In Vitro Engineered ECM‐incorporated Hydrogels for Osteochondral Tissue Repair: A Cell‐Free Approach

Abstract Prevalence of osteoarthritis has been increasing in aging populations, which has necessitated the use of advanced biomedical treatments. These involve grafts or delivering drug molecules entrapped in scaffolds. However, such treatments often show suboptimal therapeutic effects due to poor half‐life and off‐target effects of drug molecules. As a countermeasure, a 3D printable robust hydrogel‐based tissue‐repair platform is developed containing decellularized extracellular matrix (dECM) from differentiated mammalian cells as the therapeutic cargo. Here, pre‐osteoblastic and pre‐chondrogenic murine cells are differentiated in vitro, decellularized, and incorporated into methacrylated gelatin (GelMA) solutions to form osteogenic (GelO) and chondrogenic (GelC) hydrogels, respectively. Integrating the bioactive dECM from differentiated cell sources allows GelO and GelC to induce differentiation in human adipose‐derived stem cells (hASCs) toward osteogenic and chondrogenic lineages. Further, GelO and GelC can be covalently adhered using a carbodiimide coupling reaction, forming a multi‐layered hydrogel with potential application as a bioactive osteochondral plug. The designed multi‐layered hydrogel can also induce differentiation of hASCs in vitro. In conclusion, the bioactive dECM carrying 3D printed robust hydrogel offers a promising new drug and cell‐free therapeutic strategy for bone and cartilage repair and future osteoarthritis management.