Note: Descriptions are shown in the official language in which they were submitted.
1054893
. BACKGROUND OF THE INVENTION
With the development of highly inert organic
. polymers many attempts have been made to use devices utilizing
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. such materials within living mammalian bodies. Particularly
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important examples of attempts to use such polymers are in
the construction of heart valves and as replacements for
defective blood vessels. Another most interesting example
is for insulation of the wires used in pacemakers. Despite
the extremely high chemical inertness of materials such as the
many Teflons, polyethylene, and polypropylene, it has been
found that such materials are eventually either chemically
attacked by the various fluids in the body or cause thrombosis.
When used for intravascular cannulae thrombosis, thrombo-
phlebitis, and over the long term periphlebitis, may result
even when heparinized. These effects are particularly severe
at junctions between the natural vascular walls and the
polymeric insert.
It is known that copolymers of acidic monomers
such as acrylic acid with ethylene in proper proportion, when
partially neutralized, again in proper proportion, with metallic
ions show very little tendency to cause thrombosis, thrombo-
i'~ phlebitis, periphlebitis or fibrosis when placed within bloodvessels. A most desirable use for such polymers would be as
vascular replacements for defective sections of blood vessels.
When such copolymers are used in this way, none of these
effects occur to any appreciable extent within the polymeric
section itself, but there is generally thrombus formation at
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the junctions between the polymeric tube section and the blood
vessel itself, increasing in frequency and intensity with implanta-
tion time. Consequently, use of such copolymers as vascular sec-
tion.s is limited. Nevertheless, the fact that there are no
undesirable effects either within or outside of the tube itself
indicates that such materials warrant study with respect to other
uses. A,particularly valuable use for such a tube would be a cathe-
ter serving to introduce solutions of food, medication, contrast
media and monitoring devices into selected blood vessels. In addi-
tion to absence of toxicity in the modes indicated, the materialfrom which such a catheter is to be made must be formable, prefer-
ably by extrusion, be sterilizable, have adequate strength and
' flexibility and be reasonable in cost. Where the catheter is to
remain within the blood vessel for an extended period, (say up to
3 weeks), it must be resistant to corrosion by the body fluids:
otherwise, it would be impossible to leave the catheter in place,
even if the products of corrosion were completely free of toxicity.
While the catheters of U.S. Patent 3,886,947 are antithrom-
bogenic and free of tendency to cause phlebitis and periphlebitis,
certain difficulties are encountered in the manufacture and use
thereof. The difficulty in the manufacture arises from the fact
that the preferred method of manufacture
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10548~3
is by means of extrusion. It has been found that the conditions for extrusion
are critical since processing at too high a temperature results in degrada-
tion of the polymer of which the catheter is comprised. If the temperature
i8 dropped substantially, extrusion cannot be carried out at all. Conse-
quently the range over which extrusion can be carried out is rather narrow.
The second difficulty lies in the fact that the catheters of the composition
diselosed in U.S. patent 3,886,947 are relatively stiff. This makes it diffi-
eult to manipulate the catheters into branch vessels where the catheter
must bend sharply. As a result, angiograms of certain vessels cannot easily
ln be had. It therefore appears that it would be desirable to find a catheter
eomposition which could be extruded more readily which would be ~more flex-
ible and which would share the characteristics of antithrombogenicity as
well as freedom from causing phlebitis and periphlebitis.
SUMMARY OF THE INVE~TION
The present invention provides a catheter suitable for intro-
duetion o~ monitoring devices in solutions of foods, drugs and contrast media
into veins and arteries, and having low tendency to deposit thrombus or
cause thrombosis, thrombophlebitis, periphlebitis or fibrosis, comprising
a tubular structure suitable for insertion into a natural or artificial
2a opening in a body, the tubular structure including an outer surface consist-
ing of an acidic copolymer of ethylene and acrylic acid which on intravascu-
lar insertion of the catheter becomes negatively charged on the outer
surface thereof as the result of release of hydrogen ions into the environ-
ment, the negatively charged surface being anti-thrombogenic.
Catheters consisting particularly of a copolymer of about
19% by weight of acrylic acid and 81% by weight of ethylene in the unneutra-
lized state are relatively free of tendency to cause thrombosis, throm-
bophlebitis, periphlebitis or fibrosis, and are strongly resistant to
corrosion by body fluids. Such
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catheters can be placed in blood vessels for the purpose of introducing
solutions of food, medicaments, contrast media and minotoring devices over
extended periods of time. It should be noted that only the outer surface
of the catheter must be essentially free of toxic effects and resistant
to corrosion.
Preferably the acrylic acid content of the copolymer is from
about 14 to about 24% by weight, the remainder being copolymerized ethylene.
Accordingly, an object of the present invention is to pro-
vide an improved catheter suitable for intravascular insertion, said cathe-
1~ ter being low in tendency to cause thrombosis, thrombophlebitis, peri-
phlebitis or fibrosis.
Another ob;ect of the present invention is to provide an
improved catheter suitable for introduction of solution of foods or
medicaments, contrast media and monitoring devices into blood vessels over
substantial periods of time without causing any of the aforenoted effects.
A further object of the present invention is to provide
an improved catheter of which at least the outer surface conslsts of a
copolymer of an acid and ethylene, such a material being termed an "ionomer".
Still other ob~ects and advantages of the invention will in
part be obvious and will in part be apparent from the specification.
The invention accordingly comprises an article of manufacture
possessing the features, properties, and the relation of elements which will
be exemplified in the article
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. .. .
hereinafter described, and the scope of the invention will
be indicated in the claims.
,
, BRIEF DESCRIPTION OF THE DRAWINGS
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,I For a fuller understanding of the invention,
' reference is had to the following description taken in connection
with the accompanying drawings, in which
Fig, 1 is a plan view of a dog in which are
, inserted catheters in accordance with the present invention
,, and commercially available catheters;
Fig, 2 is a perspective view of a catheter in
accordance with the present invention; and
Fig. 3 is a bar graph showing the severity of
thrombosis, thrombophlebitis and periphlebitis caused by a
variety of catheters when implanted as shown in Fig. 1.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The relative thrombogenicities of polymer
, surfaces in accordance with the present invention were
, established by introducing catheters 15 (Fig. 1) into the
I venous flow of the left or right jugular and femoral veins
of pure-bred standard female Beagle hounds (Fig. 1, reference
numerals 11, 12, 13 and 14, respectively). The objective
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1054893
¦ was to find a material which could be used as a long term
indwelling intravenous or intra-arterial infusion catheter
and for cardiac catheterization. l~e catheters were kept in
the region of implantation for varying lengths of time at the
~l end of which the dog was sacrificed so that the blood vessels
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could be examined and the catheter itself could be examined
with respect to thrombogenicity. ~e degree of thrombogenicity
was rated from O to 4 with 4 b-eing the highest.
Three types of staining procedures were carried
out on the multiple veins and contained catheters to evaluate
the histology; these included --- classical Hematoxylin and Eosin,
and Van Gieson to show elastin. A histochemical stain was used
to evaluate fibrin deposition. The degrees of thrombogenicity,
phlebitis and periphlebitis were judged by a physician immediately
after removal of the test catheters from the test animals. After
examination of each catheter on removal from the test animal,
the catheter was photographed and then immersed in formaldehyde
to preserve any thrombus deposit on the catheter. Finally,
each preserved specimen was examined by the director of the
group, the director up to this point being uninformed of and
therefore unprejudiced by the judgement rendered by the previous
evaluator. Tables 1 and 2 show the results obtained in two
; sets of tests.
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~054893
The histologic results support the general observations
that the 19% ethylene acrylic acid and the 60~ neutralized 19~
ethylene acrylic acid catheters are superior to the other materials
evaluated. These results are consistent with applicant's earlier
findings as presented in the aforenoted U.S. Patent 3,886,947.
However, the relative ranking of these two materials is reversed
from the earlier finding. This may be due to a statistical varia-
tion, or, more likely, to greater experience in the preparation of
the free acid copolymer. However, even if it is assumed that minor
variations in the quality of the product and the inevitable varia-
tions in the test data make it impossible to decide, on the basis
of the histologic evidence, which of the two materials is superior,
the copolymer in the acid form has marked advantages with respect
to ease of manufacture and greater flexibility.
The test data include results, as aforenoted, on throm-
bosis, thrombophlebitis and periphlebitis. In addition, information
was collected with respect to edema, inflammatory cell infiltration,
fibroblastic infiltration with new deposition of collagen, organiza-
tion of thrombus, fibroblastic invasion and collagen deposition.
The test catheters varied somewhat in shape, depending on
the manufacture. A perspective view of a
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1054893
catheter of the 19% ethylene acrylic acid in the free acid form
is shown in Fig. 2 in which the catheter is indicated generally
by the reference numeral 16.
With one exception, the commercially available catheters
all begin to show thrombus formation within two days of implanta-
tion Two batches of tests were made on Nafion catheters, the
Nafion catheters listed in Table 1 being in the acid form and in
Table 2 being in the sodium form. As will be noted, Nafion cathe-
ters in the sodium form were remarkably free of thrombus formation
although showing strong thrombophlebitis and periphlebitis.
The acid form of the ethylene-acrylic acid copolymer has
a major advantage over the partially-neutralized form in that the
acid form i8 virtual~y comp~etely insoluble in the blood whereas
the solubility o the partially-neutralized form increases with
the degree of neutralization. Even at relatively low levels of
neutralization, the solubility is appreciable and the sodium ion,
to a substantial depth within the catheter wall, exchanges with the
hydrogen ion in the blood, gradually but substantially increasing
the pH of the blood. Both the entry of the polymer into the blood
and the increase in the pH thereof have been found to be harmful.
In the tests listéd in Table 1, six animals were used
in testing each type of catheter, catheters being examined after
implantation for periods of 30 min., 2 hrs., 2 days, 1 week, 2
weeks and 3 weeks. In the tests of Table 2, only 4 animals were
used for each type of catheter. For comparisons within each group
of tests all of the test results on each type of catheter were
included. For comparison between materials in different sets of
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1054893
tests, test data at 30 min. and at 3 weeks were omitted for the
materials listed in Table 1. The averages for the data at 2 hrs., ¦
2 days, 1 week and 2 weeks are presentedin Fig 3 in bar graph form.
All of the commercially available catheters when
evaluated on the basîs of tendency to cause all three of thrombosisl,
thrombophlebitis and periphlebitis, were found to be inferior to
catheters of 81% ethylene - 19% acrylic acid copolymer. On the
basis of these results, it is judged that the free acid copolymer
is a superior material for use in the manufacture of catheters,
particularly where said catheters are to be implanted for periods
of time up to at least two weeks. Catheters are commonly implanted
for such long periods when they are to be used for alimentation,
in~ravenous or intra-arterial infusion and for cardiac catheter-
ization, as aforenoted.
The copolymer of acrylic acid and ethylene in acid form
may also be used effectively as a coating on a flexible but non-
extensible base, even if the base is thrombogenic, since only the
exterior of the catheter makes contact with blood flowing in a
vessel.
Based on research activities to date, the materials which
might well behave similarly are copolymers of maleic anhydride
and fumaric acid with ethylene in which the weight content of the
acid ranges from about 5 to 25%. It should be noted that such
copolymers as well as the copolymer of the present invention are
negatively charged on the outer surfaces thereof when implanted,
by reason of ionization, such ionization resulting in a negative
I charge on the outer surface of the catheter. It is well known that
a negative charge on the surface of an implanted material leads to
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1054893
¦Idecrease or elimination of thrombogenicity. Furthermore, the solu-¦
i bility of the copolymers mentioned is extremely low so that both
periphlebitis and phlebitis should be low. Implantation data-indi-
cate that catheters of ethylene-acrylic acid copolymers in which
thé weight fraction of acid is between about 14 and 24% should
also give satisfactory results.
A critical point is that the catheter, when implanted in
a blood vessel, must not materially interfere with blood flow there
through, else thrombosis will be caused by the catheter regardless
of its composition, thrombosis being caused by prevention of flow
in a region proximate the catheter rather than by the presence of
¦¦the catheter as a foreign body,
¦ The value of a catheter which does not cause side effects
is enhanced by the growing tendency to keep catheters in position
for extended periods of time for alimentation and medication.
It will thus be seen that the objects set forth above,
among those made apparent from the preceding description, are effi-¦
ciently a~tained and, since certain changes may be made in the above
article without departing from the spirit and scope of the invention,
it is intended that all matter contained in the above description
and shown in the accompanying drawings shall be interpreted as
illustrative and not in a limiting sense.
It is also to be understood that the following claims are
intended to cover all of the generic and specific features of the
invention herein described, and all statements of the scope of the
invention which, as a matter of language, might be said to fall
therebetween.
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