Compositions and methods for tissue preservation
Inventors
Thatte, Hemant • Treanor, Patrick • Khuri, Shukri F. • Rousou, Laki
Assignees
US Department of Veterans Affairs • Harvard University
Publication Number
US-8945823-B2
Publication Date
2015-02-03
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 novel methods and compositions for resuscitating, storing, and preserving the functional integrity of organs and tissues, particularly focusing on organs such as the heart. The compositions maintain metabolic function by sustaining ATP levels, mitochondrial function, cardiomyocyte contractility, preventing acidosis, inhibiting apoptosis, and regulating ionontrophy and lusiotrophy through controlling calcium, sodium, potassium, and chloride ions.
The problem being solved addresses the limited availability and poor quality of donor hearts due to deterioration during current storage practices, which limit preservation time to 4-6 hours. The invention seeks to provide improved compositions and storage methods to substantially prolong preservation time, enable use of non-beating heart donors, reduce ischemia-reperfusion injury, maintain endothelial and myocardial function, and improve clinical outcomes after transplantation.
The invention includes physiological salt solutions combined with substrates for ATP production, ammonia consumption, reagents to buffer intracellular acidity, quench reactive oxygen species, and balance tissue edema/dehydration. These compositions protect endothelial cells and cardiac myocytes during storage, maintain mitochondrial membrane potential, and prevent hydration imbalances and metabolic disturbances. The invention also provides perfusion devices and systems allowing controlled circulation of the solution with temperature and flow regulation to support prolonged organ viability and resuscitation from arrested states.
Claims Coverage
The patent claims describe several inventive features related to methods for producing physiological solutions for tissue or organ preservation or resuscitation, focusing on specific compositions and preparation steps.
Method for producing physiological solution with specific salts and compounds
Mixing one or more physiological salts (such as calcium chloride, potassium chloride, potassium phosphate, magnesium chloride, magnesium sulfate, sodium chloride, and sodium phosphate), glucose, glutathione, ascorbic acid, arginine, citrulline, adenosine, carnosine, creatinine, and carnitine with water to form an aqueous physiological solution.
Addition of compounds for pH adjustment and metabolic support
Further addition of one or more compounds selected from dichloroacetate, sodium bicarbonate, and insulin to the physiological solution to adjust pH and enhance preservation properties.
pH adjustment to physiological level
Adjustment of the pH of the solution to approximately 7.4, specifically by adding sodium bicarbonate to achieve this pH level.
Comprehensive method for mixing all specified components
Mixing water with the full set of physiological salts and compounds including glucose, glutathione, ascorbic acid, arginine, citrulline, adenosine, carnosine, creatinine, and carnitine to produce the aqueous solution suitable for preserving or resuscitating tissue or organs.
Together, these claims cover methods of preparing physiological storage solutions containing defined salts and metabolic agents, adjusting them for pH, and optionally adding components like dichloroacetate and insulin to enhance tissue preservation and resuscitation.
Stated Advantages
Permits substantially longer preservation periods for donor organs compared to existing solutions.
Enables use of non-beating heart donors, potentially increasing donor pool size and availability.
Preserves structural and functional integrity of myocardium and endothelium, reducing ischemia-reperfusion injury.
Prevents organ dehydration and edema during storage and reperfusion by optimizing ionic composition.
Provides a self-sustaining system for continuous ATP and nitric oxide production, buffering acidosis, and ammonia quenching.
Improves clinical outcomes after transplantation by minimizing damage and vasculopathy associated with current storage methods.
Documented Applications
Preservation and resuscitation of harvested human or mammalian hearts for transplantation including beating, non-beating, and cadaveric donor hearts.
Extended temporal storage of organs such as heart, kidney, liver, stomach, spleen, pancreas, lung, brain, eye, intestines, bladder, skin, blood vessels, heart valves, sperm, and oocytes.
Ex vivo organ preservation and resuscitation systems and devices utilizing perfusion of preservation solutions with temperature and flow control.
Evaluation of physiological integrity of organs and tissues by measuring esterase activity, nitric oxide levels, mitochondrial membrane potential, and pH to ascertain suitability for transplantation.
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