Low-friction hydrophilicsurface for rne~c~ devices ShojiNagaokaand RyojiroAkashi Basic Research Laboratories, Toray Industries, Inc. 1 I If Tebiro, Kamakura. Kanagawa. 248 Japan {Received 76 October 1989; accepted 20 February ?SSC?J
A hydrophilic polymer surface was developed exhibiting excellent low frictional property, namely slipperiness, when in contact with water or physiological fluid due to the reaction of epoxy-containing poly(vinyl pyrrolidone) with the polyamino compound formed on the surface of the substrate. Epoxycontaining poly(vinyl pyrrolidone) was obtained by the copolymerization of vinyl pyrrolidone as a hydrophilic component, glycidyl acrylate as a binding component to the substrate, and vinyl acetate to preserve the strength of the coating layer. The surface friction coefficient depends on the molecular weight of the coated hydrophilic copolymer. It was demonstrated that a molecular weight of 400 000 or more is essential to achieve excellent low surface friction. Using rabbit models, polyurethane catheters, both with and without the hydrophilic low friction coating, were evaluated for surface friction coefficient and blood compatibility. As a result. in the c8se of coated catheters, no lesions of the intima of the blood vessels and no thrombus formations on the surfaces of the catheters were observed. However, the non-coated catheters injured the intima of the blood vessels and severe thrombus formation was found on their surfaces. Keywords: Hydrophilic coatings. poiy~vinyt pyrroiidoneJ, mechanical prapeflies, blood compatibility
Low frictional property of the surface (so-called slipperiness), is required for medical devices in contact with such devices as catheters or guide wires that are inserted into blood vessels, urethra or other parts of the body which have mucous membranes. If these devices do not have low friction, their introduction into the body is not only accompanied by pain, but there is also a danger of damage to the mucous membranes or the intima of the blood vessels, which may lead to infectious diseases or mural thrombus formation’-4. Several methods of decreasing surface friction are known. A particularly practical method involves coating with a hydrophilic polymer. This method is based mainly on the techniques of binding the water-soluble polymer, including an active hydrogen group (top coat) with polyisocyanate groups, which is coated on the substrate (under coat) by the covalent bonds. However, since such isocyanate groups are highly reactive, they become easily inactivated when exposed to the moisture in air, which is why the stability of the coatings poses many problems. Another problem is the poor antihydrolytic characteristic of the chemical bond formed, which causes low durability of the low frictional property of the surface in the body. This report describes the formation of a surface with excellent low frictional property of the surface when in Correspondence to Dr S. Nagaoka. Medical Devices and Diagnostics Department, Toray Industries. Inc., Head Office, 2-1, Nihonbashi-Muromachi 2-chome, Chuo-ku. Tokyo 103, Japan. Q 1990
Bu~e~o~h-Helnemann
Ltd. 0142-961
Z/90/06041
contact with water or physiological fluid, and its evaluation both in vitro and in vivo. We have developed the epoxy groups containing hydrophilic copolymers that form stable, covalent bonds with amino groups coated on the substrate. The epoxy group is stable in normal atmosphere, unlike the isocyanate group. The hydrophilic component of the epoxy-containing hydrophilic polymer (top coat) is biocompatible vinyl pyrrolidone (NVP). Polyamino compounds, which can be obtained by the hydrolysis of polyisocyanate under special conditions, are used as an under coat.
EXPERIMENTAL Polymer
synthesis
The molecular design of the vinyl pyrrolidone (NVP) copolymer is indicated by (1 ) the introduction of binding sites (epoxy group) which react with the amino group on the substrate, (2) the retention of the complex in water or against physical friction, and (3) high molecular weight. Regarding binding sites (l), we have examined glycidyl acrylate (GA). With respect to retention of the complex (2). which will be described in more detail later, it became clear that sufficient durability against water or physical friction cannot be obtained with only NVP and GA; a hydrophobic component is found to be needed. As the
9-06 Biomaterials
1990, Voi 1 I August
419
Low-friction surface for medical devices: S. Nagaoka and R. Akashi
Table 1 The relationship between polymerization molecular weight of the polymer obtained Run
Monomer*
Solvent’
V-65
‘fteld
(9)
(9)
Iv)
(%)
20 20 20 20 20 20 20 20 20 20
20 10 5 4 2 0 4 4 4 4
2 2 2 2 2 2 10 6 4 1
70 90 90 90 90 90 90 90 90 70
conditions and the
MW
x IO5
NC0
Primary amine Hydrolysis
NC0 1
2 3 4 5 6 7 8 9 10
*NVP/VAc/GA Polymerization
1.25 2.60 5.14 5.90 7.61 Gel 2.51 4.50 5.49 4.75
of the polyisocyanate
and its hydrolysis
A 20 cm polyurethane (Tecoflex; Thermedics Inc.) tube, with an outer diameter of 0.8 mm, was soaked in a 4% polyisocyanate (Trimethylol propaneflolyrene diisocyanate adduct: isocyanate content 13.2 wt%, Nippon Polyurethane Co.) solution of methyl ethyl ketone for 1 min. Then, it was pulled slowly up and dried for 10 min in a dry nitrogen stream at 40°C. The polyisocyanate is highly compatible with the substrate and never peels off the substrate. The coating thickness observed by the scanning electron microscopy (HITACHI S-800), was 0.2-0.3 pm. Hydrolysis of isocyanate is commonly used to form amino groups, but there is the possibility of a side reaction of the remaining free isocyanate with the amino group to create urea. To prevent this, it is recommended to achieve the reaction in alkaline water of high concentration at a low temperature6. Consequently, 0. I-3.0 N aq. NaOH was used as the hydrolysis medium. After soaking the polyisocyanatecoated polyurethane tubes for a specific amount of time at 2O”C, they were rinsed with distilled water for 3 h and dried in vacuum. Figure 1 shows the reaction scheme.
Coating of the hydrophilic polymer with the polyamine undercoat
and its reaction
After hydrolysis, the test specimen was dipped in a 4% chloroform solution of the hydrophilic copolymer, slowly
420
Polyisocyanate Figure 1
Reaction scheme of hydrolysis of polyisocyanate.
polylsocyanate polyurethane -)
= 85/l O/5 (wt/wt); ’ isopropanol. period, 3 d: temperature, 40°C.
hydrophobic component, we selected vinyl acetate (VAc) which has a suitable molecular reactivity ratio with NVP. High molecular weight (3) is closely correlated with the low frictional property of the surface. The synthesis of the polymer was based on these design indications. NVP, GA and VAc were distilled in vacuum. The polymerization was conducted in a tube by using azobisdimethyl valeronitrile (V-65) as an initiator. A specified quantity of monomers and initiator were dissolved in isopropanol. The mixture was connected to a vacuum system. Then the system was purged with nitrogen. The optimum polymerization temperature and period were 40°C and 3 d respectively. The polymerization conditions are summarized in Table 1. The products were dissolved with chloroform and precipitated in n-heptane. The purified copolymers were dried in a vacuum oven at 50°C for 3 d. The yields of the polymers were determined by the weight of the polymers obtained and the weight-average molecular weight (MW) was determined by a Waters GPC Model 244 using a polystyrene standard.
Coating
-
Biomaterials
1990, Vol 11 August
NC0
NC0
I
I
hydrolysis
c=o
I
3N NaOH
coating
e
CH3 hydrophlllc copolymer
4 capolymercholn
pro]ectlng lntotheflud
hydrophlllc
Figure 2 Schematic low-friction surface.
slhppery coating
representation
extract
-
of the reaction to form hydrophilic
pulled up, dried and coated. Then it was heated at 90°C in air for 3 h to react the epoxy groups with the amino groups. A relatively high temperature and long reaction time were employed, attributable to the lower reactivity of the aromatic amines formed in comparison with the aliphatic amines. The hydrophilic copolymer which was not bound with the polyamine undercoat was extracted by washing in distilled water at 70°C for 3 h. Figure 2 shows the reaction scheme. Next, the durability test of the coating layer was performed. The test specimen was boiled for 2 h for the acceration test to examine the stability against water and squeezed twice between wet pig skins, which is a model of biological tissue, under a compression of 10 g/cm2, to examine the mechanical strength of the coating. The change of the static friction coefficient was then measured to characterize coating durability. Poly(vinyl pyrrolidone) (PVP) and poly(hydroxyethyl methacrylate) p(HEMA) were coated on the surface of the untreated polyurethane tubes using 4% chloroform solution and dried.
Measurement
of the surface
friction
coefficient
After the durability test, the catheter was cut to a length of 5 cm and fixed on a glass plate as shown in Figure 3. Then, the catheter was wetted with physiological saline solution and a weight (100 g, cross-linked collagen film with thickness of about 100 pm, which is a kind of biological tissue model, was attached on the bottom of it using adhesive (cyanoacrylate), and wetted with the same fluid), was placed on the end of the catheter. One end of the glass plate was gradually inclined to obtain the initial inclination angle required for the weight to begin slipping. The static
Low-frxtion
surface
for medical
5.9 X 1 05. The polymer and it was difficult
plate
devices:
obtained
were :ollagen codted weight
used for the synthesis
various compositions. in chloroform
for
were
with
obtained
VAc were using
JEOL
with Test materials Figure
3
the
Evaluatfon
method
of surface
frictional
coefficient
coefficient
formula:
(,u) was
calculated
friction
according
to
Four
of
coefficient.
general
weighing
anaesthesia
urethane inserted
kg
(pentobarbital
catheter
hydrophilic
2-3
and
low frictional
bilaterally
were
surface
into the
used.
sodium),
a polyurethane
Under
a control
catheter
the
arteries
of the
were
and pulled back to the original repeated
three
After
times
longitudinal
inserted
polymer
an additional
position while
5 cm
then
and spattered
performed
microscope. from
lightly rubbing
with
AND
Tab/e
were
initiator
the
125
carbon
scanning
change
which
after
by the
conditions.
static
friction
of the hydrophilic
MW
O/5,
formed
various
of the
consists
= 85/l
The surface
friction
after the durability
= 590 000) and
hydrolysis
of poly-
The concentration
of
surface with
possible
friction
formation
coefficients
to obtain
with
N
0.1
measured
sufficient
aq.
NaOH
low frictional the
the friction
the optimal property,
even
surface
polymer with
coefficient
was
to
in the
1. But
to achieve
the durability conditions hydrolyse
for the
for 3 to 5 min at
the durability
increased
of
in Figure
after
3 N aq. NaOH
However,
reduction
conditions
One of the optimal amination
hydrophilic
polyisocyanate
before and
because
of urea as a side reaction as shown
1 to 3 N aq. NaOH,
binding
were
test.
room temperature.
electron
increased
decreased
sharply under conditions
and of
were
excised
were
and
prepared.
the sections
were
polymer
000
to
between
depends
000,
As
shown
upon
of the polymer
weights
obtained
depending
the molecular
mainly
polymerization
weight
761
in the
weight
on
the
kinetics
of
of the polymer
the
concentration
molecular
weight
of
the
hydrophilic
higher, both with a low concentration
of the
occurred molecular
increased
and the polymer weight
Nevertheless, too much,
10
gel
3200
‘Z&O0
polymer
conditions
obtained
was
FIgwe
4
hydrolysis
Change
of
FT-IR
1200
603
lriuvenumber
could not be dissolved.
polymerization
of the
polymer
of the initiator
of the monomers.
of monomers
Run 4 is one of the most desirable the
with
The examination
surfaces
molecular
conditions.
if the concentration
and
dried
of ethanol
cm-‘)
3 min).
completely
5 cm of the blood vessels
relationship
and with high concentrations formation
series
20°C.
and monomer.
The became
under
excellent
solution.
4200)
microscope.
radical polymerization, obtained
and
FT-IR
by polyisocyanate
disappeared
and 3367 the
surface
test, werefound.
It was found that the molecular
polymerization
removed
0~0~
with
(Shimazu coated
cm-‘)
(3250
(NVPNAc/GA
aminated
in 0.2 M phosphate
haematoxylin-eosin.
and the resulting
from
high
aq. NaOH.
5 shows
1%
S-800
time,
of hydrophilic
1 shows
obtained.
Hitachi
of
DISCUSSION
Polymerization conditions
a
in a graded
of the inner
by optical
RESULTS
with
parts of the catheters
sections
staining
observed
were
of the tip of the catheter
critical-point
by the
the inserted
were
(2260
of the surface
It is not
with gold palladium.
At the same
histological After
stained
dehydrated
amylacetate,
dioxide
catheters
1% glutaraldehyde
and
were
The
the
identical
NaOH and the time of hydrolysis were changed independently.
both catheters.
on the surface
the
pH 7.4,
Specimens
was
Figure coefficient the
the blood vessel was excised along
axis.
formation
was fixed with buffer,
with
3 h insertion,
thrombus
and
groups with
isocyanate the catheters
that
because
(3 N, aq. NaOH,
hydrolysis
groups
hydrolysis
were
against the intima of the blood vessels. The procedures
the
and after
same
rabbit. Then,
clear
and reaction
of the polyurethane
and amino poly-
with
(10 cm in length)
femoral
composition
of
measurement
was roughly
Figure 4 shows the FT-IR spectrum
lsocyanate
each
coating
90%).
of polyisocyanate polymer
of the surface
experiment rabbits
monomer
NMR made
obtained
after
The contents
the
before
Animal
spectrometer
with
soluble
of the surface.
,u = tan 8, and this value is used as a parameter
the surface
above
polymer
insoluble
of 5 wt%.
from 0 to 30 wt%.
yield (about
Hydrolysis hydrophilic friction
and
GA content
of the polymer feed
polymer
mentioned
of the hydrophilic
It was found that the polymers
FX-100
composition
R. Akashi
on the substrate.
conditions
purification
changed
and
in Run 5 was too viscous
to coat smoothly
The best polymerization
S. Nagaoka
spectra
of
ROO
Lion
;cm-‘8 the
surface
accompanyrng
the
of polyisocyanate.
Biomatenals
1990,
Voi
1 1 August
421
Low-friction surface for medical devices: S. Nagaoka and R. Akashi
0.3 0.2
0.2
PHEMA coating
0.1
0
0.1
I
1
I
0
10
20 Time
40
60
(min)
Figure 5 Effect of hydrolysis conditions of polyisocyanate on the surface frictional coefficient. Hydrophilic polymer: NVPNAc/GA = 85/l O/5 (wt/wt), MW = 590 000. 0. 0.1; 0, 1.0: 0, 3.0 N NaOH.
higher alkaline concentration or longer incubation time. These conditions may hydrolyse the substrate including the polyamine thin layer. Under scanning electron microscopy, the thickness of the hydrophilic layer was found to be approximately 5 pm after the durability test. This is clearly thicker than the end-toend distance of a polymer with mol. wt 590 000. Consequently, it was suggested that the hydrophilic low friction surface was bound with polyurethane substrate by the reaction between epoxy groups and amino groups at the boundary layer. The upper hydrophilic layer was rendered insoluble by the reaction between the remaining epoxy groups (cross-linking or polymerization) to form a layer with high water content, and polymer chains could project from the outermost surface with relatively free molecular motion as shown in Figure 1.
Effect of the molecular weight of the hydrophilic copolymer on the friction coefficient Figure 6 shows the static friction coefficient (slipperiness) of the polyurethane catheter fixed on the glass plate (as shown in Figure 3). coated and bound with the hydrophilic copolymer (NVP/VAc/GA = 85/l O/5 (wt/wt)) having a different molecular weight. The static friction coefficients were decreased with the increase of the molecular weight of the hydrophilic polymer up to 400 000. The static friction coefficient of an uncoated (control) polyurethane catheter was 0.32 f 0.02 (n = 5). The polyurethane catheter coated with hydrophilic p(HEMA) showed a friction coefficient of 0.18 +_ 0.02 (n = 5, shown by the arrow). This improvement is deemed not enough for protection of mucous membranes of luminal surface and manoeuverability of medical devices. The dotted line (p = 0.035) indicates the static friction coefficient of the polyurethane catheter coated with non-bonded PVP (MW = 400 000), solubilized in water. This low friction surface does not injure mucous membranes or blood vessel. But of course, this slipperiness dissipated in a short while due to the washing off of the PVP from the surface.
422
\
Biomaterials
1990, Vol 11 August
C
I
2 Molecular
I
4
I
I
6
8 x105
Weight
of Copolymer
Figure 6 Effect of molecular weight of the hydrophilic polymer on the surface frictional coefficient of the surface. Mean + SD(n = 5). NVPNAc/GA = 85/10/5 (wt/wtJ.
As shown in Figure 6, a molecular weight of the bound hydrophilic copolymer of at least 400 000 is necessary to obtain excellent low frictional property of the surface when in contact with water or physiological fluid. The dependency of the frictional property on the molecular weight of the copolymer may be explained in connection with so-called Toms effect’. Although this effect has not been fully explained in molecular terms, it is known that very small traces of water-soluble polymers added to water can greatly reduce turbulent friction on the surfaces past which the fluid flows, depending on the molecular weight of the polymers’*. When the water-soluble copolymer is bound at the outermost surface of the substrate and projecting into the water or physiological fluid with relatively free molecular motion as shown in Figure 7, the similar effect could be expected and copolymers with higher molecular weight could reduce the friction coefficient more than the copolymers with lower molecular weight.
Effect of the chemical composition of the hydrophilic polymer on the durability of low surface friction Figure 7 shows the relationship between the content of VAc in the hydrophilic polymer and the friction coefficient after durability test. In these cases, the content of GA was kept at 5 wt%. As the content of NVP was increased, the friction coefficient decreased, but, unless hydrophobic monomer (VAc) was copolymerized with 10 wt% or more, it was not possible to obtain sufficient durability, and the low surface friction deteriorated easily (Cl -+ 0 in Figure 7). These results suggest that the durability of low surface friction is closely correlated with the mechanical strength of the hydrophilic copolymer. It is essential to copolymerize the hydrophobic monomer (VAc) together with NVP and GA to make the hydrophilic low friction layer stable against boiling water or physical friction. However, if the content of VAc was over 10 wt%, the hydrophilicity of the copolymer decreased and the low surface friction property deteriorated.
Low-friction
Almost
z
no friction
vessel
C
surfaces artery
.w .-f U
E
for med/cal
devices:
was felt between
in the case of the coated Figure
3
surface
8 shows
of the
rabbit.
were covered
network,
erythrocyte,
electron
of the
and blood
polyurethane
composed
and
platelet
catheters
no thrombus
of the
in the femoral
non-coated
leucocyte,
slippery surface showed
R. Akashi
micrographs
with thrombus
contrary, all of the polyurethane
8
the catheter
3 h after insertion
All
catheters
and
catheter.
scanning
of two catheters
S. Nagaoka
of a fibrin (a). On the
with the hydrophilic
formation
or adhesion
v
of blood components
C ._0
graphs of the cross-sections
of the femoral
U
rubbed
In the case of the non-coated
I= U ._
polyurethane destroyed.
+I
elastic
3
lesions.
Figure
+I
.-
VI
catheter, There
the
were
anywhere.
the
These
in the
hydrophilic
photomicro-
arteries that were
of the femoral
no endothelial
contrary,
with
histological
the intima
cells
were
case
artery was nor
internal
catheter-induced
of the
slippery
were observed and the endothelial
3b
2b
lb
the typical
the catheters.
membrane On
"0
9 shows
with
catheter
(b).
polyurethane
surface,
no lesions
cell layer was not damaged.
CONCLUSION of
Content Figure
7
coefficient
l,
after
Effect of
of hydrophilic
the
durability
surface. test.
polymer
Mean
MW
f
= 50
VAc
composition
so (n = 5). x
(wt%) 0.
on the surface Before
A new
frictional
durability
test;
hydrophilic
been developed to the
104.
polyamino
substrate.
determined
the optimal
to be NVP/VAc/GA
chemical = 85/l
composition O/5
was
(wt/wt).
amino
compound
polyisocyanate
with
obtained
aq. NaOH
In viva experiments The
insertion
catheter
and
weight the
manipulation
with a hydrophilic
with
8
Scanning
hydrophilrc
electron
low-friction
of the
low frictional
easier than those with the non-coated
Figure
or physiological
micrographs
surface
polyurethane
of the surface
was much
have
a
3 h after
insertion:
essential
molecular of
low
(a) polyurethane
formed
on the
was composed
of vinyl
acrylate.
by
the when
depends
polymer.
friction
The
poly-
hydrolysis
of
in contact with
upon the molecular To obtain
hydrophilic
greater
than
coefficient
catheter
use has (top coat)
of high concentration.
for the
weight
polymer
coat)
coefficient,
fluid,
hydrophilic
it was
durability
catheter.
of the catheter
of the
friction,
polyurethane
for medical
and glycidyl
was
The surface frictional water
(under
copolymer
vinyl acetate,
compound
surface
a hydrophilic
The hydrophilic
pyrrolidone, As explained,
low friction
by binding
(non-coated),
was
low surface copolymer
400
000.
related
(bl polyurethane
to The
to the
cathetef
surface.
Biomatenals
1990,
Vol
1 1 August
423
Low-friction surface for medical devices: S. Nagaoka and R. Akashi
/
, lesions
endothelial cell layer
Figure 9 Histological observation of the mural section of the blood vessel after catheter manipulation (stained by haematoxylin-eosineJ. (aJ Polyurethane catheter (non-coatedJ. Catheter-induced lesions were clearly observed and endothelial cell layer was fallen off (bJ Polyurethane catheter with hydrophilic lowfriction surface. No lesions were observed and the endothelial cells formed normal monolayer.
mechanical strength of the hydrophilic copolymer, and the addition of hydrophobic vinyl acetate was essential to prevent the deterioration of the low friction coating. The polyurethane catheter coated with the hydrophilic low friction surface was easy to insert in and did not damage the blood vessel during manipulation and, furthermore, showed improved blood compatibility.
2
3
4
5 6
REFERENCES
7 1
424
Ducatman, B.S., McMichan, J.C. and Edwards, W.D., Catheterinduced lesions of the right side of the heart, JAMA 1985, 253, 791-795
Biomaterials
1990. Vol 11 August
8
Ford, SE. and Manley, P.N.. Indwelling cardiac catheters: an autopsy study of associated endocardial lesions, Arch. Pathol. Lab. Med. 1982,106, 314-317 Lange. H.W.. Galliani, CA. and Edwards, J.E.. Local complications associated with indwelling Swan-Ganz catheters: autopsy study of 36 patients, Am. J. Cardiol. 1983, 52, 1 108- 1 1 1 1 Lazarus, H.M., Lowder, J.N. and Herzig, R.H., Occlusion and infection in Broviac catheters during intensive cancer therapy, Cancer 1983, 52, 23-48 Micklus, J.M.. Coated substrate having low coefficient of friction, United States Patent Number 4, 1 19, 094, 1978 Tanaka, H., Hydrolysis of polyisocyanate. Bull. Chem. Sot. Japan. 1976,49,2821-2823 Gadd, G.E., Turbulence damping and drag reduction produced by certain additives in water, Nature 1965, 206, 463-467 Kohn, M.C., Energy stage in drag-reducing polymer solutions, J. Polym. Sci., Polym. Phys. Ed. 1973, 11, 2339-2356
A hydrophilic polymer surface was developed exhibiting excellent low frictional property, namely slipperiness, when in contact with water or physiological fluid due to the reaction of epoxy-containing poly(vinyl pyrrolidone) with the polyamino compound formed on the surface of the substrate. Epoxycontaining poly(vinyl pyrrolidone) was obtained by the copolymerization of vinyl pyrrolidone as a hydrophilic component, glycidyl acrylate as a binding component to the substrate, and vinyl acetate to preserve the strength of the coating layer. The surface friction coefficient depends on the molecular weight of the coated hydrophilic copolymer. It was demonstrated that a molecular weight of 400 000 or more is essential to achieve excellent low surface friction. Using rabbit models, polyurethane catheters, both with and without the hydrophilic low friction coating, were evaluated for surface friction coefficient and blood compatibility. As a result. in the c8se of coated catheters, no lesions of the intima of the blood vessels and no thrombus formations on the surfaces of the catheters were observed. However, the non-coated catheters injured the intima of the blood vessels and severe thrombus formation was found on their surfaces. Keywords: Hydrophilic coatings. poiy~vinyt pyrroiidoneJ, mechanical prapeflies, blood compatibility
Low frictional property of the surface (so-called slipperiness), is required for medical devices in contact with such devices as catheters or guide wires that are inserted into blood vessels, urethra or other parts of the body which have mucous membranes. If these devices do not have low friction, their introduction into the body is not only accompanied by pain, but there is also a danger of damage to the mucous membranes or the intima of the blood vessels, which may lead to infectious diseases or mural thrombus formation’-4. Several methods of decreasing surface friction are known. A particularly practical method involves coating with a hydrophilic polymer. This method is based mainly on the techniques of binding the water-soluble polymer, including an active hydrogen group (top coat) with polyisocyanate groups, which is coated on the substrate (under coat) by the covalent bonds. However, since such isocyanate groups are highly reactive, they become easily inactivated when exposed to the moisture in air, which is why the stability of the coatings poses many problems. Another problem is the poor antihydrolytic characteristic of the chemical bond formed, which causes low durability of the low frictional property of the surface in the body. This report describes the formation of a surface with excellent low frictional property of the surface when in Correspondence to Dr S. Nagaoka. Medical Devices and Diagnostics Department, Toray Industries. Inc., Head Office, 2-1, Nihonbashi-Muromachi 2-chome, Chuo-ku. Tokyo 103, Japan. Q 1990
Bu~e~o~h-Helnemann
Ltd. 0142-961
Z/90/06041
contact with water or physiological fluid, and its evaluation both in vitro and in vivo. We have developed the epoxy groups containing hydrophilic copolymers that form stable, covalent bonds with amino groups coated on the substrate. The epoxy group is stable in normal atmosphere, unlike the isocyanate group. The hydrophilic component of the epoxy-containing hydrophilic polymer (top coat) is biocompatible vinyl pyrrolidone (NVP). Polyamino compounds, which can be obtained by the hydrolysis of polyisocyanate under special conditions, are used as an under coat.
EXPERIMENTAL Polymer
synthesis
The molecular design of the vinyl pyrrolidone (NVP) copolymer is indicated by (1 ) the introduction of binding sites (epoxy group) which react with the amino group on the substrate, (2) the retention of the complex in water or against physical friction, and (3) high molecular weight. Regarding binding sites (l), we have examined glycidyl acrylate (GA). With respect to retention of the complex (2). which will be described in more detail later, it became clear that sufficient durability against water or physical friction cannot be obtained with only NVP and GA; a hydrophobic component is found to be needed. As the
9-06 Biomaterials
1990, Voi 1 I August
419
Low-friction surface for medical devices: S. Nagaoka and R. Akashi
Table 1 The relationship between polymerization molecular weight of the polymer obtained Run
Monomer*
Solvent’
V-65
‘fteld
(9)
(9)
Iv)
(%)
20 20 20 20 20 20 20 20 20 20
20 10 5 4 2 0 4 4 4 4
2 2 2 2 2 2 10 6 4 1
70 90 90 90 90 90 90 90 90 70
conditions and the
MW
x IO5
NC0
Primary amine Hydrolysis
NC0 1
2 3 4 5 6 7 8 9 10
*NVP/VAc/GA Polymerization
1.25 2.60 5.14 5.90 7.61 Gel 2.51 4.50 5.49 4.75
of the polyisocyanate
and its hydrolysis
A 20 cm polyurethane (Tecoflex; Thermedics Inc.) tube, with an outer diameter of 0.8 mm, was soaked in a 4% polyisocyanate (Trimethylol propaneflolyrene diisocyanate adduct: isocyanate content 13.2 wt%, Nippon Polyurethane Co.) solution of methyl ethyl ketone for 1 min. Then, it was pulled slowly up and dried for 10 min in a dry nitrogen stream at 40°C. The polyisocyanate is highly compatible with the substrate and never peels off the substrate. The coating thickness observed by the scanning electron microscopy (HITACHI S-800), was 0.2-0.3 pm. Hydrolysis of isocyanate is commonly used to form amino groups, but there is the possibility of a side reaction of the remaining free isocyanate with the amino group to create urea. To prevent this, it is recommended to achieve the reaction in alkaline water of high concentration at a low temperature6. Consequently, 0. I-3.0 N aq. NaOH was used as the hydrolysis medium. After soaking the polyisocyanatecoated polyurethane tubes for a specific amount of time at 2O”C, they were rinsed with distilled water for 3 h and dried in vacuum. Figure 1 shows the reaction scheme.
Coating of the hydrophilic polymer with the polyamine undercoat
and its reaction
After hydrolysis, the test specimen was dipped in a 4% chloroform solution of the hydrophilic copolymer, slowly
420
Polyisocyanate Figure 1
Reaction scheme of hydrolysis of polyisocyanate.
polylsocyanate polyurethane -)
= 85/l O/5 (wt/wt); ’ isopropanol. period, 3 d: temperature, 40°C.
hydrophobic component, we selected vinyl acetate (VAc) which has a suitable molecular reactivity ratio with NVP. High molecular weight (3) is closely correlated with the low frictional property of the surface. The synthesis of the polymer was based on these design indications. NVP, GA and VAc were distilled in vacuum. The polymerization was conducted in a tube by using azobisdimethyl valeronitrile (V-65) as an initiator. A specified quantity of monomers and initiator were dissolved in isopropanol. The mixture was connected to a vacuum system. Then the system was purged with nitrogen. The optimum polymerization temperature and period were 40°C and 3 d respectively. The polymerization conditions are summarized in Table 1. The products were dissolved with chloroform and precipitated in n-heptane. The purified copolymers were dried in a vacuum oven at 50°C for 3 d. The yields of the polymers were determined by the weight of the polymers obtained and the weight-average molecular weight (MW) was determined by a Waters GPC Model 244 using a polystyrene standard.
Coating
-
Biomaterials
1990, Vol 11 August
NC0
NC0
I
I
hydrolysis
c=o
I
3N NaOH
coating
e
CH3 hydrophlllc copolymer
4 capolymercholn
pro]ectlng lntotheflud
hydrophlllc
Figure 2 Schematic low-friction surface.
slhppery coating
representation
extract
-
of the reaction to form hydrophilic
pulled up, dried and coated. Then it was heated at 90°C in air for 3 h to react the epoxy groups with the amino groups. A relatively high temperature and long reaction time were employed, attributable to the lower reactivity of the aromatic amines formed in comparison with the aliphatic amines. The hydrophilic copolymer which was not bound with the polyamine undercoat was extracted by washing in distilled water at 70°C for 3 h. Figure 2 shows the reaction scheme. Next, the durability test of the coating layer was performed. The test specimen was boiled for 2 h for the acceration test to examine the stability against water and squeezed twice between wet pig skins, which is a model of biological tissue, under a compression of 10 g/cm2, to examine the mechanical strength of the coating. The change of the static friction coefficient was then measured to characterize coating durability. Poly(vinyl pyrrolidone) (PVP) and poly(hydroxyethyl methacrylate) p(HEMA) were coated on the surface of the untreated polyurethane tubes using 4% chloroform solution and dried.
Measurement
of the surface
friction
coefficient
After the durability test, the catheter was cut to a length of 5 cm and fixed on a glass plate as shown in Figure 3. Then, the catheter was wetted with physiological saline solution and a weight (100 g, cross-linked collagen film with thickness of about 100 pm, which is a kind of biological tissue model, was attached on the bottom of it using adhesive (cyanoacrylate), and wetted with the same fluid), was placed on the end of the catheter. One end of the glass plate was gradually inclined to obtain the initial inclination angle required for the weight to begin slipping. The static
Low-frxtion
surface
for medical
5.9 X 1 05. The polymer and it was difficult
plate
devices:
obtained
were :ollagen codted weight
used for the synthesis
various compositions. in chloroform
for
were
with
obtained
VAc were using
JEOL
with Test materials Figure
3
the
Evaluatfon
method
of surface
frictional
coefficient
coefficient
formula:
(,u) was
calculated
friction
according
to
Four
of
coefficient.
general
weighing
anaesthesia
urethane inserted
kg
(pentobarbital
catheter
hydrophilic
2-3
and
low frictional
bilaterally
were
surface
into the
used.
sodium),
a polyurethane
Under
a control
catheter
the
arteries
of the
were
and pulled back to the original repeated
three
After
times
longitudinal
inserted
polymer
an additional
position while
5 cm
then
and spattered
performed
microscope. from
lightly rubbing
with
AND
Tab/e
were
initiator
the
125
carbon
scanning
change
which
after
by the
conditions.
static
friction
of the hydrophilic
MW
O/5,
formed
various
of the
consists
= 85/l
The surface
friction
after the durability
= 590 000) and
hydrolysis
of poly-
The concentration
of
surface with
possible
friction
formation
coefficients
to obtain
with
N
0.1
measured
sufficient
aq.
NaOH
low frictional the
the friction
the optimal property,
even
surface
polymer with
coefficient
was
to
in the
1. But
to achieve
the durability conditions hydrolyse
for the
for 3 to 5 min at
the durability
increased
of
in Figure
after
3 N aq. NaOH
However,
reduction
conditions
One of the optimal amination
hydrophilic
polyisocyanate
before and
because
of urea as a side reaction as shown
1 to 3 N aq. NaOH,
binding
were
test.
room temperature.
electron
increased
decreased
sharply under conditions
and of
were
excised
were
and
prepared.
the sections
were
polymer
000
to
between
depends
000,
As
shown
upon
of the polymer
weights
obtained
depending
the molecular
mainly
polymerization
weight
761
in the
weight
on
the
kinetics
of
of the polymer
the
concentration
molecular
weight
of
the
hydrophilic
higher, both with a low concentration
of the
occurred molecular
increased
and the polymer weight
Nevertheless, too much,
10
gel
3200
‘Z&O0
polymer
conditions
obtained
was
FIgwe
4
hydrolysis
Change
of
FT-IR
1200
603
lriuvenumber
could not be dissolved.
polymerization
of the
polymer
of the initiator
of the monomers.
of monomers
Run 4 is one of the most desirable the
with
The examination
surfaces
molecular
conditions.
if the concentration
and
dried
of ethanol
cm-‘)
3 min).
completely
5 cm of the blood vessels
relationship
and with high concentrations formation
series
20°C.
and monomer.
The became
under
excellent
solution.
4200)
microscope.
radical polymerization, obtained
and
FT-IR
by polyisocyanate
disappeared
and 3367 the
surface
test, werefound.
It was found that the molecular
polymerization
removed
0~0~
with
(Shimazu coated
cm-‘)
(3250
(NVPNAc/GA
aminated
in 0.2 M phosphate
haematoxylin-eosin.
and the resulting
from
high
aq. NaOH.
5 shows
1%
S-800
time,
of hydrophilic
1 shows
obtained.
Hitachi
of
DISCUSSION
Polymerization conditions
a
in a graded
of the inner
by optical
RESULTS
with
parts of the catheters
sections
staining
observed
were
of the tip of the catheter
critical-point
by the
the inserted
were
(2260
of the surface
It is not
with gold palladium.
At the same
histological After
stained
dehydrated
amylacetate,
dioxide
catheters
1% glutaraldehyde
and
were
The
the
identical
NaOH and the time of hydrolysis were changed independently.
both catheters.
on the surface
the
pH 7.4,
Specimens
was
Figure coefficient the
the blood vessel was excised along
axis.
formation
was fixed with buffer,
with
3 h insertion,
thrombus
and
groups with
isocyanate the catheters
that
because
(3 N, aq. NaOH,
hydrolysis
groups
hydrolysis
were
against the intima of the blood vessels. The procedures
the
and after
same
rabbit. Then,
clear
and reaction
of the polyurethane
and amino poly-
with
(10 cm in length)
femoral
composition
of
measurement
was roughly
Figure 4 shows the FT-IR spectrum
lsocyanate
each
coating
90%).
of polyisocyanate polymer
of the surface
experiment rabbits
monomer
NMR made
obtained
after
The contents
the
before
Animal
spectrometer
with
soluble
of the surface.
,u = tan 8, and this value is used as a parameter
the surface
above
polymer
insoluble
of 5 wt%.
from 0 to 30 wt%.
yield (about
Hydrolysis hydrophilic friction
and
GA content
of the polymer feed
polymer
mentioned
of the hydrophilic
It was found that the polymers
FX-100
composition
R. Akashi
on the substrate.
conditions
purification
changed
and
in Run 5 was too viscous
to coat smoothly
The best polymerization
S. Nagaoka
spectra
of
ROO
Lion
;cm-‘8 the
surface
accompanyrng
the
of polyisocyanate.
Biomatenals
1990,
Voi
1 1 August
421
Low-friction surface for medical devices: S. Nagaoka and R. Akashi
0.3 0.2
0.2
PHEMA coating
0.1
0
0.1
I
1
I
0
10
20 Time
40
60
(min)
Figure 5 Effect of hydrolysis conditions of polyisocyanate on the surface frictional coefficient. Hydrophilic polymer: NVPNAc/GA = 85/l O/5 (wt/wt), MW = 590 000. 0. 0.1; 0, 1.0: 0, 3.0 N NaOH.
higher alkaline concentration or longer incubation time. These conditions may hydrolyse the substrate including the polyamine thin layer. Under scanning electron microscopy, the thickness of the hydrophilic layer was found to be approximately 5 pm after the durability test. This is clearly thicker than the end-toend distance of a polymer with mol. wt 590 000. Consequently, it was suggested that the hydrophilic low friction surface was bound with polyurethane substrate by the reaction between epoxy groups and amino groups at the boundary layer. The upper hydrophilic layer was rendered insoluble by the reaction between the remaining epoxy groups (cross-linking or polymerization) to form a layer with high water content, and polymer chains could project from the outermost surface with relatively free molecular motion as shown in Figure 1.
Effect of the molecular weight of the hydrophilic copolymer on the friction coefficient Figure 6 shows the static friction coefficient (slipperiness) of the polyurethane catheter fixed on the glass plate (as shown in Figure 3). coated and bound with the hydrophilic copolymer (NVP/VAc/GA = 85/l O/5 (wt/wt)) having a different molecular weight. The static friction coefficients were decreased with the increase of the molecular weight of the hydrophilic polymer up to 400 000. The static friction coefficient of an uncoated (control) polyurethane catheter was 0.32 f 0.02 (n = 5). The polyurethane catheter coated with hydrophilic p(HEMA) showed a friction coefficient of 0.18 +_ 0.02 (n = 5, shown by the arrow). This improvement is deemed not enough for protection of mucous membranes of luminal surface and manoeuverability of medical devices. The dotted line (p = 0.035) indicates the static friction coefficient of the polyurethane catheter coated with non-bonded PVP (MW = 400 000), solubilized in water. This low friction surface does not injure mucous membranes or blood vessel. But of course, this slipperiness dissipated in a short while due to the washing off of the PVP from the surface.
422
\
Biomaterials
1990, Vol 11 August
C
I
2 Molecular
I
4
I
I
6
8 x105
Weight
of Copolymer
Figure 6 Effect of molecular weight of the hydrophilic polymer on the surface frictional coefficient of the surface. Mean + SD(n = 5). NVPNAc/GA = 85/10/5 (wt/wtJ.
As shown in Figure 6, a molecular weight of the bound hydrophilic copolymer of at least 400 000 is necessary to obtain excellent low frictional property of the surface when in contact with water or physiological fluid. The dependency of the frictional property on the molecular weight of the copolymer may be explained in connection with so-called Toms effect’. Although this effect has not been fully explained in molecular terms, it is known that very small traces of water-soluble polymers added to water can greatly reduce turbulent friction on the surfaces past which the fluid flows, depending on the molecular weight of the polymers’*. When the water-soluble copolymer is bound at the outermost surface of the substrate and projecting into the water or physiological fluid with relatively free molecular motion as shown in Figure 7, the similar effect could be expected and copolymers with higher molecular weight could reduce the friction coefficient more than the copolymers with lower molecular weight.
Effect of the chemical composition of the hydrophilic polymer on the durability of low surface friction Figure 7 shows the relationship between the content of VAc in the hydrophilic polymer and the friction coefficient after durability test. In these cases, the content of GA was kept at 5 wt%. As the content of NVP was increased, the friction coefficient decreased, but, unless hydrophobic monomer (VAc) was copolymerized with 10 wt% or more, it was not possible to obtain sufficient durability, and the low surface friction deteriorated easily (Cl -+ 0 in Figure 7). These results suggest that the durability of low surface friction is closely correlated with the mechanical strength of the hydrophilic copolymer. It is essential to copolymerize the hydrophobic monomer (VAc) together with NVP and GA to make the hydrophilic low friction layer stable against boiling water or physical friction. However, if the content of VAc was over 10 wt%, the hydrophilicity of the copolymer decreased and the low surface friction property deteriorated.
Low-friction
Almost
z
no friction
vessel
C
surfaces artery
.w .-f U
E
for med/cal
devices:
was felt between
in the case of the coated Figure
3
surface
8 shows
of the
rabbit.
were covered
network,
erythrocyte,
electron
of the
and blood
polyurethane
composed
and
platelet
catheters
no thrombus
of the
in the femoral
non-coated
leucocyte,
slippery surface showed
R. Akashi
micrographs
with thrombus
contrary, all of the polyurethane
8
the catheter
3 h after insertion
All
catheters
and
catheter.
scanning
of two catheters
S. Nagaoka
of a fibrin (a). On the
with the hydrophilic
formation
or adhesion
v
of blood components
C ._0
graphs of the cross-sections
of the femoral
U
rubbed
In the case of the non-coated
I= U ._
polyurethane destroyed.
+I
elastic
3
lesions.
Figure
+I
.-
VI
catheter, There
the
were
anywhere.
the
These
in the
hydrophilic
photomicro-
arteries that were
of the femoral
no endothelial
contrary,
with
histological
the intima
cells
were
case
artery was nor
internal
catheter-induced
of the
slippery
were observed and the endothelial
3b
2b
lb
the typical
the catheters.
membrane On
"0
9 shows
with
catheter
(b).
polyurethane
surface,
no lesions
cell layer was not damaged.
CONCLUSION of
Content Figure
7
coefficient
l,
after
Effect of
of hydrophilic
the
durability
surface. test.
polymer
Mean
MW
f
= 50
VAc
composition
so (n = 5). x
(wt%) 0.
on the surface Before
A new
frictional
durability
test;
hydrophilic
been developed to the
104.
polyamino
substrate.
determined
the optimal
to be NVP/VAc/GA
chemical = 85/l
composition O/5
was
(wt/wt).
amino
compound
polyisocyanate
with
obtained
aq. NaOH
In viva experiments The
insertion
catheter
and
weight the
manipulation
with a hydrophilic
with
8
Scanning
hydrophilrc
electron
low-friction
of the
low frictional
easier than those with the non-coated
Figure
or physiological
micrographs
surface
polyurethane
of the surface
was much
have
a
3 h after
insertion:
essential
molecular of
low
(a) polyurethane
formed
on the
was composed
of vinyl
acrylate.
by
the when
depends
polymer.
friction
The
poly-
hydrolysis
of
in contact with
upon the molecular To obtain
hydrophilic
greater
than
coefficient
catheter
use has (top coat)
of high concentration.
for the
weight
polymer
coat)
coefficient,
fluid,
hydrophilic
it was
durability
catheter.
of the catheter
of the
friction,
polyurethane
for medical
and glycidyl
was
The surface frictional water
(under
copolymer
vinyl acetate,
compound
surface
a hydrophilic
The hydrophilic
pyrrolidone, As explained,
low friction
by binding
(non-coated),
was
low surface copolymer
400
000.
related
(bl polyurethane
to The
to the
cathetef
surface.
Biomatenals
1990,
Vol
1 1 August
423
Low-friction surface for medical devices: S. Nagaoka and R. Akashi
/
, lesions
endothelial cell layer
Figure 9 Histological observation of the mural section of the blood vessel after catheter manipulation (stained by haematoxylin-eosineJ. (aJ Polyurethane catheter (non-coatedJ. Catheter-induced lesions were clearly observed and endothelial cell layer was fallen off (bJ Polyurethane catheter with hydrophilic lowfriction surface. No lesions were observed and the endothelial cells formed normal monolayer.
mechanical strength of the hydrophilic copolymer, and the addition of hydrophobic vinyl acetate was essential to prevent the deterioration of the low friction coating. The polyurethane catheter coated with the hydrophilic low friction surface was easy to insert in and did not damage the blood vessel during manipulation and, furthermore, showed improved blood compatibility.
2
3
4
5 6
REFERENCES
7 1
424
Ducatman, B.S., McMichan, J.C. and Edwards, W.D., Catheterinduced lesions of the right side of the heart, JAMA 1985, 253, 791-795
Biomaterials
1990. Vol 11 August
8
Ford, SE. and Manley, P.N.. Indwelling cardiac catheters: an autopsy study of associated endocardial lesions, Arch. Pathol. Lab. Med. 1982,106, 314-317 Lange. H.W.. Galliani, CA. and Edwards, J.E.. Local complications associated with indwelling Swan-Ganz catheters: autopsy study of 36 patients, Am. J. Cardiol. 1983, 52, 1 108- 1 1 1 1 Lazarus, H.M., Lowder, J.N. and Herzig, R.H., Occlusion and infection in Broviac catheters during intensive cancer therapy, Cancer 1983, 52, 23-48 Micklus, J.M.. Coated substrate having low coefficient of friction, United States Patent Number 4, 1 19, 094, 1978 Tanaka, H., Hydrolysis of polyisocyanate. Bull. Chem. Sot. Japan. 1976,49,2821-2823 Gadd, G.E., Turbulence damping and drag reduction produced by certain additives in water, Nature 1965, 206, 463-467 Kohn, M.C., Energy stage in drag-reducing polymer solutions, J. Polym. Sci., Polym. Phys. Ed. 1973, 11, 2339-2356
