Engineered Granular Hydrogels for Endogenous Tissue Repair

摘要 心肌梗死（MI）和由此导致的左心室重塑可能会损害心脏功能， 最终导致心力衰竭尽管目前对这些患者的治疗选择有限， 再灌注，目前正在开发许多生物材料疗法，甚至已经发展到 临床试验我们的实验室与我们的临床合作者一直在探索使用可注射水凝胶超过 在MI急性期向心脏提供机械和生物信号， 改善心功能。通常，这些水凝胶作为一种药物递送。 心肌内材料的“口袋”仅在水凝胶外围具有初始细胞相互作用;然而， 我们现在希望设计“主动”策略，其中材料设计可以通过孔隙引导组织修复， 和工程水凝胶信号。为了实现这一目标，我们提出了粒度的发展和应用， 水凝胶-由组装的微凝胶亚单元组成，其表现出可注射性的剪切稀化特性 和细胞侵入的固有间隙孔隙度。我们的指导假设是， 水凝胶将允许细胞侵入，以增加血管密度、基质积累，并改善 MI后的功能结局。重要的是，还已知基于颗粒的材料促进促愈合， 基于其结构的反应，导致早期胶原蛋白沉积，这可以用来促进 梗死稳定。由于颗粒水凝胶的模块化性质，我们提出了三个目标，以更好地 了解它们的结构-功能特性，将其转化为MI治疗。在目标1中，我们制造 微凝胶与高通量微流体方法形成粒状水凝胶， 即颗粒尺寸和颗粒间相互作用的引入被改变。我们探索这些 参数影响细胞侵袭，血管结构的成熟，并改善心脏功能， 在啮齿动物的缺血-再灌注MI模型中评估。在目标2中，我们试图了解 在颗粒状水凝胶中添加生化信号，包括选择微凝胶的蛋白酶降解 群体和化学引诱物基质细胞衍生因子1a的局部释放进一步改善结果。 最后，在目标3中，我们期待随着先进微流体技术的发展， 制造颗粒状水凝胶，然后在临床相关的局部缺血中评估选择的组合物， 猪再灌注模型。我们的研究得到了广泛的前期工作和专业知识的支持，包括 用于心脏修复的生物材料开发（Burdick），用于颗粒制造和放大的微流体设计 （Issadore），和用于评估MI疗法的动物模型（Mexicuri/Gorman）。的意义 这项工作具有潜在的深远意义，因为它开发了一种用于MI的无细胞可注射水凝胶治疗， 在MI后早期招募内源性细胞群以限制不利的LV重塑。

Abstract Myocardial infarction (MI) and the resulting left ventricular remodeling may compromise cardiac function and eventually result in heart failure. Although there are limited current treatment options for these patients beyond re-perfusion, a number of biomaterial therapies are currently being developed and have even progressed to clinical trials. Our lab with our clinical collaborators have been exploring the use of injectable hydrogels for over a decade to provide both mechanical and biological signals to the heart during the acute phase of MI, to alter the LV remodeling response and to improve cardiac function. Often, these hydrogels are delivered as a “pocket” of material within the myocardium with initial cell interactions only at the hydrogel periphery; however, we now look to design “active” strategies where the material design can guide tissue repair through porosity and engineered hydrogel signals. To accomplish this, we propose the development and application of granular hydrogels – comprised of assembled microgel subunits that exhibit shear-thinning properties for injectability and inherent interstitial porosity for cell invasion. Our guiding hypothesis is that the injection of granular hydrogels will permit cellular invasion to increase vascular density, matrix accumulation, and improve functional outcomes after MI. Importantly, particle-based materials are also known to promote a pro-healing response based on their structure, leading to early collagen deposition, which can be leveraged to promote infarct stabilization. Due to the modular nature of granular hydrogels, we propose three Aims to better understand their structure-function properties towards their translation as an MI therapy. In Aim 1, we fabricate microgels with high-throughput microfluidic approaches to form granular hydrogels where biophysical features, namely particle size and the introduction of inter-particle interactions, are altered. We explore how these parameters influence cell invasion, the maturation of vascular structures, and improve cardiac function when assessed in an ischemia-reperfusion MI model in rodents. In Aim 2, we then seek to understand how the addition of biochemical signals in granular hydrogels, including the protease-degradation of select microgel populations and local release of the chemoattractant stromal cell derived factor 1a further improve outcomes. Lastly, in Aim 3, we look towards translation with the development of advanced microfluidics for the rapid fabrication of granular hydrogels and then evaluate select compositions in a clinically-relevant ischemia- reperfusion model in pigs. Our study is supported by extensive preliminary work and expertise, including biomaterials development for cardiac repair (Burdick), microfluidic design for particle fabrication and scale-up (Issadore), and animal models for the assessment of therapies for MI (Atluri/Gorman). The significance of this work is potentially profound, as it develops an acellular injectable hydrogel treatment for MI by recruiting endogenous cell populations in the early post-MI period to limit adverse LV remodeling.