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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 than others. For this reason a brief review of the
material chemistry is needed prior to discussing PU
1.1. Chemistry of PUs degradation. Segmented PUs can be represented by
three basic components described by the following
The nature of PU chemistry is central to under- general form:
standing why some PUs undergo degradation faster
P  ðDðCDÞn  PÞn ,
Corresponding author. Biomaterials Discipline, Faculty of Den-
tistry, University of Toronto, Toronto, Ont., Canada M5G 1G6. Tel.: where P is the polyol, D is the diisocyanate and C
+1 416 979 4903x4341; fax: +1 416 979 4936. is the chain extender. Typically, the polyol, or the so-
E-mail address: paul.santerre@utoronto.ca (J.P. Santerre). 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
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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 Once PUs were implanted, several sources were found
temperature (i.e.o25 1C) and terminated by hydroxyl to contribute to their degradation. For example, the
(–OH) groups. The chain extender is usually a small aliphatic ester linkages in polyester–urethanes are
molecule with either hydroxyl or amine end groups. The known to be susceptible to hydrolytic degradation [2].
diisocyanate is a low molecular weight compound that Polyether–urethane (PEU) materials are known to be
can react with either the polyol or chain extender. The susceptible to a degradative phenomenon involving
combination of the chain extender and the diisocyanate crack formation and propagation [3]. This is usually
components is referred to as the hard segment of the found in areas of devices where the stress level on the
polymer. polymer is high. However, the fissures may also appear
Conventional polyols are usually polyethers (with a even if no additional stress has been placed on the
repeating structure of –R–O–R0 –) or polyesters (with polymer. This micro-fissure phenomenon, known as
repeating structure of –R–CO–O–R0 –), with chain ends environmental stress cracking (ESC) is believed to be a
terminated by hydroxyl groups. 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
1.2. Bulk degradation of PUs in biomedical devices devices, oxidative degradation can be a contributing
mechanism. Implanted PEU devices that contain
While traditionally PUs have been widely used for metallic components have been subject to bulk oxida-
their excellent mechanical properties and moderately tion catalyzed by corrosion products of the metallic
good blood compatibility, they have also been singled components [4–7].
out as being problematic in terms of their long-term in The presence of enzymes in the physiological envir-
vivo biostability in tissues. This susceptibility to onment is another factor contributing to PU degrada-
biodegradation is in part an inherent feature of their tion. Even though the enzymes are designed for highly
chemistry and was appreciated by the industrial specific interactions with particular biological sub-
manufacturing community well before the detailed strates, some appear capable of recognizing and acting
studies of in vivo biodegradation began in the late upon ‘‘unnatural’’ substrates such as PU polymers.
1980s. PUs were shown in several instances to be Smith et al. [8] found that enzymes are capable of
sensitive to degradation in day-to-day applications. In altering polymer structure. A mechanistic model for the
these instances, degradation was mainly initiated during attack by hydrolytic enzymes on PUs has been proposed
the fabrication process due to elevated temperatures and by Santerre et al. [9].
the presence of liquids, and because of the difficulty to Calcification (i.e., the deposition of calcium-contain-
completely expel moisture from the reaction mixture [1]. ing apatite mineral) occurs with a wide spectrum of
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cardiovascular and non-cardiovascular medical devices. the lack of understanding associated with the molecular
In fact, calcification is the leading macroscopic cause of mechanisms contributing to the cleavage of the polymer
failure for most bioprosthetic heart valves, and it limits chains. It was the work of Ken Stokes, which initially
the functional lifetime of experimental mechanical blood provided the most comprehensive theory of in vivo
pumps and polymeric heart valves, including those made biodegradation in his description of ESC [2,4–7]. This
with PU parts [10]. explanation of the biodegradation process was adopted
It should be pointed out here that all of the in vivo after trying to explain end-point cracking observed on
degradation phenomena aforementioned are closely the surface of implanted PUs. The implicated elements
related to the surface organization of PUs. In PU-based which were suggested to be involved in the mechanism
materials, a microphase segregation process leads to the of ESC included surface oxidation (mediated by
formation of a two-microphase structure with regions neutrophil (PMN) and monocyte-derived macrophages
enriched in either hard or soft segments [11]. Because of (MDM) derived oxidants), residual stress, polyether
the mobility of the soft segments, the surface composi- soft-segment chemistry, molecular morphology, the
tion of segmented PUs varies in order to find the presence of MDM and foreign body giant cells (FBGC),
composition (or the hard/soft segments ratio) that will as well as an unknown biological element [2]. No single
minimize the interfacial free energy. In brief, PUs will group has embraced a detailed understanding of all
have a higher proportion of polar hard segments at the these elements in their studies to date and the element
interface when the environment is polar (e.g. water or that has remained the most elusive is the last one, the
blood) and more non-polar soft segments at the surface ‘‘unknown biological element’’.
when the environment is non-polar (e.g. air or vacuum). One limiting aspect of ESC is that it was defined
This particular behaviour of PUs has significant specifically for the oxidative cracking of PEUs under
importance as the host response is largely determined strain. A more encompassing definition of the biode-
by the surface composition of the material. gradation process that would include ESC as a special
case, may be better described by the term ‘‘environ-
1.3. Biostability of implanted medical devices mental biodegradation’’ since it has now been demon-
strated that the MDM-mediated degradation process is
The above degradation mechanisms have led several initiated well before cracking is observed [18]. The term
research groups to question how safe PU-made biome- ‘‘environmental’’ rightly captures the fact that there is a
dical devices are; some of them are particularly of unique environment implicated in EB with multiple
interest [4–7,12]. Mackay et al. [13] reported that early parameters (stress, biochemicals, molecular and phase
PU valves had not performed well in durability tests. structure of the polymer, metallic ions, salts, inorganic
They reported that both calcium and phosphorus were and organic acids and cells) working together towards
present in the adherent calcified plaque-like material on the degradation of a polymer in a biological medium. It
the leaflet surfaces. Vascular prostheses made of PUs is unlikely that oxidation is the only dominant chemical
were also the subject of analyses in order to identify the reaction at work in the breakdown of PUs in vivo since
causes of their degradation [14]. hydrolytic processes catalyzed by enzymes are now
Perhaps, the most often reported case of in vivo PU clearly implicated [18]. What is common to both the
degradation is that associated with the PU-covered oxidation and hydrolytic enzyme processes is the fact
silicone breast implants [15,16]. Investigators found that that their most active agents are derived from the same
following explantation of the devices that the PU foam biological source (activated white blood cells and more
was missing; with only the basal layer of the foam still specifically the MDMs and the FBGC) [19].
being visible by scanning electron microscopy (SEM) Anderson’s group initiated the use of cells (specifically
[17]. This was the clearest evidence that a biodegrada- white blood cells) for studying the breakdown process in
tion process was occurring which resulted in substantial vivo [20]. This would mark a significant turning point in
amounts of material being removed. 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
2. Environmental biodegradation (EB) and its molecular cleavage of PU chains by oxidants and enzymes [21].
reactions on PU structure Anderson’s work subsequently focused on the oxidative
mechanism in attempts to validate the Stokes theory of
2.1. Molecular reactions between biological agents and ESC, which invoked oxidation as a dominant factor in
PUs PEU degradation. They were able to show using both in
vitro oxidative reactions with CoCl2/H2O2 combinations
Early observations relating to the biodegradation of and their in vivo cage implant model that biological co-
PUs raised much controversy around the pathways factors such as a-macroglobulin derived from plasma
leading to the process. This resulted in good part from could further promote stress cracking in PEUs [22].
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Unlike the oxidative studies described above which dependence on hard segment domain formation, the
were intensely focussed on the EB mechanism for PEUs, data indicated that the polymers containing the highest
investigations looking at PU chain cleavage via the amount of labelled hard segments exhibited the least
hydrolytic pathway and specifically related to the amount of chain cleavage by the enzyme and subsequent
enzyme mediated mechanism evolved from work on TDA generation. It was concluded that the ability of the
polyester–urethanes which had been used in the Meme PU material to form stable H-bonded hard segment
breast implant prosthesis [23]. A number of reports micro-domains and other H-bonding along the chains
described the generation of aromatic diamines, such as contributed to the formation of a protective structure
toluene diamine (TDA) [24] and 4,40 methylene diamine for the enzyme hydrolysable hard segment linkages
(MDA) [25]. The biological relevance of these diamines located within the hard segments of the PEU. These
was particularly important because of their putative findings were particularly important since they corre-
carcinogenic effect [26,27]. Many of the earlier studies lated well with in vivo findings from several investiga-
were unable to effectively differentiate between what tors [5,34–36] that have identified a consistent
was actually produced via biodegradation and what may association between the elevated hardness of high
have been residue from the process manufacturing steps, hard-segment-content Pellethaness (i.e., durometers
and therefore controversy and debate surrounded the of 55D and 75D) and good in vivo biostability.
relevance of the data. Furthermore, early studies
investigating the hydrolysis mechanisms were carried 2.3. Influence of strain on molecular interactions of
out with relatively non-physiological enzymes such as polymers and biological agents
papain [24] and harsh hydrolysis conditions such as 3 N
NaOH at 150 1C which were not believed to appro- Given the knowledge that hard-segment density may
priately reflect the in vivo systems [28]. The focus was influence biodegradation, then it may be concluded that
entirely on the release of the diamines rather than any process (applied stress, thermocycling, annealing,
gaining a broader understanding of polymer chain etc.) that would perturb this structure should also affect
cleavage in relevant biological systems. the biostability of the PU [37]. The stress–strain
Santerre and Labow [29] were the first group to begin character of PUs is highly dependent on the nature of
comprehensive studies of PU cleavage using enzymes the PU hard segment [38] and their association with
known to be associated with MDM activity. Using a micro-domains has been well established for many years
polyester–urethane synthesized with toluene diisocya- [39,40]. This behaviour depends on the size and
nate (TDI) it was demonstrated that enzymes such as concentration of the hard-segment domains, the
cholesterol esterase (CE) preferably degraded ester strength of the hard-segment aggregation (intra-domain
linkages immediately adjacent to the hard segment cohesion), the ability of the segment to orient in the
rather than catalyzing the hydrolysis of the urethane in direction of stretch, and the ability of the soft segment to
the hard segment to generate TDA. The group went on crystallize under strain [41]. It has now been confirmed
to identify nine oligomeric products from the polymer by Tang et al. [42] that the biodegradation of
and completely reconstruct the polymer’s breakdown by polycarbonate PUs by MDM associated esterase activ-
enzyme [30]. ity is highly dependent of hard-segment chemistry and
hard-segment size [43]. The PU surfaces were highly
2.2. Contribution of hard-segment structure in correlated to the H-bonded state of the PU. The rank of
biodegradation the different chemical groups’ susceptibility to hydro-
lysis was as follows: non-hydrogen bonded carbona-
Further work began to examine the molecular te4non-hydrogen bonded urethane4hydrogen bonded
relationship between material chemistry and cell action carbonate4hydrogen bonded urethane. The findings
on the PUs [31] with particular interest in cellular suggest that the degree of hydrogen bonding, when
enzymes with esterase activity [32]. Using radiolabelled processed into a PU material could be an important
diisocyanates it was possible to specifically assess the parameter to consider in the design of new biostable PU
release of TDA from a polyether–urea–urethane when products [42], and in fact validates the excellent
exposed to CE [33]. In the absence of esters it was found biostability of 4,40 -methylene-bis-phenyl diisocyanate
that CE would hydrolyze the urethane to release hard (MDI) based polycarbonate PUs such as those reported
segment components. The group explored the relation- for Corethanes type materials [34].
ship between PEU hard segment size and hydrolysis by Anderson [44–49] and Stokes [2] have applied strain
CE. It was originally anticipated that as the 14C- into PU systems in order to observe its effect on the end
labelled diisocyanate content in the material increased point of EB (i.e. the bulk changes in physical character,
(i.e. hard segment content increased) there would be an measured as changes in tensile properties, fatigue life
increase in the amount of released TDA from the and resistance to tear). These studies have been carried
polymer. While biodegradation studies showed a strong out with an interest in recording strain’s influence on
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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


2500
2.4. Environmental biodegradation 2000
1500
Based on the current literature, an aspect of EB that
still requires further investigation is the molecular 1000
relationship between material and cell function, via 500
intermediary forces such as stress. Exactly what 0
molecular component(s) of the stress loaded material 0% 10% 50%
does the cell recognize in order to induce and perturb strain
polymer biodegradation is still unknown. There is
Fig. 2. Demonstration of the dynamic interaction of strain on
mounting evidence to suggest that the ‘‘unknown molecular structure and macrophage-mediated degradation of a
biological element’’ in the process of EB (which includes polycarbonate urethane (HDI-PCN-BD) synthesized from 14C-
ESC) involves a specific combination of material surface hexamethylene diisocyanate, polycarbonate diol and butanediol in a
chemical/physical structure and the differentiating state 431 stoichiometric ratio of the respective reagents. Radiolabel release
from a 14C-labelled polycarbonate PU (counts/min/mL culture
of the monocyte [53,54]. As discussed earlier the latter
solution) after 48 h incubation with macrophages (U937 cell line),
induces hydrolysis of the material very early on and the pH 7.0 and 37 1C. Under a 0.6 MPa load the polymer exhibits a 10%
nature of the degradation products themselves may strain. This condition yields a slightly lower amount of degradation (as
subsequently feedback into the cell activation loop [54]. measured by the release of radiolabelled segments from the polymer)
From data acquired at this point, EB can be modelled 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
according to Fig. 1 where the central interaction
(po0:05). In this system the hydrolysis of the carbonate groups is
between material and cells (specifically MDMs) are reduced when the PU is under strain because the soft-segment chains
described as a cyclic process which influences two line-up and crystallize, therefore reducing their vulnerability to
critical end points that continue to be of significant interaction with water and enzyme.
interest to the delivery of medical device technology in
health care, i.e. (1) degradation of biomaterials and (2) review has documented the end point of EB, the current
chronic inflammation. The model shows strain as an section has attempted to provide readers with an
external perturbation (although the perturbation could appreciation of the processes as work when biological
be metal ions or other external factors) that acts directly activities act on these materials and convey how this
on the material influencing morphology and chemical may be perturbed when external forces act on the
interactions between the polymer chains, and indirectly structure of the material. Section 3 will cover in greater
transmitting forces to MDMs (as well as other adherent detail the influence of the PUs on MDM biodegradation
cells). Recent studies have reported on the ability of function, which forms the right side of the feedback loop
induced strain, from applied stress, to influence the shown in Fig. 1.
generation of biodegradation products by MDMs
(Fig. 2) and promote the breakdown of the polymer 2.5. Considerations for the design of new PUs
by enzymes (Fig. 3) [55]. The transmission of forces to
the cells will influence their function [56,57], which in The findings describing the molecular breakdown of
turn is expected to alter the inflammatory process, and PUs to date have been of significant importance in the
feedback into the material. While Section 1 of this design of PUs for devices in general, both from the
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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 [68]. As more has become known about the process of
regulating the effect of polymer derived by-products EB, investigators have also begun to explore strategies
from the biodegradation process onto local cells and to have PUs undergo controlled degradation for the
particularly on cells related to the wound healing delivery of drugs and other applications [69]. More
pathway. For instance, the work surrounding the details on these applications will be described in Section
oxidation models reported on by Anderson [19–22] 4 of this review.
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 3. Action of PUs on inflammatory cells: effect on EB
al. [43,51,52] has described the unique protective action
of MDI in these materials with respect to their 3.1. PU degradation and inflammatory cells
hydrolysis. Likewise, the reduction of polyether seg-
ments from the soft-segment component of PUs has As highlighted in the previous section in the descrip-
been motivated by a desire to eliminate the materials’ tion of EB, it is the white blood cell and more
vulnerability to oxidation. Strategies have included the specifically the MDM that has emerged as the pre-
introduction of larger hydrocarbon segments between dominant cell type that is orchestrating the damage in
ether groups [57,58] and the incorporation of silicone biodegradation processes [44]. But it must be clearly
segments [59–61]. Work by Ward incorporated surface stated that the macrophage takes its cue from the
modifying end groups onto the terminal ends of polymer presence of the material and its unique chemistry. Work
chains to alter their biostability [62–64]. by Marchant and colleagues quantitatively determined
While the above materials have focused on changes to the cellular composition of the inflammatory exudates
the bulk PUs themselves, there have been a number of surrounding the implanted material. The temporal
studies that have introduced the use of ampiphilic variation in the acute inflammatory response, chronic
copolymer additives to modify the surface chemistry of inflammatory response, granulation tissue development
polymers while yielding no change to the chemistry of and foreign body reaction to the implanted biomaterial
the bulk polymer. Earlier work by Ward [65] introduced was determined [19]. The foreign body reaction to a
a silicone containing oligomeric surface modifying material in contact with tissue and/or blood cells
additive, which masked the oxidation sensitive surface proceeds according to the following time course. PMN
of PUs. Santerre and co-workers developed a family of appear within minutes along with monocytes, which
fluorinated surface modifying macromolecules, which then over the course of days differentiate into MDM
could reduce the extent of PU hydrolysis [66,67]. More while adherent to the material. Eventually, the blood
recently, these oligomeric polymers were used to deliver cells remaining adherent consist mainly of MDM and
anti-oxidants to the surface of polymers in order to FBGC, which may persist at the tissue–implant interface
minimize hydrolysis and pro-actively reduce oxidation for the lifetime of the implant [70].
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Understanding how cells interact with PUs, which 3.2. Implication of MDM-derived hydrolytic enzymes
may result in degradation whether it is desired or not, is
essential. The general process of EB, as exemplified by Although PMN provide HOCl and other ROS
ESC, described many years ago [4] is still not fully initially, it is unclear what their contribution is to the
elucidated. EB certainly involves the release of oxidative ultimate degradation of PU that leads to device failure.
and hydrolytic activities from the surrounding tissues, When assessing the destructive potential of PMN and
especially MDM and FBGC [49,69]. In one case ESC MDM towards a radiolabelled polyester-PU, 25 times
was simulated in an in vitro accelerated biological model more radiolabel release was elicited by MDM than
of oxidation using MDM and FeCl2. It was possible to PMN for equivalent numbers of cells [18]. An important
inhibit the action of MDM on surface cracking with a potential mechanism of MDM mediated degradation
surface of dexamethasone (an anti-inflammatory agent) towards PU was attributed to the hydrolytic activity in
modified PU [71]. Differences have been observed in the MDM, which appears to be predominantly due to two
damage caused by oxidation, with polycarbonate PUs esterases, CE [83] and monocyte-specific esterase (MSE)
being less susceptible to oxidation than PEUs [2,72]. that has similar specificity to carboxyl esterase (CXE)
Initially, it is PMN that are the primary source of [84]. Thus far, CE and CXE have caused the most
reactive oxygen species (ROS), with HOCl, one of the degradation of the PUs tested [85,86], although some
most oxidative compounds, being released in different degradation can be measured (10 times lower levels than
amounts depending on the PU surface to which the measured with CE) by the esterolytic activity of serine
PMN have adhered [73]. Because of their oxidative proteases (similar to those found in PMN) [32].
potential, PMN have been implicated in PU degradation Therefore, in order to study the foreign body reaction
as well [73], even though they do not remain at the site to PU, which may lead to degradation, many studies
of implantation when the foreign body reaction becomes have utilized in vitro MDM cell systems rather than
chronic. Adherent PMN were activated differently by a PMN [18,53,79,82,87–89]. When human monocytes,
variety of material surfaces [74,75], showing dissim- isolated from whole blood, were cultured on tissue
ilarity in the release of superoxide anion [76], mac-1 culture grade polystyrene (PS), a polyester-PU or a
expression [77], and elastase [31]. When superoxide PEU, significant differences in the amount of esterase
dismutase modified PUs were implanted into rats, activity was measured in the cell lysates after 28 days. In
PMN-rich acute inflammatory infiltrates were reduced this study, no assessment of biodegradation was made
as well as the number of FBGC. However, in another [87]. When mature MDM (14 days old) were gently
study, it was found that when PU, polyester-, polyether- trypsinized [18] and then re-seeded onto radiolabelled-
or polycarbonate-based PU were treated with HOCl, PUs, significant degradation was measured by radiola-
significant inhibition of the subsequent hydrolysis by CE bel release. SEM showed extensive physical damage of a
was observed [78,79]. Phorbol myristate acetate (PMA), polycarbonate PU [79] (Fig. 4). In addition to the
which stimulates the release of HOCl from PMN physical damage and the radiolabel release, esterase
by the activation of protein kinase C, also inhibited activity increased over the course of the 28 days that the
radiolabel release elicited by PMN from PUs. Hence, the MDM were cultured. Although esterase expression
interactive play between oxidative and hydrolytic varies in a number of pathological states [84], its role
enzyme processes is emerging as a critical area of PU in the foreign body reaction has not been established. To
biodegradation research that is still lacking in under- date, in vivo biodegradation has not been directly linked
standing. to esterases even though many in vitro cell studies
As a side note, there are external forces and/or strongly suggest that they contribute to the hydrolytic
pathological processes that can influence the role of breakdown of PUs [18,79].
reactive ROS at implant sites and this may perturb the
biodegradation pathway as well as the biocompatibility 3.3. Effect of PU chemistry on hydrolytic enzyme
of the material in the application. In the presence of synthesis and release
other factors such as exposure to infectious agents and
shear stress [80], PMN responses such as the release of The differences in PU chemistry appear to stimulate
ROS were compromised in a distinct manner, which was the synthesis and release of the enzymatic activities
related to the material surface, a phenomenon known as from MDM that cause their degradation [87]. In a study
foreign body associated infection. This often leads to using polycarbonate based PUs which were synthesized
infections and biofilm formation, which is notoriously with hexane diisocyanate (HDI), poly(1,6-hexyl 1,2-
resistant to antibiotics and usually result in the device ethyl carbonate) diol (PCN) and butanediol (BD)
having to be removed [81]. In a study by Nakaoka et al. in the ratio 4:3:1 (HDI431) and a PU synthesized
[82], MDM surrounding PU implants released ROS that with MDI:PCN:BD in the ratio 3:2:1 (MDI321),
caused tumour formation, which was dependent on the both CE and MSE were synthesized de novo from
PU surface characteristics. MDM adherent to the most degradable PU, HDI431,
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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
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J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470 7465

formulation of synthetic oligopeptide mimetics. The chain extender in the hard segment, combined with
grafted tripeptide RGD sequence supported higher either PCL and/or PEO of varying molecular weights as
adherent MDM density than surfaces grafted with other the soft segment. The PEO-based PUs were weak, tacky,
peptides such as PHSRN and PRRARV. Therefore, as amorphous materials. Those containing the PCL were
pro-biological hybrids of PUs begin to emerge for tissue relatively strong and elastomeric with increased tensile
regeneration processes and improvements to the materi- strength, modulus and ultimate strain with increasing
al’s biocompatibility, scientists will have to weigh their PCL molecular weight [96,105]. The PEO containing
impact on MDM activity in terms of biodegradation PUs adsorbed large amounts of water while the PCL
rates as well as wound healing. containing materials absorbed minimal water. The water
vapour permeance (WVP) generally followed the water
adsorption trends. Soft-segment crystallinity in the PCL
4. Design of biodegradable PUs for the in vivo containing PUs served to reduce WVP values with
environment increasing PCL molecular weight. Consistent with the
water uptake data, in vitro degradation of this family of
While traditionally investigators have used PUs as PUs as measured by mass loss, change in molecular
long-term implant materials [92] and have attempted to weight and surface alteration showed significant differ-
shield them from the biodegradation processes that were ences in the degradation rates associated with the soft-
described in the previous sections of this review, more segment component of these polymers [106]. The PEO
recent work by investigators has utilized the flexible containing PUs exhibited substantial mass loss within 56
chemistry and diverse mechanical properties of PU days in buffer with the formation of a porous material
materials to design degradable polymers for applications with little strength; conversely the PCL containing
as varied as neural conduits [93] to bone replacements polymers had modest mass loss and surface alteration
[94]. These materials have for the most part taken and retained their strength. In later work, PEO and PCL
advantage of hydrolytic mechanisms and have varied PUs were blended by simple mixing to form three-
molecular structure to control rates of hydrolysis. dimensional sponges using solvent cast/particulate
The move to degradable PU based materials has leaching methods [107]. The degradation of these PU
required a change in the diisocyanates historically used blends was characterized by a rapid initial mass loss
for their synthesis. Typically, an aromatic diisocyanate believed to be associated with loss of the PEO contain-
was employed for applications where degradation was ing PU followed by the slower degradation typical of the
not desired, such as pacemaker lead coverings, catheters, 100% PCL polymer. All blends were semi-crystalline in
and wound dressings [92]. In part because of the nature and the mechanical properties were dominated
putative carcinogenic nature of aromatic diisocyanates by the PCL PU.
[26,27], degradable PUs are more frequently made from Several investigators have combined PEO and PCL
diisocyanates such as lysine-diisocyanate (LDI, 2,6 within the same polymer structure to take advantage of
diisocyanato methyl caproate) [95–97], hexamethylene the relative influence of the two soft segments on the
diisocyanate [98,99], and 1,4 diisocyanatobutane [100] mechanical integrity of the materials and the degrada-
whose ultimate degradation products are more likely to tion rates. Cohn et al. [98] synthesized a series of
be non-toxic, i.e. lysine. biodegradable poly(ether ester) urethanes utilizing
The soft segment is typically the block of the PU used PCL–PEO–PCL triblock copolymers and hexamethy-
to modify the degradation rate and biodegradable PUs lene diisocyanate. Consistent with the results of Skarja
have been made with a variety of soft segments et al. [106], they showed that an increase in PEO or a
including polylactide or polyglycolic acid [101–103], decrease in the PCL block length increased the
polycaprolactone (PCL) [93,94,96,98–100,104], and degradation rate and decreased the soft-segment crystal-
polyethylene oxide (PEO) [96,98,104]. linity.
Expanding on the use of the triblock soft segment,
4.1. Polyethylene oxide and PCL containing Wagner et al. [100,107,108] have synthesized and
biodegradable PUs characterized a family of unique poly(ester-urethane)
urea tri-block co-polymers using PCL, polyethylene
Polyethylene oxide and PCL impart different physical glycol and 1,4 diisocyanatobutane with either lysine
and mechanical properties to the PUs that contain them. ethyl ester or putrescine, as the chain extender.
PEO is used to enhance degradation and PCL to provide These materials have shown breaking strains from
greater hydrolytic stability and elastomeric mechanical 325% to 560% and tensile strengths from 8.0 to
properties. PCL usually imparts enhanced crystallinity 20 MPa. As in other work, the PCL block length
to the PU while PEO increases hydrophilicity and water increased the initial modulus and tensile strength due
uptake. Woodhouse et al. [95,105,106] synthesized a to an increase in crystallinity and longer PEO blocks
family of PUs using LDI and a novel amino acid ester increased the degradation relative to shorter PEO
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7466 J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470

blocks. Degradation of the materials in the presence of and glycerol as degradation products. Rabbit bone
cells did not appear to produce cytotoxic compounds. In marrow stromal cells cultured on the materials for up to
recent work, Stankus et al. [109] co-spun the PCL/1,4 30 days formed multilayers of confluent cells and were
diisocyanatobutane/putrescine polymers with type 1 phenotypically similar to those grown on tissue culture
acid soluble bovine collagen into films of varying fibre PS [97].
diameters. The tensile strengths of these materials varied In a variation on the above design, Argarwal et al.
from 2 to 13 MPa Incorporation of the collagen [112] used pentane diisocyanate and sucrose with water.
generally decreased the tensile strength as well as the This scaffold differed from the glycerol containing
initial and 100% moduli, and increased smooth muscle material because it had a microtexture with both large
cell adhesion [109]. and small pores within the same foam. It supported the
Saad et al. [94,95,110] combined both a block tri- adherence and proliferation of both bone-marrow
polymer of PCL:PEO:PCL soft segment with a crystal- stromal cells and chondrocytes in vitro. In subdermal
izable soft segment, a,o dihyroxy-oligo[((R)-3-hydro- implants the investigators found that the material
xybutyrate-co-(R)-3-hydrocyalerate)-ethylene glycol] showed infiltration of both vascular cells and connective
(PHB). This family of materials (DegraPols) was tissue. Zhang et al. [113,114] produced an LDI-glucose
synthesized with either LDI or trimethyl-hexamethylene PU and an LDI-ascorbic acid, glycerol and polyethylene
diisocyanate along with the above soft segments or a glycol material. Both PUs showed good mechanical
copolyester of adipic acid and ethylene glycol, diethy- properties and biocompatibility.
lene glycol, and BD (Diorezs). The mechanical proper-
ties of these materials are dominated by the crystalline 4.3. Biodegradable hard segments
phase. These materials have been extensively character-
ized for their use as bone substitutes [94,95,110]. The Materials reported on by Woodhouse et al.
DegraPol is elastic and forms highly porous foams from [96,105,107,115] have been unique in that they specifi-
100 to 400 mm. Osteoblasts cultured on these foams cally designed enzyme sensitive linkages into the hard
proliferate, phagocytose degradation products, retain segment of the PU. This was an alternative strategy to
their phenotype and induce bone formation in a rat the non-specific hydrolysis degradation that has been
model [95,110]. more commonly employed. In vitro degradation studies
Gogolewski et al. [103,111] also combined two of PUs containing a phenylalanine diester chain
different soft segments within one polymer, incorporat- extender, LDI and either PEO or PCL showed that
ing Pluronic F-68(poly(ethylene-propylene-ethylene upon exposure to chymotrypsin and trypsin, the
oxide) and PCL within the same soft segment. They polymer had an increased susceptibility to enzyme-
used BD or 2-amino-l-butanol as the chain extender and mediated but not buffer-mediated erosion when com-
hexamethylene diisocyanate as the hard segment. They pared to the control PU [106]. These PUs released three
observed similar effects to those reported above for PEO hard-segment products upon degradation by chymo-
on the degradation rate and water uptake of the trypsin and showed enzymatic cleavage of urea, ester
polymers. Interestingly, they found that all the materials and urethane bonds [115]. Chymotrypsin cleaved the
calcified and calcification increased with material ester bonds adjacent to the phenylalanine in the novel
hydrophilicity, an observation noted of PEUs in the chain extender [115]. In an extension of ongoing work to
study of EB [10]. The structure and composition of the develop a cardiac patch, Woodhouse and collaborators
calcium crystals formed on the materials depended on have electro-spun the enzyme degradable PUs developed
the PU chemistry. Given the desire not to have by Skarja [96], coated them with collagen IV and
calcification occurring in many cardiovascular applica- incubated them with stem-cell-derived cardiomyocytes
tions [10], chemical formulation will be a restrictive (Fig. 6) [116]. These preliminary data show that the cells
factor for these biodegradable PUs. adhere to the matrix and will beat asynchronously. Of
particular interest is the extension of the stem-cell-
4.2. Use of other soft segments in biodegradable PUs derived cardiomyocytes along the same lines as the fibres
of the PU mesh scaffolding.
Agarwal et al. [97,112,113] used glycerol and/or In other work, oriented toward introducing novel
sucrose in combination with PEO, LDI and water to hard-segment moieties, Santerre and co-workers have
produce a group of biodegradable PU foams. They first utilized their knowledge of the biodegradation process
reported the development of an LDI-glycerol containing described in Fig. 2 to develop biodegradable PUs with
polymer formed by utilizing the reaction of water with linear aliphatic diisocyanates, PCL and fluoroquinolone
the diisocyanate to crosslink and form a networked antimicrobial drugs as hard-segment monomers
foam. The interconnected pores varied in size from [68,99,117]. Observing the sensitivity of MDM and
10 mm to 2 mm in diameter. The degradation of the PU related enzymes relative to hard-segment chemistry
was linear at 37 1C and showed evidence of both lysine [33,42,43] led to the conceptual design of a group of
ARTICLE IN PRESS
J.P. Santerre et al. / Biomaterials 26 (2005) 7457–7470 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
Fig. 6. Two-photon confocal micrograph image of a biodegradable conceived the area of biodegradable PUs is poised to
PU (the LDI/Phe/PCL1250) electrospun into a mesh. The red features make significant strides within the next decade as the
in the photo in the image show the electrospun PU. The green depicts requirement for synthetic elastomeric tissue engineering
embryonic stem cell derived cardiomyocytes. The image was taken 30 h
post-seeding, and the scale bar represents 20 mm.
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.
Drug Release from Epidel™ Polymer

0.5 esterase
Norfloxacin release (ug/cm2)

buffer
Acknowledgements
0.4
The authors wish to thank the editors of the
0.3 Biomaterials journal and the Board of Directors for
the Canadian Biomaterials Society for having provided
0.2 the authors with this unique opportunity to convey
International and Canadian developments occurring in
0.1 the area of PU biodegradation.

0
0 5 10 15 20 25 30 35 References
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