Impaired Wound Healing Research Articles

A Detailed Review on Diabetic Wound Healing Activity

Skin damage is known as a wound. Hemostasis, inflammatory, proliferative, and tissue remodelling or resolution are the four perfectly timed and highly planned phases that make up the normal biological process of wound healing in the human body. There are two basic categories of wounds: acute wounds and chronic wounds. Long-term negative effects on one's health are caused by the chronic metabolic condition known as diabetes mellitus, which is becoming more common. 25 percent of those with diabetes mellitus are thought to have poor wound healing due to their diabetes. Oxygenation, infection, hormones related to ageing and sex, stress, diabetes, and obesity, drugs, alcoholism, smoking, and diet are among the factors that affect wound healing. To address their basic medical needs, According to estimates, 80% of people who live in underdeveloped nations need traditional medicines, which are typically made from medicinal plants. Numerous individuals in Africa and other poor nations employ using medicinal herbs to cure diabetic wounds and associated issues due to the abundant supply With therapeutic herbs and enough conventional wisdom regarding wounds healing. Recent developments in functional genomics, nanotechnology, wound healing in diabetics, along with a better knowing the pathophysiology of chronic wounds. In the following review, detailed information about healing of diabetic wounds with mechanism, factors affecting, impairment of wound healing with its pathophysiology, herbal treatments and current advances when treating diabetic wounds are examined.

Impairment of HIF-2α Expression Induced the Compensatory Overexpression of the HIF-1α/SDF-1 Axis to Promote Wound Healing.

Glucocorticoids are common anti-inflammatory factors; however, they have been reported to have side effects that delay the wound healing process. In a previous study, we found that mesenchymal stem cells isolated from the adipose tissue of patients with long-term glucocorticoid treatment (sAT-MSC) showed impaired wound healing ability due to the downregulation of SDF-1. In this study, we aimed to clarify the mechanisms by which SDF-1 is regulated in sAT-MSC by focusing on the roles of hypoxia-inducible factors (HIFs). Our data suggested that sAT-MSC showed impairment of HIF-1α and the upregulation of HIF-2α. Notably, HIF-2α impairment resulted in the compensatory overexpression of HIF-1α and its target gene SDF-1, which improved the wound healing ability of sAT-MSC. In addition, using knockdown/knockout heterozygous HIF-2α kd/null mice (kd/null), the functions of HIF-2α in the ischemic wound healing process were clarified. With a 50% reduction in the expression of HIF-2α, kd/null mice showed significantly induced wound healing effects, which are involved in the promotion of the inflammatory phase. Specifically, kd/null mice showed the compensatory overexpression of HIF-1α, which upregulated the expression of SDF-1 and enhanced the recruitment of inflammatory cells, such as neutrophils. Our study highlighted the novel function of HIF-2α in the inflammation phase of the wound healing process through the HIF-1α/SDF-1 axis, suggesting that the physiological state of the impaired expression of HIF-2α is a new concept for wound therapy.

Recent developments in targets for ischemic foot disease.

Diabetes is a key risk factor for ischaemic foot disease, which causes pain, tissue loss, hospital admission, and major amputation. Currently, treatment focuses on revascularisation, but many patients are unsuitable for surgery and revascularisation is frequently unsuccessful. The authors describe recent research in animal models and clinical trials investigating novel medical targets for ischaemia, including theories about impaired wound healing, animal models for limb ischaemia and recent randomised controlled trials testing novel medical therapies. Novel targets identified in animal models included stimulating mobilisation of CD34+ progenitor cells through upregulating oncostatin M or microRNA-181, downregulating tumour necrosis factor superfamily member 14, or activating the Wingless pathway. Within the ischaemic limb vasculature, upregulation of apolipoprotein L domain containing 1, microRNA-130b or long noncoding RNA that enhances endothelial nitric oxide synthase expression promoted limb blood supply recovery, angiogenesis, and arteriogenesis. Similarly, administration of soluble guanylate cyclase stimulators riociguat or praliciguat or 3-ketoacyl-CoA thiolase inhibitor trimetazidine promoted blood flow recovery. Translating pre-clinical findings to patients has been challenging, mainly due to limitations in clinically translatable animal models of human disease. Promising results have been reported for administering plasmids encoding hepatocyte growth factor or intra-arterial injection of bone marrow derived cells in small clinical trials. It remains to be seen whether these high resource therapies can be developed to be widely applicable. In conclusion, an ever-expanding list of potential targets for medical revascularisation is being identified. It is hoped that through ongoing research and further larger clinical trials, these will translate into new broadly applicable therapies to improve outcomes.

A novel tension relief technique to aid the primary closure of traumatic equine wounds under excessive tension.

To achieve an excellent functional and cosmetic result, primary closure is preferred over leaving wounds to heal by secondary intention. However, traumatic wounds are often under excessive tension during wound closure and incorrect suture technique can compromise microcirculation, leading to skin necrosis and impaired wound healing. To describe an inexpensive and effective tension relief technique that helps the successful primary closure of a variety of equine wounds at high risk of dehiscence. Retrospective case series. All wounds that were managed with the Tension Tile System (TTS) at four Equine Hospitals between March 2017 and May 2021 were evaluated. The wounds were classified according to various criteria including anatomical location, time elapsed prior to surgery, depth of wound and post-surgical use of immobilisation. Outcome criteria were based on the success of primary intention healing. The duration of convalescence (weeks) after surgery was also recorded. During the study period, the TTS was used in 191/860 (22%) wounds repaired under general anaesthesia or standing sedation. Overall, primary intention healing (Group A) was achieved in 132 of 191 cases (69%, CI 62%-75%), with partial dehiscence (Group B) in a further 30/191 cases (16%, CI 11%-22%). Severe dehiscence (Group C) was recorded in 29/191 cases (15%, CI 11%-21%). The median convalescence time was 4 weeks (Range 3-15, interquartile range 4-6) in Group A. Retrospective nature of the study and subjective outcome assessment. The technique was applied to wounds under significant tension; however, this was based on a subjective assessment by the surgeons involved. The Tension Tile System is an economical and effective technique for challenging equine wounds under tension, in a variety of anatomical locations.

Pressure Ulcer Diagnosis Is Associated with Increased Mortality in Patients with End-Stage Renal Disease: A Retrospective Study.

Pressure ulcers are associated with multiple comorbidities and annually affect approximately 3 million Americans, directly accounting for approximately 60,000 deaths per year. Because patients with end-stage renal disease (ESRD) are known to present with unique factors which impair wound healing, pressure ulcers diagnosed in ESRD patients might independently increase the risk of mortality. To investigate the association between pressure ulcer diagnosis and mortality risk in the ESRD population, a retrospective analysis of the United States Renal Data System (USRDS) database was performed. The records of 1,526,366 dialysis patients who began therapy between 1 January 2005 and 31 December 2018 were included. Our analysis showed that the diagnosis of pressure ulcers in this population was independently associated with mortality even after controlling for confounding factors (p < 0.001). A Kaplan-Meier survival analysis demonstrated reduced survival in patients with a pressure ulcer diagnosis compared to those without a pressure ulcer diagnosis. These results establish pressure ulcers as a significant independent risk factor for mortality, as well as suggesting several comorbidities as potential risk factors for pressure ulcers in the ESRD population.

Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice

Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population. Given the increased incidence of cancer and the population ageing trend globally, it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer. In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation, although ageing does not affect the incidence of AOM-induced, sporadic non-inflammatory CRC. Mechanistically, reduced fibroblasts were observed in the colitis microenvironment of ageing mice. Through conditional lineage tracing, an important source of fibroblasts potentially derived from intestinal smooth muscle cells (ISMCs) was identified orchestrating intestinal wound healing and CAC initiation in young mice. However, the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice, accompanied by decreased intestinal wound healing and decreased CAC initiation. ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments. We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts. Meanwhile, the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice. Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment, decreased intestinal wound healing and decreased CAC initiation, similar to the phenotype of ageing mice. In addition, the data from intestine samples derived from inflammatory bowel disease (IBD) patients show that activation of YAP/TAZ also occurs in ISMCs from these patients. Collectively, our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation. Furthermore, our work also identified a potential source of fibroblasts involved in colitis and CAC.

Biocompatibility Study with Baby Hamster Kidney Cells on Acetobacter Xylinum Pellicle for Diabetic Foot Laceration

Diabetes mellitus, commonly known as diabetes, is a persistent metabolic condition marked by elevated blood glucose levels. This condition's global prevalence has been consistently increasing, becoming a major cause for concern in public health on an international scale. This disease can lead to various complications, including impaired wound healing. The purpose of this study is to determine the cytotoxicity level of hydrogel membranes made from Acetobacter xylinum and whether the used method is appropriate for producing proper wound healing material. The findings of the study, employing BHK Kidney cells and the MTT Assay technique, revealed that the dehydrated hydrogel membrane derived from bacterial cellulose and processed through oven drying exhibited a toxicity level of less than 50% across all samples. Additionally, the swelling test indicated a rise in water absorption when the membrane was combined with collagen material

Insulin Can Delay Neutrophil Extracellular Trap Formation In Vitro-Implication for Diabetic Wound Care?

Diabetes is a worldwide evolving disease with many associated complications, one of which is delayed or impaired wound healing. Appropriate wound healing strongly relies on the inflammatory reaction directly after injury, which is often altered in diabetic wound healing. After an injury, neutrophils are the first cells to enter the wound site. They have a special defense mechanism, neutrophil extracellular traps (NETs), consisting of released DNA coated with antimicrobial proteins and histones. Despite being a powerful weapon against pathogens, NETs were shown to contribute to impaired wound healing in diabetic mice and are associated with amputations in diabetic foot ulcer patients. The anti-diabetic drugs metformin and liraglutide have already been shown to regulate NET formation. In this study, the effect of insulin was investigated. NET formation after stimulation with PMA (phorbol myristate acetate), LPS (lipopolysaccharide), or calcium ionophore (CI) in the presence/absence of insulin was analyzed. Insulin led to a robust delay of LPS- and PMA-induced NET formation but had no effect on CI-induced NET formation. Mechanistically, insulin induced reactive oxygen species, phosphorylated p38, and ERK, but reduced citrullination of histone H3. Instead, bacterial killing was induced. Insulin might therefore be a new tool for the regulation of NET formation during diabetic wound healing, either in a systemic or topical application.

A calcium peroxide incorporated oxygen releasing chitosan-PVA patch for Diabetic wound healing

Impaired wound healing is a major healthcare problem in patients with diabetes often resulting in gangrene, microbial infection and amputation of affected limb. The delay or absence in healing process arises from several abnormalities, among them chronic hypoxia is a major concern due to its associated issues such as lack of collagen deposition, epithelization, fibroplasia, angiogenesis, and resistance to infections at the wound site. To address hypoxia, delivery of oxygen at the wound site through oxygen releasing agents have been proven to be effective therapeutics. Several oxygen releasing nanoparticles such as Sodium Percarbonate (SPC), Calcium Peroxide (CPO), Hydrogen Peroxide, Magnesium Peroxide (MPO) have been investigated in wound healing application. However, the uncontrolled/burst release of these nanotherapeutic agents and its accompanied cytotoxicity pose a barrier in expediting the healing process. In this study, a Chitosan-Polyvinyl alcohol (CS-PVA) based hydrogel containing oxygen releasing nanoparticle, calcium peroxide (CPO) was constructed to provide a slow and sustained delivery of oxygen for at least 5 days. In-vitro cell culture studies with this material using fibroblast and endothelial cell line exhibited improved biocompatibility, cell viability and enhanced proliferation in comparison with the control group. Additionally, cell migration study using scratch assay method showed superior cell migration ability of our proposed materials. Furthermore, In vivo study using diabetic rat model showed accelerated wound closure rate compared to untreated control wounds.

COVID-associated complications after reconstructive breast surgery: a retrospective cohort study.

The COVID pandemic significantly influenced reconstructive breast surgery regimens. Many surgeries were cancelled or postponed. COVID entails not only respiratory, but also coagulative symptoms. It, therefore, potentially increases the risk of postoperative complications. The incidence of perioperative COVID infection and its influence on postoperative recovery after reconstructive breast surgery is still unknown. This dual center retrospective cohort study included patients that underwent reconstructive breast surgery between March 2020 and July 2021. Post-mastectomy autologous or implant-based breast reconstruction (ABR; IBR), as well as post-lumpectomy oncoplastic partial breast reconstruction (PBR) were eligible. Patient data were extracted from electronic medical records. Data regarding COVID-19 infection was collected through a questionnaire. The primary outcome was complication rate. The ABR, IBR and PBR groups consisted of 113 (12 COVID-positive), 41 (2 COVID-positive) and 113 (10 COVID-positive) patients. In the ABR and PBR groups, postoperative complications occurred significantly more often in patients with perioperative COVID-infection. Especially impaired wound healing occurred significantly more often in the ABR and PBR breasts, but also at the donor site of ABR patients with perioperative COVID. Perioperative COVID-infection increases susceptibility to complicated wound healing after reconstructive breast surgery. A possible explanation lies in the dysregulation of haemostasis by the virus, and its direct effects on microvasculature. A hypercoagulable state results. We recommend to postpone elective breast surgery for 4-6weeks after COVID-19 infection. Also, precautionary measures remain important to minimize the risk of perioperative COVID-19 infection.

Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.

Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of cell death and a substrate of Caspase-8. However, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, CflipD377A, exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)-induced lethality, impaired skin wound healing, and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to tumor necrosis factor(TNF)-induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death-sensitizing effect of the D377A mutation depends on glutamine-469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress to ensure the execution of repair programs.

Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes.

Impaired wound healing is the most common and significant complication of Diabetes. While most other complications of Diabetes have better treatment options, diabetic wounds remain a burden as they can cause pain and suffering in patients. Wound closure and repair are orchestrated by a sequence of events aided by the release of pro-inflammatory cytokines, which are dysregulated in cases of Diabetes, making the wound environment unfavorable for healing and delaying the wound healing processes. This concise review provides an overview of the dysregulation of pro-inflammatory cytokines and offers insights into better therapeutic outcomes. Although many therapeutic approaches have been lined up nowadays to treat Diabetes, there are no proper treatment modalities proposed yet in treating diabetic wounds due to the lack of understanding about the role of inflammatory mediators, especially Pro-inflammatory mediators- Cytokines, in the process of Wound healing which we mainly focus on this review. Although complications of Diabetes mellitus are most reported after years of diagnosis, the most severe critical complication is impaired Wound Healing among Diabetes patients. Even though Trauma, Peripheral Artery Disease, and Peripheral Neuropathy are the leading triggering factors for the development of ulcerations, the most significant issue contributing to the development of complicated cutaneous wounds is wound healing impairment. It may even end up with amputation. Newer therapeutic approaches such as incorporating the additives in the present dressing materials, which include antimicrobial molecules and immunomodulatory cytokines is of better therapeutic value. The adoption of these technologies and the establishment of novel therapeutic interventions is difficult since there is a gap in terms of a complete understanding of the pathophysiological mechanisms at the cellular and molecular level and the lack of data in terms of the assessment of safety and bioavailability differences in the individuals' patients. The target-specific pro-inflammatory cytokines-based therapies, either by upregulation or downregulation of them, will be helpful in the wound healing process and thereby enhances the Quality of life in patients, which is the goal of drug therapy.

Hydrolytic hydrogels tune mesenchymal stem cell persistence and immunomodulation for enhanced diabetic cutaneous wound healing

Diabetes is associated with an altered global inflammatory state with impaired wound healing. Mesenchymal stem/stromal cells (MSC) are being explored for treatment of diabetic cutaneous wounds due to their regenerative properties. These cells are commonly delivered by injection, but the need to prolong the retention of MSC at sites of injury has spurred the development of biomaterial-based MSC delivery vehicles. However, controlling biomaterial degradation rates in vivo remains a therapeutic-limiting challenge. Here, we utilize hydrolytically degradable ester linkages to engineer synthetic hydrogels with tunable in vivo degradation kinetics for temporally controlled delivery of MSC. In vivo hydrogel degradation rate can be controlled by altering the ratio of ester to amide linkages in the hydrogel macromers. These hydrolytic hydrogels degrade at rates that enable unencumbered cutaneous wound healing, while enhancing the local persistence MSC compared to widely used protease-degradable hydrogels. Furthermore, hydrogel-based delivery of MSC modulates local immune responses and enhances cutaneous wound repair in diabetic mice. This study introduces a simple strategy for engineering tunable degradation modalities into synthetic biomaterials, overcoming a key barrier to their use as cell delivery vehicles.

Updates on Recent Clinical Assessment of Commercial Chronic Wound Care Products.

Impaired wound healing after trauma,disorders, and surgeries impact millions of people globally every year. Dysregulation inorchestrated healing mechanisms and underlying medical complications make chronic wound management extremely challenging. Besidesstandard-of-care treatments including broad spectrum antibioticsand wound-debridement,novel adjuvant therapies are clinically tested and commercialized. These include topical agents, skin substitutes, growth factor delivery, and stem cell therapies. With a goal to overcome factors playing pivotal role in delayed wound healing, researchers are exploring novel approaches to elicit desirable healing outcomes in chronic wounds. Although recent innovations in wound care products, therapies, and devices are extensively reviewed in past, a comprehensive review summarizing their clinical outcomes is surprisingly lacking. Herein, this work reviews the commercially available wound care products and their performance in clinical trials to provide a statistically comprehensive understanding of their safety and efficacy. The performance and suitability of various commercial wound care platforms, including xenogeneic and allogenic products, wound care devices, and novel biomaterials, are discussed forchronic wounds. The current clinical evaluation will provide a comprehensive understanding of the benefits and drawbacks of the most-recent approaches and will enable researchers and healthcare providers to develop next-generation technologies for chronic wound management.

Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing

Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1β, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.

The effect of long-term cigarette smoking on selected skin barrier proteins and lipids

The negative impact of cigarette smoking on the skin includes accelerated aging, pigmentation disorders, and impaired wound healing, but its effect on the skin barrier is not completely understood. Here, we studied the changes in selected epidermal proteins and lipids between smokers (45–66 years, smoking > 10 years, > 10 cigarettes per day) and non-smokers. Volar forearm epidermal and stratum corneum samples, obtained by suction blister and tape stripping, respectively, showed increased thickness in smokers. In the epidermis of smokers, we observed a significant upregulation of filaggrin, loricrin, and a trend of increased involucrin but no differences were found in the case of transglutaminase 1 and kallikrein-related peptidase 7, on the gene and protein levels. No significant changes were observed in the major skin barrier lipids, except for increased cholesterol sulfate in smokers. Liquid chromatography coupled with mass spectrometry revealed shorter acyl chains in ceramides, and an increased proportion of sphingosine and 6-hydroxysphingosine ceramides (with C4 trans-double bond) over dihydrosphingosine and phytosphingosine ceramides in smokers, suggesting altered desaturase 1 activity. Smokers had more ordered lipid chains found by infrared spectroscopy. In conclusion, cigarette smoking perturbs the homeostasis of the barrier proteins and lipids even at a site not directly exposed to smoke.

Reversal of dual epigenetic repression of non-canonical Wnt-5a normalises diabetic corneal epithelial wound healing and stem cells

Aims/hypothesisDiabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression.MethodsHuman LEC were isolated, or organ-cultured corneas were obtained, from autopsy eyes from non-diabetic (59.87±20.89 years) and diabetic (71.93±9.29 years) donors. The groups were not statistically different in age. DNA was extracted from LEC for methylation analysis using Illumina Infinium 850K MethylationEPIC BeadChip and protein was extracted for Wnt phospho array analysis. Wound healing was studied using a scratch assay in LEC or 1-heptanol wounds in organ-cultured corneas. Organ-cultured corneas and LEC were transfected with WNT5A siRNA, miR-203a mimic or miR-203a inhibitor or were treated with recombinant Wnt-5a (200 ng/ml), DNA methylation inhibitor zebularine (1–20 µmol/l) or biodegradable nanobioconjugates (NBCs) based on polymalic acid scaffold containing antisense oligonucleotide (AON) to miR-203a or a control scrambled AON (15–20 µmol/l).ResultsThere was significant differential DNA methylation between diabetic and non-diabetic LEC. WNT5A promoter was hypermethylated in diabetic LEC accompanied with markedly decreased Wnt-5a protein. Treatment of diabetic LEC and organ-cultured corneas with exogenous Wnt-5a accelerated wound healing by 1.4-fold (p<0.05) and 37% (p<0.05), respectively, and increased LESC and diabetic marker expression. Wnt-5a treatment in diabetic LEC increased the phosphorylation of members of the Ca2+-dependent non-canonical pathway (phospholipase Cγ1 and protein kinase Cβ; by 1.15-fold [p<0.05] and 1.36-fold [p<0.05], respectively). In diabetic LEC, zebularine treatment increased the levels of Wnt-5a by 1.37-fold (p<0.01)and stimulated wound healing in a dose-dependent manner with a 1.6-fold (p<0.01) increase by 24 h. Moreover, zebularine also improved wound healing by 30% (p<0.01) in diabetic organ-cultured corneas and increased LESC and diabetic marker expression. Transfection of these cells with WNT5A siRNA abrogated wound healing stimulation by zebularine, suggesting that its effect was primarily due to inhibition of WNT5A hypermethylation. Treatment of diabetic LEC and organ-cultured corneas with NBC enhanced wound healing by 1.4-fold (p<0.01) and 23.3% (p<0.05), respectively, with increased expression of LESC and diabetic markers.Conclusions/interpretationWe provide the first account of epigenetic changes in diabetic corneas including dual inhibition of WNT5A by DNA methylation and miRNA action. Overall, Wnt-5a is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea.Data availabilityThe DNA methylation dataset is available from the public GEO repository under accession no. GSE229328 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE229328).Graphical

Mechanisms and applications of adipose-derived stem cell-extracellular vesicles in the inflammation of wound healing.

Wound healing is a sophisticated process consisting of serial phases with overlaps, including hemostasis, inflammation, proliferation, and remodeling. The inflammation response is an early response that plays a crucial role in eliminating microbes and clearing damaged cell debris. However, in some pathological circumstances, such as diabetes mellitus, ischemia, trauma, deep burn, etc., abnormal inflammation can cause impaired wound healing. Adipose-derived stem cells (ADSCs) belong to the mesenchymal stem cell (MSC) family and exhibit prospective applications in tissue regeneration and dermatological repairs. ADSC-secreted extracellular vesicles (ADSC-EVs) mimic the functions of ADSCs without the concerns of cell survival, immune response, or ethical issues. Studies have revealed that ADSC-EVs can inhibit abnormal inflammation responses and accelerate wound healing through various mechanisms. Moreover, some studies explored modifications in the cargo components of ADSC-EVs to enhance their therapeutic efficacy. Given the increasing studies focusing on the potential of ADSC-EVs in wound healing, how they interfere with different phases of this process has been investigated in pieces. In this review, we summarized all up-to-date evidence to map a clearer picture of the underlying mechanisms of ADSC-EVs in inflammation response. The applications of ADSC-EVs aiming at inflammation in the healing process were also reviewed to provide therapeutic strategies for future investigators.

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men

/Objective: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180-days prior to surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P<.001) that was in the lower extremity. At 5-years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P<.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (HR:1.94, 95%CI:1.4-2.7; P<.001) compared to controls. This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

Skewing cPLA2α activity toward oxoeicosanoid production promotes neutrophil N2 polarization, wound healing, and the response to sepsis.

Uncontrolled inflammation is linked to poor outcomes in sepsis and wound healing, both of which proceed through distinct inflammatory and resolution phases. Eicosanoids are a class of bioactive lipids that recruit neutrophils and other innate immune cells. The interaction of ceramide 1-phosphate (C1P) with the eicosanoid biosynthetic enzyme cytosolic phospholipase A2 (cPLA2) reduces the production of a subtype of eicosanoids called oxoeicosanoids. We investigated the effect of shifting the balance in eicosanoid biosynthesis on neutrophil polarization and function. Knockin mice expressing a cPLA2 mutant lacking the C1P binding site (cPLA2αKI/KI mice) showed enhanced and sustained neutrophil infiltration into wounds and the peritoneum during the inflammatory phase of wound healing and sepsis, respectively. The mice exhibited improved wound healing and reduced susceptibility to sepsis, which was associated with an increase in anti-inflammatory N2-type neutrophils demonstrating proresolution behaviors and a decrease in proinflammatory N1-type neutrophils. The N2 polarization of cPLA2αKI/KI neutrophils resulted from increased oxoeicosanoid biosynthesis and autocrine signaling through the oxoeicosanoid receptor OXER1 and partially depended on OXER1-dependent inhibition of the pentose phosphate pathway (PPP). Thus, C1P binding to cPLA2α suppresses neutrophil N2 polarization, thereby impairing wound healing and the response to sepsis.