In diabetic wounds, the overexpression of reactive oxygen species (ROS) and the imbalance of the immune microenvironment surrounding immune cells, such as macrophages, can trigger a vicious cycle of inflammation in the wound area, a key factor contributing to impaired wound healing. To effectively address this challenge, this study innovatively harnessed the chelation-synergistic effect between strontium (Sr) ions, which possess immune-regulating functions, and curcumin (Cur), which exhibits antioxidant properties, to develop and design silicified strontium-curcumin chelated nanospheres (Sr-Cur NPs) with dual functions of anti-ROS and immune regulation. Subsequently, these nanospheres were formulated into a composite hydrogel (Sr-Cur@Alg) using sodium alginate. Sr-Cur@Alg successfully blocks the inflammatory vicious cycle formed by macrophages and endothelial cells under diabetic pathological conditions through TLR4/MyD88/NF-кB pathway. Specifically, it prevents macrophages in the M1 polarization state from further inducing endothelial cells to secrete large amounts of ROS, while also blocking the adverse effects of endothelial cells in this state on the continuous M1 polarization of macrophages. This innovative strategy accelerates the healing of diabetic wounds, ultimately presenting a promising therapeutic avenue for their management.

Muscle necrosis and angiogenesis are two major challenges in the treatment of lower-limb ischemic diseases. In this study, a triple-functional Sr/Si-containing bioceramic/alginate composite hydrogel with simultaneous bioactivity in enhancing angiogenesis, regulating inflammation, and inhibiting muscle necrosis was designed to treat lower-limb ischemic diseases. In particular, sodium alginate, calcium silicate and strontium carbonate were used to prepare injectable hydrogels, which was gelled within 10 min. More importantly, this composite hydrogel sustainedly releases bioactive Sr2+ and SiO32- ions within 28 days. The biological activity of the bioactive ions released from the hydrogels was verified on HUVECs, SMCs, C2C12 and Raw 264.7 cells in vitro, and the therapeutic effect of the hydrogel was confirmed using C57BL/6 mouse model of femoral artery ligation in vivo. The results showed that the composite hydrogel stimulated angiogenesis, developed new collateral capillaries, and re-established the blood supply. In addition, the bioactive hydrogel directly promoted the expression of muscle-regulating factors (MyoG and MyoD) to protect skeletal muscle from necrosis, inhibited M1 polarization, and promoted M2 polarization of macrophages to reduce inflammation, thereby protecting skeletal muscle cells and indirectly promoting vascularization. Our results indicate that these bioceramic/alginate composite bioactive hydrogels are effective biomaterials for treating hindlimb ischemia and suggest that biomaterial-based approaches may have remarkable potential in treating ischemic diseases.

Background: Aortic dissection (AD) is one of the most lethal cardiovascular diseases and is primarily characterised by phenotypic switching of various cell types with heterogeneous origins in the aortic wall. This study aimed to investigate the most disease-relevant cell populations and their molecular characteristics as potential therapeutic targets in the pathogenesis of AD.Methods: Single-cell RNA sequencing (scRNA-seq) analysis was performed on 47,303 cells from six participants to uncover the landscape of cell populations in AD. Phenotype-specific cell subpopulations and molecular signatures were investigated by integrating single-cell transcriptomes with publicly accessible bulk gene expression profiles.Findings: Our study provides a comprehensive landscape of the microenvironment in the dissected aorta and its normal counterpart at single-cell resolution. We uncovered five major macrophage populations in the aorta and established their gene expression signatures. Integrating bulk and scRNA-seq data yielded a subset of phenotype-specific macrophages that expressed a high level of CXCL3. Importantly, phenotype-specific macrophages were demonstrated to promote neutrophil activation, chemotaxis, and degranulation through the CXCL3/CXCR2 axis, which may further perpetuate inflammation and deteriorate the immune microenvironment during AD pathogenesis.Interpretation: Inflammatory and atherosclerosis-like macrophages are phenotype-specific and the most disease-relevant cell populations in AD, which may aggravate the disease through promoting neutrophil activation, chemotaxis, and degranulation through the CXCL3/CXCR2 axis.Funding Information: This work was supported by the National Natural Science Foundation of China (grant number: 81970412), Science and Technology Innovation Plan of Shanghai Science and Technology Commission (grant number: 18441902400), Xiamen Municipal Health Science and Technology Program Fund (grant number: 3502Z20194034).Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Ethics Approval Statement: This study was approved by the Ethics Committee of Zhongshan Hospital of Fudan University (IRB number B2019-231R). Healthy normal aortas and dissected aortas were collected from participants with informed written consent, and under approval of local medical ethnics from Zhongshan Hospital Fudan University.