From Gelatin to GelMA: Versatility, Challenges, and Biomedical Applications of GelMA Hydrogels

Gelatin is a natural biopolymer derived from collagen and is widely employed in biomedical applications because of its biocompatibility, biodegradability, low toxicity, water solubility, and intrinsic thermo-responsive gelation behavior. Owing to the presence of bioactive motifs and its ability to form hydrogels under mild conditions, gelatin has emerged as a promising material for tissue engineering, drug delivery, and in vitro modeling. However, the poor mechanical stability and rapid dissolution of native gelatin under physiological conditions limit its direct use in advanced biomedical systems. To overcome these drawbacks, several chemical modification strategies have been developed, among which gelatin methacryloyl (GelMA) is one of the most investigated derivatives. GelMA combines the biological advantages of gelatin with photo-crosslinkable methacryloyl groups, enabling the fabrication of stable hydrogels with tunable mechanical, rheological, and degradation properties. This review adopts a source-to-performance perspective, systematically examining how gelatin origin, processing history, molecular characteristics, and Bloom strength may influence GelMA functionalization and subsequent hydrogel network formation. Particular attention is given to Type A and Type B gelatin, while recognizing that this classification does not fully capture the variability in the gelatin precursor. The review critically discusses how precursor characteristics interact with key synthesis and formulation parameters, including the degree of substitution/functionalization (DS/DoF), polymer concentration, photoinitiator content, and photo-crosslinking conditions, ultimately affecting network formation and the mechanical, rheological, swelling, porosity, degradation, and biological properties of GelMA hydrogels. This interconnected view highlights how variability introduced at the precursor level may propagate through functionalization and crosslinking, contributing to differences in GelMA performance and limiting direct comparison among reported formulations. The implications of these material-dependent properties are examined across three major biomedical application areas: tissue engineering, controlled drug delivery, and physiologically relevant three-dimensional in vitro models. Finally, current challenges and emerging opportunities related to GelMA standardization, biofabrication, multifunctional hydrogel design, personalized medicine, and clinical translation are considered. Overall, GelMA is presented not simply as a versatile biomaterial, but as a tunable protein-derived platform whose performance depends on the interconnected effects of precursor characteristics, functionalization, formulation, and network formation.