Angiogenic Bioengineered Systems to Optimize Post-Infarction Myocardial Recovery

项目摘要 缺血性心脏病影响着全球超过1.5亿人，并且仍然是心脏病患者死亡的主要原因。 人类虽然心肌梗死后的总体死亡率有所改善，但许多患者最终死于 尽管进行了药物治疗、血运重建和重建治疗， 灌注不足仍然没有解决。靶向治疗，如细胞因子，干细胞和组织- 心肌血管再生、修复和再生的工程方法已经取得了不同的成功， 这可能是由于机械理解的局限性和次优的输送系统。因此，新的方法 显微血管重建是非常必要的。在最近的资助期间，我们进一步阐明了 血管生成细胞因子基质细胞衍生因子1（SDF）及其靶点内皮细胞的信号传导机制 祖干细胞，以更好地利用其在梗死后心肌修复过程中的治疗效果。 此外，我们合成了一种超高效的工程SDF类似物（ESA），并通过一种新的 用于延长治疗效果的生物材料。这些策略显示了强大的血管生成，改善了 心肌细胞存活，保存心肌组织生物力学，减少不利的损伤后重塑， 促进心脏功能恢复。我们还设计并构建了组织工程双层细胞 并证明了其改善血管生成和心室重塑的能力。我们终于有 将我们的工作转化为临床前大型动物模型，以评估这些疗法的潜力 进行人体临床试验。 该更新申请提出进一步定义SDF治疗作用的机制， 并优化用于大型动物和最终人类临床转化的细胞因子递送平台。目标1寻求 描述SDF/ESA分子结构，以指导具有增强功效的新型类似物的合成， 操纵SDF信号传导，以确定治疗靶向机会，并研究 微血管重建对细胞灌注、组织生物力学和心室功能的影响。目标2提出， 开发了两种创新的生物工程细胞因子递送平台，用于治疗心肌缺血。一 包括具有双重细胞因子释放模式的新型剪切稀化水凝胶， 经皮经导管输送。另一个涉及制造组织工程SDF洗脱血管 同时进行大血管和微血管重建。Aim 3致力于扩展这些创新 经皮经导管治疗和微创的大动物临床前模型的策略 合成生物导管冠状动脉旁路移植术。拟议的实验将产生重要的 了解冠状动脉疾病、心肌梗死和心力衰竭的潜在临床治疗方法。

PROJECT SUMMARY Ischemic heart disease affects over 150 million people worldwide and remains a leading cause of death for mankind. While overall mortality after myocardial infarction has improved, many patients ultimately succumb to heart failure despite pharmacologic, revascularization, and reconstructive therapies due to microvascular perfusion deficits which remain unaddressed. Targeted therapies such as cytokine, stem cell, and tissue- engineering approaches to myocardial revascularization, repair, and regeneration have had varied success, likely due to limitations in mechanistic understanding and suboptimal delivery systems. Thus, novel approaches to microrevascularization are greatly needed. In the recent funding period, we further elucidated the native signaling mechanisms of the angiogenic cytokine stromal cell-derived factor 1 (SDF) with its target, endothelial progenitor stem cells, to better harness its therapeutic effect during post-infarction myocardial repair. Furthermore, we synthesized a supra-efficient engineered SDF analog (ESA) and delivered it via a novel biomaterial for prolonged therapeutic effect. These strategies revealed robust angiogenesis, improved cardiomyocyte survival, preserved myocardial tissue biomechanics, reduced adverse post-injury remodeling, and enhanced cardiac functional recovery. We also designed and constructed a tissue-engineered bilayer cell sheet and demonstrated its ability to improve angiogenesis and ventricular remodeling. Finally, we have translated elements of our work into pre-clinical large animal models to evaluate the potential of these therapies to reach human clinical trials. This renewal application proposes to further define the mechanisms underlying the therapeutic effects of SDF, and to optimize cytokine delivery platforms for large animal and eventual human clinical translation. Aim 1 seeks to delineate SDF/ESA molecular structure to guide synthesis of novel analogs with enhanced efficacy, genetically manipulate SDF signaling to identify therapeutic targeting opportunities, and study the effects of microrevascularization on cellular perfusion, tissue biomechanics, and ventricular function. Aim 2 proposes the development of two innovative bioengineered cytokine delivery platforms for treating myocardial ischemia. One encompasses a novel shear-thinning hydrogel with dual cytokine release modalities and the capacity for percutaneous transcatheter delivery. Another involves fabricating a tissue-engineered SDF-eluting vascular conduit to enable simultaneous macro- and microrevascularization. Aim 3 strives to scale these innovative strategies to large animal pre-clinical models of percutaneous transcatheter therapeutics and minimally invasive coronary artery bypass grafting with synthesized bioconduits. The proposed experiments will yield important knowledge on potential clinical therapies for coronary artery disease, myocardial infarction, and heart failure.