Download Thermoplastic Polyurethanes as Medical Grade

Thermoplastic Polyurethanes as Medical Grade Thermoplastic Elastomer
Anthony Walder, Lubrizol Advanced Materials, Wilmington, MA
Pallavi Kulkarni, Lubrizol Advanced Materials, Wilmington, MA
Abstract:
Thermoplastic polyurethanes (TPUs) are a class of thermoplastic elastomers (TPEs) that are used in a variety of
applications. TPUs exhibit low temperature flexibility, excellent abrasion resistance, high tensile strength biocompatibility
and good processing characteristics. TPUs have found medical applications used for seconds to life-of-patient. TPU’s can
be designed with chemical resistance, hydrolytic stability and/or oxidative stability to meet the variety of applications. The
application can include moisture vapor transmitting materials for wound care, chemical resistant grade for gastric uses and
oxidative and hydrolytic stability for long term implantable devices.
Introduction:
Polyurethanes are one of the many classes of
materials used in medical devices. The properties of
polyurethanes can vary greatly. Polyurethanes range
from soft and flexible made of predominantly soft
domains to rigid but ductile materials made of
predominantly hard domains. The hard domain,
including an extender, is defined by the diisocyanate.
The soft domain is described by the macrodiol.
Combinations of diisocyanates, extenders and
macrodiols result in a class of materials known for
their strength, flexibility, processibility and
biocompatibility. The diversity of monomers
available can result in a material, which provides a
device with unique properties1,2.
Many medical devices have been improved
because of the flexibility and strength characteristics
of polyurethanes. Catheters are one of these devices3.
Catheters are a very important part of the medical
technology because they are used in many medical
procedures. Catheters are mainly used to deliver
medications, but are also used to transport fluids,
deliver devices and other applications. Developing a
catheter must include input from the practitioner, the
patient, manufacturing and marketing. Polyurethanes
offer flexibility, biocompatibility, processibility and
strength. The catheters made with polyurethanes have
unique and in most cases, superior properties
compared to the same device made from another
material.
Discussion:
Many questions must be asked in order to
design the best device. One of these questions is
what material will make the best device. Materials
available included polyurethanes, natural rubber,
metals, polyvinyl chloride, silicones, polyethylene,
polyamides, polypropylene, polystyrene,
polycarbonate, acrylics and many more. Selection of
materials for medical applications requires an
educated choice. Several questions must be
answered. What function does the device perform?
What types of tissue(s), fluid(s) and/or drug(s) will
contact the device? Where is the device going to be
placed? What is the intended and/or possible life
expectancy of the device? How is the practitioner
going to place the device? What manufacturing
method will be most practical in assembling the
device? What are the material and manufacturing
costs? What color is requested? After answering
these questions, the final material candidates should
include polyurethanes.
Currently many medical devices are made
from polyurethanes. These include: central venous
access catheters, over-the-needle catheters,
peripherally inserted central catheters, urological
stents, intra-aortic balloon pumps, epidural catheters,
condoms, PEG tubes, angioplasty catheters, etc. The
strength, processibility, biocompatibility and
versatility are only a few reasons polyurethanes are
being used in these applications. In many cases
polyurethanes offer a unique characteristic resulting
in a device with a competitive advantage.
The attributes of polyurethanes can be
contributed to their structure. Polyurethanes are
made of hard and soft domains. Polyurethanes are
synthesized from diisocyanates, macrodiols and
extenders. The diisocyanate and extender make up
the hard domains and the polyol make up the soft
domains. Common diisocyanates are methylene
dicyclohexyl diisocyanate (H12MDI, aliphatic
character) and methylene diphenyl diisocyanate
(MDI, aromatic character). Generally, MDI based
polyurethanes are stronger and more solvent resistant
than the aliphatic H12MDI materials. The primary
macrodiol for medical applications is polytetramethylene glycol. In addition, polycarbonate diols
have sparked much interest is recent years for their
biostability. The polyester diols, which usually have
better tensile strengths and are more abrasion
resistance than the polyethers, have found a place
only in short-term medical applications. This is due
to loss of physical properties when placed in the body
and unfavorable enzymatic interactions and moist
environments associated with medical applications.
A medical grade line of polyurethanes incorporating
a hydrocarbon diol was introduced recently4. The
hydrocarbon diol is bio-based and imparts a
hydrophobic surface. The extenders of choice are
linear in chemical structure which usually gives the
polymer excellent strength. Seven classes of
polyurethanes can be synthesized from these raw
materials. The classes are aromatic and aliphatic
polyetherurethanes, aromatic and aliphatic
polycarbonateurethanes, aromatic and aliphatic
polyesterurethanes and aromatic
polyhydrocarbonurethanes. The changing of the
durometer of a polyurethane is accomplished by
varying the ratio of polyol to diisocyanate and
extender and not by adding a plasticizer to a stiffer
polyurethane.
Strength:
In general, soft polyurethanes are stronger
than other soft materials. In many instances, strength
is the only reason for selecting polyurethanes.
Natural and synthetic rubbers, polydimethylsiloxane
(PDMS), flexible PVC and the emerging TPE
olefinics are not as strong as polyurethanes. This
becomes important in designing a device with the
highest flow rate possible while the outside diameter
of the tube is fixed by definition. For example, a five
French tube has an outside diameter of 1.65-mm
(0.065”). If this catheter requires a nominal strength
of 4.3-Kg (9.5-lbs.), a polyurethane catheter would
require a wall of 0.25-mm (0.010”) resulting in a
1.10-mm (0.045”) inside diameter tube. Polyether
block amides (PEBA) 5 at the same durometer, in a
tube of the same dimension, would break at
approximately 3.1-Kg (6.9-lbs). High-density
polyethylene,6 which has approximately a Shore 60D
durometer, also would break at about 3.1-Kg. In
turn, flexible PVC6 and PTFE6 would break near 2.7Kg (6.0-lbs). PDMS5 and low density polyethylene5
are lower at 2.0-Kg (4.3-lbs) and the natural rubber
and some olifinics6 at 0.9-Kg (2.0-lbs). If the tube
strength of 4.3-Kg is required, PEBA and flexible
PVC tubes would require a wall thickness of 0.38mm (0.015”) and 0.47-mm (0.0185”) and inside
diameter of 0.89-mm and 0.71-mm (0.035” and
0.028”), respectively. The ultimate tensile strength of
PDMS and natural rubber is insufficient to make
tubes with 4.3-Kg break strength.
Softening:
Softening characteristics are another unique
feature of polyurethanes. The change from 23C to
37C and direct water contact softens the material.
These materials soften to various degrees when
placed into the body. The degree of softening is
dependent on the initial hardness and the chemical
make-up of the material. Generally, low durometer
polyurethanes soften 30 to 50% when placed in 37C
water. Hard polyurethanes generally soften to a
greater extent. The change ranges from 30 to 99%
depending on the initial durometer and chemical
makeup.
Tear and Abrasion Resistance:
Many devices are placed in areas that rub
against hard materials and bend repeatedly. Without
excellent flexibility, tear resistance and abrasion
resistance, the continuing rubbing and bending would
result in weakening the device or may cause failures
in extreme cases. Polyurethanes outperform many
other common materials in flexibility, tear resistance
and abrasion resistance. Natural rubber, PDMS and
polyurethanes have good to excellent flexibility and
tear resistance. Polyurethanes outperform these
materials in abrasion resistance. For most
polyurethanes between 90A and 75D, the flexibility,
tear resistance and abrasion resistance are superior to
materials such as polyethylene, PTFE and PVC.
Biocompatibility:
The biocompatibility of polyurethanes was
established in the 1980’s7,8,9. Several studies have
shown that in general polyurethanes have better
blood compatibility than other materials. Protein
adsorption, which is the beginning of the blood
coagulation cascade, was found to be slower and/or
less than many other materials. In contrast, natural
rubber contains materials that can cause a fatal
allergic reaction. Flexible PVC contains plasticizing
agents, which may leach from the PVC into the body.
Therefore, placing PVC into a body is not desirable
because of possible biocompatibility concerns. The
durometer of polyurethanes are changed through the
ratio of monomer, not by the addition of fillers or
plasticizers.
Ease of Manufacturing:
Manufacturing a device can be made easier
by using polyurethanes. They are available in
injection molding, extrusion and solution grades as
well as in two part reactive systems. This offers the
manufacturer a choice of how to obtain the end
device. For example, complex multi-lumen tubing
can be extruded, hubs are injection molded or insert
molded over tubing, junctions are insert molded, thin
films can be solution cast over mandrels or devices,
and electronics can be encased with two part reactive
systems. Polyurethanes can be bonded using
common bonding techniques. The techniques include
uses of general adhesives, solvent bonding and melt
techniques. Polyurethanes are easily printed on and
sterilized using ETO, E-Beam or gamma sterilization
techniques.
Unlike polyurethanes, natural rubber, PMDS
and PTFE are difficult to process. Natural rubber is
not melt processible but is cast from emulsions or
compression molded. PDMS components are formed
using reactive molding, reactive extrusion or casting.
PTFE is difficult to process due to limited processing
temperatures and solubility. PTFE, natural rubber
and PVC can not be gamma sterilized.
Versatility:
Polyurethanes are much more versatile than
the above mentioned materials. Polyurethanes can
easily be colored, filled with radiopaqueing agents
and many other materials. The aliphatic
polyetherurethanes are very easily colored with dyes
or pigments. Aromatic polyurethanes are slightly
more difficult to color because these materials yellow
with time and exposure to UV or gamma sterilization.
Radiopaqueing agents are added to materials to aid in
placements of devices or for finding lost components.
The most common radiopaqueing agent is barium
sulfate. Bismuth salts, such as bismuth oxychloride,
bismuth subcarbonate and bismuth oxide are also
used as radiopaque agents in low melt processing
materials such as the aliphatic polyetherurethanes.
Tungsten, organic bromine compounds and even lead
have been used to make polyurethanes radiopaque.
Varieties of additives are used in
polyurethanes for multiple purposes. Lubricants are
added for processing improvements. Antioxidants
are added to protect the material during processing.
Antimicrobial agents such as silver metal, silver
sulfadiazene or Chlorohexadine salts have been
incorporated to reduce the chance of infection.
Anticoagulants such as heparin have been
incorporated to prevent blood clotting on the surface
or inside the tubing.
Patient Considerations:
The easiest question to answer is the
patient’s requirement. Put plainly, the patient does
not want a tube placed into their body. If the patient
needs a catheter, they prefer the least amount of pain
and discomfort during placement, use and removal.
This equates to the smallest catheter possible, best
insertion technique and the softest possible material.
Polyurethanes can satisfy most of these requirements.
Polyurethanes are stronger than most soft materials.
Therefore, the outside diameter of the catheter of a
stronger material can be smaller while holding the
inside diameter constant for the same fluid transfer.
This results in a smaller tube and reduces cutting or
moving of tissue. The strength and processibility of
polyurethanes also allows the catheter to have a
sharper/smoother tip for easier placement. This
results in less pain during placement and reduces
trauma. Polyetherurethanes soften in the body. The
degree of softening is related to the durometer in the
material. Hard materials (Shore durometers of 65 to
75D) soften as much as 95% at body temperatures of
37C and 100% humidity. Soft materials (i.e. 75A)
soften only 20 to 30%.
Examples:
Wound care is an example where
polyurethanes excel. TPU can easily be processed
into thin films and secondary processed to make the
wound care device. Another attribute of
polyurethanes is breathability can be designed into
the material. Wounds have difference characteristics
and many types heal faster if kept moist but not too
moist. Polyurethanes can be designed to achieve the
correct moisture level at the wound site. For example
a typical 85A Shore Durometer aromatic
polyetherurethane has a MVTR10 approximately
850g/m2/day. Aromatic polyurethane designed for
breathability at the same 85A will have a MVTR
approximately 4000g/m2/day. A typical aliphatic
polyether urethane will have the same MVTR as the
aromatic counterpart but an aliphatic polyether
urethane design for breathability can have a MVTR
approximately 8000 g/m2/day. Unlike other materials
that are used in wound care such PVC (which must
be perforated) the moisture is transported through a
film that will not allow large molecules to transport
through. The hydrocarbon based polyurethanes can
slow the moisture transportation rate over a typical
polyurethane. The same Shore Durometer
hydrocarbon based polyurethane has a MVTR
approximately 260 g/m2/day.
Catheters enter the body in different
locations, end up in different areas of the body and
perform different functions. Four catheter types best
illustrate this difference: gastric feeding devices,
over-the-needle (O-T-N) catheters, Peripherally
inserted central catheters (PICC) and central venous
access catheters (CVA). Gastric feeding device are
placed either through the nose to the stomach or
through the stomach to the small intestine (nasal
gastric feeding tubes) or placed directly into the
stomach through a small incision in the abdomen
(percutaneous endoscopic gastrostomy [PEG] feeding
tube). Feeding tubes are exposed to gastric fluid plus
nutritional product and medicines. O-T-N catheters
are usually inserted in the arm or hand and are used
to deliver fluids and non-caustic drugs. PICCs are
inserted in the arm and the tip is placed near the
heart. PICCs are used for long term, usually greater
than 30 days, drug deliveries. The CVA catheters are
inserted in the subclavian and the tip proceeds to the
heart. These catheters are usually placed for less than
30-days where caustic and/or incompatible drugs are
being used. The materials requirements for an over-
the-needle-catheter differ from the peripherally
inserted central catheter and from the central venous
access catheter material requirements.
Gastric Feeding Devices:
Gastric feeding devices are used to supply
nutrients and/or medicine directly to the gastric
system for a short term (days) to longer term
(months). The material is exposed to the
hydrolyzing characteristics of the gastric fluids.
Therefore most gastric feeding tubes are made from
silicone or polyurethane. Polyesterurethanes are not
used in these applications. Polycarbonateurethanes
have excellent oxidative and hydrolytic stability in
blood but in the gastric environment will hydrolyze
in weeks to months. The polyurethane of choice are
the polyetherurethanes. For comfort of the patient,
softer is better.
O-T-N Catheter:
Over-the-needle catheter’s function is to
supply short-term access to the circulatory system to
supply fluids or medications. The catheter is usually
placed by an IV nurse. The O-T-N catheter’s design
is basically a cannula attached to a hub. The
assembly is placed over a needle assembly for
placement.
Tip
Cannula
Hub
Figure 1
O-T-N Catheter
Historically, the cannula of O-T-N catheters
has progressed from natural rubber, to PVC, and
presently to PTFE and polyurethanes. The
progression of materials is due to the improvement in
biocompatibility and strength. Polyurethanes are the
latest materials to be used for O-T-N catheters. The
two major reasons for the move towards
polyurethanes from PTFE are strength and softening.
The strength of polyurethanes allows for thinner
walled tubes and the ability of form a sharper tip.
Therefore, the polyurethane catheter has greater fluid
flow at the same gauge size as a PTFE catheter. The
sharper tip allows the catheter to be placed with less
pain and trauma than the blunter PTFE catheter. The
ability of the polyurethane catheter to soften adds
greatly to the patient’s comfort.
Selecting the best polyurethane is also based
on the column strength of a material for insertion.
Using this basis, the Shore D durometer range is
between 60D and 75D. Lower than 60D, the cannula
stiffness is not sufficient to allow for an easy
insertion. Above 75D, the flexibility of the tube is
not desirable. If replacing a material with a
polyurethane, caution should be taken in selecting a
polyurethane. The durometer measurement should
not solely be used. The column strength of a tube is
more closely related to the flexural modulus of the
material than the durometer. Within the polyurethane
family, classes of polyurethanes may have different
flexural moduli even at the same durometer. The
class of polyurethane best suited for O-T-N catheters
is the aromatic polyetherurethanes. The aromatic
polyetherurethanes have slightly better kink
properties than the aliphatic materials and the
softening characteristics are better suited for
insertion.
Becton Dickinson’s Insyte uses a
proprietary aromatic polyetherurethane. Insyte has a
cannula made of clear polyurethane with a
radiopaque strip. The processibility of polyurethanes
makes this configuration possible.
Johnson and Johnson (Current user Smiths
Medical) has developed a clear radiopaque cannula,
Optiva. The versatility of polyurethanes allowed
for the development of a proprietary aliphatic
polyetherurethane that uses a brominated compound
for radiopacity.
The function of the O-T-N catheter hub is to
connect the cannula to a syringe, IV tubing or other
device to deliver medications, fluids or remove
blood. The hub must be made of a stiff material that
is dimensionally stable to 135F minimum. Tight
tolerances of the universal connection systems and
threads require dimensional stability. The high
durometer polyester and polyetherurethanes meet
these requirements. In this application, the benefits
of polyurethanes may not justify the cost of the
material. Polypropylene and other commodity
plastics meet most of the physical properties
requirements at a lower material cost.
PIC Catheter:
PICCs are also inserted into the arm.
However, the tip of the catheter proceeds to the heart.
The catheter is used normally for 30 days but
occasionally is used longer. Placement of the
catheter involves accessing the vein using a splittable
needle. The needle is removed and in small
increments, the catheter threaded into the vein until
the tip is positioned near the heart. The material
Using polycarbonate-based polyurethanes
has several advantages over PDMS. First, the
material is stronger. These materials have tensile
strengths of 34.5 to 48.2 MPa (5,000 to 7,000 psi)
which is twice that of PDMS. Second, these
materials are stiffer at ambient conditions allowing a
polycarbonate polyurethane tube to be placed easier
than the PDMS tube. The initial stiffness is offset by
the softening characteristics of these materials in the
body.
The catheter tubing and hub for the PICC
are separate items in the catheter kit. The patient is
measured and the PICC tubing has to be cut to length
to be assured the tip of the catheter is properly
placed. To aid in placement, the distance from the tip
is printed on the tubing. The hub is placed on the end
of the tube in a separate step. The hub has the same
material requirements as for O-T-N catheter and
again the material cost may not justify the use of
polyurethanes.
Soft Tip
Holes
Junction
In recent years, aliphatic and aromatic
polycarbonateurethanes have been developed. The
soft grades of these materials have been implanted
without showing signs of surface pitting or crazing9.
The materials are available in durometers as soft as
Shore 70A. These soft materials soften even further,
approximately 30%, in the body.
CVA Catheter:
CVA catheters differ from both the PICC
and O-T-N catheters. The catheter tip is placed near
the heart as the PICC but CVA catheters are inserted
into the chest unlike the O-T-N and PIC catheters.
The O-T-N and PICC are single lumen tubes. CVA
catheters usually have more than one lumen. This
results in a more complex manufacturing process.
es
Placement and patient comfort requires a
soft material. Secondly, the PICC may be in the
body for more than 90 days. PDMS was initially
found to satisfy the softness and biostability
requirements. The common polyetherurethanes were
found to degrade as seen by the presence of pitting
and crazing of the surface in implant studies2,. The
surface pitting and crazing would cause weakening of
the catheter and/or would support tissue growth.
P ri n
Ext te d Cl
e
ens
io n a r
Tu b
requirements for this type of catheter differ from the
O-T-N catheter.
Color Coded Hubs
Figure 2
PICC
Figure 3
CVA Catheter
Printed Tube
Cut to length
Hub
Tip
CVA catheters are placed using an
introducer and a guidewire. The cannula of the
central catheter requires ample stiffness to push the
catheter through the skin and into the vein. Soft
materials used for the PICC catheter would be
difficult to place while the stiff materials of O-T-N
catheters would be much more than required. Shore
durometers of 85A to 55D are best suited for this
application. Classes of polyurethane best suited for
this application are the aliphatic and aromatic
polyether or polycarbonateurethanes. The benefit of
biostability may not justify the cost and decreased
softening characteristics of polycarbonateurethanes.
In comparing the aromatic and aliphatic polyetherurethanes, the aliphatic polyetherurethanes have
slight advantages in softening, processing, filler
choices and coloring.
Tubes with more than one lumen offer a
manufacturing challenge. The first challenge is
making a multilumen tube. The second is to plug and
cut holes in the tubing such that the medications
being administered do not enter the vein at the same
place. The third challenge is to connect each lumen
to an extension tube. The fourth is to attach a hub to
the extension tube.
The multilumen tube is manufactured using
an extrusion process. The most common multilumen
is a three-lumen tube with a single large lumen and
two smaller lumens. Nevertheless, a variety of
configurations can also be extruded to satisfy specific
applications.
Tipping the CVA catheter is more
complicated than the O-T-N and PIC catheters. Not
only does the cut end of the catheter have to be
smoothed, each lumen of the catheter must dispense
the medications along a different area of the catheter.
Holes can be cut into the side of the cannula using
lasers or by a simple cutting or punching technique
allowing the medication transported in the lumen to
be delivered at different areas of the catheter. Since
the hole is not at the tip of the catheter tubing, the
lumens between the hole and the tip of the catheter
must be filled to prevent blood and medication from
being trapped. The unwanted section of the lumen
can be filled with a plug, which may be solvent, melt
or adhesive bonded. The lumen may also simply be
filled with an epoxy, a silicone or urethane adhesive.
A sharp end is not desirable on a catheter
placed near the heart. Rounding the cut end may be
done using solvents or more commonly by
thermoforming the desired configuration. Stiffer
cannulas may present a problem in the heart. In some
cases, a soft material is bonded to the tip of the
catheter. A soft tube can be melt bonded to the tip
while creating the desired tip configuration at the
same time.
Bonding the extension tubing to the cannula
can be accomplished by using an insert molding
technique. The extension tubes themselves should be
made of a material similar to the cannula. Generally,
the extension tube material must be soft, flexible,
printable and clear. Insert molding the extension
tubing to the cannula accomplishes two functions at
once. The extension tubes are bonded to the cannula
and the lumens of the cannula are separately
connected to the extension tubes. The material used
must also be soft and flexible. In this case, the
material is opaque and may be colored to identify
different sizes and types of CVA catheters.
Material used for the hub has the same
requirements as for the O-T-N and PIC catheters.
However, CVA catheters have an additional
requirement in bonding to the extension tube. The
Shore 80D aromatic polyetherurethanes meet all
these requirements. The materials are stiff, hold
dimensions to 150F, are lipid resistant and bond
very well to other polyurethanes. In addition to insert
molding these materials, a hub made of these
materials can be easily solvent bonded to the
extension tube. When exposed to solvents or lipids
polycarbonate may crack or craze, whereas
polyurethanes will not under the same conditions.
Polypropylene is very difficult to bond to extension
tubing.
Conclusion:
Polyurethanes have found uses in many
medical applications. Several reasons for considering
polyurethanes for medical applications are their
strength, processibility, biocompatibility and
flexibility. Selecting the best polyurethane for an
application requires input from many sources. The
patient prefers a soft, painless and comfortable
device. The practitioner requires consistent, easy to
place and maintain devices. The manufacturer
prefers options in assembling the device.
Polyurethanes meet all the requirements and offer
marketing distinct properties resulting in devices with
a competitive advantage.
In general, the aliphatic polyetherurethanes
are selected for their softening characteristics,
processibility, colorability and versatility in fillers
selection. The aromatic polyetherurethanes are
selected for strength, chemical resistance and kink
characteristics. The polycarbonateurethanes are
selected for biostable applications. These are only a
few reasons to select polyurethanes for medical
devices.
New materials are constantly being
developed with added features. For example,
polyurethanes that absorb water while retaining
physical properties may result in commercial
expandable catheters. Polyurethanes that absorb 20
times their weight in water may be used as coatings
or absorbents. New monomers may also result in
softer polyurethanes. Improvements in existing
products and the development of new devices will
result in discovering more unique properties of
polyurethanes and lead into the development of new
materials.
References:
1.
S. Gogolewski, “Selected Topics in
Biomedical Polyurethanes. A review,”
Colloid & Polym. Sci. Vol. 267, No. 9, pp.
757-785 (1989)
2.
A.J. Coury, P.C. Slaikeu, P.T. Cahalan, K.B.
Stokes C.M. Hobot, “Factors and
Interactions Affecting the Performance of
Polyurethane Elastomers in Medical
Devices”, J. Biomat. Appl., Vol. 3, pp. 130179 Oct. 1988
3.
R.J. Zdrahala, D.D. Solomon, D.J. Lentz,
C.W. McGray, “Thermoplastic
Polyurethanes. Materials for Vascular
Catheters” Polyurethanes in Biomedical
Engineering II, H. Plank, Et.al., ed., Elsevier
Science Pub., Amsterdam, pp. 1-18 (1987)
4.
ATOCHEM Inc. product literature on
PEBAX, polyether block amides (PEBA),
form 12.87 ATOCHEM S.A.
5.
Lubrizol Press release of Tecothane™ Soft
line of Thermoplastic Hydrocarbon based
polyurethanes at MD&M West; 2012 and
2013
6.
Ultimate tensile properties were found in
Plastics Technology 1992/93 Manufacturing
Handbook & Buyers Guide, A Bill
Publication (1992).
7.
M.D. Lehah, S.L. Cooper Polyurethanes in
Medicine. CRC Press, Boca Raton,
FL(1986)
8.
B.D. Bakker, C.A. Van Blitterswijk, W.Th.
Daems, J.J. Grote, “Biocompatibility of Six
Elastomers In Vitro” J. Biomed. Mater. Res.,
22 423-439 (1988)
9.
S.R. Hanson, L.A. Harker, B.D. Ratner, A.S.
Hoffman, “ In Vivo Evaluation of Artificial
Surfaces with a Non-human Primate Model
of Arterial Thrombosis,” J. Lab. Clin. Med.,
95, 289-304 (1980)
10.
MVTR are determined by the MOCON test
in 25 micron film per ASTM D96.