Genipin-Crosslinked Gelatin Hydrogels with Controlled Molecular Weight: A Strategy to Balance Processability and Performance

Gelatin-based hydrogels are promising materials for pharmaceutical and biomedical applications due to their biocompatibility, biodegradability, and tunable gel-forming behavior. However, their thermo-sensitivity and limited processability often restrict their practical use in advanced drug delivery or tissue engineering systems. In this study, low-molecular-weight gelatin (LMWG) was obtained from native gelatin through controlled degradation with hydroxylamine, aiming to enhance processability while maintaining functional amino groups for crosslinking. Hydrogels prepared from both native gelatin and LMWG were crosslinked with genipin, a natural and biocompatible compound, and comprehensively characterized in terms of structural, mechanical, and biological properties. LMWG exhibited superior processability, remaining liquid at room temperature, which facilitates the preparation of different formulations and the potential incorporation of bioactive compounds into the crosslinked hydrogels. Compared with gelatin-genipin hydrogels, LMWG-genipin hydrogels showed higher swelling capacity, slightly increased porosity, and improved flexibility without significant loss of mechanical integrity. Rheological analysis confirmed both hydrogels’ viscoelastic properties with differences in their thermo-sensitive behavior. Cytocompatibility assays using L929 fibroblasts demonstrated low toxicity as well as proliferation of cells seeded on the materials. Overall, the combination of molecular weight modulation and crosslinking by genipin provides a simple and effective strategy to develop gelatin-based hydrogels suitable for pharmaceutical formulations, tissue-engineering scaffolds, and controlled-release systems.