Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or...
Reexamination Certificate
2000-04-10
2003-05-27
Lankford, Jr., Leon B. (Department: 1651)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
C435S002000, C435S001300, C435S366000, C435S372000, C435S374000, C436S018000
Reexamination Certificate
active
06569615
ABSTRACT:
FIELD OF INVENTION
Generally, the present invention relates to the field of tissue preservation. In particular, the present invention relates to a solution for prolonged organ preservation, and more particularly to an aqueous salt solution for the preservation of graphs prior to transplantation. The invention also provides a method of preserving or maintaining an organ, comprising contacting the organ with an aqueous salt solution for organ preservation or maintenance.
BACKGROUND
Many different tissue and organ preservation solutions have been designed, as investigators have sought to lengthen the time that a tissue or organ may remain extra-corporeally, as well as to maximize function of the organ following implantation. Several of the key solutions that have been used over the years include: 1) the Stanford University solution [see, e.g., Swanson, D. K., et al., Journal of Heart Transplantation, (1988), vol. 7, No. 6, pages 456-467 (mentions composition of the Stanford University solution)]; 2) a modified Collins solution [see, e.g., Maurer, E. J., et al., Transplantation Proceedings, (1990), vol. 22, No. 2, pages 548-550; Swanson, D. K., et al., supra (mention composition of modified Collins solution)]; and 3) the University of Wisconsin solution (Belzer, et al., U.S. Pat. No. 4,798,824, issued Jan. 17, 1989). Of those, the University of Wisconsin (UW) solution is currently regarded as the best. (See, e.g., Maurer, E. J., et al., supra).
In addition to the composition of the tissue and organ preservation and maintenance solution, the method of tissue and organ preservation also affects the success of preservation. Several methods of cardiac preservation have been studied in numerous publications: 1) warm arrest/cold ischemia; 2) cold arrest/macroperfusion; 3) cold arrest/microperfusion; and 4) cold arrest/cold ischemia. The first method involves arresting the heart with a warm cardioplegic solution prior to exsanguination and cold preservation, but this method fails because of the rapid depletion of myocardial energy stores during the warm period. The second method, which involves arresting the heart with a cold preservation solution, is better; but continuous perfusion of the heart with preservation solution during the storage period fails because of the generation of toxic oxygen radicals. In addition, the procedure of the second method is cumbersome and does not lend itself to easy clinical use. The third method, first described in the journal
Nature
in 1972 in a system called “trickle perfusion,” is better but also cumbersome. The fourth method of preservation is that of a cold cardioplegic arrest followed by a period of cold immersion of the heart. The fourth method is currently the standard method of cardiac preservation. This fourth method reliably preserves hearts for periods of up to six (6) hours, but less than four (4) hours is considered ideal for this method. Since a longer preservation time is desirable, attempts have been made to improve preservation solutions in such a way as to reliably preserve hearts and other organs for longer periods of time.
Though the University of Wisconsin (UW) solution is currently the industry standard of organ preservation solutions, it is limited in the length of preservation time that it provides. Other solutions have been proposed (see, for example, U.S. Pat. No. 5,552,267 to Stern), however, these have limited use do to the complicated nature of the composition.
The relationship between the long-term patency and endothelial cell preservation has been established. Endothelial cells are known to be important mediators in regulating platelet, anticoagulant, procoagulant, and fibrinolytic functions. These activities of the endothelium allow for control of blood flow as well as thrombosis or blood clotting when there is endothelial injury. Presently, storage solutions are limited in the length of storage (up to 125 minutes) and protection provided to the endothelium. This time frame is insufficient depending on the type of operation being performed (i.e. whether or not a valve replacement or carotid endarterectomy will be needed along with bypass) and on the surgeon performing the operation.
Currently available storage solutions used during bypass surgery vary from normal saline, to physiological salt solutions, to heparinized blood. These solutions do not provide an adequate environment for endothelial or smooth muscle cell support. Normal saline lacks an energy source such as glucose. The pH of saline solutions tend to be low in the 6 to 7 range which is hostile to these fragile cells. Heparinized blood has only been shown to provide adequate storage of veins only up to 90 minutes. All of the currently available solutions are deficient in the combination of free radical scavengers, antioxidants, and nitric oxide synthase substrates that can provide a protective environment for cellular support during this time period where much damage occurs.
What is needed is a physiological salt solution that would prolong the storage and protection available to harvested bypass conduits and other organs such as those used for transplantation in excess of 24 hours on the basis of cell viability and the integrity of key cell regulatory pathways, including nitric oxide synthesis.
SUMMARY OF INVENTION
Generally, the present invention relates to the field of tissue preservation. In particular, the present invention relates to a solution for prolonged organ preservation, and more particularly to an aqueous salt solution for the preservation of graphs prior to transplantation. The invention also provides a method of preserving or maintaining an organ, comprising contacting the organ with as aqueous salt solution for organ preservation or maintenance.
Adequate preservation of organs intended for transplantation is critical to the proper functioning of the organ following implantation. This invention concerns an organ preservation or maintenance solution that can preserve organs intended for transplantation for periods of time that are longer than the currently best solution available. In particular, the present invention concerns the preservation of venous and arterial graphs. A longer preservation time is desired to enable cross-matching of donor and recipient to improve subsequent survival, as well as to allow for coast to coast and international transportation of organs to expand the donor and recipient pools. Experimental work for this invention has focused on the heart and heart tissues, but the organ preservation or maintenance solution of the subject invention may be used for other organs, and for tissues and cells, as well.
The organ preservation or maintenance solution of the present invention shows a substantial improvement over the prior art for increasing the preservation time for organs intended for transplantation. (See Experimental section). The organ preservation or maintenance solution of this subject invention shall be referred to as the GALA solution (named after Glutathione, Ascorbic acid, L-Arginine).
The present invention differs from other organ preservation solutions of the prior art in a number of respects. In our experiments, none of these solutions were able to preserve the structural integrity and function of saphenous vein endothelium for more than 2 hours. The present invention includes NOS substrates and antioxidants and is simple to prepare, being composed of a limited number of ingredients. Additionally, it does not require the elimination of sodium, calcium and chloride from the solution, as does at least one prior art solution (see U.S. Pat. No. 5,552,267 to Stern, et al.). In these regards, the present invention is improved over prior art compositions in that it permits the viability of tissue to be maintained longer than in traditional solutions and it is easier to prepare.
The GALA solution of the present invention is based on Hank's balanced saline solution. Hank's balanced salt solution (HBSS) is a commercially available physiological salt solution containing D-glucose 1 g/L, ca
Biswas Kunda
Khuri Shukri
Michel Thomas
Thatte Hemant
Lankford , Jr. Leon B.
Medlen & Carroll LLP
The United States of America as represented by the Department of
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