Grants We Funded

Abstract
Project Summary: Soft tissue injuries may result in complex wounds with exposed critical structures such as bone, tendon, blood vessels, nerve, and hardware. The gold standard in these scenarios is reconstruction with flaps, which entails moving skin/muscle/fat with an intact blood supply into the wound. These procedures result in additional scarring and functional loss. Biologic wound therapies such as acellular allograft matrices, have become an important part of wound reconstruction but can fail to reliably reconstruct these wounds due to their lack of blood supply. We propose a technology that addresses the shortcomings of biologic wound products and flaps while matching the reliability of flaps by bioengineering an off-the-shelf allograft-based composite, vasculature-engineered reconstructive dressing (COVERED) through decellularization and vasculature recellularization using induced pluripotent stem cells (iPSCs). Human iPSCs are capable of relining the vascular network of an off-the-shelf tissue engineered allograft. In contrast to the other stem cells, they have the advantages of being easier to harvest and multiply. The funding of this proposal will achieve (1) An optimized method of re-endothelialization of decellularized fasciocutaneous free flaps with hiPSCs ex vivo, using a bioreactor we developed, (2) An understanding of how the extracellular matrix in the different compartments of the allograft free flap (e.g. adipose, dermis, vasculature) induce differentiation of the iPSCs, (3) A bioengineered tissue flap comprised of recellularized, functional vascular endothelium capable of survival on host vasculature upon grafting in a rodent model. This will set the foundation for scale-up efforts toward clinically-relevant flap sizes using tissue engineering protocols defined within the scope of this funding opportunity as well as experience harvesting cadaveric tissue flaps, which we anticipate using in the to-scale version of these efforts. To date, there have been no commercialization successes of a tissue engineered graft with this level of complexity. This is due in part to a lack of similar predicate technologies that would have outlined a pathway for how an engineered tissue process should be defined and executed. The scope of our proposal seeks to provide groundwork for the inaugural technology that gains FDA approval, providing a foundation on which the field of regenerative medicine can build and refine future bioengineered technologies of this type. Impact Statement: The proposed research offers the prospect of a paradigm shift in microvascular reconstruction. Wounds with exposed critical structures such as tendon, bone, and hardware, can be a challenge to heal. Currently, the most reliable method of reconstructing these wounds is transplanting flaps of skin or muscle with its own blood supply, which causes additional pain, scarring and loss of function. By creating a tissue engineered flap with functional vasculature, achieving the goal of this research could eliminate the need for flap harvesting for many clinical scenarios. The clinical impact of our proposed therapy is a tissue engineered vascularized construct that offers what traditional biologic wound products cannot: immediate, reliable, and durable coverage of critical structures.

Biography
Dr. Mario G. Solari is an Assistant Professor in the Department of Plastic Surgery. He is board certified in Plastic Surgery and performs reconstructive surgery including head and neck, chest, abdominal wall, and extremities following trauma or cancer surgery. He specializes in microvascular reconstructive surgery of the head and neck and reconstruction after craniofacial trauma. <br /> Dr. Solari performed his undergraduate studies at The Johns Hopkins University in Baltimore and earned his medical degree from Tufts University in Boston. He completed his plastic surgery residency at the University of Pittsburgh, including a two-year extramural NIH fellowship (NRSA) studying the immunology of vascularized composite tissue allotransplantation. Following residency, he completed a reconstructive microsurgery fellowship at The University of Texas MD Anderson Cancer Center in Houston. <br /> Dr. Solari is the Director of the Vascularized Composite Allotransplantation and Microsurgery Research Laboratory and Member Faculty of the McGowan Institute for Regenerative medicine. His laboratory has won multiple awards and has been funded by major grants from the Department of Defense. He has received the Plastic Surgery Educational Foundation Basic Science Research Fellowship as well as the American Association of Plastic Surgeons/Plastic Surgery Foundation Academic Scholarship Award. His current research goals focus on engineering vascularized scaffolds for complex wound reconstruction.