Delivery of Angiogenic Therapy from Flowable Hyaluronic Acid Porous Scaffolds Results in Functional Improvement without Anti‐Inflammatory Agents

Abstract Ischemic stroke, a blockage in the vasculature of the brain that results in insufficient blood flow, is one of the world's leading causes of disability. The cascade of inflammation and cell death that occurs immediately following stroke drives vascular and functional loss that does not fully recover over time, and no Food and Drug Administration (FDA)‐approved therapies exist that stimulate regeneration post‐stroke. A hyaluronic acid (HA)‐based hydrogel was previously developed that delivered heparin nanoparticles alone, to reduce glial reactivity, and heparin nanoparticles with vascular endothelial growth factor (VEGF) bound to their surface, to promote angiogenesis. However, the inclusion of the naked heparin nanoparticles warranted concern over the development of bleeding complications. Here, it is explored how microporous annealed particle (MAP) scaffolds functionalized with VEGF coated heparin nanoparticles can both reduce glial reactivity and promote angiogenesis – without the inclusion of free heparin nanoparticles. It is showed that the updated design successfully promotes de novo tissue formation, including the development of mature vessels and neurite sprouting, and leads to functional improvement in a photothrombotic stroke model. In addition, increased astrocyte infiltration is found into the infarct site correlated with mature vessel formation. This work demonstrates how the biomaterial design can enhance endogenous regeneration post‐stroke while eliminating the need for excess heparin.