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

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.

总结 尽管立法和联邦倡议，如儿科设备联盟赠款计划，旨在 促进儿科医疗器械开发，儿科心脏病患者的创新仍然落后 成人设备的进步，使儿童需要重建心脏手术， 人口所有可植入生物材料（戊二醛牛心包、异种移植瓣膜和导管， 冷冻保存的同种异体移植物、自体心包和胶原生物支架）以及一些人工聚合物 经受由钙化驱动的结构退化（通过被动钙沉积和 钙结合蛋白）和-如我们小组所发现的-通过糖氧化， 糖基化蛋白的掺入和交联形成，改变了 生物材料 这个重新提交的申请有两个首要目标：了解加速结构化的机制， 儿童心脏补片、带瓣管道和人工生物心脏瓣膜的退化，并测试缓解情况 通过使用幼年动物模型在体外和体内延长这些器械的使用寿命的策略。在临床上， 其目标是通过减轻 加速失效的基础机制。初步结果包括一个儿科特定的生物登记， 心脏设备，使用儿童血清开发精确的药物敏感性测定 患者和成人，吸收蛋白质的整体蛋白质组学分析，以及两只幼年动物的利用 模型（牛心包的大鼠皮下植入物和接受手术或 经导管主动脉瓣、二尖瓣或肺动脉瓣置换术）以评估增强的蛋白质吸收的作用， 和钙化。我们还开发了减轻蛋白质吸收的方法。根据这些数据将测试 假设减轻可植入生物材料的蛋白质吸收将减少钙化， 可植入生物材料的结构退化。由于我们公布的初步数据，以及 支持文献显示，糖化和钙化前体在儿童中过度表达，我们相信， 我们的缓解策略对儿科患者特别有效。总的来说，这个项目符合一个 NIH-NHLBI的核心任务是通过以下方式提高多种儿科医疗器械的耐用性： 精准医疗方法