A promising trend in tissue engineering is using biomaterials to improve the control of drug concentration in targeted tissue. These vehicular systems are of specific interest when the required treatment time window is higher than the stability of therapeutic molecules in the body. Herein, the capacity of silk fibroin hydrogels to release different molecules and drugs in a sustained manner was evaluated. We found that a biomaterial format, obtained by an entirely aqueous-based process, could release molecules of variable molecular weight and charge with a preferential delivery of negatively charged molecules. Although the theoretical modeling suggested that drug delivery was more likely to be driven by Fickian diffusion, the external media had a considerable influence on the release, with lipophilic organic solvents such as acetonitrile-methanol (ACN-MeOH) intensifying the release of hydrophobic molecules. Second, we found that silk fibroin could be used as a vehicular system to treat a variety of brain disorders as this biomaterial sustained the release of different factors with neurotrophic (brain-derived neurotrophic factor) (BDNF), chemoattractant (C-X-C motif chemokine 12) (CXCL12), anti-inflammatory (TGF-β-1), and angiogenic (VEGF) capacities. Finally, we demonstrated that this biomaterial hydrogel could release cholesteronitrone ISQ201, a nitrone with antioxidant capacity, showing neuroprotective activity in an in vitro model of ischemia-reoxygenation. Given the slow degradation rate shown by silk fibroin in many biological tissues, including the nervous system, our study expands the restricted list of drug delivery-based biomaterial systems with therapeutic capacity for both short- and especially long-term treatment windows and has merit for use with brain pathologies.

We thank Soledad Martinez for the excellen ttechnical assistance and Alejandro Escobar-Peso for his assistance in neuronal culture experiments. This study was partially funded by the Ministerio de Ciencia e Innovación (PID2020-116403RB-I00, funded by MCIN/AEI/10.13039/501100011033), the Comunidad de Madrid (IND2018/BMD-9804, MINA-CM-S2022/BMD-7236, IND2023/BMD-28865, PIPF-2022_SAL-GL2512, and PEJ-2019-AI/SAL-12703), the European Union’s EIC-Pathfinder Program under the projects THOR (grant agreement number 101099719) and ISOS (grant agreement number 101130454), and funded by the Instituto de Salud Carlos III and cofunded by the European Regional Development Fund (FEDER) (project RD21/0006/0019).

Peer reviewed