Tuning Collagen Molecular Aggregation Behavior: Solvent Shielding in a Biphasic Polar System for Oxidized Sodium Alginate-Mediated Cross-Linking

Precise regulation of the collagen molecular aggregation behavior is an indispensable prerequisite for constructing functional collagen-based biomaterials. This study innovatively proposes a sustainable strategy to tune collagen molecular aggregation behavior using oxidized sodium alginate (OSA) as a cross-linker within a biphasic acetic acid/1-ethyl-3-methylimidazolium acetate solvent system. Such a polar solvent environment effectively shields electrostatic interactions between OSA and collagen, resulting in a homogeneous cross-linked network. The results indicated that the critical aggregation concentration of collagen was 1.70 mg/mL in the AA/[EMIM][Ac] solvent system and revealed a [NH₂]/[CHO] ratio-governed aggregation transition. Beyond the threshold ratio of 1:20, OSA exhibited optimal cross-linking efficiency, thereby driving the formation of large-sized collagen aggregates. Finally, molecular docking simulations of the binding interactions between collagen and OSA were conducted to validate the experimental findings. This work affords a practical methodology for developing high-performance OSA-mediated collagen-based biomaterials while achieving the biological resources transformation and valorization.