Chronic diabetic wounds heal poorly due to a persistently imbalanced microenvironment involving inflammation and bacterial infection. Notably, oxidative stress, driven by mitochondrial damage, perpetuates inflammation and hinders repair. Existing therapeutic materials struggle to simultaneously address infection, inflammation, and oxidative stress through combined drug delivery and targeted activation of mitophagy. To tackle these intertwined challenges, we designed a bee ovum-inspired hydrogel (BOV) that mimics the parasitic wasp egg strategy, firm host adhesion and staged bioactive secretion, to programmatically remodel the wound microenvironment. The BOV consists of a borate-ester-crosslinked hyaluronic acid network providing robust wet adhesion and self-healing properties. It encapsulates gelatin-coated ZIF-8@Myricetin (Myr) nanoparticles and polyhexamethylene biguanide (PHMB), which are released sequentially in response to the wound's acidic, high-reactive oxygen species (ROS), and high-matrix metalloproteinase-9 (MMP-9) microenvironment: PHMB first exerts antibacterial action to control infection, followed by Myricetin release to scavenge ROS and suppress inflammation. Beyond antioxidant effects, BOV further activates the SIRT1/FOXO3a/BNIP3 pathway to promote mitophagy, clearing damaged mitochondria and thereby mitigating oxidative stress at its source. In vivo, BOV reduced bacterial burden, alleviated inflammatory response, and enhanced collagen deposition, and re-epithelialization. This study translates a natural parasitic strategy into a programmable drug-delivery platform, offering a promising approach for refractory diabetic wound therapy through microenvironment-responsive sequential treatment and upstream mitochondrial homeostasis restoration.
Yanan Xue, Ying Lu, Yiran Lin et al.· Materials Today Bio· 0 citations
Diabetic foot ulcers (DFUs) are common and serious problems in diabetes patients. They also represent one of the leading causes of non-traumatic lower limb amputation worldwide. Despite improvements in clinical care, numerous standard therapies fail to completely close chronic diabetic wounds. Cell-free fat extract (Ceffe) aids tissue repair and angiogenesis but its clinical worth is greatly reduced by rapid diffusion and enzymatic degradation in the wound. Silk fibroin methacryloyl (SilMA) can be formulated into a photocrosslinked hydrogel capable of sustained delivery of bioactive factors, whereas polydopamine (pDA) provides durable wet-tissue adhesion. In this work, we developed a multifunctional composite hydrogel pSilMA@Ceffe (polydopamine-coated SilMA hydrogel loaded with Ceffe) that integrates the prolonged release properties of SilMA with the tissue-binding strength of pDA to enhance healing of refractory diabetic wounds. We prepared and characterized pSilMA@Ceffe with respect to physicochemical properties, printability, and release kinetics. Cellular assays and diabetic mouse models employed used to assess biocompatibility. Cell proliferation, migration, and tube formation were evaluated using in vitro assays, while full-thickness skin wounds in db/db mice were used to determine in vivo efficacy. Wound closure was monitored at multiple time points, and tissue regeneration was assessed via H&E, Masson's trichrome, and immunofluorescent staining for CD31, keratin 1 (K1), Ki-67, and type I collagen (Col-1). The final hydrogel had satisfactory 3D printability, stable tissue adhesion, and constant long-term release of Ceffe. It supported cell survival and significantly enhanced proliferation, migration, and angiogenic activity in culture. In diabetic mice, pSilMA@Ceffe accelerated wound healing, neovascularization, and cell proliferation, and promoted more organized collagen deposition in the regenerating dermis. Combining photocrosslinkable handling with robust pro-regenerative activity, pSilMA@Ceffe represents an effective and translatable candidate for the clinical treatment of chronic diabetic wounds.
Qinhao Gu, Ze-Xin Fu, Lu Wang et al.· Journal of Biomaterials Appl...· 0 citations
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