Injection of Microporous Annealing Particle (MAP) Hydrogels in the Stroke Cavity Reduces Gliosis and Inflammation and Promotes NPC Migration to the Lesion

Abstract

With the number of deaths due to stroke decreasing, more individuals are forced to live with crippling disability resulting from the stroke. To date, no therapeutics exist after the first 4.5 hours after the stroke onset, aside from rest and physical therapy. Following stroke, a large influx of astrocytes and microglia releasing pro-inflammatory cytokines leads to dramatic inflammation and glial scar formation, affecting brain tissue's ability to repair itself. Pathological conditions such as a stroke trigger neural progenitor cells (NPCs) proliferation and migration toward the damaged site. However, these progenitors are often found far from the cavity or the peri-infarct tissue. Post stroke tissue remodeling results in a compartmentalized cavity that can directly accept a therapeutic material injection. Here, we show that the injection of a porous hyaluronic acid hydrogel into the stroke cavity significantly reduces the inflammatory response following stroke while increasing peri-infarct vascularization compared to non-porous hydrogel controls and stroke only controls. In addition, we show that the injection of our material impacts NPCs proliferation and migration at the subventricular zone niche and results, for the first time, in NPC migration into the stroke site.

Structured Macroporous Hydrogels: Progress, Challenges, and Opportunities

“…These MAP scaffolds can be delivered via injection along with other cells/ growth factors and show significant success in promoting cell proliferation and wound healing compared to similar nonporous scaffolds. [185][186][187] Building on this, the Anseth lab has reported a microporous microgel scaffold composed of multiarmed PEG-based polymers crosslinked via reactive octyneazide chemistry. [188] The microgels were synthesized via an inverse suspension polymerization, demonstrating control over particle size by changing the rate of shear applied.…”

“…[185] This method, developed in the Segura lab, uses a microfluidic emulsion approach to assemble monodisperse microgel building blocks which can then subsequently be annealed to each other in situ to form microporous annealed particle (MAP) scaffolds. [185] The microgel building blocks can be composed of either multiarmed PEG-vinyl sulfone [185] or hyaluronic acid [186,187] decorated with two orthogonal peptide substrates used for subsequent annealing via noncanonical amide linkages. These MAP scaffolds can be delivered via injection along with other cells/ growth factors and show significant success in promoting cell proliferation and wound healing compared to similar nonporous scaffolds.…”

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…The aforementioned micro-porous HA-RGD hydrogels stimulated NSPC proliferation in the SVZ-an effect not seen with nanoporous gels (Figures 2A,F-H) (Nih et al, 2017). While neuroblasts were reported to have migrated into the gels, it is unclear how the material stimulated NSPC proliferation.…”

“…Recently, the effect of hydrogel structure alone on tissue repair was investigated by comparing a micro-porous HA hydrogel, synthesized by crosslinking HA-RGD microbeads in situ, to a nano-porous hydrogel while keeping the bulk moduli and biochemical signaling the same (Figures 2A-E) (Nih et al, 2017). Both structures reduced the thickness of the glial scar and degree of macrophage activation in the peri-infarct region; however, the magnitude of this effect was greatly increased in the microporous gel.…”

“…Advances in material design that have been implemented in other tissue systems, such as modifications to material porosity, topography and mechanical cues to control the cellular response to the biomaterial, can be adapted for brain repair. Only recently has porosity been explored in the context of brain repair; a micro-porous HA hydrogel, injected into the stroke cavity, demonstrated that porosity can be used to achieve superior cellular infiltration and attenuation of the inflammatory response compared to non-porous hydrogels (Nih et al, 2017). Future work may include optimizing the pore size of a material for the desired cellular response, such as for neurogenesis, axonogenesis or vasculogenesis.…”