Advances in regenerative medicine increasingly demand biofabrication platforms that are not only biocompatible but also safe and compliant with clinical and regulatory expectations. Here, we present a new class of photoinitiator-free hydrogels based on light-induced [2+2] cycloaddition of conjugated double bonds integrated within modified biopolymers. This approach eliminates the use of traditional photoinitiators, whose cytotoxic degradation by-products pose a significant limitation to clinical translation.

Natural polymers were functionalized with photo-responsive moieties such as coumarin, cinnamic acid, and vinylbenzoic acid through carbodiimide-mediated coupling reactions, resulting in a library of hybrid biomaterials with tunable physical and chemical properties. These Clean-Cure hydrogels demonstrated efficient UV-Vis-induced crosslinking, excellent printability for 3D bioprinting applications, and favorable rheological characteristics tailored for extrusion-based systems.

Extensive in vitro evaluation confirmed their high cytocompatibility (MTT assay), minimal genotoxicity (comet assay), and photoprotective effects for embedded cells. Constructs maintained structural integrity while supporting cell viability over time, as assessed by FDA/PI live-dead staining and microscopy. Importantly, the materials fulfill key safety and performance criteria expected of next-generation scaffolds, supporting their alignment with ISO 10993 guidelines and EMA/FDA translational pathways.

This initiator-free strategy provides a robust and safer alternative for clinical-grade hydrogel development, positioning the Clean-Cure series as a promising platform for tissue engineering, advanced bioprinting, and medical device integration. These materials offer a new paradigm in scaffold design—merging biological relevance with regulatory readiness.