GB1579627A

GB1579627A - Biological prosthesis and method for the production thereof

Info

Publication number: GB1579627A
Application number: GB15177/77A
Authority: GB
Original assignee: Polystan AS
Current assignee: Polystan AS
Priority date: 1976-04-12
Filing date: 1977-04-12
Publication date: 1980-11-19
Also published as: NO143192C; NO143192B; FR2347921B3; SE7704058L; NO771250L; DK139607B; FI771074A; DK169076A; DE2715466A1; DK139607C; FR2347921A1

Description

(54) A BIOLOGICAL PROSTHESIS AND METHOD FOR THE PRODUCTION THEREOF (71) We, POLYSTAN A/S, a Danish Company of Generatorves 41, DK, 2730 Herlev Denmark, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to a biological prosthesis and method for the production thereof, which prosthesis according to its form is intended for implanation or transitory extracorporal usage.

The use of prostheses in the broad sense of the concept, whereby is to be understood both purely mechanical devices, transplants and tissue grafts to replace or support missing, defective or inadequate body parts, has been known for a long time.

Examples of mechanical prostheses include metal bone parts, false teeth, glass eyes and heart valve prostheses. The latter may be formed as ball valves, see, for example Danish Patent No. 129,902 and U.S. Patent No. 3,325,827, or disc valves, see, for example U.S. Patent No. 3,376,409.

These mechanical heart valve prostheses have proved to suffer serious drawbacks.

They require much space and may injure the inside wall of the heart. Their operation is often heard by the patient and they may damage the blood cells so as to give rise to traumatic conditions. They produce turbulence in the blood and deposits of blood coagula and protein materials are often inclined to form on parts of the valves and may cause emboli upon detachment. Anticoagulants have been used to reduce the danger thereof, but this is cumbersome and may also lead to complications.

In transplanting tissue, including whole organs such as kidneys, between individuals of the same species (allotransplantation) or between alien individuals (heterotransplantation) and in implanatation of biological prostheses a major problem is immunological reactions from the host organism or injurious effects of the transplant on the host organism, particularly through antibody formation.

Particularly when implanting heart valves, whether human heart valves from recently deceased patients or alien heart valves from pigs, for instance, these are very frail, may undergo degeneration and degradation and may involve the danger of premature sclerosis in addition to the said immunological reaction.

It has been attempted to remedy this frailty by a kind of tanning. In particular, aldehydes are used for this purpose, such as glutaric acid dialdehyde (glutaraldehyde), which by formation of cross-links imparts to the tissue improved tensile strength while retaining the necessary flexibility and less susceptibility to enzymatic action. An eventual degenerative change cannot, however, be avoided in this case either.

The prior art has further suggested stents for heart valves, see, for example U.S.

Patent Nos. 3,548,418, 3,570,014 and 3,759,823. Admittedly, these stents provide correct positioning of the valves and some improvement of the fate of such valves, but numerous cases of breaking have nevertheless been observed after a few years, and also there is a danger of immunological reactions and in growth by the surrounding tissue onto the stent after implantation.

Besides, the stent itself has a narrowing effect on the flow path, and also deposits of blood coagula on the stent may produce a secondary change together with the danger of emboli, particularly at the early stage after the operative insertion, should these coagulae become detached.

Similar problems are known from implanation of other non-biological prostheses, such as artificial partitions and artificial vessels, where there is often noticed an excessive ingrowth of the surrounding connective tissue.

In particular with regard to vascular prostheses it is not possible or only possible with difficulty to use, as is preferred, a ring of non-biological material for the sewing operation at the site of anastomoses. Admittedly, this will prevent a local immunological reaction but does not achieve a smoothly operating anastomsis due to excessive healing reaction and scar shrinkage. This problem, naturally, is especially marked in vascular prostheses of small diameter.

The present invention provides a biological prosthesis for implantation of extracorporeal usage, comprising a stabilised biological tissue which is at least in part impregnated and/or coated with a physiologically compatible synthetic polymeric material. By impregnating and/or coating according to the invention a biological base material, for example heart valves from pigs, calves or sheep, with a polymeric material the following particular advantages are achieved: 1. The base material is better protected against attacks by the host organism, such as enzymatic disintegration and denaturation of the proteins.

2. Immunological reactions on the part of the host organism are prevented to a greater extent than was previously possible.

3. There is obtained a surface which according to the selected polymeric material may even be superior to the natural surface of the organism in tcrms of preventing protein deposits such as fibrinogen and albumins by ccrtain pathological conditions.

4. The prosthetic material (base material) is rcinforccd to provide improved strength and durability.

The selected biological base material may be stabilized prior to or after coating and/or impregnation, for example by treatment with stabilized glutaraldehyde. As, some of the solvents for the polymers employed may have a tanning cffect per Se, it is in some cases possible by suitable selection of the solvents to supplement or even completely eliminate the treatment, for instance with glutaraldehyde.

The polymcric material must be selected according to the desired application (according to the knowledge of one skilled in the arty, for example based on whether the prosthesis is to be implanted or is intended for transitory extracorporeal us agc, e.g. in assisted or total extracorporeal blood circulation (where by wav of example a pig's lung treated according to the invention might be used transitorily in open heart operations).

The prostheses may in principle be produced by employing any physiologically compatible polymers material, but preferred arc: Silicones, for example the cold-hardening one-component adhesive available under the trade name "Silicone 416 RTV", acrylic polymers and copolymers, for example prepared from acrylic acid or methacrylic acid and/or esters thereof, such as "Strathcylde Acryl Copolymers", and polyurethanes both two-component polyurethanes, for example prepared from polyesters (e.g. 'De- smophen"), and polyisocyanates ("Desmodur"), and one-component polyurethanes ("Desmolak"). Desmophen, Desmodur and Desmolak are Trade Marks.

For heart valves especially preferred are inelastic polymeric materials, for example acrylic polymers or copolymers. In general, in the coating of surfaces contributing to the maintenance of blood circulation the polymers employed must be non-thrombogenic.

For the treatment of products to be permanently fixed to the host tissue there are preferably used polymers having a positive affinity to the tissue and which may in some cases advantageously be thrombogenic. A particularly interesting example of a prosthesis of this type according to the invention is a vascular prosthesis, especially for small vessels as in such cases because of the above described problems in using biological materials it was necessary to use vascular prostheses of non-biological material. By subjecting a stabilized vessel of biological material, for example a pig's or calf's vein or artery, to the coating and/or impregnation technique of the invention there is obtained a prosthesis whose original dimensions and physical properties are substantially preserved; or - particularly where strength characteristics are concerned - are improved, which makes it possible to establish a satisfactory anastomosis. In addition to reinforcing the vessel, the coating and/or impregnation prevents local immunological reactions. It has been found to be preferable in order to obtain a perfectly operating anastomosis that the inside of the vessel should not be impregnated. In the case of small vessels. the impregnation process should therefore take place from the outside of the vessel and be stopped before it reaches the inner endothelial layer. As the polymeric material used for such impregnation thus does not come into contact with the blood circulating through the vessel and anastomosis, the material need not be nonthrombogenic. For coating and/or impregnating the vascular system of lungs and other extracorporally used organs it is necessary to select an elastic polymer such as a silicone. Particularly where the lungs are concerned, the polymer should have good diffusion properties with respect to oxygen and carbon dioxide.

In the foregoing the invention has primarily been described in relation to biological prostheses which are coated and/or impregnated and used in their original form. It is a specifically significant feature of the coating and/or impregnation process that it does not change or only to a small extent changes the form and structure of the biological material.

However, the invention is not limited to such prostheses, it being also possible to treat biological materials such as thin membranes to be formed prior to or after coating and/or impregnation into prostheses of a desired form. An example of such a suitable biological material is the pericardium of pigs or calves which were earlier used in stabilized form, for example as vascular prostheses or within heart surgery. In this case, however, the material provided to have a series of the above explained drawbacks, particularly inadequate strength.

By treating such pericardium there is obtained a strong material which may be shaped, for instant cut, into prostheses for a number of applications, both within heart surgery, e.g. for heat valve prostheses of varying configuration and size, and within vascular surgery and treatment of burns.

This flexibility may be an extremely valuable feature of the claimed invention.

It has been found to be desirable for these applications to preserve the surface cell layer of the pericardium, the mesothelium, in non-coated or non-impregnated form, for which reason the treatment with polymeric material is advantageously performed from the non-mesothelial side. If desired, such one-sidedly treated pericardium may be folded with the treated side turned inwardly to obtain a prosthesis exhibiting both good strength characteristics and a completely untreated mesothelial surface.

The invention further relates to a process for preparing a biological prosthesis which comprises treating a biological tissue with a solution of the desired polymer or a precursor thereof in one or more solvents, preferably ethyl acetate, toluene, ethanol, acetone or methyl ethyl ketone. By "precursor" is meant a substance which forms the synthetic polymeric material in situ in the tissue.

Where the biological tissue base material is a heart valve, the method according to the invention is advantageously carried out by immersing the heart valve after stabilization with glutaraldehyde or one or more organic solvents in a solution of the polymer in an organic solvent, preferably that used for stabilization.

Where the biological base material is a lung, the method according to the invention is advantageously carried out by perfusing the lung, after stabilization and optional washing with an organic solvent, with a solution of the polymer in an organic solvent; followed by a pure organic solvent and, if desired, by a stabilizing solution.

The application of the polymeric material may basically be effected by a coating method known per se which is adapted to the nature of the biological base material and the employed polymer. This question and other aspects of the invention will be further explained below and in the illustrative examples provided.

To facilitate insertion of the prostheses according to the invention, regions thereof, generally the marginal regions, where they are to be attached, may be provided with a material suitable as basis for the necessary sutures or for adhesives, particularly a polymer (which is the same as of different from said polymeric material) such as polytetrafluoroethylene or polyesters such as polyethyleneterephthalate. This is especially advantageous in case of heart valves where one may affix a thin strip which is then sewed or adhered to the desired location in the heart.

EXAMPLE 1: Treatment of heart valve with acrylicpolymer The heart valve, in this case an aortic valve from a pig, was removed from a stabilizing solution of glutaraldehyde in an aqueous phosphate buffer. The valve was immersed in acetone which was allowed to evaporate, after which the valve was placed in a 2 weight percent solution of "Strathclyde Acryl Polymer Series 3" (a copolymer of methylmethacrylate and dimethylaminoethylmethacrylate) in a mixture of equal parts of acetone and absolute ethanol. The valve was removed after 10 minutes and following dripping off and air drying for a few seconds (10 to 15 sec.) it was transferred to a glutaraldehyde solution.

This treatment resulted in a coating in the form of an invisible thin film. By varying especially the polymer concentration and the immersion period it is possible to obtain thicker or thinner membranes, and more or less penetration with polymer is obtainable, to thereby approximate a polymeric valve in the borderline case.

EXAMPLE 2: Treatment of heart valve with twocomponent polyurethane The heart valve was pretreated with glutaraldehyde and the surface was dried lightly with acetone similar to Example 1. It was then placed in a solution of the below polyurethane components "Desmophen 1300" and "Desmodur IL 1251" in ethyl acetate. The mixture has a pot-life of about 5 minutes, and the valve was removed prior thereto to allow excessive solution to drip off and ensure by rotation of the valve a uniform distribution of the polyurethane.

Polyester "Desmophen 1300" (Bayer) Acid number: below 20 OH-number: about 4 Colour number (DIN 6162): max. 4 Density (DIN 51 757): 1.13 g/cm3 Viscosity at 200C measured as 50% solu tion in xylene: 60-90 cP Polyisocyanate "Desmodur IL 1251" (Bayer) NCO contents: about 6.3% colour number (DIN 6162): max. 4 Density (DIN 51757): 1.09 g/cm3 Flash point (DIN 53213): avout -4 C Viscosity at 20"C: 650+200 cP Monomer isocyanate contents based on solventless "Desmodur" < 0.7% EXAMPLE 3: Treatment of pulmonary circulation with silicone polymer A pig's lung pretreated in glutaraldehyde solution is connected to a respirator and perfusion apparatus. After initial circulation of a physiological saline solution there is introduced an approximately 5 weight percent solution of a one-component roomtemperature vulcanizing silicone caoutchouc ("Silicone 416 RTV") in a suitable organic solvent such as methyl ethyl ketone, acetone, toluene or ethyl acetate, whereby remaining water is quickly flushed away, and the pure solution is recirculated for 10 minutes, for example, using microfiltration.

The silicone polymer is thereby deposited in a vulcanized state as a thin film on the inside surface of the lung, and at the end of the desired recirculating period there is introduced pure solvent to remove any residual unvulcanized silicone. The solvent is then removed by perfusion with glutaraldehyde solution, and the latter may advantageously be used as a storage medium.

WHAT WE CLAIM IS: 1. A biological prosthesis for implantation or temporary extracorporeal usage, comprising a stabilized biological tissue which is at least in part impregnated and/or coated with a physiologically compatible synthetic polymeric material.

2. A biological prosthesis as claimed in claim 1, wherein the polymeric material employed is a silicone, an acrylic polymer or copolymer or a polyurethane.

3. A biological prosthesis as claimed in claim 1 or claim 2 wherein the biological tissue is a heart valve or a section of pericardium.

4. A biological prosthesis as claimed in any of claims 1 to 3, in which the impregnated and/or coated tissue is provided with an attachment margin of a polymer material.

5. A biological prosthesis as claimed in claim 4, wherein the said polymer material is polytetrafluoroethylene or a polyester such as polyethylene terephthalate.

6. A biological prosthesis according to any of the preceding claims, substantially as herein described.

7. A process for preparing a biological prosthesis as in claim 1, which comprises treating a biological tissue with a solution of the desired polymeric material or a precursor thereof in one or more solvents.

8. A process as claimed in claim 7 in which the solvent is ethyl acetate, toluene, ethanol, acetone or methyl ethyl ketone.

9. A process as claimed in claim 7 or claim 8 wherein the biological tissue is immersed in a solution of the polymer or a precursor thereof in an organic solvent.

10. A process as claimed in any of claims 7 to 9 in which a separate stabilization step is effected before or after the treatment with a polymer or polymer precursor.

11. A process as claimed in claim 10 in which the stabilization step comprises treatment with glutaraldehyde and/or an organic solvent.

12. A process as claimed in any of claims 7 to 11 substantially as herein described.

13. A biological prothesis produced by a process according to any of claims 7 to 12.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

Polyester "Desmophen 1300" (Bayer) Acid number: below 20 OH-number: about 4 Colour number (DIN 6162): max. 4 Density (DIN 51 757): 1.13 g/cm3 Viscosity at 200C measured as 50% solu tion in xylene:

60-90 cP Polyisocyanate "Desmodur IL 1251" (Bayer) NCO contents: about 6.3% colour number (DIN 6162): max. 4 Density (DIN 51757): 1.09 g/cm3 Flash point (DIN 53213): avout -4 C Viscosity at 20"C: 650+200 cP Monomer isocyanate contents based on solventless "Desmodur" < 0.7% EXAMPLE 3: Treatment of pulmonary circulation with silicone polymer A pig's lung pretreated in glutaraldehyde solution is connected to a respirator and perfusion apparatus. After initial circulation of a physiological saline solution there is introduced an approximately 5 weight percent solution of a one-component roomtemperature vulcanizing silicone caoutchouc ("Silicone 416 RTV") in a suitable organic solvent such as methyl ethyl ketone, acetone, toluene or ethyl acetate, whereby remaining water is quickly flushed away, and the pure solution is recirculated for 10 minutes, for example, using microfiltration.

The silicone polymer is thereby deposited in a vulcanized state as a thin film on the inside surface of the lung, and at the end of the desired recirculating period there is introduced pure solvent to remove any residual unvulcanized silicone. The solvent is then removed by perfusion with glutaraldehyde solution, and the latter may advantageously be used as a storage medium.

WHAT WE CLAIM IS: 1. A biological prosthesis for implantation or temporary extracorporeal usage, comprising a stabilized biological tissue which is at least in part impregnated and/or coated with a physiologically compatible synthetic polymeric material.
2. A biological prosthesis as claimed in claim 1, wherein the polymeric material employed is a silicone, an acrylic polymer or copolymer or a polyurethane.
3. A biological prosthesis as claimed in claim 1 or claim 2 wherein the biological tissue is a heart valve or a section of pericardium.
4. A biological prosthesis as claimed in any of claims 1 to 3, in which the impregnated and/or coated tissue is provided with an attachment margin of a polymer material.
5. A biological prosthesis as claimed in claim 4, wherein the said polymer material is polytetrafluoroethylene or a polyester such as polyethylene terephthalate.
6. A biological prosthesis according to any of the preceding claims, substantially as herein described.
7. A process for preparing a biological prosthesis as in claim 1, which comprises treating a biological tissue with a solution of the desired polymeric material or a precursor thereof in one or more solvents.
8. A process as claimed in claim 7 in which the solvent is ethyl acetate, toluene, ethanol, acetone or methyl ethyl ketone.
9. A process as claimed in claim 7 or claim 8 wherein the biological tissue is immersed in a solution of the polymer or a precursor thereof in an organic solvent.
10. A process as claimed in any of claims 7 to 9 in which a separate stabilization step is effected before or after the treatment with a polymer or polymer precursor.
11. A process as claimed in claim 10 in which the stabilization step comprises treatment with glutaraldehyde and/or an organic solvent.
12. A process as claimed in any of claims 7 to 11 substantially as herein described.
13. A biological prothesis produced by a process according to any of claims 7 to 12.