Mechanically Compliant, Precision-Porous Brain Implants Reduce the Foreign Body Reaction and Guide Regeneration

Central nervous system (CNS) diseases and injuries might be treated by implanted devices, tissue regenerative scaffolds, or drug delivery platforms. However, inflammatory CNS responses limit these interventions and may worsen outcomes following damage to the CNS. Via the foreign body reaction, macrophages and glial cells trigger a "glial scar" around implants, reducing device performance, scaffold regenerative ability, or drug delivery potential. Previous studies have shown that stiffness of CNS implants significantly affects glial encapsulation, but few studies have investigated materials that truly match brain tissue stiffness. Porous precision-templated scaffolds with uniform, interconnected, 40 µm spherical pores have shown favorable healing outcomes and a reduced foreign body reaction (FBR) in numerous soft and hard tissue applications. To quantify the effects of both hydrogel compliance (stiffness) and pore size on glial encapsulation, we implanted poly(2-hydroxyethyl methacrylate-co-glycerol methacrylate) (pHEMA/GMA) scaffolds of varying stiffness and pore size for 4 weeks in rat brain. We observed reduced astrocyte encapsulation around porous templated scaffolds (PTS) compared to solid hydrogel rods, reduced pro-inflammatory macrophage polarization for softer hydrogels versus stiffer hydrogels, and the presence of new blood vessels, neuronal markers, and neurogenesis within the pores. Utilizing soft, precision-porous hydrogels could provide a strategy for mitigating glial scarring and improving regeneration in implant-based CNS treatments.