CA1257561A

CA1257561A - Method of forming an antithrombogenic layer and a medical device utilizing the same

Info

Publication number: CA1257561A
Application number: CA000472376A
Authority: CA
Inventors: Martinus H. Kuypers
Original assignee: PPG Hellige BV
Current assignee: PPG Hellige BV
Priority date: 1984-01-20
Filing date: 1985-01-18
Publication date: 1989-07-18
Also published as: EP0149693A1; JPS60160965A; DE3472370D1; EP0149693B1

Abstract

APPLICATION OF
MARTINUS H. KUYPERS
METHOD OF FORMING AN ANTITHROMBOGENIC LAYER
AND A MEDICAL DEVICE UTILIZING THE SAME
ABSTRACT
An antithrombogenic layer is formed on a medical device by preparing an aqueous solution of a photosensitive polymer, a cross-linking salt and heparin; coating the medical device with said solution and exposing the coated device to ultraviolet radiation to induce cross-linking of the polymer.

Description

~Z575~

1. Field of the Invention This invention relates to medical devices. ~ore speciEically, the present invention is directed to a method for forming an antithrombogenic layer and a medical device utilizing the same.

2. Description of the Prior Art Sensor catheters used as an indwelling catheter in a patient blood environment can monitor physiological values such as pressure, oxygen, pH, etc. over some period of time.
During a long blood contact time, the blood can clot on the surfaces of the sensor-catheter. This clotting is caused by the cascacadic biochemical mechanism of the blood, forming deposits called thrombi. This thrombogeneration can be initi-ated by the bio-incompatibility of a foreign surface with respect to the chemical, physical and mechanical properties of such surfaceO The thrombus-forming is not only limited to the foreign surface since the collision of a blood pla-telet with the foreign surface can irritate the biochemical behavior of that platelet which can result in thrombus forming in a remote part of a blood circulating system. It is important to control this biochemical reaction to avoid thrombogeneration which can dramatically generate embolism or can at least impair the functionality of the sensor-catheter. In many cases the monitoring with a sensor-catheter will be done during a short time, e.g., during catherization for diagnostical purposes. In those cases the thrombogenic processes can be controlled by the administration of anti-coagulants, of which heparin is the most widely used. However, heparin administration during a ~25'7~56'~

longer pe~od of time can lead to adverse effects, e.g., to osteoporosis (softening of the bony tissue) and to the so-called "heparin rebound effect" in which heparin activi~y returns somewhere in the bloodstream some hours after its neutralization. During monitoring in the vascular system of the newborn baby, the heparin can f~, fl~
initiate even more problems'~-$be-~*~e metabolism of the baby.
As is known from a review article ~Heparinized polymers as thromboresistant biomaterials" published by JO E. Wilson in Polym. plast. Technol. Eng 16(2) 119-208 (1981), several trials have been made to bind heparin to the surfaces of medical devices which must be introduced into the bloodstream. In the literature there is still also a controversial dispute about the activity and the antithrombogenic mechanism of heparin.
According to J. E. Wilson (op. cit.), the antithrombogenity may be caused by the leaching of heparin from the polymer. The microatmosphere of the dissolved heparin around the device causes the antithrombogenity.
The binding of heparin to the polymer results in a decrease of its activity. Contrary to this explanation, M. F. A. Goosen and M. V. Sefton in an ar~icle "Properties of a heparin-poly(vinylal~ohol)-hydrogel coating" published in the Journal of Biomed. Mat. Res., Vol. 17, 359-373 (1983), showed that chemical binding of heparin in polyvinylalcohol effects positively the antithrombogenity of the polymer. They have proved that no heparin leached out from the P.V.A. hydrogel during their biological activity measurements.

~5~6~

SUMMARY OF THE INVENTION
It is the object of the present invention to proviae an improved method of forming such antithrombogenic layers on medical devices such as catheters, sensors and medical instru-ments.
In accomplishing this and other objects, there has been provided, in accordance with the present invention, an improved method of forming an antithrombogenic layer including the steps of preparing an aqueous solution of a photosensitive polymer, a cross-linking salt and heparin, coating a surface with the solution and exposing the coating to ultraviolet radiation. A medical device such as a catheter made in accord-ance with the aforesaid method is at least partially coated with the antithrombogenic layer in the area to be contacted by a blood environment.
In accordance with a further aspect of the invention, there is provided a medical device comprising a support sub-strate and an antithrombogenic layer which has been exposed to ultraviolet radiation and including a combination of a photo-sensitive polymer, a cross linking salt and heparin adhering onat least a desired portion of an outside surface of said substrate.
BRIEF DESCRIPTION OF THE DRAWING
A better understanding of the present invention may be had when the following detailed description is read in connection with the accompanying drawing, in which thP single figure is a cross-sectional illustration of a medical device surface coated with an antithrombogenic layer made according to the method of the present invention.

~ ~, 7~6~
-4a- 72542-2 DESCRIPTION OF THE PREFERRED EMBODIMENT
.
The new method described herein is easy to perform and relies on the well-known principles of lithography.
particular advantage of applying this method to sensors is the fact that the same method can be used for depositing other layers and coatings of the sensor such as hydrophylic layers and electrical connections in the form of printed circuits. In this way the same type of manufacturing ,, i ~7~

equipment can be used for depositing different kinds of coatings and layers. ~ suitable lithographic method and several modifications thereof are described in detail in the book "Photoresist: Materials and Processes" by William S. DeForest, published by McGraw-Hill, Inc. in 1975.
In a preferred embodiment of the new method a photosensitive cross-linking agent is used. The adhesion of the antithrombogenic layer to a polymeric surface can be p~ z~9 achieved by chemical ~ h~lising of the polymeric _., . .,~
surface by chemical etching in chromic-sulphuric acid, resulting in the formation of C-OH, C=O, -O-C=O and S03H
groups. The cross-linking agent will also react with some of these groups resulting in an adhering P.V.A.-heparin coating, i.e., the heparin is firmly bound to the P.V.A.
matrix.
The single drawing shows an oxygen sensor of the Clark type manufactured in accordance w;th the method of the present invention using lithographic methods. An insulating substrate 2, e.g., silicon, supports a cathode 1 and an anode 3 which are deposited on the substrate in the known manner of printed or integrated circuits. Both p l - / ~ c electrodes are covered by a layer 7 of h~7~r~h~1 c polymer which is protected on the outside by means of a membrane 5. For activating the sensor either an electrolyte can be deposited as a salt underneath the membrane 5 during the lithographic preparation of the cell, or the electrolyte can be derived from the biological fluid surrounding the sensor during its application whereby the electrolyte is brought into contact with the electrodes 1,3 and the space between them. For this purpose, holes 6 in the membrane 5 _5_ ~257~

7254~-2 permit access of the electrolyte to the hydrophilic polymer layer 7 .so that -the electrolyte can pass along this layer to cathode 1 for activa-ting the cell.
Oxygen or any other constituent of the fluid under examination diffuses through the membrane 5 and the layer 7 to cathode 1, therewith influencing the electrochemical process between electrodes 1 and 3. These electrodes are connected to a source of DC (not shown), and the amount of current induced by the reduction and oxidation process at the cathode 1 and the anode 3, respectively, is a measure for determining the content of oxygen within the biological medium into which the sensor is inserted.
Instead of silicon another insulating substrate such as glass or ceramic may be usedO
~ hen using the cell, the direct access of oxygen through the holes 6 must be minimized since this results in a change or increase of the oxygen diffusion through the selectively permeable membrane 5 to the electrodes. For this reason the distance d of holes 6 from the cathode 1 is ar larger, e.g., five times larger, than the width w of the active front surface area of cathode 1.
The thickness h of the hydrophilic polymer layer 7 is very small, preEerably less than 4u. Accordingly, essentially all of the oxy-gen reaching cathode 1 stems from a diffusion through membrane 5 and the oxygen portion entering through holes 6 and traveling along hydrophilic polymer layer 7 can be neglected. This layer may be made of hydrogel such as polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, hydroxyethylmethacrylate or derivates of these compounds. The cathode 1 preferably is made of noble metal such as gold and the anode 3 may consist of ~ ~ 7 ~s~ ~
silver. The hydrophylic polymer layer 7 may act as a sieve which is permeable for the electrolyte, oxygen, carbon dioxide and relatively small biological organic molecules such as glucose, but it is impermeable for large biological molecules such as proteins.
In accordance with the method of the present invention, an antithrombogenic layer 8 is deposited on the outside surface of membrane 5 covering also the walls of holes 6 and those surace portions o~ layer 7 which are exposed by the holes 6. This layer 8, in accordance with the invention, is essentially deposited by the same lithographic method as is used for depositing the hydophylic layer 7. The hydrophylic-polymer layer 8 contains heparin and may be of a structure which is permeable for the electrolyte, oxygen, carbon dioxide and relatively small biological organic molecules such as glucose, but it is impermeable for large biological molecules such as proteins. In this case layer 8 in addition to its antithrombogenic function at least partially provides the sieve function of layer 7. The photo cross-linking of the layer 8 is subsequently induced by an exposure to ultraviolet radiation for a short period of time, e.g., two minutes using a 5 degree divergence at .45M collimated ultraviolet light source o 200 watt, with a wavelength of 80~ between 300 and 600 NM, a peak at 360 NM and a collection angle of 0.8 r~ steradians.
Accordingly, it may be seen that there has been provided, in accordance with the present invention, an improved method for forming an antithrombogenic coating and a medical device utilizing the same.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of forming an antithrombogenic layer characterized by the steps of preparing an aqueous solution of a photosensitive polymer, a cross-linking salt and heparin;
coating an insulating substrate with said solution and exposing the coated substrate to ultraviolet radiation to induce cross-linking of the polymer.

2. A method according to Claim 1, and further characterized in that the antithrombogenic layer is cross-linked to such an extent that large biological molecules cannot penetrate the layer.

3. A method according to Claim 1 and further characterized by the step of chemically hydrophilizing the substrate by chemical etching in chromic-sulphuric acid before coating the surface with said solution.

4. A method according to Claim 2 and further characterized by the step of chemically hydrophilizing the substrate by chemical etching in chromic-sulphuric acid before coating the surface with said solution.

5. A medical device comprising a support substrate and an antithrombogenic layer including a cross-linked polymer formed from polyvinyl alcohol and heparin on at least a portion of an outside surface of said substrate.

6. A device as set forth in Claim 5 wherein said substrate is a housing for a pair of electrodes separated by an electrolyte space within said housing and means for admitting a component of fluid to be analyzed into the space between said electrodes.

- 8a -

7. A device as set forth in Claim 5 wherein said substrate is a catheter.

8. A device as set forth in Claim 5 wherein said substrate is an outside surface of a medical instrument.

9. A device as set forth in Claim 5 wherein said substrate is a chemical sensor.

10. A device as set forth in Claim 9 wherein said sensor is a pH sensor.

11. A medical device comprising a support substrate and an antithrombogenic layer which has been exposed to ultraviolet radiation and including a combination of a photosensitive polymer, a cross-linking salt and heparin adhering on at least a desired portion of an outside surface of said substrate.

12. A device as set forth in Claim 11 wherein said sub-strate is a housing for a pair of electrodes separated by an electrolyte space within said housing and means for admitting a component of fluid to be analyzed into the space between said electrodes.

13. A device as set forth in Claim 11 wherein said sub-strate is a catheter.

14. A device as set forth in Claim 11 wherein said sub-strate is an outside surface of a medical instrument.

15. A device as set forth in Claim 11 wherein said sub-strate is a chemical sensor.

16. A device as set forth in Claim 15 wherein said sensor is a pH sensor.

17. A device as set forth in Claim 11 wherein said layer is cross-linked by said radiation to such an extent to prevent the penetration of said layer by large biological molecules.

18. A device as set forth in Claim 11 wherein said polymer is a hydrophilic polymer.

19. A device as set forth in Claim 11 wherein said desired portion of the outside surface of said substrate is a polymeric surface.

20. A device as set forth in Claim 19 wherein said poly-meric surface has been chemically hydrophilised by etching with chromic sulphuric acid to achieve the adhering of said layer.

21. A device as set forth in Claim 11 wherein said sub-strate is an electrically insulating substrate.