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 在此II阶段SBIR应用程序中，Vivita Technologies，Inc。（加利福尼亚州戴维斯）旨在验证其专利技术 （长矛平台 - 美国9,220,733）开发未结合，免疫兼容和再生 心脏瓣膜更换的异构生物材料。在美国，100,000个心脏阀更换程序 每年执行每年17亿美元的负担。虽然当前的生物植物 （戊二醛固定的牛心包或猪主动脉瓣）优于机械替代品， 固定过程仅允许由于慢性免疫排斥和结果而导致成人长寿约10年 生物材料的机械故障。此外，此固定过程使生物材料与 受体细胞再生，再生和修复。这些缺陷领导了民族心脏，肺和 血液研究所：心脏外科手术工作组建议将来支持基本生物材料研究 心脏瓣膜假体。为了避免积极拒绝未固定的动物组织，脱细胞方案聚焦 通过去除细胞成分来减少免疫燃烧；然而，细胞和 脱细胞后的非细胞免疫成分在体内免疫回报中。通过定位 长矛平台本身去除免疫障碍物本身会产生未固定的生物材料（裸露的补丁 - US 9,827,350）避免了移植动物组织经历的快速免疫抑制，而 维持本地细胞外基质（ECM）结构 - 连接关系对于植入物寿命至关重要 功能。实际上，裸露的斑块（1）引起最小的移植物特异性适应性免疫响应，从而避免 相关的计算，（2）似乎是先天免疫系统的“自我”，支持与接收者的集成 组织和（3）促进了快速的非免疫细胞再生和结果再生。该提议将 为下一代心脏瓣膜更换的裸露补丁商业化提供了几种见解。 从临床大小的裸露斑块中去除抗原的均匀性将在整个不同区域进行量化 大补丁（AIM 1）。长矛平台的灭菌能力将通过微生物挑战来量化 测试以告知对末端灭菌的需求（AIM 2）。消除残差的比率将被量化为 告知必要的制造清洗程序（AIM 3）。裸露的结构 - 功能仪式特性 补丁将在一系列存储温度和时间范围内进行量化，以告知产品保质期（AIM 4）。最后， 通过裸露斑块制造的阀导管将在关键的FDA IDE中进行评估，从而可以进行体内研究 在卵线主动脉模型中，血液动力学性能和再生能力在6个月内（AIM 5）。像我们一样 成功的第一阶段努力，所有目标都将与我们的战略合作伙伴之一合作执行 心脏阀制造商。成功完成此第二阶段工作将提供关键的制造见解 并验证裸露的斑块作为下一代心脏阀生物材料以克服有限的寿命 随后需要与当前生物植物相关的重复替换手术。