Bioengineering Strategies to Modulate Inflammation, Synaptogenesis, and Extracellular Vesicle Production for Ischemic Stroke Repair

Abstract

Ischemic stroke remains a leading cause of adult disability, with acute therapeutic strategies such as intravenous thrombolysis and mechanical thrombectomy largely unchanged since 2015. Beyond these interventions, functional recovery relies primarily on physical rehabilitation, and more than half of stroke survivors aged 65 or older live with long-term mobility impairment. This work develops and characterizes astrocyte-inspired biomaterials and biophysical technologies that engage the endogenous window of neural plasticity during the subacute phase following stroke to promote neural network rewiring and enhance the translational potential of bioactive therapeutics. The first study investigated the effect of scaffold chemistry on post-stroke tissue response using dibenzocyclooctyne (DBCO)-modified microporous annealed particle (MAP) hydrogels. DBCO functionalization inhibited astrocyte migration but, at low modification levels, significantly enhanced axonal elongation, identifying DBCO as a bioactive cue capable of modulating lipid deposition and regenerative outcomes. The second study employed MAP scaffolds to co-deliver synaptogenic thrombospondin-1 (TSP-1) and angiogenic vascular endothelial growth factor (VEGF) nanoparticles into the infarct cavity. This treatment promoted synaptogenesis without disrupting angiogenesis, though excessive synapse formation constrained axonal extension, leading to modest behavioral recovery. Finally, an acoustofluidic stimulation platform was developed to improve the yield of astrocyte-derived extracellular vesicles (EVs). This device increased EV secretion up to eight-fold across reactive astrocyte states, providing a scalable biomanufacturing tool and a potential diagnostic platform for assessing astrocyte mechanoreactivity. Collectively, these studies advance the development and design of technologies which promote post-ischemic neural circuit reorganization and functional recovery.