Antioxidant and Immunomodulatory Polymer Vesicles for Effective Diabetic Wound Treatment through ROS Scavenging and Immune Modulating.

Chronic diabetic wound patients usually show high glucose levels and systemic immune disorder, resulting in high reactive oxygen species (ROS) levels and immune cell dysfunction, prolonged inflammation, and delayed wound healing. Herein, we prepared an antioxidant and immunomodulatory polymer vesicle for diabetic wound treatment. This vesicle is self-assembled from poly(ε-caprolactone)36-block-poly[lysine4-stat-(lysine-mannose)22-stat-tyrosine)16] ([PCL36-b-P[Lys4-stat-(Lys-Man)22-stat-Tyr16]). Polytyrosine is an antioxidant polypeptide that can scavenge ROS. d-Mannose was introduced to afford immunomodulatory functions by promoting macrophage transformation and Treg cell activation through inhibitory cytokines. The mice treated with polymer vesicles showed 23.7% higher Treg cell levels and a 91.3% higher M2/M1 ratio than those treated with PBS. Animal tests confirmed this vesicle accelerated healing and achieved complete healing of S. aureus-infected diabetic wounds within 8 days. Overall, this is the first antioxidant and immunomodulatory vesicle for diabetic wound healing by scavenging ROS and regulating immune homeostasis, opening new avenues for effective diabetic wound healing.

5-aminolevulinic acid photodynamic therapy for chronic wound infection in rats with diabetes.

Recent research indicated that ulcers and peripheral vascular disease resulting from drug-resistant bacterial infections are the main causes of delayed healing in chronic diabetic wounds. 5-Aminolevulinic acid (ALA) is a second-generation endogenous photosensitizer. The therapeutic effect and mechanism of ALA-mediated photodynamic therapy (ALA-PDT) on methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds in diabetic rats were investigated in this study. The results revealed the promising antibacterial effects of ALA-PDT MRSA in vitro, with a minimum inhibitory concentration and minimum bactericidal concentration of 250 and 500 µM, respectively. ALA-PDT also changed the permeability and structural integrity of bacterial cell membranes by producing reactive oxygen species. Meanwhile, ALA-PDT accelerated wound healing in MRSA-infected diabetic rats, with 5 % ALA-PDT achieving complete sterilization in 14 days and wound closure in 21 days. Treatment with 5 % ALA-PDT additionally improved the histopathological appearance of skin tissue, as well as fibrosis, inflammatory cytokine release, and angiogenesis-related protein expression. These findings indicated that ALA-PDT significantly promoted the healing of MRSA-infected wounds in diabetic rats by eliminating bacteria, inhibiting inflammation, generating granulation tissues, promoting neovascularization, and restoring damaged nerves. In addition, the healing mechanism was related to the activation of inflammatory and angiogenesis pathways through the regulation of tumor necrosis factor-alpha and interleukin-6 expression and upregulation of CD206, CD31, and VEGF. These findings underscored the potential role of ALA-PDT in promoting the healing of chronic diabetic wounds.

Integrating Data Mining with Metabolomics to Analyze the Mechanism of the "Pearl-Borneol" Pair in Promoting Healing of Diabetic Wounds.

INTRODUCTION: Chronic diabetic wounds pose a significant threat to the health of diabetic patients, representing severe and enduring complications. Globally, an estimated 2.5% to 15% of the annual health budget is associated with diabetes, with diabetic wounds accounting for a substantial share. Exploring new therapeutic agents and approaches to address delayed and impaired wound healing in diabetes becomes imperative. Traditional Chinese medicine (TCM) has a long history and remarkable efficacy in treating chronic wound healing. In this study, all topically applied proprietary Chinese medicines (pCMs) for wound healing officially approved by the National Medical Products Administration (NMPA) were collected from the NMPA TCM database. Data mining was employed to obtain a high-frequency TCM ingredients pair, Pearl-Borneol (1:1). METHOD: This study investigated the effect and molecular mechanism of the Pearl-Borneol pair on the healing of diabetic wounds by animal experiments and metabolomics. The results from animal experiments showed that the Pearl-Borneol pair significantly accelerated diabetic wound healing, exhibiting a more potent effect than the Pearl or Borneol treatment alone. Meanwhile, the metabolomics analysis identified significant differences in metabolic profiles in wounds between the model and normal groups, indicating that diabetic wounds had distinct metabolic characteristics from normal wounds. Moreover, Vaseline-treated wounds exhibited similar metabolic profiles to the wounds from the model group, suggesting that Vaseline might have a negligible impact on diabetic wound metabolism. In addition, wounds treated with Pearl, Borneol, and Pearl-Borneol pair displayed significantly different metabolic profiles from Vaseline-treated wounds, signifying the influence of these treatments on wound metabolism. Subsequent enrichment analysis of the metabolic pathway highlighted the involvement of the arginine metabolic pathway, closely associated with diabetic wounds, in the healing process under Pearl- Borneol pair treatment. Further analysis revealed elevated levels of arginine and citrulline, coupled with reduced nitric oxide (NO) in both the model and Vaseline-treated wounds compared to normal wounds, pointing to impaired arginine utilization in diabetic wounds. Interestingly, treatment with Pearl and Pearl-Borneol pair lowered arginine and citrulline levels while increasing NO content, suggesting that these treatments may promote the catabolism of arginine to generate NO, thereby facilitating faster wound closure. Additionally, borneol alone significantly elevated NO content in wounds, potentially due to its ability to directly reduce nitrates/nitrites to NO. Oxidative stress is a defining characteristic of impaired metabolism in diabetic wounds. RESULTS: The result showed that both Pearl and Pearl-Borneol pair decreased the oxidative stress biomarker methionine sulfoxide level in diabetic wounds compared to those treated with Vaseline, indicating that Pearl alone or combined with Borneol may enhance the oxidative stress microenvironment in diabetic wounds. CONCLUSION: In summary, the findings validate the effectiveness of the Pearl-Borneol pair in accelerating the healing of diabetic wounds, with effects on reducing oxidative stress, enhancing arginine metabolism, and increasing NO generation, providing a mechanistic basis for this therapeutic approach.

Enhancing diabetic wound healing through anti-bacterial and promoting angiogenesis using dual-functional slow-release microspheres-loaded dermal scaffolds.

Bacterial infections and the degeneration of the capillary network comprise the primary factors that contribute to the delayed healing of diabetic wounds. However, treatment modalities that cater to effective diabetic wounds healing in clinical settings are severely lacking. Herein, a dual-functional microsphere carrier was designed, which encapsulates polyhexamethylene biguanide (PHMB) or recombinant human vascular endothelial growth factor (rhVEGF) together. The in vitro release experiments demonstrated that the use of the microspheres ensured the sustained release of the drugs (PHMB or rhVEGF) over a period of 12 days. Additionally, the integration of these controlled-release microspheres into a dermal scaffold (DS-PLGA@PHMB/rhVEGF) imbued both antibacterial and angiogenic functions to the resulting material. Accordingly, the DS-PLGA@PHMB/rhVEGF scaffold exhibited potent antibacterial properties, effectively suppressing bacterial growth and providing a conducive environment for wound healing, thereby addressing the drawbacks associated with the susceptibility of rhVEGF to deactivation in inflammatory conditions. Additionally, the histological analysis revealed that the use of the DS-PLGA@PHMB/rhVEGF scaffold accelerated the process of wound healing by inhibiting inflammatory reactions, stimulating the production of collagen formation, and enhancing angiogenesis. This provides a novel solution for enhancing the antibacterial and vascularization capabilities of artificial dermal scaffolds, providing a beacon of hope for improving diabetic wound healing.

3D Porous Polymer Scaffold-Conjugated KGF-Mimetic Peptide Promotes Functional Skin Regeneration in Chronic Diabetic Wounds.

The re-epithelialization process gets severely dysregulated in chronic nonhealing diabetic foot ulcers/wounds. Keratinocyte growth factor (KGF or FGF-7) is the major modulator of the re-epithelialization process, which regulates the physiological phenotypes of cutaneous keratinocytes. The existing therapeutic strategies of growth factor administration have several limitations. To overcome these, we have designed a KGF-mimetic peptide (KGFp, 13mer) based on the receptor interaction sites in murine KGF. KGFp enhanced migration and transdifferentiation of mouse bone marrow-derived MSCs toward keratinocyte-like cells (KLCs). A significant increase in the expression of skin-specific markers Bnc1 (28.5-fold), Ck5 (14.6-fold), Ck14 (26.1-fold), Ck10 (187.7-fold), and epithelial markers EpCam (23.3-fold) and Cdh1 (64.2-fold) was associated with the activation of ERK1/2 and STAT3 molecular signaling in the KLCs. Further, to enhance the stability of KGFp in the wound microenvironment, it was conjugated to biocompatible 3D porous polymer scaffolds without compromising its active binding sites followed by chemical characterization using Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, dynamic mechanical analysis, and thermogravimetry. In vitro evaluation of the KGFp-conjugated 3D polymer scaffolds revealed its potential for transdifferentiation of MSCs into KLCs. Transplantation of allogeneic MSCGFP using KGFp-conjugated 3D polymer scaffolds in chronic nonhealing type 2 diabetic wounds (db/db transgenic, 50-52 weeks old male mice) significantly enhanced re-epithelialization-mediated wound closure rate (79.3%) as compared to the control groups (Untransplanted -22.4%, MSCGFP-3D polymer scaffold -38.5%). Thus, KGFp-conjugated 3D porous polymer scaffolds drive the fate of the MSCs toward keratinocytes that may serve as potential stem cell delivery platform technology for tissue engineering and transplantation.

Human Periodontal Ligament Stem Cells (hPDLSCs) Spontaneously Differentiate into Myofibroblasts to Repair Diabetic Wounds.

Advanced glycation end product (AGE) accumulation due to diabetes causes vascular and neurological lesions, delaying healing. The use of stem cells could overcome these problems. Although many studies have shown the potential beneficial effects of stem cell therapies in the treatment of chronic and refractory skin ulcers, their delivery methods are still under investigation. Human periodontal ligament stem cells (hPDLSCs) can spontaneously differentiate into myofibroblasts in specific cultures; therefore, they have the potential to effectively treat diabetic wounds and may also have applications in the field of medical cosmetics. The myofibroblastic differentiation ability of hPDLSCs in the presence of AGEs was evaluated by the expression of α-SMA and COL1A1 using RT-qPCR and WB technology. Wound healing in diabetic mice, induced by streptozotocin (STZ) and assessed using H&E staining, Masson staining, and immunohistochemical (IHC) and immunofluorescence (IF) staining, was used to validate the effects of hPDLSCs. In the wound tissues, the expression of α-SMA, COL1A1, CD31, CD206, iNOS, and vimentin was detected. The findings indicated that in H-DMEM, the expression of COL1A1 exhibited a significant decrease, while α-SMA demonstrated an increase in P7 cells, ignoring the damage from AGEs (p < 0.05). In an STZ-induced diabetic C57BL/6J mice whole-skin defect model, the healing rate of the hPDLSCs treatment group was significantly higher than that in the models (on the 7th day, the rate was 65.247% vs. 48.938%, p < 0.05). hPDLSCs have been shown to spontaneously differentiate into myofibroblasts in H-DMEM and resist damage from AGEs in both in vivo and in vitro models, suggesting their potential in the field of cosmetic dermatology.

Enhancing diabetic wound healing with a pH/glucose dual-responsive hydrogel for ROS clearance and antibacterial activity.

Currently, the treatment of diabetic wounds in clinical practice is still unsatisfactory due to the risks of oxidative damage and bacterial infection during the healing process. An optimal wound dressing should exhibit robust capabilities in scavenging reactive oxygen species (ROS) and combatting bacterial growth. In this study, we utilized borax as a crosslinker and prepared a pH/glucose dual-responsive composite hydrogel based on poly(vinyl alcohol) (PVA), sodium alginate (SA), and tannic acid (TA). This hydrogel, loaded with cerium dioxide, serves as an effective ROS scavenger, promoting wound closure by reducing the level of ROS in the wound area. Additionally, the hydrogel can release the antibacterial drug ofloxacin in response to the low pH and high glucose microenvironment in infected wounds. Results from skin defect model in diabetic mice demonstrated this ROS-scavenging and antibacterial hydrogel can suppress inflammation and accelerate wound healing. In summary, our work provides a new perspective on a local and stimulus-responsive drug delivery strategy for treating diabetic wounds.

Multifunctional Microneedle Patch Based on Metal-Phenolic Network with Photothermal Antimicrobial, ROS Scavenging, Immunomodulatory, and Angiogenesis for Programmed Treatment of Diabetic Wound Healing.

In diabetic patients with skin injuries, bacterial proliferation, accumulation of reactive oxygen species (ROS) in the tissues, and impaired angiogenesis make wound healing difficult. Therefore, eliminating bacteria, removing ROS, and promoting angiogenesis are necessary for treating acute diabetic wounds. In this study, benefiting from the ability of polyphenols to form a metal-phenolic network (MPN) with metal ions, TA-Eu MPN nanoparticles (TM NPs) were synthesized. The prepared photothermal agent CuS NPs and TM NPs were then loaded onto the supporting base and needle tips of PVA/HA (PH) microneedles, respectively, to obtain PH/CuS/TM microneedles. Antibacterial experiments showed that microneedles loaded with CuS NPs could remove bacteria by the photothermal effect. In vitro experiments showed that the microneedles could effectively scavenge ROS, inhibit macrophage polarization to the M1 type, and induce polarization to the M2 type as well as have the ability to promote vascular endothelial cell migration and angiogenesis. Furthermore, in vivo experiments showed that PH/CuS/TM microneedles accelerated wound healing by inhibiting pro-inflammatory cytokines and promoting angiogenesis in a diabetic rat wound model. Therefore, PH/CuS/TM microneedles have efficient antibacterial, ROS scavenging, anti-inflammatory, immunomodulatory, and angiogenic abilities and hold promise as wound dressings for treating acute diabetic wounds.

Preclinical and Clinical Studies on the Use of Extracellular Vesicles Derived from Mesenchymal Stem Cells in the Treatment of Chronic Wounds.

To date, the widespread implementation of therapeutic strategies for the treatment of chronic wounds, including debridement, infection control, and the use of grafts and various dressings, has been time-consuming and accompanied by many challenges, with definite success not yet achieved. Extensive studies on mesenchymal stem cells (MSCs) have led to suggestions for their use in treating various diseases. Given the existing barriers to utilizing such cells and numerous pieces of evidence indicating the crucial role of the paracrine signaling system in treatments involving MSCs, extracellular vesicles (EVs) derived from these cells have garnered significant attention in treating chronic wounds in recent years. This review begins with a general overview of current methods for chronic wound treatment, followed by an exploration of EV structure, biogenesis, extraction methods, and characterization. Subsequently, utilizing databases such as Google Scholar, PubMed, and ScienceDirect, we have explored the latest findings regarding the role of EVs in the healing of chronic wounds, particularly diabetic and burn wounds. In this context, the role and mode of action of these nanoparticles in healing chronic wounds through mechanisms such as oxygen level elevation, oxidative stress damage reduction, angiogenesis promotion, macrophage polarization assistance, etc., as well as the use of EVs as carriers for engineered nucleic acids, have been investigated. The upcoming challenges in translating EV-based treatments for healing chronic wounds, along with possible approaches to address these challenges, are discussed. Additionally, clinical trial studies in this field are also covered.

Varying ratios of M/G in alginate to modulate macrophages polarization and its application for wound healing in diabetic.

Alginate (SA) comprises repeating unis of ß-1, 4 linked ß-D-mannuronic acid (M) and α-L-guloronic acid (G) in varying proportions. The M/G ratio greatly impacts its anti-inflammatory properties in tissue healing wound, as less knowledge reported. This study examined the performances of both SA and SA hydrogel crosslinked with copper ions (SA-Cu) with different M/G ratios are studied. SA with higher M/G ratios stimulated macrophage migration and shifted from M0 to the pro-inflammatory Ml phenotype, while lower M/G ratios shifted from M1 to the pro-repair M2 phenotype. Furthermore, SA-Cu hydrogels with lower M/G ratios exhibited enhanced cross-linking degree, mechanical and rheological properties, as well Cu releasing rate. The reason may be attributed to a relative easy binding between Cu ions and G unit among Cu ions, M unit and G unit. In vitro cell evaluation showed that SA-Cu hydrogel with M/G ratio of 1:1 activated M2 macrophages and up-regulated anti-inflammatory cytokines expression more effectively than those of SA-Cu ratios (2:1) and (1:2). In vivo, SA-Cu hydrogel with M/G ratio of 1:1 expedited diabetic wound healing, accelerating infiltration and phenotype shift of M2 macrophages, and enhancing anti-inflammatory factors, epithelialization and collagen deposition in healing phases. This research highlights the significant role of M/G ratios in SA materials in influencing macrophage behavior and inflammatory responses, which would benefit its application field.

A Multifunctional Hydrogel Fabricated by Direct Self-Assembly of Natural Herbal Small Molecule Mangiferin for Treating Diabetic Wounds.

Clinical studies have continually referred to the involvement of drug carrier having dramatic negative influences on the biocompatibility, biodegradability, and loading efficacy of hydrogel. To overcome this deficiency, researchers have proposed to directly self-assemble natural herbal small molecules into a hydrogel without any structural modification. However, it is still a formidable challenge due to the high requirements on the structure of natural molecules, leading to a rarity of this type of hydrogel. Mangiferin (MF) is a natural polyphenol of C-glucoside xanthone with various positive health benefits, including the treatment of diabetic wounds, but its poor hydrosolubility and low bioavailability significantly restrict the clinical application. Inspired by these, with heating/cooling treatment, a carrier-free hydrogel (MF-gel) is developed by assembling the natural herbal molecule mangiferin, which is mainly governed through hydrogen bonds and intermolecular π-π stacking interactions. The as-prepared hydrogel has injectable and self-healing properties and shows excellent biocompatibility, continuous release ability, and reversible stimuli-responsive performances. All of the superiorities enable the MF-based hydrogel to serve as a potential wound dressing for treating diabetic wounds, which was further confirmed by both the vitro and vivo studies. In vitro, the MF-gel could promote the migration of healing-related cells from peripheral as well as the angiogenesis and displays the capacity of mediating inflammation response by scavenging the intracellular ROS. In vivo, the MF-gel accelerates wound contraction and healing via inflammatory adjustment, collagen deposition, and angiogenesis. This study provides a facile and effective method for diabetic wound management and emphasizes the direct self-assembly hydrogel from natural herbal small molecule.

Development and functional testing of a novel in vitro delayed scratch closure assay.

As the development of chronic wound therapeutics continues to expand, the demand for advanced assay systems mimicking the inflammatory wound microenvironment in vivo increases. Currently, this is performed in animal models or in in vitro cell-based models such as cell culture scratch assays that more closely resemble acute wounds. Here, we describe for the first time a delayed scratch closure model that mimics some features of a chronic wound in vitro. Chronic wounds such as those suffered by later stage diabetic patients are characterised by degrees of slowness to heal caused by a combination of continued localised physical trauma and pro-inflammatory signalling at the wound. To recreate this in a cell-based assay, a defined physical scratch was created and stimulated by combinations of pro-inflammatory factors, namely interferon, the phorbol ester PMA, and lipopolysaccharide, to delay scratch closure. The concentrations of these factors were characterised for commonly used human keratinocyte (HaCaT) and dermal fibroblast (HDF) cell lines. These models were then tested for scratch closure responsiveness to a proprietary healing secretome derived from human Wharton's jelly mesenchymal stem cells (MSCs) previously validated and shown to be highly effective on closure of acute wound models both in vitro and in vivo. The chronically open scratches from HaCaT cells showed closure after exposure to the MSC secretome product. We propose this delayed scratch closure model for academic and industrial researchers studying chronic wounds looking for responsiveness to drugs or biological treatments prior to testing on explanted patient material or in vivo.

Mg-gallate metal-organic framework-based sprayable hydrogel for continuously regulating oxidative stress microenvironment and promoting neurovascular network reconstruction in diabetic wounds.

Chronic diabetic wounds are the most common complication for diabetic patients. Due to high oxidative stress levels affecting the entire healing process, treating diabetic wounds remains a challenge. Here, we present a strategy for continuously regulating oxidative stress microenvironment by the catalyst-like magnesium-gallate metal-organic framework (Mg-GA MOF) and developing sprayable hydrogel dressing with sodium alginate/chitosan quaternary ammonium salts to treat diabetic wounds. Chitosan quaternary ammonium salts with antibacterial properties can prevent bacterial infection. The continuous release of gallic acid (GA) effectively eliminates reactive oxygen species (ROS), reduces oxidative stress, and accelerates the polarization of M1-type macrophages to M2-type, shortening the transition between inflammation and proliferative phase and maintaining redox balance. Besides, magnesium ions adjuvant therapy promotes vascular regeneration and neuronal formation by activating the expression of vascular-associated genes. Sprayable hydrogel dressings with antibacterial, antioxidant, and inflammatory regulation rapidly repair diabetic wounds by promoting neurovascular network reconstruction and accelerating re-epithelialization and collagen deposition. This study confirms the feasibility of catalyst-like MOF-contained sprayable hydrogel to regulate the microenvironment continuously and provides guidance for developing the next generation of non-drug diabetes dressings.

Functional biomacromolecules-based microneedle patch for the treatment of diabetic wound.

Diabetic wounds are a common complication of diabetes. The prolonged exposure to high glucose and oxidative stress in the wound environment increases the risk of bacterial infection and abnormal angiogenesis, leading to amputation. Microneedle patches have shown promise in promoting the healing of diabetic wounds through transdermal drug delivery. These patches target the four main aspects of diabetic wound treatment: hypoglycemia, antibacterial action, inflammatory regulation, and tissue regeneration. By overcoming the limitations of traditional administration methods, microneedle patches enable targeted therapy for deteriorated tissues. The design of these patches extends beyond the selection of needle tip material and biomacromolecule encapsulated drugs; it can also incorporate near-infrared rays to facilitate cascade reactions and treat diabetic wounds. In this review, we comprehensively summarize the advantages of microneedle patches compared to traditional treatment methods. We focus on the design and mechanism of these patches based on existing experimental articles in the field and discuss the potential for future research on microneedle patches.

Insights of biopolymeric blended formulations for diabetic wound healing.

Diabetic wounds (DWs) pose a significant health burden worldwide, with their management presenting numerous challenges. Biopolymeric formulations have recently gained attention as promising therapeutic approaches for diabetic wound healing. These formulations, composed of biocompatible and biodegradable polymers, offer unique properties such as controlled drug release, enhanced wound closure, and reduced scarring. In this review, we aim to provide a comprehensive overview of the current state of research and future prospects regarding the application of biopolymeric formulations for diabetic wound healing. The review begins by highlighting the underlying pathophysiology of DWs, including impaired angiogenesis, chronic inflammation, and compromised extracellular matrix (ECM) formation. It further explores the key characteristics of biopolymeric materials, such as their biocompatibility, biodegradability, and tunable physicochemical properties, which make them suitable for diabetic wound healing applications. The discussion further delves into the types of biopolymeric formulations utilized in the treatment of DWs. These include hydrogels, nanoparticles (NP), scaffolds, films, and dressings. Furthermore, the review addresses the challenges associated with biopolymeric formulations for diabetic wound healing. In conclusion, biopolymeric formulations present a promising avenue for diabetic wound healing. Their unique properties and versatility allow for tailored approaches to address the specific challenges associated with DWs. However, further research and developments are required to optimize their therapeutic efficacy, stability, manufacturing processes, and regulatory considerations. With continued advancements in biopolymeric formulations, the future holds great promise for improving the management and outcomes of DWs.

Narrative review on nanoparticles based on current evidence: therapeutic agents for diabetic foot infection.

Diabetes's effects on wound healing present a major treatment challenge and increase the risk of amputation. When traditional therapies fail, new approaches must be investigated. With their submicron size and improved cellular internalisation, nanoparticles present a viable way to improve diabetic wound healing. They are attractive options because of their innate antibacterial qualities, biocompatibility, and biodegradability. Nanoparticles loaded with organic or inorganic compounds, or embedded in biomimetic matrices such as hydrogels, chitosan, and hyaluronic acid, exhibit excellent anti-inflammatory, antibacterial, and antioxidant properties. Drug delivery systems (DDSs)-more precisely, nanodrug delivery systems (NDDSs)-use the advantages of nanotechnology to get around some of the drawbacks of traditional DDSs. Recent developments show how expertly designed nanocarriers can carry a variety of chemicals, transforming the treatment of diabetic wounds. Biomaterials that deliver customised medications to the wound microenvironment demonstrate potential. Delivery techniques for nanomedicines become more potent than ever, overcoming conventional constraints. Therapeutics for diabetes-induced non-healing wounds are entering a revolutionary era thanks to precisely calibrated nanocarriers that effectively distribute chemicals. This review highlights the therapeutic potential of nanoparticles and outlines the multifunctional nanoparticles of the future that will be used for complete wound healing in diabetics. The investigation of novel nanodrug delivery systems has the potential to revolutionise diabetic wound therapy and provide hope for more efficient and focused therapeutic approaches.

Teicoplanin-Decorated Reduced Graphene Oxide Incorporated Silk Protein Hybrid Hydrogel for Accelerating Infectious Diabetic Wound Healing and Preventing Diabetic Foot Osteomyelitis.

Developing hybrid hydrogel dressings with anti-inflammatory, antioxidant, angiogenetic, and antibiofilm activities with higher bone tissue penetrability to accelerate diabetic wound healing and prevent diabetic foot osteomyelitis (DFO) is highly desirable in managing diabetic wounds. Herein, the glycopeptide teicoplanin is used for the first time as a green reductant to chemically reduce graphene oxide (GO). The resulting teicoplanin-decorated reduced graphene oxide (rGO) is incorporated into a mixture of silk proteins (SP) and crosslinked with genipin to yield a physicochemically crosslinked rGO-SP hybrid hydrogel. This hybrid hydrogel exhibits high porosity, self-healing, shear-induced thinning, increased cell proliferation and migration, and mechanical properties suitable for tissue engineering. Moreover, the hybrid hydrogel eradicates bacterial biofilms with a high penetrability index in agar and hydroxyapatite disks covered with biofilms, mimicking bone tissue. In vivo, the hybrid hydrogel accelerates the healing of noninfected wounds in a diabetic rat and infected wounds in a diabetic mouse by upregulating anti-inflammatory cytokines and downregulating matrix metalloproteinase-9, promoting M2 macrophage polarization and angiogenesis. The implantation of hybrid hydrogel into the infected site of mouse tibia improves bone regeneration. Hence, the rGO-SP hybrid hydrogel can be a promising wound dressing for treating infectious diabetic wounds, providing a further advantage in preventing DFO.

Substrate stiffness regulates type II diabetic fibroblast phenotype and metabolic activity.

In people living with diabetes, impaired wound healing is a major concern as the formation of ulcerated wounds can drastically reduce both the effectiveness of the healing process and the quality of life of the patient. The healing of dermal wounds in particular involves a patient's fibroblasts building up a strong extracellular matrix of mostly collagen I and collagen III fibers, which the cells of diabetic patients struggle to do. Extracellular matrix stiffness, and growth substrate stiffness in general, have already been shown to have a significant effect on the growth and development of already existent cells, and in diabetic dermal fibroblasts, morphological and physiological characteristics associated with the healing process appear to be altered from their healthy state. In this study we utilized a PDMS surface with a stiffness comparable to a wound environment (16 kPa) and a softer surface (0.2 kPa) to study the effects on diabetic and normal fibroblasts. We found diabetic fibroblast morphology became more fibroblast like when placed on the softer surfaces. This was demonstrated by a 15.6% decrease in the aspect ratio and a 16.4% increase in the circularity. The presence of the stress fibers was decreased by 19.4% in diabetic fibroblasts when placed on a softer surface. The proliferation rate of the diabetic fibroblasts was unaffected by the change in stiffness, but the metabolic activity greatly decreased (76%) on the softer surface. The results suggest that the softer surface may have a therapeutic effect on diabetic fibroblast metabolic activity. Further studies could focus on investigating this relationship and utilize it in tunable biomaterials to facilitate and accelerate the healing process for diabetic wounds.

Acellular fish skin grafts in the treatment of diabetic wounds: Advantages and clinical translation.

Diabetic wounds cannot undergo normal wound healing due to changes in the concentration of hyperglycemia in the body and soon evolve into chronic wounds causing amputation or even death of patients. Diabetic wounds directly affect the quality of patients and social medical management; thus researchers started to focus on skin transplantation technology. The acellular fish skin grafts (AFSGs) are derived from wild fish, which avoids the influence of human immune function and the spread of the virus through low-cost decellularization. AFSGs contain a large amount of collagen and omega-3 polyunsaturated fatty acids and they have an amazing effect on wound regeneration. However, after our search in major databases, we found that there were few research trials in this field, and only one was clinically approved. Therefore, we summarized the advantages of AFSGs and listed the problems faced in clinical use. The purpose of this paper is to enable researchers to better carry out original experiments at various stages.