3d Printed Multi-Growth Factors Delivery Patches with Decellularized Extracellular Matrix-Based Hybrid Inks Via Aza-Michael Addition for Promoting Cerebral Angiogenesis

Abstract

Generally, brain angiogenesis is a tightly regulated process, which scarcely occurred in the absence of specific pathological conditions. Delivery of exogenous angiogenic factors enables the induction of desired angiogenesis by stimulating neovasculature formation. However, effective strategies of mimicking the angiogenesis process with exogenous factors have not yet been fully explored. Herein, we develop a 3D printed spatiotemporally compartmentalized cerebral angiogenesis inducing (SCAI) hydrogel patch, releasing dual angiogenic growth factors (GFs), using extracellular matrix-based hybrid inks. We introduce a new hybrid biomaterial-based ink for printing patches through dual crosslinking mechanisms: Chemical crosslinking with aza-Michael addition reaction with combining methacrylated hyaluronic acid (HAMA) and vascular-tissue-derived decellularized extracellular matrix (VdECM), and thermal crosslinking of VdECM. 3D printing technology, 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.

Keywords: Tissue Engineering, 3D printing technology, Dual-crosslinking decellularized extracellular matrix hydrogel, Drug delivery system, Cerebral angiogenesis