Ventral hernias are a frequent complication after abdominal surgery, occurring in nearly 33% of the over two million patients undergoing laparotomies in the United States each year. Currently, hernia repairs using synthetic meshes and biologic grafts have demonstrated only limited success with 24-43% of repairs failing to heal. Biologic grafts are recommended in complicated hernias where synthetic meshes are contraindicated. However biologic grafts often prematurely lose strength and integrity resulting in hernia recurrence. The only current strategy to increase biologic graft durability involves chemical cross-linking of collagen. However, such cross-linking reduces graft biocompatibility and frequently elicits an adverse host response. Hence, there is an unmet need for biologic grafts that are both biocompatible and mechanically durable. Our preliminary work demonstrates the feasibility of using a novel hydrogel coating to modulate cellular infiltration into a biologic graft as a potential strategy to mitigate graft resorption. A non-resorbable tyramine- substituted hyaluronan (TS-HA) coating on a biologic graft (dermis) prevented cell attachment in vitro and reduced cellular infiltration, resorption and hernia occurrence at 8 weeks in a rat hernia repair model; however, the non-resorbable TS-HA coating was associated with a moderate foreign body reaction and encapsulation. The objective of this proposal is to design and investigate resorbable TS-HA coating formulations as a biocompatible strategy for improving graft durability and hernia repair outcomes. We hypothesize that transiently inhibiting cellular infiltration from inflamed visceral/peritoneal tissues during the initial inflammatory phases of wound repair (0-4 weeks) will mitigate premature graft resorption, but subsequently allow constructive remodeling in the absence of foreign body reaction and encapsulation, leading to improved durability and ultimately repair outcomes. Our approach will be to design TS-HA coatings with varying resorption rates and apply these coatings to the visceral surface of a commonly used biologic graft for hernia repair - allograft human acellular dermis matrix (HADM) (Specific Aim 1). We will investigate graft resorption, cellular and regenerative extracellular matrix (ECM) outcomes, herniation and biomechanical properties of TS- HA coated- and uncoated-HADM grafts (current clinical standard) in the well-established rat intraperitoneal hernia repair model (Specific Aim 2). If successful, this high risk/high reward proposal will address the primary limitation of poor durability of biologic grafts without compromising their inherent ?biologic? benefits. Results from this study will support future efforts to investigate TS-HA hydrogel coatings for improving the durability of biologic grafts used in other soft tissue repair applications such as rotator cuff tendon or pelvic floor repair.
Ventral abdominal wall hernias occur in nearly one-third of the over two million patients undergoing laparotomies in the United States each year, and many of these hernias require surgical repair. An estimated 350,000 ventral hernia repair surgeries are performed annually, involving total healthcare costs of US $3.2 billion. Currently, ventral hernia repairs using synthetic meshes and biological grafts have demonstrated only limited success with 24-43% of repairs failing to heal, yet the mechanism for failure remains unknown. We propose an innovative biomaterials approach to investigate the cellular mechanisms of biologic graft failure and develop engineered biologic grafts that will provide consistently successful surgical outcomes in ventral hernia repair.
