The Role of Intermediate Water in Enhancing Blood and Cellular Compatibility of Chitosan-Based Biomaterials

Tissue engineering and regenerative medicine require biomaterials that balance blood compatibility with cell adhesion, proliferation, and differentiation. Chitosan and its derivatives, owing to their biocompatibility, biodegradability, and functional versatility, have been extensively explored for biomedical applications, including vascular grafts and tissue engineering scaffolds. This study investigates the effect of chemical modifications on the water state of chitosan derivatives─specifically, free water (FW), intermediate water (IW), and nonfreezing water (NFW)─and their implications for protein interactions, platelet adhesion, and mesenchymal stem cell (MSC) behavior. By incorporating hydrophilic and hydrophobic groups, the hydration of chitosan derivatives was precisely controlled, which significantly influenced blood compatibility and cell adhesion. Hexanoyl glycol chitosan (HGC) demonstrated reduced platelet adhesion, low fibrinogen denaturation, and favorable MSC adhesion, making it a promising candidate for applications requiring both enhanced blood compatibility and regenerative potential. These findings underscore the importance of hydration water modulation in designing advanced biomaterials for blood-contacting and regenerative medicine applications.