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bioRxiv · 10.1101/2025.10.20.683259

Delivery of a novel porous hybrid thermoresponsive hydrogel into the stroke infarct reduces reactive astrogliosis and promotes neural progenitor cell proliferation

Bhuiyan, M. H.·Hinkley, S. F. R.·Ali, M. A.·Clarkson, A. N.
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Abstract

Stroke remains a leading cause of adult disability, driven in part by the formation of a non-permissive extracellular matrix environment that limits endogenous repair. Injectable biomaterials that can modulate this microenvironment while enabling localised therapeutic delivery, represent a promising strategy for post-stroke brain regeneration. Here, we report the development of a thermoresponsive hybrid hydrogel composed of chitosan, {beta}-glycerophosphate, silk fibroin, polyvinyl alcohol and polyvinyl pyrrolidone, engineered to provide a tuneable physicochemical properties and enhanced biological functionalities for intracerebral delivery. Systemic optimisation identified a formulation (F6) that exhibited rapid gelation at physiological temperature, appropriate viscoelastic properties, a microporous architecture, and controlled biodegradation, conducive to cellular infiltration and molecular transport. In a mouse model of photothrombotic stroke, intracerebral delivery of the F6 hydrogel attenuated reactive astrogliosis and microglial activation in the peri-infarct region, while enhancing neurogenesis in the subventricular zone. Notably, incorporation of brain-derived neurotrophic factor within the hydrogel significantly improved functional recovery over 8 weeks, demonstrating the capacity of this system to act as a localised delivery platform for neuro-regenerative therapeutics. Together, this study establishes a tuneable thermoresponsive hydrogel platform that integrates structural support with controlled therapeutic delivery, highlighting its potential as a minimally invasive strategy for modulating the post-stroke microenvironment and promoting functional recovery.

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Bhuiyan, M. H., Hinkley, S. F. R., Ali, M. A., Clarkson, A. N.. 2025-10-21. Delivery of a novel porous hybrid thermoresponsive hydrogel into the stroke infarct reduces reactive astrogliosis and promotes neural progenitor cell proliferation. https://doi.org/10.1101/2025.10.20.683259

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