Diabetic Wound Research Articles

Literature Review on the Effectiveness of Modern Dressing in the Wound Care Process on Diabetic Wound Healing

Background: Diabetes mellitus is a health problem due to insulin deficiency or insulin resistance that causes high blood glucose. A frequent complication is diabetic ulcer, which is a condition of partial or complete tissue deformity. If it does not get proper treatment, it is very risky to get an infection that leads to amputation.Diabetes Mellitus (DM) has become a prevalent disease, imposing a significant burden on public health due to its widespread occurrence and association with numerous disabilities and fatalities. Uncontrolled DM can lead to severe metabolic complications and long-term vascular issues, including microangiopathy and macroangiopathy. Additionally, individuals with DM are highly susceptible to foot infections, which can escalate into gangrene if not properly managed. Purpose: To determine the effectiveness of modern dressing in the wound care process on diabetic wound healing. Methods: Data collection used descriptive analysis and literature study. The databases used were PubMed, CINAHL, ProQuest and Web of Science. Journal inclusion criteria used PICO and article analysis was conducted by 6 authors. Findings: The evaluated article's findings elucidate the patient's degree of comfort and the more important healing process. It has been demonstrated that contemporary wound care applications make patients feel more at ease as their wounds heal, greatly aiding nurses in nursing care. Modern wound care is a practice that will evolve in response to advancements in nursing science; in this instance, it centers on how comfortable patients are while obtaining wound care-related medical treatments. Therefore, nurses must advance the knowledge behind the use of contemporary wound care to promote patient comfort and hasten the healing process. Conclusion: Modern wound care enhances patient comfort and accelerates healing, greatly supporting nursing practice. With evolving knowledge in nursing science, nurses need to master these methods to maximize patient comfort and recovery in wound care

Exos-Loaded Gox-Modified Smart-Response Self-Healing Hydrogel Improves the Microenvironment and Promotes Wound Healing in Diabetic Wounds.

Wound management has always been a challenge in the clinical treatment of diabetes. In this study, glucose oxidase (GOx) is grafted onto natural pullulan polysaccharides, and oxidization is carried out to form a self-healing hydrogel using carboxymethyl chitosan by means of reversible Schiff base covalent bonding. The smart-response drug release properties of this natural self-healing hydrogel are demonstrated in diabetic wounds by taking advantage of two key factors, namely the pH-responsive nature of Schiff base bonding and the fact that GOx reduces the pH in diabetic wounds. To further enhance the biological functions of the hydrogel dressing, exosomes (Exos) are introduced into the hydrogel system. The GOx present in the hydrogel system improves the high-glucose microenvironment of diabetic wounds, releasing H2O2 to impart antimicrobial effects, and ensuring that the hydrogel realizes a smart-response function. The carboxymethyl chitosan component used to construct the hydrogel plays an effective antibacterial role. Moreover, the Exos loaded into the hydrogel effectively promotes neovascularization of the wound. The Exos also regulates macrophage polarization and reduces the levels of persistent inflammation in diabetic wounds. These results suggest that this smart responsive, multifunctional, and self-healing hydrogel dressing is ideal for the management of diabetic wounds.

Hyperglycemia Targeting Nanomotors for Accelerated Healing of Diabetic Wounds by Efficient Microenvironment Remodeling

AbstractMultifunctional nanoagents are robust to remodel environments for managing chronic diabetic wounds. However, their delivery primarily relies on Brownian motion and randomly enhanced diffusion. Here, taking advantage of wound heterogeneity, such as the uneven distribution of glucose, hyperglycemia targeting nanomotors are proposed. They are capable of efficiently targeting hyperglycemic interfaces in diabetic wounds for significantly accelerating their healing by employing endogenous glucose‐activated cascade reactions and responding to local glucose gradients. Compared to previous counterparts, they show a four‐fold enhancement in effective coverage within 60 s and a multiplied accumulation at hyperglycemic interfaces, facilitating deep penetration. Correspondingly, the downregulation of glucose levels is apparently enhanced, while pH‐lowering and oxygen‐supplying are both improved. In comparison to the counterparts delivered by passive diffusion and randomly enhanced diffusion, the hyperglycemia targeting nanomotor‐based spray accelerates the wound healing upon diabetic mice by approximately 30% and 23%, resulting from the restricted inflammatory response, effective reactive oxygen species (ROS) scavenging and elevated vascular endothelial growth factor levels (VEGF). This study presents a generally efficient approach to facilitating the targeted delivery of nanoagents for the effective management of diabetic wounds by utilizing wound heterogeneity, which can be extended to other therapeutic systems.

A wearable and stretchable dual-wavelength LED device for home care of chronic infected wounds.

Phototherapy can offer a safe and non-invasive solution against infections, while promoting wound healing. Conventional phototherapeutic devices are bulky and limited to hospital use. To overcome these challenges, we developed a wearable, flexible red and blue LED (r&bLED) patch controlled by a mobile-connected system, enabling safe self-application at home. The patch exhibits excellent skin compatibility, flexibility, and comfort, with high safety under system supervision. Additionally, we synthesized a sprayable fibrin gel (F-gel) containing blue light-sensitive thymoquinone and red light-synergistic NADH. Combined with bLED, thymoquinone eradicated microbes and biofilms within minutes, regardless of antibiotic resistance. Furthermore, NADH and rLED synergistically improved macrophage and endothelial cell mitochondrial function, promoting wound healing, reducing inflammation, and enhancing angiogenesis, as validated in infected diabetic wounds in mice and minipigs. This innovative technology holds great promise for revolutionizing at-home phototherapy for chronic infected wounds.

Nanomedicine Innovations for Diabetes Management: Revolutionizing Diagnosis, Treatment, and Monitoring

Diabetes mellitus, a widespread metabolic disease characterized by high blood sugar levels, affects many people globally. The limitations of conventional diagnostic and therapeutic approaches necessitate exploring innovative strategies. Nanotechnology shows remarkable potential for revolutionizing the field of diabetes theranostics (combined diagnosis and treatment) by enabling accurate diagnosis and precise treatment delivery. This article provides a comprehensive review of the latest advancements in nanomaterials for diagnosing and treating diabetes. It explores the applications of various nanomaterials, including inorganic and organic nanoparticles, nanocomposites, and nanostructured biosensors, in biomarker detection, glucose monitoring, insulin delivery, and addressing diabetes-related complications. The study focuses on the synthesis and functionalization of nanomaterials for diabetes, covering both traditional and environmentally friendly synthesis methods. This study looks into how nanomaterials can be used to carry natural antidiabetic extracts, recombinant insulin, and other antidiabetic drugs, to make them more bioavailable, targetable, and effective. However, the review also talks about the problems that come with using nanosensors to diagnose diabetes. It also looks at the newest developments in nanosensors for biomarker detection, implantable devices, and continuous glucose monitoring. Additionally, the review examines the potential of nanomaterials in the management of diabetic sequelae, including diabetic nephropathy, cardiovascular disorders, retinopathy, and wound healing. We underscore the significance of nanomaterials in islet transplantation, as they provide immunological protection and enhance the viability and efficacy of islets. This study provides useful insights into the prospects and challenges connected with the rapidly growing field of nanotechnology in diabetic theranostics through a comprehensive examination of the current landscape. Academics, clinicians, and stakeholders engaged in developing innovative nanomaterial-based approaches to accurately diagnose and effectively manage diabetes will find this resource highly helpful.

The Quantitative InVivo Assessment of Diabetic andNon-Diabetic Skin Wound Healing Using Phasor-FLIM Approach.

A quantitative assessment of wound status in a murine model was developed using phasor plot presentation of fluorescence lifetime imaging microscopy (FLIM) data. The quantitative assessment is based on calculating Bhattacharyya distance between g coordinates of FLIM data phasor plot density distributions of wound and healthy skin. The approach was validated for both diabetic and non-diabetic mice wounds, including during low-dose photodynamic therapy (LDPDT). Analysis revealed a shift in the FLIM data phasor plot g coordinates, suggesting altered metabolic processes involved in wound healing. Bhattacharyya distances in the LDPDT groups were closer to zero compared to the control group, which was not treated by LDPDT. Bhattacharyya distances in the non-diabetic LDPDT groups were closer to zero compared to the diabetic LDPDT groups that is consistent with the literature regarding the positive role of LDPDT in accelerating wound healing and the role of diabetes mellitus in impairing wound healing.

Material Technologies for Improved Diabetic Foot Ulcer (DFU) Treatment: A Questionnaire Study of Healthcare Professionals’ Needs

Background/Objectives: Diabetic foot ulcers (DFUs) are a common and severe complication of diabetic patients, with significant global prevalence and associated health burdens, including high recurrence rates, lower-limb amputations, and substantial associated economic costs. This study aimed to understand the user needs of healthcare professionals treating diabetic foot ulcers for newly developed material technologies. Methods: An open-ended questionnaire was used to identify user needs, identify the limitations of current treatments, and determine the specific requirements for ideal treatment. This information was used to develop a list of key considerations for creating innovative material technologies to improve diabetic wound treatment results. Results: Most respondents indicated that they followed published treatment guidelines for DFUs but noted that treatment often required a case-specific approach. Antibiotics and surgical debridement were commonly used for infection control. The participants showed a strong preference for wound dressings with lasting antibacterial properties. Respondents identified ideal properties for new products, including ease of use, enhanced antibacterial properties, affordability, and targeted biological activity. The respondents also highlighted the importance of a holistic approach to DFU management, integrating product development with comprehensive care strategies and patient education. Conclusions: This study highlights the complexity of DFU care, emphasizing that no single product can address all treatment needs. Future materials could focus on combination therapies and specific use cases. Additionally, understanding global variations in treatment practices and educating users on the proper application of newly developed material technologies is crucial for improving the management of DFUs and patient outcomes.

Oxygen-Bonded Amorphous Transition Metal Dichalcogenides with pH-Responsive Reactive Oxygen Biocatalysis for Combined Antibacterial and Anti-inflammatory Therapies in Diabetic Wound Healing.

Diabetic wound healing is a formidable challenge, often complicated by biofilms, immune dysregulation, and hindered vascularization within the wound environments. The intricate interplay of these microenvironmental factors has been a significant oversight in the evolution of therapeutic strategies. Herein, the design of an efficient and versatile oxygen-bonded amorphous transition metal dichalcogenide biocatalyst (aRuS-Or) with pH-responsive reactive oxygen biocatalysis for combined antibacterial and anti-inflammatory therapies in promoting diabetic wound healing is reported. Leveraging the incorporation of Ru─O bonds, aRuS-Or exhibits optimized adsorption/desorption behavior of oxygen intermediates, thereby enhancing both the reactive oxygen species (ROS) generation activity in acidic conditions and ROS scavenging performance in neutral environments. Remarkably, aRuS-Or demonstrates exceptional bactericidal potency within infected milieus through biocatalytic ROS generation. Beyond its antimicrobial capability, post-eradication, aRuS-Or serves a dual role in mitigating oxidative stress in inflammatory wounds, providing robust cellular protection and fostering an M2-phenotype polarization of macrophages, which is pivotal for accelerating the wound repair process. The findings underscore the multifaceted efficacy of aRuS-Or, which harmoniously integrates high antibacterial action with anti-inflammatory and pro-angiogenic properties. This triad of functionalities positions aRuS-Or as a promising candidate for the comprehensive management of complex diabetic ulcers, addressing the unmet needs in the current therapeutics.

Inhibition of microRNA-181c-5p rescues diabetes-impaired angiogenesis through activation of key mediators of angiogenesis, cell survival and novel genes, elmo3 and trib1

Abstract Introduction Patients with diabetes have impaired angiogenesis and poor coronary collateral vessel formation post-myocardial infarction (MI), which associates with higher mortality. There is a significant unmet clinical need for new agents that stimulate angiogenesis in response to ischaemia in diabetes. We have identified that miR-181c-5p has anti-angiogenic properties, but it’s role in diabetes remains unknown. Aim To elucidate the role of miR-181c-5p in diabetes-impaired angiogenesis. Methods Human coronary artery endothelial cells were transfected with a miR-181c-5p inhibitor (antimiR-181c-5p) or negative control (antimiR-Neg), exposed to glucose (5–25mM, 48h) then underwent Matrigel tubulogenesis assay or Boyden Chamber migration assay. Levels of proteins important for angiogenesis (e.g., VEGFA, p-ERK2, p-eNOS) were determined by Western Blot. Whole transcriptome sequencing was performed in vitro to identify novel gene targets of miR-181c-5p. In vivo, diabetic mice underwent hindlimb ischaemia or wound healing surgery and were injected with antimiR-181c-5p or antimiR-Neg. Tissues were extracted early (day 3) and late (days 10-14) post-surgery. Hindlimb blood-flow reperfusion was measured by Laser Doppler imaging. Hindlimb apoptosis was assessed by TUNEL and necrotic area was assessed by H&E. Wound area was calculated daily. Neovascularisation was assessed by CD31 (capillaries) and α-actin (arterioles) immunostaining. Results Inhibition of miR-181c-5p increased endothelial tubule number (+28%, P<0.01), tubule length (+12%, P<0.01) and cell migration (+67%, P<0.05). This associated with increased VEGFA (+21%, P<0.05) and p-ERK2 (+32%, P<0.05). Whole transcriptome and pathway analysis revealed changes to angiogenesis pathways and identified a first-time involvement of genes Elmo3 and Trib1 in the pro-angiogenic action of antimiR-181c-5p in diabetes. In vivo, inhibition of miR-181c-5p increased blood flow reperfusion to ischaemic hindlimbs (+30%, P<0.001) and arteriolar density (+45%, P<0.05) in diabetic mice. Mechanistically, this was associated with early changes to mediators of angiogenesis, Erk2 mRNA (+35%, P<0.05), p-ERK2 (+35%, P<0.05) and Trib1 mRNA (+80%, P<0.05); cell survival, Bcl-2 mRNA (+44%, P<0.05); and late apoptotic clearance, Elmo3 mRNA (+57%, P<0.001). Furthermore, this was also associated with an increase in late stage hindlimb apoptosis (+94%, P<0.05) and reduced necrotic area (-90%, P<0.05) in diabetic mice. Inhibition of miR-181c-5p increased diabetic wound closure (+22%, P<0.01), wound capillaries (+61%, P<0.05), Bcl-2 mRNA (+52%, P<0.05) and Elmo3 mRNA (+50%, P<0.05) in diabetic wounds. Conclusions Inhibition of miR-181c-5p rescues diabetes-impaired angiogenesis by activation of angiogenesis and cell survival mediators, and through novel genes, Trib1 and Elmo3. Our findings have implications for a novel miRNA-based strategy that improves myocardial neovascularisation and the prognosis of diabetic patients post-MI.

High glucose combined with lipopolysaccharide stimulation inhibits cell proliferation and migration of human HaCaT keratinocytes by impacting redox homeostasis and activating the polyol pathway.

High glucose level and chronic inflammation are characteristic features of diabetic cutaneous wounds. Keratinocytes make up the epidermis and play an important role in skin repair. However, metabolomic changes of keratinocytes in chronic diabetic ulcers have not been fully studied. This study used high levels of glucose combined with lipopolysaccharide to treat human HaCaT keratinocytes. Untargeted metabolomic combined with colorimetric assays were used to explore the changes of keratinocyte metabolites and related metabolic pathways caused by high glucose and lipopolysaccharide. Results demonstrated that high glucose combined with lipopolysaccharide treatment increased intracellular reactive oxygen species and impaired proliferation and migration of keratinocytes. Untargeted metabolomics analysis identified a total of 273 differential metabolites. Redox metabolism associated metabolites were largely altered. Reduced nicotinamide adenine dinucleotide, gamma-glutamylcysteine, superoxide dismutase activity and SOD2 gene expression were significantly upregulated while nicotinamide adenine dinucleotide, glutathione, glutathione peroxidase, several types of lysophosphatidylcholine, lysophosphatidylinositol, and GPR55 gene expression were downregulated. Alterations of glutathione and nicotinamide adenine dinucleotide were verified by colorimetric assays. For the first time, high glucose and LPS were observed to boost the levels of fructose, aldose reductase and sorbitol dehydrogenase of the polyol pathway in HaCaT cells. Further treatment of HaCaT with fructose leading to inhibition of cell proliferation and migration. Our data suggest high glucose combined with lipopolysaccharide significantly altered redox homeostasis associated metabolites and activate the polyol pathway in keratinocytes to impact cell proliferation and migration, providing new strategies for the treatment of chronic diabetic ulcers.

Platelet Extracellular Vesicles Loaded Gelatine Hydrogels for Wound Care.

Platelet extracellular vesicles (pEVs)isolated from clinical-grade human platelet concentratesare attracting attention as a promising agent for wound healing therapies. Although pEVs have shown potential for skin regeneration, their incorporation into wound bandages has remained limitedly explored. Herein, gelatine-based hydrogel (PAH-G) foams for pEVs loading and release are formulated by crosslinking gelatine with poly(allylamine) hydrochloride (PAH) in the presence of glutaraldehyde and sodium bicarbonate. The optimized PAH-G hydrogel foam, PAH0.24G37, displayed an elastic modulus G' = 8.5 kPa at 37°C and retained a rubbery state at elevated temperatures. The excellent swelling properties of PAH0.24G37 allowed to easily absorb pEVs at high concentration (1×1011 particles mL-1). The therapeutic effect of pEVs was evaluated in vivo on a chronic wound rat model. These studies demonstrated full wound closure after 14 days upon treatment with PAH0.24G37@pEVs. The maintenance of a reduced-inflammatory environment from the onset of treatment promoted a quicker transition to skin remodeling. Promotion of follicle activation and angiogenesis as well as M1-M2 macrophage modulation are evidenced. Altogether, the multifunctional properties of PAH0.24G37@pEVs addressed the complex challenges associated with chronic diabetic wounds, representing a significant advance toward personalized treatment regimens for these conditions.

Procyanidin capsules provide a new option for long-term ROS scavenging in chronic inflammatory diseases

Chronic inflammatory diseases such as diabetic wounds and osteoarthritis are significant threats to human health. Failure to scavenge longstanding excessive reactive oxygen species (ROS) is an important cause of chronic inflammatory diseases, yet existing treatments that provide long-lasting therapeutic effects are limited. Here, procyanidin capsules were synthesized in a simple one-step way using calcium carbonate as a template. The biosafety of procyanidin capsules in vitro and in vivo was monitored by cytotoxicity and pathological sections. The therapeutic effect of procyanidin capsules in diabetic wounds and osteoarthritis was accessed by pathological evaluation combined with the quantification of inflammatory markers. The data showed that procyanidin capsules could long-term scavenge excessive ROS and effectively promote articular cartilage repair in osteoarthritis, accelerating diabetic wound healing. Lastly, transcriptome analysis suggested that procyanidin capsules commonly regulated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling in diabetic wounds and osteoarthritis. This study provides a straightforward protocol for creating procyanidin capsules, while presenting a promising new therapeutic option for long-term scavenging ROS in chronic inflammatory diseases.

Non-electrophilic NRF2 activators promote wound healing in human keratinocytes and diabetic mice and demonstrate selective downstream gene targeting

The transcription factor NRF2 plays an important role in many biological processes and is a promising therapeutic target for many disease states. NRF2 is highly expressed in the skin and is known to play a critical role in diabetic wound healing, a serious disease process for which treatment options are limited. However, many existing NRF2 activators display off-target effects due to their electrophilic mechanism, underscoring the need for alternative approaches. In this work, we investigated two recently described non-electrophilic NRF2 activators, ADJ-310 and PRL-295, and demonstrated their efficacy in vitro and in vivo in human keratinocytes and Leprdb/db diabetic mice. We also compared the downstream targets of PRL-295 to those of the widely used electrophilic NRF2 activator CDDO-Me by RNA sequencing. Both ADJ-310 and PRL-295 maintained human keratinocyte cell viability at increasing concentrations and maintained or improved cell proliferation over time. Both compounds also increased cell migration, improving in vitro wound closure. ADJ-310 and PRL-295 enhanced the oxidative stress response in vitro, and RNA-sequencing data showed that PRL-295 activated NRF2 with a narrower transcriptomic effect than CDDO-Me. In vivo, both ADJ-310 and PRL-295 improved wound healing in Leprdb/db diabetic mice and upregulated known downstream NRF2 target genes in treated tissue. These results highlight the non-electrophilic compounds ADJ-310 and PRL-295 as effective, innovative tools for investigating the function of NRF2. These compounds directly address the need for alternative NRF2 activators and offer a new approach to studying the role of NRF2 in human disease and its potential as a therapeutic across multiple disease states.

Plasmonic Supramolecular Nanozyme-Based Bio-Cockleburs for Synergistic Therapy of Infected Diabetic Wounds.

Diabetic wounds are a major devastating complication of diabetes due to hyperglycemia, bacterial invasion, and persistent inflammation, and the current antibiotic treatments can lead to the emergence of multidrug-resistant bacteria. Herein, a bimetallic nanozyme-based biomimetic bio-cocklebur (GNR@CeO2@GNPs) is designed and synthesized for diabetic wound management by depositing spiky ceria (CeO2) shells and gold nanoparticles (GNPs) on a gold nanorod (GNR) nanoantenna. The plasmonic-enhanced nanozyme catalysis and self-cascade reaction properties simultaneously boost the two-step enzyme-mimicking catalytic activity of GNR@CeO2@GNPs, leading to a significant improvement in overall therapeutic efficacy rather than mere additive effects. Under the glucose activation and 808nm laser irradiation, GNR@CeO2@GNPs material captures photons and promotes the transfer of hot electrons from GNR and GNPs into CeO2, realizing a "butterfly effect" of consuming local glucose, overcoming the limited antibacterial efficiency of an individual PTT modality, and providing substantial reactive oxygen species. In vitro and in vivo experiments demonstrate the material's exceptional antibacterial and antibiofilm properties against Gram-negative and Gram-positive bacteria, which can reduce inflammation, promote collagen deposition, and facilitate angiogenesis, thereby accelerating wound healing. This study provides a promising new strategy to develop plasmonic-enhanced nanozymes with a catalytic cascade mode for the antibiotic-free synergistic treatment of infected diabetic wounds.

The Effect of a HealiAid ® Collagen Wound Dressing on Wound Healing in Patients: A Randomized Double-Blind Pilot Clinical Trial

Wound healing is a complex, multi-phase process. With rising healthcare costs, an aging population, and increasing chronic disease prevalence, the burden of wound care is escalating. Thus, finding safe and effective methods to accelerate wound healing is crucial. This study aims to explore the safety and efficacy of HealiAid® Collagen Wound Dressing in treating various types of wounds, including venous ulcers, diabetic foot ulcers, pressure ulcers, and burns. A clinical trial was conducted on 18 subjects with venous ulcers, diabetic foot wounds, pressure ulcers, and burn wounds. The study assessed the effectiveness of HealiAid in different wound types by analyzing its thermal stability, porous structure, biocompatibility, and clinical efficacy. Wound healing was strictly monitored, and the safety and tolerability of the dressing were evaluated. The results showed that HealiAid Collagen Wound Dressing has excellent thermal stability and structural integrity. Its porous microstructure enhances cell adhesion and tissue regeneration, demonstrating significant healing effects across various wound types, including venous ulcers, diabetic foot wounds, pressure ulcers, and burns. No serious adverse reactions were reported, and endotoxin levels were well below safety standards. This study confirms the safety and efficacy of HealiAid Collagen Wound Dressing in treating multiple wound types. Its outstanding thermal stability, porous structure, and biocompatibility make it a promising option for clinical wound care

Biomimetic Nanozyme-Decorated Smart Hydrogel for Promoting Chronic Refractory Wound Healing.

Chronic refractory wounds have become a serious threat to human health and are characterized by prolonged inflammation, recurrent bacterial infections, and elevated ROS levels. However, current therapeutic strategies usually target a unilateral healing function and are unable to tackle the complexity and sensitivity of chronic refractory wound healing. This study fabricated a biomimetic nanozyme based on rhein (Cu-rhein NSs), which effectively mimics the activity of superoxide dismutase (SOD) for scavenging various free radicals. Additionally, zinc oxide microspheres (ZnO MSs) were prepared to enhance the antibacterial activity and mechanical properties of the modified hydrogel. Cu-rhein NSs and ZnO MSs were comodified onto an extracellular matrix-mimetic dual-network smart hydrogel constructed from oxidized sodium alginate, gelatin, and borax via dynamic borate and Schiff base bonds. The smart hydrogel presented the good biocompatibility and targeted the unique acidic microenvironment with high oxidative stress of chronic refractory wounds, intelligently releasing bionic nanozymes to effectively eliminate bacteria, reduce inflammatory responses, and scavenge multiple free radicals for reducing ROS. In vivo experiments on the rat model based on diabetic infection showed that the smart hydrogel could effectively eliminate bacteria, promote vascular regeneration and collagen deposition, reduce inflammatory response, and accelerate the healing of diabetic-infected wounds (almost complete healing within 14 days). The advantages of an intelligent, biomimetic tissue regeneration cascade management strategy against diabetic infected wound healing are highlighted.

Metformin Syncs CeO2 to Recover Intra- and Extra-Cellular ROS Homeostasis in Diabetic Wound Healing.

Excessive generation of reactive oxygen species (ROS) poses a huge obstacle to the healing process of diabetic wounds, resulting in chronic, non-healing wounds. While numerous anti-ROS therapeutics have been developed, satisfied intra- and extra- cellular ROS homeostasis is hard to be established in diabetic wounds. To address this issue, a nanoparticle via loading metformin and CeO2 into mesoporous silica (MSN@Met-CeO2) is designed and synthesized, which is then encapsulated within ROS-responsive hydrogel and shaped as microneedles (MNs) for better application in diabetic wounds. Interestingly, a unique metformin-cerium chelate (Ce· 3Metformin) is formed during the synthesis of MSN@Met-CeO2 MN, which significantly strengthened the inhibitory effect of metformin on mitochondrial complex I. With the presence of Ce· 3Metformin, MSN@Met-CeO2 MN performed a remarkable effect on intracellular mtROS reduction as well as extracellular ROS elimination, the latter is primarily accomplished through the dissociative CeO2 in MSN@Met-CeO2 MN. In the mouse diabetic wound model, MSN@Met-CeO2 MN exhibited a superior pro-healing effect with accelerated inflammation resolution and enhanced angiogenesis, thus highlighting its significant potential for clinical application.

Drug conjugates crosslinked bioresponsive hydrogel for combination therapy of diabetic wound

Basic fibroblast growth factor (bFGF) has proved to be effective for wound healing, yet its effectiveness is extremely retarded in diabetic wounds due to the severe oxidative stress in wound beds. To solve this issue, herein a novel combination therapy of bFGF and N-acetylcysteine (NAC, antioxidant) was devised for improved diabetic wound repair. To avoid rapid loss of both drugs in the wound beds, a bioresponsive hydrogel (bFGF-HSPP-NAC) was engineered by incorporating bFGF and NAC into polymer-drug conjugates (HSPP) via thiol-disulfide exchange reactions. In response to oxidative stress (e.g., reactive oxygen species), the disulfide bonds (SS) within the hydrogel are broken into thiol groups (-S-H), thereby promoting hydrogel degradation and enabling controlled drug release. Initially, NAC is released to scavenge free radicals and ameliorate oxidative damage. Subsequently, bFGF is released to expedite tissue regeneration. This combinatorial strategy is tailored to the specific characteristics of the wound microenvironment at various stages of diabetic wound healing, thereby achieving therapeutic efficacy. The results indicate that the bFGF-HSPP-NAC hydrogel markedly enhances re-epithelialization, collagen deposition, hair follicle regeneration, and neovascularization. In conclusion, the bioresponsive bFGF-HSPP-NAC hydrogel demonstrates significant potential for application in combinatorial therapeutic approaches for diabetic wound healing.

A Multi-Responsive Hydrogel Combined With Mild Heat Stimulation Promotes Diabetic Wound Healing by Regulating Inflammatory and Enhancing Angiogenesis.

The repair of diabetic wound still encounters huge challenges, such as disordered inflammatory regulation and impaired neovascularization. Here, a pH/ROS/glucose responsive and photothermal hydrogel is developed for diabetic wound healing. The hydrogel is formed through cross-linkage between phenylboronic acid-modified carboxymethyl chitosan (CMCS-PBA) and oxide dextran (OXD), utilizing Schiff base and phenylboronate ester bonds. Additionally, insulin-like growth factor 1 C domain (IGF-1C) and deferoxamine-loaded polydopamine nanoparticles (D@P) are incorporated into the hydrogel. The hydrogel demonstrates sustained drug release, excellent photo thermal effect, prominent antioxidant, antibacterial and anti-inflammatory activities, desirable mechanical and tissue adhesive properties, enhanced tube formation, and cell migration. Furthermore, the hydrogel combined with mild heat treatment can regulate chronic inflammation by promoting the transformation of macrophages from M1 phenotype to M2 phenotype and enhance angiogenesis by up-regulating the expression levels of angiogenesis-related factors such as hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), CD31, and α-SMA, thus greatly accelerates the wound healing in streptozotocin (STZ)-induced diabetic mice. Therefore, this multi-responsive and multifunctional hydrogel holds potential as a therapeutic strategy for diabetic wounds.

The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.

Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages, yet paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NF-κB component, RELA, leading to increased RELA/NF-κB-mediated inflammatory gene expression. Furthermore, RNA-Seq in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally coregulate overlapping genes. Finally, in diabetic wound macrophages, STAT3 expression and STAT3/SETDB2 binding were increased. We have identified what we believe to be a novel STAT3/SETDB2 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.