Multifunctional nanozyme-embedded hydrogels for advanced diabetic wound management.

Cutaneous wound healing, especially diabetic wound healing, is a common clinical challenge. Reactive oxygen species (ROS) and bacterial infection are two major detrimental states that induce oxidative stress and inflammatory responses and impede angiogenesis and wound healing. A derivative of the metabolite itaconate, 4-octyl itaconate (4OI) has attracted increasing research interest in recent years due to its antioxidant and anti-inflammatory properties. In this study, 4OI-modified black phosphorus (BP) nanosheets are incorporated into a photosensitive, multifunctional gelatin methacrylamide hydrogel to produce a new photothermal therapy (PTT) and photodynamic therapy (PDT) system with antibacterial and antioxidant properties for diabetic wound regeneration. Under laser irradiation, the 4OI-BP-entrapped hydrogel enables rapid gelation, forming a membrane on wounds, and offers high PTT and PDT efficacy to eliminate bacterial infection. Without laser irradiation, BP acts as a carrier and controls the release of 4OI, with which it synergistically enhances antioxidant activity, thus alleviating excessive ROS damage to endothelial cells, promoting neovascularization, and facilitating faster diabetic wound closure. These findings indicate that 4OI-BP-entrapped multifunctional hydrogel provides a stepwise countermeasure with antibacterial and antioxidant properties for enhanced diabetic wound healing and may lead to novel therapeutic interventions for diabetic ulcers.

A Zn-MOF-GOx-based cascade nanoreactor promotes diabetic infected wound healing by NO release and microenvironment regulation

The treatment of diabetic chronic wounds is still faced with great challenges, mainly due to wound infection, excessive inflammation, and peripheral vascular disease in the wound area. Therefore, it is of great importance to develop a novel multifunctional hydrogel with high efficiency to accelerate diabetic wound healing. Curcumin (Cur), a Chinese herbal, has shown great potential in enhancing the healing of diabetic chronic wounds because of its immunomodulatory and pro-angiogenic properties. However, its low aqueous solubility, poor bioavailability, and chemical instability have limited its clinical applications. To address these current bottlenecks, novel poly(vinyl alcohol) (PVA)-chitosan (CS)/sodium alginate (SA)-Cur (PCSA) hydrogels were prepared for the first time, and they demonstrated all of the above intriguing performances by the Michael addition reaction of CS and Cur. PCSA hydrogels show multiple dynamic bonds, which possess strong mechanical properties (tensile stress: ∼0.980 MPa; toughness: ∼258.45 kJ/m3; and compressive strength: ∼7.38 MPa at strain of 80%). These intriguing performances provided an optimal microenvironment for cell migration and proliferation and also promoted the growth of blood vessels, leading to early angiogenesis. Importantly, the experimental results demonstrated that PCSA hydrogels can effectively transform pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages without the need for additional ingredients in vitro. Benefiting from these characteristics, a full-thickness diabetic wound in a rat model demonstrated that PCSA hydrogels can effectively accelerate wound healing via ROS-scavenging, downregulation of IL-1β, and upregulation of CD31 expression, resulting in angiogenesis and collagen deposition. This strategy not only provides a simple and safe Cur-based hydrogel for diabetic wound healing but also highlights the significant potential for the development of high-performance biomaterials for promoting diabetic wound healing using traditional Chinese medicine.

Sulfated chitosan rescues dysfunctional macrophages and accelerates wound healing in diabetic mice

Au-Pt nanozyme-based multifunctional hydrogel dressing for diabetic wound healing.

Diabetic wounds are more likely to develop into complex and severe chronic wounds. The objective of this study is to develop and assess a reactive oxygen species (ROS)-responsive multifunctional injectable hydrogel for the purpose of diabetic wound healing. A multifunctional hydrogel (HA@Cur@Ag) is successfully synthesized with dual antioxidant, antibacterial, and anti-inflammatory properties by crosslinking thiol hyaluronic acid (SH-HA) and disulfide-bonded hyperbranched polyethylene glycol (HB-PBHE) through Michael addition; while, incorporating curcumin liposomes and silver nanoparticles (AgNPs). The HA@Cur@Ag hydrogel exhibits favorable biocompatibility, degradability, and injectivity. The outcomes of in vitro and in vivo experiments demonstrate that the hydrogel can effectively be loaded with and release curcumin liposomes, as well as silver ions, thereby facilitating diabetic wound healing through multiple mechanisms, including ROS scavenging, bactericidal activity, anti-inflammatory effects, and the promotion of angiogenesis. Transcriptome sequencing reveals that the HA@Cur@Ag hydrogel effectively suppresses the activation of the tumour necrosis factor (TNF)/nuclear factor κB (NF-κB) pathway to ameliorate oxidative stress and inflammation in diabetic wounds. These findings suggest that this ROS-responsive multifunctional injectable hydrogel, which possesses the ability to precisely coordinate and integrate intricate biological and molecular processes involved in wound healing, exhibits notable potential for expediting diabetic wound healing.

Diabetic wounds remain a great challenge for clinicians due to the multiple bacterial infections and oxidative damage. Exosomes, as an appealing nanodrug delivery system, have been widely applied in the treatment of diabetic wounds. Endovascular cells are important component cells of the vascular wall. Herein, we investigated the effects of HUCMSCs and HUC-Exos (exosomes secreted by HUCMSCs) on diabetic wound healing. In this study, HUVECs were coincubated with HUCMSCs, and HUC-Exos were utilized for in vitro and in vivo experiments to verify their roles in the regulation of diabetic wound healing. Our results demonstrated that HUCMSCs have the ability to regulate oxidative stress injuries of endothelial cells through exosomes and accelerate diabetic cutaneous wound healing in vitro. The present study suggests that HUC-Exos accelerate diabetic cutaneous wound healing, providing a promising therapeutic strategy for chronic diabetic wound repair.

Hyaluronic acid methacryloyl/chitosan methacryloyl/3-methacrylamidophenylboronic acid multifunctional hydrogel loading exosome for diabetic wound healing

Near-infrared light-responsive multifunctional hydrogel releasing peptide-functionalized gold nanorods sequentially for diabetic wound healing

Angiogenesis and vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow–derived progenitor cell mobilization and homing

A novel hydrogel loaded with plant exosomes and stem cell exosomes as a new strategy for treating diabetic wounds.

Multifunctional dynamic chitosan-guar gum nanocomposite hydrogels in infection and diabetic wound healing.

The accumulation of reactive oxygen species (ROS) in diabetic wounds leads to inflammation and impaired neovascularization. Recent studies have indicated that carbon dot nanozymes (C-dots) exhibiting superoxide dismutase (SOD)-like activity can neutralize excessive ROS and mitigate diseases associated with oxidative stress. Our study was designed to evaluate the therapeutic impact of C-dots on the healing of diabetic wounds and to unravel the complex molecular mechanisms through which these nanozymes modulate oxidative stress and inflammatory responses within the wound microenvironment. We synthesized C-dots from carbon fiber and confirmed their structure using transmission electron microscopy. The presence of carbon-carbon double bonds on the C-dots was verified with X-ray photoelectron spectroscopy. We assessed the scavenging capacity of C-dots for superoxide anion, hydroxyl radical, and nitric oxide radical using electron spin resonance spectroscopy. Their SOD-like activity and total antioxidant capacity were evaluated with commercial assay kits. In vitro experiments showed that C-dots effectively scavenged excessive ROS, protecting human keratinocytes, vascular endothelial cells, and fibroblasts from oxidative stress-induced damage. Concurrently, C-dots increased the migratory capacity of fibroblasts. In a streptozocin-induced diabetic mice model, C-dots application enhanced skin wound healing, evidenced by accelerated re-epithelialization and orderly collagen matrix assembly. Mechanistic investigations indicated that C-dots markedly suppressed ROS generation and diminished the levels of inflammatory cytokines in the wound environment. Additionally, C-dots induced an M2 polarization phenotype in macrophages and promoted neovascularization, indicating a transition from the inflammatory to the proliferative phase. Quantitative proteomic analysis was conducted to further clarify the underlying mechanisms of C-dots in ameliorating diabetic wounds. C-dots represent a robust nanomaterial-based strategy for treating diabetic wounds, with the ability to accelerate healing by alleviating oxidative stress, mitigating harmful inflammatory responses, and fostering angiogenesis. This highlights their significant therapeutic potential in the field of biomedicine.

Photodriven nanoreactor with a hydrogen-insulin double act repairs diabetic wounds through Nrf2 pathway activation

Rationale: Chronic nonhealing diabetic wound therapy and complete skin regeneration remains a critical clinical challenge. The controlled release of bioactive factors from a multifunctional hydrogel was a promising strategy to repair chronic wounds.Methods: Herein, for the first time, we developed an injectable, self-healing and antibacterial polypeptide-based FHE hydrogel (F127/OHA-EPL) with stimuli-responsive adipose-derived mesenchymal stem cells exosomes (AMSCs-exo) release for synergistically enhancing chronic wound healing and complete skin regeneration. The materials characterization, antibacterial activity, stimulated cellular behavior and in vivo full-thickness diabetic wound healing ability of the hydrogels were performed and analyzed.Results: The FHE hydrogel possessed multifunctional properties including fast self-healing process, shear-thinning injectable ability, efficient antibacterial activity, and long term pH-responsive bioactive exosomes release behavior. In vitro, the FHE@exosomes (FHE@exo) hydrogel significantly promoted the proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs). In vivo, the FHE@exo hydrogel significantly enhanced the healing efficiency of diabetic full-thickness cutaneous wounds, characterized with enhanced wound closure rates, fast angiogenesis, re-epithelization and collagen deposition within the wound site. Moreover, the FHE@exo hydrogel displayed better healing outcomes than those of exosomes or FHE hydrogel alone, suggesting that the sustained release of exosomes and FHE hydrogel can synergistically facilitate diabetic wound healing. Skin appendages and less scar tissue also appeared in FHE@exo hydrogel treated wounds, indicating its potent ability to achieve complete skin regeneration.Conclusion: This work offers a new approach for repairing chronic wounds completely through a multifunctional hydrogel with controlled exosomes release.