Engineered Granular Hydrogels for Endogenous Tissue Repair

摘要 心肌梗死(MI)和由此导致的左心室重构可能损害心功能和 最终导致心力衰竭。尽管目前对这些患者的治疗选择有限，但 再灌流，目前正在开发一些生物材料疗法，甚至已经进展到 临床试验。多年来，我们的实验室和临床合作者一直在探索可注射水凝胶的使用 在心肌梗塞急性期向心脏提供机械和生物信号的十年，以改变 改善左室重构反应，改善心功能。通常，这些水凝胶作为一种 心肌内物质的“口袋”，其初始细胞相互作用仅在水凝胶外围；然而， 我们现在希望设计一种“主动”策略，使材料设计能够通过孔洞引导组织修复 和经过改造的水凝胶信号。为了实现这一点，我们提出了颗粒的开发和应用 水凝胶-由聚集的微凝胶亚单位组成，表现出可注射的剪切稀释性 和固有的间质孔隙率导致细胞侵袭。我们的指导性假设是注射颗粒剂 水凝胶将允许细胞侵入，增加血管密度，基质堆积，并改善 心肌梗死后的功能结果。重要的是，以颗粒为基础的材料也被认为可以促进愈合 根据它们的结构做出反应，导致早期胶原沉积，这可以被利用来促进 心肌梗死稳定。由于颗粒状水凝胶的模块化性质，我们提出了三个目标来更好地 了解它们的结构-功能特性，并将其翻译为心肌梗死疗法。在目标1中，我们捏造 具有高通量微流控方法形成颗粒状水凝胶的微凝胶，其中生物物理特征， 即颗粒大小和颗粒间相互作用的引入被改变。我们探讨了这些 参数影响细胞侵袭，血管结构成熟，并改善心功能时 在啮齿类动物的缺血-再灌注心肌梗死模型中进行评估。在目标2中，我们然后试图理解 在颗粒状水凝胶中添加生化信号，包括选择的微凝胶的蛋白酶降解 群体和局部释放的趋化基质细胞衍生因子1a进一步改善了结果。 最后，在目标3中，随着先进的微流体技术的发展，我们展望了翻译的快速发展 制造颗粒状水凝胶，然后评估临床相关的缺血- 猪再灌流模型。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)，用于粒子制造和放大的微流控设计 和用于心肌梗塞治疗评估的动物模型(Atluri/Gorman)。的重要意义。 这项工作具有潜在的深远意义，因为它开发了一种通过以下方式治疗心肌梗塞的脱细胞可注射水凝胶疗法 在心肌梗死后早期招募内源性细胞群体以限制不利的左室重构。

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.