Novel xenogeneic extracellular matrix biomaterial for cardiovascular prostheses

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ABSTRACT In this Phase I SBIR application, ViVita Technologies, Inc. (Davis, CA) aims to validate our patented technology (ViVita Process – US 9,220,733) toward development of an immune-compatible xenogeneic leaflet biomaterial for heart valve replacements. In the U.S., 100,000 heart valve replacement procedures are performed annually, a $755 million burden. Although current bioprostheses (glutaraldehyde-fixed bovine pericardium (Fixed BP) or porcine aortic valve) are superior to mechanical alternatives, the fixation process only permits longevity of ~10 years due to chronic immune rejection of the biomaterial and resultant mechanical failure. Further, this fixation process renders the material incompatible with recipient cellular regeneration and repair. These deficiencies have 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 implanted untreated, animal tissues, decellularization protocols focused on removal of immunogenic cellular components; however, persistence of both cellular and non-cellular immunogenic components following decellularization have been demonstrated to elicit in vivo immune responses. By targeting removal of the immunological barriers themselves, the ViVita Process is capable of producing unfixed biomaterials (ViVita BP) that avoid the rapid immune destruction experienced by transplanted animal tissues. The ViVita Process eliminates the two most critical barriers to discordant xenotransplantation (galactose-α(1,3)-galactose (α-gal) and major histocompatibility complex I (MHC I)), and removes 80% of hydrophilic and 60% of lipophilic minor histocompatibility xenoantigens from ViVita BP, while maintaining native extracellular matrix (ECM) structure-function relationships. In a leporine model, ViVita BP elicited minimal graft-specific adaptive immune response, absence of associated calcification, and innate immune recognition as self in origin, facilitating integration with recipient tissue. In a porcine carotid defect model, these benefits resulted in rapid vascular regeneration. This proposal will determine the extent to which preservation of native ECM functional properties will allow ViVita BP heart valve leaflets to meet or exceed all in vitro ISO 5840-2:2015 valve hydrodynamic performance assessments (Aim 1). Specifically, we will compare ViVita BP to current FDA-approved materials, and identify the correlation between flexural and hemodynamic properties. Further, this proposal will determine the extent to which native ECM preservation and reduced antigenicity will prevent destructive recipient in vivo graft-specific innate and adaptive immune responses to ViVita BP, thereby fostering regenerative responses (Aim 2). Specifically, recipient adaptive, innate, and regenerative responses to ViVita BP and Fixed BP will be quantified in an ovine intravascular model. Both Aims will be performed in collaboration with our strategic partner, a leading heart valve manufacturer. Successful completion of this Phase 1 proposal will provide critical validation of ViVita BP as a next generation heart valve leaflet biomaterial.