Treatment Of Diabetic Wounds Research Articles

Preparation of therapy-grade extracellular vesicles from adipose tissue to promote diabetic wound healing.

Background: Treatment of diabetic wounds is a major challenge in clinical practice. Extracellular vesicles (EVs) from adipose-derived stem cells have shown effectiveness in diabetic wound models. However, obtaining ADSC-EVs requires culturing vast numbers of cells, which is hampered by the need for expensive equipment and reagents, extended time cost, and complicated procedures before commercialization. Therefore, methods to extract EVs from discarded tissue need to be developed, for immediate application during surgery. For this reason, mechanical, collagenase-digestive, and constant in-vitro-collective methods were designed and compared for preparing therapy-grade EVs directly from adipose tissue. Methods: Characteristics and quantities of EVs were detected by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting firstly. To investigate the biological effects of EVs on diabetic wound healing, angiogenesis, proliferation, migration, and inflammation-regulation assays were then evaluated in vitro, along with a diabetic wound healing mouse model in vivo. To further explore the potential therapeutic mechanism of EVs, miRNA expression profile of EVs were also identified and analyzed. Results: The adipose tissue derived EVs (AT-EVs) were showed to qualify ISEV identification by nanoparticle tracking analysis and Western blotting and the AT-EVs yield from three methods was equal. EVs also showed promoting effects on biological processes related to diabetic wound healing, which depend on fibroblasts, keratinocytes, endothelial cells, and macrophages both in vitro and in vivo. We also observed enrichment of overlapping or unique miRNAs originate from different types of AT-EVs associated with diabetic wound healing for further investigation. Conclusion: After comparative analyses, a mechanical method was proposed for preparing immediate clinical applicable EVs from adipose tissue that would result in reduced preparation time and lower cost, which could have promising application potential in treating diabetic wounds.

Self-Assembling Peptide SCIBIOIII Hydrogel for Three-Dimensional Cell Culture That Promotes Wound Healing in Diabetic Mice.

An important clinical challenge is improving the healing rate of diabetic chronic wounds, and developing new approaches that can promote chronic wound healing is essential. A new biomaterial that has demonstrated great potential for tissue regeneration and repair is self-assembling peptides (SAPs); however, they have been less studied for the treatment of diabetic wounds. Here, we explored the role of an SAP, SCIBIOIII, with a special nanofibrous structure mimicking the natural extracellular matrix for chronic diabetic wound repair. The results showed that the SCIBIOIII hydrogel in vitro has good biocompatibility and can create a three-dimensional (3D) culture microenvironment for the continuous growth of skin cells in a spherical state. The SCIBIOIII hydrogel in diabetic mice (in vivo) significantly improved wound closure, collagen deposition, and tissue remodeling and enhanced chronic wound angiogenesis. Thus, the SCIBIOIII hydrogel is a promising advanced biomaterial for 3D cell culture and diabetic wound tissue repair.

Supramolecular Hydrogels for Precisely Controlled Antimicrobial Peptide Delivery for Diabetic Wound Healing

Diabetic wound patients are often exposed to bacterial infections with delayed healing process due to hyperglycemia in the damaged skin tissue. Antimicrobial peptides (AMPs) have been investigated for the treatment of infection-induced diabetic wounds, but their low stability and toxicity have limited their further applications to diabetic chronic wound healing. Here, we developed a precisely controlled AMP-releasing injectable hydrogel platform, which could respond to infection-related materials of matrix metalloproteinases (MMPs) and reactive oxygen species (ROS). The injectable supramolecular hydrogel was prepared by the simple mixing of hyaluronic acid modified with cyclodextrin (HA-CD) and adamantane (Ad-HA). Ad-HA was conjugated with AMP via the cyclic peptide linker composed of MMP and ROS cleavable sequence (Ad-HA-AMP). Remarkably, only when the AMP-tethered hydrogel was exposed to both MMP and ROS simultaneously, AMP was released from the hydrogel, enabling the controlled release of AMP without causing cytotoxicity. In addition, we confirmed the enhanced serum stability of the Ad-HA-AMP conjugate. The antimicrobial activity of Ad-HA-AMP was maintained much longer than that of the native AMP. Finally, we could demonstrate the greatly improved wound-healing effect of AMP-tethered hydrogels with enhanced safety for the treatment of infection-induced diabetic chronic wounds. Taken together, we successfully demonstrated the feasibility of sHG-AMP for diabetic chronic wound healing.

Naturally derived dual dynamic crosslinked multifunctional hydrogel for diabetic wound healing

Diabetic wound treatments remain a significant challenge for regenerative medicine due to the unicity of clinical dressings, which lack systemic multifunction with injectability, self-healing ability, moderate tissue adhesion, anti-inflammation and antibacterial abilities, and guidance of tissue repair. Herein, a naturally derived multifunctional hydrogel dressing composed of keratin, protocatechuic aldehyde (PA) and iron ions is fabricated through a simple mixing process, circumventing the use of any extra crosslinking agents or functional modification. Our findings showed that a dual dynamic crosslinked network was constructed through a dynamic thiol-aldehyde addition reaction between thiol groups in keratin and aldehyde groups in PA, and catechol-metal ions coordination bonds between catechol groups in PA and Fe3+, and realized good injectability, mechanical performance, self-healing ability, tissue adhesion and antibacterial properties of the hydrogel. Moreover, the incorporation of phellopterin (PP), a natural compound derived from traditional Chinese herb Angelica dahurica endowed the hydrogel with anti-inflammation properties. The PP-loaded hydrogel shortened inflammation duration and accelerated wound repair in the full-thickness wounds of streptozotocin-induced diabetic mice, notably by promoting macrophage polarization towards anti-inflammatory phenotype and resolving local inflammation. The PP-loaded hydrogel achieved almost wound closure after only 10 days for a diabetic wound of 6 mm in diameter. This study demonstrated that the PP-loaded dynamic crosslinked multifunctional hydrogel had a great potential in the treatment of diabetic wounds.

Developing integrated care: Treating foot wounds in people with diabetes mellitus exposed by Covid-19

Background: Diabetes mellitus is a chronic disease that affects many people around the world. WHO predicts the prevalence in 2030 will increase to 61 percent and it is estimated that 70 percent will become a pandemic in developing countries including Indonesia. Various complications require long-term care and require regular monitoring. One of the complications that is often experienced is diabetic foot ulcers which have increased in cases during the Covid-19 pandemic so that they require optimal service.Purpose: Developing a nursing service model for type 2 diabetes mellitus (DM) patients, especially the treatment of diabetic foot wounds associated with the covid-19 pandemic.Method: Research design using quasi-experiment with a plan pre and post-test without control group design, namely comparing the condition of the wound, the effectiveness of the length of time for healing based on the frequency of wound care between 26 respondents who were exposed to covid-19 and 34 respondents who were not exposed. Data analysis used the chi-square test.Results: There is a difference in healing based on the frequency of treating diabetic foot wounds between those exposed to covid-19 and not exposed to obtain a p-value of 0.013 <0.05. There is a difference in healing based on the frequency of treating diabetic foot wounds in patients exposed to covid-19 between those who have arterial injuries and those who do not have arterial injuries, obtaining a p-value of 0.049 <0.05. Then there are differences in the condition of leg injuries before and after being treated in patients who are not exposed to covid-19, obtaining a p-value of 0.00 <0.05. Whereas in patients exposed to covid-19, there was no difference with a p-value of 0.160 > 0.05.Conclusion: All hypotheses proposed except for the hypothesis that there is a difference in the condition of the wound between those exposed to covid-19 and those who were not exposed before and after being given treatment.Suggestion: In providing wound care to diabetic patients, it should be started by reviewing their history of having been exposed to covid-19. Furthermore, an assessment is made of whether the patient has an arterial wound so that the wound care that will be given is more appropriate and effective.

Analysis of the mechanism underlying diabetic wound healing acceleration by Calycosin-7-glycoside using network pharmacology and molecular docking

BackgroundDiabetic wounds represent a severe clinical challenge in which impaired M2 macrophage polarization and continuous macrophage glycolysis play crucial roles. Calycosin-7-glucoside (CG) is an isoflavone component in Astragali Radix (AR), which has become a research focus for treating diabetic wounds following reports indicating that it has anti-inflammatory effects. However, the mechanism through which CG can treat diabetic wounds is yet to be deciphered. PurposeThis study aimed to evaluate the therapeutic effect of CG on diabetic wounds and its underlying mechanism. MethodsThe potential mechanism underlying the treatment of diabetic wounds by CG was screened using bioinformatics. The therapeutic effects of CG were then investigated using a db/db diabetic wound model. Moreover, an LPS- and IFN-γ-induced RAW264.7 cell inflammation model was used to elucidate the mechanism underlying the therapeutic effects of CG against diabetic wounds. ResultsNetwork pharmacology predicted that the AMPK pathway could be the main target through which CG treats diabetic wounds. In db/db diabetic mice, CG could accelerate wound healing and promote granulation tissue regeneration. Protein chip technology revealed that CG increased the production of M-CSF, G-CSF, GM-CSF, IL-10, IL-13, and IL-4 but not that of MCP-1, IL-1β, IL-1α, TNF-α, and TNF-RII. Moreover, CG elevated the proportion of Ly6CLo/- anti-inflammatory monocytes in peripheral blood and M2 macrophages in the wound. The ELISA and flow cytometry analyses revealed that CG enhanced the levels of IL-10, VEGF, CD206, and Arg-1 expression whereas it considerably reduced the levels of IL-1, IL-6, IL-12, TNF-α, CD86, and iNOS expression. Meanwhile, CG increased the macrophage mitochondrial membrane potential and decreased the mitochondrial ADP/ATP ratio and glycolysis rate of M1 macrophages through the ROS/AMPK/STAT6 pathway. ConclusionsThe network pharmacology and molecular dockin identified the AMPK pathway as a critical pathway for treating diabetic wounds using topical CG application. CG was found to promote anti-inflammatory monocyte recruitment and decrease the mitochondrial glycolysis rate to induce M2 macrophage polarization via the ROS/AMPK/STAT6 pathway. These results suggest that CG might be a promising therapeutic agent for diabetic wounds.

Charge‐Driven Self‐Assembled Microspheres Hydrogel Scaffolds for Combined Drug Delivery and Photothermal Therapy of Diabetic Wounds

AbstractThe treatment of diabetic wound remains a big clinical challenge. Hydrogel that can provide physical barrier and humidity displays amazing potentials for managing the diabetic wounds healing. Herein, a new charge‐driven self‐assembled microsphere hydrogel scaffold (SMHS) is reported based on an electric charge interaction, by combining use of black phosphorus (BP)‐contained chitosan methacryloyl (CS) microspheres with positive charge and basic fibroblast growth factor‐contained hyaluronic acid methacryloyl (HA) microspheres with negative charge. The weak charge attraction among microspheres gives the SMHS the injectable characteristic. Due to the existence of BP, near‐infrared (NIR) irradiation has obvious effects on the degradation and drug release behaviors of SMHS. Significantly, SMHS that combines the short‐term physical (photothermal) intervention and long‐term chemical (drug release) intervention may be promising in spatio‐temporal regulation of regenerative microenvironment. SMHS with NIR irradiation (SMHS+NIR) can promote cell proliferation, cell migration, angiogenesis and macrophage polarization. Moreover, in diabetic rat skin wounds, SMHS+NIR significantly accelerates the wound healing process by simultaneously inhibiting the inflammatory response, promoting angiogenesis and tissues remodeling. The outcome of this research not only provides a biomaterial for diabetic wounds healing, but also demonstrates a new strategy for designing novel hydrogel‐based biomaterials which have the free editing and combination functions.

Advances in Zebrafish for Diabetes Mellitus with Wound Model.

Diabetic foot ulcers cause great suffering and are costly for the healthcare system. Normal wound healing involves hemostasis, inflammation, proliferation, and remodeling. However, the negative factors associated with diabetes, such as bacterial biofilms, persistent inflammation, impaired angiogenesis, inhibited cell proliferation, and pathological scarring, greatly interfere with the smooth progress of the entire healing process. It is this impaired wound healing that leads to diabetic foot ulcers and even amputations. Therefore, drug screening is challenging due to the complexity of damaged healing mechanisms. The establishment of a scientific and reasonable animal experimental model contributes significantly to the in-depth research of diabetic wound pathology, prevention, diagnosis, and treatment. In addition to the low cost and transparency of the embryo (for imaging transgene applications), zebrafish have a discrete wound healing process for the separate study of each stage, resulting in their potential as the ideal model animal for diabetic wound healing in the future. In this review, we examine the reasons behind the delayed healing of diabetic wounds, systematically review various studies using zebrafish as a diabetic wound model by different induction methods, as well as summarize the challenges and improvement strategies which provide references for establishing a more reasonable diabetic wound zebrafish model.

Development and evaluation of Resveratrol-loaded liposomes in hydrogel-based wound dressing for diabetic foot ulcer.

Diabetic foot wounds (DFUs) are counted as one of the most common microvascular complications associated with poorly controlled and chronic diabetes mellitus. It confers a serious challenge to clinical practice, surmounting hyperglycemia-induced disturbance in angiogenesis and endothelial dysfunction, with limited fruitful intervention to control the manifestations of DFUs. Resveratrol (RV) can improve endothelial function and has strong pro-angiogenic properties for the treatment of diabetic foot wounds. The present study aims to design an RV-loaded liposome-in-hydrogel system to effectively heal diabetic foot ulcers. A thin-film hydration method was used to prepare RV-loaded liposomes. Liposomal vesicles were assessed, for various characteristics such as particle size, zeta potential, and entrapment efficiency. The best-prepared liposomal vesicle was then incorporated into 1% carbopol 940 gel to develop a hydrogel system. The RV-loaded liposomal gel showed improved skin penetration. To assess the efficacy of the developed formulation, a diabetic foot ulcer animal model was used. The topical application of the developed formulation significantly reduced blood glucose and increased glycosaminoglycans (GAGs) to improve ulcer healing as well as wound closure on day 9. Faster re-epithelization, proliferation of fibroblast, formation of collagen, and reduced inflammatory cell infiltration at the wound site were also noted. Results indicate that RV-loaded liposomes in hydrogel-based wound dressing significantly accelerate wound healing in diabetic foot ulcers by restoring the altered wound healing process in diabetics.

The effectiveness of cell-derived exosome therapy for diabetic wound: A systematic review and meta-analysis.

The prevalence of diabetes among the elderly population is significant and rising annually. One of the most severe and frequent complications of diabetes mellitus is the diabetic wound, which has long-term negative effects on patients' finances, mental health, and functional abilities. Exosomes, a cell-free therapy, have emerged as a promising novel treatment for diabetic wounds, but their mechanism is still not entirely understood. Therefore, we conducted this meta-analysis to assess the effectiveness of exosomes in the management of diabetic wounds. We searched PubMed, the Cochrane Library, EMBASE, and Web of Science for pertinent studies that described the therapeutic benefits of exosomes on diabetic wound models that were released before October 17, 2022. The outcome indicators consisted of wound healing rate, neovascular density, re-epithelialization rate, collagen deposition, scar width, and inflammatory factors. RevMan 5.4 software was used to conduct all statistical analyses. A total of 21 studies with 323 animals were identified in this meta-analysis. Pooled analyses demonstrated that exosome therapy was shown to be superior to control therapy in terms of wound healing rate (SMD = 5.42; 95 %CI = 4.40-6.44; P<0.00001), neovascular density (SMD = 5.48; 95 %CI = 4.31-6.64; P<0.00001), re-epithelialization rate (SMD = 5.06; 95 %CI = 3.75-6.37; P<0.00001), collagen deposition (SMD = 4.78; 95 %CI = 3.58-5.98; P<0.00001), scar width (SMD = -8.10; 95 %CI = -10.31 to -5.89; P<0.00001). Additionally, the expression of inflammatory factors was significantly downregulated in the exosome treatment group. According to this meta-analysis of the current trials, exosome therapy can enhance the quality of diabetic wounds, especially when used in conjunction with novel dressings. To demonstrate the most efficient exosomes and therapeutic parameters for the treatment of diabetic wounds, future studies should conduct sizable, randomized, double-blind trials with high-quality, long-term follow-ups.

Recent Advances in Nano-Drug Delivery Systems for the Treatment of Diabetic Wound Healing.

Diabetes mellitus (DM) induced wound healing impairment remains a serious health problem and burden on the clinical obligation for high amputation rates. Based on the features of wound microenvironment, biomaterials loading specific drugs can benefit diabetic wound treatment. Drug delivery systems (DDSs) can carry diverse functional substances to the wound site. Nano-drug delivery systems (NDDSs), benefiting from their features related to nano size, overcome limitations of conventional DDSs application and are considered as a developing process in the wound treatment field. Recently, a number of finely designed nanocarriers efficiently loading various substances (bioactive and non-bioactive factors) have emerged to circumvent constraints faced by traditional DDSs. This review describes various recent advances of nano-drug delivery systems involved in mitigating diabetes mellitus-based non-healing wounds.

Exosomes derived from Nr-CWS pretreated MSCs facilitate diabetic wound healing by promoting angiogenesis via the circIARS1/miR-4782-5p/VEGFA axis.

Mesenchymal stem cell (MSC)-derived exosomes (Exos) were reported to a prospective candidate in accelerating diabetic wound healing due to their pro-angiogenic effect. MSCs pretreated with chemistry or biology factors were reported to advance the biological activities of MSC-derived exosomes. Hence, this study was designed to explore whether exosomes derived from human umbilical cord MSCs (hucMSCs) preconditioned with Nocardia rubra cell wall skeleton (Nr-CWS) exhibited superior proangiogenic effect on diabetic wound repair and its underlying molecular mechanisms. The results showed that Nr-CWS-Exos facilitated the proliferation, migration and tube formation of endothelial cells in vitro. In vivo, Nr-CWS-Exos exerted great effect on advancing wound healing by facilitating the angiogenesis of wound tissues compared with Exos. Furthermore, the expression of circIARS1 increased after HUVECs were treated with Nr-CWS-Exos. CircIARS1 promoted the pro-angiogenic effects of Nr-CWS-Exos on endothelial cellsvia the miR-4782-5p/VEGFA axis. Taken together, those data reveal that exosomes derived from Nr-CWS-pretreated MSCs might serve as an underlying strategy for diabetic wound treatment through advancing the biological function of endothelial cells via the circIARS1/miR-4782-5p/VEGFA axis.

Nanozyme-based Therapeutic Systems for Diabetic Wound Treatment

Therapeutic DeliveryAhead of Print EditorialNanozyme-based therapeutic systems for diabetic wound treatmentZheng Luo, Shan Jiang, Yun-Long Wu & Zibiao LiZheng LuoFujian Provincial Key Laboratory of Innovative Drug Target Research & State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, ChinaInstitute of Materials Research & Engineering (IMRE), Agency for Science, Technology & Research (A*STAR), 2 Fusionopolis Way, Innovis #08-03, Singapore, 138634, SingaporeSearch for more papers by this author, Shan JiangFujian Provincial Key Laboratory of Innovative Drug Target Research & State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, ChinaSearch for more papers by this author, Yun-Long Wu*Author for correspondence: E-mail Address: wuyl@xmu.edu.cnFujian Provincial Key Laboratory of Innovative Drug Target Research & State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, ChinaSearch for more papers by this author & Zibiao Li **Author for correspondence: E-mail Address: lizb@imre.a-star.edu.sghttps://orcid.org/0000-0002-0591-5328Institute of Materials Research & Engineering (IMRE), Agency for Science, Technology & Research (A*STAR), 2 Fusionopolis Way, Innovis #08-03, Singapore, 138634, SingaporeInstitute of Sustainability for Chemicals, Energy & Environment (ISCE), Agency for Science, Technology & Research (A*STAR), 1 Pesek Road, Jurong Island, Singapore, 627833, SingaporeDepartment of Materials Science & Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore, 117576, SingaporeSearch for more papers by this authorPublished Online:9 Jun 2023https://doi.org/10.4155/tde-2023-0008AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleKeywords: biomaterialsdiabetesmultifunctionnanozymewound healing

Therapeutic Efficacy of Polymeric Biomaterials in Treating Diabetic Wounds—An Upcoming Wound Healing Technology

Diabetic wounds are one of the serious, non-healing, chronic health issues faced by individuals suffering from diabetic mellitus. The distinct phases of wound healing are either prolonged or obstructed, resulting in the improper healing of diabetic wounds. These injuries require persistent wound care and appropriate treatment to prevent deleterious effects such as lower limb amputation. Although there are several treatment strategies, diabetic wounds continue to be a major threat for healthcare professionals and patients. The different types of diabetic wound dressings that are currently used differ in their properties of absorbing wound exudates and may also cause maceration to surrounding tissues. Current research is focused on developing novel wound dressings incorporated with biological agents that aid in a faster rate of wound closure. An ideal wound dressing material must absorb wound exudates, aid in the appropriate exchange of gas, and protect from microbial infections. It must support the synthesis of biochemical mediators such as cytokines, and growth factors that are crucial for faster healing of wounds. This review highlights the recent advances in polymeric biomaterial-based wound dressings, novel therapeutic regimes, and their efficacy in treating diabetic wounds. The role of polymeric wound dressings loaded with bioactive compounds, and their in vitro and in vivo performance in diabetic wound treatment are also reviewed.

Tumor tissue derived extracellular vesicles promote diabetic wound healing

The diabetic wound nowadays remains a major public health challenge, which is characterized by overproduced reactive oxygen species (ROS). However, the current therapy for diabetic wounds is limited for reliable data in the general application. The growth of tumors has been revealed to share parallels with wound healing. Extracellular vesicles (EVs) derived from breast cancer have been reported to promote cell proliferation, migration and angiogenesis. The tumor tissue-derived EVs (tTi-EVs) of breast cancer performance a feature inheritance from original tissue and might accelerate the diabetic wound healing. We wonder whether the tumor-derived EVs are able to accelerate diabetic wound healing. In this study, tTi-EVs were extracted from breast cancer tissue via ultracentrifugation and size exclusion. Subsequently, tTi-EVs reversed the H2O2-induced inhibition of fibroblast proliferation and migration. Moreover, tTi-EVs significantly accelerated wound closure, collagen deposition and neovascularization, and finally promoted wound healing in diabetic mice. The tTi-EVs also reduced the level of oxidative stress in vitro and in vivo. Besides, the biosafety of tTi-EVs were preliminarily confirmed by blood tests and morphological analysis of major organs. Collectively, the present study proves that tTi-EVs can suppress oxidative stress and facilitate diabetic wound healing, which puts forward a novel function of tTi-EVs and provides potential treatment for diabetic wounds.

Platelet-rich plasma-loaded bioactive chitosan@sodium alginate@gelatin shell-core fibrous hydrogels with enhanced sustained release of growth factors for diabetic foot ulcer healing

The ability of autologous platelet-rich plasma (PRP) gel to promote rapid wound healing without immunological rejection has opened new avenues for the treatment of diabetic foot wounds. However, PRP gel still suffers from the quick release of growth factors (GFs) and requires frequent administration, thus resulting in decreased wound healing efficiency, higher cost as well as greater pain and suffering for the patients. In this study, the flow-assisted dynamic physical cross-linked coaxial microfluidic three-dimensional (3D) bio-printing technology, combined with the calcium ion chemical dual cross-linking method was developed to design PRP-loaded bioactive multi-layer shell-core fibrous hydrogels. The prepared hydrogels exhibited outstanding water absorption-retention capacity, good biocompatibility as well as a broad-spectrum antibacterial effect. Compared with clinical PRP gel, these bioactive fibrous hydrogels displayed a sustained release of GFs, reducing the administration frequency by 33 % availably during the wound treatment, but more prominent therapeutic effects such as effective reduced inflammation, in addition to promoting the growth of granulation tissue and angiogenesis, the formation of high-density hair follicles, and the generation of regular ordered and high-density collagen fiber network, which suggested great promise as exceptional candidates for treatment of diabetic foot ulcer in clinical settings.

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

Treatment for chronic diabetic wounds remains a clinical challenge. Wound healing process occurs in three phases: inflammation, proliferation and remodeling. Several factors including bacterial infection, decreased local angiogenesis and diminished blood supply delay wound healing. There is an urgent need to develop wound dressings with multiple biological effects for different stages of diabetic wound healing. Here, we develop a multifunctional hydrogel with two-stage sequential release upon near-infrared (NIR) stimulation, antibacterial activity and pro-angiogenic efficacy. This hydrogel consists of covalently crosslinked bilayer structure, with the lower thermoresponsive poly(N-isopropylacrylamide)/gelatin methacrylate (NG) layer and the upper highly stretchable alginate/polyacrylamide (AP) layer embedding different peptide-functionalized gold nanorods (AuNRs) in each layer. Antimicrobial peptide-functionalized AuNRs released from NG layer exert antibacterial effects. After NIR irradiation, the photothermal transition efficacy of AuNRs synergistically enhances bactericidal efficacy. The contraction of thermoresponsive layer also promotes the release of embedded cargos during early stage. The pro-angiogenic peptide-functionalized AuNRs released from AP layer promote angiogenesis and collagen deposition by accelerating fibroblast and endothelial cell proliferation, migration and tube formation during the subsequent healing phases. Therefore, the multifunctional hydrogel with effective antibacterial activity, pro-angiogenic efficacy and sequential release behaviors is a potential biomaterial for diabetic chronic wound healing.

Current and future outlook of loaded components in hydrogel composites for the treatment of chronic diabetic ulcers.

Due to recalcitrant microangiopathy and chronic infection, traditional treatments do not easily produce satisfactory results for chronic diabetic ulcers. In recent years, due to the advantages of high biocompatibility and modifiability, an increasing number of hydrogel materials have been applied to the treatment of chronic wounds in diabetic patients. Research on composite hydrogels has received increasing attention since loading different components can greatly increase the ability of composite hydrogels to treat chronic diabetic wounds. This review summarizes and details a variety of newly loaded components currently used in hydrogel composites for the treatment of chronic diabetic ulcers, such as polymer/polysaccharides/organic chemicals, stem cells/exosomes/progenitor cells, chelating agents/metal ions, plant extracts, proteins (cytokines/peptides/enzymes) and nucleoside products, and medicines/drugs, to help researchers understand the characteristics of these components in the treatment of diabetic chronic wounds. This review also discusses a number of components that have not yet been applied but have the potential to be loaded into hydrogels, all of which play roles in the biomedical field and may become important loading components in the future. This review provides a "loading component shelf" for researchers of composite hydrogels and a theoretical basis for the future construction of "all-in-one" hydrogels.

Highly efficient bacteria-infected diabetic wound healing employing a melanin-reinforced biopolymer hydrogel

Owing to hyperglycemia-related metabolic abnormalities that cause oxidative stress, recurrent infections, and vascular lesions, the therapeutic management of diabetic wounds is still unsatisfactory. Herein, we present a hydrogel (GCM) wound dressing loaded with melanin nanoparticles in a polysaccharide matrix (biguanide chitosan and oxidized β-glucan) for efficient healing of bacterially infected diabetic wounds. By a simple local injection, a protective GCM hydrogel barrier is established over the wound to rapidly stop bleeding and neutralize inflammatory cytokines. Subsequently, the GCM hydrogel achieves an accelerated transfer from the inflammatory process to the healing phase of the wound because of its excellent photothermal antimicrobial and reactive oxygen species scavenging properties. Additionally, GCM hydrogel has a three-dimensional network structure that dramatically enhances cell proliferation, migration, and angiogenesis by creating favorable ecological conditions for cell survival. Notably, our GCM hydrogel can help treat a variety of bacteria-infected diabetic wounds like skin and oral ulcer wounds. Collectively, this work provides a new option for diabetic wound treatment.

Flaps for lower limb diabetic wound reconstruction: A systematic review and meta-analysis

The treatment of chronic diabetic wounds includes wound dressing, debridement, flap surgery, and amputation. For suitable patients with nonhealing wounds, locoregional flaps or free flaps may be used. This paper aims to review the outcomes of flap surgery and identify the risk factors for flap loss. MEDLINE, Embase, and Cochrane Library were searched. Articles reporting flap loss outcomes for flap surgery in lower limb chronic diabetic wounds were included. Case reports and case series with fewer than five patients were excluded. A subset of articles was used for revascularization subgroup analysis and another subset for meta-analysis of risk factors for flap loss. In the free flap group, the total flap failure rate was 7.14% and partial flap failure rate was 7.54%. The rate of major complications requiring operative takeback was 19.0%. Early mortality was 2.76%. In the locoregional flap group, the total flap failure rate was 3.24% and partial flap failure rate was 5.36%. The rate of major complications requiring operative takeback was 13.3%. There was no early mortality. The rate of free flap loss was 18.2% with revascularization, significantly higher than 6.66% without revascularization. Our findings concur with previously published studies on flap loss and complications in diabetic lower limb wounds. There is an increased risk of flap loss in patients who require free flap and revascularization compared to patients who only require free flap. This could be because of the fragile and fibrotic vessels found in diabetics with comorbid atherosclerosis.