Bioinspired non-expansive biodegradable matrix promotes blood vessel organoid development for ischemic stroke repair

Tissue engineering-based vascular reconstruction represents a promising therapeutic strategy for ischemic stroke. However, in the confined stroke cavity, conventional implants are unable to simultaneously provide swelling-resistant support and growth-permissive internal space, which are crucial for effective revascularization. To address this limitation, we develop a bioinspired, non-expansive biodegradable matrix (NEBM) through covalent/non-covalent assembly of commercially available, clinical-grade natural polymers. We show that NEBM recapitulates key features of brain ECM—including porous microstructure and tissue-matched stiffness—to deliver structural stability. Moreover, its progressively degradable structure establishes a dynamic remodeling niche that directs cellular behavior toward promoting angiogenesis. Compared to commercial Matrigel-based matrix, NEBM fosters blood vessel organoids (BVOs) development with higher vascular density, larger vessel diameters, and more distinct arterial features. In both subcutaneous and stroke transplantation models, we find that NEBM facilitates the integration of BVOs with the host vasculature. Strikingly, this revascularization in stroke cavity stimulates neurogenesis, contributing to significant functional recovery. As such, our study provides valuable guidance to design clinically translatable matrices for organ repair and regeneration in confined environments.