Immune-compatible, unfixed, xenogeneic extracellular matrix for heart valve prostheses

ABSTRACT In this Phase II SBIR application, ViVita Technologies, Inc. (Davis, CA) aims to validate its patented technology (SPEAR Platform – US 9,220,733) towards development of unfixed, immune-compatible, and regenerative xenogeneic biomaterials for heart valve replacements. In the U.S., 100,000 heart valve replacement procedures are performed annually, representing a $1.7 billion annual burden. Although current bioprostheses (glutaraldehyde-fixed bovine pericardium or porcine aortic valves) are superior to mechanical alternatives, the fixation process only permits longevity of ~10 years in adults due to chronic immune rejection and resultant mechanical failure of the biomaterial. Further, this fixation process renders the biomaterial incompatible with recipient cellular repopulation, regeneration, and repair. These deficiencies led the National Heart, Lung, and Blood Institute: Cardiac Surgery Working Group to recommend future support of basic biomaterial research for heart valve prostheses. To avoid aggressive rejection of unfixed animal tissues, decellularization protocols focus on reducing immunologic burden via removal of cellular components; however, persistence of both cellular and non-cellular immunogenic components following decellularization elicits in vivo immune responses. By targeting removal of immunological barriers themselves, the SPEAR Platform produces unfixed biomaterials (BARE patch – US 9,827,350) that avoid the rapid immune destruction experienced by transplanted animal tissues, while maintaining the native extracellular matrix (ECM) structure-function relationships critical for implant longevity and function. Indeed, BARE patch (1) elicits minimal graft-specific adaptive immune response, thereby avoiding associated calcification, (2) appears as “self” to the innate immune system, facilitating integration with recipient tissue, and (3) promotes rapid non-immune cellular repopulation and resultant regeneration. This proposal will provide several insights into commercialization of BARE patches for next-generation heart valve replacements. Uniformity of antigen removal from clinical-sized BARE patches will be quantified throughout different regions of large patches (Aim 1). Sterilization capacity of SPEAR Platform will be quantified by microorganism challenge testing to inform the need for terminal sterilization (Aim 2). Rate of residuals elimination will be quantified to inform the necessary manufacturing wash procedures (Aim 3). Structure-function-durability properties of BARE patch will be quantified at a range of storage temperatures and times to inform product shelf life (Aim 4). Finally, a valved conduit fabricated from BARE patch will be assessed in pivotal FDA IDE enabling studies for in vivo hemodynamic performance and regenerative capacity over 6 months in an ovine aortic model (Aim 5). Like our successful Phase I effort, all Aims will be performed in collaboration with one of our strategic partners, a leading heart valve manufacturer. Successful completion of this Phase II work will provide critical manufacturing insights and validation of BARE patches as next generation heart valve biomaterials to overcome the limited longevity and subsequent need for repeat replacement surgeries associated with current bioprostheses.