Management Of Diabetic Wounds Research Articles

A Burning Grass and Removing Root Immunoregulatory Strategy Toward Chronic Wounds Therapy by MnO2 Nanoparticle Incorporated Hyaluronic Acid Hydrogel

AbstractComplex immune microenvironment of diabetic wound possesses polarization misalignment of macrophages and excessive inflammatory response, which prolong the healing process. Consequently, developing hydrogel dressings with immunoregulatory ability shows huge potential in clinical management of diabetic wound. Nevertheless, recent immunoregulatory strategies are mainly focusing on switching the proinflammatory M1‐type to anti‐inflammatory M2‐type macrophages by using high‐cost dressings composed of cytokines and cells. Considering the hyperpolarized M1 macrophages of diabetic wounds as wild grass of wasteland, a burning grass and removing root immunoregulatory strategy toward wound healing is developed based on dopamine‐manganese dioxide nanoparticle incorporated high molecular weight hyaluronic acid (HHA) hydrogel. The self‐healing and injectable hydrogel is formed by boronate ester bonds between the HHA grafted with phenylboronic acid and polyvinyl alcohol. Notably, in vitro and vivo results confirm that the HHA components can burn the grass by switching M1 to M2 in the inflammatory microenvironment while the dopamine‐manganese dioxide nanoparticles can remove the root by relieving M1 polarization through eliminating reactive oxygen species. The comprehensive immunoregulation ability enables the hydrogel as effective therapeutic that improves wound healing, and shows reliable potential in clinical dressings for the management of diabetic wounds.

Small extracellular vesicles: Yields, functionalization and applications in diabetic wound management

AbstractDiabetic wounds have imposed a significant burden on both patients and society with prolonged healing processes hindered by dysfunctional skin repair cells. Small extracellular vesicles (sEVs), as the important media for intercellular communications, show promising therapeutic potential in treating diabetic wounds by restoring cellular functions. However, low yields and limited bio‐function of sEVs greatly challenge their large‐scale clinical use. Here, we briefly overview the biogenesis and cellular uptake of sEVs, emphasize current advances in improving the yields of sEVs and optimizing the function of sEVs with engineering approaches, and summarize the applications of engineered sEVs in diabetic wound treatment. Furthermore, the undissolved issues during the clinical transformation of engineered sEVs are also discussed. This critical review aims to provide meaningful guidance for future applications of engineered sEVs in the management of diabetic wounds.

A sensitive non-enzymatic dual-conductive biosensor for continuous glucose monitoring

BackgroundDiabetes and diabetic wound management have always been urgent issues for global healthcare. In the demand for blood glucose monitoring and wound management, phenylboronic acid (PBA)-based glucose biosensors are effective assistance due to their excellent glucose specificity, high sensitivity, and response stability. Nevertheless, PBA-based glucose biosensors still have challenges in terms of wide linearity and large deformation requirements. Therefore, it is necessary to develop PBA-based glucose biosensors with satisfactory mechanical properties, high response sensitivity, excellent stability, and wide linearity. ResultsIn this work, a glucose-responsive PBA-based biosensor was successfully synthesized for the first time. The sensor materials exhibited excellent mechanical properties with an elongation at break reached up to 1000%, and the healing efficiency was over 90% within 30 min at 45 °C. Furthermore, the biosensor exhibited exceptional electromechanical responsiveness, stability, high sensitivity, and wide linearity due to the specificity of phenylboronic acid to glucose and the construction of a special HCNT/PEDOT:PSS dual conductive structure. In addition, the assembled biosensor displayed remarkable glucose, pH and temperature responses, exhibiting a linear response to glucose concentration range from 0.20 mM to 2.0 mM, with a sensitivity coefficient of 47.11 mA mM−1 and regression coefficient of 0.942. Moreover, the sensor materials showed satisfactory cytocompatibility, hemocompatibility, and antibacterial properties against Escherichia coli and Staphylococcus aureus. SignificanceFor the first time, a dual conductive structural glucose biosensor based on PBA-based copolymer was synthesized. In addition to excellent glucose sensitivity and response stability, the biosensor has a wide linearity range, excellent self-healing property, and satisfactory mechanical performance. As a promising substitute for non-enzymatic glucose biosensors, this new material with special structure and characteristics would also be beneficial to wound management in diabetic patients.

3D-exosomes laden multifunctional hydrogel enhances diabetic wound healing via accelerated angiogenesis

Impaired vascular networks, local insufficiency of neovascularization, and tissue inflammation caused by the accumulation of reactive oxygen species (ROS) and bacterial infections contribute to the delayed healing of wounds in patients with diabetes. Thus, an urgent need is to develop effective diabetic wound treatments that promote angiogenesis, inhibit bacterial infections, and reduce oxidative damage and tissue inflammation. Exosome therapy promotes angiogenesis and wound healing. However, traditional exosomes have limitations such as low yield and rapid release. Compared with two-dimensional (2D) cell culture, three-dimensional (3D) cell culture results in a higher yield of exosomes and better healing effects. In this study, we designed a multifunctional hydrogel with 3D-exosome-sustained release features to improve diabetic wound healing. Chitosan-grafted-dihydrocaffeic acid (CS-DA) and benzaldehyde-terminated Pluronic®F127 (PF127-CHO) were combined using a dynamic Schiff base bond to form a dynamic hydrogel network and simultaneously fused tannic acid (TA) and 3D adipose-derived mesenchymal stem cells-derived exosomes (3D ADSCs-Exos, referred to in this study as 3D-Exo). The phosphoric acid groups of 3D-Exo combine with the polyphenol groups of DA/TA through reversible interactions, enabling the sustained release of 3D-Exo. The CS-DA/PF/TA/3D-Exo hydrogel exhibited tissue-adhesive, self-healing, antibacterial, anti-inflammatory, and antioxidant properties. The CS-DA/PF/TA/3D-Exo hydrogel significantly accelerated the recovery of diabetic wounds by promoting angiogenesis and collagen deposition in vivo. Furthermore, rapid hemostasis was achieved owing to the wet tissue adhesion and platelet activation of the hydrogel. In general, this multifunctional hydrogel could be used as a wound dressing for diabetic wound management.

Multifunctional Drugs-Loaded Carbomol Hydrogel Promotes Diabetic Wound Healing via Antimicrobial and Immunoregulation.

Diabetic wound healing poses a significant clinical dilemma. Bacterial infection and immune dysregulation are the predominant reasons. However, conventional wound dressings with a single treatment approach often limit therapeutic efficacy and continue working with difficulty. These limitations cause high treatment failure for diabetic wounds. In this study, we developed a multiple drug-loaded carbomer hydrogel containing Que/Van/Rif (QVR-CBMG) for the simultaneous treatment of infection and immune dysregulation. Honeycomb-like QVR-CBMG hydrogel exhibits excellent abilities to eliminate bacterial infection and biofilms in vitro. Moreover, QVR-CBMG hydrogel possesses an immunomodulatory capacity via affecting the Sirt3/SOD2 signaling pathway to promote M2 macrophages. Furthermore, QVR-CBMG hydrogel effectively promotes wound healing in diabetic rats through several mechanisms. The multidrug-loaded wound dressing not only eliminates bacterial infection and facilitated angiogenesis but also promotes collagen deposition and remodulates the local immune microenvironment in the areas of wounds. In summary, this synthetic strategy to eliminate infection and regulate immune disorders has potential translational value for the prevention and management of diabetic wounds.

Ultrasmall MnOx Nanodots Catalyze Glucose for Reactive Oxygen Species‐Dependent Sequential Anti‐Infection and Regeneration Therapy

The management of diabetic wounds poses significant challenges due to persistent bacterial infections and chronic inflammation caused by hyperglycemia. Herein, a sequential two‐phase treatment strategy involving a reactive oxygen species (ROS) burst in the first phase for anti‐infection is proposed, followed by a benign level of ROS in the second phase for wound regeneration. To this end, ultra‐small manganese oxide nanodots (BM‐NDs) are incorporated into a gelatin methacrylamide (GelMA) hydrogel via a ROS‐responsive linker to form GelMA@BM dressing. The BM‐NDs catalyze a self‐cascade reaction that decomposes glucose into hydrogen peroxide, generates hydroxyl radicals (·OH), and simultaneously depletes glutathione. Upon application on diabetic wounds, BM‐NDs are rapidly released from the hydrogel due to endogenous ROS exposure, leading to high levels of ·OH that effectively eliminate bacteria and promote macrophage polarization to M1 phenotype, thereby facilitating phagocytosis of bacteria. With the consumption of glucose and degradation of BM‐NDs, ROS in the wound area declines to a benign level, which stimulates polarization of M2 macrophages and promotes wound healing. This two‐phase treatment strategy based on GelMA@BM dressing demonstrates potent antibacterial and pro‐healing efficacy, showcasing its potential for clinical translation.

Biocompatible polyvinyl alcohol nanofibers loaded with amoxicillin and salicylic acid to prevent wound infections.

Diabetic wounds are one of the most challenging clinical conditions in diabetes, necessitating the development of new treatments to foster healing and prevent microbial contamination. In this study, polyvinyl alcohol was used as a matrix polymer, and amoxicillin (AMX) and salicylic acid (SA) were selected as bioactive compounds with antimicrobial (with AMX) and anti-inflammatory action (with SA) to obtain innovative drug-loaded electrospun nanofiber patches for the management of diabetic wounds. Scanning electron microscope images revealed the uniform and beadless structure of the nanofiber patches. Mechanical tests indicated that AMX minimally increased the tensile strength, while SA significantly reduced it. The patches demonstrated effective antibacterial activity against both gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) strains. The potential of these patches in the development of novel wound dressings is highlighted by the excellent biocompatibility with fibroblast cells maintained for up to 7 d.

Bletilla striata composite nanofibrous membranes prepared by emulsion electrospinning for enhanced healing of diabetic wounds.

Diabetic wounds impose enormous distress and financial burden on patients, and finding effective dressings to manage wounds is critical. As a Chinese herbal medicine with a long history of Clinical application, Bletilla striata has significant medicinal effects in the therapy of various wounds. In this study, PLA and the pharmacodynamic substances of Bletilla striata were prepared into fibrous scaffolds by emulsion electrospinning technology for the management of diabetic wounds in mice. The results of scanning electron microscopy showed that the core-shell structure fibre was successfully obtained by emulsion electrospinning. The fibre membrane exhibited excellent water absorption capability and water vapor transmission rate, could inhibit the growth of Staphylococcus aureus and Pseudomonas aeruginosa, had good compatibility, and achieved excellent healing effect on diabetic wounds. Especially in the in vivo wound healing experiment, the wound healing rate of composite fibre membrane treatment reached 98.587 ± 2.149% in 16days. This work demonstrated the good therapeutic effect of the developed fibrous membrane to diabetic wound, and this membrane could be potentially applied to chronic wound healing.

Spray-coating of a hydrophobic poly(tetrafluoroethylene) membrane with a copolymer containing sulfobetaine methacrylamide to boost hydration and reduce biofouling in view of improving diabetic wound management and alleviate the immune response

In spite of being an application that tends to be overlooked by membranologists, chronic skin wound healing can be tackled by innovating approaches starring advanced porous membrane materials creating a suitable environment for wound management. Here, we fabricated porous poly(tetrafluoroethylene) membranes decorated with sulfobetaine methacrylamide moieties using a spray-coating method following surface activation by plasma. The zwitterionization permitted to reach improved hydration (WCA of 70°, down from 114°) and quasi-neutral zeta potential (−3 mV up from −68 mV) which rationalized low non-specific protein adsorption (reduced by 88% with fibrinogen), low bacterial and blood fouling (Escherichia coli and whole blood attachment decreased by 98% and 92%, respectively), all the while maintaining very high survival rate of fibroblasts (89%). Improved hydrophilicity and porous features arose in a water vapor transmission rate (>3000 g m−2.day−1) thought to be appropriate to the healing of highly exuding chronic wounds. Applied on skin wounds of diabetic rats, the zwitterionic antifouling biocompatible porous membranes led to faster closure than a commercial dressing (87% vs. 79% after 14 days) by efficiently alleviating the inflammation response. From a histological analysis ran during the inflammation period, infiltrates in the tissue were measured to be 830 ± 240 cells/mm2, against 1507 ± 321 cells/mm2 with the commercial material. Thus, the results of this work demonstrate the benefit of using antifouling porous membranes which reduce the immune response, leading to better and faster healing of chronic wounds. This widens the range of applications for such membranes.

Platelet Rich Plasma Loaded Multifunctional Hydrogel Accelerates Diabetic Wound Healing via Regulating the Continuously Abnormal Microenvironments.

Continuous oxidative stress and cellular dysfunction caused by hyperglycemia are distinguishing features of diabetic wounds. It has been a great challenge to develop a smart dressing that can accelerate diabetic wound healing through regulating abnormal microenvironments. In this study, a platelet rich plasma (PRP) loaded multifunctional hydrogel with reactive oxygen species (ROS) and glucose dual-responsive property is reported. It can be conveniently prepared with PRP, dopamine (DA) grafted alginate (Alg-DA), and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (ABO) conjugated hyaluronic acid (HA-ABO) through ionic crosslinks, hydrogen-bond interactions, and boronate ester bonds. The hydrogel possesses injectability, moldability, tissue adhesion, self-healing, low hemolysis, and hemostasis performances. Its excellent antioxidant property can create a low oxidative stress microenvironment for other biological events. Under an oxidative stress and/or hyperglycemia state, the hydrogel can degrade at an accelerated rate to release a variety of cytokines derived from activated blood platelets. The result is a series of positive changes that are favorable for diabetic wound healing, including fast anti-inflammation, activated macrophage polarization toward M2 phenotype, promoted migration and proliferation of fibroblasts, as well as expedited angiogenesis. This work provides an efficient strategy for chronic diabetic wound management and offers an alternative for developing a new-type PRP-based bioactive wound dressing.

A glucose-responsive nitric oxide release hydrogel for infected diabetic wounds treatment.

Bacteria-infected chronic wound is one of the most serious complications of diabetes and characterized with high morbidity and risk of lower extremity amputation. Nitric oxide (NO) represents a promising strategy to accelerate wound healing through down-regulating inflammation, promoting angiogenesis and bacterial eradication. However, stimuli-responsive and control release of NO at the wound microenvironment remains a challenge. In this work, an injectable, self-healing and antibacterial hydrogel characterized with glucose-responsive and constant NO release behaviors has been engineered for diabetic wound management. The hydrogel (CAHG) is prepared by in situ crosslinking of L-arginine (L-Arg)-coupled chitosan and glucose oxidase (GOx)-modified hyaluronic acid based on Schiff-base reaction. The system is capable of mediating a continuous release of hydrogen peroxide (H2O2) and NO by the cascaded consumption of glucose and L-Arg in the presence of hyperglycemia environment. In vitro studies demonstrate that bacteria proliferation is significantly inhibited by CAHG hydrogel involving in the cascaded release of H2O2 and NO. More importantly, a full-thickness skin wound model on a diabetic mouse demonstrates that H2O2 and NO release from CAHG hydrogel exhibits a superior efficiency for wound healing through bacterial inhibition, down-regulation of pro-inflammatory factors and the elevation of M2-type macrophage, contributing to the collagen deposition and angiogenesis. In conclusion, CAHG hydrogel with excellent biocompatibility and glucose-responsive NO release characteristic can serve as a highly efficient therapeutic strategy for diabetic wound treatment.

Aplikasi mHEALTH dalam Manajemen Luka Diabetik

This study aims to determine the use of mHealth in diabetic wound management. The research method uses a literature review approach through content analysis with a search method using an electronic database consisting of ProQuest, PubMed, Science Direct, Scopus, Sage, and SpringerLink with the keywords "telemedicine," "telehealth," "mobile health," "diabetic ulcer.", and "diabetic wound" published year 2018-2022. The search results obtained 612 articles, and 12 papers were reviewed after filtering. The results showed that there were four essential components in using health for diabetic wound management, namely counseling/consultation, use of wearable devices, routine foot temperature checks, and recommendations for diabetic wound care. In conclusion, mHealth positively and effectively impacts diabetic wound management.
 Keywords: Diabetic Wounds, Management, mHealth, Telehealth, Telemedicine

Panthenol Citrate Biomaterials Accelerate Wound Healing and Restore Tissue Integrity.

Impaired wound healing is a common complication for diabetic patients and effective diabetic wound management remains a clinical challenge. Furthermore, a significant problem that contributes to patient morbidity is the suboptimal quality of healed skin, which often leads to reoccurring chronic skin wounds. Herein, a novel compound and biomaterial building block, panthenol citrate (PC), is developed. It has interesting fluorescence and absorbance properties, and it is shown that PC can be used in soluble form as a wash solution and as a hydrogel dressing to address impaired wound healing in diabetes. PC exhibits antioxidant, antibacterial, anti-inflammatory, and pro-angiogenic properties, and promotes keratinocyte and dermal fibroblast migration and proliferation. When applied in a splinted excisional wound diabetic rodent model, PC improves re-epithelialization, granulation tissue formation, and neovascularization. It also reduces inflammation and oxidative stress in the wound environment. Most importantly, it improves the regenerated tissue quality with enhanced mechanical strength and electrical properties. Therefore, PC could potentially improve wound care management for diabetic patients and play a beneficial role in other tissue regeneration applications.

A tetramethylpyrazine-loaded hyaluronic acid-based hydrogel modulates macrophage polarization for promoting wound recovery in diabetic mice

The failure of wound healing often causes lower limb disability and amputation of diabetic patients. Current strategies for diabetic wound management often fail to achieve the expected outcomes, and emerging alternatives are urgently needed. Recent advances in the identification of active compounds from traditional herbal medicines provide promising therapeutics for tissue repair and regeneration. In this study, the pro-healing effects of tetramethylpyrazine (TMP, a natural alkaloid found in Ligusticum chuanxiong Hort) for diabetic wounds were for the first time demonstrated. The cutaneous healing was mainly achieved by TMP-mediated macrophage polarization from pro-inflammatory to pro-healing phenotype. In addition, the topical administration of TMP was facilitated by the hyaluronic acid (HA) hydrogel for promoting the full-thickness wounds in the experimental diabetic mice. Consequently, TMP-loaded HA hydrogel (TMP-HA) profoundly accelerated the wound closure in comparison with TMP-loaded INTRASITE Gel (it is a commercial hydrogel), which was evident with the inflammation mitigation, the angiogenesis enhancement, and the collagen deposition. Our work reveals the macrophage-modulatory function of TMP for diabetic wound healing and demonstrates great potential of TMP-HA for clinical application.

Two-Pronged Microbe Delivery of Nitric Oxide and Oxygen for Diabetic Wound Healing.

Chronic inflammation and hypoxia in the microenvironment of diabetic foot ulcers (DFUs) can result in sustained vascular impairment, hindering tissue regeneration. While both nitric oxide and oxygen have been shown to promote wound healing in DFUs through anti-inflammatory and neovascularization, there is currently no available therapy that delivers both. We present a novel hydrogel consisting of Weissella and Chlorella, which alternates between nitric oxide and oxygen production to reduce chronic inflammation and hypoxia. Further experiments indicate that the hydrogel accelerates wound closure, re-epithelialization, and angiogenesis in diabetic mice and improves the survival of skin grafts. This dual-gas therapy holds promise as a potential treatment option for the management of diabetic wounds.

A simple yet effective hydrogel dressing for advanced microenvironmental management of diabetic wounds with intrinsic regulation

Diabetic wounds are challenging to heal due to high glucose levels, and oxidative stress, impaired immune response and delayed angiogenesis. Hydrogel dressings capable of adapting and improving multiple microenvironments have broad prospects for application in clinical diabetes wound healing. In this study, we developed a photocrosslinked chitosan hydrogel using the antioxidant molecule “lipoic acid”, eliminating the need for additional photoinitiators. The obtained hydrogel exhibited respectable adhesion (adhesion strengths to iron, wood and skin are 0.045 MPa, 0.049 MPa and 0.041 MPa, respectively), photo-induced self-healing, and responsiveness to pH, H2O2 and glucose. Notably, as compared to conventional injectable methacrylated chitosan hydrogel, LAMC hydrogels displayed the abilities to regulate the wound environment, such as reducing oxidative stress, blood sugar levels, and pH, and creating a favorable microenvironment for wound healing. Exosome-loaded LAMC hydrogels enabled targeted exosome release based on glucose concentration, pH, and H2O2 to promote angiogenesis and accelerate healing. Our study offers a novel method for preparing injectable chitosan hydrogels and introduces a new strategy for developing drug-delivery systems that effectively promote diabetic wound healing, potentially transforming current therapeutic approaches.

H2S-releasing versatile hydrogel dressing with potent antimicrobial, anti-inflammatory, epithelialization and angiogenic capabilities for diabetic wound healing

Smart hydrogel dressings capable of simultaneously highly effective antimicrobial, anti-inflammatory, and promoting re-epithelialization and angiogenesis are urgently needed for the management of diabetic wounds. Herein, a H2S-releasing multifunctional hydrogel was developed by utilizing the dynamic Schiff base reaction between carboxymethyl chitosan (CMC) and polyhexamethylene guanidine (PHMG)-modified aldehyde F108 (PFC). Diallyl trisulfide (DATS) was encapsulated into the PFC nanoparticles. Apart from possessing the essential properties necessary for an idealized hydrogel dressing, such as excellent injectability, tissue adhesion, self-healing, and stimulus–response degradation, the DATS@PFC&CMC also utilized the synergistic effect of the PHMG and DATS to provide an efficient antimicrobial effect; the H2S was slowly released from the DATS under the action of GSH and exerted excellent anti-inflammatory effects, by inhibiting the expression of p-ERK and p-STAT3 in activated macrophages, and promoting macrophage polarization to the M2 phenotype. Strikingly, following the completion of the efficient antimicrobial and anti-inflammatory effects, the continuously generated H2S further significantly accelerated the proliferation, migration, and vascularization of endothelial cells by extending the activation of the p-p38 and p-ERK1/2. Owing to superior performances, DATS@PFC&CMC significantly promoted the healing of diabetic wounds induced by streptozotocin with good biocompatibility. This study demonstrates that DATS@PFC&CMC is a versatile hydrogel dressing with great potential for the management of diabetic wounds.

Purpurolide C-based microneedle promotes macrophage-mediated diabetic wound healing via inhibiting TLR4-MD2 dimerization and MYD88 phosphorylation

Delayed wound healing in diabetes is a global challenge, and the development of related drugs is a clinical problem to be solved. In this study, purpurolide C (PC), a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum, was found to promote diabetic wound healing. To investigate the key regulation targets of PC, in vitro RNA-seq, molecular docking calculations, TLR4-MD2 dimerization SDS-PAGE detection, and surface plasmon resonance (SPR) were performed, indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation. Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing. Furthermore, a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC (PC@MLIP MN) was developed, which overcame the poor water solubility and weak skin permeability of PC, so that successfully punctured the skin and delivered PC to local tissues, and accurately regulated macrophage polarization in diabetic wound management. Overall, PC is an anti-inflammatory small molecule compound with a well-defined structure and dual-target regulation, and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.

Engineering homologous platelet-rich plasma, platelet-rich plasma-derived exosomes, and mesenchymal stem cell-derived exosomes-based dual-crosslinked hydrogels as bioactive diabetic wound dressings

The management of diabetic wounds remains a critical therapeutic challenge. Platelet-rich plasma (PRP) gel, PRP-derived exosomes (PRP-Exos), and mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated therapeutic potential in wound treatment. Unfortunately, their poor mechanical properties, the short half-lives of growth factors (GFs), and the burst release of GFs and exosomes have limited their clinical applications. Furthermore, proteases in diabetic wounds degrade GFs, which hampers wound repair. Silk fibroin is an enzyme-immobilization biomaterial that could protect GFs from proteases. Herein, we developed novel dual-crosslinked hydrogels based on silk protein (SP) (sericin and fibroin), including SP@PRP, SP@MSC-Exos, and SP@PRP-Exos, to promote diabetic wound healing synergistically. SP@PRP was prepared from PRP and SP using calcium gluconate/thrombin as agonist, while SP@PRP-Exos and SP@MSC-Exos were derived from exosomes and SP with genipin as crosslinker. SP provided improved mechanical properties and enabled the sustained release of GFs and exosomes, thereby overcoming the limitations of PRP and exosomes in wound healing. The dual-crosslinked hydrogels displayed shear-induced thinning, self-healing, and eradication of microbial biofilms in a bone-mimicking environment. In vivo, the dual-crosslinked hydrogels contributed to faster diabetic wound healing than PRP and SP by upregulating GFs expression, down-regulating matrix metalloproteinase-9 expression, and by promoting an anti-NETotic effect, angiogenesis, and re-epithelialization. Hence, these dual-crosslinked hydrogels have the potential to be translated into a new generation of diabetic wound dressings.

Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing

Cellular senescence describes a state of permanent proliferative arrest in cells. Studies have demonstrated that diabetes promotes the pathological accumulation of senescent cells, which in turn impairs cell movement and proliferation. Historically, senescence has been perceived to be a detrimental consequence of chronic wound healing. However, the underlying mechanism that causes senescent cells to remain in diabetic wounds is yet to be elucidated. Ferroptosis and ferritinophagy observed in diabetes are due to iron metabolism disorders, which are directly associated with the initiation and progression of diabetes. Herein, we reveal that senescent fibroblasts in diabetic wounds are resistant to ferroptosis and that impaired ferritinophagy may be a contributing cause. Further, the expression of NCOA4, a key factor that influences ferritinophagy, is decreased in both diabetic wound tissue and high glucose-induced senescent fibroblasts. Moreover, NCOA4 overexpression could render senescent fibroblasts more vulnerable to ferroptosis. A faster wound healing process was also linked to the induction of ferroptosis. Thus, resistance to ferroptosis impedes the removal of senescent fibroblasts; promoting ferritinophagy could reverse this process, which may have significant implications for the management of diabetic wounds.