Infusible Extracellular Matrix for Treating Myocardial Infarction

可溶性细胞外基质治疗心肌梗死

• 批准号: 10504948
• 负责人: Karen L Christman
• 金额: $ 73.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504948
• 关键词: Acute myocardial infarction; Address; Aging; Alternative Therapies; Animals; Apoptosis; Arrhythmia; Balloon Angioplasty; Binding; Biocompatible Materials; Cardiac; Cardiac Myocytes; Catheters; Cause of Death; Cell Survival; Cell Therapy; Cells; Chronic; Clinical; Development; Echocardiography; Endothelial Cells; Endothelium; Extracellular Matrix; Family suidae; Fibrosis; Functional disorder; Geometry; Germ Cells; Goals; Heart; Heart failure; Histologic; Histology; Holter Electrocardiography; Hydrogels; Immune; Immunohistochemistry; Infiltration; Infusion procedures; Injectable; Injections; Intervention; Intravenous; Knowledge; Lead; Left; Left Ventricular Function; Liquid substance; Magnetic Resonance Imaging; Mediating; Meta-Analysis; Metabolism; Modeling; Myocardial; Myocardial Infarction; Myocardium; Patients; Phase I Clinical Trials; Phenotype; Pre-Clinical Model; Rattus; Regenerative Medicine; Reperfusion Therapy; Rest; Route; Safety; Technology; Temperature; Therapy trial; Tissue Engineering; Tissues; Treatment Efficacy; Tumor-infiltrating immune cells; Vascular Permeabilities; Ventricular; Western World; Work; aged; base; cardiac repair; cost; cytokine; healing; heart function; immunoregulation; improved; minimally invasive; neovascularization; novel therapeutics; polarized cell; receptor; regeneration potential; repaired; response; scaffold; sex; single-cell RNA sequencing; transcriptomics; translational study

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.

概括 尽管最近的组织工程和再生医学取得了进步，但心肌衰竭（HF） 梗塞（MI）仍然是美国和西方世界其他地区死亡的主要原因。之一 我们的目标是开发用于MI治疗的新型，微创组织工程的疗法。 尽管细胞疗法已被广泛研究以治疗MI和HF，但初始细胞的荟萃分析 治疗试验仅表明对心脏功能有适度的影响。刺激内源性的可注射生物材料 维修是一种有吸引力的，可能更有效的替代方法，因为疗法仍然可以最低递送 通过导管侵入性，但可能会脱离架子，并大大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，源自脱细胞猪心肌外基质（ECM），IS 通过跨十大记录导管可传递。该材料在室温下是液体，并形成 注射时多孔和纤维脚手架，我们已经显示出来促进了促进免疫电池 极化，其他内源性细胞浸润和亚急性和慢性MI模型中的心脏修复。这个初始 工作导致了MI后患者成功的I期临床试验。但是，这种方法不适合 由于与跨性别注射有关的安全问题治疗急性MI患者。因此，重要 在患者有资格接受这种疗法之前，会发生损害和重塑。与 可以在急性MI患者中作为介入的心膜输送，冠状动脉内输注作为介入 心脏病专家已经在进行气球血管成形术。因此，我们最近开发了一种新的不利形式 ECM（IECM）可以通过冠状内输注以覆盖并填补损坏的脉管系统的间隙 治愈组织。我们已经表明，在鼠后重新灌注后立即交付时，这是有效的 急性MI模型和试验性猪研究。在急性MI中，我们假设IECM促进了内皮细胞的存活 以及将免疫球浸入亲塑造表型的极化，其次是 已经证明血管通透性降低会导致心肌细胞存活率提高。我们的 初步结果为使用我们的新IECM技术治疗急性MI提供了强有力的支持。在这个 提案，我们将更好地了解IECM技术的免疫调节和再生潜力 并进行翻译研究，目的是为急性MI开发新的疗法。