**4. Conclusions**

Gelatin based hydrogels are currently the focus of much interest in di fferent fields of biomedical relevance. Even the raw material from di fferent sources including fish skin has been described to have a potential for cell therapies for cutaneous wound, [24] whereas crosslinked gelatin hydrogels or gelatin blends hydrogel have been developed for three-dimensional (3D) cell culture platform [45]. The possibility to use gelatin based hydrogels as carrier for the controlled release of biologically active unstable compounds further adds to the opportunities o ffered by this system. In this frame the present work explored the potential of gelatin from porcine skin and cross-linked gelatin (HGel-B) or chitosan/gelatin blends (HGel-C) to incorporate DHICA, a melanin-related metabolite endowed with marked antioxidant and cell di fferentiation stimulation activity and its methyl ester, a more stable compound with a remarkable antioxidant profile. Both indole compounds were e ffectively incorporated into the pristine gelatin hydrogels and were smoothly released in PBS at pH 7.4, whereas only DHICA was released to a significant extent at pH 5.5, an observation of relevance for the implementation of devices for topical applications. Di fferent incorporation and release profiles where exhibited by the two indoles for HGel-B and HGel-C. The higher a ffinity of DHICA for HGel-C likely reflects the higher hydrophilic character of the indole and of the cross-linked gelatins itself containing substantial amounts of chitosan as evidenced by FT-IR analysis. More interestingly, gelatin-based hydrogels o ffer protection to DHICA against air oxidation. Indeed, the cross-linked gelatins incorporating the indoles exhibited a marked antioxidant activity that persisted overtime and was not lost even after prolonged

storage of the material. All together these results highlight gelatins as easily accessible biocompatible materials that could warrant a sustained release of labile bioactives under physiologically relevant conditions. The variability of the loading extent and kinetics of release of the three gelatin types investigated would sugges<sup>t</sup> that proper modification of the raw material can allow tuning of the time scale of delivery for different therapeutical applications.

**Author Contributions:** Conceptualization, A.N., L.C., L.P.; investigation, M.L.A., G.P.; writing—original draft, A.N.; writing—review editing, L.P., L.C.; supervision, A.N., L.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** SEM and ATR/FT-IR analyses were carried out by M.L.A. at the Institut de Science et d'Ingénierie Supramoléculaires (University of Strasbourg, France) in the laboratories of the research group lead by Luisa De Cola. We acknowledge the access to these facilities and Mari Carmen Ortega for analysis of data and helpful discussion.

**Conflicts of Interest:** The authors declare no conflict of interest.
