Sustained oxygen-releasing hydrogel implants enhance flap regeneration by promoting mitochondrial biogenesis under mild hypoxia

In regenerative medicine, effective management of tissue ischemia in surgical skin flaps is crucial, yet challenging, particularly because inadequate blood flow often leads to necrosis at the distal flap tips. This study aimed to examine the therapeutic potential of catalase-coated oxygen-generating microparticles embedded in gelatin methacryloyl (cOMP-GelMA) hydrogel to establish an optimized environment conducive to tissue regeneration. Using a large 3 × 9 cm² rat random-pattern skin flap model, flap survival and regeneration were evaluated across four groups: control, pure GelMA hydrogel, and cOMP-GelMA hydrogel with two concentrations of cOMPs (0.2 % and 0.5 % w/v). These findings revealed that cOMP-GelMA comprising 0.2 % OMP significantly enhanced angiogenesis, arteriogenesis, mitochondrial biogenesis, and antioxidant capacity compared to 0.5 % cOMP-GelMA. Furthermore, the alleviation of the inflammatory response was more pronounced at lower cOMP concentrations than at higher concentrations. These results demonstrate that mild hypoxia, facilitated by moderate oxygen delivery, is beneficial for tissue repair and regeneration through peroxisome proliferator-activated receptor gamma coactivator 1-alpha- and hypoxia-inducible factor 1-alpha-dependent signaling pathways. This study highlights the innovative aspect of using a large-scale model to explore the therapeutic benefits of mild hypoxia and suggests that controlled oxygen delivery by cOMPs can improve the long-term functional recovery of ischemic tissues.