Development of 3D Printed Spatiotemporal Multi-Drugs Delivery Hydrogel Patches with Decellularized Extracellular Matrix-Based Hybrid Inks for Promoting Cerebral Angiogenesis

Abstract

Significance of therapeutic angiogenesis has been spotlighted for the treatment of cerebral ischemia; however, effective strategies of mimicking angiogenesis process have not been developed yet. Herein, a 3D printed spatiotemporally compartmentalized cerebral angiogenesis inducing (SCAI) hydrogel patch, releasing dual angiogenic growth factors (GFs), using extracellular matrix-based hybrid inks was fabricated. A new hybrid biomaterial-based ink for printing patches through dual crosslinking mechanisms was developed: Chemical crosslinking with aza-Michael addition reaction with combining methacrylated hyaluronic acid (HAMA) and vascular tissue-derived decellularized extracellular matrix (VdECM), and thermal crosslinking. 3D printing, a useful approach to fabricate the patch-type drug delivery systems with fabrication versatility with customizable systems and multiple biomaterials, is adopted to print three-layered hydrogel patch with spatially separated dual GFs as outer- and inner-layers that provide tunable release profiles of multiple GFs and fabrication versatility. Consequently, these layers of the patch spatiotemporally separated with dual GFs, induces excellent neovascularization in the brain area, monitored by label-free photoacoustic microscopy in vivo. The developed multi-GFs releasing patch may offer a promising therapeutic approach for the cerebral ischemic diseases to reinforce neovascularization and for the next generation therapeutics of spatiotemporal drugs releasing such as ischemic heart diseases, diabetes, and even use as vaccines.