Immunology of xenogeneic extracellular matrix scaffolds for heart valve tissue engineering

心脏瓣膜组织工程异种细胞外基质支架的免疫学

• 批准号: 10608128
• 负责人: Leigh Gareth Griffiths
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608128
• 关键词: Address; Age; American Heart Association; Animal Model; Antigen Targeting; Antigens; Biocompatible Materials; Biological; Biomaterials Research; Bioprosthesis device; Cardiac Surgery procedures; Cattle; Child; Chronic; Clinical; Development; Disease; Ensure; Excision; Experimental Designs; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Fibrosis; Generations; Glutaral; Goals; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valves; Heterophile Antigens; Human; Immune; Immune Tolerance; Immune mediated destruction; Immune response; Immunologics; Immunology; In Vitro; Individual; Inflammatory; Innate Immune Response; Knowledge; Life; Macrophage; Mediating; Modeling; Molecular Structure; National Heart, Lung, and Blood Institute; Outcome; Patients; Phase; Play; Population; Prevalence; Procedures; Production; Property; Protein Chemistry; Proteomics; Protocols documentation; Recommendation; Regenerative response; Reporting; Residual state; Role; Safety; Sheep; Signal Transduction; Site; Source; Tissue Engineering; Tissues; Translations; United States; Xenograft procedure; adaptive immune response; calcification; cardiac tissue engineering; clinical practice; clinical translation; design; experimental study; heart valve replacement; immunogenic; immunogenicity; implantation; improved; in vivo; innovation; insight; longitudinal design; next generation; oxidation; pericardial sac; prevent; rational design; receptor; regenerative; response; scaffold; sheep model; success; translation to humans; translational barrier; valve replacement; working group

ABSTRACT: American Heart Association estimates a 2.5% prevalence of valvular heart disease in the US, requiring over 100,000 valve replacements annually. Current replacement heart valves are far from ideal, leading the NHLBI cardiac surgery working group to recommend increased support for heart valve biomaterial research. Although glutaraldehyde fixed xenogeneic tissue valves (e.g., bovine pericardium (BP)) improve short-term survival, chronic graft-specific immune responses persist, resulting in long-term biomaterial damage, calcification and ultimately failure (~2-10 yr depending on age at implantation). Indeed, NHLBI xenotransplantation working group noted that biomaterial antigenicity represents the primary translational barrier to expanding the use of xenogeneic tissues in clinical practice. Unfixed BP in which human-relevant antigens are eliminated has potential to serve as an immunologically-acceptable extracellular matrix (ECM) scaffold for heart valve bioprostheses. However, identifying human-relevant BP antigens and facilitating their removal from candidate ECM scaffolds represent critical translational barriers for development of such biomaterials. We hypothesize that elimination of human- relevant antigens can be achieved by employing targeted antigen solubilization steps during BP ECM scaffold production. This proposal seeks to define primary BP antigens responsible for initiating graft-specific immune responses in human patients (Aim 1, Phase 1), quantify removal (Aim 1, Phase 2) and target elimination of such human-relevant antigens from BP ECM scaffolds (Aim 1, Phase 3). Unfixed ECM scaffolds that avoid destructive graft-specific adaptive immune responses have potential to modulate constructive pro-regenerative recipient innate immune responses. Our group has previously demonstrated that retention of native tissue ECM niche in BP scaffolds is critical to promoting pro-regenerative in vivo recipient responses. However, extent to which exposure of natural matricryptic sites can further enhance pro-regenerative innate immune polarization towards intact BP ECM scaffolds remains unknown. We hypothesize that ECM niche and matricryptic signal exposure are critical factors in modulating human macrophage polarization and ultimate in vivo scaffold fate. This proposal aims to determine mechanisms (i.e., ECM niche component and macrophage receptor) by which differing sources of matricryptic signal exposure modulate human macrophage polarization (Aim 2, Phase 1) and combine optimal levels of each matricryptic exposure source toward maximizing pro-regenerative polarization (Aim 2, Phase 2). Aim 1 and 2 factors identified as having potential to positively modulate in vivo scaffold fate in humans will be validated using an in vivo ovine heart valve replacement model (Aim 3). Completion of this proposal will provide mechanistic insights into human-relevant antigens responsible for initiating graft-specific immune response towards current clinically-utilized xenogeneic biomaterials, define mechanisms by which matricryptic signaling modulates human macrophage polarization and leverage these findings towards development of next generation immunologically-acceptable pro-regenerative unfixed BP ECM scaffolds for heart valve replacements.

摘要： 美国心脏协会估计，在美国，瓣膜性心脏病的患病率为2.5%， 每年更换10万个瓣膜。目前的置换心脏瓣膜远非理想，导致NHLBI 心脏外科工作组建议增加对心脏瓣膜生物材料研究的支持。虽然 戊二醛固定的异种组织瓣膜（例如，牛心包（BP））改善短期存活， 慢性移植物特异性免疫反应持续存在，导致长期的生物材料损伤、钙化和 最终失败（约2-10岁，取决于植入时的年龄）。事实上，NHLBI异种移植工作组 注意到生物材料抗原性代表了扩大异种免疫应用的主要翻译障碍， 组织在临床实践中。其中人类相关抗原被消除的未固定BP具有用作 用于心脏瓣膜生物假体的免疫学上可接受的细胞外基质（ECM）支架。然而，在这方面， 鉴定人类相关BP抗原并促进其从候选ECM支架中去除代表了 这是开发此类生物材料的关键转化障碍。我们假设消灭人类- 相关抗原可以通过在BP ECM支架构建过程中采用靶向抗原溶解步骤来获得 生产该建议旨在确定负责启动移植物特异性免疫的主要BP抗原， 在人类患者中的反应（目标1，阶段1），定量去除（目标1，阶段2）和靶向消除这种 来自BP ECM支架的人相关抗原（目标1，阶段3）。不固定ECM支架，避免破坏性 移植物特异性适应性免疫应答具有调节建设性促再生受体潜力 先天免疫反应我们的小组先前已经证明，保留天然组织ECM龛， BP支架对于促进促再生的体内受体反应至关重要。然而，在多大程度上， 暴露天然基质密码位点可以进一步增强促再生先天免疫极化， 完整的BP ECM支架仍然未知。我们假设ECM小生境和基质信号暴露是 调节人巨噬细胞极化和最终体内支架命运的关键因子。这项建议 旨在确定机制（即，ECM小生境成分和巨噬细胞受体）， 基质密码信号暴露源调节人巨噬细胞极化（Aim 2，阶段1）并与联合收割机 每种基质分解曝光源朝向最大化前再生极化的最佳水平（目标2， 阶段2）。目的1和2因子被鉴定为具有正向调节人体内支架命运的潜力 将使用体内绵羊心脏瓣膜置换模型（Aim 3）进行确认。完成本提案将 提供了对负责启动移植物特异性免疫的人类相关抗原的机制见解， 对目前临床使用的异种生物材料的反应，定义了基质植入的机制。 信号调节人类巨噬细胞极化，并利用这些发现发展下一个 产生免疫学上可接受的用于心脏瓣膜置换的促再生未固定BP ECM支架。