Novel xenogeneic extracellular matrix biomaterial for cardiovascular prostheses

摘要 在第一阶段SBIR应用中，ViVita Technologies，Inc.（Davis，CA）旨在验证我们的专利技术（ViVita Process - US 9，220，733），以开发用于心脏瓣膜置换的免疫相容性异种小叶生物材料。在美国，每年进行100，000例心脏瓣膜置换手术，负担7.55亿美元。尽管目前的生物瓣膜（戊二醛固定的牛心包（固定BP）或猪主动脉瓣）上级机械替代品，但由于生物材料的慢性免疫排斥和导致的机械失效，固定过程仅允许约10年的寿命。此外，这种固定过程使材料与受体细胞再生和修复不相容。这些缺陷导致国家心脏、肺和血液研究所：心脏外科工作组建议未来支持心脏瓣膜假体的基础生物材料研究。为了避免植入的未处理的动物组织的侵袭性排斥，脱细胞方案集中于去除免疫原性细胞组分;然而，脱细胞后细胞和非细胞免疫原性组分的持续存在已被证明引发体内免疫应答。通过靶向去除免疫屏障本身，ViVita工艺能够生产未固定的生物材料（ViVita BP），避免移植动物组织经历的快速免疫破坏。ViVita工艺消除了不一致异种移植的两个最关键障碍（半乳糖-α（1，3）-半乳糖（α-gal）和主要组织相容性复合物I（MHC I）），并从ViVita BP中去除了80%的亲水性和60%的亲脂性次要组织相容性异种抗原，同时保持了天然细胞外基质（ECM）结构-功能关系。在兔模型中，ViVita BP引起最小的移植物特异性适应性免疫应答，不存在相关钙化，先天免疫识别为自身起源，促进与受体组织的整合。在猪颈动脉缺损模型中，这些益处导致快速血管再生。本提案将确定天然ECM功能特性的保留程度，使ViVita BP心脏瓣膜瓣叶满足或超过所有体外ISO 5840-2：2015瓣膜流体动力学性能评估（目标1）。具体而言，我们将比较ViVita BP与当前FDA批准的材料，并确定弯曲和血流动力学特性之间的相关性。此外，该提议将确定天然ECM保存和抗原性降低将防止破坏性受体体内移植物特异性先天性和适应性免疫应答对ViVita BP的程度，从而促进再生应答（目的2）。具体而言，将在绵羊血管内模型中定量受体对ViVita BP和固定BP的适应性、先天性和再生性反应。这两个目标都将与我们的战略合作伙伴，一家领先的心脏瓣膜制造商合作。成功完成该1期提案将为ViVita BP作为下一代心脏瓣膜瓣叶生物材料提供关键确认。

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.