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

摘要 在此第二阶段SBIR应用中，ViVita Technologies，Inc.(加利福尼亚州戴维斯)旨在验证其专利技术 (Spear Platform-US 9,220,733)朝着非固定、免疫兼容和可再生的方向发展 心脏瓣膜置换用异种生物材料。在美国，10万例心脏瓣膜置换手术 每年执行，相当于每年17亿美元的负担。尽管目前的生物假体 (戊二醛固定的牛心包或猪主动脉瓣)优于机械替代品， 由于慢性免疫排斥和由此产生的免疫排斥反应，固定过程只允许成年人寿命约10年 生物材料的机械故障。此外，该固定过程使得生物材料与 受体细胞的再繁殖、再生和修复。这些缺陷导致国家心肺和 血液研究所：心脏外科工作组建议未来支持基础生物材料研究 心脏瓣膜假体。为了避免对未固定的动物组织的侵略性排斥，脱细胞协议的重点是 关于通过去除细胞成分来减少免疫负担；然而，细胞和 脱细胞后的非细胞免疫原性成分可在体内引起免疫反应。通过锁定目标 清除免疫屏障本身，鱼叉平台产生非固定的生物材料(裸露的贴片 -9,827,350美元)，避免了移植的动物组织经历的快速免疫破坏，而 维持天然细胞外基质(ECM)结构-功能关系对种植体寿命和 功能。事实上，裸露的贴片(1)引起的移植物特异性适应性免疫反应最小，从而避免了 相关的钙化，(2)对先天免疫系统而言，表现为“自我”，便于与受体整合。 组织，以及(3)促进快速的非免疫细胞再繁殖和由此产生的再生。这项提议将 为下一代心脏瓣膜置换裸露补片的商业化提供几点见解。 从临床大小的裸露斑块中去除抗原的一致性将在不同的区域进行量化 大补丁(目标1)。鱼叉平台的杀菌能力将通过微生物挑战来量化 检测以告知终端灭菌的必要性(目标2)。残差消除率将被量化为 告知必要的制造清洗程序(目标3)。裸混凝土的结构-功能-耐久性能 补丁将在一定的储存温度和时间范围内进行量化，以告知产品的保质期(目标4)。最后， 由裸露贴片制成的带瓣管道将在Pivotal FDA IDE体内启用研究中进行评估 在绵羊主动脉模型中6个月的血流动力学表现和再生能力(目标5)。就像我们 成功的第一阶段工作，所有目标将与我们的一个战略合作伙伴合作实现，该战略合作伙伴是一家领先的 心脏瓣膜制造商。成功完成此第二阶段工作将提供关键的制造洞察力 并验证裸露的补片是下一代心脏瓣膜生物材料，以克服有限的寿命 以及随后需要与当前生物假体相关的重复替换手术。

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.