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

摘要 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，儿科心脏病患者创新继续落后 成人设备的进步使需要重建心脏手术的儿童得不到充分的服务 人口。所有可植入生物材料(戊二醛牛心包、异种移植瓣膜和管道、 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 受钙化驱动的结构退化(通过被动的钙沉积和吸收 钙结合蛋白)和--正如我们小组发现的--通过糖氧化作用，这种作用通过永久性的 糖化蛋白质和交联键的形成改变了结构和机械特性 生物材料。 这份重新提交的申请有两个首要目标：了解加速结构的机制 儿童心脏补片、带瓣管道和生物瓣膜的退化及其缓解试验 通过使用幼年动物模型，在体外和体内延长这些设备的寿命的策略。在临床上， 其目标是通过减少儿科患者的心脏再手术次数 加速破坏的基础机理。初步结果包括儿科专用生物登记 移植心脏装置，利用儿科血清进行精密药物敏感性分析的进展 患者和成人，吸收蛋白的全球蛋白质组学分析，以及两种幼年动物的利用 模型(大鼠牛心包皮下移植和幼年绵羊手术或 经导管主动脉瓣、二尖瓣或肺动脉瓣置换术)以评估增强蛋白质吸收的作用， 和钙化。我们还开发了减少蛋白质吸收的方法。基于这些数据将测试 认为减少可植入生物材料的蛋白质吸收将减少钙化和 植入性生物材料的结构退化。由于我们公布的和初步的数据以及 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 我们的缓解策略将对儿科患者特别有效。总体而言，这个项目与一个 NIH-NHLBI的核心任务之一是通过 精准医学方法。

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.