ARTICLE IN PRESS

Biomaterials 26 (2005) 7457–7470

www.elsevier.com/locate/biomaterials

Understanding the biodegradation of polyurethanes: From classical

implants to tissue engineering materials
J.P. Santerrea,b,c,, K. Woodhouseb,c, G. Laroched,e, R.S. Labowf
a
Faculty of Dentistry, University of Toronto, Toronto, Ont., Canada M5G 1G6
b
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ont., Canada M5S 3G9
c
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ont., Canada M5S 3E5
d
Department of Mining, Metallurgical, and Materials Engineering, Université Laval, Qué., Canada G1K 7P4
e
Unité de Biotechnologie et de Bioingénerie, Centre de recherce de l’Hôpital St-Franc- ois d’Assise, CHUQ, 10 rue de l’Espinay, Qué., Canada G1L 3L5
f
University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, Ont., Canada K1Y 4W7
Available online 18 July 2005

Abstract

After almost half a century of use in the health field, polyurethanes (PUs) remain one of the most popular group of biomaterials
applied for medical devices. Their popularity has been sustained as a direct result of their segmented block copolymeric character,
which endows them with a wide range of versatility in terms of tailoring their physical properties, blood and tissue compatibility,
and more recently their biodegradation character. While they became recognized in the 1970s and 1980s as the blood contacting
material of choice in a wide range of cardiovascular devices their application in long-term implants fell under scrutiny with the
failure of pacemaker leads and breast implant coatings containing PUs in the late 1980s. During the next decade PUs became
extensively researched for their relative sensitivity to biodegradation and the desire to further understand the biological mechanisms
for in vivo biodegradation. The advent of molecular biology into mainstream biomedical engineering permitted the probing of
molecular pathways leading to the biodegradation of these materials. Knowledge gained throughout the 1990s has not only yielded
novel PUs that contribute to the enhancement of biostability for in vivo long-term applications, but has also been translated to form
a new class of bioresorbable materials with all the versatility of PUs in terms of physical properties but now with a more integrative
nature in terms of biocompatibility. The current review will briefly survey the literature, which initially identified the problem of PU
degradation in vivo and the subsequent studies that have led to the field’s further understanding of the biological processes
mediating the breakdown. An overview of research emerging on PUs sought for use in combination (drug+polymer) products and
tissue regeneration applications will then be presented.
r 2005 Elsevier Ltd. All rights reserved.

Keywords: Degradation; Biodegradation; Polyurethanes; Oxidation; Hydrolysis; Enzymes; Implants; Polymers; Macrophages; Bioresorbable;
Biostability; Tissue regeneration; Scaffolds

1. Polyurethanes (PUs) and their breakdown
1.1. Chemistry of PUs
The nature of PU chemistry is central to under-
standing why some PUs undergo degradation faster
Corresponding author. Biomaterials Discipline, Faculty of Den-
tistry, University of Toronto, Toronto, Ont., Canada M5G 1G6. Tel.:
+1 416 979 4903x4341; fax: +1 416 979 4936.
E-mail address: paul.santerre@utoronto.ca (J.P. Santerre).
than others. For this reason a brief review of the
material chemistry is needed prior to discussing PU
degradation. Segmented PUs can be represented by
three basic components described by the following
general form:
P
ðDðCDÞn
PÞn ,
where P is the polyol, D is the diisocyanate and C
is the chain extender. Typically, the polyol, or the so-
called soft segment, is an oligomeric macromonomer

0142-9612/$ - see front matter r 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2005.05.079
 ARTICLE IN PRESS
7458 J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470

Nomenclature PCN 1,6-hexyl 1,2-ethyl carbonate diol

PEO polyethylene oxide
BD butanediol PEU polyether-PU
CE cholesterol esterase PHB a,o dihydroxy-oligo[(R)-3-hydroxybutyrate-
CXE carboxyl esterase co-(R)-3-hydrocyalerate)-ethyleneglycol]
EB environmental biodegradation PHSPN prolyl-histidyl-seryl-prolyl-asparagine
ED ethylene diamine PMA phorbol myristate acetate
ESC environmental stress cracking PMN neutrophil
FBGC foreign body giant cell PRRARV prolyl-argininyl-argininyl-alanyl-argini-
HDI hexane diisocyanate nyl-valine
HDI431HDI:PCN:BD (4:3:1) PS polystyrene
HMDI hydrogenated MDI PTMO polytetramethylene oxide
IL-1 interleukin-1 PU polyurethane
LDI lysine diisocyanate RGD argininyl-glycyl-aspartate
MDA methylene diamine ROS reactive oxygen species
MDI 4,40 -methylene-bis-phenyl diisocyanate SEM scanning electron microscopy
MDI321 MDI:PCN:BD (3:2:1) TDA toluene diamine
MDM monocyte-derived macrophage TDI toluene diisocyanate
MIO metal ion oxidation WVP water vapour permeance
MSE monocyte specific esterase XPS X-ray photoelectron spectroscopy
PCL polycaprolactone

comprising a chain having a low glass transition
temperature (i.e.o25 1C) and terminated by hydroxyl
(–OH) groups. The chain extender is usually a small
molecule with either hydroxyl or amine end groups. The
diisocyanate is a low molecular weight compound that
can react with either the polyol or chain extender. The
combination of the chain extender and the diisocyanate
components is referred to as the hard segment of the
polymer.
Conventional polyols are usually polyethers (with a
repeating structure of –R–O–R0 –) or polyesters (with
repeating structure of –R–CO–O–R0 –), with chain ends
terminated by hydroxyl groups.
1.2. Bulk degradation of PUs in biomedical devices
While traditionally PUs have been widely used for
their excellent mechanical properties and moderately
good blood compatibility, they have also been singled
out as being problematic in terms of their long-term in
vivo biostability in tissues. This susceptibility to
biodegradation is in part an inherent feature of their
chemistry and was appreciated by the industrial
manufacturing community well before the detailed
studies of in vivo biodegradation began in the late
1980s. PUs were shown in several instances to be
sensitive to degradation in day-to-day applications. In
these instances, degradation was mainly initiated during
the fabrication process due to elevated temperatures and
the presence of liquids, and because of the difficulty to
completely expel moisture from the reaction mixture [1].
Once PUs were implanted, several sources were found
to contribute to their degradation. For example, the
aliphatic ester linkages in polyester–urethanes are
known to be susceptible to hydrolytic degradation [2].
Polyether–urethane (PEU) materials are known to be
susceptible to a degradative phenomenon involving
crack formation and propagation [3]. This is usually
found in areas of devices where the stress level on the
polymer is high. However, the fissures may also appear
even if no additional stress has been placed on the
polymer. This micro-fissure phenomenon, known as
environmental stress cracking (ESC) is believed to be a
result of residual polymer surface stress, which may have
been introduced during fabrication of the device and not
sufficiently reduced by annealing. In some biomedical
devices, oxidative degradation can be a contributing
mechanism. Implanted PEU devices that contain
metallic components have been subject to bulk oxida-
tion catalyzed by corrosion products of the metallic
components [4–7].
The presence of enzymes in the physiological envir-
onment is another factor contributing to PU degrada-
tion. Even though the enzymes are designed for highly
specific interactions with particular biological sub-
strates, some appear capable of recognizing and acting
upon ‘‘unnatural’’ substrates such as PU polymers.
Smith et al. [8] found that enzymes are capable of
altering polymer structure. A mechanistic model for the
attack by hydrolytic enzymes on PUs has been proposed
by Santerre et al. [9].
Calcification (i.e., the deposition of calcium-contain-
ing apatite mineral) occurs with a wide spectrum of
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J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470
cardiovascular and non-cardiovascular medical devices.
In fact, calcification is the leading macroscopic cause of
failure for most bioprosthetic heart valves, and it limits
the functional lifetime of experimental mechanical blood
pumps and polymeric heart valves, including those made
with PU parts [10].
It should be pointed out here that all of the in vivo
degradation phenomena aforementioned are closely
related to the surface organization of PUs. In PU-based
materials, a microphase segregation process leads to the
formation of a two-microphase structure with regions
enriched in either hard or soft segments [11]. Because of
the mobility of the soft segments, the surface composi-
tion of segmented PUs varies in order to find the
composition (or the hard/soft segments ratio) that will
minimize the interfacial free energy. In brief, PUs will
have a higher proportion of polar hard segments at the
interface when the environment is polar (e.g. water or
blood) and more non-polar soft segments at the surface
when the environment is non-polar (e.g. air or vacuum).
This particular behaviour of PUs has significant
importance as the host response is largely determined
by the surface composition of the material.
1.3. Biostability of implanted medical devices
The above degradation mechanisms have led several
research groups to question how safe PU-made biome-
dical devices are; some of them are particularly of
interest [4–7,12]. Mackay et al. [13] reported that early
PU valves had not performed well in durability tests.
They reported that both calcium and phosphorus were
present in the adherent calcified plaque-like material on
the leaflet surfaces. Vascular prostheses made of PUs
were also the subject of analyses in order to identify the
causes of their degradation [14].
Perhaps, the most often reported case of in vivo PU
degradation is that associated with the PU-covered
silicone breast implants [15,16]. Investigators found that
following explantation of the devices that the PU foam
was missing; with only the basal layer of the foam still
being visible by scanning electron microscopy (SEM)
[17]. This was the clearest evidence that a biodegrada-
tion process was occurring which resulted in substantial
amounts of material being removed.
2. Environmental biodegradation (EB) and its molecular
reactions on PU structure
2.1. Molecular reactions between biological agents and
PUs
Early observations relating to the biodegradation of
PUs raised much controversy around the pathways
leading to the process. This resulted in good part from
7459
the lack of understanding associated with the molecular
mechanisms contributing to the cleavage of the polymer
chains. It was the work of Ken Stokes, which initially
provided the most comprehensive theory of in vivo
biodegradation in his description of ESC [2,4–7]. This
explanation of the biodegradation process was adopted
after trying to explain end-point cracking observed on
the surface of implanted PUs. The implicated elements
which were suggested to be involved in the mechanism
of ESC included surface oxidation (mediated by
neutrophil (PMN) and monocyte-derived macrophages
(MDM) derived oxidants), residual stress, polyether
soft-segment chemistry, molecular morphology, the
presence of MDM and foreign body giant cells (FBGC),
as well as an unknown biological element [2]. No single
group has embraced a detailed understanding of all
these elements in their studies to date and the element
that has remained the most elusive is the last one, the
‘‘unknown biological element’’.
One limiting aspect of ESC is that it was defined
specifically for the oxidative cracking of PEUs under
strain. A more encompassing definition of the biode-
gradation process that would include ESC as a special
case, may be better described by the term ‘‘environ-
mental biodegradation’’ since it has now been demon-
strated that the MDM-mediated degradation process is
initiated well before cracking is observed [18]. The term
‘‘environmental’’ rightly captures the fact that there is a
unique environment implicated in EB with multiple
parameters (stress, biochemicals, molecular and phase
structure of the polymer, metallic ions, salts, inorganic
and organic acids and cells) working together towards
the degradation of a polymer in a biological medium. It
is unlikely that oxidation is the only dominant chemical
reaction at work in the breakdown of PUs in vivo since
hydrolytic processes catalyzed by enzymes are now
clearly implicated [18]. What is common to both the
oxidation and hydrolytic enzyme processes is the fact
that their most active agents are derived from the same
biological source (activated white blood cells and more
specifically the MDMs and the FBGC) [19].
Anderson’s group initiated the use of cells (specifically
white blood cells) for studying the breakdown process in
vivo [20]. This would mark a significant turning point in
regards to our appreciation for the biological processes
at work in EB. Their group would rapidly invoke several
biological mechanisms that could contribute to the
cleavage of PU chains by oxidants and enzymes [21].
Anderson’s work subsequently focused on the oxidative
mechanism in attempts to validate the Stokes theory of
ESC, which invoked oxidation as a dominant factor in
PEU degradation. They were able to show using both in
vitro oxidative reactions with CoCl2/H2O2 combinations
and their in vivo cage implant model that biological co-
factors such as a-macroglobulin derived from plasma
could further promote stress cracking in PEUs [22].
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7460 J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470
Unlike the oxidative studies described above which
were intensely focussed on the EB mechanism for PEUs,
investigations looking at PU chain cleavage via the
hydrolytic pathway and specifically related to the
enzyme mediated mechanism evolved from work on
polyester–urethanes which had been used in the Meme
breast implant prosthesis [23]. A number of reports
described the generation of aromatic diamines, such as
toluene diamine (TDA) [24] and 4,40 methylene diamine
(MDA) [25]. The biological relevance of these diamines
was particularly important because of their putative
carcinogenic effect [26,27]. Many of the earlier studies
were unable to effectively differentiate between what
was actually produced via biodegradation and what may
have been residue from the process manufacturing steps,
and therefore controversy and debate surrounded the
relevance of the data. Furthermore, early studies
investigating the hydrolysis mechanisms were carried
out with relatively non-physiological enzymes such as
papain [24] and harsh hydrolysis conditions such as 3 N
NaOH at 150 1C which were not believed to appro-
priately reflect the in vivo systems [28]. The focus was
entirely on the release of the diamines rather than
gaining a broader understanding of polymer chain
cleavage in relevant biological systems.
Santerre and Labow [29] were the first group to begin
comprehensive studies of PU cleavage using enzymes
known to be associated with MDM activity. Using a
polyester–urethane synthesized with toluene diisocya-
nate (TDI) it was demonstrated that enzymes such as
cholesterol esterase (CE) preferably degraded ester
linkages immediately adjacent to the hard segment
rather than catalyzing the hydrolysis of the urethane in
the hard segment to generate TDA. The group went on
to identify nine oligomeric products from the polymer
and completely reconstruct the polymer’s breakdown by
enzyme [30].
2.2. Contribution of hard-segment structure in
biodegradation
Further work began to examine the molecular
relationship between material chemistry and cell action
on the PUs [31] with particular interest in cellular
enzymes with esterase activity [32]. Using radiolabelled
diisocyanates it was possible to specifically assess the
release of TDA from a polyether–urea–urethane when
exposed to CE [33]. In the absence of esters it was found
that CE would hydrolyze the urethane to release hard
segment components. The group explored the relation-
ship between PEU hard segment size and hydrolysis by
CE. It was originally anticipated that as the 14C-
labelled diisocyanate content in the material increased
(i.e. hard segment content increased) there would be an
increase in the amount of released TDA from the
polymer. While biodegradation studies showed a strong
dependence on hard segment domain formation, the
data indicated that the polymers containing the highest
amount of labelled hard segments exhibited the least
amount of chain cleavage by the enzyme and subsequent
TDA generation. It was concluded that the ability of the
PU material to form stable H-bonded hard segment
micro-domains and other H-bonding along the chains
contributed to the formation of a protective structure
for the enzyme hydrolysable hard segment linkages
located within the hard segments of the PEU. These
findings were particularly important since they corre-
lated well with in vivo findings from several investiga-
tors [5,34–36] that have identified a consistent
association between the elevated hardness of high
hard-segment-content Pellethaness (i.e., durometers
of 55D and 75D) and good in vivo biostability.
2.3. Influence of strain on molecular interactions of
polymers and biological agents
Given the knowledge that hard-segment density may
influence biodegradation, then it may be concluded that
any process (applied stress, thermocycling, annealing,
etc.) that would perturb this structure should also affect
the biostability of the PU [37]. The stress–strain
character of PUs is highly dependent on the nature of
the PU hard segment [38] and their association with
micro-domains has been well established for many years
[39,40]. This behaviour depends on the size and
concentration of the hard-segment domains, the
strength of the hard-segment aggregation (intra-domain
cohesion), the ability of the segment to orient in the
direction of stretch, and the ability of the soft segment to
crystallize under strain [41]. It has now been confirmed
by Tang et al. [42] that the biodegradation of
polycarbonate PUs by MDM associated esterase activ-
ity is highly dependent of hard-segment chemistry and
hard-segment size [43]. The PU surfaces were highly
correlated to the H-bonded state of the PU. The rank of
the different chemical groups’ susceptibility to hydro-
lysis was as follows: non-hydrogen bonded carbona-
te4non-hydrogen bonded urethane4hydrogen bonded
carbonate4hydrogen bonded urethane. The findings
suggest that the degree of hydrogen bonding, when
processed into a PU material could be an important
parameter to consider in the design of new biostable PU
products [42], and in fact validates the excellent
biostability of 4,40 -methylene-bis-phenyl diisocyanate
(MDI) based polycarbonate PUs such as those reported
for Corethanes type materials [34].
Anderson [44–49] and Stokes [2] have applied strain
into PU systems in order to observe its effect on the end
point of EB (i.e. the bulk changes in physical character,
measured as changes in tensile properties, fatigue life
and resistance to tear). These studies have been carried
out with an interest in recording strain’s influence on
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J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470 7461

gross material oxidation [2,44], MDM-induced degrada- Stress induced

Strain
tion [49] and enzyme catalyzed degradation [48]. Pre-
incubation of PEUs with a non-physiological enzyme
Inflammation of the
(papain), significantly decreased the mechanical stability Environmental Biological Activities Tissues
Degradation
of the materials, and specifically decreased their tensile of the Material
strength and fatigue lifetime [48]. While these studies
were extremely valuable in terms of identifying clinical Material Morphology
outcomes they did not provide direct information on the and Chemistry MDM
molecular mechanisms at work within the material.
-Defines an indirect pathway
Molecular techniques such as those described by Wang via the material
-MDM: monocyte derived macrophage
et al. [50] are very sensitive and can identify degradation
processes well before classical microscopy techniques Structural Changes
Degradation Products
can detect them [29,30]. These methods have been used
to complement both X-ray photoelectron spectroscopy Fig. 1. Model for environmental biodegradation of polyurethanes.
(XPS) [30] and atomic force microscopy surface analysis
[51,52] techniques in order to explain the mechanism of
EB in both TDI [30] and MDI [52] based PUs. 3000

counts per minute/mL

2.4. Environmental biodegradation
Based on the current literature, an aspect of EB that
still requires further investigation is the molecular
relationship between material and cell function, via
intermediary forces such as stress. Exactly what
molecular component(s) of the stress loaded material
does the cell recognize in order to induce and perturb
polymer biodegradation is still unknown. There is
mounting evidence to suggest that the ‘‘unknown
biological element’’ in the process of EB (which includes
ESC) involves a specific combination of material surface
chemical/physical structure and the differentiating state
of the monocyte [53,54]. As discussed earlier the latter
induces hydrolysis of the material very early on and the
nature of the degradation products themselves may
subsequently feedback into the cell activation loop [54].
From data acquired at this point, EB can be modelled
according to Fig. 1 where the central interaction
between material and cells (specifically MDMs) are
described as a cyclic process which influences two
critical end points that continue to be of significant
interest to the delivery of medical device technology in
health care, i.e. (1) degradation of biomaterials and (2)
chronic inflammation. The model shows strain as an
external perturbation (although the perturbation could
be metal ions or other external factors) that acts directly
on the material influencing morphology and chemical
interactions between the polymer chains, and indirectly
transmitting forces to MDMs (as well as other adherent
cells). Recent studies have reported on the ability of
induced strain, from applied stress, to influence the
generation of biodegradation products by MDMs
(Fig. 2) and promote the breakdown of the polymer
by enzymes (Fig. 3) [55]. The transmission of forces to
the cells will influence their function [56,57], which in
turn is expected to alter the inflammatory process, and
feedback into the material. While Section 1 of this
2500
2000
1500
1000
500
0
0% 10% 50%
strain
Fig. 2. Demonstration of the dynamic interaction of strain on
molecular structure and macrophage-mediated degradation of a
polycarbonate urethane (HDI-PCN-BD) synthesized from 14C-
hexamethylene diisocyanate, polycarbonate diol and butanediol in a
431 stoichiometric ratio of the respective reagents. Radiolabel release
from a 14C-labelled polycarbonate PU (counts/min/mL culture
solution) after 48 h incubation with macrophages (U937 cell line),
pH 7.0 and 37 1C. Under a 0.6 MPa load the polymer exhibits a 10%
strain. This condition yields a slightly lower amount of degradation (as
measured by the release of radiolabelled segments from the polymer)
when compared to the no strain sample. When the strain is increased to
50% under a load of 1 MPa, the degradation is significantly reduced
(po0:05). In this system the hydrolysis of the carbonate groups is
reduced when the PU is under strain because the soft-segment chains
line-up and crystallize, therefore reducing their vulnerability to
interaction with water and enzyme.
review has documented the end point of EB, the current
section has attempted to provide readers with an
appreciation of the processes as work when biological
activities act on these materials and convey how this
may be perturbed when external forces act on the
structure of the material. Section 3 will cover in greater
detail the influence of the PUs on MDM biodegradation
function, which forms the right side of the feedback loop
shown in Fig. 1.
2.5. Considerations for the design of new PUs
The findings describing the molecular breakdown of
PUs to date have been of significant importance in the
design of PUs for devices in general, both from the
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7462 J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470
Fig. 3. SEM for a polycarbonate-based PU degraded by cholesterol esterase (160 units/ml, previously defined [42]), incubated for 4 weeks: (a) prior
to incubation, (b) incubated with enzyme/0% strain, (c) incubated with enzyme/50% strain.
aspect of controlling physical function in the device, and
regulating the effect of polymer derived by-products
from the biodegradation process onto local cells and
particularly on cells related to the wound healing
pathway. For instance, the work surrounding the
oxidation models reported on by Anderson [19–22]
and Stokes [2,4–7] were instrumental in guiding the
development of MDI polycarbonate urethanes by
Pinchuck and others [34,56]. Recent work by Tang et
al. [43,51,52] has described the unique protective action
of MDI in these materials with respect to their
hydrolysis. Likewise, the reduction of polyether seg-
ments from the soft-segment component of PUs has
been motivated by a desire to eliminate the materials’
vulnerability to oxidation. Strategies have included the
introduction of larger hydrocarbon segments between
ether groups [57,58] and the incorporation of silicone
segments [59–61]. Work by Ward incorporated surface
modifying end groups onto the terminal ends of polymer
chains to alter their biostability [62–64].
While the above materials have focused on changes to
the bulk PUs themselves, there have been a number of
studies that have introduced the use of ampiphilic
copolymer additives to modify the surface chemistry of
polymers while yielding no change to the chemistry of
the bulk polymer. Earlier work by Ward [65] introduced
a silicone containing oligomeric surface modifying
additive, which masked the oxidation sensitive surface
of PUs. Santerre and co-workers developed a family of
fluorinated surface modifying macromolecules, which
could reduce the extent of PU hydrolysis [66,67]. More
recently, these oligomeric polymers were used to deliver
anti-oxidants to the surface of polymers in order to
minimize hydrolysis and pro-actively reduce oxidation
[68]. As more has become known about the process of
EB, investigators have also begun to explore strategies
to have PUs undergo controlled degradation for the
delivery of drugs and other applications [69]. More
details on these applications will be described in Section
4 of this review.
3. Action of PUs on inflammatory cells: effect on EB
3.1. PU degradation and inflammatory cells
As highlighted in the previous section in the descrip-
tion of EB, it is the white blood cell and more
specifically the MDM that has emerged as the pre-
dominant cell type that is orchestrating the damage in
biodegradation processes [44]. But it must be clearly
stated that the macrophage takes its cue from the
presence of the material and its unique chemistry. Work
by Marchant and colleagues quantitatively determined
the cellular composition of the inflammatory exudates
surrounding the implanted material. The temporal
variation in the acute inflammatory response, chronic
inflammatory response, granulation tissue development
and foreign body reaction to the implanted biomaterial
was determined [19]. The foreign body reaction to a
material in contact with tissue and/or blood cells
proceeds according to the following time course. PMN
appear within minutes along with monocytes, which
then over the course of days differentiate into MDM
while adherent to the material. Eventually, the blood
cells remaining adherent consist mainly of MDM and
FBGC, which may persist at the tissue–implant interface
for the lifetime of the implant [70].
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J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470
Understanding how cells interact with PUs, which
may result in degradation whether it is desired or not, is
essential. The general process of EB, as exemplified by
ESC, described many years ago [4] is still not fully
elucidated. EB certainly involves the release of oxidative
and hydrolytic activities from the surrounding tissues,
especially MDM and FBGC [49,69]. In one case ESC
was simulated in an in vitro accelerated biological model
of oxidation using MDM and FeCl2. It was possible to
inhibit the action of MDM on surface cracking with a
surface of dexamethasone (an anti-inflammatory agent)
modified PU [71]. Differences have been observed in the
damage caused by oxidation, with polycarbonate PUs
being less susceptible to oxidation than PEUs [2,72].
Initially, it is PMN that are the primary source of
reactive oxygen species (ROS), with HOCl, one of the
most oxidative compounds, being released in different
amounts depending on the PU surface to which the
PMN have adhered [73]. Because of their oxidative
potential, PMN have been implicated in PU degradation
as well [73], even though they do not remain at the site
of implantation when the foreign body reaction becomes
chronic. Adherent PMN were activated differently by a
variety of material surfaces [74,75], showing dissim-
ilarity in the release of superoxide anion [76], mac-1
expression [77], and elastase [31]. When superoxide
dismutase modified PUs were implanted into rats,
PMN-rich acute inflammatory infiltrates were reduced
as well as the number of FBGC. However, in another
study, it was found that when PU, polyester-, polyether-
or polycarbonate-based PU were treated with HOCl,
significant inhibition of the subsequent hydrolysis by CE
was observed [78,79]. Phorbol myristate acetate (PMA),
which stimulates the release of HOCl from PMN
by the activation of protein kinase C, also inhibited
radiolabel release elicited by PMN from PUs. Hence, the
interactive play between oxidative and hydrolytic
enzyme processes is emerging as a critical area of PU
biodegradation research that is still lacking in under-
standing.
As a side note, there are external forces and/or
pathological processes that can influence the role of
reactive ROS at implant sites and this may perturb the
biodegradation pathway as well as the biocompatibility
of the material in the application. In the presence of
other factors such as exposure to infectious agents and
shear stress [80], PMN responses such as the release of
ROS were compromised in a distinct manner, which was
related to the material surface, a phenomenon known as
foreign body associated infection. This often leads to
infections and biofilm formation, which is notoriously
resistant to antibiotics and usually result in the device
having to be removed [81]. In a study by Nakaoka et al.
[82], MDM surrounding PU implants released ROS that
caused tumour formation, which was dependent on the
PU surface characteristics.
7463
3.2. Implication of MDM-derived hydrolytic enzymes
Although PMN provide HOCl and other ROS
initially, it is unclear what their contribution is to the
ultimate degradation of PU that leads to device failure.
When assessing the destructive potential of PMN and
MDM towards a radiolabelled polyester-PU, 25 times
more radiolabel release was elicited by MDM than
PMN for equivalent numbers of cells [18]. An important
potential mechanism of MDM mediated degradation
towards PU was attributed to the hydrolytic activity in
MDM, which appears to be predominantly due to two
esterases, CE [83] and monocyte-specific esterase (MSE)
that has similar specificity to carboxyl esterase (CXE)
[84]. Thus far, CE and CXE have caused the most
degradation of the PUs tested [85,86], although some
degradation can be measured (10 times lower levels than
measured with CE) by the esterolytic activity of serine
proteases (similar to those found in PMN) [32].
Therefore, in order to study the foreign body reaction
to PU, which may lead to degradation, many studies
have utilized in vitro MDM cell systems rather than
PMN [18,53,79,82,87–89]. When human monocytes,
isolated from whole blood, were cultured on tissue
culture grade polystyrene (PS), a polyester-PU or a
PEU, significant differences in the amount of esterase
activity was measured in the cell lysates after 28 days. In
this study, no assessment of biodegradation was made
[87]. When mature MDM (14 days old) were gently
trypsinized [18] and then re-seeded onto radiolabelled-
PUs, significant degradation was measured by radiola-
bel release. SEM showed extensive physical damage of a
polycarbonate PU [79] (Fig. 4). In addition to the
physical damage and the radiolabel release, esterase
activity increased over the course of the 28 days that the
MDM were cultured. Although esterase expression
varies in a number of pathological states [84], its role
in the foreign body reaction has not been established. To
date, in vivo biodegradation has not been directly linked
to esterases even though many in vitro cell studies
strongly suggest that they contribute to the hydrolytic
breakdown of PUs [18,79].
3.3. Effect of PU chemistry on hydrolytic enzyme
synthesis and release
The differences in PU chemistry appear to stimulate
the synthesis and release of the enzymatic activities
from MDM that cause their degradation [87]. In a study
using polycarbonate based PUs which were synthesized
with hexane diisocyanate (HDI), poly(1,6-hexyl 1,2-
ethyl carbonate) diol (PCN) and butanediol (BD)
in the ratio 4:3:1 (HDI431) and a PU synthesized
with MDI:PCN:BD in the ratio 3:2:1 (MDI321),
both CE and MSE were synthesized de novo from
MDM adherent to the most degradable PU, HDI431,
 ARTICLE IN PRESS
7464 J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470

Fig. 4. SEM photomicrograph of MDM on a polycarbonate PU.

Monocytes, isolated from whole blood were differentiated for 14 days
on polystyrene. They were removed by gentle trypsinization and re-
seeded onto HDI431 and cultured for 21 days (  1500). Previously
published in [79]. Permission from publisher requested.

when 35S-methionine was incorporated into the cellular

protein. When immunoblotting analysis was carried out
on the conditioned media of MDM adherent to HDI431
and MDI321 with antibodies to CE and MSE,
significantly more MSE was released from the MDM
on HDI431. Moreover, there were significantly more
multinucleated cells on HDI431 than MDI321 (Fig. 5)
[87]. Multinucleation of MDM has been related to the
degree of cellular activation leading to the secretion of
degradative enzymes [90].
In addition to the material surface chemistry, the Fig. 5. FBGC formation is modulated by material surface. Repre-
different topography of the surfaces on PUs may also sentative phase contrast photomicrographs demonstrating the extent
contribute to their degradability as well as how they of cellular multi-nucleation on different surfaces. Monocytes from
activate MDM [51]. The generation of the proinflam- three different donors were cultured on polystyrene for 14 days,
trypsinized and re-seeded on to (A). polystyrene, (B) HDI431, or (C)
matory cytokine, interleukin (IL)-1, from MDM cul- MDI321 for 48 h before fixation. Phase contrast images were
tured on a PU membrane, which was smooth and photographed and overlayed with a DAPI image. Arrows point to
hydrophobic was greater than from MDM on porous individual nuclei within one cell. Bar, 20 mm. Previously published in
and hydrophilic membranes [91]. However, in a recent [87]. Permission from publisher requested.
study by Christenson et al. [72], there was no difference
in adhesion of monocytes to polycarbonate PUs and
PEUs even though there were differences in phase Another important factor in considering MDM-
separation and mechanical properties of the two types of mediated degradation, is protein adsorption to the PU
soft-segment-PUs tested. Hence, the multi-factorial surface. Plasma proteins adsorb in a specific manner,
aspect of the biological response to these copolymer which in contact with biomaterials may influence the
systems renders the challenge towards understanding subsequent attachment of MDM [9,67]. In a study by
and controlling these pathways a complicated task. Kao [88], fibronectin was employed as a model in the
 ARTICLE IN PRESS
J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470
formulation of synthetic oligopeptide mimetics. The
grafted tripeptide RGD sequence supported higher
adherent MDM density than surfaces grafted with other
peptides such as PHSRN and PRRARV. Therefore, as
pro-biological hybrids of PUs begin to emerge for tissue
regeneration processes and improvements to the materi-
al’s biocompatibility, scientists will have to weigh their
impact on MDM activity in terms of biodegradation
rates as well as wound healing.
4. Design of biodegradable PUs for the in vivo
environment
While traditionally investigators have used PUs as
long-term implant materials [92] and have attempted to
shield them from the biodegradation processes that were
described in the previous sections of this review, more
recent work by investigators has utilized the flexible
chemistry and diverse mechanical properties of PU
materials to design degradable polymers for applications
as varied as neural conduits [93] to bone replacements
[94]. These materials have for the most part taken
advantage of hydrolytic mechanisms and have varied
molecular structure to control rates of hydrolysis.
The move to degradable PU based materials has
required a change in the diisocyanates historically used
for their synthesis. Typically, an aromatic diisocyanate
was employed for applications where degradation was
not desired, such as pacemaker lead coverings, catheters,
and wound dressings [92]. In part because of the
putative carcinogenic nature of aromatic diisocyanates
[26,27], degradable PUs are more frequently made from
diisocyanates such as lysine-diisocyanate (LDI, 2,6
diisocyanato methyl caproate) [95–97], hexamethylene
diisocyanate [98,99], and 1,4 diisocyanatobutane [100]
whose ultimate degradation products are more likely to
be non-toxic, i.e. lysine.
The soft segment is typically the block of the PU used
to modify the degradation rate and biodegradable PUs
have been made with a variety of soft segments
including polylactide or polyglycolic acid [101–103],
polycaprolactone (PCL) [93,94,96,98–100,104], and
polyethylene oxide (PEO) [96,98,104].
4.1. Polyethylene oxide and PCL containing
biodegradable PUs
Polyethylene oxide and PCL impart different physical
and mechanical properties to the PUs that contain them.
PEO is used to enhance degradation and PCL to provide
greater hydrolytic stability and elastomeric mechanical
properties. PCL usually imparts enhanced crystallinity
to the PU while PEO increases hydrophilicity and water
uptake. Woodhouse et al. [95,105,106] synthesized a
family of PUs using LDI and a novel amino acid ester
7465
chain extender in the hard segment, combined with
either PCL and/or PEO of varying molecular weights as
the soft segment. The PEO-based PUs were weak, tacky,
amorphous materials. Those containing the PCL were
relatively strong and elastomeric with increased tensile
strength, modulus and ultimate strain with increasing
PCL molecular weight [96,105]. The PEO containing
PUs adsorbed large amounts of water while the PCL
containing materials absorbed minimal water. The water
vapour permeance (WVP) generally followed the water
adsorption trends. Soft-segment crystallinity in the PCL
containing PUs served to reduce WVP values with
increasing PCL molecular weight. Consistent with the
water uptake data, in vitro degradation of this family of
PUs as measured by mass loss, change in molecular
weight and surface alteration showed significant differ-
ences in the degradation rates associated with the soft-
segment component of these polymers [106]. The PEO
containing PUs exhibited substantial mass loss within 56
days in buffer with the formation of a porous material
with little strength; conversely the PCL containing
polymers had modest mass loss and surface alteration
and retained their strength. In later work, PEO and PCL
PUs were blended by simple mixing to form three-
dimensional sponges using solvent cast/particulate
leaching methods [107]. The degradation of these PU
blends was characterized by a rapid initial mass loss
believed to be associated with loss of the PEO contain-
ing PU followed by the slower degradation typical of the
100% PCL polymer. All blends were semi-crystalline in
nature and the mechanical properties were dominated
by the PCL PU.
Several investigators have combined PEO and PCL
within the same polymer structure to take advantage of
the relative influence of the two soft segments on the
mechanical integrity of the materials and the degrada-
tion rates. Cohn et al. [98] synthesized a series of
biodegradable poly(ether ester) urethanes utilizing
PCL–PEO–PCL triblock copolymers and hexamethy-
lene diisocyanate. Consistent with the results of Skarja
et al. [106], they showed that an increase in PEO or a
decrease in the PCL block length increased the
degradation rate and decreased the soft-segment crystal-
linity.
Expanding on the use of the triblock soft segment,
Wagner et al. [100,107,108] have synthesized and
characterized a family of unique poly(ester-urethane)
urea tri-block co-polymers using PCL, polyethylene
glycol and 1,4 diisocyanatobutane with either lysine
ethyl ester or putrescine, as the chain extender.
These materials have shown breaking strains from
325% to 560% and tensile strengths from 8.0 to
20 MPa. As in other work, the PCL block length
increased the initial modulus and tensile strength due
to an increase in crystallinity and longer PEO blocks
increased the degradation relative to shorter PEO
 ARTICLE IN PRESS
7466 J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470
blocks. Degradation of the materials in the presence of
cells did not appear to produce cytotoxic compounds. In
recent work, Stankus et al. [109] co-spun the PCL/1,4
diisocyanatobutane/putrescine polymers with type 1
acid soluble bovine collagen into films of varying fibre
diameters. The tensile strengths of these materials varied
from 2 to 13 MPa Incorporation of the collagen
generally decreased the tensile strength as well as the
initial and 100% moduli, and increased smooth muscle
cell adhesion [109].
Saad et al. [94,95,110] combined both a block tri-
polymer of PCL:PEO:PCL soft segment with a crystal-
izable soft segment, a,o dihyroxy-oligo[((R)-3-hydro-
xybutyrate-co-(R)-3-hydrocyalerate)-ethylene glycol]
(PHB). This family of materials (DegraPols) was
synthesized with either LDI or trimethyl-hexamethylene
diisocyanate along with the above soft segments or a
copolyester of adipic acid and ethylene glycol, diethy-
lene glycol, and BD (Diorezs). The mechanical proper-
ties of these materials are dominated by the crystalline
phase. These materials have been extensively character-
ized for their use as bone substitutes [94,95,110]. The
DegraPol is elastic and forms highly porous foams from
100 to 400 mm. Osteoblasts cultured on these foams
proliferate, phagocytose degradation products, retain
their phenotype and induce bone formation in a rat
model [95,110].
Gogolewski et al. [103,111] also combined two
different soft segments within one polymer, incorporat-
ing Pluronic F-68(poly(ethylene-propylene-ethylene
oxide) and PCL within the same soft segment. They
used BD or 2-amino-l-butanol as the chain extender and
hexamethylene diisocyanate as the hard segment. They
observed similar effects to those reported above for PEO
on the degradation rate and water uptake of the
polymers. Interestingly, they found that all the materials
calcified and calcification increased with material
hydrophilicity, an observation noted of PEUs in the
study of EB [10]. The structure and composition of the
calcium crystals formed on the materials depended on
the PU chemistry. Given the desire not to have
calcification occurring in many cardiovascular applica-
tions [10], chemical formulation will be a restrictive
factor for these biodegradable PUs.
4.2. Use of other soft segments in biodegradable PUs
Agarwal et al. [97,112,113] used glycerol and/or
sucrose in combination with PEO, LDI and water to
produce a group of biodegradable PU foams. They first
reported the development of an LDI-glycerol containing
polymer formed by utilizing the reaction of water with
the diisocyanate to crosslink and form a networked
foam. The interconnected pores varied in size from
10 mm to 2 mm in diameter. The degradation of the PU
was linear at 37 1C and showed evidence of both lysine
and glycerol as degradation products. Rabbit bone
marrow stromal cells cultured on the materials for up to
30 days formed multilayers of confluent cells and were
phenotypically similar to those grown on tissue culture
PS [97].
In a variation on the above design, Argarwal et al.
[112] used pentane diisocyanate and sucrose with water.
This scaffold differed from the glycerol containing
material because it had a microtexture with both large
and small pores within the same foam. It supported the
adherence and proliferation of both bone-marrow
stromal cells and chondrocytes in vitro. In subdermal
implants the investigators found that the material
showed infiltration of both vascular cells and connective
tissue. Zhang et al. [113,114] produced an LDI-glucose
PU and an LDI-ascorbic acid, glycerol and polyethylene
glycol material. Both PUs showed good mechanical
properties and biocompatibility.
4.3. Biodegradable hard segments
Materials reported on by Woodhouse et al.
[96,105,107,115] have been unique in that they specifi-
cally designed enzyme sensitive linkages into the hard
segment of the PU. This was an alternative strategy to
the non-specific hydrolysis degradation that has been
more commonly employed. In vitro degradation studies
of PUs containing a phenylalanine diester chain
extender, LDI and either PEO or PCL showed that
upon exposure to chymotrypsin and trypsin, the
polymer had an increased susceptibility to enzyme-
mediated but not buffer-mediated erosion when com-
pared to the control PU [106]. These PUs released three
hard-segment products upon degradation by chymo-
trypsin and showed enzymatic cleavage of urea, ester
and urethane bonds [115]. Chymotrypsin cleaved the
ester bonds adjacent to the phenylalanine in the novel
chain extender [115]. In an extension of ongoing work to
develop a cardiac patch, Woodhouse and collaborators
have electro-spun the enzyme degradable PUs developed
by Skarja [96], coated them with collagen IV and
incubated them with stem-cell-derived cardiomyocytes
(Fig. 6) [116]. These preliminary data show that the cells
adhere to the matrix and will beat asynchronously. Of
particular interest is the extension of the stem-cell-
derived cardiomyocytes along the same lines as the fibres
of the PU mesh scaffolding.
In other work, oriented toward introducing novel
hard-segment moieties, Santerre and co-workers have
utilized their knowledge of the biodegradation process
described in Fig. 2 to develop biodegradable PUs with
linear aliphatic diisocyanates, PCL and fluoroquinolone
antimicrobial drugs as hard-segment monomers
[68,99,117]. Observing the sensitivity of MDM and
related enzymes relative to hard-segment chemistry
[33,42,43] led to the conceptual design of a group of

J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470
Fig. 6. Two-photon confocal micrograph image of a biodegradable
PU (the LDI/Phe/PCL1250) electrospun into a mesh. The red features
in the photo in the image show the electrospun PU. The green depicts
embryonic stem cell derived cardiomyocytes. The image was taken 30 h
post-seeding, and the scale bar represents 20 mm.
Drug Release from Epidel™ Polymer
0.5 esterase
Norfloxacin release (ug/cm2)
buffer
0.4
0.3
0.2
0.1
0
0 5 10 15 20
Time (days)
Fig. 7. Biodegradation of a polyesterurethane, synthesized from
trimethyl hexamethylene diisocyanate, polycaprolactone and norflox-
acin, in the presence of phosphate buffer solution or cholesterol
esterase solution (37 1C, pH 7.0). Cumulative release of Norfloxacin
drug is measured by high-performance liquid chromatography and is
plotted relative to the surface area of exposed polymer to the
degradation medium.
drug polymers (EpidelTM) [117]. The polymer chemistry
is designed to be degraded by enzymes that are
generated by inflammatory white blood cells. The
release of antibacterial agents is therefore promoted by
a clinical event such as implantation [99]. Since this
event involves the activation of MDM, then the required
enzymatic reactions associated with EB are up-regulated
ARTICLE IN PRESS
7467
and hence free drug is released as a degradation product.
Once healing occurs, the level of enzyme production will
decrease and thus antibiotic release would decrease. The
release of the drug occurs from within the polymer to
counter the formation of biofilm and subsequent
biomaterials related infections (Fig. 7). Changing
diisocyanates and the distribution of drug monomers
modulates drug delivery doses [68].
5. Summary
With knowledge, new opportunity is almost always
found. This review of literature presented biomedical
PUs from their early conceptual design through events
that at one time cast the future of PUs into doubt.
However, through careful analysis of the EB mechan-
isms a better understanding of the materials and their
behaviour in vivo has been acquired. While new and
more bioresistant formulations of PUs have been
conceived the area of biodegradable PUs is poised to
make significant strides within the next decade as the
requirement for synthetic elastomeric tissue engineering
scaffolds increases. With this development will come a
greater understanding of how segmented copolymers in
general induce cellular responses and interact with the
body’s host response system.
Acknowledgements
The authors wish to thank the editors of the
Biomaterials journal and the Board of Directors for
the Canadian Biomaterials Society for having provided
the authors with this unique opportunity to convey
International and Canadian developments occurring in
the area of PU biodegradation.
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