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

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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.