Digestion-free approach towards the generation of ECM-based sol-gel systems

Extracellular matrix (ECM)–derived biomaterials are essential for regenerative medicine, tissue engineering, and advanced tissue modeling. Conventional methods for generating ECM-based sol–gel systems rely on enzymatic or chemical digestion, which often com-promises native protein structure and functionality. This study aimed to establish a digestion-free strategy for preparing ECM sol–gels. We exploited the swelling of ECM proteins in chaotropic agent–containing media to obtain stable dispersions (sols). Hya-luronic acid was introduced as a sacrificial gel medium, enabling efficient removal of chaotropic agents while maintaining dispersion stability. The method was validated using both a simple matrix (rat tail tendon, a conventional source of collagen I) and a complex matrix (porcine skin). The process was governed by viscosity-driven stabili-zation: dispersion efficiency was proportional to protein concentration and inversely proportional to processing temperature. Atomic force microscopy (AFM) topography analysis confirmed sol–gel transition and demonstrated restoration of collagen micro-structure and fibrillar networks to a native-like state. Collectively, these findings establish a versatile, digestion-free approach to producing biocompatible ECM sol–gel systems suitable for various applications.