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

用于心脏瓣膜假体的免疫相容性、未固定、异种细胞外基质

• 批准号: 10478303
• 负责人: Maelene L Wong
• 金额: $ 75.13万
• 依托单位: VIVITA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-23 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478303
• 关键词: Adult; American Heart Association; Animals; Anisotropy; Antibiotics; Antifungal Agents; Antigens; Basement membrane; Biocompatible Materials; Biomaterials Research; Bioprosthesis device; Blood Vessels; Blood flow; Cardiac Surgery procedures; Cardiovascular system; Cattle; Chemicals; Chronic; Clinical; Collaborations; Detergents; Development; Dose; Endothelium; Excision; Extracellular Matrix; Failure; Family suidae; Fostering; Funding; Future; Generations; Glutaral; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valves; Immune; Immune mediated destruction; Immune response; Immune system; Immunologics; Implant; Innate Immune System; Legal patent; Life; Longevity; Manufacturer Name; Mechanics; Mediating; Methodology; Methods; Modeling; National Heart, Lung, and Blood Institute; Natural regeneration; Operative Surgical Procedures; Organ; Outcome; Patients; Performance; Phase; Physiological; Population; Prevalence; Procedures; Process; Production; Property; Protocols documentation; Regenerative Medicine; Regenerative capacity; Regenerative response; Repeat Surgery; Reporting; Research; Residual state; Safety; Saline; Sheep; Small Business Innovation Research Grant; Sterility; Sterilization; Structure; Structure-Activity Relationship; Surface; Technology; Temperature; Testing; Time; Tissue Engineering; Tissues; Translating; Transplantation; Validation; Work; Xenograft procedure; adaptive immune response; aging population; animal tissue; aortic valve; base; biomaterial compatibility; biomaterial incompatibility; calcification; clinical practice; commercialization; cost; cytotoxicity; design; experience; experimental study; heart valve replacement; hemodynamics; immunogenic; in vivo; insight; macrophage; manufacturing process; mechanical properties; microorganism; next generation; novel; pericardial sac; regeneration function; regenerative; repaired; sample fixation; scale up; sheep model; success; working group

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.

抽象的 在第二阶段 SBIR 申请中，ViVita Technologies, Inc.（加利福尼亚州戴维斯）旨在验证其专利技术 （SPEAR 平台 - US 9,220,733）致力于开发非固定、免疫相容和再生的 用于心脏瓣膜置换的异种生物材料。在美国，进行了 100,000 例心脏瓣膜置换手术 每年执行一次，相当于每年 17 亿美元的负担。尽管目前的生物假体 （戊二醛固定牛心包或猪主动脉瓣）优于机械替代方案， 由于慢性免疫排斥和由此产生的结果，固定过程仅允许成人约 10 年的寿命 生物材料的机械失效。此外，这种固定过程使得生物材料与 受体细胞的再增殖、再生和修复。这些缺陷导致国民心、肺、 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。为了避免未固定的动物组织的强烈排斥，去细胞化方案的重点是 通过去除细胞成分来减轻免疫负担；然而，细胞和 去细胞化后的非细胞免疫原性成分引发体内免疫反应。通过定位 消除免疫屏障本身，SPEAR 平台生产未固定的生物材料（BARE 贴片） – US 9,827,350）避免了移植动物组织经历的快速免疫破坏，同时 维持对植入物寿命至关重要的天然细胞外基质 (ECM) 结构-功能关系 功能。事实上，BARE 贴片 (1) 引起最小的移植物特异性适应性免疫反应，从而避免 相关的钙化，(2) 对先天免疫系统来说表现为“自身”，促进与受体的整合 组织，(3) 促进快速的非免疫细胞再增殖和由此产生的再生。该提案将 提供了有关用于下一代心脏瓣膜置换术的 BARE 贴片商业化的一些见解。 临床大小的 BARE 贴片中抗原去除的均匀性将在不同区域进行量化 大斑块（目标 1）。 SPEAR平台的灭菌能力将通过微生物挑战来量化 进行测试以告知是否需要进行最终灭菌（目标 2）。残留消除率将量化为 告知必要的生产清洗程序（目标 3）。 BARE 的结构-功能-耐久性特性 将在一系列储存温度和时间下对补丁进行量化，以告知产品保质期（目标 4）。最后， 由 BARE 贴片制成的带阀导管将在关键的 FDA IDE 中进行评估，以便进行体内研究 绵羊主动脉模型 6 个月内的血流动力学性能和再生能力（目标 5）。就像我们的 第一阶段工作取得成功后，所有目标都将与我们的战略合作伙伴之一（领先的 心脏瓣膜制造商。第二阶段工作的成功完成将提供关键的制造见解 并验证 BARE 贴片作为下一代心脏瓣膜生物材料以克服有限的寿命 以及随后需要重复与当前生物假体相关的替换手术。