Auxetic Ventricular Support Device for Chronic Myocardial Infarction

项目摘要 在美国，大约每40秒就有一人发生心肌梗死（MI）。虽然死亡率 由于急性心肌梗死在过去二十年中有所减少，长期后果和合并症 与慢性心肌梗死相关的风险增加。在许多情况下，MI后左心室（LV）重构表现为 LV结构和功能的进行性变化。这种重塑可以启动一个退行性循环， 梗塞区域周围改变的心肌壁力学导致心脏机械性代偿失调， 结果对梗塞区造成更大的压力。这种不利的左心室重构是大约 70%的心力衰竭（HF）病例每年导致约10万美国人死亡。当前疗法 慢性MI、HF和LV重塑的治疗包括药物治疗，如ACE抑制剂和β- 阻滞剂、冠状动脉血运重建术、贴片型心室支持装置（VSD），以及 机械泵型心室辅助装置（VAD）。然而，药物干预是权宜之计， 而VAD具有高度侵入性且昂贵，VSD对射血无贡献且可损害舒张功能， 填充。NIBIB R21探索性/发展性研究补助金提案探讨了 一种不寻常的"拉胀"材料，在拉伸时会变得更厚（而不是更薄）， 提供了一种被动地恢复心脏梗塞区域的泵送功能的新方法。通过固定 补丁样的心室支持装置（auxVSD）扩大梗死组织，我们计划利用 能量浪费在非跳动的梗死上，而不是伸展和扩张auxVSD，这反过来会 收缩时，血管收缩，血管 并允许在灌装过程中灌装。目标1将集中在设计，制造和测试潜在的拉胀 结构和材料。机械模拟将用于识别和优化拉胀结构， 由于拉胀效应而具有位移和力的有利组合。与此同时， 将制造物理模型用于体外力学测试，以告知 模拟，以及提供有关auxVSD的预期性能的初步信息， 简化的心脏组织样MRI体模的设置。在目标2中，auxVSD的有效性将在 慢性MI的临床前大型动物模型，使用位移敏感的DENSE MRI评价其体内 性能（与传统VSD相比），通过动态 调节梗塞区的心脏力学。该项目的设计既具有平移性，又具有高度交叉性- 纪律处分程序尽管这一探索性建议具有风险性，但组建的研究小组和 环境非常适合最大限度地成功实现拟议目标的机会， 将为未来的R01产生初步数据，R01可能会从这项研究中发展出来， 改变当前工程设计思维，因为它涉及慢性心肌梗死修复。

PROJECT SUMMARY Approximately every 40 seconds, someone will suffer a myocardial infarction (MI) in the US. While mortality due to acute MI has decreased over the past two decades, long-term consequences and comorbidities associated with chronic MI are increasing. In many cases, post-MI left ventricular (LV) remodeling manifests as progressive changes in LV structure and function. This remodeling can initiate a degenerative cycle in which altered myocardial wall mechanics around the infarcted region cause the heart to mechanically decompensate, resultantly placing still more strain on the infarct. Such adverse LV remodeling is the cause of approximately 70% of all heart failure (HF) cases, which kill approximately 100,000 Americans each year. Current therapies for chronic MI, HF, and LV remodeling include pharmacological treatments such as ACE-inhibitors and β- blockers, coronary revascularization procedures, patch-type ventricular support devices (VSD), and mechanical pump-type ventricular assist devices (VADs). However, drug interventions are stopgap remedies, while VADs are highly invasive and expensive, and VSDs do not contribute to ejection and can impair diastolic filling. This NIBIB R21 Exploratory/Developmental Research Grant proposal explores the potential for an unusual class of “auxetic” materials, which counterintuitively get thicker (rather than thinner) when stretched, to provide a novel means of passively restoring pumping function to the infarcted region of the heart. By fixing a patch-like auxetic ventricular support device (auxVSD) to the expanding infarcted tissue, we plan to harness the energy wasted on the non-beating infarct to instead stretch and expand an auxVSD, which would in turn stiffen and press against the infarct tissue, contributing to the ejection of blood during systole, while softening and allowing filling during diastole. Aim 1 will focus on the design, fabrication, and testing of potential auxetic structures and materials. Mechanical simulations will be used to identify and optimize auxetic structures in silico that possess a favorable combination of displacement and force due to the auxetic effect. Concurrently, physical models will be fabricated for in vitro mechanical testing to inform the real-world feasibility of the simulations, as well as provide preliminary information regarding the expected performance of an auxVSD in the setting of a simplified cardiac tissue-like MRI phantom. In Aim 2 the efficacy of an auxVSD will be tested in a preclinical large animal model of chronic MI using displacement-sensitive DENSE MRI to evaluate its in vivo performance (vs. traditional VSD) for improving regional and global cardiac function through the dynamic modulation of cardiac mechanics in the infarct zone. The project design is both translational and highly cross- disciplinary. Despite the risky nature of this exploratory proposal, the assembled research team and environment are ideally suited to maximize the chances of successfully achieving the proposed aims, which would generate preliminary data for a future R01 that could evolve from this research, with the potential to transform current engineering design thinking as it relates to chronic myocardial infarction repair.