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-?(1,3)-galactose (?-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: Edwards Lifesciences. Successful completion of this Phase 1 proposal will provide critical validation of ViVita BP as a next generation heart valve leaflet biomaterial.
Public Health Relevance Statement: NARRATIVE American Heart Association estimates the U.S. prevalence of heart valve disease to be 2.5%, requiring 100,000 heart valve replacement procedures per year at a cost of $755 million (2010). Current heart valve replacement biomaterials are subject to recipient immune-mediated attack, which limits implant longevity and necessitates repeat surgeries to replace damaged valves. ViVita Technologies, Inc. has developed a novel platform methodology (ViVita Process) to remove immunological barriers from animal-derived tissues, producing an unfixed bovine pericardium (ViVita BP) biomaterial which is compatible with patients immune system, integrates with their body, and fosters regeneration over timea biomaterial which may prove to be an ideal heart valve replacement biomaterial that can also be translated to diverse cardiovascular applications.
Project Terms: adaptive immune response; American Heart Association; animal tissue; Animals; Antigens; aortic valve; Area; B-Lymphocytes; base; Biocompatible Materials; Biological; Biological Preservation; Biomaterials Research; Bioprosthesis device; Blood; Blood Vessels; Buffers; calcification; Calcified; Cardiac Surgery procedures; cardiovascular prosthesis; Cardiovascular system; Cattle; Chronic; Clinical; clinical practice; Collaborations; cost; Defect; Descending aorta; design; Detergents; Development; Excision; experience; Extracellular Matrix; Failure; Family suidae; FDA approved; Foreign Bodies; Fostering; Funding; Future; Galactose; Generations; Glutaral; Heart; Heart Valve Diseases; Heart Valve Prosthesis; heart valve replacement; Heart Valves; hemodynamics; Heterophile Antigens; Histocompatibility; hydrophilicity; Immune; Immune response; Immune system; immunogenic; Immunologics; Implant; implantation; In Vitro; in vivo; in vivo Model; Infiltration; Legal patent; Life Expectancy; lipophilicity; Longevity; Lung; Major Histocompatibility Complex; mechanical properties; Mechanics; Mediating; Methodology; Methods; Minor; Modeling; National Heart, Lung, and Blood Institute; Natural regeneration; next generation; novel; Organ; Oryctolagus cuniculus; Outcome Measure; Patients; Performance; Pericardial sac structure; Phase; Physiological; pressure; Prevalence; prevent; primary outcome; Procedures; Process; Production; Property; Prosthesis; Protein Chemistry; Protocols documentation; Publishing; regenerative; Regenerative response; Regimen; repaired; Repeat Surgery; Reporting; response; sample fixation; scaffold; Sheep; Site; Small Business Innovation Research Grant; Smooth Muscle; Sodium Dodecyl Sulfate; Stents; Structure-Activity Relationship; success; Surface; T-Lymphocyte; Technology; Testing; Time; Tissue Engineering; Tissues; Translating; Transplantation; Validation; Work; working group; Xenograft procedure
