Angiogenic Granular Biomaterials for Brain Repair after Ischemic Stroke

Abstract

There is still a significant need to develop regenerative therapies that improves functional recovery for stroke patients that develop disabilities. Not only does an ideal therapy stimulate tissue reorganization for positive indications of regeneration, it must also produce functional recovery as that has the largest quality of life impact on patients with stroke-related disabilities. As such, we have established a consistent photothrombotic stroke model and behavioral assessment workflow for our studies. Patients, and stroke animal models, undergo stroke-induced enhanced endogenous plasticity and pro-repair mechanisms in the subacute phase after stroke onset, making it an attractive opportunity for therapeutic intervention. We have designed a biocompatible granular hydrogel, microporous annealed particle (MAP) scaffold to be injected with our angiogenic clustered VEGF heparin nanoparticle (CLUVENA) into the stroke infarct 5 days after photothrombotic stroke. Our combined MAP-CLUVENA was able to attenuate astrogliosis and promote significant angiogenesis with perfused vessels growing throughout the infarct as early as day 15. At day 35, we observed signs of vessel maturation and axonal sprouting that led to functional recovery. Taking the next step in translation by improving clinical relevance, we repeated the study in an aged female mouse model and showed MAP-CLUVENA still maintains therapeutic efficacy in attenuating astrogliosis and enhancing angiogenesis throughout the infarct. Although numerous preclinical studies still need to be done, our engineered MAP-CLUVENA hydrogel is a promising intervention for subacute ischemic stroke clinical translation.