Auxetic Ventricular Support Device for Chronic Myocardial Infarction

项目总结 在美国，大约每40秒就会有人患上心肌梗塞(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，长期后果和共病 与慢性心肌梗死相关的疾病正在增加。在许多情况下，心肌梗死后左室(LV)重构表现为 左心室结构和功能的渐进性变化。这种重塑会引发一种退化循环，在这种循环中 梗死区周围心肌壁机械结构的改变会导致心脏机械失代偿， 结果是给梗塞带来了更多的压力。这种不良的左心室重构是导致大约 70%的心力衰竭(HF)病例，每年导致大约10万美国人死亡。当前的治疗方法 对于慢性心肌梗死、心力衰竭和左心室重构，包括药物治疗，如血管紧张素转换酶抑制剂和β- 阻滞剂、冠状动脉血运重建程序、贴片式心室支持装置(VSD)和 机械泵式心脏辅助装置(VAD)。然而，药物干预是权宜之计， 虽然VAD具有高度侵入性且价格昂贵，但VSD不会促进射血并可能损害舒张期 填饱肚子。这份NIBIB R21探索性/开发性研究助学金计划探讨了 一种不同寻常的“伸展”材料，拉伸时会变厚(而不是变薄)，这与直觉相反 提供了一种被动恢复心脏梗死区泵血功能的新方法。通过修复一个 对于不断扩大的脑梗塞组织，我们计划利用补片状扩张的脑室支持装置 浪费在非搏动心肌梗死上的能量反而延长和扩大了AuxVSD，这反过来又会 硬化并压迫梗塞组织，有助于收缩时的血液排出，同时软化。 并允许在舒张期充盈。目标1将专注于潜在延伸剂的设计、制造和测试 结构和材料。将使用力学模拟来识别和优化伸展结构 由于伸展作用，具有良好的位移和力组合的硅质岩。同时， 将制造用于体外机械测试的物理模型，以告知现实世界中 模拟，并提供有关在 简化的心脏组织样核磁共振体模的设置。在目标2中，将在 用位移敏感的高密度磁共振成像评价慢性心肌梗塞的临床前大动物模型 通过动态改善局部和全球心功能的绩效(与传统VSD相比) 心肌梗死区心脏力学的调节。项目设计既是平移的，又是高度交叉的- 纪律处分。尽管这一探索性建议具有风险，但召集起来的研究团队和 环境非常适合最大限度地成功实现拟议目标的机会，这 将为未来的R01生成初步数据，这些数据可能会从这项研究演变而来，有可能 改变当前与慢性心肌梗死修复相关的工程设计思维。

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.