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

基本信息

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
项目类别：
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

项目摘要

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 申请中，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），以开发用于美国 100,000 个心脏瓣膜置换术的免疫相容性异种瓣叶生物材料。尽管目前的生物假体（戊二醛固定）每年都会进行心脏瓣膜置换手术，但费用高达 7.55 亿美元。牛心包（固定血压）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，这种固定过程使材料与机械不相容。这些缺陷导致国家心脏、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，以避免出现严重排斥反应。植入未经处理的动物组织，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以通过靶向去除免疫屏障本身来引发体内免疫反应。 ViVita Process 能够生产未固定的生物材料 (ViVita BP)，避免移植的动物组织经历的快速免疫破坏 ViVita Process 消除了不协调异种移植的两个最关键的障碍。（半乳糖-α(1,3)-半乳糖 (α-gal) 和主要组织相容性复合体 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-功能关系在兔动物模型中，ViVita BP 引发了最小的移植物特异性适应性免疫反应，没有相关的钙化和先天免疫。在猪颈动脉缺损模型中，这些益处可导致血管快速再生，从而确定原生 ECM 功能特性的保留程度，从而满足 ViVita BP 心脏瓣膜的要求。或超过所有体外 ISO 5840-2:2015 阀门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，并确定弯曲和弯曲之间的相关性。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对 ViVita BP 的体内移植物特异性先天性和适应性免疫反应，从而促进再生反应（目标 2）。 ViVita BP 和固定血压的先天和再生反应将在绵羊血管内模型中进行量化，这两个目标将与我们的战略合作伙伴（一家领先的心脏瓣膜制造商）合作成功完成。该第一阶段提案将为 ViVita BP 作为下一代心脏瓣膜小叶生物材料提供关键验证。