METHOD OF FORMING AN ANTITHROMBOGENIC LAYER ON MEDICAL DEVICES

Abstract: An antithrombogenic layer is formed on medical devices by preparing an aqueous solution of a photosensitive polymer, a cross-linking salt and heparin; coating the medical device with said solution; exposing the coated device to ultraviolet radiation.

Description: Method of forming an Antithrombogenic Layer on Medical Devices The invention relates to a method of forming on medical devices an antithrombogenic layer comprising polyvinyl alcohol and heparin. Sensor catheters used as an indwelling catheter can monitor physiological values such as pressure, oxygen, pH etc. over some period of time. During a long contacttime, the blood can clot on the surfaces of the sensorcatheter. This clotting is caused by the cascacadic biochemical mechanism of the blood, forming deposits called thrombus. This thrombogeneration can be initiated by the bio-incompatibility of a foreign surface in respect to the chemical, physical and mechanical properties of the surface. The thrombus-forming is not only limited to the foreign surface, but the collision of a blood platelet with the foreign surface can irritate the biochemical behaviour of that platelet which can result in thrombus forming in a remote part of the 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 catheterisation for diagnostical purposes. In those cases the thrombogenic processes can be controlled by the administration of anti-coagulantia, of which heparin is the most widely used. However, heparin administration during a longer period 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 activity returns somewhere in the bloodstream some hours after its neutralisation. During monitoring in the vascular system of the newborn baby, the heparin can initiate even more problems in the instable metabolism of the baby. As is known from a review article "Heparinised polymers as thromboresistant biomaterials" published by J. 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 a controversial dispute about the activity and the antithrombogenic mechanism of heparin. According to J. E. Wilson (see above), 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 article "Properties of a heparin-poly(vinylalcohol)-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 could prove that no heparin leached out from the P.V.A. hydrogel during their biological activity measurements. It is the object of the present invention to disclose an improved method of forming such antithrombogenic layers on medical devices such as catheters, sensors and medical instruments. The new method as described in claim 1 is easy to perform and relies on the well-known principles of lithography. A 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 equipment can be used for depositing different kinds of coatings and layers. The 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 crosslinking agent is used. The invention also extends to medical devices provided with an antithrombogenic coating or layer deposited by performing the method as claimed. The adhesion of the antithrombogenic layer to a polymeric surface can be achieved by chemical hydrophylising of the polymeric surface by chemical etching in chromicsulphuric acid, resulting in the formation of C-OH, C=O, -O-C=O and S03H groups. The crosslinking agent will also react with some of these groups resulting in an adhering P.V.A.-heparin coating. 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 with lithographic methods. A silicon substrate 2 supports a cathode 1 and an anode 3 which are deposited on the substrate in the known manner of printed or integrated circuits. Both electrodes are covered by a layer 7 of hydrophylic polymer which is protected on the outside by means of a membrane 5. For activating the sensor either the electrolyte can be deposited as a salt underneath the membrane 5 during the lithographic preparation of the cell, or the electrolyte is derived from the biological fluid surrounding the sensor during its application and then has to be brought into contact with the electrodes and the space between them. For this purpose holes 6 within membrane 5 permit access of the electrolyte to the hydrophylic polymer layer 7 so that the electrolyte can pass along this layer to cathode 1 for activating the cell. Oxygen or any other constituent of the fluid under examination diffuses through membrane 5 and layer 7 to cathode 1, therewith influencing the electrochemical process between electrodes 1 and 3. These electrodes are connected to a source of DC, and the amount of current induced by the reduction and oxidation process at the cathode and the anode, 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 ceramics may be used. When using the cell, it must be prevented that the direct access of oxygen through the holes 6 results in a change or increase of the oxygentdiffusion through the selectively permeable membrane 5 to the electrodes. For this reason the distance d of holes 6 from the cathode 1 is by far larger, e.g. five times larger than the width w of the active front surface area of cathode 1. The thickness h of the hydrophylic polymer layer 7 is very small, preferably less than 4cur. Therewith most or essentially all of the oxygen reaching cathode 1 therefore stems from diffusion through membrane 5 and the oxygen portion entering through holes 6 and travelling along hydrophylic polymer layer 7 can be neglected. This layer may be made of hydrogel such as polyvinyl alcohol, polyvinyl pyrrolidon, polyacrylamiden, hydroxyethylmetacrylate or derivates of these compounds. The cathode preferably is made of noble metal such as gold and the anode may consist of silver. The hydrophylic polymer 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 present invention an antithrombogenic layer 8 is deposited on theoutsidesurface of membrane 5 covering also the walls of holes 6 and those surface portions of layer 7 which form the bottom of those holes. This layer 8 in accordance with the invention is essentially deposited by the same lithographic method as is used for depositing the hydrophylic layer 7. The hydrophylic-polymer layer 8 containing heparin 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.

Claims: Claims: 1. Method of forming on medical devices an antithrombo genic layer comprising polyvinyl alcohol and heparin, c h a r a c t e r i z e d b y the steps of: a) preparing an aqueous solution of a photosensitive polymer, a cross-linking salt and heparin; b) coating the medical device with said solution; c) exposing the coated device to ultraviolet radiation. 2. Method according to claim 1, c h a r a c t e r i z e d i n t h a t the antithr#itogenic laYer is cross linked to such an extent that large biological molecules cannot penetrate the interior of the sensor. 3. Method according to claim 1 or 2 of forming an anti thrombogenic layer on a polymeric surface, c h a r a c t e r i z e d i n t h a t before coating the surface with said solution, this surface is chemically hydrophylised by chemical etching in chromic-sulphuric acid. 4. Applying the method of claims 1, 2 or 3 for coating a chemical or physical sensor such as a pressure, pH or oxygen sensor with an antithrombogenic layer. 5. Applying the method of claims 1, 2 or 3 for coating a catheter with an antithrombogenic layer. 6. Applying the method of claims 1, 2 or 3 for coating a medical instrument with an antithrombogenic layer. 7. A medical device at least partially coated with an anti thrombogenic layer by performing the method of claims 1, 2 or 3.

Inventors: KUYPERS, MARTINUS HENRICUS
Applicants: PPG HELLIGE B.V.
Application year: 1984
Main classification: A61L27
IPC codes: A61N1, A61L33