Endothelial Cells Angiogenesis in Sulfated Glycosaminoglycan (GAG) Hydrogels Enhanced by Bioactive Glass‐Released Ions

Abstract The successful clinical translation of large‐scale tissue‐engineered constructs is significantly hindered by the lack of functional vascularization, which is crucial for delivering oxygen and nutrients to cells. Current in vitro angiogenesis models often rely on murine tumor‐derived extracellular matrix (ECM) materials, which suffer from non‐defined composition and batch‐to‐batch variability, and on the delivery of growth factors at non‐physiological concentrations. Hydrogels offer a superior alternative for the rational design of biomimetic ECM environments, because of their versatility in tuning biochemical and mechanical properties. This study presents a novel growth factor‐free hydrogel composed of gelatin, chondroitin sulfate, and laminin, designed to promote endothelial cell (EC) angiogenesis in vitro. The hydrogel's mechanical properties are precisely controlled by varying its crosslinking degree, attesting that a softer substrate (Young's modulus ≈80 Pa) significantly boosts ECs tube formation. Furthermore, the angiogenic process is enhanced by several hours with ions released by bioactive glass 58S (BG58S), specifically calcium and silicon. Finally, the expression of angiogenesis‐related genes and the production of matrix remodeling enzymes is augmented in the presence of BG58S‐conditioned medium. It is believed that this bioinstructive sulfate GAG based hydrogel represents a promising solution for vascularizing 3D cellular constructs, marking a significant step toward the clinical application of tissue engineering products.