Wenqian Zhang

Healing skin wounds with anatomic and functional integrity, especially under chronic pathological conditions, remain an enormous challenge. Due to their outstanding regenerative potential, mesenchymal stem cells (MSCs) have been explored in many studies to determine the healing ability for difficult-to-treat diseases. In this article, we review current animal studies and clinical trials of MSC-based therapy for chronic wounds, and discuss major challenges that confront future clinical applications. We found that a wealth of animal studies have revealed the versatile roles and the benefits of MSCs for chronic wound healing. MSC treatment results in enhanced angiogenesis, facilitated reepithelialization, improved granulation, and accelerated wound closure. There are some evidences of the transdifferentiation of MSCs into skin cells. However, the healing effect of MSCs depends primarily on their paracrine actions, which alleviate the harsh microenvironment of chronic wounds and regulate local cellular responses. Consistent with the findings of preclinical studies, some clinical trials have shown improved wound healing after transplantation of MSCs in chronic wounds, mainly lower extremity ulcers, pressure sores, and radiation burns. However, there are some limitations in these clinical trials, especially a small number of patients and imperfect methodology. Therefore, to better define the safety and efficiency of MSC-based wound therapy, large-scale controlled multicenter trials are needed in the future. In addition, to build a robust pool of clinical evidence, standardized protocols, especially the cultivation and quality control of MSCs, are recommended. Altogether, based on current data, MSC-based therapy represents a promising treatment option for chronic wounds. Impact statement Chronic wounds persist as a significant health care problem, particularly with increasing number of patients and the lack of efficient treatments. The main goal of this article is to provide an overview of current status of mesenchymal stem cell (MSC)-based therapy for chronic wounds. The roles of MSCs in skin wound healing, as revealed in a large number of animal studies, are detailed. A critical view is made on the clinical application of MSCs for lower extremity ulcers, pressure sores, and radiation burns. Main challenges that confront future clinical applications are discussed, which hopefully contribute to innovations in MSC-based wound treatment.

The clinical applications of currently used photosensitizers are limited by high costs, inconvenient preparation, suboptimal biodegradability, and a lack of biological activity. Humic acids (HAs) show photothermal activity and can be used as a photosensitizer for photothermal therapy. In the presence of various functional groups, HAs are endowed with anti-inflammatory and antioxidant activities. The solubility of HAs is dependent on the pH value, which is soluble in neutral to alkaline conditions and undergoes a conformational change to a coiled and compact structure in acidic conditions. Additionally, Cu2+ is an emerging therapeutic agent for cutaneous wounds and can be chelated by HAs to form complexes. In this study, we explore the ability of HAs to modulate the inflammatory response, particularly macrophage polarization, and the potential underlying mechanism. We fabricate a near-infrared (NIR)/pH dual-responsive Cu-HAs nanoparticle (NP)-based poly(vinyl alcohol) (PVA) hydrogel film loaded with SEW2871 (SEW), a macrophage recruitment agent, to treat bacteria-infected cutaneous wounds. The results show that HAs could promote M2 macrophage polarization in a dose-dependent manner. The Cu-HAs NPs successfully eradicated bacterial infection through NIR-induced local hyperthermia. This PVA@Cu-HAs NPs@SEW hydrogel film improves tissue regeneration by promoting M2 macrophage polarization, alleviating oxidative stress, enhancing angiogenesis, and facilitating collagen deposition. These findings highlight the therapeutic potential of PVA@Cu-HAs NPs@SEW hydrogel film for the treatment of bacterially infected cutaneous wound healing.

Abstract The drug‐resistant bacterial‐infected skin wound is still a severe healthcare problem. Uncontrolled bacterial infection, abundant reactive oxygen species (ROS) content, and prolonged inflammatory response are detrimental to wound healing. Moreover, excessive vessel growth can result in unsatisfactory scar formation. Herein, a three‐step regenerative strategy based on a bilayered gelatin/acryloyl β ‐cyclodextrin (BGACD) hydrogel containing physical host–guest complexations and chemical crosslinks is proposed. The hydrogel is loaded with humic acids (HAs) and astragaloside IV (AS) in the lower layer and verteporfin (Vt) in the upper layer. Different gelatin/acryloyl β ‐cyclodextrin ratios endow the lower and upper layers of the hydrogel with different degradation rates. Under light irradiation, the combination of HAs‐induced photothermal therapy (PTT) and verteporfin‐induced photodynamic therapy effectively inhibits MRSA growth. The HAs and astragaloside IV are released from the lower layer to scavenge ROS and promote M2 macrophage polarization and angiogenesis during the inflammation and early proliferation phases, while verteporfin releases from the upper layer suppress excessive vessel growth during the late proliferation and remodeling phases. The HAs‐AS@Vt@BGACD hydrogel successfully achieves rapid and scarless wound healing in an MRSA‐infected wound model in rats. Therefore, the HAs‐AS@Vt@BGACD hydrogel shows promising potential for the treatment of drug‐resistant bacteria‐infected skin wound healing.

Abstract Atmospheric nitrous acid (HONO) chemistry is of critical importance to air quality during polluted haze events, especially in China. However, current air quality models (such as WRF-CHEM, WRF-CMAQ, Box-MCM) generally underestimate the concentration of HONO, leading to a lack of fundamental understanding of haze pollution. Here, by combining field observations during haze events in Beijing and modeling results, we developed the new parameterization scheme for heterogeneous nitrogen dioxide (NO 2 ) reaction on aerosol surfaces with the synergistic effects of relative humidity and ammonia, which has not been considered in existing air quality models. Including NO 2 heterogeneous reactions into modeling significantly improves the estimation accuracy of HONO and OH levels, with the contribution reaching up to 91% and 78% during pollution episodes. The OH derived by HONO can partly explain high concentrations of particulate matter. Together, our work provides a new approach to illustrate the formation of HONO, OH, and haze with the consideration of heterogeneous NO 2 → HONO chemistry.