Injectable, Micellar Chitosan Self‐Healing Hydrogel for Asynchronous Dual‐Drug Delivery to Treat Stroke Rats

Abstract Stroke is a common disease with high mortality worldwide. The endogenous neural regeneration during the intracerebral hemorrhage (ICH) stroke is restricted by the brain cavity, inflammation, cell apoptosis, and neural scar formation. Biomaterials serving as temporary supporting matrices are highly demanded as injectable implants for brain tissue regeneration. Herein, a chitosan micellar self‐healing hydrogel (CM hydrogel) with comparable modulus (≈150 Pa) to brain, shape adaptability, and proper swelling (≈105%) is developed from phenolic chitosan (PC) and a micellar crosslinker (DPF). Two model drugs are individually packaged in the hydrophilic network and hydrophobic micelle cavities of CM hydrogel, and they feature asynchronous releasing kinetics, including a first‐order rapid release for hydrophilic drug and a zero‐order sustained release for hydrophobic drug. The dual‐drug loaded CM (CMD) hydrogel delivers two clinical drugs corresponding to the anti‐inflammatory and neurogenesis phases of the stroke to ICH rats through brain injection. The rats receiving CMD hydrogel show behavioral improvement (≈84% recovery) and balanced brain midline shift (≈0.98 left/right hemibrain ratio). Immunohistochemistry reveals neurogenesis (doublecortin‐ and nestin‐ positive cells) and evidence of angiogenesis (≈18 µm diameter vessels lined with CD31‐positive cells). The injectable CMD hydrogel offers a novel asynchronous drug delivery platform for treating ICH stroke.