Curcumin-incorporated 3D bioprinting gelatin methacryloyl hydrogel reduces reactive oxygen species-induced adipose-derived stem cell apoptosis and improves implanting survival in diabetic wounds

Abstract

Background Gelatin methacryloyl (GelMA) hydrogels loaded with stem cells have proved to be an effective clinical treatment for wound healing. Advanced glycation end product (AGE), interacting with its particular receptor (AGER), gives rise to reactive oxygen species (ROS) and apoptosis. Curcumin (Cur) has excellent antioxidant activity and regulates intracellular ROS production and apoptosis. In this study, we developed a Cur-incorporated 3D-printed GelMA to insert into adipose-derived stem cells (ADSCs) and applied it to diabetic wounds. Methods GelMA hydrogels with Cur were fabricated and their in vitro effects on ADSCs were investigated. We used structural characterization, western blot, ROS and apoptosis assay to evaluate the antioxidant and anti-apoptotic activity, and assessed the wound healing effects to investigate the mechanism underlying regulation of apoptosis by Cur via the AGE/AGER/nuclear factor-κB (NF-κB) p65 pathway. Results A 10% GelMA scaffold exhibited appropriate mechanical properties and biocompatibility for ADSCs. The circular mesh structure demonstrated printability of 10% GelMA and Cur-GelMA bioinks. The incorporation of Cur into the 10% GelMA hydrogel showed an inhibitory effect on AGEs/AGER/NF-κB p65-induced ROS generation and ADSC apoptosis. Furthermore, Cur-GelMA scaffold promoted cell survival and expedited in vivo diabetic wound healing. Conclusions The incorporation of Cur improved the antioxidant activity of 3D-printed GelMA hydrogel and mitigated AGE/AGER/p65 axis-induced ROS and apoptosis in ADSCs. The effects of scaffolds on wound healing suggested that Cur/GelMA-ADSC hydrogel could be an effective biological material for accelerating wound healing.

Different Curcumin-Loaded Delivery Systems for Wound Healing Applications: A Comprehensive Review

“…The loaded curcumin mitigated ROS production and enhanced the healing process. The loaded stem cells augmented the role of curcumin in improving the wound healing properties [ 129 ]. Clinical studies should be carried out for more investigations.…”

Adipose-Derived Stem Cells for the Treatment of Diabetic Wound: From Basic Study to Clinical Application

“…The combination of ASCs and acellular dermal matrix (ADM) can also enhance wound repair in diabetic mice models, in which ADM support the proliferation and growth of ASCs ( 61 , 77 ). Besides, artificial engineered scaffolds such as gelatin gel, artificial dermis, and porous polymer ultrathin films have been studied as ASCs delivering technologies ( 78 , 79 , 81 , 82 ). A bioprinted gelatin methacryloyl hydrogel scaffolds has been shown to present a higher resistance to anoxic environment ( 82 ).…”

“…Besides, artificial engineered scaffolds such as gelatin gel, artificial dermis, and porous polymer ultrathin films have been studied as ASCs delivering technologies ( 78 , 79 , 81 , 82 ). A bioprinted gelatin methacryloyl hydrogel scaffolds has been shown to present a higher resistance to anoxic environment ( 82 ). This indicated that artificial scaffold delivery system may become a future choice in refractory wounds treatment, especially in diabetic wounds.…”

“…As the survival rate of ASCs is limited in traditional injection, biological scaffolds cell delivery systems provide appropriate environment for cell adhesion, proliferation, and differentiation (73,74). In recent studies, ASCs can be delivered by nanosheets, artificial gel, artificial dermis, cell matrix derived hydrogels, silk fibroin, acellular dermal matrix based and gene-activated scaffolds (49,52,61,(75)(76)(77)(78)(79)(80)(81)(82)(83). Natural scaffolds are becoming popular because of the well biocompatibility.…”

Application of Metal–Organic Framework in Diagnosis and Treatment of Diabetes

“…Many exogenous antioxidants can protect the body from the oxidative damage caused by excessive production of ROS, such as alpha-lipoic acid, curcumin, green tea, polyphenols, etc. [ 157 , 158 ]. For example, the study showed that α-lipoic acid may restore the endothelial cell function disrupted by hyperglycemia through the 3-MST/H 2 S pathway.…”