Novel xenogeneic extracellular matrix biomaterial for cardiovascular prostheses

用于心血管假体的新型异种细胞外基质生物材料

• 批准号: 9254357
• 负责人: Maelene L Wong
• 金额: $ 22.5万
• 依托单位: VIVITA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2018-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254357
• 关键词: American Heart Association; Animals; Antigens; Area; B-Lymphocytes; Biocompatible Materials; Biological; Biological Preservation; Biomaterials Research; Bioprosthesis device; Blood; Blood Vessels; Buffers; Calcified; Cardiac Surgery procedures; Cardiovascular system; Cattle; Chronic; Clinical; Collaborations; Defect; Descending aorta; Detergents; Development; Excision; Extracellular Matrix; FDA approved; Failure; Family suidae; Foreign Bodies; Fostering; Funding; Future; Galactose; Generations; Glutaral; Heart; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valves; Heterophile Antigens; Histocompatibility; Immune; Immune response; Immune system; Immunologics; Implant; In Vitro; Infiltration; Legal patent; Life Expectancy; Longevity; Lung; Major Histocompatibility Complex; Manufacturer Name; Mechanics; Mediating; Methodology; Methods; Minor; Modeling; National Heart, Lung, and Blood Institute; Natural regeneration; Organ; Oryctolagus cuniculus; Outcome Measure; Patients; Performance; Phase; Physiological; Prevalence; Procedures; Process; Production; Property; Prosthesis; Protein Chemistry; Protocols documentation; Publishing; Regenerative response; Regimen; Repeat Surgery; Reporting; Sheep; Site; Small Business Innovation Research Grant; Smooth Muscle; Sodium Dodecyl Sulfate; Stents; Structure-Activity Relationship; Surface; T-Lymphocyte; Technology; Testing; Time; Tissue Engineering; Tissues; Translating; Transplantation; Validation; Work; Xenograft procedure; adaptive immune response; animal tissue; aortic valve; base; calcification; cardiovascular prosthesis; clinical practice; cost; design; experience; heart valve replacement; hemodynamics; hydrophilicity; immunogenic; implantation; in vivo; in vivo Model; lipophilicity; mechanical properties; next generation; novel; pericardial sac; pressure; prevent; primary outcome; regenerative; repaired; response; sample fixation; scaffold; success; working group

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.

抽象的 在这一 I 期 SBIR 应用中，ViVita Technologies, Inc.（戴维斯，加利福尼亚州）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相容性异种瓣叶生物材料。在美国，每年进行 10 万例心脏瓣膜置换手术，造成 7.55 亿美元的负担。尽管目前的生物假体（戊二醛固定牛心包（固定 BP）或猪主动脉瓣）优于机械替代品，但由于生物材料的慢性免疫排斥和由此产生的机械故障，固定过程仅允许约 10 年的寿命。此外，这种固定过程使得材料与受体细胞的再生和修复不相容。这些缺陷促使国家心、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。为了避免对植入的未经处理的动物组织产生强烈排斥，去细胞化方案的重点是去除免疫原性细胞成分；然而，去细胞化后细胞和非细胞免疫原性成分的持续存在已被证明可引发体内免疫反应。通过以消除免疫屏障本身为目标，ViVita Process 能够生产未固定的生物材料 (ViVita BP)，从而避免移植动物组织经历的快速免疫破坏。 ViVita Process 消除了不一致异种移植的两个最关键障碍（半乳糖-α(1,3)-半乳糖 (α-gal) 和主要组织相容性复合物 I (MHC I)），并从 ViVita BP 中去除 80% 的亲水性和 60% 的亲脂性次要组织相容性异种抗原，同时保留天然细胞外基质 （ECM）结构-功能关系。在兔模型中，ViVita BP 引发了最小的移植物特异性适应性免疫反应，没有相关的钙化，并且先天免疫识别为自身，促进与受体组织的整合。在猪颈动脉缺损模型中，这些益处导致血管快速再生。该提案将确定原生 ECM 功能特性的保留程度，使 ViVita BP 心脏瓣膜满足或超过所有体外 ISO 5840-2:2015 瓣膜流体动力学性能评估（目标 1）。具体来说，我们将 ViVita BP 与当前 FDA 批准的材料进行比较，并确定弯曲和血液动力学特性之间的相关性。此外，该提案将确定天然 ECM 保留和降低的抗原性将在多大程度上防止受者体内移植物特异性对 ViVita BP 的先天和适应性免疫反应的破坏性，从而促进再生反应（目标 2）。具体而言，将在绵羊血管内模型中量化接受者对 ViVita BP 和固定血压的适应性、先天性和再生反应。这两个目标都将与我们的战略合作伙伴（一家领先的心脏瓣膜制造商）合作实现。第一阶段提案的成功完成将为 ViVita BP 作为下一代心脏瓣膜小叶生物材料提供关键验证。