Manipulating Hydrogel Microstructure for the Purpose of Brain Repair After Stroke
Stroke is the leading cause of adult disability in the United States. The severe and highly reactive inflammation immediately following stroke onset leads to a series of destructive events including neuronal death and a clearance of cellular debris. The brain’s defense mechanism is to compartmentalize the injured tissue via a highly reactive and neurotoxic astrocytic scar that acts as a physical and chemical barrier to recovery. There has been much debate whether reactive astrocytes are beneficial in the recovery process. Highly reactive astrocytes are neurotoxic while pro-recovery astrocytes are crucial in synaptogenesis and coordinating neural circuits. Thus, one therapeutic strategy emerges whereby limiting highly reactive astrocytes and promoting pro-recovery astrocytes could prove beneficial. The brain’s liquefactive necrosis and compartmentalization leads to a stroke cavity that can accept a large volume transplant without causing further damage. This cavity provides an opportunity for biomaterial tissue regeneration strategies. Biomaterials, specifically polymeric hydrogels can act as extra cellular matrix (ECM) mimics by providing neighboring cells with mechanical structure and biochemical cues. Most hydrogel studies conducted in the brain utilize the hydrogel solely as a delivery vehicle for small molecule, growth factor, or stem cell transplantation. This dissertation focuses on engineering the biomaterial itself to unlock its inherit therapeutic potential, focusing on manipulation of astrocyte reactivity. A novel class of injectable microporous annealing particle (MAP) hydrogels is used and optimized for direct injection into the stroke cavity for brain repair. This material’s backbone is first transitioned to hyaluronic acid (HA), a glycosaminoglycan commonly found in the native brain ECM. The mechanical properties such as void space and pore size are fully characterized and the material is engineered to match the mechanical stiffness of rodent brain. The HA MAP gel is tested in vitro and proven to be cell friendly. This hydrogel is used in two different rodent stroke models and shown to have anti-inflammatory effects. Deeper investigation into astrocyte reactivity in response to the hydrogel injection shows the MAP gel is capable of decreasing highly reactive astrocytes and promoting infiltration of pro-recovery astrocytes into the stroke. This pro-recovery astrocyte infiltration is also correlated with neuronal axon penetration into the lesion. Finally, long-term studies show the MAP gel is capable of better preserving brain shape and function. The unlocking of the inherit hydrogel therapeutic potential will hopefully allow for more focus placed on the optimization of biomaterials in the field of stroke regeneration, rather than simply being used as delivery vehicles.