Developing a Novel Preservation Solution for VCA Transplantation
Abstract
We will address the following FY19 Reconstructive Transplant Research Program Focus Area(s): Advance existing or develop innovative ex vivo tissue preservation strategies to extend the timeline between procurement and transplantation: 1. Develop novel approaches and models for perfused, hypothermic, high subzero and low subzero, or static preservation strategies. 2. Determine the extent to which VCA tissue preservation technology impacts VCA immunogenicity to be addressed. 3. Describe the ultimate applicability and impact of the research. Over half of all combat-related casualties in the U.S. military since 2006 were sustained in improvised explosive device (IED)-related incidences. Up to 80% of those involved wounds to the hands and or face. Victims of such attacks are often left permanently disfigured and, in some cases, with extremities and/or portions of their face missing. The current technology available to reconstruct the Wounded Warrior after severe trauma to the extremity or face consists of taking tissue from non-injured portions of the body to reconstruct what has been lost. The surgical techniques are often inadequate to completely restore the patient to their pre-injury status. In addition, these techniques require multiple revision procedures, prolonged rehabilitation, and complications and functional restrictions that occur because of the need to surgically relocate the patient’s own (autologous) tissue. One solution to the overwhelming need for tissue for reconstruction is the use of tissue (such as a hand) taken from a deceased donor and transplanted to the living recipient. These organ transplants are called vascularized composite tissue allografts (VCAs), as they include multiple tissues types such as bone, tendon, muscle, and skin together with the vasculature that supplies blood to these tissues. During transplantation, blood supplying oxygen to tissues of the VCA is necessarily temporarily cut off when the VCA is removed from the donor and before the blood supply is reestablished in the recipient. To prevent injury to the VCA during this time, it is cooled to 4°C in a process referred to as cold preservation. However, the VCA can only tolerate a limited amount of cold preservation before the VCA is irreversibly injured. Furthermore, increasing periods of cold preservation are more likely to incite a robust inflammatory and rejection response when the recipient s blood supply is reconnected. This inflammatory response causes injury to the transplanted VCA and greatly influences transplant outcome. The limited amount of time a VCA can be preserved hampers proper matching of the transplant to the recipient (which increases the risk of rejection), restricts the ability to pre-treat the transplant with potentially protective agents, and places a geographical restriction on who can receive the organ. The consequence is that many viable VCAs cannot be given to the best-matched recipients and go either unused or are transplanted into a less-ideal candidate. We propose to develop innovative tissue preservation strategies to decrease tissue injury associated with cold storage prior to transplantation and reperfusion following transplantation, using novel hypothermic, perfused, and static preservation strategies in the well-established transplant model. Specifically, we will identify the cellular death pathways that are activated during cold preservation and transplantation. We will block the cell death pathways using specific novel inhibitors to reduce VCA injury, inflammation, and rejection. Using this approach, we hope to improve the function and long-term survival of these crucial transplants. We believe inhibiting cell death during VCA preservation and transplantation is the key to ensuring the transplanted organs are fully functional and have minimal complications. The loss of limbs and disfigurement are among the most debilitating conditions suffered by military personn
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010859
Entities
People
- Evan Farkash
Organizations
- United States Army
- University of Michigan