Engineered Granular Hydrogels for Endogenous Tissue Repair

摘要

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.