Mechanisms of accelerated calcification and structural degeneration of implantable biomaterials in pediatric cardiac surgery

小儿心脏手术中植入生物材料加速钙化和结构退化的机制

• 批准号: 10655959
• 负责人: Giovanni Ferrari
• 金额: $ 54.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655959
• 关键词: Acceleration; Adolescent; Adult; Age; Allografting; Animal Model; Architecture; Autologous; Automobile Driving; Biochemistry; Biocompatible Materials; Biological Assay; Biomechanics; Bioprosthesis device; Blood; Calcium; Calcium-Binding Proteins; Cardiac; Cardiac Surgery procedures; Cattle; Cellular Infiltration; Chemistry; Child; Childhood; Clinical; Collagen; Crosslinker; Cryopreservation; Data; Deposition; Development; Device or Instrument Development; Devices; Disease; Disparity; Failure; Glutaral; Goals; Grant; Growth and Development function; Heart Valves; Impairment; Implant; In Vitro; Inflammatory Response; Literature; Longevity; Mechanics; Medical Device; Methodology; Mission; Mitral Valve; Modeling; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Outcome; Patients; Performance; Physiologic pulse; Polymers; Preclinical Testing; Predisposition; Proteins; Proteomics; Publishing; Rattus; Reconstructive Surgical Procedures; Repeat Surgery; Role; Series; Serum Proteins; Sheep; Sprague-Dawley Rats; Statutes and Laws; Structure; System; Testing; Thick; Translating; Underserved Population; United States National Institutes of Health; Work; Xenograft procedure; absorption; aortic valve; base; bioscaffold; calcification; calcium absorption; cardiac device; crosslink; glycation; implant material; implantable device; improved; in vivo; in vivo evaluation; innovation; juvenile animal; overexpression; oxidation; pediatric patients; pericardial sac; precision medicine; programs; protein protein interaction; pulmonary valve replacement; subcutaneous; uptake; young adult; Acceleration; Adolescent; Adult; Age; Allografting; Animal Model; Architecture; Autologous; Automobile Driving; Biochemistry; Biocompatible Materials; Biological Assay; Biomechanics; Bioprosthesis device; Blood; Calcium; Calcium-Binding Proteins; Cardiac; Cardiac Surgery procedures; Cattle; Cellular Infiltration; Chemistry; Child; Childhood; Clinical; Collagen; Crosslinker; Cryopreservation; Data; Deposition; Development; Device or Instrument Development; Devices; Disease; Disparity; Failure; Glutaral; Goals; Grant; Growth and Development function; Heart Valves; Impairment; Implant; In Vitro; Inflammatory Response; Literature; Longevity; Mechanics; Medical Device; Methodology; Mission; Mitral Valve; Modeling; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Outcome; Patients; Performance; Physiologic pulse; Polymers; Preclinical Testing; Predisposition; Proteins; Proteomics; Publishing; Rattus; Reconstructive Surgical Procedures; Repeat Surgery; Role; Series; Serum Proteins; Sheep; Sprague-Dawley Rats; Statutes and Laws; Structure; System; Testing; Thick; Translating; Underserved Population; United States National Institutes of Health; Work; Xenograft procedure; absorption; aortic valve; base; bioscaffold; calcification; calcium absorption; cardiac device; crosslink; glycation; implant material; implantable device; improved; in vivo; in vivo evaluation; innovation; juvenile animal; overexpression; oxidation; pediatric patients; pericardial sac; precision medicine; programs; protein protein interaction; pulmonary valve replacement; subcutaneous; uptake; young adult

SUMMARY Despite legislation and federal initiatives, such as the Pediatric Device Consortia Grants Program, intended to facilitate pediatric medical device development, innovation for pediatric cardiac patients continues to lag behind the advances made for adult devices, making children requiring reconstructive heart surgery an underserved population. All implantable biomaterials (glutaraldehyde bovine pericardium, xenograft valves and conduits, cryopreserved allografts, autologous pericardium, and collagen bioscaffolds) as well as some artificial polymers are subjected to structural degeneration driven by calcification (via passive calcium deposition and absorption of calcium-binding proteins) and – as discovered by our group – by glyco-oxidation, which via permanent incorporation of glycated protein and cross-links formation, alters the architecture and mechanical proprieties of biomaterials. This resubmitted application has two overarching goals: to understand the mechanisms of accelerate structural degeneration of cardiac patches, valved conduits, and bioprosthetic heart valves in children and to test mitigation strategies to extend the lifespan of these devices in vitro and in vivo by using juvenile animal models. Clinically, the goal is to reduce the need for multiple cardiac re-operations in pediatric patients by mitigating the mechanisms at the base of the accelerated failure. Preliminary results include a pediatric-specific bioregistry of explanted cardiac devices, the development of precision medicine susceptibility assays using sera from pediatric patients and adults, global proteomic analysis of absorbed proteins, and the utilization of two juvenile animal models (rat subcutaneous implants of bovine pericardium and juvenile sheep undergoing surgical or transcatheter aortic, mitral, or pulmonary valve replacement) to assess the role of enhanced protein absorption, and calcification. We also developed methodologies to mitigate protein absorption. Based on these data will test the hypothesis that mitigation of protein absorption of implantable biomaterial will reduce calcification and structural degeneration of implantable biomaterial. Since our published and preliminary data, as well as supporting literature, show that glycation and calcification precursors are overexpressed in children, we believe that our mitigation strategies will be particularly efficient in pediatric patients. Overall, this project aligns with one of the core missions of the NIH-NHLBI to improve the durability of multiple pediatric medical devices via a precision medicine approach.

概括 尽管立法和联邦倡议，例如儿科装置财团计划，旨在 促进儿科医疗装置的开发，儿科心脏病患者的创新继续落后 为成人设备取得的进步，使需要重建性心脏手术的儿童服务不足 人口。所有可植入的生物材料（戊二醛牛心包，特征阀和导管， 冷冻保存的异源，自体心包和胶原蛋白生物遵循）以及一些人造聚合物 通过计算进行结构变性驱动（通过被动钙沉积和遗憾 钙结合蛋白）和 - 正如我们组发现的 - 通过糖氧化，通过永久性 掺入糖化蛋白和交联的形成，改变了结构和机械礼节 生物材料。 该重新提交的应用程序具有两个总体目标：了解加速结构的机制 儿童心脏斑块，瓣膜导管和生物假心脏瓣膜的变性并测试缓解 通过使用青少年动物模型，可以在体外和体内延长这些设备的寿命的策略。临床上 目的是减少儿科患者多次心脏重新运动的需求 加速故障底部的机制。初步结果包括儿科特异性的生物学。 露天心脏设备，使用小儿血清的精密药物敏感性测定的开发 患者和成人，吸收蛋白的全球蛋白质组学分析以及两种少年动物的利用 模型（大鼠皮下牛心包和少年绵羊接受手术或 经导管主动脉，二尖瓣或肺动脉瓣替代）评估增强蛋白滥用蛋白的作用， 和计算。我们还开发了减轻蛋白质滥用的方法。基于这些数据将测试 减轻蛋白质吸收可植入生物材料的假设将减少钙化和 可植入生物材料的结构变性。由于我们发布和初步数据以及 支持文献，表明儿童的糖化和计算前体过表达 我们的缓解策略将在小儿患者中特别有效。总体而言，该项目与一个 NIH-NHLBI的核心任务，以提高多个小儿医疗设备的耐用性 精密医学方法。