Building upon Current Practices by Perfusion and Mechanism-Based Supplementation of Hypothermic Organ Storage Solutions for Longer Duration Storage of VCAs
Abstract
Objectives and Rationale: In the United States, there are approximately 150,000 civilian limb amputations performed annually in addition to high-profile military cases. Over 10 years ago, more than 1,000 military men and women had lost an arm or leg in the conflicts in Iraq and Afghanistan, and 20 percent had lost two or more limbs. At this time, about 150 hand transplants have been performed. Treatment of patients is limited by the short time from procurement to transplantation. If you only have 6 hours, you cannot go far to procure and return with the tissue. Our technology will provide 24-36 hours for procurement and transplantation of organs or tissues. This will improve immunological matching, reduce the development of changes that induce immune reactions, and improve the size, sex, and color of the hands available for specific patients. This work is directly responsive to the FY20 RTRP Investigator-Initiated Research Award Focus Areas, “Advance existing or develop innovative ex vivo tissue preservation strategies to extend the timeline between procurement and transplantation”; “Develop novel approaches and models for perfused, hypothermic, high-subzero and low-subzero or static preservation strategies”; and “Determine the extent to which VCA tissue preservation technology impacts VCA immunogenicity.” This proposal targets the development of improved preservation methods for vascularized composite allotransplant tissues to radically improve restorative and reconstructive medicine. Hand surgeons are often called upon to reattach severed parts such as fingers, thumbs, hands, forearms, and, more recently, faces. These complex tissues were recently included as organs by the Department of Health and Human Services in the definition of organs governing the operation of the U.S. Organ Procurement and Transplantation Network. It is well established in the scientific literature that hypothermic machine perfusion preservation methods are effective for storage of internal organs, particularly kidneys. The team of experts assembled for this project is among the best in their respective disciplines. The Tissue Testing Technologies group was responsible for the kidney system that has been employed in more than 121,000 kidney transplant cases in 32 countries. A larger system developed for livers is presently in clinical studies approved by the U.S. Food and Drug Administration. Dr. Brandacher and his colleagues are one of the most experienced clinical and research teams for human extremity transplantation and animal limb model research. Our objectives include adaptation of existing clinical and hypothermic preservation solutions and perfusion devices for abdominal organs for limb extremities. In Aim 1, farm pig hind limb tissues will be studied, as well as 15 compounds impacting specific mechanisms that lead to tissue damage after prolonged storage in the cold. We will first evaluate each compound alone and in combinations in tissue culture. Then the best performing formulation(s) will be evaluated to determine their effectiveness at minimizing the development of donor tissue damage and injury. In Aim 2, we will first assess modification of the clinical devices in use and settings for perfusion. Then we will treat minipig limbs by hypothermic perfusion using the best supplement formulation(s) from Aim 1, using the clinical organ preservation solution for 24-36 hours. The Brandacher group will transplant limbs using a more immunologically defined miniature pig strain as donors and recipients with immunosuppression. Assays to assess the effectiveness of this novel approach will include recipient immune responses to treated and control donor tissues that have been perfused with clinical preservation solutions without supplements for 12 hours (12 hours is the outer limit of current clinical practice), morphological studies, and biomechanics assays. Ultimate Applicability and Impact: The current short duration
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110688
Entities
People
- Kelvin Brockbank
Organizations
- United States Army