Jiayi Mao’s research while affiliated with Shanghai Jiao Tong University and other places

Skin soft‐tissue expansion, a key technique for tissue regeneration, promotes tissue repair by applying sustained mechanical tension. However, prolonged tension leads to the accumulation of apoptotic cells and impaired macrophage efferocytosis, thereby disrupting immune homeostasis and inhibiting regeneration. In this study, an ultrasound‐driven electric‐conversion hydrogel system (SHG@GBT) is developed, integrating piezoelectric heterojunctions with a reorganized hydrogel network. This system modulates macrophage efferocytosis through ultrasound‐generated electrical signals, optimizing the immune microenvironment and promoting regeneration. Piezoelectric heterojunctions are created by coupling the interfaces of graphene oxide (GO) and barium titanate (BTO) at multiple scales and are embedded in a reorganized network formed by cross‐linking oxidized hyaluronic acid and hydrazide‐modified hyaluronic acid. The mechanical compatibility of the hydrogel and the ultrasound response of the heterojunctions enhanced energy conversion efficiency, with the GO/BTO heterojunction improving BTO polarization and the GO network optimizing charge transfer. Under ultrasound stimulation, the local electric field generated by BTO activated macrophage calcium ion channels, increasing calcium influx and enhancing efferocytosis, angiogenesis, and collagen synthesis. In vivo studies have shown reduced accumulation of apoptotic cells and improved blood perfusion. This study introduces a noninvasive immune modulation strategy to optimize the efficacy and safety of skin soft tissue expansion.

Hyperglycemia and bacterial colonization in diabetic wounds aberrantly activate Nod-like receptor protein 3 (NLRP3) in macrophages, resulting in extensive inflammatory infiltration and impaired wound healing. Targeted suppression of the NLRP3 inflammasome shows promise in reducing macrophage inflammatory disruptions. However, challenges such as drug off-target effects and degradation via lysosomal capture remain during treatment. In this study, engineered apoptotic bodies (BHB-dABs) derived from adipose stem cells loaded with β-hydroxybutyric acid (BHB) were synthesized via biosynthesis. These vesicles target M1-type macrophages, which highly express the folic acid receptor in the inflammatory microenvironment, and facilitate lysosomal escape through 1,2-distearoyl-sn-propyltriyl-3-phosphatidylethanolamine–polyethylene glycol functionalization, which may enhance the efficacy of NLRP3 inhibition for managing diabetic wounds. In vitro studies demonstrated the biocompatibility of BHB-dABs, their selective targeting of M1-type macrophages, and their ability to release BHB within the inflammatory microenvironment via folic acid and folic acid receptor signaling. These nanovesicles exhibited lysosomal escape, anti-inflammatory, mitochondrial protection, and endothelial cell vascularization properties. In vivo experiments demonstrated that BHB-dABs enhance the recovery of diabetic wound inflammation and angiogenesis, accelerating wound healing. These functionalized apoptotic bodies efficiently deliver NLRP3 inflammasome inhibitors using a dual strategy of targeting macrophages and promoting lysosomal escape. This approach represents a novel therapeutic strategy for effectively treating chronic diabetic wounds.

The growing discussion on "interdisciplinary integration" brings attention to the "interprofessional education" (IPE) in the field of plastic surgery. IPE not only improves the precision and effectiveness of plastic and reconstructive surgery but also plays an important role in personalized treatment. Whereas, the implementation of IPE in plastic and reconstructive surgery field faces huge difficulties such as technology combination, standard making, and lacking of qualified talents. This article individually summarizes the latest developments in the integration of plastic and reconstructive surgery with engineering, basic science, and human science. It looks forward to the future practice and innovation of IPE in the field of plastic and reconstructive surgery, analyzes the challenges in cultivating innovative professional talents, and proposes methods to overcome these difficulties in a way that invites further discussion.

Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as “nuclear activating miRNAs” for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRT‒PCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs. Graphical abstract

Efferocytosis, by phagocytosing and processing apoptotic cells in injured skin, directly influences the immune microenvironment. However, the comprehensive widespread inflammation and disrupted efferocytosis in injured skin cannot be effectively halted. Herein, “Grid Efferocytosis” strategy within injury site is proposed, which segments the inflammation regulatory into grid microdomains, and further rectifies intra‐grid immune microenvironment to accelerate tissue repair. GelMA/PLA/Laponite gridded fiber membranes (GPL) are custom‐designed via near‐field electrostatic printing, and then coated with HAMA‐PBA/EGCG hydrogel by photo‐crosslinking and dynamic borate bonding to form a composite fiber membrane (GPL‐E). Gridded modulation via GPL‐E confines the entire chaotic inflammatory microenvironment into controllable microinflammatory niches. Leveraging the hydrogel coating and boronic ester bond dissociation induced by microenvironmental glucose and reactive oxygen species, GPL‐E achieves dynamic anti‐glucose and anti‐oxidation within microdomains, reconstructing macrophage efferocytosis. Notably, the “grid efferocytosis” recruits repair cells into the grid by magnesium ion release triggered by Laponite exposure on fibers, and enhances endothelial cell vascularization by ≈2.5‐fold. In a mouse diabetic ischemic flap model, implantation of grid GPL‐E maintains flap‐to‐base fusion, attenuates inflammatory infiltration & spread, and improves blood perfusion for flap survival. This study demonstrates that “Grid Efferocytosis” rectifies the immune microenvironment, fostering tissue repair and regeneration.

The dynamic balance between hypoxia and oxidative stress constitutes the oxygen‐related microenvironment in injured tissues. Due to variability, oxygen homeostasis is usually not a therapeutic target for injured tissues. It is found that when administered intravenously, mesenchymal stem cells (MSCs) and in vitro induced apoptotic vesicles (ApoVs) exhibit similar apoptotic markers in the wound microenvironment where hypoxia and oxidative stress co‐existed, but MSCs exhibited better effects in promoting angiogenesis and wound healing. The derivation pathway of ApoVs by inducing hypoxia or oxidative stress in MSCs to simulate oxygen homeostasis in injured tissues is improved. Two types of oxygen‐related environmental stressed ApoVs are identified that directly target endothelial cells (ECs) for the accurate regulation of vascularization. Compared to normoxic and hypoxic ones, oxidatively stressed ApoVs (Oxi‐ApoVs) showed the strongest tube formation capacity. Different oxygen‐stressed ApoVs deliver similar miRNAs, which leads to the broad upregulation of EC phosphokinase activity. Finally, local delivery of Oxi‐ApoVs‐loaded hydrogel microspheres promotes wound healing. Oxi‐ApoV‐loaded microspheres achieve controlled ApoV release, targeting ECs by reducing the consumption of inflammatory cells and adapting to the proliferative phase of wound healing. Thus, the biogenerated apoptotic vesicles responding to oxygen‐related environmental stress can target ECs to promote vascularization.

Effectively eliminating apoptotic cells is precisely controlled by a variety of signaling molecules and a phagocytic effect known as efferocytosis. Abnormalities in efferocytosis may bring about the development of chronic conditions, including angiocardiopathy, chronic inflammatory diseases and autoimmune diseases. During wound healing, failure of efferocytosis leads to the collection of apoptosis, the release of necrotic material and chronic wounds that are difficult to heal. In addition to the traditional phagocytes‐macrophages, other important cell species including dendritic cells, neutrophils, vascular endothelial cells, fibroblasts and keratinocytes contribute to wounding healing. This review summarizes how efferocytosis‐mediated immunomodulation plays a repair‐promoting role in wound healing, providing new insights for patients suffering various cutaneous wounds. image

The cellular functions, such as tissue‐rebuilding ability, can be directly affected by the metabolism of cells. Moreover, the glucose metabolism is one of the most important processes of the metabolism. However, glucose cannot be efficiently converted into energy in cells under ischemia hypoxia conditions. In this study, a high‐energy intermediate fructose hydrogel (HIFH) is developed by the dynamic coordination between sulfhydryl‐functionalized bovine serum albumin (BSA‐SH), the high‐energy intermediate in glucose metabolism (fructose‐1,6‐bisphosphate, FBP), and copper ion (Cu²⁺). This hydrogel system is injectable, self–healing, and biocompatible, which can intracellularly convert energy with high efficacy by regulating the glucose metabolism in situ. Additionally, the HIFH can greatly boost cell antioxidant capacity and increase adenosine triphosphate (ATP) in the ischemia anoxic milieu by roughly 1.3 times, improving cell survival, proliferation and physiological functions in vitro. Furthermore, the ischemic skin tissue model is established in rats. The HIFH can speed up the healing of damaged tissue by promoting angiogenesis, lowering reactive oxygen species (ROS), and eventually expanding the healing area of the damaged tissue by roughly 1.4 times in vivo. Therefore, the HIFH can provide an impressive perspective on efficient in situ cell energy supply of damaged tissue.