Chronic Diabetic Wound Healing Research Articles

Enzyme-mediated multifunctional self-healing lysozyme hydrogel for synergistic treatment of chronic diabetic wounds

Self-healing hydrogels have attracted significant attention in chronic diabetic wound healing due to their potential to minimize the risk of secondary infections caused by joint movement or dressing rupture. Herein, a multifunctional self-healing hydrogel mediated utilizing an enzyme-triggered cascade reaction based on dynamic imine bonds was designed. The hydrogel employs three enzymes: lysozyme (LYZ), glucose oxidase (GOx), and catalase (CAT), as building blocks. GOx catalyzes the conversion of glucose and 1-thio-β-d-glucose (β-GlcSH) into hydrogen peroxide (H2O2), gluconic acid (GA), and hydrogen sulfide (H2S). Subsequently, CAT eliminates H2O2, protecting the imine bonds from oxidative damage. The acidic environment created by GA decreases the pH and regulates the crosslinking density of imine bonds, enhancing the self-healing capability and porosity of the hydrogel. This feature enables the sustained release of the drug rosuvastatin calcium (RCa) to promote endothelial cell migration and vascular regeneration. Combined with the antioxidative and anti-inflammatory effects of released H2S gas and the antibacterial properties of lysozyme, this hydrogel exhibits promising therapeutic efficacy for the synergistic treatment of chronic diabetic wounds.

Nanocomposite conductive r(GO/BSA) hydrogel as an effective dressing for rapid chronic diabetic wound healing

Conductive hydrogels, with their soft, hydrated interface and superior electrical conductivity, represent a groundbreaking solution for diabetic wound healing. However, developing a conductive hydrogel with excellent biocompatibility has proven to be challenging. This study presents the synthesis of a novel conductive hydrogel composed of bovine serum albumin (BSA) protein and graphene oxide (GO) for the treatment of diabetic wounds. The prepared hydrogel is mildly reduced by ascorbic acid to facilitate charge-transfer and enhance its conductivity. Hydrogel is optimized for enhanced mechanical and electrical properties by changing the concentration of GO within the BSA matrix. The nanocomposite hydrogel demonstrates superior antibacterial properties and enhanced biocompatibility compared to the BSA hydrogel. The prepared hydrogel is investigated for wound healing capacity in a rat model, where it demonstrates rapid healing of chronic diabetic wound. The improved therapeutic outcomes are attributed to the hydrogel's ability to facilitate cellular activities through enhanced electrical conductivity by maintaining continuous electrical signal at the wound site. The presented findings suggest that nanocomposite protein-based conductive hydrogel not only hold great potential for advanced diabetic wound care and have potential for future innovation in tissue engineering, regenerative medicine and beyond.

Injectable natural hydrogel with spatiotemporal self-strengthening, antibacterial and anti-inflammatory properties for treating diabetic wound

Injectable hydrogel dressings provide a promising approach for treating diabetic wounds as they conform to irregular surfaces and foster new tissue development in a moist environment. Nevertheless, post-injection mechanical performance is often mediocre, coupled with inadequate antibacterial protection. Herein, we prepared an injectable hydrogel dressing (CBGT@PDA) consisting of double-network hydrogel (CBGT) and polydopamine nanoparticles (PDA NPs) as a multi-targeted combination therapy system oriented to chronic diabetic wound healing. Efficient enzymatic reactions combined with a slow quaternization procedure regulate the mechanical attributes of injectable hydrogels, offering spatiotemporal self-strengthening and exceptional antibacterial capabilities. The hydrogel system is also equipped with scavenged ROS function, bioadhesion characteristics and remarkable biocompatibility, thus exhibiting high improvement in the healing of the diabetic wound. We believe such injectable hydrogels with spatiotemporal self-strengthening capabilities in both of mechanical and antibacterial properties will provide new insight into the hydrogel-based wound dressing and broaden the application of the bioinspired hydrogels in biomedical fields.

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.

Chitosan-taurine nanoparticles cross-linked carboxymethyl chitosan hydrogels facilitate both acute and chronic diabetic wound healing

Wound dressing diligently facilitate healing by fostering hemostasis, immunoregulation, the angiogenesis, and collagen deposition. Our methodology entails fabricating chitosan-taurine nanoparticles (CS-Tau) through an ionic gelation method. The morphology of CS-Tau was observed utilizing Transmission electron microscopy (TEM), scanning electron microscopy (SEM) and Dynamic Light Scattering (DLS). The nanoparticles are subsequently incorporated into carboxymethyl chitosan hydrogels for crosslinking by EDC-NHS, yielding hydrogel dressings (CMCS-CS-Tau) designed to extend the duration of taurine release. In vitro investigations confirmed that these innovative compound dressings displayed superior biodegradation, biocompatibility, cytocompatibility, and non-toxicity, in addition to possessing anti-inflammatory properties, and stimulating the proliferation and mobility of human umbilical vein endothelial cells (HUVECs). Experiments conducted on mice models with full-thickness skin removal demonstrated that CMCS-CS-Tau efficaciously aided in wound healing by spurring angiogenesis, and encouraging collagen deposition. CMCS-CS-Tau can also minimize inflammation and promote collagen deposition in chronic diabetic wound. Hence, CMCS-CS-Tau promotes both acute and chronic diabetic wound healing. Furthermore, the sustained release mechanism of CMCS-CS-Tau on taurine reveals promising potential for extending its clinical utility in relation to various biological effects of taurine.

Hydroxypropyl methylcellulose reinforced bilayer hydrogel dressings containing L-arginine-modified polyoxometalate nanoclusters to promote healing of chronic diabetic wounds

Diabetes-related slow healing of wounds is primarily driven by bacterial infections and angiogenesis disorder and presents a substantial hurdle in clinical treatment. To solve the above problems, an advanced multifunctional hydrogel system based on natural polymer was created here to facilitate wound healing in patients with chronic diabetes. The prepared dressing was composed of an outer hydrogel containing polyvinyl alcohol and hydroxypropyl methyl cellulose in dimethyl sulfoxide and water as binary solvents, and an inner hydrogel containing chitosan quaternary ammonium salt, flaxseed gum, and polyvinyl alcohol. Thus, a polysaccharide based bilayer hydrogel (BH) with superior mechanical strength and biocompatibility was created. This bilayer hydrogel could easily bind to dynamic tissue surfaces, thereby generating a protective barrier. Meanwhile, L-arginine-modified polyoxometalate (POM@L-Arg) nanoclusters were loaded in the inner hydrogel. They released NO when stimulated by the peroxide microenvironment of diabetic wounds. NO as a signal molecule regulated vascular tension and promoted cell proliferation and migration. Additionally, because of the synergistic effect of NO and the chitosan quaternary ammonium salt, the hydrogel system exhibited excellent antibacterial performance. The NO released reduced the levels of proinflammatory factors IL-6 and TNF-α in the diabetic wounds, which thus accelerated wound healing. In short, BH + POM@L-Arg is expected to serve as an ideal wound dressing as it exerts a good promotion effect on diabetes-related wound healing.

Spatiotemporal modulation of immune microenvironment via composite hydrogel brakes for diabetic wound healing

Uncontrolled programmed polarization of macrophages plays an important role in chronic diabetic wound healing. Therefore, correcting programmed macrophage polarization while inducing new tissue remodelling through materials and preventing scar formation is desirable. Herein, a composite hydrogel brake that enables spatiotemporal regulation of the immune microenvironment was constructed to promote skin tissue regeneration. The system was based on thiolated hyaluronic acid to reshape the programmed polarization of macrophages, methacrylate gelatin as a mechanical support, and poly (L-lactic acid) nanoparticles loaded with TGF-β receptor antagonists to inhibit scar formation. Notably, the composite hydrogel acts as a double brake: in the early stage, self-induced M2-type polarization is achieved with the help of thiols; the TNF and NLRP signalling pathways are downregulated; and the immune microenvironment is regulated. During tissue remodeling, the long-term biological effect of TGF-β secretion by M2-type macrophages is interrupted by the slow release of antagonists, which inhibits excessive collagen deposition and prevents scar formation. The dual effect of restraint on reprogramming macrophage polarization and inhibiting scar formation was further confirmed in a diabetic rat skin defect model. Therefore, based on the immunological mechanism, a composite hydrogel brake was specifically designed to regulate the immune microenvironment, induce new tissue remodelling, and provide a promising clinical strategy for treating chronic diabetic wounds.

Tannic acid and silicate-functionalized polyvinyl alcohol-hyaluronic acid hydrogel for infected diabetic wound healing.

Healing of chronic diabetic wounds is challenging due to complications of severe inflammatory microenvironment, bacterial infection and poor vascular formation. Herein, a novel injectable polyvinyl alcohol-hyaluronic acid-based composite hydrogel was developed, with tannic acid (TA) and silicate functionalization to fabricate an 'all-in-one' hydrogel PTKH. On one hand, after being locally injected into the wound site, the hydrogel underwent a gradual sol-gel transition in situ, forming an adhesive and protective dressing for the wound. Manipulations of rheological characteristics, mechanical properties and swelling ability of PTKH could be performed via regulating TA and silicate content in hydrogel. On the other hand, PTKH was capable of eliminating reactive oxygen species overexpression, combating infection and generating a cell-favored microenvironment for wound healing acceleration in vitro. Subsequent animal studies demonstrated that PTKH could greatly stimulate angiogenesis and epithelization, accompanied with inflammation and infection risk reduction. Therefore, in consideration of its impressive in vitro and in vivo outcomes, this 'all-in-one' multifunctional hydrogel may hold promise for chronic diabetic wound treatment.

Stem Cell-Derived Extracellular Vesicles: Promising Therapeutic Opportunities for Diabetic Wound Healing.

Wound healing is a sophisticated and orderly process of cellular interactions in which the body restores tissue architecture and functionality following injury. Healing of chronic diabetic wounds is difficult due to impaired blood circulation, a reduced immune response, and disrupted cellular repair mechanisms, which are often associated with diabetes. Stem cell-derived extracellular vesicles (SC-EVs) hold the regenerative potential, encapsulating a diverse cargo of proteins, RNAs, and cytokines, presenting a safe, bioactivity, and less ethical issues than other treatments. SC-EVs orchestrate multiple regenerative processes by modulating cellular communication, increasing angiogenesis, and promoting the recruitment and differentiation of progenitor cells, thereby potentiating the reparative milieu for diabetic wound healing. Therefore, this review investigated the effects and mechanisms of EVs from various stem cells in diabetic wound healing, as well as their limitations and challenges. Continued exploration of SC-EVs has the potential to revolutionize diabetic wound care.

An injectable hydrogel of Enteromorpha polysaccharide/gelatin–derivatives inspired by siderophores and biocatalysis for addressing all phases of chronic diabetic wound healing

Given that chronic diabetic wounds are difficult to cure because of disruptions in the four healing phases (hemostasis, immune regulation, cell proliferation, and tissue regeneration), wound dressings promoting all of these phases and thus accelerating diabetic wound healing are highly desirable. To address this need, inspired by siderophore-Fe3+ chelation and horseradish peroxidase (HRP) catalysis, we synthesized a tyramine-modified Enteromorpha prolifera polysaccharide and dopamine-modified gelatin and used them to fabricate an injectable hydrogel (PG-Fe) featuring interpenetrating polymer networks facilitated by catecholate/carboxylate-Fe3+ coordination bonding and HRP-mediated covalent bonding between phenolic groups. PG-Fe exhibited good injectability, rapid gelation (11.5 s), suitable mechanical properties, enhanced tissue adhesiveness (50.5 kPa), and rapid self-healing (60 s) because of its intrinsic moieties and introduced modifications. Furthermore, it exhibited enhanced antioxidant, anti-inflammatory, cell adhesion, and migration effects. Consequently, PG-Fe simultaneously addressed all four wound healing phases, thereby shortening the closure time of normal and chronic diabetic wounds to 21 days. Following application, PG-Fe could be decomposed using a desferrioxamine solution and easily removed. Taken together, our study provides a novel strategy for fabricating injectable hydrogels that exhibit desirable physicochemical properties and enhanced biological functions to accelerate all phases of chronic diabetic wound healing.

Earthing Method as a Lifestyle Medicine to Accelerate the Healing of Chronic Diabetic Wounds

Diabetes mellitus (DM) type 2 is a non-communicable disease that causes death number 6 worldwide. Caused by resistance to insulin, accompanied by many complications, including neuropathy (peripheral nerve damage), diabetic ulcers, heart disease, kidney failure, hypertension, retinopathy (damage to the retina in the eyes), blindness, leg amputation, stroke, and death. Diabetic wounds do not heal because of microbial infections in the wounds, accompanied by high blood sugar levels. This study aims to analyze the effect of earthing/grounding on chronic diabetes wound healing. This research was conducted in June-December 2023 in Karanganyar Regency, Central Java. The population in this study were clients with type 2 diabetes mellitus. Earthing intervention was carried out for 1 hour every day for 30 days. The sample size was 21 respondents taken by the purposive sampling method. Statistical analysis shows a P value of 0.000<0.000 and a Z-score of -4.032. Shows the significant effect of earthing/grounding therapy on accelerating diabetes mellitus wound healing. It is highly recommended for clients with type 2 DM to apply earthing/grounding as part of Lifestyle Medicine, which is integrated into life habits to cure infections and speed up wound healing, thereby preventing amputations.

Multifunctional Hydrogel of Recombinant Humanized Collagen Loaded with MSCs and MnO2 Accelerates Chronic Diabetic Wound Healing.

Chronic wound repair is a clinical treatment challenge. The development of multifunctional hydrogels is of great significance in the key aspects of treating chronic wounds, including reducing oxidative stress, promoting angiogenesis, and improving the natural remodeling of extracellular matrix and immune regulation. In this study, we prepared a composite hydrogel, sodium alginate (SA)@MnO2/recombinant humanized collagen III (RHC)/mesenchymal stem cells (MSCs), composed of SA, MnO2 nanoparticles, RHC, and MSCs. The hydrogel has high mechanical properties and good biocompatibility. In vitro, SA@MnO2/RHC/MSCs hydrogel effectively enhanced the formation of intricate tubular structures and angiogenesis and showed synergistic effects on cell proliferation and migration. In vivo, the SA@MnO2/RHC/MSCs hydrogel enhanced diabetes wound healing, rapid re-epithelization, favorable collagen deposition, and abundant wound angiogenesis. These findings demonstrated that the combined effects of SA, MnO2, RHC, and MSCs synergistically accelerate healing, resulting in a reduced healing time. These observed healing effects demonstrated the potential of this multifunctional hydrogel to transform chronic wound care and improve patient outcomes.

Tetrahedral framework nucleic acids’ role in facilitating chronic diabetic wound repair via the endoplasmic reticulum-mitochondrial pathway

Under diabetic circumstances, keratinocytes are constantly exposed to hyperglycaemic micromilieu, leading to disrupted differentiation and increased chronic wound susceptibility during to sustained endoplasmic reticulum (ER) stress (ERS) and mitochondrial dysfunction during hyperglycaemia. As mitochondrial respiratory chain activity is a primary generator of intracellular reactive oxygen species (ROS), we postulated that tFNAs could potentially boost mitochondrial function and energy metabolism in the presence of oxidative stress. To this end, we first explored the ER-mitochondrial (ER-MITO) axis-associated intracellular transportation of tetrahedral framework nucleic acids (tFNAs). tFNAs are transported to the ER and mitochondria via caveolae-mediated endocytosis, thereby regulating the ER-MITO axis. Additionally, tFNAs reduce ERS by downregulating PERK-ATF 4-CHOP, thereby stabilising mitochondrial dynamics, improving energy metabolism, maintaining membrane potential polarisation, and scavenging generated reactive oxygen species to counteract oxidative stress during hyperglycaemia. Consequently, tFNAs restore cell proliferation, migration, and differentiation and enhance chronic wound healing and skin graft survival. Furthermore, tFNAs repaired the diabetic skin mechanical barrier, underscoring their versatility of ER-MITO axis modulation. Overall, this study highlights the importance of tFNAs in ER-MITO axis modulation and a novel therapeutic approach for chronic diabetic wound healing.

A ROS/glucose stimulated-responsive ADSCs-derived exosomes-release hydrogel system for diabetic wound healing

With numerous attempts at chronic wound healing in recent years, significant challenges pertaining to diabetic wound healing have arisen. These challenges result from excessive oxidative stress, vulnerability to bacterial infection, and persistent inflammation during the healing process. In response to the lack of a specific exosomes-sustained release system tailored for diabetic wounds, a reactive oxygen species (ROS)/glucose dual-responsive stimulated exosomes-released self-healing antibacterial antioxidant conductive multifunctional hydrogel has been developed, utilizing a simplistic “one-pot” method. This innovative hydrogel is constructed from a harmonious blend of polydopamine grafted MXene (PMX), chlorogenic acid (CA), L-ascorbate-2-phosphate trisodium slat (L), and adipose-derived stem cells (ADSCs) derived exosomes (E) with phenylboronic acid modified flaxseed gum (LG-PBA), chemically cross-linked with polyvinyl alcohol (PVA) to generate dynamic phenylboronate ester bond, to obtain P-LP-PMX-CA-L@E hydrogel. It was further demonstrated that the ROS/glucose-responsive exosomes-released P-LP-PMX-CA-L@E hydrogel integrated system could reduce ROS and inflammatory response by repairing the electron transfer chain, thereby facilitating skin damage repair in a mouse type I diabetic model. In conclusion, the multifunctional P-LP-PMX-CA-L@E hydrogel, endowed with stimuli-responsive exosomes release capability, exhibits a promoting effect on the healing of chronic diabetic wounds and offers a localized exosomes dual-response release strategy for the treatment of type I diabetic wounds.

Phenolic Ligand-Metal Charge Transfer Induced Copper Nanozyme with Reactive Oxygen Species-Scavenging Ability for Chronic Wound Healing.

Chronic wounds frequently arise as a complication in diabetic patients, and their management remains a significant clinical hurdle due to their nonhealing nature featured by heightened oxidative stress and impaired healing cells at the wound site. Herein, we present a 2D copper antioxidant nanozyme induced by phenolic ligand-metal charge transfer (LMCT) to eliminate reactive oxygen species (ROS) and facilitate the healing of chronic diabetic wounds. We found that polyphenol ligands coordinated on the Cu3(PO4)2 nanosheets led to a strong charge transfer at the interface and regulated the valence states of Cu. The obtained Cu nanozyme exhibited efficient scavenging ability toward different oxidative species and protected human cells from oxidative damage. The nanozyme enhanced the healing of diabetic wounds by promoting re-epithelialization, collagen deposition, angiogenesis, and immunoregulation. This work demonstrates the LMCT-induced ROS scavenging ability on a nanointerface, providing an alternative strategy of constructing metal-based nanozymes for the treatment of diabetic wounds as well as other diseases.

Janus Nanofiber Membranes with Photothermal‐Enhanced Biofluid Drainage and Sterilization for Diabetic Wounds

AbstractDiabetic wounds are difficult to heal, and the key to wound healing is exudate management and effective disinfection. Inspired by the asymmetric wettability of Janus‐structured lotus leaves, herein the study has presented the design of a biomimetic asymmetric Janus membrane that integrates unidirectional biofluid drainage and photothermal‐enhanced evaporation/sterilization capabilities for accelerating diabetic wound healing. This Janus membrane is prepared by electrospinning polyacrylonitrile (PAN) nanofiber membrane containing polydopamine (PDA) on the surface of polypropylene (PP) nonwoven membrane. Such PP/PANx%PDA Janus membrane enables antigravity “pumping” of the water from the hydrophobic PP layer to the hydrophilic PANx%PDA layer within 22 s through contact points on the Janus interface. The incorporation of 30 wt% PDA in PAN imparts high photoabsorption and photothermal responsiveness, facilitating continuous volatilization of the exudate, achieving twice the displacement of water, and causing irreversible damage to bacteria. As a result, it effectively alleviates inflammation and cellular fibrosis while promoting collagen deposition due to its structure and antibacterial properties. Impressively, such photothermal‐enhanced Janus membrane achieves an impressive closure rate of 96.7% for diabetic wounds, better than that of (59.8%) for conventional bandages. Therefore, this asymmetric Janus membrane offers a promising alternative for the healing of chronic diabetic wounds.

Wound pH-Modulating Strategies for Diabetic Wound Healing.

Significance: Chronic diabetic wounds on the lower extremities (diabetic foot ulcers, DFU) are one of the most prevalent and life-threatening complications of diabetes, responsible for significant loss of quality of life and cost to the health care system. Available pharmacologic treatments fail to achieve complete healing in many patients. Recent studies and investigational treatments have highlighted the potential of modulating wound pH in DFU. Recent Advances: Data from in vitro, preclinical, and clinical studies highlight the role of pH in the pathophysiology of DFU, and topical administration of pH-lowering agents have shown promise as a therapeutic strategy for diabetic wounds. In this critical review, we describe the role of pH in DFU pathophysiology and present selected low-molecular-weight and hydrogel-based pH-modulating systems for wound healing and infection control in diabetic wounds. Critical Issues: The molecular mechanisms leading to pH alterations in diabetic wounds are complex and may differ between in vitro models, animal models of diabetes, and the human pathophysiology. Wound pH-lowering bandages for DFU therapy must be tested in established animal models of diabetic wound healing and patients with diabetes to establish a comprehensive benefit-risk profile. Future Directions: As our understanding of the role of pH in the pathophysiology of diabetic wounds is deepening, new treatments for this therapeutic target are being developed and will be tested in preclinical and clinical studies. These therapeutic systems will establish a target product profile for pH-lowering treatments such as an optimal pH profile for each wound healing stage. Thus, controlling wound bed pH could become a powerful tool to accelerate chronic diabetic wound healing.

Bilirubin/morin self-assembled nanoparticle-engulfed collagen/polyvinyl alcohol hydrogel accelerates chronic diabetic wound healing by modulating inflammation and ameliorating oxidative stress

Chronic diabetic wounds pose a serious threat to human health and safety because of their refractory nature and high recurrence rates. The formation of refractory wounds is associated with wound microenvironmental factors such as increased expression of proinflammatory factors and oxidative stress. Bilirubin is a potent endogenous antioxidant, and morin is a naturally active substance that possesses anti-inflammatory and antioxidant effects. Both hold the potential for diabetic wound treatment by intervening in pathological processes. In this study, we developed bilirubin/morin-based carrier-free nanoparticles (BMn) to treat chronic diabetic wounds. In vitro studies showed that BMn could effectively scavenge overproduced reactive oxygen species and suppress elevated inflammation, thereby exerting a protective effect. BMn was then loaded into a collagen/polyvinyl alcohol gel (BMn@G) for an in vivo study to maintain a moist environment for the skin and convenient biomedical applications. BMn@G exhibits excellent mechanical properties, water retention capabilities, and in vivo safety. In type I diabetic mice, BMn@G elevated the expression of the anti-inflammatory factor IL-10 and concurrently diminished the expression of the proinflammatory factor TNF-α in the tissues surrounding the wounds. Furthermore, BMn@G efficiently mediated macrophage polarization from the M1-type to the M2-type, thereby fostering anti-inflammatory effects. Additionally, BMn@G facilitated the conversion of type III collagen fiber bundles to type I collagen fiber bundles, resulting in a more mature collagen fiber structure. This study provides a promising therapeutic alternative for diabetic wound healing.

Multifunctional nanocomposites mediated novel hydrogel for diabetic wound repair.

The regeneration and repair of diabetic wounds, especially those including bacterial infection, have always been difficult and challenging using current treatment. Herein, an effective strategy is reported for constructing glucose-responsive functional hydrogels using nanocomposites as nodes. In fact, tannic acid (TA)-modified ceria nanocomposites (CNPs) and a zinc metal-organic framework (ZIF-8) were employed as nodes. Subsequent crosslinking with 3-acrylamidophenylboronic acid achieved functional nanocomposite-hydrogels (TA@CN gel, TA@ZMG gel) by radical-mediated polymerization. Compared with a simple physically mixed hydrogel system, the mechanical properties of TA@CN gel and TA@ZMG gel are significantly enhanced due to the intervention of the nanocomposite nodes. In addition, this kind of nanocomposite hydrogel can realize the programmed loading of drugs and release of drugs in response to glucose/PH, to coordinate and promote its application in the regeneration and repair of diabetic wounds and infected diabetic wounds. Specifically, TA@CN gel can remove reactive oxygen species and generate oxygen through its various enzymatic activities. At the same time, it can effectively promote neovascularization, thus promoting the regeneration and repair of diabetic wounds. Furthermore, glucose oxidase-loaded TA@ZMG gel exhibits glucose response and pH-regulating functions, triggering programmed metformin (Met) release by degrading the metal-organic framework (MOF) backbone. It also exhibited additional synergistic effects of antibacterial activity, hair regeneration and systemic blood glucose regulation, which make it suitable for the repair of more complex infected diabetic wounds. Overall, this novel nanocomposite-mediated hydrogel holds great potential as a biomaterial for the healing of chronic diabetic wounds, opening up new avenues for further biomedical applications.

Micro-environment triple-responsive hyaluronic acid hydrogel dressings to promote antibacterial activity, collagen deposition, and angiogenesis for diabetic wound healing.

The clinical treatment of chronic diabetic wounds is a long-standing thorny issue. Strategies targeting the diabetic micro-environment have been developed to promote wound healing. However, it remains challenging to reverse the adverse conditions and re-activate tissue regeneration and angiogenesis. In this work, we develop injectable hydrogels that are responsive to acidic conditions, reactive oxygen species (ROS), and high glucose levels in a diabetic wound micro-environment to sustainably deliver tannic acid (TA) to augment antibacterial, anti-inflammatory, and anti-oxidative activities. This triple-responsive mechanism is designed by introducing dynamic acylhydrazone and phenylboronic ester bonds to crosslink modified hyaluronic acid (HA) chains. At a diabetic wound, the acylhydrazone bonds may be hydrolyzed at low pH. Meanwhile, glucose may compete with TA, and ROS may oxidize the C-B bond to release TA. Thus, sustained release of TA is triggered by the diabetic micro-environment. The released TA effectively scavenges ROS and kills bacteria. In vivo experiments on diabetic mice demonstrate that the hydrogel dressing highly promotes angiogenesis and extracellular matrix (ECM) deposition, leading to eventual full healing of diabetic skin wounds. This micro-environment-triggered triple-responsive drug release provides a promising method for chronic diabetic wound healing.