Autonomously Assembling Nanomaterial Scaffolds for Treating Myocardial Infarction

描述(由申请人提供)：每年大约有75万美国人会有新的心肌梗死(MI)，大约50万人会有复发性心肌梗死。这些患者中约有37%将在一年内死于心肌梗死，而在那些存活的患者中，三分之二没有完全恢复，导致极大的患者群体进展为心力衰竭。目前还没有直接存在的治疗方法 解决心肌梗死后发生并导致心力衰竭的负性左心室(LV)重塑过程。这些令人震惊的统计数据要求开发新的创新疗法来治疗心肌梗塞。这项研究计划将在心肌梗塞后修复心脏组织的治疗设计中建立一个新的范例。具体地说，我们的计划是开发自组装材料，编程为在心肌梗死后立即在受损的心脏组织中形成修复支架。目前，这种早期治疗是不可能的，因为它需要直接将材料注射到炎症组织中，构成不可接受的风险。在提出的前所未有的方法中，材料被设计为静脉注射，而不是直接注入心脏组织。它们将循环并组装成修复支架，以响应受损心脏组织中存在的炎性酶(基质金属蛋白酶，MMPs)。我们假设，如果这样的物质能在心肌梗死后的第一天内送到患者的心脏，这 可以通过立即稳定细胞外基质框架，然后促进细胞渗透来改变典型的梗塞过程，从而防止重大损害。拟议的研究计划将开发能够形成支架材料结构的新型纳米颗粒，以响应受损心脏组织中的MMPs。这种酶引导的组装过程已经在体外初步研究中得到了证实。我们的目标是在已建立的活体动物模型中优化和测试这些纳米颗粒。因此，我们的首要目标是开发自主组装的纳米材料支架，这种支架可以通过静脉注射输送，靶向急性心肌梗死的区域，防止和/或减缓心肌梗死后的负性左心室重构，并改善心肌梗死后的心功能。

DESCRIPTION (provided by applicant): Each year approximately three quarters of a million Americans will have a new myocardial infarction (MI), and approximately half a million will have a recurrent MI. Approximately 37% of these patients will die from the MI within one year, and of those who do survive, two-thirds do not make a complete recovery, leading to an extremely large patient population that progresses to heart failure. No current therapies exist that directly address the negative left ventricular (LV) remodeling process that occurs post-MI and results in heart failure. These staggering statistics necessitate the development of new innovative therapies for MI. This research program will establish a new paradigm in the design of treatments for healing heart tissue post-MI. Specifically our plan is to develop self-assembling materials programmed to form a healing scaffold in damaged heart tissue immediately following MI. Currently, such early treatment is not possible because it would require direct injection of materials into inflamed tissue constituting an unacceptable risk. In the proposed, unprecedented approach, the materials are designed to be injected intravenously rather than directly into heart tissue. They will circulate, and assemble into the healing scaffold in response to inflammatory enzymes present in damaged heart tissue (matrix metalloproteinases, MMPs). We hypothesize that, if such a material could be delivered to a patient's heart within the first day post-MI, this could prevent significant damage by immediately stabilizing the extracellular matrix framework, and then promoting cell infiltration to alter the typical infarct process. The proposed research program will develop novel nanoparticles capable of forming a scaffold material architecture in response to MMPs in damaged heart tissue. This process of enzyme-directed assembly has been proven in vitro in preliminary studies. We aim to optimize and test these nanoparticles in established in vivo animal models. Our overarching aim is therefore to develop autonomously assembling nanomaterial scaffolds, which can be delivered via IV injection, target the area of acute MI, prevent and/or slow negative left ventricular remodeling, and improve cardiac function post-MI.