Hyaluronic acid (HA), the only non-sulfated glycosaminoglycan (GAG), is essential for maintaining the extracellular matrix's structural and functional integrity. Its bioactivity is determined by interactions between HA fragments of different molecular weights and specific receptors, which influence downstream signaling pathways. This review systematic summarizes the correlation between HA molecular weight dynamic changes and bioactivities focusing on imbalance of HA degradation and metabolism due to various pathological processes. Outline the core transduction mechanisms of HA receptors and signaling pathways, and innovatively hypothesize that discrepancies in cellular distribution with HA-molecular weights dependent lead to the activation of different signaling pathways from the perspective of molecular weight affecting cellular distribution. Finally, it addresses challenges in studying HA's biofunctions and provides new perspectives for future research.

The impaired wound-healing process in diabetic patients poses a significant clinical challenge due to local immune dysregulation and impaired angiogenesis. This study introduces a novel therapeutic approach using an SBMA/GelMA hydrogel loaded with naringenin (NRN) to restore the immune environment and promote angiogenesis in diabetic wounds. The hydrogel, synthesized via photo-crosslinking, exhibits excellent biocompatibility and inherent antibacterial properties, creating an optimal environment for wound healing. By incorporating NRN, a natural compound with therapeutic potential, the hydrogel enables sustained and controlled release of NRN, ensuring prolonged therapeutic effects. In vitro studies showed that the NRN-loaded SBMA/GelMA hydrogel effectively activated PPARα, suppressing the Sting pathway. This led to enhanced M2 macrophage polarization and increased angiogenesis. In vivo experiments with diabetic wound models further validated the hydrogel's therapeutic potential. The hydrogel significantly accelerated wound healing, evidenced by reduced wound size, enhanced re-epithelialization, and increased angiogenesis. Immunohistochemical analysis demonstrated a shift towards an anti-inflammatory M2 macrophage phenotype within the wound microenvironment. This study provides valuable insights into the mechanisms of wound healing in diabetic conditions and offers new avenues for developing advanced materials for diabetic wound management.

Nonhealing perineal wounds have been reported to be common after proctectomy for Crohn's disease (CD). We performed a systematic review and meta-analysis of perineal wound healing after proctectomy for CD and assessed the risk factors for nonhealing.

A comprehensive literature search was conducted in PubMed, Embase, and Scopus databases from 2010 to 2023, and articles reporting perineal wound healing rates after proctectomy for CD were included. Data on study characteristics and proportion of healed wounds, and risk factors, were extracted. Random-effects meta-analysis was performed to estimate the pooled proportion and 95% CIs using the "meta" package in R. Heterogeneity was assessed using the I2 statistic.

We identified 501 articles, of which 252 remained after de-duplication. After screening, 4 retrospective cohort studies involving 333 patients were included. Across the 4 studies, the pooled proportion of completely healed perineal wounds at 6 months was 65% (95% CI 52%-80%), and 70% (95% CI 60%-83%) at 12 months. Significant heterogeneity was found between studies (I2 = 86% at 6 months). Three studies examined risk factors for impaired healing after proctectomy. One study identified preoperative perineal sepsis as the only independent factor associated with impaired healing (P = .001) on multivariable analysis. In 1 study, male sex, shorter time from diversion to proctectomy, and higher preoperative C-reactive protein levels were all associated with delayed healing in univariate analysis. Another study found that close rectal dissection was associated with significantly lower healing rates than total mesorectal excision (P = .01). Prior use of tumor necrosis factor inhibitors was not associated with wound healing outcomes.

This meta-analysis revealed complete perineal healing in only 70% of patients 12 months after proctectomy for CD. This highlights knowledge gaps, including the identification of modifiable risk factors and methods for preventing or as rescue therapy, such as vacuum-assisted closure and flap reconstruction, for nonhealing perineal wounds after proctectomy for CD. Poor perineal wound healing outcomes are likely related to imperfectly understood underlying inflammatory dysregulation and systemically impaired wound healing in patients with CD.

Diabetic wounds are difficult to treat clinically because they heal poorly, often leading to severe complications such as infections and amputations. Hydrogels with smart self-healing properties show great promise for treating diabetic wounds. These hydrogels are capable of continuously and dynamically responding to changes in the wound environment, feature improved mechanical qualities and the capacity to self-heal damage. We explore the latest developments in smart self-healing hydrogels for diabetic wound healing in this review. First, we systematically summarize the obstacles in treating diabetic wounds. We then highlighted the significance of smart self-healing hydrogels, explaining their stimulus-responsive mechanisms and self-healing design approaches, along with their applications in addressing these challenges. Finally, we discussed the unresolved obstacles and potential avenues for future research. We anticipate that this review will facilitate the continued refinement of smart self-healing hydrogels for diabetic wound dressings, aiming for broader clinical adoption.

Delayed wound healing is among the major peripheral complications of diabetes. Synergistic treatment of diabetic wounds (DW) with phytochemicals and non-invasive techniques has shown promising results. The synergistic effect of vanillin and photobiomodulation (PBM) on DW healing, and their modulatory effect on oxidative stress and glucose metabolism was investigated in DW fibroblast cells (WS1). DW cells were treated with vanillin and vanillin + PBM. Control consisted of WS1 cells, untreated DW cells, and DW cells treated with PBM. Diabetes was induced by repeated growth in complete MEM containing high D-glucose (22.6 mM/L). Wounds were induced by central scratching. Cells were treated with vanillin at various concentrations for 2 h prior to PBM at 660 nm with a fluence of 5 J/cm2 for an irradiation time of 780 s, followed by 24 h incubation. Induction of DW led to a decreased glutathione level, and decreased superoxide dismutase, catalase, glutathione reductase, glyoxalase, and Na/K-ATPase activities, while concomitantly increasing the activities of fructose-1,6-bisphosphatase, glucose 6-phosphatase, E-NTPDase, and 5-lipoxygenase. These levels and activities were reversed following treatment with 12 μg/mL vanillin, and 6 μg/mL vanillin + PBM having the best effects. However, treatment with 24 μg/mL vanillin and vanillin + PBM showed no significant effects. Except for cells treated with 24 μg/mL vanillin and vanillin + PBM, morphological analysis indicated wound closures compared to the controls. These results indicate the synergistic therapeutic effect of vanillin + PBM on the management of diabetic wounds, with 6 μg/mL vanillin + PBM displaying the best effect.

Diabetes mellitus (DM)-associated wounds, characterized by chronic bacterial infections and elevated glucose levels, present significant challenges to effective healing. To overcome these issues, a novel transdermal drug delivery system was developed, integrating microneedles (MNs) with biofilm-penetrating capability, the wound-healing properties of hyaluronic acid (HA), the antibacterial effects of silver nanoparticles (AgNPs), and the glucose-lowering action of insulin (Ins). Named HAMNs@AgNPs-Ins, this system demonstrated optimal morphological characteristics, robust mechanical strength, and 100 % skin penetration efficiency. It exhibited sustained antibacterial activity in vitro, ensured skin safety, and provided controlled, steady blood glucose reductions, achieving a 72.29 % reduction at 8 h, compared to the sharp decline seen with subcutaneous injection. Additionally, wound healing experiments showed a significant improvement in the healing rate of 89.66 ± 1.34 % in the HAMNs@AgNPs-Ins group, compared to 48.19 ± 9.03 % in the control group. These results underscore the potential of HAMNs@AgNPs-Ins as an effective treatment for DM-associated wounds.

The evolution of wound monitoring techniques has seen a significant shift from traditional methods like ruler-based measurements to the use of AI-assisted assessment of wound tissues. This progression has been driven by the need for more accurate, efficient, and non-invasive methods for wound assessment and treatment planning. The proposed approach aims to automate wound analysis and reduce efforts to manage chronic wounds. The snake's approach is used to extract wound areas and geometrical measures are used to monitor the rate of wound healing. A segmentation based on the color thresholding and K-means technique was carried out and demonstrated the effectiveness of the thresholding technique in mapping the wound tissues. The three proportions of wound tissues necrosis, slough, granulation and wound size are combined with three features from the patient's medical record and transmitted to the Support Vector Machine (SVM), Naive Bayes (NB) and Decision Tree (DT) classifiers. Finally, this work is ended with a comparative study that shows the efficiency and the interest of the proposed approach.

Oral wounds in diabetes mellitus (DM) often delay healing due to reduced angiogenesis and increased inflammatory response in the local microenvironment, even leading to graft necrosis and implant failure. Therefore, developing an effective program to promote healing is of great clinical value. Much of the current research is focused on promoting wound healing through surface adhesive materials that exert a pro-angiogenic, anti-inflammatory effect. However, the application of surface bonding materials in the oral cavity is very limited due to the humid and friction-prone environment. Decellularized extracellular adipose tissue (DAT) is an easily accessible and biocompatible material derived from adipose tissue. To further explore the potential of DAT, we used multi-omics to analyze its composition and possible mechanisms. Proteomic studies revealed that DAT contains anti-inflammatory, pro-angiogenic proteins that promote DM tissue regeneration. To adapt to the moist and chewing friction environment of the mouth, we modified DAT into a temperature-sensitive hydrogel material that can be injected intramucosally. DAT hydrogel has been verified to promote angiogenesis and exert anti-inflammatory effects through macrophage phenotypic transformation. Meanwhile, transcriptome analysis suggested that the inhibitory effect of DAT on the interleukin 17 signaling pathway might be a key factor in promoting DM oral wound healing. In conclusion, after multi-omic analysis, DAT hydrogel can exert good pro-angiogenic and anti-inflammatory effects through the interleukin 17 signaling pathway and can be adapted to the specific environment of the oral cavity. This provides a potential way to promote DM oral wound healing in a clinical setting.

Stem cell-derived extracellular vesicles (SC-EVs) are one huge promise in skin regenerative medicine, similar in advantages to stem cells with low immunerejection and tumor formations. These microvesicles are laden with microRNAs, which assist in wound healing via angiogenesis and immune modulation. However, quick degradation and poor cellular uptake limit their regenerative capacity. Thanks to their adjustable characteristics, hydrogels can act as vehicles for transporting and sustainably releasing miRNA-SC-EVs at injury sites. Therefore, a systematic literature review was conducted on miRNA-enriched SC-EVs incorporated into hydrogels in animal skin regeneration models published from 2010 to 2024 (PROSPERO ID: CRD42024588072). Out of the 89 records, 12 met the criteria. Diabetic wounds are characterized by chronic inflammation, oxidative stress, and defective macrophage polarization, resulting in less satisfactory regeneration. The hydrogels tackled these issues by shifting macrophages from a pro-inflammatory M1 phenotype to a healing M2 phenotype, promoting collagen production, enhancing fibroblast movement, and boosting angiogenesis. Burn injuries frequently lead to slow recovery due to hypertrophic scarring, extended inflammation, and infection. Hyaluronic acid (HA)-derived hydrogels, infused with miR-21-5p and surface-treated with polydopamine and cationic antimicrobial peptides, promoted wound healing by lowering scarring and demonstrating anti-inflammatory, anti-apoptotic, and pro-angiogenic characteristics. The cell adhesion of these hydrogels can be enhanced by adding MOFs, chitosan, and extracellular matrix elements. The application of stimulus-responsive or stage-specific hydrogels is another mode of targeted healing. Further research and clinical trials will enhance the wound-healing efficiency of hybrid hydrogels.

Chronic wounds pose a significant healthcare challenge, impacting millions of patients worldwide and burdening healthcare systems substantially. These wounds often occur as comorbidities and are prone to infections. Such infections hinder the healing process, complicating clinical management and proving recalcitrant to therapy. The environment within the wound itself poses challenges such as lack of oxygen, restricted blood flow, oxidative stress, ongoing inflammation, and bacterial presence. Traditional systemic treatment for such chronic peripheral wounds may not be effective due to inadequate blood supply, resulting in unintended side effects. Furthermore, topical applications are often impervious to persistent biofilm infections. A growing clinical concern is the lack of effective therapeutic modalities for treating chronic wounds. Additionally, the chemically harsh wound microenvironment can reduce the effectiveness of treatments, highlighting the need for drug delivery systems that can deliver therapies precisely where needed with optimal dosages. Compared to cell-based therapies, exosome-based therapies offer distinct advantages as a cell-free approach for chronic wound treatment. Exosomes are of endosomal origin and enable cell-to-cell communications, and they possess benefits, including biocompatibility and decreased immunogenicity, making them ideal vehicles for efficient targeting and minimizing off-target damage. However, exosomes are rapidly cleared from the body, making it difficult to maintain optimal therapeutic concentrations at wound sites. The hydrogel-based approach and development of biocompatible scaffolds for exosome-based therapies can be beneficial for sustained release and prolong the presence of these therapeutic exosomes at chronic wound sites. Engineered exosomes have been shown to possess stability and effectiveness in promoting wound healing compared to their unmodified counterparts. Significant progress has been made in this field, but further research is essential to unlock their clinical potential. This review seeks to explore the benefits and opportunities of exosome-based therapies in chronic wounds, ensuring sustained efficacy and precise delivery despite the obstacles posed by the wound environment.

Diabetic wounds are a significant clinical challenge due to impaired healing processes often exacerbated by elevated matrix metalloproteinases (MMPs). Cinnamomum zeylanicum, known for its anti-inflammatory and antioxidant properties, has shown potential in promoting wound healing. This study investigates the molecular docking and experimental validation of Cinnamomum zeylanicum's effects on diabetic wound healing, focusing on its interaction with matrix metalloproteinases-8 (MMP-8) and 9 (MMP-9).

Molecular docking studies were performed to predict the binding affinity of Cinnamomum zeylanicum compounds to MMP-8 and MMP-9. Diabetic wound healing was evaluated using in vivo models where wounds were induced and treated with Cinnamomum zeylanicum extract. Various parameters were measured, including wound contraction, hydroxyproline content, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels. Biochemical analyses included glucose levels, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), and histomorphological examination of skin tissues.

Molecular docking results indicated a high binding affinity of Cinnamomum zeylanicum's bioactive compounds with MMP-8 and MMP-9, suggesting potential inhibition. Experimental validation showed significant improvement in wound contraction and increased hydroxyproline content, indicating enhanced collagen synthesis. Antioxidant enzyme activities (SOD, GPx, CAT) were significantly elevated, while MDA levels were reduced, reflecting decreased oxidative stress. Biochemical analysis demonstrated improved glucose homeostasis with reduced FBG and enhanced OGTT responses. Histomorphological studies revealed improved tissue architecture and re-epithelialization in treated wounds.

Cinnamomum zeylanicum exhibits promising potential in diabetic wound healing by modulating MMP-8 and MMP-9 activities, enhancing antioxidant defenses, and improving glucose regulation. These findings support its therapeutic application for diabetic wounds, providing a foundation for further clinical investigations.

IntroductionDiabetes related foot ulcers (DFUs) are common complications of type 2 diabetes mellitus (T2DM), affecting 15-25% of individuals living with diabetes and significantly contributing to healthcare costs ($9-13 billion annually in the U.S.). Without effective management, these wounds often lead to severe outcomes like amputations. This study aims to examine the association of semaglutide on DFU management.MethodsThis retrospective cohort study utilized TriNetX US Research Network data to assess the impact of semaglutide, a GLP-1 receptor agonist, on DFU outcomes between 2013 and 2023. The study compared outcomes between semaglutide users with DFU (Cohort A, N = 6329) and non-users with DFU (Cohort B, N = 118,821) across 64 healthcare organizations. We matched participants by age, gender, race, and ethnicity; however, we excluded patients with certain co-morbidities. Statistical analysis, such as chi-square analysis and risk ratio, using TriNetX software evaluated different complication outcomes.ResultsSemaglutide users with DFU demonstrated lower relative risks for complications compared to non-users. Within 1 year, semaglutide users were associated with lower relative risks for wound healing complications (0.19% vs 0.38%), chronic non-healing wounds (0.75% vs 1.23%), chronic pain (4.44% vs 8.06%), wound care (2.42% vs 4.86%), wound dehiscence (0.26% vs 0.56%), and amputation (2.34% vs 5.21%) (p < .05). Similar trends persisted over 5 years. While these findings highlight potential benefits of semaglutide with patients with DFU, causation cannot be inferred due to the study's observational design.ConclusionSemaglutide use was associated with favorable outcomes in patients with diabetes-related foot ulcers, including reductions in wound-related complications. While these findings suggest potential benefits of semaglutide as an adjunct in DFU management, further research is needed to confirm these associations and to better understand the mechanisms involved.

The pathophysiology of burn wound conversion is not fully understood. Animal models are needed to elucidate the underlying mechanisms and develop treatments. Here, we established a new reproducible mouse model that simulates this process, thereby facilitating studies of burn wound conversion.

After anesthesia and depilation, 75 mice were randomly assigned to 5-, 15-, and 25-s contact groups, and a top hat-shaped brass template was heated in boiling water and applied to the lateral abdomen. The wound area was calculated from photographs and the percentage of the surviving area was determined. Histological samples were collected 1-96 h after injury.

A 15-s contact time produced the desired 50 %-75 % interspace necrosis at 96 h after injury. The 5-s contact group had a mostly preserved interspace, while the 25-s contact group exhibited near-complete necrosis. Histologically, significant differences between the 5- and 15-s contact groups were seen in cutaneous appendage denaturation and panniculus carnosus denaturation early after injury.

Exposing mice to the heated template for 15 s provides a reproducible model for studying burn wound conversion mechanisms and treatments, facilitating further elucidation of burn pathophysiology and evaluation of therapies to prevent burn wound conversion.

Diabetic wounds, characterized by their chronic nature, represent a critical challenge for patients with diabetes, often leading to amputation and mortality. Although stem cells show great promise, their use is limited by challenges related to stability and tumorigenicity. The secretome of stem cells, comprising molecules released by these cells, offers a potential alternative to the challenges associated with stem cell therapy and provides a promising solution for diabetic wound healing.

We conducted a systematic review and meta-analysis of relevant preclinical studies to evaluate the effectiveness of stem cell secretomes in treating diabetic wounds.

The protocol registration for this systematic review and meta-analysis was recorded in the PROSPERO database (CRD42023473726). Databases were searched from their inception until November 20, 2023. The quality assessment of the included studies was performed utilizing the CAMARADES 10-item Quality Checklist. Statistical analyses were conducted using a random-effects model to calculate standardized mean differences (SMD) and 95% confidence intervals (CI), with heterogeneity assessed via the I² statistic. The primary outcome evaluated was the wound closure rate, while secondary outcomes included parameters such as the number of fibroblasts, neutrophils, and macrophages.

Twenty studies were included, comprising 382 animal subjects, and five of which were eligible for quantitative evaluation in a meta-analysis. The stem cell secretome significantly improved the wound closure rate (SMD = 9.63; 95% CI = 2.01 -17.25; P = 0.01, I2 = 76%) and reduced the number of neutrophils (SMD =  -8.47; 95% CI =  -13.05 to -3.90; P = 0.0003) and macrophages (SMD = -5.32; 95% CI = -9.09 to -1.55; P = 0.006).

This review suggests that stem cell secretomes have potential as a novel therapeutic strategy for diabetic wound healing, enhancing wound closure rates and reducing inflammation. These findings support the use of stem cell secretomes as a safer and more stable alternative to direct stem cell therapy, but further clinical studies are needed to confirm these results in human patients.

Diabetic wound healing poses a significant challenge due to the intricate disruptions in cellular and molecular processes induced by hyperglycaemia, leading to delayed or impaired tissue repair. Computational techniques offer a promising avenue for unravelling the complexities of diabetic wound healing by elucidating the molecular mechanisms involved.

This study utilized in silico molecular docking and dynamics simulations to explore the potential therapeutic effectiveness of olivetol, a phenolic compound, in the context of diabetic wound healing. Furthermore, computational methodologies, encompassing pkCSM, Swiss ADME, OSIRIS® property explorer, PASS online web resource, and MOLINSPIRATION® software, were employed to forecast the pharmacokinetic properties, biological actions, and in vitro analyses, such as MTT and scratch assays, to evaluate the therapeutic effectiveness of olivetol in wound healing.

Our findings have revealed olivetol to be a promising candidate for targeting multiple pathways implicated in diabetic wound healing. Its ability to modulate inflammation, oxidative stress, extracellular matrix remodeling, angiogenesis, and cell signaling suggests a multifaceted approach to promoting effective wound repair. Moreover, olivetol has been found to demonstrate strong binding affinity with key MRSA target proteins, indicating its potential as an antimicrobial agent against MRSA infections in diabetic wounds. The in vitro MTT assay demonstrated cell viability with an IC50 value of 40.80 μM, highlighting its cytotoxicity potential. Additionally, the scratch assay confirmed promising wound healing activity, showcasing its effectiveness in promoting cell migration and closure.

Olivetol emerges as a promising candidate for targeted interventions in non-healing diabetic wounds, particularly due to its ability to address prolonged inflammation, a common obstacle in diabetic wound healing.

Diabetic wounds, a significant complication of Type 2 Diabetes Mellitus (T2DM), face delayed healing due to impaired inflammation, angiogenesis, and collagen synthesis. This study explores Febuxostat, a xanthine oxidase inhibitor for its therapeutic potential in wound healing. Combining computational approaches and in-vitro assays, the study evaluates its effects on key wound healing pathways, cell viability, migration.

The potential of Febuxostat in diabetic wound healing was studied using in-silico tools for Molecular docking and ADMET profiling, alongside Molecular dynamics (MD) simulations. Toxicity was assessed with OSIRIS Explorer, and biological activity was predicted using the PASS tool. In-vitro MTT and scratch assays on L929 cells further validated cytotoxicity and wound healing efficacy.

Docking analysis revealed strong binding affinities to key wound healing targets, including VEGF (-9.11 kcal/mol) and NFKβ (-8.62 kcal/mol). Pharmacokinetic studies highlighted favorable skin permeability, supporting topical applications. Toxicity predictions indicated a safe profile. Molecular dynamics simulations demonstrated stable protein-ligand complexes, particularly with VEGF. Cytotoxicity studies on L929 cells revealed an IC50 of 6.08 μM and the scratch assay demonstrated significant wound healing activity, highlighting its effectiveness in promoting cell migration and closure.

Febuxostat shows remarkable potential in enhancing diabetic wound healing by promoting cell migration, targeting wound-healing proteins, as demonstrated through in-silico and in-vitro studies. This drug is poised to effectively treat diabetic wounds, accelerating healing and reducing complications. Rigorous pre-clinical and clinical evaluations are essential to validate its safety, efficacy, and therapeutic potential.

Preclinical studies for wound healing disorders are an essential step in translating discoveries into therapies. Also, they are an integral component of initial safety screening and gaining mechanistic insights using an in vivo approach. Given the complexity of the wound healing process, existing guidelines for animal testing do not capture key information due to the inevitable variability in experimental design. Variations in study interpretation are increased by complexities associated with wound aetiology, wounding procedure, multiple treatment conditions, wound assessment, and analysis, as well as lack of acknowledgement of limitation of the model used. Yet, no standards exist to guide reporting crucial experimental information required to interpret results in translational studies of wound healing. Consistency in reporting allows transparency, comparative, and meta-analysis studies and avoids repetition and redundancy. Therefore, there is a critical and unmet need to standardise reporting for preclinical wound studies. To aid in reporting experimental conditions, The Wound Reporting in Animal and Human Preclinical Studies (WRAHPS) Guidelines have now been created by the authors working with the Wound Care Collaborative Community (WCCC) GAPS group to provide a checklist and reporting template for the most frequently used preclinical models in support of development for human clinical trials for wound healing disorders. It is anticipated that the WRAHPS Guidelines will standardise comprehensive methods for reporting in scientific manuscripts and the wound healing field overall. This article is not intended to address regulatory requirements but is intended to provide general guidelines on important scientific considerations for such studies.

Diabetes is a complex global healthcare burden involving multiple organ systems with its prevalence on the rise. SGLT2 inhibitors enhance glucose excretion. The objective of our literature review was to determine the association between cutaneous adverse drug reactions (CADRs) and the use of SGLT2 inhibitors. We collected data on CADRs related to the use of SGLT2 inhibitors from all available published articles and studied their details to understand the patterns of their association. PubMed, Cochrane, Google, and Embase were searched for relevant articles. A total of 37 papers were included and studied. Most articles were case reports followed by pharmacovigilance studies, case series, and reviews. The cutaneous findings ranged from benign eruptions to severe reactions. The available literature suggests a strong link between the use of SGLT2 inhibitors and Fournier's gangrene/necrotizing fasciitis. T2DM patients using SGLT2 inhibitors have also developed fixed drug eruptions, drug-induced pruritus, and Sweet syndrome/acute febrile neutrophilic dermatosis, among other skin lesions. We found that SGLT2 inhibitors present a risk of developing CADRs. Raising awareness among healthcare providers regarding CADRs to SGLT2 inhibitors can reduce complications, minimize hospitalizations, and improve patient care in the vulnerable population of diabetes patients.

Chronic wounds represent a persistent clinical challenge due to prolonged inflammation and impaired tissue repair mechanisms. Cannabidiol (CBD), recognized for its anti-inflammatory and pro-healing properties, shows therapeutic promise in wound care. However, its delivery via lipid nanoparticles (LNPs) remains challenging due to CBD's inherent instability and low bioavailability. This study developed and characterized a novel hydrogel scaffold composed of CBD-loaded LNPs (CBD/LNPs) integrated into a polyvinyl alcohol (PVA) and sodium alginate (SA) matrix, designed to enhance wound repair and mitigate inflammation. The characteristics of the hydrogel scaffold were observed including the degree of swelling and LNPs' release profiles. Furthermore, in the results, CBD/LNPs displayed enhanced stability and reduced cytotoxicity compared to unencapsulated CBD. In vitro assays demonstrated that CBD/LNPs significantly promoted fibroblast migration in gap-closure wound models and reduced intracellular reactive oxygen species, supporting their potential as a biocompatible and efficacious agent for cellular repair and oxidative stress attenuation. In vivo experiments using adult male Wistar rats with aseptic cutaneous wounds revealed that treatment with CBD/LNP-PVA/SA hydrogel scaffold significantly accelerated wound closure relative to blank hydrogel controls, demonstrating a substantial reduction in the wound area over time. Histological analysis confirms notable improvements in skin morphology in wounds treated with CBD/LNP-PVA/SA hydrogel scaffold with evidence of accelerated epithelialization, enhanced collagen deposition, and increased dermal thickness and vascularization. Additionally, skin histology showed a more organized epidermal layer and reduced inflammatory cell infiltration in CBD/LNP-PVA/SA hydrogel scaffold-treated wounds, corresponding to a 35% increase in the wound closure rate by day 28 post-treatment. These findings suggest that CBD/LNP-PVA/SA hydrogel scaffolds facilitate inflammation resolution and structural wound healing through localized, sustained CBD delivery. The dual anti-inflammatory and wound-healing effects position CBD/LNP-PVA/SA hydrogel scaffold as a promising approach for chronic wound management. Future investigations are warranted to elucidate the mechanistic pathways by which CBD modulates the skin architecture and to explore its translational applications in clinical wound care.

Diabetic foot ulcers (DFUs) are a microvascular complication that affects almost 21 % of the diabetic population. DFUs are characterized by lower limb abnormalities, chronic inflammation, and a heightened hypoxic environment. The challenge of healing these chronic wounds arises from impaired blood flow, neuropathy, and dysregulated cell death processes. The pathogenesis of DFUs involves intricate mechanisms of programmed cell death (PCD) in different cell types, which include keratinocytes, fibroblasts, and endothelial cells. The modes of cell death comprise apoptosis, autophagy, ferroptosis, pyroptosis, and NETosis, each defined by distinct biochemical hallmarks. These diverse mechanisms contribute to tissue injury by inducing neutrophil extracellular traps and generating cellular stressors like endoplasmic reticulum stress, oxidative stress, and inflammation. Through a comprehensive review of experimental studies identified from literature databases, this review synthesizes current knowledge on the critical signaling cascades implicated in programmed cell death within the context of diabetic foot ulcer pathology.

The incidence of chronic wounds is steadily increasing each year, yet conventional treatments for chronic wounds yield unsatisfactory results. The delayed healing of chronic wounds significantly affects patient quality of life, placing a heavy burden on patients, their families, and the healthcare system. Therefore, there is an urgent need to find new treatment methods for chronic wounds. Plant-derived exosome-like nanovesicles (PELNs) may be able to accelerate chronic wound healing. PELNs possess advantages such as good accessibility (due in part to high isolation yields), low immunogenicity, and good stability. Currently, there are limited reports regarding the role of PELNs in chronic wound healing and their associated mechanisms, highlighting their novelty and the necessity for further research. This review aims to provide an overview of PELNs, discussing isolation methods, composition, and their mechanisms of action in chronic wound healing. Finally, we summarize future opportunities and challenges related to the use of PELNs for the treatment of chronic wounds, and offer some new insights and solutions.

Chronic wounds require more sophisticated care than standard wound care because they are becoming more severe as a result of diseases like diabetes. By resolving shortcomings in existing methods, 3D-bioprinting offers a viable path toward personalized, mechanically strong, and cell-stimulating wound dressings.

This review highlights the drawbacks of traditional approaches while navigating the difficulties of managing chronic wounds. The conversation revolves around employing natural biomaterials for customized dressings, with a particular emphasis on 3D-bioprinting. A thorough understanding of the uses of 3D-printed dressings in a range of chronic wound scenarios is provided by insights into recent research and patents.

The expert view recognizes wounds as a historical human ailment and emphasizes the growing difficulties and expenses related to wound treatment. The expert acknowledges that 3D printing is revolutionary, but also points out that it is still in its infancy and has the potential to enhance mass production rather than replace it. The review highlights the benefits of 3D printing for wound dressings by providing instances of smart materials that improve treatment results by stimulating angiogenesis, reducing pain, and targeting particular enzymes. The expert advises taking action to convert the technology's prospective advantages into real benefits for patients, even in the face of resistance to change in the healthcare industry. It is believed that the increasing evidence from in-vivo studies is promising and represents a positive change in the treatment of chronic wounds toward sophisticated 3D-printed dressings.

Diabetic foot ulcers, as one of the chronic wounds, are a serious challenge in the global healthcare system which have shown notable growth in recent years. DFU is associated with impairment in various stages of wound healing, including angiogenesis. Aberrant expression of microRNAs (miRNAs) involved in the disruption of the balance between angiogenic and anti-angiogenic factors, plays a crucial role in angiogenesis dysfunction. Alteration in the expression of angiomiRNAs (angiomiRs) have the potential to function as biomarkers in chronic wounds. Additionally, considering the rising importance of therapeutic RNAs, there is potential for utilizing angiomiRs in wound healing to induce angiogenesis. This review aims to explore angiogenesis in chronic wounds and investigate the mechanisms mediated by pro- and anti-angiomiRs in the context of diabetic foot ulcers.

Non-healing diabetic wounds represent a significant clinical challenge globally, necessitating innovative approaches in drug delivery to enhance wound healing. Understanding the pathogenesis of these wounds is crucial for developing effective treatments. Bioactive dressings and polymeric nanofibers have emerged as promising modalities, with silk biomaterials gaining attention for their unique properties in diabetic wound healing.

The purpose of this review is to examine the challenges and innovations in treating non-healing diabetic wounds, emphasizing the global burden and the need for effective solutions. This review explores the complex mechanisms of wound healing in diabetes and evaluates the therapeutic potential of bioactive dressings and polymeric nanofibers. Special focus is given to the application of silk biomaterials, particularly silk fibroin, for wound healing, detailing their properties, mechanisms, and clinical translation. This review also describes various nanofiber fabrication methods, especially electrospinning technology, and presents existing evidence on the effectiveness of electrospun silk fibroin formulations.

Recent advancements highlight the potential of silk biomaterials in diabetic wound healing, owing to their biocompatibility, mechanical strength, and controlled drug release properties. Electrospun silk fibroin-based formulations have shown promising results in preclinical and clinical studies, demonstrating accelerated wound closure and tissue regeneration.

Non-healing diabetic wounds present a significant healthcare burden globally, necessitating innovative therapeutic strategies. Bioactive dressings and polymeric nanofibers, particularly silk-based formulations fabricated through electrospinning, offer promising avenues for enhancing diabetic wound healing. Further research is warranted to optimize formulation parameters and validate efficacy in larger clinical trials.

Diabetic foot complications are serious issues resulting from uncontrolled diabetes, primarily affecting the feet. Common complications include diabetic neuropathy, ulcers, PAD, Charcot foot, and gangrene. Preventive measures include controlling blood glucose levels, regular foot inspections, proper foot care, wearing appropriate footwear, and seeking prompt medical attention. A holistic approach to diabetic foot management is crucial due to the complex interplay of physiological, psychological, and environmental factors. Glycaemic control is essential for mitigating neuropathy and vasculopathy, while cardiovascular risk factors like hypertension and dyslipidemia are crucial for preventing complications. In South Africa, podiatrists play a crucial role in diabetic foot care, offering specialized expertise in the assessment, management, and prevention of foot complications associated with diabetes mellitus. They collaborate closely with other healthcare professionals to ensure comprehensive and coordinated care.Pharmacological management is a crucial aspect of podiatric care in the UK, where podiatrists use various medications to treat foot conditions effectively. In South Africa, podiatrists lack prescribing authority, leading to limited treatment options, dependency on referrals, and disparities in access to care. This fragmented approach can compromise patient outcomes, especially in chronic conditions like diabetes. To improve patient outcomes and promote optimal foot condition management, policy reforms, interdisciplinary collaboration, and professional advocacy efforts are needed.Policy recommendations for expanding podiatrist prescribing privileges include legislative reforms, regulatory framework updates, and professional accreditation. Legislative reforms could involve amending existing healthcare laws or introducing new regulations that recognize podiatrists as authorized prescribers. Regulatory framework updates should involve working with regulatory bodies to establish prescribing standards, prescribing limitations, and mechanisms for ongoing oversight and accountability. Professional accreditation should ensure educational programs for podiatrists incorporate training in pharmacology, pharmacotherapy, and prescribing practices to prepare graduates for the expanded scope of practice.Stakeholders in South Africa can improve diabetes management by advocating for policy reforms, professional recognition, and patient empowerment initiatives. By aligning policy, practice, education, research, and advocacy efforts, stakeholders can create a supportive ecosystem that fosters innovation, collaboration, and continuous improvement in diabetic foot care.

Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.

Chronic diseases often hinder the natural healing process, making wound infections a prevalent clinical concern. In severe cases, complications can arise, potentially leading to fatal outcomes. While allopathic treatments offer numerous options for wound repair and management, the enduring popularity of herbal medications may be attributed to their perceived minimal side effects. Hence, this review aims to investigate the potential of herbal remedies in efficiently treating wounds, presenting a promising alternative for consideration.

A literature search was done including research, reviews, systematic literature review, meta-analysis, and clinical trials considered. Search engines such as Pubmed, Google Scholar, and Scopus were used while retrieving data. Keywords like Wound healing 'Wound healing and herbal combinations', 'Herbal wound dressing', Nanotechnology and Wound dressing were used.

This review provides valuable insights into the role of natural products and technology-based formulations in the treatment of wound infections. It evaluates the use of herbal remedies as an effective approach. Various active principles from herbs, categorized as flavonoids, glycosides, saponins, and phenolic compounds, have shown effectiveness in promoting wound closure. A multitude of herbal remedies have demonstrated significant efficacy in wound management, offering an additional avenue for care. The review encompasses a total of 72 studies, involving 127 distinct herbs (excluding any common herbs shared between studies), primarily belonging to the families Asteraceae, Fabaceae, and Apiaceae. In research, rat models were predominantly utilized to assess wound healing activities. Furthermore, advancements in herbal-based formulations using nanotechnology-based wound dressing materials, such as nanofibers, nanoemulsions, nanofiber mats, polymeric fibers, and hydrogel-based microneedles, are underway. These innovations aim to enhance targeted drug delivery and expedite recovery. Several clinical-based experimental studies have already been documented, evaluating the efficacy of various natural products for wound care and management. This signifies a promising direction in the field of wound treatment.

In recent years, scientists have increasingly utilized evidence-based medicine and advanced scientific techniques to validate the efficacy of herbal medicines and delve into the underlying mechanisms of their actions. However, there remains a critical need for further research to thoroughly understand how isolated chemicals extracted from herbs contribute to the healing process of intricate wounds, which may have life-threatening consequences. This ongoing research endeavor holds great promise in not only advancing our understanding but also in the development of innovative formulations that expedite the recovery process.

Diabetes, a chronic metabolic disorder disrupting blood sugar regulation, has emerged as a prominent silent pandemic. Uncontrolled diabetes predisposes an individual to develop fatal complications like cardiovascular disorders, kidney damage, and neuropathies and aggravates the severity of treatable infections. Escalating cases of Type 1 and Type 2 diabetes correlate with a global upswing in diabetes-linked mortality. As a growing global concern with limited preventive interventions, diabetes necessitates extensive research to mitigate its healthcare burden and assist ailing patients. An altered immune system exacerbated by chronic hyperinflammation heightens the susceptibility of diabetic individuals to microbial infections, including notable viruses like SARS-CoV-2, dengue, and influenza. Given such a scenario, we scrutinized the literature and compiled molecular pathways and signaling cascades related to immune compartments in diabetics that escalate the severity associated with the above-mentioned viral infections in them as compared to healthy individuals. The pathogenesis of these viral infections that trigger diabetes compromises both innate and adaptive immune functions and pre-existing diabetes also leads to heightened disease severity. Lastly, this review succinctly outlines available treatments for diabetics, which may hold promise as preventive or supportive measures to effectively combat these viral infections in the former.

Background and objectives: Diabetic foot stands out as one of the most consequential and devastating complications of diabetes. Many factors, including VIPS (Vascular management, Infection management, Pressure relief, and Source of healing), influence the prognosis and treatment of diabetic foot patients. There are many studies on VIPS, but relatively few studies on "sources of healing". Nutrients that affect wound healing are known, but objective data in diabetic foot patients are insufficient. We hypothesized that "sources of healing" would have many effects on wound healing. The purpose of this study is to know the affecting factors related to the source of healing for diabetic foot patients. Materials and Methods: A retrospective review identified 46 consecutive patients who were admitted for diabetic foot management from July 2019 to April 2021 at our department. Several laboratory tests were performed for influencing factor evaluation. We checked serum levels of total protein, albumin, vitamin B, iron, zinc, magnesium, copper, Hb, HbA1c, HDL cholesterol, and LDL cholesterol. These values of diabetic foot patients were compared with normal values. Patients were divided into two groups based on wound healing rate, age, length of hospital stay, and sex, and the test values between the groups were compared. Results: Levels of albumin (37%) and Hb (89%) were low in the diabetic foot patients. As for trace elements, levels of iron (97%) and zinc (95%) were low in the patients, but levels of magnesium and copper were usually normal or high. There were no differences in demographic characteristics based on wound healing rate. However, when compared to normal adult values, diabetic foot patients in our data exhibited significantly lower levels of hemoglobin, total protein, albumin, iron, zinc, copper, and HDL cholesterol. When compared based on age and length of hospital stay, hemoglobin levels were significantly lower in both the older age group and the group with longer hospital stays. Conclusions: Serum levels of albumin, Hb, iron, and zinc were very low in most diabetic foot patients. These low values may have a negative relationship with wound healing. Nutrient replacements are necessary for wound healing in diabetic foot patients.

Despite advancements in wound care, wound healing remains a challenge, especially in individuals with type 2 diabetes. Cell sheet technology has emerged as an efficient and promising therapy for tissue regeneration and wound repair. Among these, bilayered human keratinocyte-fibroblast cell sheets constructed using temperature-responsive culture surfaces have been shown to mimic a normal tissue-like structure and secrete essential cytokines and growth factors that regulate the wound healing process.

This study aimed to evaluate the safety and therapeutic potential of human skin cell sheets to treat full-thickness skin defects in a rat model of type 2 diabetes.

Our findings demonstrate that diabetic wounds transplanted with bilayered cell sheets resulted in accelerated re-epithelialization, increased angiogenesis, enhanced macrophage polarization and regeneration of tissue that closely resembled healthy skin. In contrast, the control group that did not receive cell sheet transplantation presented characteristic symptoms of impaired and delayed wound healing associated with type 2 diabetes.

The secretory cytokines and the upregulation of Nrf2 expression in response to cell sheet transplantation are believed to have played a key role in the improved wound healing observed in diabetic rats. Our study suggests that human keratinocyte-fibroblast cell sheets hold great potential as a therapeutic alternative for diabetic ulcers.

Chronic diabetic wounds have been an urgent clinical problem, and wound dressings play an important role in their management. Due to the design of traditional dressings, it is difficult to achieve adaptive adhesion and on-demand removal of complex diabetic wounds, real-time monitoring of wound status, and dynamic adjustment of drug release behavior according to the wound microenvironment. Smart hydrogels, as smart dressings, can respond to environmental stimuli and achieve more precise local treatment. Here, we review the latest progress of smart hydrogels in wound bandaging, dynamic monitoring, and drug delivery for treatment of diabetic wounds. It is worth noting that we have summarized the most important properties of smart hydrogels for diabetic wound healing. In addition, we discuss the unresolved challenges and future prospects in this field. We hope that this review will contribute to furthering progress on smart hydrogels as improved dressing for diabetic wound healing and practical clinical application.

The treatment of wounds using the body's own resources is a promising approach to support the physiological regenerative process. To advance this concept, we evaluated the effect of nanofat (NF) on wound healing. For this purpose, full-thickness skin defects were created in dorsal skinfold chambers of wild-type mice. These defects were filled with NF generated from the inguinal subcutaneous adipose tissue of green fluorescent protein (GFP)+ donor mice, which was stabilized using platelet-rich plasma (PRP). Empty wounds and wounds solely filled with PRP served as controls. Wound closure, vascularization and formation of granulation tissue were repeatedly analyzed using stereomicroscopy, intravital fluorescence microscopy, histology and immunohistochemistry over an observation period of 14 days. PRP + NF-treated wounds exhibited accelerated vascularization and wound closure when compared to controls. This was primarily due to the fact that the grafted NF contained a substantial fraction of viable GFP+ vascular and lymph vessel fragments, which interconnected with the GFP- vessels of the host tissue. Moreover, the switch from inflammatory M1- to regenerative M2-polarized macrophages was promoted in PRP + NF-treated wounds. These findings indicate that NF markedly accelerates and improves the wound healing process and, thus, represents a promising autologous product for future wound management.

The use of ozonized water is gaining importance in medicine due to its effects on hyperglycemia and wound healing mechanisms.

This experiment was conducted to assess the impacts of intradermal administration of ozonated water on acute skin wound healing in a diabetic rat model. Sixty-four adult male Wistar rats were randomly divided into two groups: an ozonated water group (O3W) and a control group (CG). Experimental diabetes was chemically induced in the rats by the intraperitoneal administration of 60 mg/kg streptozotocin. One week later, full-thickness skin surgical wounds (1 cm2) were created between the two shoulders of the rats under general anesthesia. The wounds were then daily irrigated with normal saline (CG) or intradermally injected with 1 mL of ozonated water at 10 mg/L O3W. Wound healing was evaluated through macroscopic analysis, measuring wound size, diameter, and percentage of contraction rate before wounding and at 3, 7, 9, 12, 14, 18, 21, 24, and 28 days post-wounding. On days 7, 14, 21, and 28 after induction of the wounds, the body weights and blood glucose levels of rats (8 per group) were measured before the rats were euthanized. Moreover, the morphological structure of the tissue, vascular endothelial and transforming growth factor (VEGF and TGF) affinity and gene expression were examined.

The O3W group had significantly lower blood glucose levels and wound size and gained body weight. Additionally, epithelial vascularization, stromal edema, TGF, and VEGF gene expression significantly improved in the O3W group.

Therefore, ozonated water has the potential to enhance and promote cutaneous wound healing in diabetic rats.

Establishing a common language that allows univocal and objective communication in describing wounds and their healing is of utmost importance in defining the diagnostic hypothesis and proper wound management. To measure the level of agreement on the description of wounds, an international study was performed among experts of different professional backgrounds on several common terms used to describe ulcerative lesions. A panel of 27 wound care experts anonymously completed a multiple-choice questionnaire on 100 images of 50 ulcerative lesions. The participants were asked to describe each image using a set of pre-defined terms. An expert data analyst interpreted the questionnaires to map the level of agreement on the used terminology. Our findings show a very low level of agreement among experts in using the proposed terminology to describe the wound bed, the wound edge, and the surrounding skin conditions. Efforts should be planned to find a consensus on the correct use of terminology for wound description. To this aim, partnership, consensus, and agreement with educators in medicine and nursing are necessary.

This study aims to investigate the potential therapeutic effect of exosomes derived from macrophages loaded with curcumin (Exos-cur) on the healing of diabetic wounds. As a new type of biomaterial, Exos-cur has better stability, anti-inflammation, and antioxidation biological activity. In in vitro experiments, Exos-cur can promote the proliferation, migration, and angiogenesis of HUVECs (human umbilical vein endothelial cells) while reducing the ROS (reactive oxygen species) produced by HUVECs induced by high glucose, regulating the mitochondrial membrane potential, reducing cell oxidative damage, and inhibiting oxidative stress and inflammation. In the in vivo experiment, the Exos-cur treatment group had an increased percentage of wound closure and contraction compared with the diabetic wound control group. Hematoxylin-eosin staining (HE) and Masson staining showed that the Exos-cur treatment group had more advanced re-epithelialization, and the generated mature granulation tissue was rich in a large number of capillaries and newly deposited collagen fibers. Western blot and immunofluorescence analyses showed that Exos-cur can inhibit inflammation by activating the Nrf2/ARE pathway, upregulate the expression of wound healing-related molecules, promote angiogenesis, and accelerate wound healing in diabetic rats. These results show that Exos-cur has a good therapeutic effect on diabetic skin defects and provide experimental evidence for the potential clinical benefits of Exos-cur.

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 16 days. 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.

Diabetic ulcers (DUs) are one of the most serious complications of diabetes mellitus. The application of a functional dressing is a crucial step in DU treatment and is associated with the patient's recovery and prognosis. However, traditional dressings with a simple structure and a single function cannot meet clinical requirements. Therefore, researchers have turned their attention to advanced polymer dressings and hydrogels to solve the therapeutic bottleneck of DU treatment. Hydrogels are a class of gels with a three-dimensional network structure that have good moisturizing properties and permeability and promote autolytic debridement and material exchange. Moreover, hydrogels mimic the natural environment of the extracellular matrix, providing suitable surroundings for cell proliferation. Thus, hydrogels with different mechanical strengths and biological properties have been extensively explored as DU dressing platforms. In this review, we define different types of hydrogels and elaborate the mechanisms by which they repair DUs. Moreover, we summarize the pathological process of DUs and review various additives used for their treatment. Finally, we examine the limitations and obstacles that exist in the development of the clinically relevant applications of these appealing technologies. This review defines different types of hydrogels and carefully elaborate the mechanisms by which they repair diabetic ulcers (DUs), summarizes the pathological process of DUs, and reviews various bioactivators used for their treatment.

One of challenges that faces diabetes is the wound healing process. The delayed diabetic wound healing is caused by a complicated molecular mechanism involving numerous physiological variables. Low-dose photodynamic therapy (LDPDT) provides excellent results in rejuvenation and wound healing. In this study, the LDPDT effect on diabetic wounds in mice was studied using two photosensitizers, 5-aminolevulinic acid and methylene blue, and two laser dose expositions of 1 J/cm² and 4 J/cm² by Raman spectroscopy (RS). The latter was used as a noninvasive method, providing specific information about tissue state based on the fundamental vibrational modes of its molecular components. RS allows high spatial resolution acquisition of biochemical and structural information through the generation of point spectra or spectral images. An approach to in vivo quantitative assessment of diabetic wound healing state was developed. This approach is based on an application of the principal component analysis combined with the Mahalanobis metrics to skin Raman spectra, in particular, intensities of the amide I and CH₂ bands.

In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research.