Infusible Extracellular Matrix for Treating Myocardial Infarction

摘要 尽管组织工程和再生医学最近取得了进展，但心肌梗死后的心力衰竭(HF) 心肌梗死(MI)仍然是美国和西方世界其他地区的主要死亡原因。其中之一 我们的目标是开发新的、微创的组织工程疗法来治疗心肌梗死。 虽然细胞疗法已经被广泛研究用于治疗心肌梗死和心力衰竭，但初始细胞的荟萃分析 治疗试验表明，对心脏功能只有轻微的影响。可注射生物材料，刺激内源性 修复是一种有吸引力的，潜在更有效的选择，因为治疗仍然可以最小限度地提供 通过导管进行侵入性治疗，但可以现成，并显著降低了成本和并发症 与细胞产品相比。PI的实验室开发了第一个心脏特异性注射水凝胶，一种心肌 基质水凝胶，来源于脱细胞的猪心肌细胞外基质(ECM)，是 可通过经心内膜注射导管释放。这种材料在室温下是液体，形成一种 注射后的多孔和纤维支架，我们已经表明它促进了免疫细胞的重塑 在亚急性和慢性心肌梗死模型中，极化、其他内源性细胞浸润和心脏修复。这个首字母 这项工作导致了一项在心肌梗塞后患者中进行的成功的I期临床试验。然而，这种方法并不适用于 治疗急性心肌梗塞患者，因为与心内膜下注射相关的安全问题。因此，意义重大 甚至在患者有资格接受这种治疗之前，心脏的损伤和重塑就会发生。与之形成鲜明对比的是 急性心肌梗死患者经心内膜下注射、冠状动脉内输液可作为介入性治疗 心脏病专家已经在进行球囊血管成形术。因此，我们最近开发了一种新的不可融合的形式 可通过冠状动脉内输注的细胞外基质(IECM)覆盖和填充受损血管的缝隙 治愈组织。我们已经证明，在大鼠再灌流后立即给予这种药物是有效的 急性心肌梗死模型和先导性猪研究。在急性心肌梗死中，我们假设iECM促进内皮细胞存活 和浸润性免疫细胞的极化到支持重塑的表型，这继而与 已经证明，血管通透性的降低可以改善心肌细胞的存活率。我们的 初步结果为使用我们的iECM新技术治疗急性心肌梗死提供了强有力的支持。在这 建议，我们将更好地了解iECM技术的免疫调节和再生潜力 并进行转化性研究，目的是开发一种治疗急性心肌梗塞的新疗法。

Summary Despite recent advances in tissue engineering and regenerative medicine, heart failure (HF) following myocardial infarction (MI) continues to be the leading cause of death in the U.S., and the rest of the western world. One of our goals is the development of new, minimally invasive tissue-engineered therapies for the treatment of MI. While cell therapies have been extensively studied for the treatment of MI and HF, meta-analyses of initial cell therapy trials suggest only a modest effect on cardiac function. Injectable biomaterials that stimulate endogenous repair are an attractive, potentially more effective alternative since therapies could still be delivered minimally invasively via catheter, yet could be off the shelf and have significantly reduced costs and complications compared to cell products. The PI’s lab developed the first cardiac specific injectable hydrogel, a myocardial matrix hydrogel, which is derived from decellularized porcine myocardial extracellular matrix (ECM) and is deliverable via a transendocardial injection catheter. This material is liquid at room temperature and forms a porous and fibrous scaffold upon injection, which we have shown promotes pro-remodeling immune cell polarization, other endogenous cell infiltration and cardiac repair in subacute and chronic MI models. This initial work led to a successful Phase I clinical trial in post-MI patients. However, this approach is not amenable to treating acute MI patients because of safety issues related to transendocardial injections. Therefore, significant damage and remodeling of the heart will occur before a patient is even eligible for this therapy. In contrast to transendocardial delivery, intracoronary infusion can be performed in acute MI patients as interventional cardiologists are already performing a balloon angioplasty. We therefore recently developed a new infusible form of ECM (iECM) that can be delivered via intracoronary infusion to coat and fill gaps of damaged vasculature to heal the tissue. We have already shown this is effective when delivered immediately post-reperfusion in a rat acute MI model and in a pilot pig study. In acute MI, we hypothesize that iECM promotes endothelial cell survival and polarization of infiltrating immune cells to a pro-remodeling phenotype, which secondarily along with an already demonstrated reduction in vascular permeability results in improved cardiomyocyte survival. Our preliminary results provide strong support for the use of our new iECM technology for treating acute MI. In this proposal, we will better understand the immunomodulatory and regenerative potential of our iECM technology and perform translational studies with the goal of developing a novel therapy for acute MI.