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Method for processing and preserving collagen-based tissues for transplantationRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Maintaining Blood Or Sperm In A Physiologically Active State Or Compositions Thereof Or Therefor Or Methods Of In Vitro Blood Cell Separation Or TreatmentMethod for processing and preserving collagen-based tissues for transplantation description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060210960, Method for processing and preserving collagen-based tissues for transplantation. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATION [0001] This application is a continuation-in-part of copending application Ser. No. 835,138 filed Feb. 12, 1992 which is a continuation-in-part of copending application Ser. No. 07/709,504 filed Jun. 3, 1991 which is a continuation-in-part of application Ser. No. 07/581,584 filed Sep. 12, 1990. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to methods for procuring decellularizing and further processing and dry preserving collagen-based tissues derived from humans and animals for transplantation into humans or other animals. These methods produce a tissue product that consists of a selectively preserved extracellular protein matrix that is devoid of certain viable cells which normally express major histocompatibility complex antigenic determinants and other antigens which would be recognized as foreign by the recipient. This extracellular protein matrix is made up of collagen and other proteins and provides a structural template which may be repopulated with new viable cells that would not be rejected by the host. These viable cells may be derived from the host (autologous cells) before or after transplantation or from an alternative human source including foreskin, umbilical cord or aborted fetal tissues. More particularly, this invention relates to the procurement and processing of collagen-based tissues such that complications following implantation (including but not limited to immunorejection, contracture, calcification, occlusion, and infection) are significantly reduced relative to current implant procedures and materials. [0004] 2. Description of the Related Art [0005] Tissue and organ transplantation is a rapidly growing therapeutic field as a result of improvements in surgical procedures, advancements in immunosuppressive drugs and increased knowledge of graft/host interaction. Despite major advancements in this field, modern tissue transplantation remains associated with complications including inflammation, degradation, scarring, contracture, calcification (hardening), occlusion and rejection. There are numerous investigations underway directed toward the engineering of improved transplantable tissue grafts, however, it is generally believed in the industry that ideal implants have yet to be produced. [0006] Autologous or self-derived human tissue is often used for transplant procedures. These procedures include coronary and peripheral vascular bypass surgeries, where a blood vessel, usually a vein, is harvested from some other area of the body and transplanted to correct obstructed blood flow through one or more critical arteries. Another application of autologous tissue is in the treatment of third degree burns and other full-thickness skin injury. This treatment involves grafting of healthy skin from uninjured body sites to the site of the wound, a process called split-skin grafting. Additional applications of autologous tissue transplantation include bone, cartilage and fascia grafting, used for reconstructive procedures. [0007] The motive for using autologous tissue for transplantation is based upon the concept that complications of immunorejection will be eliminated, resulting in enhanced conditions for graft survival. Unfortunately, however, other complications can ensue with autologous transplants. For example, significant damage can occur to several tissue components of transplanted veins during harvesting and prior to implantation. This damage can include mechanical contraction of the smooth muscle cells in the vein wall leading to loss of endothelium and smooth muscle cell hypoxia and death. Hypoxic damage can result in the release of cellular lysosomes, enzymes which can cause significant damage to the extracellular matrix. Following implantation, such damage can lead to increased platelet adhesion, leucocyte and macrophage infiltration and subsequently further damage to the vessel wall. The end result of such damage is thrombosis and occlusion in the early post implant period. Even in the absence of such damage, transplanted autologous veins typically undergo thickening of the vessel wall and advancing atherosclerosis leading to late occlusion. The exact cause of this phenomena is uncertain but may relate to compliance mismatch of the vein in an arterial position of high blood pressure and flow rate. This phenomena may be augmented and accelerated by any initial smooth muscle cell and matrix damage occurring during procurement. Occlusion of transplanted veins can necessitate repeat bypass procedures, with subsequent re-harvesting of additional autologous veins, or replacement with synthetic conduits or non-autologous vessels. [0008] Another example of complications resulting from autologous tissue transplantation is the scarring and contracture that can occur with split-skin grafts for full-thickness wound repair. Split-skin grafts are typically mechanically expanded by the use of a meshing instrument, which introduces a pattern of small slits in the skin. The split-skin graft is then stretched to cover a larger wound area. Dividing epidermal cells will ultimately grow into and cover the areas of the slits, however, the underlying dermal support matrix does not readily expand into these areas. The dermal matrix, composed primarily of collagen, other extracellular protein matrix proteins, and basement membrane complex, is responsible for the tensile, flexible nature of skin. Absence of a dermal matrix results in scarring and contracture in the area of the slits. This contracture can be severe and in cases of massively burned patients that undergo extensive split-skin grafting, can necessitate subsequent release surgical procedures to restore joint movement. [0009] When the supply of transplantable autologous tissues is depleted, or when there is no suitable autologous tissue available for transplant (e.g., heart valve replacement), then substitutes may be used, including man-made synthetic materials, animal-derived tissues and tissue products, or allogeneic human tissues donated from another individual (usually derived from cadavers). Man-made implant materials include synthetic polymers (e.g. (PTFE) polytetrafluroethylene, Dacron and Goretex) sometimes formed into a tubular shape and used as a blood flow conduit for some peripheral arterial bypass procedures. Additionally, man-made synthetics (polyurethanes) and hydrocolloids or gels may be used as temporary wound dressings prior to split-skin grafting. [0010] Other man-made materials include plastics and carbonized metals, fashioned into a prosthetic heart valve, utilized for aortic heart valve replacement procedures. Synthetic materials can be made with low immunogenicity but are subject to other limitations. In the case of mechanical heart valves, their hemodynamic characteristics necessitate life-long anticoagulant therapy. Synthetic vascular conduits, often used in above-the-knee peripheral vascular bypass procedures, are subjected to an even higher incidence of occlusion than autologous grafts. In many cases, a preference is made for a biological implant which can be a processed animal tissue or a fresh or cryopreserved allogeneic human tissue. [0011] Animal tissues (bovine or porcine) chemically treated are commonly used as replacements for defective human heart valves, and have been used in the past for vascular conduits. The concept in the chemical processing is to stabilize the structural protein and collagen matrix by cross-linking with glutaraldehyde or a similar cross-linking agent. This treatment also masks the antigenic determinants, such that the human host will not recognize the implant as foreign and precludes an immunorejection response. Glutaraldehyde-treated tissues, however, will not allow in-migration of host cells which are necessary for remodeling, and will gradually harden as a result of calcification. For this reason, glutaraldehyde-treated tissues generally require replacement in 5-7 years. Glutaraldehyde-treated bovine veins have been used in the past for vascular bypass bypass procedures, however, their use has been discontinued due to the unacceptable incidence of aneurysm formation and occlusion. [0012] The use of allogeneic transplant tissues has been applied to heart valve replacement procedures, arterial bypass procedures, bone, cartilage, and ligament replacement procedures and to full-thickness wound treatment as a temporary dressing. The allogeneic tissue is used fresh, or may be cryopreserved with the use of DMSO and/or glycerol, to maintain viability of cellular components. It is thought that the cellular components contain histocompatibility antigens, and are capable of eliciting an immune response from the host. In many cases, the patient receiving the allogeneic transplant undergoes immunosuppressive therapy. Despite this therapy, many allogeneic transplants, including heart valves and blood vessels, undergo an inflammatory response, and fail within 5-10 years. Allogeneic skin is typically rejected within 1-5 weeks of application, and has never been demonstrated to be permanently accepted by the host, even with the use of immunosuppressive drugs. [0013] Alternative processing methods have been developed by others that are intended to address the limitations of allogeneic and animal-derived transplant tissues. Freeze-drying is used routinely in the processing of allogeneic bone for transplantation. It has been found that the freeze drying process results in a graft which elicits no significant rejection response as compared to fresh or cryopreserved allogeneic bone. The freeze-dried bone following implant acts as a template, which is subsequently remodelled by the host. When the freeze-drying process has been applied to more complex tissues such as heart valves, the results have been mixed but overall unsatisfactory. A study was conducted in which 15 allogeneic heart valves were processed by freeze-drying prior to transplantation. Most of the freeze-dried valves failed due to mechanical causes in the early post-graft interval. Those freeze-dried valves which did not fail, however, demonstrated prolonged functionality (up to 15 years). [0014] Enzymes and detergent processing has also been used to remove antigenic cells from collagen-based transplantable tissues. Organic solvents and detergent treatments have been used successfully with relatively simple tissues such as dura mater used in reconstructive surgical procedures. Chemical processing of more complex structures such as heart valves, vascular conduits and skin, however, has had only limited success in clinical applications. [0015] The invention of this patent is a comprehensive processing technique that addresses potential damaging events in the preparation of complex collagen-based tissues for transplantation. The technology combines both biochemical and physical processing steps to achieve the ideal features of template function such that the tissue graft can be remodeled for long-term maintenance by the host. BRIEF SUMMARY OF THE INVENTION [0016] In its preferred form, the method of this invention includes the steps of processing biological tissues including treatment with a stabilizing solution to reduce procurement damage, treatment with a processing solution to remove cells and other antigenic tissue components, treatment with a cryoprotectant solution, freezing and storage under specific conditions to avoid functionally significant damaging ice crystal formation, drying under conditions to prevent damaging ice recrystallization, storage in the dry state at above freezing temperatures, rehydration under specific conditions and with a rehydration solution to minimize surface tension damage and further augment the selective preservation of the matrix, and reconstitution with viable cells that will not be rejected by the host. DESCRIPTION OF THE PREFERRED EMBODIMENTS [0017] The present invention provides a method for processing and preserving collagen-based biological tissues for transplantation, through steps of chemical pretreatment and cell removal, cryopreparation, dry stabilization, drying, rehydration and cellular reconstitution. The processing and preservation method is designed to generate a transplantable biological tissue graft that specifically meets the following criteria: [0018] (a) provides an extracellular protein and collagen matrix which can be remodelled and repaired by the host, [0019] (b) provides an intact basement membrane for secure reattachment of viable endothelial or epithelial cells, [0020] (c) does not elicit an immune response by the host, [0021] (d) does not calcify, and [0022] (e) can be easily stored and transported at ambient temperatures. [0023] In the preferred embodiment, the biological tissue to be processed is first procured or harvested from a human cadaver or animal donor and immediately placed in a stabilizing transportation solution which arrests and prevents osmotic, hypoxic, autolytic and proteolytic degradation, protects against bacterial contamination and reduces mechanical damage that can occur with tissues that contain smooth muscle components (e.g. blood vessels). The stabilizing solution generally contains an appropriate buffer, one or more antioxidants, one or more oncotic agents, an antibiotic, one or more protease inhibitors, and in some cases, a smooth muscle relaxant. [0024] In the preferred embodiment, the tissue is then incubated in a processing solution to remove viable antigenic cells (including epithelial cells, endothelial cells, smooth muscle cells and fibroblasts) from the structural matrix without damaging the basement membrane complex or the structural integrity of the collagen matrix. The processing solution generally contains an appropriate buffer, salt, an antibiotic, one or more detergents, one or more protease inhibitors, and/or one or more enzymes. Treatment of the tissue with this processing solution must be at a concentration for a time duration such that degradation of the basement membrane complex is avoided and the structural integrity of the matrix is maintained including collagen fibers and elastin. [0025] After the tissue is decellularized, it is preferably incubated in a cryopreservation solution. In the preferred embodiment, this solution generally contains one or more cryoprotectants to minimize ice crystal damage to the structural matrix that could occur during freezing, and one or more dry-protective components, to minimize structural damage alteration during drying and may include a combination of an organic solvent and water which undergoes neither expansion or contraction during freezing. As an alternate method, the decellularized tissue matrix can be fixed with a crosslinking agent such as glutaraldehyde and stored prior to transplantation. Following incubation in this cryopreservation solution, the tissue is packaged inside a sterile container, such as a glass vial or a pouch, which is permeable to water vapor yet impermeable to bacteria. Continue reading about Method for processing and preserving collagen-based tissues for transplantation... Full patent description for Method for processing and preserving collagen-based tissues for transplantation Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method for processing and preserving collagen-based tissues for transplantation patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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