DOI: 10.1002/adma.200702377
Biodegradable Xylitol-Based Polymers**
By Joost P. Bruggeman, Christopher J. Bettinger, Christiaan L.E. Nijst, Daniel S. Kohane,
and Robert Langer*
Synthetic biodegradable polymers have made a consider-
able impact in various fields of biomedical engineering, such as
drug delivery and tissue engineering. The design of synthetic
biodegradable polymers for bioengineering purposes is
challenging because of the application-specific constraints on
the physical properties, including mechanical compliance and
degradation rates, and the need for biocompatibility and low
cytotoxicity.
[1]
The monomer selection frequently limits the
range of required material properties. Our goal was to design a
class of synthetic biopolymers based on a monomer that
possesses a wide range of properties that are biologically
relevant. This monomer ideally should be: (1) multifunctional
to allow the formation of randomly crosslinked networks
and a wide range of crosslinking densities; (2) nontoxic;
(3) endogenous to the human metabolic system; (4) FDA
approved; and (5) preferably inexpensive. We chose xylitol as
it meets these criteria. We hypothesized that biodegradable
polyesters could be obtained through copolymerization
reactions with polycarboxylic acids; the hydration of such
biodegradable polymers could be controlled by tuning the
different compositions and stoichiometry of the reacting
monomer. Here, we describe xylitol-based polymers that
realize this design. Polycondensation of xylitol with water-
soluble citric acid yielded biodegradable, water-soluble
polymers. Acrylation of this polymer resulted in an elastomeric

tries. Polycondensation of xylitol with citric acid resulted in a
water-soluble prepolymer (designated PXC prepolymer), of
which the M
w
was 298 066 g/mol and the M
n
was 22 305 g/mol
(PDI 13.4), compared to linear poly(ethylene glycol) (PEG)
standards. To crosslink the water-soluble PXC prepolymer in
an aqueous environment, we functionalized the hydroxyl
groups of PXC with vinyl groups (designated PXCma) using
methacrylic anhydride, as previously described for photo-
crosslinkable hyaluronic acid.
[4,5]
During this reaction, the M
w
and M
n
of the polymer did not change appreciably. The
PXCma prepolymer was photopolymerized in a 10% (w/v)
aqueous solution using a photoinitiator. This is referred to as
the PXCma hydrogel. The synthetic route for these polymers is
summarized in Scheme 1.
Fourier-transform infrared (FT–IR) spectroscopy con-
firmed ester bond formation in all polymers (Fig. 1A), with
a stretch at 1740 cm
À1
, which corresponds to ester linkages. A
broad stretch was also observed at approximately 3448 cm
À1

¨
l-Van Vloten Fonds. CJB was funded
by a Charles Stark Draper Laboratory Fellowship. C.L.E.N.
acknowledges the financial support of Shell and KIVI. This work
was funded by NIH grant HL060435 and through a gift from Richard
and Gail Siegal.
Adv. Mater. 2008, 9999, 1–6 ß 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1
COMMUNICATION
xylitol to sebacic acid for PXS 1:1, (1.08:2) xylitol to sebacic
acid for PXS 1:2, and (1.02:1) xylitol to citric acid for PXC. The
degree of substitution of xylitol monomers with a methacrylate
group was found to be 44% for the PXCma prepolymer
(average percentage of xylitol monomers modified with a
methacrylate group).
Ideally, the mechanical properties of an implantable
biodegradable device should match its implantation site to
minimize mechanical irritation to surrounding tissues and
should permit large deformations,
[2]
inherent to the dynamic in
vivo environment. All xylitol-based polymers revealed elastic
properties (Fig. 1B and C). The PXS 1:1 elastomer had an
average Young’s modulus of (0.82 Æ 0.15) MPa with an average
elongation at failure of (205.2 Æ 55.8%) and an ultimate tensile
stress of (0.61 Æ 0.19) MPa. Increasing the crosslink density by
doubling the feed ratio of the sebacic acid monomer resulted in
a stiffer elastomer. The PXS 1:2 elastomer had a Young’s
modulus of (5.33 Æ 0.40) MPa, an average elongation-at-failure
of (33.1 Æ 4.9%) and an ultimate tensile stress of (1.43 Æ 0.15)

by about one order of magnitude (from (10 517.4 Æ 102) g/mol
for PXS 1:1 to (1585.1 Æ 43) g/mol for PXS 1:2, Table 1) and
decreased as more crosslinking entities were introduced. Such
an appreciable difference cannot be obtained by changing the
condensation parameters of PXS 1:1. The increased crosslink
density in PXS 1:2 also resulted in significantly less equilibrium
hydration as determined by mass differential of PXS 1:2 in
ddH
2
O (24 h at 37 8C), when compared to PXS 1:1,
(4.1 Æ 0.3%) and (12.6 Æ 0.4%), respectively; PXS 1:2 also
showed a lower sol content (i.e. the fraction of free, unreacted
macromers within the elastomeric construct, Table 1). The
addition of more sebacic acid molecules to the polymer affects
the water-in-air contact angle (PXS 1:1 (26.58 Æ 3.68), PXS 1:2
(52.78 Æ 5.78), after 5 min), as more aliphatic monomers are
being introduced; this observation is in agreement with the
findings above.
The equilibrium hydration of PXCma hydrogels determined
by mass differential was (23.9 Æ 6.2%) after 24 h at 37 8C.
Volumetric-swelling analysis revealed that the polymer
volume fraction in the relaxed state (v
r
) was (6.9 Æ 0.1%)
and the polymer volume fraction in the swollen state (v
s
) was
(5.8 Æ 0.2%), whereby v
r
was measured immediately after

5
10
15
20
25
30
35
40
100806040200
Strain (%)
Stress (kPa)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
250200150100500
Elongation (%)
Stress (MPa)
720122017202220272032203720
Wavenumber (cm
-1
)
% Transmittance
PXS 1:1 PXS 1:2 PXC PXCma

The mechanical properties of the PXCma hydrogel discs were
similar to those of the previously reported photocured
hyaluronic acid hydrogels (50 kDa, 2–5% (w/v)),
[4]
although
the PXCma hydrogel showed a lower compression modulus for
a similar ultimate-compression stress. The
physical properties of the elastomers and the
hydrogel are summarized in Table 1.
Xylitol-based biopolymers degrade in
vivo. After subcutaneous implantation,
approximately 5% of the mass of the
hydrogel was found to remain after 10 days.
The degradation rate of PXS elastomers
varied according to the stoichiometric ratios.
PXS 1:1 had fully degraded after 7 weeks.
However, (76.7 Æ 3.7%) of the PXS 1:2
elastomer still remained after 28 weeks
(Fig. 1D). This demonstrates that the
in-vivo-degradation kinetics of xylitol-based
elastomers can be tuned in addition to the
crosslink density, surface energy, and equili-
brium hydration. Thus, this polymer platform
describes a range of physical properties that
allow a tuneable in vivo degradation rate.
The PXS 1:2 elastomers were optically
transparent during the first 15 weeks in
vivo and turned opaque upon degradation
(in week 28).
Compared to the prevalently used syn-

confirmed with a (1-(4,5- dimethylthiazol-2-yl)-3,5- diphenylte-
trazolium bromide) (MTT) assay, compared to HFFs with no
PXCma in the growth media (Fig. 2C). Clinical and histologic
assessments showed that none of the animals exhibited an
abnormal post-operative healing process after subcutaneous
implantation. The PXS 1:1 and 1:2 discs were encased in a
Figure 2. (A) Phase-contrast images (10x) of human primary fibroblasts after 5 days of in vitro
culture, seeded on PLGA (i), PXS 1:1 (ii) and PXS 1:2 (iii). Bars represent 250 mm. (B) Growth
rates of fibroblasts on PLGA, PXS 1:1 and PXS 1:2, expressed as cell differential. (C) MTT assay
of fibroblasts exposed to different PXCma prepolymer fractions in their growth medium.
(D) Representative images of H&E-stained sections of subcutaneous implantation sites of
(i) PLGA discs, (ii) PXS 1:1 discs, (iii) PXS 1:2 discs, (iv) 10% (w/v) PXCma hydrogel discs, 1 week
after implantation. (v) Shows the PXS 1:1 implantation site at week 5 ($73% had degraded) and
(vi) shows PXS 1:2 at week 12 (no degradation). The arrow (i) points to a vessel of the fibrous
capsule surrounding the PLGA implant, where some perivascular infiltration is observed.
P ¼ polymer, FC ¼ fibrous capsule, M ¼ muscle. Inserts are 5x overviews, full images are
magnified 25Â. Bars represent 100 mm.
4 www.advmat.de
ß 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2008, 9999, 1–6
COMMUNICATION
translucent tissue capsule after one week, which did not
become more substantial throughout the rest of the study.
Histological sections confirmed that the polymer/tissue inter-
face was characterized by a mild fibrous-capsule formation
(Fig. 2Dii and iii). No abundant inflammation was seen in the
surrounding tissues and the sections showed a quiet polymer/
tissue interface, which was characteristic for the PXS
elastomers after the first week in vivo. Furthermore, no
perivascular infiltration was noted in the surrounding tissues of
the PXS discs. This quiescent tissue response was evident when

an important compound in the food industry, where it has an
established history as a sweetener with proven anticariogenic
activity.
[11]
Moreover, it has an antimicrobial effect on
upper-airway infections caused by Gram-positive strepto-
cocci.
[12–15]
Although xylitol has been studied in polymer
synthesis, others have typically utilized it as an initiator
[16]
or
altered xylitol to yield linear polymers by protecting three
of the five functional groups.
[17]
They were produced in
sub-kilogram quantities without the use of organic solvents or
cytotoxic additives. Xylitol-based polymers are endotoxin-free
and do not impose a potential immunological threat like
biological polymers extracted from tissues or produced by
bacterial fermentation, such as collagen and hyaluronic
acid.
[18,19]
In addition, the mechanical properties of xylitol-
based elastomers correspond to biologically relevant values
that fall close to or are equal to those of various tissues, such as
acellular peripheral nerves,
[20]
small diameter arteries,
[21]

initiator under exposure of $4 mW/cm
2
ultraviolet light (lamp model
100AP, Blak-Ray). All PXS 1:1 and 1:2 elastomers were produced by
further polycondensation (120 8C, 140 mTorr for 4 days). The
prepolymers were sized using gel permeation chromatography using
THF or filtered ddH
2
O as eluentia and Styragel columns (series of
HR-4, HR-3, HR-2, and HR-1, Waters, Milford, MA, USA). FT-IR
analysis was carried out on a Nicolet Magna-IR 550 spectrometer.
1
H-NMR spectroscopy was performed on a Varian Unity-300 NMR
spectrometer;
1
H-NMR spectra of the PXS prepolymers were
determined in C
2
D
6
O and spectra of the PXCma prepolymers were
obtained in D
2
O. The chemical composition of the prepolymers was
determined by calculating the signal integrals of xylitol and compared
to the signal integrals of sebacic acid or citric acid. The signal intensities
showed peaks of (–OC
H
2
(CH(OR))

bone-shaped polymer strips and conducted on an Instron 5542
(according to the American Society for Testing and Materials (ASTM)
standard D412-98a). Compression analysis of the photocrosslinked
PXCma hydrogels was performed as described previously. [5]
Differential scanning calorimetry (DSC) was performed as reported
previously. [24] The mass density was measured using a pycno-
meter (Humboldt, MFG. CO).Thecrosslinkdensity(n)and
M
c
were calculated from the following equations for an ideal
elastomer: [25]
n ¼
E
0
3RT
¼
r
M
c
(1)
where E
0
is the Young’s modulus, R the universal gas constant, T
temperature and r is the mass density. According to Peppas et al., [26]
this rubber-elasticity theory can also be utilized to calculate the
effective M
c
for hydrogels that show elastic behavior and were
prepared in the presence of a solvent:
t ¼