Background: Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing.Results: We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing.Conclusions: PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing.Graphic

The treatment of diabetic wounds remains a major challenge in clinical practice, with chronic wounds characterized by multiple drug‐resistant bacterial infections, angiopathy, and oxidative damage to the microenvironment. Herein, a novel in situ injectable HA@MnO₂/FGF‐2/Exos hydrogel is introduced for improving diabetic wound healing. Through a simple local injection, this hydrogel is able to form a protective barrier covering the wound, providing rapid hemostasis and long‐term antibacterial protection. The MnO₂/ε‐PL nanosheet is able to catalyze the excess H₂O₂ produced in the wound, converting it to O₂, thus not only eliminating the harmful effects of H₂O₂ but also providing O₂ for wound healing. Moreover, the release of M2‐derived Exosomes (M2 Exos) and FGF‐2 growth factor stimulates angiogenesis and epithelization, respectively. These in vivo and in vitro results demonstrate accelerated healing of diabetic wounds with the use of the HA@MnO₂/FGF‐2/Exos hydrogel, presenting a viable strategy for chronic diabetic wound repair.

Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.

Background: Studies of the novel coronavirus-induced disease COVID-19 in Wuhan, China, have elucidated the epidemiological and clinical characteristics of this disease in the general population. The present investigation summarizes the clinical characteristics and early prognosis of COVID-19 infection in a cohort of patients with fractures. Methods: Data on 10 patients with a fracture and COVID-19 were collected from 8 different hospitals located in the Hubei province from January 1, 2020, to February 27, 2020. Analyses of early prognosis were based on clinical outcomes and trends in laboratory results during treatment. Results: All 10 patients presented with limited activity related to the fracture. The most common signs were fever, cough, and fatigue at the time of presentation (7 patients each). Other, less common signs included sore throat (4 patients), dyspnea (5 patients), chest pain (1 patient), nasal congestion (1 patient), headache (1 patient), dizziness (3 patients), abdominal pain (1 patient), and vomiting (1 patient). Lymphopenia (<1.0 × 10⁹ cells/L) was identified in 6 of 10 patients, 9 of 9 patients had a high serum level of D-dimer, and 9 of 9 patients had a high level of C-reactive protein. Three patients underwent surgery, whereas the others were managed nonoperatively because of their compromised status. Four patients died on day 8 (3 patients) or day 14 (1 patient) after admission. The clinical outcomes for the surviving patients are not yet determined. Conclusions: The clinical characteristics and early prognosis of COVID-19 in patients with fracture tended to be more severe than those reported for adult patients with COVID-19 without fracture. This finding may be related to the duration between the development of symptoms and presentation. Surgical treatment should be carried out cautiously or nonoperative care should be chosen for patients with fracture in COVID-19-affected areas, especially older individuals with intertrochanteric fractures. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.