Polyether Polyurethanes: Biostable

or Not?

KENNETH B. STOKES, B.CHEM.

Medtronic, Inc
6700 Shingle Creek Parkway
Minneapolis, MN 55430
ABSTRACT

Certain polyether polyurethanes have been shown to be biostable in long-

term implant studies. Others retain good bulk properties, but have been shown
to develop cracks on their tissue contacting surfaces. Two cracking mechanisms
have been identified, in vivo stress cracking and metal ion oxidation. Stress
cracking is the result of an interaction between the in vivo mammalian envi-
ronment and residual stress (strain) in the implanted polymer. Mild autooxida-
tion can be initiated by stress cracking. More extensive autooxidation can be
initiated and propagated by corrosion of metallic device components, especially
the corrosion products of cobalt. Both mechanisms are controllable, thus, do not
necessarily preclude the use of polyether polyurethanes in implantable devices.
KEY WORDS

Polyether polyurethanes, biostability, stress cracking, metal ion oxidation.

INTRODUCTION

olyurethane elastomers offer unique combinations of properties to

Pthose developing implantable biomedical devices. These polymers
are well known for their excellent toughness combined with flexibility,
durability and biocompatibility [1]. The short term use of these materi-
als appears to be well accepted. While some aliphatic polyester polyure-
thanes have excellent physical properties, they are subject to hydrolytic
degradation, rendering them unsuitable for long-term implant [1]. In
contrast, polyether polyurethanes are generally recognized as hydro-

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 229

lytically stable at neutral and basic pH. Thus, they have been exten-
sively evaluated for use in chronically implantable devices such as arti-
ficial hearts, heart valves, shunts, indwelling catheters and many
more-including cardiac and neurologic pacing leads.
The stability of several polyether polyurethanes has been established
in long-term animal tests [2,3]. The human experience in pacing with
Pellethanes 2363-55D and 80A exceeds 12 years with implants begin-
ning in 1975 (Neuro) and 1977 (cardiovascular). In general, the human
experience has been good. In spite of this, controversy developed over
the biostability of these polymers in the mid 1980s when it was dis-
covered that the insulation failure rates on certain lead models was
higher than others. Two mechanisms have been discovered that can af-
fect implanted polyether polyurethanes, stress cracking and autooxida-
tion [4,5]. Thus, we find an apparent paradox where some materials
have been shown to be biostable, yet may be affected by degradation
mechanisms. Are polyether polyurethanes biostable or are they not?
We do know that the answer to this question is not a simple yes or no.
Certainly no material is entirely stable in an absolute sense. Thus, the
existence of degradation mechanisms in implanted devices must be ac-
ceptable if the rate of change is slow enough to assure that clinical fail-
ure does not occur within the expected lifetime of the device. This must,
in fact, be the definition of biostability.
Because our experience has dealt primarily with cardiac pacing, our
testing naturally concentrates on this technology. Nonetheless, it is
possible that our experience will apply to other fields of biomedical
device technology

11IATERIALS

Polymer Structure (Configuration)

While there are virtually an infinite number of possible polyure-
thanes, only four types have achieved prominence for use in chronic im-
plantable devices. The chemical structures of these polymers have been
presented in detail elsewhere in this same volume, thus, will be only
briefly reviewed here [6,7].
Biomer (Ethicon) is the reaction product of diphenyl methane diisocy-
anate (MDI) with polytetramethylene oxide diol (PTMO), using a short
chain diprimary amine as the chain extender. The urea groups so
formed make thermal processing difficult. Thus, this polyether urea
polyurethane is typically applied from solution (usually dimethyl acet-
amide). Because Biomer per se is not generally available for manufac-

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turing human use devices, other companies have developed their own
versions. Surethane (Cardiac Control Systems) is believed to be equiva-
lent to Biomer and is used to insulate one company’s cardiac pacing
leads [8]. An extrusion grade of Biomer using water as the chain ex-
tender (thereby reducing the urea linkages by a factor of 2) has also
been evaluated in our studies.
Cardiothane-51 (Kontron, formerly Avcothane-51 from Avco) is the
product of MDI and PTMO with a butane diol (BD) chain extender and
acetoxy terminated polydimethyl siloxane. Theoretically, this is a mois-
ture cured (cross-linked) coating material.
Tecoflex (Thermedics) is formed through the reaction of dicyclohexyl
methane diisocyanate and PTMO using BD as a chain extender. Sev-
eral hardness grades, including Shore 80A (Tecoflex EG 80A) and Shore
60D (T~coflex EG 60D) are available. The differences in hardness are
achieved by using a higher molecular weight PTMO in Tecoflex EG
80A compared to %coflex EG 60D. A series of polymers apparently sim-
ilar in composition to Ibcoflex was offered by K. J. Quinn (Q-thane).
The Pellethane resins, 2363-80A and 55D have been the most exten-
sively tested polymers in our studies since they are used on all but a
few models of cardiac pacing leads. These polymers are the reaction
products of MDI, PTMO and BD, with a slight excess of isocyanate. The
isocyanate end groups can react with urethane groups to form ther-
mally labile allophonate cross-links (allowing thermoplastic extrusion
and injection molding). Several Shore A hardnesses, 80A, 90A and 55D,
are believed to be achieved by varying the ratios of PTMO to MDI and
BD. Pellethane 2363-80AE is similar to Pellethane 2363-80A, but with
hydroxyl end groups.
Several additional polymers will be briefly mentioned. These include
peroxide cured (Vesta) and enhanced tear resistant (Dow-Corning) sili-
cone rubbers, Rimplast PTSE BS-1204 (Petrarch, silicone-styrene/eth-

ylene butylene/styrene IPN), Rimplast PTEU 205 (Petrarch, polyether-

polyurethane-silicone IPN) and Tecoflex SU55 (Thermedics, polyether
polycycloaliphatic urethane-silicone copolymer).
Polymer Morphology (Conformation)

Polyether polyurethanes are block copolymers that have also been

called segmented urethanes. They are composed of long flexible PTMO
chains (soft segments) interspersed with rigid hard segments. In the
case of the Pellethanes, for example, the hard segments are the MDI/
BD polyurethane block. These polymers derive their excellent physical
properties from 2 factors. Urethane (and to an even greater extent urea)

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 231

groups in the hard segments readily develop hydrogen bonding in the

solid state. These hydrogen bonds act as cross-links. In addition, the
hard and soft segments tend to separate into different phases like oil
and water. This phase separation results in more crystalline islands of
hard segments, dispersed in a more amorphous soft segment phase.
Thus, the phase separated hard segments act as a reinforcing filler for
the polymer. These factors produce the excellent combinations of high
tensile strength and elongation with high tear resistance and varying
degrees of flexibility that polyurethanes are known for. For a more thor-
ough review of polyurethane morphology, reviews by Coury et al. or
Lelah and Cooper are recommended [1,7].

BIOSTABILITY TESTING OF 14IOLDED SPECIMENS

In theory, the polyether polyurethanes should be biostable [1]. They

are appreciably damaged by hydrolysis under most implant condi-
not
tions. As is true with most organic polymers, they are known to be sus-
ceptible to various degradation mechanisms, including photo and ther-
mal oxidative processes. These mechanisms, of course, cannot occur in
uiuo because the necessary relatively high heat and specific wave-
lengths of light are not present. Many devices including cardiac pacing
leads are implanted in the venous system and capillary bed where the
oxygen tension is low relative to the atmosphere, rendering autooxida-
tive mechanisms even more unlikely.
There are, however, many hydrolytic and oxidative enzymes in vivo.
These catalyse reactions that in most instances could not otherwise oc-
cur. It has been commonly believed that enzymes function by confor-

mally fitting a specific molecular shape. It is diflicult to visualize such

mechanisms in bulk polymer when the absorption or adsorption of an
enzyme must necessarily alter its conformation. Darby and Kaplan
found that polyether polyurethanes are resistant to enzymes such as
those generated by A. Niger, as long as the number of methylene
groups between ether oxygens was ~ 4 [9]. No damage was done in
their studies with :5 3 methylenes between ethers and &dquo;negligible&dquo;
damage occurred with 4 (~g. PTMO). Thus, there appears to be no a
priori reason to expect polyether polyurethanes to lack biostability.
The mammalian body presents a very complex, not thoroughly un-
derstood, hostile environment. The only way one can be certain that a
previously unsuspected degradation mechanism for a given polymer
does not exist in vivo is to test the polymer in vivo. Furthermore, if such
a mechanism does exist, the testing must continue long enough to
assess the rate of degradation. This is necessary to determine if the

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232

rate of degradation is or is not acceptable for a given device. In our

judgement, such tests should last at least 1 and preferably 2 years
when assessing a polymer’s suitability for long-term implant. One of
the first such long-term biostability studies of a polyether polyure-
thane was reported by Boretos in 1972 [2]. He studied the physical prop-
erties of Biomer as a function of implant time, proving that polymer’s
biostability.
The biostability of Pellethanes 2363-80A and 55D was evaluated over
a 2 year period in the late 1970s. Miniature tensile specimens were in-

jection molded on a ram press. The ethylene oxide sterilized specimens

were implanted subcutaneously in rats. Explants were evaluated as a
function of implant time by measuring tensile strength, elongation,
density, weight and dimensions. Surfaces were examined by scanning
electron microscopy. Molecular morphology, molecular weight and the
polymers chemistry were monitored by differential scanning calorime-
try, inherent viscosity and infrared spectroscopy, respectively. The
results of this study have been reported in detail elsewhere [3,10].
In summary, however, tensile strength decreased within the first 3

Table 1. Physical property changes in injection molded Pellethane and Tecoflex

polyether polyurethanes after 24 months implant.

* 16 to 18 months implant.

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Figure 1. Surface of tensile specimen showing cold flow-s. This occurs when the polymer
chills too quickly on the mold surface as molten polymer is still entering the cavity. The
ridge down the center of the specimen is flash from the molding process. 95 x .

Figure 2. Surface of Pellethane 2363-80A tensile specimen after 18 months implant

in a canine. The surface has wrinkled due to shrinkage of the specimen after molding.
5000 x.

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234

months, then stabilized as about 1.6 to 1.8% weight was gained. When
specimens were vacuum dried, their weight returned to original values
(see Table 1). The mechanical properties of dried specimens increased
upon drying, but not quite to the original values. This was not entirely
unexpected since a slight nonreversible change could occur as a result
of extraction or absorption. At high magnification, evidence of &dquo;cold
flows&dquo; (a molding defect) was found at one location on the specimen
which may also have resulted in some slight nonreversibility (Figure 1)
[10]. Other surfaces of the specimens had a wrinkled appearance, due to
mold shrinkage (Figure 2). There was no microscopic evidence of crack-
ing or any other untoward results. Density remained virtually un-
changed at 1.120 (80A) and 1.162 (55D). DSC showed only that mois-
ture was absorbed. There was no evidence of morphologic or chemical
change at the end of the 2 year study. There was no evidence of degra-
dation and no trends showing continuously declining properties. Thus,
the aged polymer properties remained acceptable for the intended pur-
pose (pacing lead insulation).
Subsequently, other polymers have been similarly tested. These in-
clude Tecoflex EG 80A and EG 60D, Pellethane 2363-80AE, Q-thane
PE97 and Cardiothane-51 coatings on Pellethane 2363-80A. In these
cases, the tensile specimens were injection molded on more modern
screw machines, using conditions recommended by the polymer manu-
facturers. This produced more uniform specimens (without cold flows).
Pellethane 2363-80AE gained 2.2% weight after 24 months implant,
which was completely reversed by vacuum drying (Table 1). Density in-
creased from 1.116 t .003 to 1.127 di .002. There were no changes in
the (bulk) infrared spectrum. Inherent viscosity decreased about 15%.
tensile strength decreased 32% while elongation did not change appre-
ciably. Vacuum drying completely reversed the change in tensile
strength. At high magnifications, however, shallow cracks were found
in the surfaces (Figure 3). Thus, the bulk polymer appears to be reason-
ably biostable, but some question exists about the material-tissue in-
terface.
Tecoflex EG 80A gained 2.6% weight after 16 months implant (table
1). This was not completely reversed by vacuum drying, suggesting that
some non-volatile material had been absorbed. The tensile strength of
the wet specimen increased 22% after implant. Drying the specimen
caused an even greater increase of 69% total. Elongation increased
only 13% (dry). No changes in the (bulk) infrared spectrum were ob-
served. The inherent viscosity of bulk polymer increased slightly
(16%), indicating that an increase in molecular weight occurred. By the
time the Thcoflex resins were evaluated, questions had been posed

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 235

Figure 3. Cracks in Pellethane 2363-80AE tensile specimen surface after 24 months im-
plant in a rat. 500 x.

about the biostability of surfaces. Thus, slices were taken from the
specimens’ surfaces for molecular weight determination (Table 2). Both
the weight and number average molecular weights of the surface mate-
rial decreased by 40% after 18 months implant. Shallow cracks in the
surfaces were seen on the scanning electron microscope. Thus, this
polymer did exhibit evidence of degradation both on surfaces and in its
bulk.
Tecoflex EG 60D gained 2% weight in vivo which was reversible (Ta-
ble 1). No changes in (bulk) infrared spectra were observed. The in-
herent viscosity of bulk polymer increased 50% in 18 months, then de-
creased to within 10% of the original value within the next 8 months.

Table 2. Molecular weight of Tecoflex polyether polyurethane surface material

as a function of implant time.

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236

Slices of surface material showed decreases of 20% in weight average

molecular weight and 16% in the number average value (Table 2). Thus,
the dispersivity decreased from 1.13 to 1.09. Microscopic cracks were
found by scanning electron microscopy. Tensile strength decreased
32%, but this was completely reversed by vacuum drying. Elongation
did not change appreciably in the wet polymer, but decreased by 17%
when vacuum dried. Thus, this polymer showed evidence of bulk stabil-
ity, but with some degradation on the surface.
Cardiothane-51 was evaluated as a coating on Pellethane 2363-SOA.
The molded specimens were dipped in Cardiothane-51 solution which
was then dried and post-treated as recommended by the manufacturer.
The coating cracked and lest adhesion (or vice versa) as a function of
implant time. The substrate did not crack.
The Q-thane PE97 cycloaliphatic polymer exhibited severe cracking
and degradation within 3 months implant. Thus, the study of this poly-
mer was terminated.
Are polyether polyurethanes biostable? Pellethanes 2363-80A and
55D developed small changes in tensile properties early in the experi-
ment that were not entirely reversible. On the other hand, properties
were stable after the acute changes. With no significant changes in
other properties, they certainly appeared to be biostable. In spite of
this, cracking and degradation has been observed on implanted devices
made from these materials. Pellethane 2363-80AE appears to be even
more stable than 80A or 55D according to physical property tests, but
developed shallow microscopic cracks in surfaces. Tecoflex EG 60D ex-
hibited slight irreversible losses in tensile properties with significant
changes in bulk and surface molecular weight and microscopic crack-
ing of surfaces. The long-term biostability of Tecofiex EG 80A appears
to be questionable. Neither Cardiothane-51 coatings on Pellethane
2363-80A substrates nor Q-thane PE97 appear to be suitable for long-
term implant in our tests. Of course, the differences in performance of
these materials might be explained on the basis of their composition.
Another factor to keep in mind, however, are the differences in molding
processes used to make the specimens. As will be discussed later, this
may help to explain the microscopic cracking found by scanning elec-
tron microscopy on the surfaces of some polymer specimens. It is evi-
dent, however, that polyether polyurethanes cannot be said to be bio-
stable as a class.

,
STRESS CRACKING

When stress cracking has occurred, it has been manifested in 2 ways.

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Figure 4. Early cardiac pacing lead 14 months postimplant. Residual tension in the in-
sulation resulted in cracks perpendicular to the device axis. The residual tension was so
great that it pulled the cracks into (relatively) large gaps. 14 x.

Figure 5. Stress cracks in polyurethane insulation of an explanted pacing lead. Cir-

cumferential strain where the polymer tubing was expanded over a larger diameter elec-
trode resulted in cracks perpendicular to the strain vector. 14 x.

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 238

In some cases, microscopic cracking occurred to a shallow depth and

stabilized. Because these microscopic cracks present a dull whitish ap-
pearance, the term frosting has been used to describe them. The other
manifestation of stress cracking is ruptures entirely through the bulk
of the polymer.

Stress Cracking to Rupture on Pacing Leads

When deep cracks and ruptures occur in the bulk polymer of cardiac
pacing lead insulation, they are always oriented at right angles to an
identifiable strain vector. Some examples of such strain vectors are dis-
tortions in the insulation caused by tight fixating ligatures, expansion
of polymer tubing over noncompressible parts (such as electrodes), ex-
cessively sharp kinks or bends in the device or tubing shrunk fit over
conductor coils using swelling solvents (Figures 4, 5). The cracks have
rough, often spiculated walls suggestive of a craze origin. Intact craze
bundles have been observed between crack walls and at the bottoms of
deep, propagating cracks (Figures 6, 7). The polymer between cracks is
(subjectively) still very tough and strong. We developed a punch to cut
microscopic tensile specimens with a necked-down area of .51 mm by
1.3 mm. This punch was used to cut specimens from polymer between
deep cracks. We discovered that there was no significant change in ten-
sile strength or elongation in such cracked material [11]. No signifi-
cant changes in molecular weight or conventional (grating) infrared
spectra have been detected on surfaces or in the bulk of such cracked
material [12]. -

Figure 6. A stress crack in explanted Pellethane 2363-80A which still retains substan-
tial craze structure. 700 x.

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Figure 7. An apparently propagating stress crack in Pellethane 2363-80A which dis-
plays a craze tip at its bottom. 200 x.

Figure 8. Shallow microscopic stress cracks in an explanted leads outer polyurethane

surface. A tight fixating ligature was placed on the lead to the left of the micrograph.
Cracks decrease in apparent depth as a function of distance from the ligature.

239

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240

Frosting on Pacing Leads

Polymer with frosted surfaces have many of the same characteristics

as deeply cracked material. These cracks are also derived from crazes,
but are oriented parallel and at right angles to strain vectors (Figure
8). Cracks are typically deepest just adjacent to a source of strain, and
decrease uniformly in depth as a function of distance from the source of
strain-until they disappear [11]. Frosted surfaces are sometimes also
found at apparently random locations, not clearly associated with an
obvious strain. The cracks always have remarkably uniform depths
(Figure 9). Polymer samples with frosted surfaces have been mounted
under tension for electron microscopy. These specimens have the ap-
pearance of square blocks on an undamaged substrate (Figure 10). The
cracks do not propagate when the substrate is strained. It is generally
believed that cracks in polymers propagate as a result of crazes at crack
tips. Nonetheless, there are no crazes at the base of frosted cracks at
5000 x . Thus, these cracks appear to have stabilized. Our examination
of animal explants for over 3 years implant revealed no evidence that
frosted cracks propagate with time [11]. Beyersdorf did a study on car-
diac pacing leads removed from humans. He found no statistically sig-
nificant correlation between crack depth and implant time [131. As is
true of severely cracked polymer, the bulk molecular weight and in-

Figure 9. A cross section showing very shallow cracks in the tissue contacting surface of
an explanted pacing lead near a tight ligature. Note the very uniform depth of crack-

ing. 14 x.

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 241

Figure 10. An explanted specimen similar to that shown in Figures 5, 8, and 9 has been
mounted under fixed strain. This strain pulled the cracks apart revealing what looks like
an undamaged substrate (no craze tips are visible at up to 5000 x). No crack propagation
occurred. Thus, these are stable, nonpropagating cracks. 510 x.

frared spectra of frosted material does not show any evidence of chemi-
cal degradation in our studies [12].

Initial Hypotheses .

The symptoms of the above phenomena are consistent with a stress

cracking mechanism as defined by Whittington (&dquo;the cracking or craz-
ing of an article when exposed to certain chemicals and stress&dquo;) [14]. As
has been described in detail elsewhere, the residual stress must exceed
some critical value for cracking to occur [4]. Of course, strained poly-
mers undergo stress relaxation at ambient and 37 degrees Celsius, but
to an asymptotic value, not zero. Since residual stress is generated and
maintained by strain, there must also be a critical strain for cracking
to occur. The time required to crack must then be dependent on the
amount of strain exceeding the critical value. Another characteristic of
most stress cracking mechanisms is an induction period, since time is
required for interaction with the chemical component of the mecha-
nism. The amount of residual stress is dependent on any applied strain
and any pre-existing stresses at the molecular level due to morphologic
factors. Polymer morphology varies with process parameters such as
melt temperature, cooling rate, orientation, annealing, etc. Thus, stress
cracking must also vary with processing conditions. A third character-
istic of the mechanism, therefore, should be variation in critical strain
and induction period as a function of processing conditions.

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242

Stress Cracking Tests on Pellethane 2363-80A

An accelerated stress cracking test was developed on the premise

that cracking will occur relatively rapidly at very high strains [4J. Fig-
ure eight shaped wire mandrels or polysulfone dumbbells (13 mm long)
were inserted in tubing. The tubing was then strained in a fixture.

Tight ligatures were placed at each end of the mandrels to fix the
strain. Up to 4 such specimens were tied end to end in strings of up to
4 pieces each. Then up to 4 such ethylene oxide sterilized strings of
specimens were implanted subcutaneously in rabbits.
In early studies, specimens included strains ranging from 0 to 500%
elongation in increments of 100%. Explants were made weekly for 12
weeks. All specimens were examined by optical and scanning electron
microscopy. Pellethane 2363-80A tubing extruded into a very cold tank
developed cracks at 100% elongation in 1 week. Simply switching to a
hot take-off tank (slowing the heat transfer rate) increased the induc-
tion period to 4 to 5 weeks and the critical strain to 200-300% elonga-
tion [12]. Some variation in these findings occurred in later tests as a
function of raw material lot, but process sensitivity remained a consis-
tent finding. Annealing the specimen to produce 100% stress relaxa-
tion completely eliminated cracking in this test [4,12]..
A factorial experiment was done to evaluate and verify the effects
and interactions of various processing parameters on the stress crack
resistance of Pellethane 2363-80A. Since the existence of induction pe-
riods, critical strains, etc. had been demonstrated in previous experi-
ments, the new test could be simplified. We implanted all specimens for
12 weeks only, on a go/no go basis. If cracking occurred, the timing was
not important since the ultimate goal was no cracks. The variables
tested were hot and cold heat transfer in the extrusion take-off tank,
baking or not baking tubing in air prior to strain, no strain and 400%
elongation, annealing to 100% stress relaxation or not annealing speci-
mens after strain and the effects of extraction of tubing prior to speci-
men assembly. Each variable combination was represented once in each
of 36 rabbits for a total of 576 specimens. The optical microscopic re-
sults were analyzed by BMDP, SAS and StatGraphics Statistical pro-
grams.
There were several statistically significant effects and interactions in
the 32 processing combinations evaluated. The outstanding primary ef-
fect (cause of ESC) was clearly shown to be excessive stress (strain) in
the absence of annealing. The single most important factor preventing
ESC was annealing to 100% stress relaxation. Slow heat transfer on ex-
trusion also improved stress crack resistance, but to a lesser degree

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 243

than annealing. Thus, this study confirmed with high statistical con-
fidence that the mechanism is a form of stress cracking, that it criti-
cally depends on applied and morphologic strain and that it can be pre-
vented by .annealing processes. A very interesting observation in this
study was the fact that most process combinations exhibited significant
animal to animal variation, e.g., &dquo;biologic variance&dquo;’ In fact, cracking
only occurred in 40% of the rabbits. Thus, unless the processing was
just right (or just wrong), the animals’ chemistry did or did not interact
with residual stress to cause cracking. We can, therefore, redefine the
mechanism of in vivo stress cracking as the formation of crazes or
cracks through the interaction of residual stress with the biologic
(mammalian) environment of certain individuals. -

Oxidative Stress Cracking

Oxidative stress cracking is a tempting and often proposed possibility

to explain the observed facts. While conventional grating infrared
spectroscopy techniques have shown no changes in cracked surfaces,
Fourier transform infrared spectroscopy (FTIR) using attenuated total
reflectance reveals definite evidence of oxidation on cracked surfaces.
The key findings are a substantial reduction in PTMO ether stretch
(1110 cm-1), the-appearance of a new ester carbonyl (1175 cm-’) and
changes in bonded and unbonded carbonyl stretch (1703 and 1730
em-1). On electron micrographs of cracked surfaces, the outer micron or
less is much brighter than the substrate (Figures 9, 10). Remembering
that these micrographs are photographs of a television image gener-
ated by an electron beam, it is evident that (in the absence of charging)
the surface material has a different &dquo;electron density&dquo; than the bulk.
Thus, the surface of cracked material is somehow different than un-
cracked surfaces or bulk. These findings support the contention that an
extremely thin layer of oxidized polymer exists on cracked surfaces.
But, is oxidation a cause or a result of cracking? Several tests were
done to try and answer this question.
Pellethane 2363-80A tubing was extruded from pellets that had been
extracted in chloroform to remove low molecular weight polymer, anti-
oxidant and extrusion lubricant. By compounding with the extruder,
antioxidant and extrusion lubricant were added back so that testing
could be done in the absence of antioxidant, absence of extrusion lubri-
cant or the absence or presence of both. Accelerated in vivo stress crack-
ing tests showed that the presence or absence of these additives had a
slight to negligible effect on Pellethane 2363-80A and no significant ef-

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244

fect at all on Pellethanes 2363-55D or 2106-80A (commercial grade of

2363) [4].
All attempts to produce oxidative stress cracking in vitro have failed,
even when strained specimens were immersed for 12 weeks in fre-
quently refreshed 3% hydrogen peroxide or other strong oxidants.
Baking in air must result in the initiation of autooxidation on the
surface. In the factorial experiment discussed above, however, there was
only a very slight increase in cracking when the polymer was baked in
air prior to strain.
Oxidative stress cracking can be defined as crazing or cracking due to
an interaction between autooxidation or an oxidizing environment and
stress. If processed appropriately, strained Pellethane 2363-80A tubing
cracks rapidly (weeks) in the low oxygen in vivo environment, but it
does not crack in strong oxidizing in vitro environments or in air.
Cracking is neither significantly accelerated by removal of protective
antioxidants or extrusion lubricant nor by baking in air. Thus, these
data do not appear to support an oxidative stress cracking mechanism.
If the cracking mechanism is not caused by oxidation, then why are
autooxidation products detected on cracked surfaces by FTIR? As noted
above, stress cracks are formed from crazes. As craze bundles break,
many millions of polymer molecules are broken, each generating 2 free
radicals. Since these free radicals cannot recombine because of tension,
they must react with antioxidant (rapidly depleting it) or any available
oxygen. When those options are exhausted, the free radicals migrate by
disproportionation, generating many more free radicals [15]. By defini-
tion, this means that stress cracking initiates autooxidation. Since au-
tooxidation in solids is diffusion limited, its rate slows significantly in
the bulk (near surface), leaving a very thin layer of oxidized polymer.
Thus, stress cracking appears to be a cause of autooxidation, not a re-
sult of autooxidation.

Enzymatic Stress Cracking

’

Gladhill et al., Marchant et al. and Smith et al. have independently

demonstrated that certain unstrained polyether polyurethane surfaces
can be mildly affected by inflammatory enzymes, but without signifi-
cant degradation [16-18]. It is then tempting to assume that an enzy-
matic stress cracking mechanism exists where residual strain exacer-
bates surface damage, resulting in cracking. However, when strained
Pellethane 2363-80A samples are immersed in frequently exchanged
37°C enzyme solutions (such as buffered papain, a-chymotrypsin or

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 245

leucine amino peptidase), no cracking has occurred. Additional tests

are in progress at another laboratory to confirm this.

Calcification Stress Cracking

A calcification stress cracking mechanism has been proposed by
Thoma et al. [19]. He proposed that calcium ion can be chelated by the
ether soft segment, embrittling the surface, allowing stress cracking to
occur. As has been discussed above, in vivo stress cracks are derived
from crazes, which are a ductile-not brittle phenomenon. When ex-
planted cracked samples are analyzed by electron dispersive analysis
by X-ray in our laboratory we commonly observe traces of calcium as
well as other biologic residues (such as potassium and chlorine). When
the specimens are rinsed in water (sonicated), however, the biologic res-
idues, including calcium, are usually removed. When strained Pelle-
thane 2363-80A specimens are immersed in saturated 37°C CaClz,
CaHP04, or 3% calcium lactate solution for 12 weeks, no cracking oc-
curs. Thus, we find it difficult to accept a calcification stress cracking
mechanism at this point.

Absorptive Stress Cracking

One of the first proposed mechanisms was based on the hypothesized
absorption of biologic material. When material is absorbed, the poly-
mer surface is plasticized. In effect, the &dquo;yield strength&dquo; of the poly-
mer’s surface is reduced to the level of residual stress. Then, crazes, fol-
lowed by cracks can occur. Pellethane 2363-80A is readily plasticized by
lecithin or glycolic acid. Nonetheless, exposure of strained specimens in
37°C emulsions or solutions of lecithin, synthetic plasma or glycolic
acid for 12 weeks did not result in cracking. Thus, a strictly absorptive
mechanism does not seem likely either.

Other Forms of Stress Cracking

In fact, stress cracking has not been duplicated in vitro in spite of ex-
tensive attempts. A partial list of the media we have tried so far is pre-
sented in Table 3. It is particularly interesting to note that in vitro in
blood, plasma, or serum, stress cracking does not occur, whereas it does
occur in vivo in blood, subcutaneous, intramuscular and other living

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246

Table 3. Partial lisi of in vitro Pellethane 2363-80A media used in stress

cracking tests at 37°C.

tissues. Thus, we still have not identified the chemical portion of the
stresscracking mechanism. A new hypothesis that is currently under
investigation is that a living cellular interaction is required.

The Residual Stress Component of Stress Cracking

When polymers are molded or extruded, sudden cooling can freeze

the outer (surface) molecules in their molten or amorphous conforma-
tion. The bulk cools slower, allowing more rapid crystallization or
phase separation. Thus, the surface and bulk morphologies can be dif-
ferent, giving rise to residual stresses and neutral axes. Orientation
can also induce significant residual stresses. All of these stress risers
can vary as a function of molding or extrusion process, especially heat
transfer rates. The faster the heat transfer rate the more residual

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 247

stress can be built into the polymer. Even more residual stress can be
built in during device manufacture, during implant and by normal
body motions. Relatively large localized stress can be generated at sur-
faces by imposed deformations such as bending or fixation ligatures.
Cracks will propagate until the driving stress is relieved, sometimes at
neutral axes. The depth of cracks will vary with the intensity of resid-
ual stress. Cracks, therefore, must be deepest adjacent to stress risers,
decreasing in depth and density as a function of distance from the
source of strain.
The above theory may help explain why Pellethanes 2363-80A and
55D tensile specimens did not crack in vivo, while other polyether poly-
urethanes did in early studies. The Pellethane 2363-80A and 55D spec-
imens were molded on a ram press. The resin must be very hot (in fact,
overheated) because heat is transferred to the pellets from the wall of
the ram barrel by convection only. The mold was not temperature con-
trolled, so it also heated up. Thus, these specimens were made with a
very hot melt and a warm mold, which appears to be optimum condi-
tions to minimize stress cracking. The later specimens were made on a
screw machine. This allowed molding at much lower temperatures, us-

ing both shear and heat to melt the polymer, shooting it into a rela-
tively cool mold. These are conditions that can maximize residual
stresses. Extruders are also screw machines which push molten poly-
mer into a cold take off tank to form tubing. Thus, the apparent para-
dox of in vivo cracking on devices made from polymers shown to be
biostable in early tests can be explained on the basis of different pro-
cessing conditions, maximizing or minimizing residual molecular
strains, causing or preventing stress cracking.

Accelerated Stress Cracking Tests on Other Polymers

Numerous polymers in addition to Pellethane 23fi3-80A have been
subjected the accelerated in vivo stress cracking test with results
to
summarized in Table 4 [4]. Tubing was extruded either by the polymer
manufacturer or by processes recommended by the polymer manufac-
turer. Note that in addition to the data in Table 4, tests on Pellethane
2363-55D have demonstrated very fine shallow, microscopic cracking
only at the limits of the test (e.g., at 500% elongation). In addition, very
shallow stress cracking has been observed on explanted Pellethane
2363-55D devices. Thus, it appears that all polyether polyurethanes
are susceptible to stress cracking phenomena to widely varying de-
grees. So far, only one correlative factor is evident in addition to the

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Figure 11. The wall of a crack in oxidized polymer (similar to Figure 12). The lumen of
the tubing is to the upper left. The crack wall is mirror smooth with no evidence of craz-
ing. 830 x.

Figure 12. Cracks the surface of an oxidized piece of Pellethane 2363-80A. Notice the
random morphology of cracks and lack of crazing. 480 x.

250

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 251

effects of processing conditions. The susceptibility to stress cracking ap-

pears to be directly proportional to the ether content of the polymer.
Extensive processing studies have only been done on Pellethanes 2363-
80A and 55D. It may be, however, that process sensitivity is also a func-
tion of ether content.

AUTOOXIDATION

Cracking has been found inside pacing leads that does

some cardiac
not match the characteristics of stress cracking. The phenomenon has
been described in detail elsewhere [5,11]. In summary, the cracks have
mirror smooth walls with no evidence of crazing (Figure 11). They may
be oriented with stress vectors, but can also be random (Figure 12). The
cracked polymer is either soft and gummy or hard and brittle. It is usu-
ally associated with corrosion of conductor coils (Figure 13). Infrared
spectra of bulk polymer show significant loss of PTMO ether stretch
(1110 cm-1) relative to amide III (1220 cm-1) and urethane ether (1080
cm-1); and changes in the bonded and free carbonyl bands (1730 and
1703 cm-1) (Figure 14). When degradation is severe, a new (ester) peak
appears at 1175 cm-1. Atomic absorption spectrophotometry and elec-
tron dispersive analysis by x-ray typically show elevated metallic con-
tent in the bulk and on surfaces [5,11].

Thermally Accelerated in vitro 1èsts

Coury et al. studied the effects of various metal ions and oxidizers on
Pellethane 2363-80A at elevated temperature. He found that nitric acid
(oxidizing acid) oxidized the polymer while strong base (NaOH) or hy-
drochloric acid (reducing acid) did not [201. Metal ions with electrode
potentials a .7V(M° M+ + E) caused oxidative degradation as dem-
=

onstrated by changes in molecular weight, stress-strain properties and

infrared (FTIR) spectra. Coury also showed that other polyether poly-
urethanes are susceptible to oxidation by silver ion in direct proportion
to their ether content [5]. That is, the higher the ether content, the
more severe damage was done in his test. Thus, certain metal ions can
interact with ether linkages to cause autooxidative degradation.

Accelerated 37° in aitro Tests

The process of polymer autooxidation requires oxygen for its initia-

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Figure 13. Surface of DBS (silver-MP35N-composite) conductor coil wire showing crystal-
line metallic corrosion products near oxidized Pellethane 2363-80A insulation. 1000 x.

Figure 14. Tracings of Pellethane 2363-80A bulk infrared spectra. Top: spectrum of
unimplanted polymer. Center: spectrum from an explanted, severely cracked lead or lead
insulation degraded in 3% hydrogen peroxide at 37°C. Bottom: spectrum of nearly disin-
tegrated polymer in the presence of cobalt after 6 months in 3%, 37 °C hydrogen peroxide
or 1 year subcutaneous implant in a rabbit.

252

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 253

tion and propagation. The venous system and capillary bed where car-
diac pacing leads are placed is a low oxygen environment compared to
air. One possible source of oxygen in vivo is the inflammatory process,
especially as related to exocytosis [21,22]. Various phagocytes, such as
macrophages, are known to release hydrogen peroxide, hydroxyl radi-
cal, hydroperoxyl radical and superoxide anion. These chemicals and
many others must be deposited on the outer surfaces of an implanted
device as a consequence of the normal inflammatory &dquo;foreign body&dquo; pro-
cess. Pacing leads were immersed in 37°, 3fob HzO2 for periods of up to
six months [23]. The peroxide was replaced with fresh solution every
other day to assure maximum activity. A good qualitative correlation
with the actuarial performance of implanted leads was found. Those
lead models with the lowest in aivo actuarial survival also performed
poorly in the peroxide test [23,24]. Those that had not experienced oxi-
dative degradation in humans were not damaged in the peroxide test.
The same analytical results were obtained with leads immersed in per-
oxide and explanted from humans and animals. The same corrosion of
conductor coils was observed, the same optical and electron microscopic
appearance and texture of cracked material was seen, the same infra-
red spectra were obtained, etc. Thus, this test may have some predictive
value to evaluate the oxidative stability of an implantable device.

Figure 15. Nearly disintegrated Pellethane 2363-80A tubing over a cobalt mandrel after
6 months immersion in 3%, 37°C hydrogen peroxide. A comparable appearance is found
on some similar specimens after 2:1 1 year implant in a rabbit. 46 x.

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 254

Table 5. alo retention of tensile strength and elongation of Pellethanes 2363-

80A and 55D tubing in the presence of various materials after 6 months
immersion in 3%, 37°C hydrogen peroxide.

’Significant if P < .05 compared to unimmersed control.

In Uitro Materials Variables Study

A series of peroxide tests were done to determine just what metal-
polymer interactions exist at 37 ° C in pacing leads [5]. Conductor coils
were made of various alloys used in cardiac pacing (Elgiloy, MP35N,
304 stainless steel and DBS-a silver/MP35N composite) and their
component pure metals (Ni, Mo, Fe, Ag). Chromium (also a component
of these alloys) was not available in wire form of the correct size, so
powder was used. Cobalt was tested as mandrels, machined to resemble
a coil surface. Additional metals used in pacing were included as coils

(Pt and Ti). Controls were empty tubing and glassballs. The tubing was
dilated in acetone, then shrunk fit over the coil/mandrel/powder to
assure about .13 mm interference fit over the 1.9 mm o.d. coils or man-
drels. The tubing was extruded Pellethane 2363-80A (P80A) or 55D
(P55D) with a wall thickness of .13 mm. The ends of the 6&dquo; long speci-
mens were sealed to assure that no direct fluid leakage could occur. The

specimens were immersed in frequently exchanged 37 ° C-3% H202 for

six months. Within three days droplets were found on the inner walls
of P80A tubing. Gas generation (0~ by mass spectroscopy) caused the

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 255

tubing to swell over Co, Ag, Pt and possibly Cr. By the end of the experi-
ment, substantial residues were found inside P80A samples containing
Fe (rust red) and Ti (cream-colored) > MP35N (cream-colored) > DBS
(white flakes) and silver (purple) > 304SS demonstrating that corro-
sion had occurred. Only traces of residues were found inside P55D spec-
imens in the presence of chromium, DBS, Elgiloy, glass (all whitish)
and cobalt (blue flakes). The P80A tubing disintegrated over cobalt
(Figure 15). Fine shallow cracks were observed in the presence of Ti
and DBS. Pellethane 2363-55D lumen surfaces cracked in the pressure
of Co and Ma The other P80A and P55D samples appeared to be un-
damaged optically, but some changes in tensile strength and elonga-
tion occurred (see Table 5).
Infrared spectra of P80A over Co showed extensive loss of PTMO
ether (1110 cm-i) relative to urethane ether (1080 crri 1) and amide III
(1220 cm-l) with the generation of a relatively large ester carbonyl at
1175 cm-1, the loss of CH, symmetrical stretch at 2860 cm-’ vs. asym-
metrical stretch at 2940 cm-1 and substantial changes in the complex
between 760 and 860 (Figure 14). Pellethane 2363-55D has less PTMO
ether compared to P80A to begin with. Nonetheless, there were clear
changes in the P55D infrared spectra in the presence of Co, which were
essentially the same as those found in Pellethane 2363-80A in the pres-
ence of Co. The other tubing specimens exhibited little to no change in

Figure 16. Pellethane 2363-80A lumen surface after 1 year subcutaneous implant in rab-
bits. Stripes of cracks are located at places where the metallic coil wires touch the poly-
mer. 100 x .

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 256

infrared spectra except for the lumens of P80A tubing over DBS and
Elgiloy. These spectra were similar to those described above. The bulk
polymer spectra were unchanged.
Thus, this in vitro study shows that significant bulk degradation of
P80A and P55D can occur in the presence of hydrogen peroxide and Co
and Mo, whereas surface damage was done where polymer contacted Ti
and DBS. Some bulk changes in the presence of Co bearing alloys,
MP35N and Elgiloy are presumed to be due to release of Co ions.

In UIUO Materials Variables Study

A similar study was conducted in vivo [5]. The specimens were much
shorter, however (13 mm long). The specimens were implanted in rab-
bits as four strings of four specimens each, similar to the in vivo accel-
erated ESC test. Explants were done after 8, 12, 18, and 24 months.
Analysis of the 18 month specimens is almost complete while evalua-
tion of 24 month samples is in progress.
After 18 months implant, P80A samples over cobalt had appearances
ranging from severe cracking in 60% of the rabbits (similar to Figure
15) to no visible cracking (at 100 x) in 40%. Cracks occurred in lumen
surfaces only where the coil and tubing made contact in the presence
Elgiloy (cracks found in 2 of 5 animals) and MP35N (once in 5 animals)
(Figure 16). No cracks were seen on P55D lumen surfaces. In the pres-
ence of Co, the tensile strength and elongation of cracked P80A sam-

ples were severely reduced, whereas those specimens with no cracks

had essentially normal mechanical properties (Table 6). Other signifi-
cant, but less severe changes in P80A mechanical properties were seen
in the presence of Mo, Cr, DBS, Fe and Ti. P55D experienced loss of me-
chanical properties in the presence of Co, MP35N, Cr, glass, Fe, Ag, Ti
and Ni. Surface FTIR of P80A lumens showed essentially no change in
the ratios of urethane ether (1080 cm-0, PTMO ether (1110 cm-1) and
amide III (1220 cm-1), except in the presence of cobalt (Figure 14). The
molecular weight (Mw) of P80A over Co samples ranged from -60%
lower to +19% higher than controls, depending on the rabbit. On the
average the Mw of P80A in the presence of Co was 33% lower than the
control, which was significant (P = .005). DBS also produced a signifi-
cant loss in P80A Mw(P .046). Molecular weight data on P55D spec-
=

imens are not yet available.

Thus, these data generally confirm the validity of the in vitro 37 ° C
peroxide test, demonstrating that Pellethanes 2363-80A and 55D are
subject to metal ion oxidation, especially in the presence of Co corro-
sion products.

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 257

Table 6. alo retention of tensile strength and elongation of Pellethanes 2363-

80A and 55D tubing in the presence of various materials
(18 months postimplant in rabbits).

’Significantif P < .05 compared to empty specimen. &dquo;

2Range 0-100%.

CONCLUSIONS

Early long-term animal tests demonstrated the biostability of Bio-

mer and Pellethanes 2363-80A and 55D. However, Pellethane 2363-80A
has subsequently been shown to be very process sensitive. If processed
in such a way as to leave residual stresses in the polymer, it can develop
microscopic cracks in tissue contacting surfaces due to an in vivo stress
cracking mechanism. Very deep stress cracks can occur in response to
applied strain in excess of a critical value. In vivo stress cracking can
be defined as the formation of crazes or cracks in a polymer by interac-
tions between residual stress and the mammalian body in susceptible
individuals. In vivo stress cracking of P80A can be prevented by con-
trolling manufacturing processes, annealing to 100% stress relaxation
and controlling implant stresses. In general, the resistance of polyether
polyurethanes to in vivo stress cracking appears to vary as a function
of ether content. Thus, Pellethane 2363-55D, Tecvflex EG60D and an-
nealed (100% stress relieved) Pellethane 2363-80A specimens have ex-
cellent in vivo stress crack resistance.
An in vivo autooxidative degradation process in polyether polyure-

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 258

thanes can be accelerated by the corrosion products of metallic compo-

nents of an implanted device. The corrosion products of cobalt appear to
be the strongest oxidizers. Again, the extent (or rate) of oxidative
damage appears to vary as a function of ether content.
Thus, some polyether polyurethanes are biostable with 2 conditions.
The device must be relatively free of residual stress (strain) and should
be used in a relatively low stress (strain) configuration. If metallic com-
ponents of the device cannot be avoided, significant corrosion (espe-
cially corrosion generating cobalt based ions) must be prevented.

REFERENCES

1. Lelah, M. D. and S. L. Cooper. Polyurethanes

in Medicine. Boca Raton:CRC
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2. Boretos, J. W. J. Biomed. Mater. Res., 6:473 (1972).
3. Stokes, K. B. and K. Cobian. Biomaterials, 3:225 (1982).
4. Stokes, K., P. Urbanski and K. Cobian. In Polyurethanes in Biomedical En-
gineering II. H. Planck et al., eds. Amsterdam:Elsevier, pp. 109-127
(1987).
5. Stokes, K., A. Coury and P. Urbanski. J. Biomater. Appl.,
1:411-448 (1987).
6. Szycher, M. J. Biomater. Appl., 3(2):000 (1988).
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diac Pacing. K. Steinbach et al., eds. Darmstadt:Steinkopff-verlag, pp.
323-330 (1983).
9. Darby, R. and A. Kaplan. Applied Microbiology, 16:900-905 (1968).
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tura, pp. 173-198 (1985).
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Gebelein, ed. New York:Plenum, pp. 147-158 (1985).
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eds. Amsterdam:Elsevier, pp. 287-290 (1985).
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Technomic, p. 90 (1968).
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19. Thoma, R. J. J. Biomater. Appl., 1:449-486 (1987).

20. Coury, A. J., P. T. Cahalan, E. L. Schultz and K. B. Stokes. Second World
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ABOUT THE AUTHOR

Kenneth Stokes is a Corporate Research Fellow

at Medtronic, Inc. in Minneapolis, Minnesota. He
has conducted and/or managed biomedical re-
search there since 1970 with emphasis on poly-
mer biocompatibility and biostability, electrode

technology and device design.

Prior to 1970 he was employed as a Research
Chemist by General Mills Chemicals, Inc. in Min-
neapolis. In this capacity he conducted research
on polymer synthesis, processing, morphology,
degradation and stabilization.
Mr. Stokes is a member of the Society for Biomaterials and the Amer-
ican Chemical Society, divisions of Polymer Chemistry and Polymeric
Materials: Science and Engineering. He holds numerous patents in the
areas of polymer synthesis, polymer stabilization and implantable de-
vices. He has contributed over 60 papers and book chapters in the car-
diac pacing and biomaterials literature. His research and prototype
device design led to the widespread use of polyether polyurethanes in
implanted cardiac and neurologic pacing leads. Work on electrode tech-
nology has led to the development of a glucocorticosteroid eluting elec-
trode which requires very low stimulation energies through control of
inflammation.

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