Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Heart valve – Flexible leaflet
Reexamination Certificate
2001-02-27
2003-07-15
Willse, David H. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Heart valve
Flexible leaflet
C600S036000, C008S094110, C623S915000, C623S916000, C623S917000, C623S918000
Reexamination Certificate
active
06592618
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to improved methods for preserving heart valves that have been removed from donor animals for transplantation into humans. The method involves treating the valves in a manner that reduces their expression of antigens causing inflammation after transplantation.
BACKGROUND OF THE INVENTION
Diseased heart valves maybe replaced with either mechanical or natural tissue prostheses. In the latter case, porcine valves are often used because of their similarity to valves in humans. The prior art teaches methods for removing heart valves from a pig, treating them with chemical solutions to aid in their preservation and then implanting them into a patient (U.S. Pat. Nos. 3,983,581; 4,035,849; and 5,861,028). Unfortunately, transplanted valves sometimes undergo relatively rapid degeneration and may need to be replaced. Methods for improving the biological performance of these valves would represent a clear advance in the treatment of cardiac patients.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that porcine cardiac valvular tissue continuously expresses antigens (e.g., major histocompatibility complex, “MHC,” class II antigens), that cause inflammation upon implantation into a human host. Inflammation is believed to contribute to a decrease in the functional half-life of the xenografts. Therefore, a method has been developed in which valves are cultured in vitro (preferably in the presence of a biologically active substance modifying their immunological profile) prior to freezing or chemical preservation. In particular, it has been found that primate serum causes a decreased expression of MHC class II antigens in porcine valves. Thus, a valve is produced with a reduced tendency to undergo post-surgical deterioration.
In its first aspect, the invention is directed to a method of preparing a heart valve for transplantation by removing it from a donor animal; culturing it in vitro for a period of time sufficient to reduce antigens that cause inflammation after transplantation; and then preserving the valve by freezing or chemical treatment. Alternatively, the cultured valves may be implanted directly into a patient. It has been found that porcine valves cultured for 48 hours in the presence of primate serum (preferably baboon serum) show an essentially complete loss of MHCII antigens. It is expected that serum from other species distinct from the donor animal may also be used. In addition, the invention encompasses the heart valves prepared by these methods.
In a second aspect, the invention is directed to a heart valve obtained from a donor animal for transplantation into a human. These valves express less than 10% of the MHCII antigens normally found in the valve prior to, or immediately after, removal from the donor animal. Preferably, the donor is a pig and the level of MHCII antigens is reduced to less than 1%.
Finally, the invention is directed to the improvement in heart valve transplantation characterized by the in vitro culturing of valves after removal from a donor animal. Again, the objective of culturing is to reduce inflammation-causing antigens as much as possible. As discussed above, the incubation should generally be performed in the presence of an agent (e.g., primate serum) that aids in reducing antigen levels.
DETAILED DESCRIPTION OF THE INVENTION
Natural tissue heart valves for surgical implantation are typically obtained from porcine donors and must be preserved until surgery can be performed on an appropriate recipient. Although methods have been developed for surgically removing valves from animals and preserving them either by freezing or by treatment with chemicals, improved methods are needed to avoid the degeneration of valves post-implantation.
It has been found that valves derived from pigs express antigens that lead to inflammation upon implantation into humans. If, after removal from donor animals, the valves are incubated in vitro, the MHCII class of inflammatory antigens rapidly decreases so that, by 48 hours, such antigens are essentially absent. Incubations should generally be carried out in the presence of serum derived from a species other than the donor animal (e.g., primate serum) and should preferably be terminated in less than 5 days. Typically serum should comprise between 5% and 20% by volume of the growth medium.
Any of the standard methods for obtaining, culturing and preserving valves known in the art are compatible with the invention as is any type of growth medium provided that it contains serum as discussed above. Similarly, the actual implantation may be accomplished using standard surgical procedures. The valves produced by the methods disclosed herein should exhibit less inflammation in patients and have a substantially increased functional life.
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patent: 3983581 (1976-10-01), Angell et al.
patent: 4035849 (1977-07-01), Angell et al.
patent: 5861028 (1999-01-01), Angell
patent: 5882328 (1999-03-01), Levy et al.
patent: 6214407 (2001-04-01), Laube et al.
patent: 6383732 (2002-05-01), Stone
patent: 198 34 396 (2000-02-01), None
patent: 0 994 185 (2000-04-01), None
Chen, et al., “Decreased Porcine Valve Antigenicity With In Vitro Culture,”Ann. of Thorac. Surg.71:S393-S395 (2001).
Ohkado, et al., “Problems in Preservation of Allogeneic Heart Valves and Vessels,”Transplantation Proceedings 31:2047-2048 (1999).
Abstract for All above.
Adams David H.
Chen Raymond H.
Blanco Javier S.
Fitch Even Tabin & Flannery
Sanzo Michael A.
The Brigham and Women's Hospital Inc.
Willse David H.
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