Generation of Probiotic‐Based Multifunctional Hydrogels Capable of Carrying Oxygen and Anti‐Inflammatory Drugs and Their Effect on Cell Viability Under Hypoxic Conditions

ABSTRACT Hypoxia and chronic inflammation have an interdependent relationship, as they stimulate each other. Under inflammation, hypoxia occurs in tissues and under hypoxia, transcription factors induce overproduction of pro‐inflammatory cytokines, causing the chronic inflammatory process. There are very few studies that combine O 2 with anti‐inflammatory agents to simultaneously reduce the effects of hypoxia and inflammation. However, despite the important role of probiotic metabolites in regulating pro‐inflammatory cytokines, none of these studies have addressed the combined use of O 2 , anti‐inflammatory agents, and probiotic metabolites to effectively inhibit the harmful effects of hypoxia and inflammation. In this context, we report a biomaterial (GA‐ Rut PMOF‐CAP) consisting of a GelMA‐Alginate (GA) hydrogel matrix incorporating rutin‐loaded, perfluorocarbon‐functionalized periodic mesoporous organosilica ( Rut PMOF) nanoparticles and probiotic‐loaded alginate microcapsules (CAP), capable of delivering sustained O 2 , probiotic‐derived metabolites, and pH‐sensitive anti‐inflammatory drug release. GA‐ Rut PMOF‐CAP, which provides approximately 90% release of the anti‐inflammatory drug (Rut) at pH 6.0, > 5% O 2 release within the first 5 days under hypoxic conditions, and release of probiotic metabolites over a 7‐day incubation period. GA‐ Rut PMOF‐CAP does not increase the production of reactive oxygen species (ROS) during 1 and 7 day incubation periods under hypoxic conditions. Furthermore, GA‐ Rut PMOF‐CAP supports cell viability under hypoxia and promotes a decrease in TNF‐α levels under LPS‐stimulated normoxic conditions; this demonstrates that GA‐ Rut PMOF‐CAP has beneficial effects on cells under inflammatory‐like conditions.