Taming Endothelial Activation and Local Inflammation to Rescue VCAs from Preservation Injury
Abstract
Thousands of Americans suffer from severe and irreplaceable tissue loss secondary to combat-related injuries, other traumatic events, or surgical resections. During combat, Soldiers often suffer devastating injuries to unprotected body areas such as the limbs, face, and neck. Where tissue loss involves the extremities, prosthetics can be used to restore some mechanical function, but are of limited use in that they lack sensation, are difficult to handle, and look unnatural. The outcomes of conventional facial reconstruction, which uses tissues from another location in the patient’s own body to reconstruct the face, are limited because the human body does not contain other tissues that can replicate the intricate anatomy and functions of the face. For patients with this type of injury, vascularized composite allotransplantation (VCA) has shown superior results. A VCA is a collection of different types of tissue (skin, muscle, bone) that is transplanted as a whole unit and contains blood vessels that can be connected to the recipient’s blood vessels to allow blood flow to the transplant. However, at this juncture, VCAs come from cadaver sources, and it usually takes several hours up to a day for the donor tissue to be transported to the needy recipient. Therefore, the current VCA donor pool is limited to the local region because prolonged cold storage damages tissues, making them more prone to rejection despite concomitant immunosuppressive medications given to the recipient after transplantation. Novel preservation strategies that safely protect complex VCA tissues against cold ischemia-induced injury and extend the actual time between procurement and transplantation are urgently needed. Successful application of such strategies prior to surgery could also minimize the requirement for post-transplant medications to make VCA more successful and accessible to individuals in need, both wounded military personnel and civilians. As no specific donor or recipient interventions exist to prolong these times, this proposal addresses two Focus Areas identified by the Fiscal Year 2017 Reconstructive Transplant Research Program: (1) Development of ex vivo VCA tissue preservation strategies to extend the time between procurement and transplantation and (2) Studying immune system regulation as specifically applied to VCA. The current project arises from the long-term experience and expertise of the UCLA and the Johns Hopkins transplant research teams. UCLA is one of the largest solid organ transplant centers in the country. Its research group, headed over the past two decades by Dr. Kupiec-Weglinski, has been leading the effort to minimize cold ischemia-induced tissue injury in liver transplant recipients, both experimentally and clinically. Recently, they have developed a new drug, called TSGL-Ig, which protects graft vasculature against ischemia damage and can extend the amount of time that a liver can be exposed to cold storage and still be usable with good results in a mouse transplant model. The Hopkins group has pioneered the field of VCA by establishing the largest clinical program for upper-extremity transplantation in the United States. Its research team, headed by Dr. Brandacher, has also pioneered the development and implementation of small (mouse and rats) and large (pig) animal models, thereby advancing VCA basic immunology research field to a new level. We herein propose to translate the approaches that were very successful in liver and renal injury models to a limb transplant model in mice and in pigs. We expect to detect significant improvements in the ability of VCA limb grafts to tolerate extended periods of cold storage prior to transplantation by preventing subsequent influx of damaging cells and inducing protection in VCA vessels, muscles, and skin components. If this is the case, we will have identified important new means by which to improve the function of VCAs and extend the radius of possib
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810795
Entities
People
- Gerald Brandacher
Organizations
- Johns Hopkins University
- United States Army