Living and Injectable Porous Hydrogel Microsphere with Paracrine Activity for Cartilage Regeneration

Abstract Paracrine is an important mechanism in mesenchymal stem cells (MSCs) that promotes tissue regeneration. However, anoikis is attributed to unsuitable adhesion microenvironment hindered this paracrine effect. In this study, a living and injectable porous hydrogel microsphere with long‐term paracrine activity is constructed via the freeze‐drying microfluidic technology and the incorporation of platelet‐derived growth factor‐BB (PDGF‐BB) and exogenous MSCs. Benefiting from the porous structure and superior mechanical property of methacrylate gelatin (GelMA) hydrogel microspheres (GMs), exogenous stem cells are able to adhere and proliferate on GMs, thereby facilitating cell‐to‐extracellular matrix (ECM) and cell‐to‐cell interactions and enhancing paracrine effect. Furthermore, the sustained release of PDGF‐BB can recruit endogenous MSCs to prolong the paracrine activity of the living GMs. In vitro and in vivo experiments validated that the living GMs exhibit superior secretion properties and anti‐inflammatory efficacy and can attenuate osteoarthritis (OA) progression by favoring the adherent microenvironment and utilizing the synergistic effect of exogenous and endogenous MSCs. Overall, a living injectable porous hydrogel microsphere that can enhance the paracrine activity of stem cells is fabricated and anticipated to hold the potential of future clinical translation in OA and other diseases.