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: 10626122
• 负责人: Maelene L Wong
• 金额: $ 74.42万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626122
• 关键词: Adult; American Heart Association; Animals; Anisotropy; Antibiotics; Antifungal Agents; Antigens; Aorta; Basement membrane; Biocompatible Materials; Biomaterials Research; Bioprosthesis device; Blood Vessels; Blood flow; Cardiac Surgery procedures; Cardiovascular system; Cattle; Chemicals; Chronic; Clinical; Collaborations; Detergents; Development; Diagnosis; 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; Macrophage; Manufacturer; Marketing; Mechanics; Mediating; Membrane; 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; Recommendation; 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; biomaterial compatibility; biomaterial incompatibility; calcification; clinical practice; commercialization; cost; cytotoxicity; design; experience; experimental study; heart valve replacement; hemodynamics; immunogenic; in vivo; insight; manufacture; 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.

摘要 在此阶段II SBIR应用中，ViVita Technologies，Inc.（戴维斯，加利福尼亚州）旨在验证其专利技术 （SPECIAL平台- US 9，220，733），以开发不固定的、免疫相容的和再生的免疫球蛋白。 异种生物材料用于心脏瓣膜置换。在美国，100，000例心脏瓣膜置换手术 每年进行，每年的负担为17亿美元。虽然目前的生物假体 （戊二醛固定的牛心包或猪主动脉瓣）上级机械替代品， 由于慢性免疫排斥和由此产生的免疫排斥，固定过程仅允许成人寿命约10年。 生物材料的机械失效。此外，该固定过程使得生物材料与生物相容性不相容。 受体细胞再增殖、再生和修复。这些缺陷导致国家心脏，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， 人工心脏瓣膜为了避免未固定的动物组织的侵袭性排斥反应，脱细胞方案关注 通过去除细胞成分减少免疫负担;然而，细胞和 去细胞化后的非细胞免疫原性组分增强体内免疫应答。通过靶向 去除自身的免疫屏障，SPRESSTM平台产生未固定的生物材料（BARE补片 - US 9，827，350），其避免了移植动物组织所经历的快速免疫破坏，而 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补丁（1）激发了最小的移植物特异性适应性免疫应答，从而避免了免疫缺陷。 相关钙化，（2）对先天免疫系统表现为“自我”，促进与受体的整合 组织，和（3）促进快速的非免疫细胞再增殖和由此产生的再生。这项建议会 为下一代心脏瓣膜置换术的BARE补片商业化提供了一些见解。 将在不同区域内定量从临床尺寸BARE贴片去除抗原的均匀性。 大斑块（目标1）。将通过微生物挑战对SPECTRA平台的灭菌能力进行量化 测试以告知是否需要进行最终灭菌（目标2）。残留物消除率将被量化， 告知必要的生产清洗程序（目标3）。BARE的结构-功能-耐久性 将在一系列储存温度和时间下定量贴剂，以告知产品有效期（目标4）。最后， 由BARE补片制成的带瓣管道将在关键的FDA IDE中进行评估， 在绵羊主动脉模型中6个月的血流动力学性能和再生能力（目标5）。像我们 成功的第一阶段的努力，所有的目标将与我们的战略合作伙伴之一，一个领先的 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 并确认BARE补片作为下一代心脏瓣膜生物材料，以克服寿命有限的问题 以及随后需要与当前生物假体相关的重复置换手术。