Novel xenogeneic extracellular matrix biomaterial for cardiovascular prostheses

摘要 在此第一阶段SBIR应用中，ViVita Technologies，Inc.(加利福尼亚州戴维斯)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兼容异种小叶生物材料。在美国，每年进行10万例心脏瓣膜置换手术，这是7.55亿美元的负担。虽然目前的生物假体(戊二醛固定的牛心包(固定BP)或猪主动脉瓣)优于机械替代材料，但由于生物材料的慢性免疫排斥和由此导致的机械故障，固定过程仅允许使用约10年。此外，这种固定过程使材料与受体细胞的再生和修复不相容。这些不足导致国家心肺和血液研究所：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。为了避免移植的未经处理的动物组织发生侵袭性排斥反应，脱细胞方案的重点是去除免疫原性细胞成分；然而，脱细胞后细胞和非细胞免疫原性成分的持久性已被证明能在体内引发免疫反应。通过针对免疫屏障本身的清除，ViVita工艺能够生产非固定生物材料(ViVita BP)，避免移植动物组织所经历的快速免疫破坏。ViVita过程消除了异种移植的两个最关键的障碍(半乳糖-α(1，3)-半乳糖(α-GAL)和主要组织相容性复合体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，同时保持了天然的细胞外基质结构-功能关系。在Leporine模型中，ViVita BP诱导了最低限度的移植物特异性适应性免疫反应，没有相关的钙化，以及天然免疫识别为自身起源，促进了与受体组织的整合。在猪颈动脉缺陷模型中，这些好处导致了血管的快速再生。该提案将确定在多大程度上保留本地ECM功能特性，使ViVita BP心脏瓣膜叶达到或超过所有体外ISO 5840-2：2015瓣膜流体动力性能评估(目标1)。具体地说，我们将比较ViVita BP和目前FDA批准的材料，并确定弯曲性能和血流动力学特性之间的相关性。此外，这项提案将确定在多大程度上保留本地ECM和降低抗原性，将在多大程度上防止体内移植物特异性先天免疫反应和对ViVita BP的适应性免疫反应，从而促进再生反应(目标2)。具体来说，受体对ViVita BP和固定BP的适应性、先天和再生反应将在绵羊血管内模型中进行量化。这两个目标都将与我们的战略合作伙伴、领先的心脏瓣膜制造商合作实现。这一第一阶段提案的成功完成将为ViVita BP作为下一代心脏瓣膜生物材料提供关键的验证。

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.