Compositions and methods for tissue preservation
Inventors
Thatte, Hemant • Treanor, Patrick • Khuri, Shukri F. • KHURI, LEGAL REPRESENTATIVE RANDA, null • Rousou, Laki
Assignees
US Department of Veterans Affairs • Harvard University
Publication Number
US-8211628-B2
Publication Date
2012-07-03
Expiration Date
2028-02-19
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Abstract
Methods and compositions for resuscitating, storing, and preserving functional integrity of organs and tissues. Metabolic function is maintained by sustaining ATP levels, mitochondrial function, cardiomyocyte contractility, prevention of acidosis, inhibition of induction of apoptosis, maintaining ionontrophy and lusiotrophy by regulating calcium, sodium, potassium and chloride ions.
Core Innovation
The invention provides methods and compositions for resuscitating, storing, and preserving functional integrity of organs and tissues, specifically focusing on maintaining metabolic function by sustaining ATP levels, mitochondrial function, cardiomyocyte contractility, preventing acidosis, inhibiting apoptosis induction, and regulating ion balance including calcium, sodium, potassium, and chloride ions. It also includes improved compositions, methods, and devices to preserve functional integrity and restore function to non-functioning or deteriorated organs, thereby extending preservation time beyond current limits.
The problem being solved arises from the limited availability and poor quality of donor hearts due to deterioration during storage, with current preservation solutions limiting storage to 4-6 hours and resulting in accelerated vasculopathy after transplantation. The invention addresses the urgent need for long-term storage solutions that maintain both structural and physiological integrity of donor hearts, including the use of non-beating heart donors and enabling transport over longer distances to increase donor pool size.
The compositions contain a physiological salt solution combined with substrates for ATP production, reagents that consume ammonia, buffer intracellular acidity, quench reactive oxygen species, and balance tissue edema or dehydration. The invention enables preservation and resuscitation at normothermic temperatures and can maintain the donor organ in a viable state for extended periods ranging from hours to days. Additionally, the invention includes perfusion devices and systems that circulate preservation solutions, maintain specific biochemical cycles for continuous ATP and nitric oxide generation, provide temperature control, oxygenation, filtering, and flow control to maintain physiological conditions ex vivo.
Claims Coverage
The claims include three independent claims focusing on methods for preserving or resuscitating biological tissues using compositions comprising specific physiological salt solutions and biochemical agents.
Composition containing specific physiological salt solution and metabolic agents
A method for preserving or resuscitating a biological tissue or organ by bringing it into contact with a composition comprising a physiological salt solution combined with glutathione, ascorbic acid, arginine, citrulline, adenosine, creatine, glucose, insulin, carnitine, and dichloroacetate.
Physiological salt solution with defined ionic components
The physiological salt solution comprises water and one or more salts selected from calcium chloride, potassium chloride, potassium phosphate, magnesium chloride, magnesium sulfate, sodium chloride, sodium bicarbonate, and sodium phosphate.
Application to a variety of biological tissues and organs
The methods apply to preserving or resuscitating biological tissues or organs selected from the group consisting of heart, kidney, liver, stomach, spleen, pancreas, lung, brain, eye, intestines, and bladder.
The independent claims cover methods utilizing a composition with a physiological salt solution containing specified salts and metabolic substrates and protective agents to preserve or resuscitate a broad range of biological tissues and organs.
Stated Advantages
Provides substantially longer preservation periods beyond the current 4-6 hour limit for donor hearts.
Enables the use of non-beating heart donors, thereby increasing the donor pool.
Preserves the structural and functional integrity of the myocardium and endothelium during storage.
Minimizes ischemia-reperfusion injury and prevents edema and acidosis through ionic and biochemical regulation.
Supports continuous metabolic activity including ATP production and nitric oxide generation via a self-sustaining system.
Allows for transport of organs to alternate geographic locations under viable preservation conditions.
Documented Applications
Preservation and resuscitation of harvested human hearts for transplantation.
Maintenance and storage of other organs and tissues including kidney, liver, stomach, spleen, pancreas, lung, brain, eye, intestines, bladder, skin, blood vessels, heart valves, sperm, and oocytes.
Use in perfusion systems and devices for ex vivo organ preservation and evaluation.
Evaluation of organ viability through biological indices such as esterase activity, nitric oxide production, and mitochondrial membrane potential.
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