Abstract
Intracerebral hemorrhage (ICH) is a subtype of stroke that leads to severe functional impairments and poses a significant global health burden. Current clinical treatments often have limited efficacy, resulting in unsatisfactory outcomes. Herein, we report a combined strategy of brain neuroprotection and endogenous neuroregeneration for enhanced ICH treatment via an injectable biomimetic hydrogel with efficient reactive oxygen species (ROS) scavenging and therapeutics delivery. The hydrogel is mainly composed of thiolated gelatin (G-SH) and thiolated hyaluronan (HA-SH) to biomimetic extracellular matrix, in which the thiols act not only as crosslinkers through a thiol-ene click reaction, but also as ROS scavenger. By adjusting the ratio of G-SH to HA-SH, the hydrogel is optimized in terms of gelation time, modulus, degradation rate, microstructure, ROS scavenging ability, and compatibility with cells, tissues, and blood. In vitro, the hydrogel demonstrates the ability to scavenge intracellular ROS and modulate macrophage polarization through the JAK2/STAT3 signaling pathway. When encapsulated with insulin-like growth factor 1 (IGF-1), it further promotes the proliferation, migration, and differentiation of neural stem cells (NSCs) and enhances endothelial cell angiogenesis. In vivo, notably, the hydrogel encapsulated with chondroitinase ABC (ChABC) and IGF-1 effectively scavenges tissue ROS, regulates the activation and polarization of microglia/macrophages, providing neuroprotection. It also reduces glial scarring while facilitating the proliferation and migration of endogenous NSCs and promotes angiogenesis, all contributing to neuroregeneration. These combined effects lead to enhanced neuronal and myelin repair, resulting in improved cognitive and motor functions. Overall, this combined strategy of neuroprotection and neuroregeneration is a promising approach for enhanced ICH treatment.
Published Version
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