic interaction that
drove gel formation. This system is appropriate for
in situ gel forming whereby entrapment and depot
formation can be envisaged with minimally invasive
therapy.
NEWLY SYNTHESIZED OR STUDIED
POLYMERIC BIOMATERIALS
Polycarbonate
Polycarbonate in its pure form is an amorphous
polymer that possesses low moisture absorption,
and is not susceptible to microbial attack, which
implies non-biodegradability of the polymer. How-
ever, the mechanical properties of the polymer attract
researchers keen to develop polycarbonate-based
material that can withstand mechanical loading while
tissue is being regenerated. Since resorbability is the
main problem, Bourke et al.10 investigated a member
of the tyrosine-derived polycarbonates that was not
only resorbable, but also possessed high strength. The
structure of this material is shown in Fig. 4(a). How-
ever, in that study, the degradation rate was shown to
be very slow, with no mass loss observed after 30 weeks
of incubation in PBS, at 37 ◦ C.
In the first phase, Bourke et al. fabricated this mate-
rial by melt extrusion at 60–90 ◦ C, which was above
the glass transition temperature. In the second phase,
they tried the melt-spinning technique at 181–183 ◦ C.
The fabricated fibres were aligned to mimic the
structure of ACL (anterior cruciate ligament). The
ultimate tensile strength of this material was found
to be comparable with natural ACL (57 MPa). Sub-
cutaneous implantation using a rat model revealed
tissue ingrowth 4 weeks post-operative with mainly
fibroblast-like structures observed surrounding the
fibres. Interestingly, although the structure was intact
8 weeks post-implantation, strength retention dropped
to 40%; this was in contrast to in vitro studies which
showed almost 90% strength retention, which implied
that the in vivo environment induced molecular relax-
ation, causing reduction in strength.
Further studies based on polycarbonate’s good
biocompatibility and ease of biochemical modification
towards cell adhesivity11 have been undertaken.
Using the polycondensation technique, copolymers of
poly ethylglycol/poly(desamino tyrosyl-tyrosine ethyl
ester carbonate) (PEG/poly(DTE carbonate)) were
obtained to study keratinocyte migration. It was
concluded that PEG provided a better attachment and
migration substrate for fibroblasts and keratinocytes,
whereas poly(DTE carbonate) acted to maintain the
structural integrity of the graft.
Polyphosphazene
The search for polymeric materials that are versatile
for various hard and soft tissue engineering appli-
cations has generated interest in another group of
polyphosphazene-based materials.12 – 14 The unique
properties arise from the unusual flexible backbone
allowing torsional and angular freedom within the

Polym Int 56:145–157 (2007) 149

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M Martina, DW Hutmacher

(a)

(b)

(c)

Figure 3. (a) Soft-PCL scaffold fabricated via a rapid prototyping technique (unpublished data). (i) High flexibility of scaffold is demonstrated; (ii, iii)
swelling ability is demonstrated (soft segments in polymer chain allow scaffold to swell up to 1.5 times). (b) Light micrographs of soft-PCL
(P) alginate/thrombin (M) construct seeded with human adipose derived precursor cells (hADAS). Formulations of cell aggregates and extracellular
material (white arrows) illustrate cell proliferation upon culturing: (i) day 1, (ii) day 7, (iii) day 22, (iv) day 42. Bar represents 100 µm. (c) Environmental
scanning electron micrograph (left) of scaffold/cell construct after 3 weeks of culturing exhibited intact cell/alginate/thrombin structure (M) inside the
soft-PCL pore morphology. Confocal laser micrograph (right) of soft-PCL (P) alginate/thrombin construct after 3 weeks of culturing. Cell viability is
shown by life/death assay (FDA; green fluorescence in confocal laser micrograph) inside the alginate/thrombin matrix. (Cells are indicated by white
arrows).

P–N skeletal system (Fig. 5(a)). The most com- technology enables fabrication of this polymer derived
mon fabrication technique is thermal ring-opening from polydichlorophosphazene using two different
polymerization of dichlorophosphazene. The current substituents. These substituents induce highly tuned

150 Polym Int 56:145–157 (2007)

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 Biodegradable polymers in tissue engineering

(a) (b)

(c)

(d)

Figure 4. Structures of (a) poly(desamino tyrosyl-tyrosine ethyl ester carbonate) (poly(DTE carbonate)), modified from of Bourke et al.;10
(b) PPF/PPF-DA crosslinked, modified from of Horch et al.;25 (c) poly DTH-adipate for R = hexyl and y = 4, modified from of Schachter and Kohn;42
(d) soft segment and hard segment of poly(ether ester amide), modified from Deschamps et al.44

(a)

(b)

(c)

Figure 5. Preparation schemes of (a) polydichlorophosphazene, modified from Ambrosio et al.;12 (b) PEUU, modified from Stankus et al.;24
(c) poly(glycerol sebacate), modified from Wang et al.33

Polym Int 56:145–157 (2007) 151

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M Martina, DW Hutmacher
properties such as crystallinity, degradability, and
hydrophilicity/hydrophobicity which provide the ver-
satility of the polymers.
Ambrosio et al.12 explored amino acid ester
polyphosphazene in bone tissue engineering. They
chose poly[(ethylglycinate phosphazene)-co-(p-me-
thylphenoxy phosphazene)] (PPHOS) in combination
with hydroxyapatite (HA) to develop a composite.
Degradation was achieved by incorporating side chains
that sensitized the polymer backbone to hydrolysis;
in this case, the amino acid side chains. Phenoxy
side chains inhibited degradation, and in this study,
PPHOS/HA remained stable mechanically and main-
tained a compressive modulus of around 200 MPa,
after 12 weeks’ degradation in vitro. PLAGA/HA con-
structs that were used as a control showed almost
insignificant compressive modulus. Degradation prod-
ucts could easily be detoxified by the body as the
degradation by-products are amino acids, phosphates,
and ammonia. PPHOS possesses a combination of
surface- and bulk-eroding properties.
Other types of polyphosphazene, those with
polyethyloxybenzoate and polypropyloxybenzoate,
were combined with HA resulting in composites
suitable for bone grafts.15 Syntheses of these polyphos-
phazene/HA composites were achieved through
acid–base reactions to form HA precursors, which
increased the pH of the solution and in the presence
of polyphosphazenes resulted in carboxyl formation in
the surface layer. These carboxyl groups then reacted
with calcium ions to form calcium crosslinks on the
surface, which played a role in nucleation and deposi-
tion of HA.
In another study, a PPHOS/PLAGA blend exhibited
a higher pH in the degradation solution compared to
PLAGA.13 The buffering phenomenon was attributed
to phosphates which were shown to be present in the
solution using 31 P NMR. Cell adhesion experiments
using MC3T3-E1 cells revealed PPHOS/HA to
possess a similar cell attachment and proliferation
when compared to tissue culture plastic (TCPS).
Nair and colleagues14 investigated the effect of sol-
vent, needle diameter, solution concentration, and
applied voltage on the fabrication of polyphosphazene
nanofibre scaffolds. Using chloroform as the solvent
produced the most uniform fibres. Decreasing the nee-
dle diameter resulted in decreased fibre diameter, but
too fine a needle produced fibres with beads. Increas-
ing the solution concentration generally resulted in
larger fibre diameters. The applied voltage affected the
shape of the nanofibres generated: 27–30 kV resulted
in a curly or distorted shape, 33 kV resulted in cylindri-
cal and rod-like structures, while 36 kV gave even finer
and more distinct rod-like structures. Investigation
of the polyphosphazene nanofibres extended to cell
compatibility studies. In vitro cell adhesion of bovine
coronary artery endothelial cells showed adhesion 24 h
post-seeding. The materila also exhibited cytocom-
patibility to osteoblast cell lines, MC3T3-E1, which
adhered and proliferated for 7 days. This presents an
152
opportunity for this material to be utilized in appli-
cations such as coatings to enhance tissue integration
and wound dressings.
Trimethylene carbonate-based materials
The elastomeric properties of poly(trimethylene car-
bonate) (poly(TMC)) make it a potential can-
didate for scaffold-based soft tissue engineering
applications.16 – 19 Interestingly, this polymer exhibits
slow degradation in vitro, but rapid degradation
in vivo.16 Poly(TMC) showed negligible mass loss
after 2 years in physiological solution, in which degra-
dation mainly occurred due to hydrolysis of ester
bonds. In contrast, in vivo implantation of polymer
discs into Wistar rats resulted in a high degradation
rate based on a cell-triggered surface erosion mecha-
nism. After 52 weeks, implanted poly(TMC) was 1%
of its initial mass.
Incorporation of other monomers such as D,L-
lactide acid (DLLA) or ε-caprolactone (CL) mod-
ulated the degradation properties in vitro as well as
in vivo. In vivo degradation characteristics of these
copolymers coincided well with in vitro degradation
behaviour, in which hydrolysis was mainly responsi-
ble for both conditions. TMC/DLLA decreased to
1% of the initial mass after 52 weeks, with rapid loss
observed after week 12, while TMC/CL displayed a
linear and continuous reduction throughout a year of
investigation, with mass loss less than 7% of the initial
mass. The difference in degradation behaviour of the
two copolymers was caused by autocatalytic activity of
DLLA, which did not occur in TMC/CL.
Furthermore, the in vivo tissue response of these
copolymers is similar to sterile inflammatory reactions
followed by normal foreign body reactions, which are
commonly seen after implantation of biodegradable
polymers.
Due to its flexibility, poly(TMC/DLLA) was tai-
lored towards heart tissue engineering applications.17
Poly(TMC/DLLA), although glassy at room temper-
ature, was rubbery at body temperature which made it
difficult to achieve a porous structure. A combination
of coprecipitation, compression moulding, and salt
leaching techniques were used to produce a porous
stable scaffold with a pore size of around 100 µm, a
porosity of 85–95%, and a compressive modulus up
to 430 kPa. In vitro degradation studies in physiolog-
ical solution showed that porous scaffolds shrunk by
up to 65% after the third week. Preliminary investi-
gation of cell compatibility using rat cardiomyocytes
showed average cell attachment and proliferation on
the copolymer surface compared to normal TCPS
plates.
Poly(TMC/CL) was explored for nerve grafting.16
Human dermal fibroblasts (HDFs) were subjected
to extracts of the polymer. Results showed that HDFs
subjected to the extraction vehicle maintained high cell
viability and cell metabolism activity. Schwann cells
were plated onto copolymer discs and demonstrated
good proliferation, with a higher proliferation rate after
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6 days compared with those cells plated onto PLGA.
Implanted tubular poly(TMC/CL) scaffolds were still
smooth and flexible at 60 days post-implantation, and
adhered well to the surrounding tissue. In another
in vivo study, a lesion in the spinal cord of female
Wistar rats exhibited extensive growth of Schwann
cells and extracellular matrix after implantation of
poly(TMC/CL) to the lesion.20
Grijpma et al.19 also explored the possibility of a
photocrosslinkable polymer via UV functionalization
of poly(TMC/CL) or poly(TMC/DLLA) with fumaric
acid monoethyl ester (FAME).
Polyurethanes
Polyurethanes are another area of investigation,
especially for soft tissue engineering applications,
in contrast to aliphatic linear polyesters that are
better suited to hard tissue engineering due to their
high glass transition temperature and high modulus.
Polyurethanes exhibit a wide range of properties
through variability of the hard segment (diisocyanate),
the soft segment (polyethers or polyesters), the chain
extenders, and the ratios in which they are reacted.
Previously, polyurethanes had a limited usage due
to the toxicity of their degradation product (2,4-
diaminotoluene). Hence, the challenge presented was
to develop polyurethanes with non-toxic degradation
products.
Non-toxic polyurethanes with diisocyanate replace-
ments which could give rise to non-toxic degrada-
tion products have been developed by at least two
groups.21 – 24 Guan et al.23 synthesized the polymers
made from PCL and 1,4-diisocyanatobutane (BDI)
with putrescine as chain extender (poly(etherurethane
urea), PEUU) (Fig. 5(b)). BDI was used because,
upon degradation, it would release putrescine, a
polyamine that is essential for cell growth and pro-
liferation. Zhang et al.22 synthesized polyurethane
from highly pure lysine diisocyanate (hard segment)
and polymerized it with glucose, which resulted in
major degradation products lysine and glucose (LDI-
glucose).
Scaffold fabrication routes for these polyurethanes
include thermally induced phase separation, electro-
spinning, and water foaming. These create differ-
ent porosities, surface-to-volume ratios, and three-
dimensional structures, with concomitant changes in
mechanical properties which are wide-ranging and can
be varied to suit potential applications in the biomed-
ical field, such as engineering blood vessels and bone
(Table 1).
The degradation mechanisms of the polymers
are important and need to be investigated further.
Non-toxic degradation products are necessary and,
moreover, mechanical properties are also influenced
by degradation mechanisms. LDI-glucose polymer,
for example, is degraded by hydrolysis of urethane
bonds to liberate lysine, glucose, ethanol, and CO2 .
Ethanol could inhibit cell–cell adhesion, but a study
reported that concentrations less than 30 mM (0.5%
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Biodegradable polymers in tissue engineering
v/v) are harmless to the cell.21 Moreover, in contrast
to PLA and PLGA degradation mechanisms, the
study showed no significant increase in pH of the
solution. PEUU degradation products were also
shown to be non-toxic to endothelial cells. The
polymer showed a linear degradation with no signs
of autocatalytic effects when compared to PLA
or PLGA degradation behaviour.23 Scaffolds were
prepared by thermally induced phase separation and a
subsequent solvent extraction technique. The results
were porous structures (porosity >80%) with pore
diameters ranging from 12 to 232 µm. The pore shape
was dependent upon the quenching temperature and
polymer concentration. The tensile strength of these
polymers during degradation decreased by about 12%
after 1 week and 31% after 2 weeks from the initial
value of 0.57–1.69 MPa.
Stankus et al.24 were able to machine these
polyurethanes via electrospinning to produce scaffolds.
The tensile strength of the nanofibres produced ranged
from 2 to 13 MPa and breaking strains from 160 to
280%. Incorporation of type I bovine collagen reduced
the tensile strength, but also reduced water contact
angles. This represents an increase in hydrophilicity
and, in turn, enhanced attachment of rat smooth
muscle cells.
In vitro and in vivo observations demonstrated that
these polymers had no harmful effects on cell viability,
growth, and proliferation. Subcutaneous implantation
using rat models revealed that LDI-glucose polymer
did not enhance capsule formation, accumulation of
foreign body giant cells, or tissue necrosis.22
The versatility of these polyurethanes was demon-
strated through attempts to enhance cell and tissue
compatibility via: addition of soft segments with PEG
to the backbone in order to enhance hydrophilicity;
mixing with collagen type I for better cell attachment;
and addition of ascorbic acid to the polymer mixture
to enhance osteoblast lineage progression. All of these
proved to be feasible. Polyurethane-based materials
are consequently considered promising candidates for
biomaterial-based applications.
Polyfumarate
Polyfumarate-based materials have been developed
mainly for bone tissue engineering.25 – 28 The main
advantages of these materials are their injectable
and in situ crosslinkable properties.29,30 With
N-vinylpyrrolidone (N-VP) as crosslinker, Payne
et al.28 showed during an in vitro study that fully
crosslinked poly(propylene fumarate) (PPF) had
potential as a substrate for supporting rat osteoblasts.
Cell proliferation, ALP activity, and osteocalcin and
calcium production of cells on fully crosslinked PPF
did not exhibit significant differences with those
cells grown on TCPS. Poly(caprolactone fumarate)
(PCLF) and poly(ethylene glycol fumarate) (PEGF)
were also investigated as injectable, self-crosslinkable
polymers which circumvented the requirement for
crosslinking agents that may be toxic. The polymers
153
M Martina, DW Hutmacher
were shown to harden and self-crosslink when under
physiological conditions, and tissue compatibility
studies using rat models demonstrated no inflamma-
tory reactions.29,30
Bone and soft tissue responses have been inves-
tigated in New Zealand white rabbit models.27 A
PEG block was added in order to make a hydrogel
(oligo(PEG fumarate), OPF). Tissue response and
in vitro degradation behaviour of four groups were
investigated. The groups included longer PEG blocks,
higher crosslinking density, and the addition of cell-
adhesive peptides to the hydrogels. Hydrogels with
higher crosslinking were observed to have the least
mass loss after 12 weeks in vitro. As the degradation
product was fumaric acid, a drop in pH was expected.
A pH drop of not more than 0.5 was reported (which
was considered to be harmless to the cells). In contrast,
in vivo results suggested that hydrogels with longer
PEG block resulted in more tissue infiltration, and
hence more active degradation. Fibrous capsule for-
mation with 5–15 cell layers including inflammatory
cells was observed for all groups.
Degradation rate and degree of swelling were also
dependent on the degree of crosslinking per macromer
chain. Less crosslinking gave rise to an increase in
water uptake and increased swelling. As degradation
occurred mainly due to the cleavage of ester bonds
within the crosslinked network by hydrolysis, a greater
number of chains were accessible to water and so
the polymer degraded faster. The higher the water
uptake, the faster the degradation. One type of OPF
investigated even appeared soft and jelly-like after
12 weeks under physiological conditions.
As the applications of polyfumarate-based materials
were first investigated for bone substitutes, mechanical
properties are an ultimate concern. Cortical bone has
a compressive modulus in the range 17–20 GPa, com-
pressive strength of 106–144 MPa, flexural modulus
of 15.5 GPa, and flexural strength of about 180 MPa.
This presents a major challenge for the tissue engineer
using polyfumarate-based materials. This unique char-
acteristic of bone is a result of its composite make-up
comprising the interaction of inorganic material, i.e.
HA, with organic material such as collagen fibres.
Researchers have considered ways to optimize the
mechanical properties of poyfumarate-based polymers
using the principle of bone architecture.25,26
Horch et al.25 developed PPF/poly(propylene
fumarate diacrylate) (PPF/PPF-DA) (Fig. 4(b)) with
a surface modification using carboxylate alumoxane
nanoparticles. The polymer composites were gener-
ated by mixing in a chloroform solvent, and the solvent
was then removed by rotary evaporation and high-
vacuum drying. Crosslinking was achieved by UV
radiation. Interactions of the inorganic and organic
matrix were achieved by covalent bonding, and the
presence of organophilic chains in the organic matrix
enhanced dispersion. Covalent bonding alone was not
enough; dispersion played a key role in the mechanical
154
properties of the composite. Without proper disper-
sion, the inorganic particles tended to aggregate and
create crack propagation sites, which, in turn, made
compressive fracture and flexural fracture strength
worse than that of PPF/PPF-DA.
Flexural testing was done on samples fabricated
by injecting a nanocomposite mixture into a mould,
and crosslinking the mixture using UV radiation.
The samples that showed enhanced dispersion and
covalent bonding with PPF/PPF-DA matrix exhibited
the best flexural modulus of more than threefold
higher (5.4 GPa) compared with blank PPF/PPF-DA,
which has a flexural strength of 1.5 GPa. Compressive
strength, however, was not significantly affected by
these modifications.
Incorporation of β-tricalcium phosphate (β-TCP)
was also attempted to enhance the mechanical
properties of polyfumarate-based polymers.26 The
polymer was produced by radical polymerization using
benzoyl peroxide and dimethyltoluidine as initiator
and accelerator. N-VP was used as crosslinking
reagent. Scaffolds were then fabricated by mixing
PPF with β-TCP and leachable porogen NaCl.
Groups with β-TCP concentrations of 0.5 g g−1 of
PPF exhibited bending strengths of up to 16 MPa,
compressive strengths of up to 79 MPa, moduli
in bending of up to 1270 MPa, and moduli in
compression of up to 1020 MPa. An approximately
twofold increase in bending and compressive strength
and bending and compression modulus for a twofold
increase in β-TCP concentration was observed.
Mechanical testing showed compression and bending
modulus of elasticity to be of the same order of
magnitude as that of trabecular bone.
Polyorthoester
Polyorthoester is a hydrophobic polymer fabricated by
polycondensation of diketene acetals and diols. This
fabrication creates ortho-ester bonds that are stable at
neutral pH, but hydrolyse rapidly at phagosomal pH,
i.e. pH 5.5. Today, it is mainly used in drug delivery
systems.31,32
Poly(glycerol sebacate)
The search for soft and mechanically stable elastomeric
materials to be implanted in dynamic environments
led to the investigation of polymers that are anal-
ogous with vulcanized rubber, having a crosslinked
three-dimensional network in combination with ran-
dom coil characteristics. Polycondensation of glycerol
and sebacic acid renders a polymer having hydro-
gen bonding interactions through hydroxyl proline
hydroxyl groups.33,34 With building blocks made of
glycerol (a basic building block of lipids) and sebacic
acid (a natural metabolic intermediate in ω-oxidation
of medium- to long-chain fatty acids), such materi-
als are expected to be biocompatible and non-toxic
(Fig. 5(c)).
The hydrophilic characteristics of the material are
a result of the hydroxyl groups attached to its
Polym Int 56:145–157 (2007)
DOI: 10.1002/pi

backbone. The material is insoluble but swells in
water by approximately 2%. It is totally amorphous
at 37 ◦ C like vulcanized rubber, a thermoset polymer.
However, the uncrosslinked polymer can be melted to
a liquid form which is soluble in common organic
solvents. It is tougher than hydrogels with tensile
strength of less than 0.5 MPa and tensile strain
more than 300%.33 In vivo and in vitro investigations
showed an acceptable biocompatibility. In vitro studies
using NIH 3T3 fibroblast cell lines grown in PGS-
coated Petri dishes exhibited higher cell growth
compared with PLGA-coated Petri dishes. An in vivo
study with Sprague-Dawley rats showed less fibrous
capsule formation compared to PLGA control after
subcutaneous implanation.
While simple foams were fabricated using a salt
leaching technique, lithography was used to fabricate
capillary networks.34 The surface of the wafer-like
scaffold was coated by a pentapeptide derived from
fibronectin to improve cell attachment. Adherence
of the HUVEC to the PGS was observed and
proliferation occurred for at least 10 days. After
14 days, the surface of the network was nearly
confluent and cultures were kept for up to 4 weeks.
PGS has another potential application as nerve
guides.35 In vitro studies demonstrated PGS as
non-toxic to Schwann cells and supported better
proliferation compared to PLLA. In vivo studies
revealed less inflammatory response possibly due to
its degradation profile via surface erosion.
Elastic shape-memory polymers
Lendlein and Langer36,37 investigated polymers that
could change shape by increases in temperature. This
thermally induced shape-memory effect required two
components: a switching segment, having transition
temperature to fix temporary shape, and a segment for
crosslinking to determine the permanent shape. The
switching segment used was oligo(ε-caprolactone)diol
or dimethacrylates, while crosslinking segments were
either n-butylacrylate or oligo(p-dioxanone)diol.
The mechanism of changing the shape from
permanent to temporary relies on the transition
temperature of the material. A polymer in a permanent
shape is heated above Ttrans while applying an external
stress. The temporary shape is obtained by reducing
the temperature to below Ttrans . Releasing the external
stress and heating up the material will reform the
temporary shape back to the permanent shape.
Using this mechanism, prior to surgery, implants
can be compressed to a smaller and more compact
temporary shape, inserted by minimally invasive
surgery, and then using body heat, it will expand back
to the permanent shape. Another possible application
is as sutures in endoscopic surgery, whereby the suture
knot can be applied loosely in its temporary shape,
followed by an increase in the temperature, which
would tighten the knot as it goes back to its permanent
shape.
Polym Int 56:145–157 (2007)
DOI: 10.1002/pi
Biodegradable polymers in tissue engineering
Another development by Lendlein and co-workers38
as regards elastic shape-memory polymers was light-
induced shape-memory polymers. With a similar
mechanism to that of a heat-sensitive shape-memory
polymer, this too consisted of two segments: molecular
switches that were photoresponsive, and netpoints for
covalent crosslinking that determined the permanent
shape, using cinnamic acid as a molecular switch.
When the polymer was stretched, the coiled segments
of amorphous polymer chain were elongated. Upon
exposure to UV radiation of wavelength >260 nm,
the elongated segments were partially fixed due to the
formation of new photoresponsive crosslinks. If the
loading was removed and the polymer exposed to UV
radiation of wavelength <260 nm, the crosslinks were
cleaved and the polymer returned to its original shape.
The discovery of this material eliminated temperature
constraints associated with thermally induced shape-
memory polymers for medical applications.
Polypyrrole
Electronic interaction is one of the factors that may
influence neuronal tissue regeneration and growth.
A class of polymers that have also been explored in
the field of nerve tissue engineering are conducting
polymers. Polypyrrole (PPy) is an electrodeposited
polymer that can be doped to modify its physical,
chemical, and electrical properties, and has conse-
quently emerged as a potential candidate for scaffolds
in neuronal tissue regeneration.39 Using PPy doped
with polystyrene-sulfonate (PSS) and sodium dode-
cylbenzene sulfonate (NaDBS) at different deposition
temperatures and solvents, George et al.39 investi-
gated the influence of these parameters on neural
tissue growth in vivo. Immunofluorescence analysis of
the neural tissue displayed a more complete bridging
when compared to a Teflon implant, which is cur-
rently a gold standard for neural implants. The data
presented implied that PPy implants generally exhib-
ited greater tissue integration and less inflammation.
The feasibility of incorporation of neuronal growth
factors (NGFs) was also shown, with even more neu-
ral tissue formation observed for NGF-incorporated
implants.
Moreover, the conductivity of PPy can be exploited
for the fabrication of bioelectrical circuits that integrate
electrical and neural signals. Cui et al. investigated
the use of PPy as a neural probe.40,41 These neural
probes facilitated the functional stimulation and
recording from the peripheral or central nervous
system. The conductivity of PPy might induce selective
neurons to attach to the electrode and achieve
neuronal tissue regeneration. However, problems were
encountered, including loss of the ability to record
neural activity with time. Modifications by patterning
peptide or peptide/protein polymer blends on the
surface were explored to enhance interaction and
anchorage between electrode and neurons.
155
M Martina, DW Hutmacher
Polyarylates
Schachter and Kohn introduced an interesting
concept of using a group of polyarylates for drug
delivery vehicles as an alternative to conventional
PLA, PGA, or PLGA systems.42 The polyarylates
(Fig. 4(c)) used were tyrosine-derived polymers which
possessed sites for interaction with peptides. Some
possible interactions included hydrogen bonding and
hydrophobic interactions. Addition of PLGA system
as a ‘delayed excipient’ induced a decrease of
internal pH during its degradation, and weakened the
sensitive interaction between peptide and polymer.
Using Integrillin as the drug model, the glass
transition temperature of the system varied in the
range 36–40 ◦ C as the amount of loaded drug varied.
The delayed time of the Integrillin release increased
as the initial molecular weight of the PLGA increased.
While degradation of PLGA affected the release of the
peptide, degradation of the polyarylates did not have
such an effect. Preliminary in vitro studies showed the
polymer to be versatile towards drug release kinetics
by tuning in the pendant chain and the backbone unit.
Poly(ether ester amide)
Another candidate for drug delivery systems arises
from the family of poly(ether ester amide)s (PEEAs).
They are mainly fabricated by polycondensation of
PEG and diester-diamide to create an amphiphilic
system.43,44 Diester-diamide acts as a hydrophobic
block for creating reversible physical crosslinks that
account for stronger mechanical properties in the
swollen state. In this case, PEG is the ‘soft’ segment
and diester-diamide acts as the ‘hard’ segment
(Fig. 4(d)).
The structure gives versatility allowing the tailoring
of hydrogels to suit different drug release profiles.
Bezemer et al.43 fabricated the polymer by a two-step
mechanism. The first step involved transesterification
of diamide-dimethyl ester monomers with PEG, and
the second step was polycondensation at 220 ◦ C. The
resulting polymers had an intrinsic viscosity ranging
from 0.58 to 0.78 dL g−1 , and they were not completely
amorphous; both depended on the length of the
polymer blocks. It was shown that the soft segment
length in a microsphere influenced the degree of
swelling, in vitro degradation, and release rate.43
Cytocompatibility was investigated using
HUVEC.44 These surfaces did not perform as pos-
itively as TCPS, possibly due to the PEO con-
tent. Deschamps et al.44 implanted a low-content-
PEG PEEA subcutaneously in rats. Mass loss was
7–12 wt% at 14 weeks post-implantation and a slow
decrease in intrinsic viscosity led to bulk hydrolysis
degradation. Tissue responses were found to be sim-
ilar to tissue reactions observed upon implantation of
other biodegradable polymers. Fibrous capsules were
observed, with macrophages and blood vessel infiltra-
tion accompanied by cracks on the polymer surface.
156
A porous scaffold was also fabricated from this mate-
rial using compression moulding followed by a salt
leaching technique.
Another amphiphilic drug delivery system uses a
PCL-based polymer construct containing hydrophilic
PEEA.45 The possibility of using PCL macromers
of different molecular weights changed the PEEA
properties including crystallinity and the hydrophilic-
ity/hydrophobicity, and this would affect the drug
release rate. In vitro drug release studies using three
different drugs of different natures revealed that PEEA
successfully enhanced the completion of drug release.
An acidic drug was released rapidly after 2 h incuba-
tion, while a drug of a basic nature exhibited longer
controlled release.
Poly(amido amine)
The use of hydrogels as matrices for tissue engineering
applications and the search for versatile, easily fab-
ricated, biodegradable, and biocompatible matrices
continue. One novel hydrogel is made of poly(amido
amine), a polycationic polymer in nature. It con-
tains ter-amino and amido groups regularly arranged
along the polymer chain, obtained by Michael-type
polyaddition of primary or secondary amines to bis-
acrylamides. The method of fabrication made it
possible to have side substituents with biomimick-
ing properties, such as carboxyl, ter-amino, hydroxyl,
allyl, or bioactive molecules like proteins and peptides.
In vitro assays performed by Ferruti et al.46 inves-
tigated cytotoxicity, compatibility, and proliferation
of the materials and the cells in contact with them.
Biological evaluation results exhibited non-toxicity,
comparable cell proliferation (more than 70%) to nor-
mal TCPS plates, and normal cell morphology.
Furthermore, degradation products were non-toxic
and the rate of degradation could be fine tuned
depending on the structure and degree of crosslinking,
which, in turn, affected the degradation via a hydrolysis
mechanism. For example, hybrids of PAA and BSA
(bovine serum albumin) degraded fully up to 8 months
in simulated body fluids.46 It was suspected that this
was because of the protective characteristics of BSA.
Apart from providing a protective layer, BSA made the
hybrid substrate more supportive to cell adhesion and
proliferation. An attempt to make it more bioactive was
achieved by incorporating agmatine, a decarboxylated
product of arginine, derived from RGD sequences.47
Cell adhesion and proliferation assays exhibited up to
80% capacity compared to normal polystyrene culture
plates.
CONCLUSIONS
Biodegradable synthetic polymers, from a material
standpoint, are a key area of interest for the devel-
opment of new scaffold-based tissue engineering
strategies. A critical issue in scaffold-based tissue
engineering is the assembly of cells and extracel-
lular material into a three-dimensional architecture
Polym Int 56:145–157 (2007)
DOI: 10.1002/pi

that allows for both structure and functionality that
mimics the native tissue that is being replaced
and/or repaired. As the scaffolds for tissue engi-
neering will be implanted in the human body, the
scaffold materials should be non-antigenic, non-
carcinogenic, non-toxic, non-teratogenic, and possess
high cell/tissue biocompatibility so that they will
not trigger pathological reactions after implantation.
In addition to materials issues, the macro- and
microstructural properties of the scaffold are also very
important. In general, the scaffolds require individual
external shape and well-defined internal structure with
interconnected porosity to host most cell types. From
a biological point of view the designed matrix should
serve various functions, including (1) as an immobi-
lization site for transplanted cells, (2) formation of a
protective space to prevent unwanted tissue growth
into the wound bed and allow healing with dif-
ferentiated tissue, (3) directing migration or growth
of cells via surface properties of the scaffold, and
(4) directing migration or growth of cells via release of
soluble molecules such as growth factors, hormones,
and/or cytokines. Some technology platforms of FDA-
approved polymeric degradable scaffold systems have
already found promising clinical applications. New
polymers are under development and their applica-
tions need to be a part of the systemic approach
to tissue engineering; namely the need to coordi-
nate interaction between the parameters of scaffolds,
cells, bioreactors, and biomolecular factors as well as
the controlling features of the host response to re-
implanted constructs, including phenomena of angio-
genesis, inflammation, and immune response. Based
on these results, novel therapeutic options in the area
of polymeric scaffold-based tissue replacement can be
expected in the 21st century.
ACKNOWLEDGEMENTS
The work reported in this review was supported in part
by the Biomedical Research Council (BMRC) grants
R-397-000-005-305 (to DWH). The authors thank
Maria Woodruff for editing the manuscript.
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