Targeting Microperfusion to Improve Vascular Composite Quality and Allotransplantation Outcome
Abstract
Vascular composite allotransplantation or VCA is the removal of a block of tissue from one human (the donor) and its attachment to another (the recipient). The tissues block is made up of skin, muscle, and bone, hence use of the word "composite." By design, VCA is becoming an accepted correction of composite tissue loss (e.g., limb amputation) or catastrophic injury such as abdominal trauma and severe facial damage. Improving VCA outcome is of significant interest to the Department of Defense as there are an estimated 1,700 amputee Service members and 600 Warfighters with severe facial disfigurements resulting from their participation in the Afghanistan and Iraq conflicts; these numbers are expected to rise with future conflicts due to significant improvements in survival rates from injuries that were previously lethal. Certainly some injured Veterans will opt for an artificial limb (prosthesis) and/or tissue grafting of their tissue for injury treatment, but for those that desire (and qualify), the goal of the present study is to present VCA as a complete and optimized therapeutic option. VCA has a lot in common with the more standard "organ transplant," most notably that both are typically gifted/donated from deceased individuals. The brain death of the donor produces a significant stress on the other tissues and organs. While significant progress has been made in the VCA surgical techniques and anti-rejection drug regimens, less attention has been directed to care of the tissue composite donor. And yet it is the status of the donor that often drives tissue availability and short-term VCA outcome. An unexplored area on how donor status impacts the vascular composites is the effect of brain death on small molecules called SNOs or S-nitrosothiols. SNOs control many important body functions including oxygen delivery and cell activity. When we studied brain death, we found that SNO levels were disrupted and the disruptions related to markers of injury and reductions in oxygen delivery. Importantly, using a drug we designed, we found that the SNO problems could be reversed to improve oxygen delivery and reduce tissue injury. We want to now see if this treatment of the donor improves tissue function in the VCA recipient. This study will be conducted in animals to make sure the planned therapy is safe and effective. At the same time, we also want to document SNO changes in human donors; this will provide the building blocks for conducting a follow-on clinical trial of our therapy. It should not be lost that SNO therapy has the potential to also improve the number and quality of solid organs available for transplant. The advances made here with VCA should also advance donor support and transplant research in general. In this regard, it is worth noting that similar to civilians, aging Veterans suffer from chronic diseases of the lungs, heart, and vasculature -- conditions that are characterized by disruptions in SNO homeostasis and for which in the end stage, organ transplant is the best and sometimes the only effective treatment. Importantly, the incidence rates are significantly higher and the age of onset lower in former military personnel compared to the general population. This project addresses the Reconstructive Transplant Research Focus Area of Improved Access to Reconstructive Transplantation, with a specific emphasis on Component 1: Improved tissue preservation techniques or technologies to extend the radius of donor procurement. During the 2-year duration, we will test a novel method for improving the quality/viability of vascularized tissue composites for allotransplant. Completion of the planned experiments will produce exciting new insights on the key roles of SNOs in regulating donor status and form the basis for a follow-on clinical trial testing if a drug that can increase the amount of SNOs in the body can increase the number and quality of tissue composites suitable for transplant.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610520
Entities
People
- James Reynolds
Organizations
- Case Western Reserve University
- United States Army