Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1β, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.

The continuous imbalance of the diabetic wound microenvironment is an important cause of chronic nonhealing, which manifests as a vicious cycle between excessive accumulation of reactive oxygen species (ROS) and abnormal healing. Regulating the microenvironment by suppressing wound inflammation, oxidative stress, and bacterial infection is a key challenge in treating diabetic wounds. In this study, ROS‐responsive hydrogels are developed composed of silk fibroin methacrylated (SFMA), modified collagen type III (rCol₃MA), and lipid nanoparticles (LNPs). The newly designed hydrogel system demonstrated stable physicochemical properties and excellent biocompatibility. Moreover, the release of antimicrobial peptide (AMP) and puerarin (PUE) demonstrated remarkable efficacy in eradicating bacteria, regulating inflammatory responses, and modulating vascular functions. This multifunctional hydrogel is a simple and efficient approach for the treatment of chronic diabetic infected wounds and holds tremendous potential for future clinical applications.

Treatment of chronic wounds using traditional surgical procedures is challenging because of the low graft take rates. This study investigated the combination approach of split-thickness autografts with harvested skin cell suspension for chronic wound treatment. This randomized clinical trial enrolled patients with chronic wounds between March 2012 and December 2013. Patients who were assigned randomly to the active treatment received a split-thickness autograft combined with harvested skin cell suspension. Control patients received the split-thickness autograft alone. The primary outcome was the rate of complete wound closure by postoperative day 28. Analysis was by intention to treat. Patients who achieved wound closure were followed up for a minimum of 6 months to evaluate the quality of healing. A total of 88 patients were included, 44 in each group. More patients achieved complete wound closure in the skin cell group than in the control group (41 versus 34 patients; P = 0·035). Complete wound closure was observed at a median of 14 (95 per cent c.i. 12·0 to 16·0) days in the skin cell group and 20 (15·7 to 24·3) days in the control group (P = 0·001). The skin cell group had significantly fewer complications (4 versus 11 patients; P = 0·047). The autografted sites displayed better physical attributes and a reduced tendency for wound recurrence in the skin cell group. Complementary split-thickness autologous skin grafting with autologous skin cells harvested using ReCell® (Avita Medical, Cambridge, UK) technology improved the healing rate of chronic wounds. Registration number: UMIN000011966 (http://www.umin.ac.jp/ctr).

Diabetic wound healing remains a significant clinical challenge because of hyperglycaemia-induced cellular senescence, impaired angiogenesis, and chronic inflammation. To address these issues, we developed a multifunctional hydrogel (GelMA/PNS/Alg@IGF-1) that integrates gelatine methacryloyl (GelMA), Panax notoginseng saponins (PNS), and sodium alginate microspheres encapsulating insulin-like growth factor-1 (IGF-1). This hydrogel was engineered to achieve gradient and sustained release of bioactive agents to target senescence and promote vascular repair. In vitro studies demonstrated that the hydrogel significantly reduced oxidative stress, suppressed senescence markers and senescence-associated secretory phenotypes, and restored endothelial cell function under high-glucose conditions by inhibiting NF-κB pathway activation. Transcriptomic analysis revealed the modulation of pathways linked to inflammation, apoptosis, and angiogenesis. This hydrogel accelerated diabetic wound closure in a rat model in vivo and enhanced collagen deposition, granulation tissue formation, and neovascularization. Furthermore, the hydrogel mitigated oxidative stress and cellular senescence and promoted tissue remodelling. The synergistic effects of PNS and IGF-1 within the hydrogel established a pro-regenerative microenvironment to address both pathological ageing and vascular dysfunction. These findings highlight GelMA/PNS/Alg@IGF-1 as a promising therapeutic platform for diabetic wound management, as this material offers dual anti-senescence and proangiogenic efficacy to overcome the complexities of chronic wound healing.