More than 43,000 Americans die each year from liver disease, making it the 10th leading disease- related cause of death in the US. Cirrhosis with irreversible injury and scarring of the liver is the most prevalent cause of liver failure and is attributable to alcohol abuse as well as hepatitis. Although alcohol has been the primary cause of cirrhosis, the Center for Disease Control has predicted that hepatitis-related deaths will increase to 38,000 a year unless improved treatments are developed. The shortage of organs for transplantation continues to be a major impediment to providing optimal treatment for patients with end stage liver failure. There is no dialysis-equivalent therapy for these patients and the prospect of death while waiting for a transplantable organ is a realistic probability. The long-term goal of this SBIR proposal is to increase the number and quality of donor livers available for transplantation by developing a clinically usable, portable, hypothermic perfusion method of liver preservation that will reliably preserve human livers for at least 24 hours. The device can also be employed for liver quality evaluation ex vivo under physiologic conditions. The objective of this Phase I proposal is to test and determine feasibility of an intermediate near room temperature, 18-22oC, deep hypothermic oxygenated blood perfusion strategy in combination with a prototype liver transport device for preservation of porcine heart beating donor liver functions for 24 hours. This device concept has potential advantages compared with both normothermic and profound, 4-6oC hypothermic preservation strategies. The prototype liver transport device will be subjected to design review to optimize its design during the course of these experiments. The experimental livers will be compared with control livers stored on ice using current clinical methods. Both controls and experimental hypothermic perfusion groups will be assessed by oxygenated blood perfusion ex vivo at 37oC. The normothermic perfusion test circuit will include the liver transport device with additional heat exchange and oxygenation capacity. During testing perfusate and bile samples will be collected at frequent intervals and prioritized end point assays performed to measure (1) metabolic acidosis and hypoglycemia, (2) reduced or absent bile production, (3) Kupffer cell activation, and (4) sinusoidal endothelial cell dysfunction which would lead to reduced blood flow upon reperfusion. If we are successful in this Phase I feasibility study, we will subsequently propose a Phase II study in which porcine liver preservation for 48 hours is attempted and ex vivo and in vivo testing is combined with perfusion solution optimization. Forty-eight hours of porcine liver preservation would provide preclinical safety and efficacy data to support progression, with FDA permission, to clinical studies of human livers for up to 24 hours of preservation.
The innovative technical breakthroughs in this proposal will have a significant impact on critical national needs for transplantable livers. Conservatively the availability of longer term liver preservation strategies post-mortem may generate significant numbers, equivalent to ~25% more transplantable livers, from expanded criteria heart beating donors and short-term warm ischemic non-heart beating donors. This increase in organ supply should decrease patient waiting times for organs and the number of patients who die waiting for a liver.
