Grants We Funded

Abstract

Impact Statement: Implant-based breast reconstruction following a mastectomy frequently utilizes sheets of acellular dermal matrix (ADM) to provide mechanical and soft tissue support for effective healing and good clinical outcomes. Clinical complications can occur when ADM do not integrate and heal effectively due to insufficient intimate contact with vascularized host tissue. Through the inclusion of an injectable ADM hydrogel with sheets, we can create a conductive environment where the host tissue maintains contact with the ADM, to enhance the natural cellular and biologic signaling, improve healing, and improve clinical outcomes.

Project Summary: In 2020, an estimated 279,100 new cases of breast cancer and 42,690 deaths will occur in the U.S. Breast cancer mortality rate has steadily declined since 1990, therefore, the clinical focus has shifted to reconstruction after mastectomy rather than mortality from disease. A substantial proportion of these patients undergo implant based-breast reconstruction after mastectomy, frequently with acellular dermal matrix (ADM) soft tissue support of the implant and overlying skin. An ADM is dermal tissue that has been treated to remove antigenic donor cellular material leaving an extracellular matrix scaffold that induces host cellular invasion, tissue regeneration and revascularization. Successful clinical outcomes rely on the effective incorporation into the patient's soft tissue through a process of vascular ingrowth resulting in increased ADM oxygen saturation after implantation. In 2019, the FDA investigated existing data on ADMs and concluded that no ADM product had been approved for soft tissue support in breast reconstruction despite fifteen years of published safety data. Therefore, demonstration of the biologic superiority of utilizing ADM in pre-clinical models, has become paramount. The complex nature of wound healing in ADM assisted breast reconstruction includes coordinated cellular and cytokine signaling phases of inflammation and tissue remodeling. Successful incorporation results in vascularized ADM that supports the reconstruction. However, incomplete integration can occur when intimate contact between the ADM and the vascularized skin envelop is compromised leading to a persistent and dysregulated early phase inflammation, resulting in clinical complications. Recently, hydrogels derived from decellularized extracellular matrix materials have shown great promise in promoting tissue remodeling and arteriogenesis in compromised tissues. We propose to promote intimate ADM/host contact through the inclusion of decellularized dermal matrix hydrogel allowing for a rapid and efficient conduction of cells and biologic signaling to the ADM for enhanced integration, using a novel murine model of ADM-assisted breast reconstruction. In addition, we will investigate the role of radiation therapy on effective hydrogel-assisted ADM integration. We hypothesize that the natural ECM components in a flowable hydrogel will provide an effective regenerative scaffold will increase neovascularization and new tissue remodeling in the ADM, leading to improved healing.

Biography
Patrick Cottler is a bioengineer with a BS from Purdue University and a MS and PhD in Biomedical Engineering from the University of Virginia. Upon completion of his dissertation, he founded Cottler Technologies, LLC to continue research and development of this technology and has successfully submitted proposals for and been a principal investigator on several Phase I and II SBIR grants. Dr. Cottler has experience in developing medical technologies and testing in laboratory and animal models, published relevant results, and managed several Phase I and II programs in biomaterials and wound repair. He also has experience in developing and utilizing animal models for biomaterial integration, wound healing, and hemorrhage control. During his time as a Senior Research Scientist in the biotechnology sector of industry, he managed a variety of innovative wound healing technologies and instrumentation development programs, with patents related to his work with novel medical devices. Dr. Cottler left industry to join the faculty of the Department of Plastic Surgery at the University of Virginia in 2014 as the Director of Resident Research. During this time, Dr. Cottler has developed several research programs, including investigating acellular dermal matrices and the wound healing response to their integration. Dr. Cottler works closely with residents on applied research projects, and will manage all scientific, technical, and contractual aspects of the program.