Wound Macrophages Research Articles

Fabrication and characterization of PVA@PLA electrospinning nanofibers embedded with Bletilla striata polysaccharide and Rosmarinic acid to promote wound healing

In this study, a novel nanofiber material with Polylactic acid (PLA), natural plant polysaccharides-Bletilla striata polysaccharide (BSP) and Rosmarinic acid (RA) as the raw materials to facilitate wound healing was well prepared through coaxial electrospinning. The morphology of RA-BSP-PVA@PLA nanofibers was characterized through scanning electron microscopy (SEM), and the successful formation of core-shell structure was verified under confocal laser microscopy (CLSM) and Fourier transform infrared spectroscopy (FTIR). RA-BSP-PVA@PLA exhibited suitable air permeability for wound healing, as indicated by the result of the water vapor permeability (WVTR) study. The results of tension test results indicated the RA-BSP-PVA@PLA nanofiber exhibited excellent flexibility and better accommodates wounds. Moreover, the biocompatibility of RA-BSP-PVA@PLA was examined through MTT assay. Lastly, RA-BSP-PVA@PLA nanofibers can induce wound tissue growth, as verified by the rat dorsal skin wound models and tissue sections. Furthermore, RA-BSP-PVA@PLA can facilitate the proliferation and transformation of early wound macrophages, and down-regulate MPO+ expression of on the wound, thus facilitating wound healing, as confirmed by the result of immunohistochemical. Thus, RA-BSP-PVA@PLA nanofibers show great potential as wound dressings in wound healing.

Single-cell RNA-Seq analysis of diabetic wound macrophages in STZ-induced mice

The crucial role of macrophages in the healing of chronic diabetic wounds is widely known, but previous in vitro classification and marker genes of macrophages may not be fully applicable to cells in the microenvironment of chronic wounds. The heterogeneity of macrophages was studied and classified at the single-cell level in a chronic wound model. We performed single-cell sequencing of CD45 + immune cells within the wound edge and obtained 17 clusters of cells, including 4 clusters of macrophages. One of these clusters is a previously undescribed population of macrophages possessing osteoclast gene expression, for which analysis of differential genes revealed possible functions. We also analysed the differences in gene expression between groups of macrophages in the control and diabetic wound groups at different sampling times. We described the differentiation profile of mononuclear macrophages, which has provided an important reference for the study of immune-related mechanisms in diabetic chronic wounds.Graphical

317 Healthy repair of injured skin requires mitochondrial repurposing in wound macrophages

Cells of the monocyte/macrophage lineage (MFs) are an essential component of the body’s innate ability to restore tissue function after injury. Yet, the molecular signals required to coordinate the transition from pro-inflammatory clearance of injury-associated MFs to pro-resolution signals that rebuild tissue architecture and restore homeostasis remain unresolved. Here we decipher whether metabolic reprogramming drives MF activation and function in healing tissues. By combining multiple methods including generation of genetically modified mouse models, bulk and single cell transcriptomic analysis of wound MFs at different stages and functional metabolic analysis, we demonstrate that skin injury induces distinct metabolic programs in wound MFs, which drive stage specific and critical repair functions over the time course of healing.

Blood-Induced Inflammation in Hemophilia

We previously showed that the acute-phase reactants IL-6, CRP and LBP are elevated in the blood of hemophilia patients in response to acute and recent bleeding. The systemic elevation of acute-phase markers in hemophilia patients was associated with increased activation of monocytes, which exhibit deficits of M2 markers such as CSF1-R, CD163 and Tie2. These deficits correlate with impaired differentiation of monocytes into macrophages thus resulting in the diminished ability of hemophilia macrophages to invade clot and phagocytose red blood cells. As macrophages are central to wound healing and tissue regeneration, we hypothesize that the diminished phagocytic activity of hemophilia macrophages contributes to blood-induced inflammation and joint degeneration in hemophiliacs with hemarthrosis. To assess the effect of joint bleeding on inflammation, we induced a needle-puncture injury of the knee in transgenic mice with hemophilia A. While this process produced only a minor injury in coagulation competent control mice, we observed an extensive hematoma on d1 and d7 in the knees of hemophilia mice as shown by gross and histological examination. By day 28, the hematoma was completely absorbed. The degenerative changes of the knee joints that followed the bleeds included synovia hyperplasia, fibrosis and decline in bone density. Joint bleeding reached a plateau on day 1-7 in hemophilia mice. Immunohistochemistry for myeloperoxidase revealed during this time a massive influx of neutrophil granulocytes into punctured joints that subsided at day 28 when the hematoma was replaced by arthrofibrosis. In addition, acute bleeding-induced inflammation was reflected by a steep increase of interleukin 6 in the blood circulation of knee-punctured hemophilia mice that reached a maximum at day 7 and then fell towards baseline levels at day 28. CD68-positive wound macrophages, on the other hand, were first observed in punctured knees on day 7 and persisted until the end of the observation period on day 28, when most of the macrophages were loaded up with hemosiderin. None of these complications occurred in punctured wildtype mice with normal clotting activity. The deposition of hemosiderin-loaded macrophages in the punctured joints of hemophilia mice suggests that failure to remove red blood cells from the wound area leads to inflammation and subsequent joint degeneration. This failure to clear red blood cells and their proinflammatory components appeared to be specific to hemophilia mice, as we observed rapid absorption of sizable hematomas after injection of anticoagulated blood into the knee joint of coagulation-competent wildtype mice, which in contrast to punctured hemophilia mice showed no signs of inflammation or joint destruction 7 days after blood injection. Together, these data show that hemarthrosis in hemophilia represents a relevant inflammatory stimulus that correlates strongly with joint degeneration. Moreover, the data indicate that inflammation in hemophilia is caused by impaired removal of red blood cells from injured joints, which may lead to the release of pro-inflammatory hemoglobin degradation products and subsequent arthrofibrosis.

Macrophages in Skin Wounds: Functions and Therapeutic Potential

Macrophages regulate cutaneous wound healing by immune surveillance, tissue repair and remodelling. The depletion of dermal macrophages during the early and middle stages of wound healing has a detrimental impact on wound closure, characterised by reduced vessel density, fibroblast and myofibroblast proliferation, delayed re-epithelization and abated post-healing fibrosis and scar formation. However, in some animal species, oral mucosa and foetal life, cutaneous wounds can heal normally and remain scarless without any involvement of macrophages. These paradoxical observations have created much controversy on macrophages' indispensable role in skin wound healing. Advanced knowledge gained by characterising macrophage subsets, their plasticity in switching phenotypes and molecular drivers provides new insights into their functional importance during cutaneous wound healing. In this review, we highlight the recent findings on skin macrophage subsets, their functional role in adult cutaneous wound healing and the potential benefits of targeting them for therapeutic use.

A fucoidan-gelatin wound dressing accelerates wound healing by enhancing antibacterial and anti-inflammatory activities

Microbial infections and the slow regression of inflammation are major impediments to wound healing. Herein, a tilapia fish skin gelatin-fucose gum-tannic acid (Gel&Fuc-TA) hydrogel wound dressing (Gel&Fuc-TA) was designed to promote wound healing by mixing and reacting tannic acid (TA) with tilapia fish skin gelatin (Gel) and fucoidan (Fuc). Gel&Fuc-TA hydrogel has a good network structure as well as swelling and release properties, and shows excellent antibacterial, antioxidant, cell compatibility, and hemostatic properties. Gel&Fuc-TA hydrogel can promote the expression of vascular endothelial growth factor (VEGF), platelet endothelial cell adhesion molecule-1 (CD-31), and alpha-smooth muscle actin (α-SMA), enhance collagen deposition, and accelerate wound repair. Gel&Fuc-TA hydrogel can change the wound microbiome, reduce wound microbiome colonization, and decrease the expression of microbiome-related proinflammatory factors, such as lipopolysaccharide (LPS), Toll-like receptor 2 (TLR2), and Toll-like receptor 4 (TLR4). Gel&Fuc-TA hydrogel effectively regulates the conversion of wound macrophages to the M2 (anti-inflammatory phenotype) phenotype, decreases the expression of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), and increases the expression of arginase-1 (Arg-1), interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), thereby reducing the inflammatory response. In summary, Gel&Fuc-TA hydrogel prepared using a rational green cross-linking reaction can effectively accelerate wound healing.

Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.

The myeloid mineralocorticoid receptor regulates dermal angiogenesis and inflammation in glucocorticoid-induced impaired wound healing.

Delayed wound healing is among the deleterious consequences of over-activation of the mineralocorticoid receptor (MR) induced by topical dermocorticoids. The role of dermal inflammation and angiogenesis in the benefits of MR blockade is unknown. Skin wounds were made on C57Bl6 mice after topical pretreatment with the dermocorticoid clobetasol. The impact of topical MR blockade by canrenoate on inflammation, angiogenesis, and the wound macrophage phenotype was analysed 5 days post-wounding. Similar experiments were conducted on mice with genetic deletion of the MR in myeloid cells. Topical inhibition of the MR with canrenoate improved delayed wound healing through the resolution of prolonged inflammation in glucocorticoid-pretreated mouse skin. This effect was associated with a higher ratio of anti-inflammatory macrophages versus pro-inflammatory macrophages in wounds treated by canrenoate. Furthermore, MR blockade led to upregulated expression of pro-angiogenic factors and improved impaired angiogenesis in wounds of glucocorticoid-pretreated skin. Finally, deletion of MR expression by myeloid cells reproduced the benefits of topical pharmacological MR blockade. Topical MR antagonism facilitates the switching of macrophages towards an anti-inflammatory phenotype, which improves prolonged inflammation and induces angiogenesis to accelerate wound healing delayed by glucocorticoid treatment.

Age-Related Alterations in Macrophage Distribution and Function Are Associated With Delayed Cutaneous Wound Healing.

Ageing-related delays and dysregulated inflammation in wound healing are well-documented in both human and animal models. However, cellular and molecular changes underlying this impairment in healing progression are not fully understood. In this study, we characterised ageing-associated changes to macrophages in wounds of young and aged mice and investigated transcriptomic differences that may impact the progression of wound healing. Full-thickness wounds created on the dorsum of C57BL/6J young and aged mice were excised on Days 3 and 7 post-wounding for analysis by immunohistochemistry, flow cytometry, and RNA sequencing. Our data revealed that macrophages were significantly reduced in aged wounds in comparison to young. Functional transcriptomic analyses showed that macrophages from aged wounds exhibited significantly reduced expression of cell cycle, DNA replication, and repair pathway genes. Furthermore, we uncovered an elevated pro-inflammatory gene expression program in the aged macrophages correlated with poor inflammation resolution and excessive tissue damage observed in aged wounds. Altogether, our work provides insights into how poorly healing aged wounds are phenotypically defined by the presence of macrophages with reduced proliferative capacity and an exacerbated inflammatory response, both of which are pathways that can be targeted to improve healing in the elderly.

Topical Aspirin Administration Improves Cutaneous Wound Healing in Diabetic Mice Through a Phenotypic Switch of Wound Macrophages Toward an Anti-inflammatory and Proresolutive Profile Characterized by LXA4 Release.

Patients with diabetes present a persistent inflammatory process, leading to impaired wound healing. Since nonhealing diabetic wound management shows limited results, the introduction of advanced therapies targeting and correcting the inflammatory status of macrophages in chronic wounds could be an effective therapeutic strategy to stop the sustained inflammation and to return to a healing state. In an excisional skin injury in a diet-induced diabetic murine model, we demonstrate that topical administration of low-dose aspirin (36 μg/wound/day) improves cutaneous wound healing by increasing wound closure through the promotion of the inflammation resolution program of macrophages. This treatment increased efferocytosis of wound macrophages from aspirin-treated diabetic mice compared with untreated diabetic mice. We also show that aspirin treatment of high-fat-fed mice oriented the phenotype of wound macrophages toward an anti-inflammatory and proresolutive profile characterized by a decrease of LTB4 production. The use of diabetic mice deficient for 5-LOX or 12/15-LOX demonstrated that these two enzymes of acid arachidonic metabolism are essential for the beneficial effect of aspirin on wound healing. Thus, aspirin treatment modified the balance between pro- and anti-inflammatory eicosanoids by promoting the synthesis of proresolving LXA4 through 5-LOX, LTA4, 12/15-LOX signaling. In conclusion, the restoration of an anti-inflammatory and proresolutive phenotype of wound macrophages by the topical administration of low-dose aspirin represents a promising therapeutic approach in chronic wounds.

Burn-Induced Local and Systemic Immune Response: Systematic Review and Meta-Analysis of Animal Studies

Because burn injuries are often followed by a derailed immune response and excessive inflammation, a thorough understanding of the occurring reactions is key to preventing secondary complications. This systematic review, which includes 247 animal studies, shows the postburn response of 14 different immune cell types involved in immediate and long-term effects in both wound tissue and circulation. Peripheral blood neutrophil and monocyte numbers increased directly after burns, whereas thrombocyte numbers increased near the end of the first week. However, lymphocyte numbers were decreased for at least 2 weeks. In burn wound tissue, neutrophil and macrophage numbers accumulated during the first 3 weeks. Burns also altered cellular functions because we found an increased migratory potential of leukocytes, impaired antibacterial activity of neutrophils, and enhanced inflammatory mediator production by macrophages. Neutrophil surges were positively associated with burn size and were highest in rats. Altogether, this comprehensive overview of the temporal immune cell dynamics shows that unlike normal wound healing, burn injury induces a long-lasting inflammatory response. It provides a fundamental research basis to improve experimental set-ups, burn care, and outcomes.

CGAS-STING Mediated Inflammation In Diabetic Wound Macrophages Is Regulated By Histone Demethylase JMJD3

Abstract Recent work has shown that the cGAS-STING inflammatory pathway is elevated in conditions that are marked by chronic inflammation, such as obesity and diabetes. Using single cell RNA (scRNA) sequencing from human wounds, we show that the Sting gene is increased in diabetic wound macrophages. Histone demethylase JMJD3 specifically demethylates lysine 27 on histone 3 (H3K27me3) - a repressive mark for gene transcription. Using diabetic mice, we note on ChIP analysis, a decrease in the H3K27me3 repressive mark at the STING promoter in diabetic wound macrophages relative to littermate controls, with subsequently enhanced STING protein levels by western blot. Additionally, scRNA from wound macrophages obtained from a novel murine strain deficient in Jmjd3 in myeloid-cell lineages (Jmjd3f/fLyz2Cre+), revealed significantly decreased Sting gene levels. Further, ChIP analysis of H3K27me3 levels at the STING promoter from Jmjd3f/fLyz2Cre+ wound macrophages reveal increased H3K27me3 levels compared to littermate controls, with a concomitant decrease in STING protein as determined by western blot. Mechanistically, we use mRNA, protein and ChIP studies to reveal that in diabetic wound macrophages, IL6 is responsible for increased JMJD3 leading to increased JAK1,3/STAT3 activity and increased STING production. Wound healing curves from diabetic mice locally treated with macrophage-specific nanoparticles against JMJD3 showed significantly improved healing, and decreased STING protein production in these wounds. Taken together, this data highlights a unique epigenetic regulator of STING production in diabetic wound macrophages and provides a viable cell-specific, nanotherapeutic approach to non-healing diabetic wounds. Supported by NIH (F32DK126471), Vascular and Endovascular Surgical Society Resident Research Award

Helminth TGF-β mimic, TGM, increases leukocyte migration and activation while also enhancing cutaneous wound healing and tissue regeneration.

Abstract Intestinal parasites express excretory/secretory (ES) molecules, which modulate the type-2 immune response including anti-inflammatory and tissue repair mechanisms. TGF-β mimic (TGM), an ES molecule secreted by Heligmosomoides polygyrus (Hp), binds TGF-β receptors yet lacks structural homology to TGF-β and distinct receptor interactions. We now demonstrate that TGM enhanced wound healing using an in vivo wound biopsy model in which TGM, in a 1.5% carboxymethylcellulose solution, was topically administered beneath a Tegaderm layer. Through histological analysis, greater restoration of normal tissue structure in the wound beds of TGM treated mice was observed during mid to late stage wound healing. These observations included accelerated re-epithelialization as well as hair follicle regeneration, in the absence of increased scarring. Using flow cytometric, histological and gene expression analyses, differential expansion of myeloid populations at different stages of wound healing was observed. This included enhanced early accumulation and persistence of migratory Ly6C+ macrophages in TGM-treated wounds during the early inflammatory phase. Additionally, at mid-stage wound healing, we observed increased CD301b+ myeloid populations, a subset that is critical to efficient tissue restoration. In summary, TGM can enhance skin wound healing and associated recruitment of specific macrophage subsets and elevation of type 2 cytokines. This study indicates a role for TGM as a potential novel therapeutic option for enhanced wound healing.

In vivo fluorescence lifetime imaging of macrophage intracellular metabolism during wound responses in zebrafish.

The function of macrophages in vitro is linked to their metabolic rewiring. However, macrophage metabolism remains poorly characterized in situ. Here, we used two-photon intensity and lifetime imaging of autofluorescent metabolic coenzymes, nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD), to assess the metabolism of macrophages in the wound microenvironment. Inhibiting glycolysis reduced NAD(P)H mean lifetime and made the intracellular redox state of macrophages more oxidized, as indicated by reduced optical redox ratio. We found that TNFα+ macrophages had lower NAD(P)H mean lifetime and were more oxidized compared to TNFα- macrophages. Both infection and thermal injury induced a macrophage population with a more oxidized redox state in wounded tissues. Kinetic analysis detected temporal changes in the optical redox ratio during tissue repair, revealing a shift toward a more reduced redox state over time. Metformin reduced TNFα+ wound macrophages, made intracellular redox state more reduced and improved tissue repair. By contrast, depletion of STAT6 increased TNFα+ wound macrophages, made redox state more oxidized and impaired regeneration. Our findings suggest that autofluorescence of NAD(P)H and FAD is sensitive to dynamic changes in intracellular metabolism in tissues and can be used to probe the temporal and spatial regulation of macrophage metabolism during tissue damage and repair.

The Immune-Centric Revolution in the Diabetic Foot: Monocytes and Lymphocytes Role in Wound Healing and Tissue Regeneration-A Narrative Review.

Monocytes and lymphocytes play a key role in physiologic wound healing and might be involved in the impaired mechanisms observed in diabetes. Skin wound macrophages are represented by tissue resident macrophages and infiltrating peripheral blood recruited monocytes which play a leading role during the inflammatory phase of wound repair. The impaired transition of diabetic wound macrophages from pro-inflammatory M1 phenotypes to anti-inflammatory pro-regenerative M2 phenotypes might represent a key issue for impaired diabetic wound healing. This review will focus on the role of immune system cells in normal skin and diabetic wound repair. Furthermore, it will give an insight into therapy able to immuno-modulate wound healing processes toward to a regenerative anti-inflammatory fashion. Different approaches, such as cell therapy, exosome, and dermal substitute able to promote the M1 to M2 switch and able to positively influence healing processes in chronic wounds will be discussed.

MOF Expression Regulates Interferon β in Diabetic Wound Macrophages and Impairs Tissue Repair

MOF Expression Regulates Interferon β in Diabetic Wound Macrophages and Impairs Tissue Repair

Improved healing and macrophage polarization in oral ulcers treated with photobiomodulation (PBM).

The effect of photobiomodulation (PBM) treatment on wound healing and macrophage polarization was investigated in vivo. Animal models of oral ulcers were simulated through chemically induced oral ulcers in rats. PBM treatment using an infrared pulsed laser was used to treat oral ulcers in the animal models. Twelve Sprague-Dawley rats were randomly divided into four groups depending on set absorbed energy: Group 1 (control), Group 2 (30 J), Group 3 (60 J), and Group 4 (100 J). Laser treatment was performed every other day for 8 days after ulcer confirmation. Parameters used were as follows: wavelength 808 nm, power output 50 mW, spot size 10 mm, frequency 10 Hz, and pulse duration 1 millisecond. Ulcers were measured to determine the effect of the treatments over time. Histology, immunostaining, and real-time polymerase chain reaction analyses were performed to evaluate the effect of PBM treatment on macrophage-related (IL-6/IL-10) and wound-healing-related (TNF-α/TGF-β/MMP-2) cytokine expression. Histological examinations indicate that the PBM treatment stimulated a higher level of wound recovery after 8 days of treatment at 60 J absorbed energy compared to other treatment groups. Analyses of relative gene expression of proinflammatory, anti-inflammatory, and tissue remodeling cytokines indicate that the macrophages in the tissue samples were predominantly characterized as M2 subtypes (alternatively activated), which possibly accounts for the accelerated tissue repair in the animal model of oral ulcer. This preliminary study stands as a proof of concept regarding the potential use of infrared laser PBM treatment for oral ulcers which have not been previously investigated upon. PBM treatment affects macrophage polarization and enhances wound healing. Further experimentation will be conducted to expand the understanding of how PBM treatment affects the healing mechanism of ulcers.

Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing

Wound healing is a coordinated process that initially relies on pro-inflammatory macrophages, followed by a pro-resolution function of these cells. Changes in cellular metabolism likely dictate these distinct activities, but the nature of these changes has been unclear. Here, we profiled early- versus late-stage skin wound macrophages in mice at both the transcriptional and functional levels. We found that glycolytic metabolism in the early phase is not sufficient to ensure productive repair. Instead, by combining conditional disruption of the electron transport chain with deletion of mitochondrial aspartyl-tRNA synthetase, followed by single-cell sequencing analysis, we found that a subpopulation of early-stage wound macrophages are marked by mitochondrial ROS (mtROS) production and HIF1α stabilization, which ultimately drives a pro-angiogenic program essential for timely healing. In contrast, late-phase, pro-resolving wound macrophages are marked by IL-4Rα-mediated mitochondrial respiration and mitohormesis. Collectively, we identify changes in mitochondrial metabolism as a critical control mechanism for macrophage effector functions during wound healing.

Oncostatin M Improves Cutaneous Wound Re-Epithelialization and Is Deficient under Diabetic Conditions

Impaired re-epithelialization characterized by hyperkeratotic nonmigratory wound epithelium is a hallmark of nonhealing diabetic wounds. In chronic wounds, the copious release of oncostatin M (OSM) from wound macrophages is evident. OSM is a potent keratinocyte (KC) activator. This work sought to understand the signal transduction pathway responsible for wound re-epithelialization, the primary mechanism underlying wound closure. Daily topical treatment of full-thickness excisional wounds of C57BL/6 mice with recombinant murine OSM improved wound re-epithelialization and accelerated wound closure by bolstering KC proliferation and migration. OSM activated the Jak-signal transducer and activator of transcription pathway as manifested by signal transducer and activator of transcription 3 phosphorylation. Such signal transduction in the human KC induced TP63, the master regulator of KC function. Elevated TP63 induced ITGB1, a known effector of KC migration. In diabetic wounds, OSM was more abundant than the level in nondiabetic wounds. However, in diabetic wounds, OSM activity was compromised by glycation. Aminoguanidine, a deglycation agent, rescued the compromised KC migration caused by glycated OSM. Finally, topical application of recombinant OSM improved KC migration and accelerated wound closure in db/db mice. This work recognizes that despite its abundance at the wound site, OSM is inactivated by glycation, and topical delivery of exogenous OSM is likely to be productive in accelerating diabetic wound closure.

Modulation of macrophages by a paeoniflorin-loaded hyaluronic acid-based hydrogel promotes diabetic wound healing.

The impaired wound healing in diabetes is a central concern of healthcare worldwide. However, current treatments often fail due to the complexity of diabetic wounds, and thus, emerging therapeutic approaches are needed. Macrophages, a prominent immune cell in the wound, play key roles in tissue repair and regeneration. Recent evidence has demonstrated that macrophages in diabetic wounds maintain a persistent proinflammatory phenotype that causes the failure of healing. Therefore, modulation of macrophages provides great promise for wound healing in diabetic patients. In this study, the potential of paeoniflorin (PF, a chemical compound derived from the herb Paeonia lactiflora) for the transition of macrophages from M1 (proinflammatory phenotype) to M2 (anti-inflammatory/prohealing phenotype) was confirmed using ex vivo and in vivo experimental approaches. A hydrogel based on high molecular weight hyaluronic acid (HA) was developed for local administration of PF in experimental diabetic mice with a full-thickness wound. The resultant formulation (HA-PF) was able to significantly promote cutaneous healing as compared to INTRASITE Gel (a commercial hydrogel wound dressing). This outcome was accompanied by the amelioration of inflammation, the improvement of angiogenesis, and re-epithelialization, and the deposition of collagen. Our study indicates the significant potential of HA-PF for clinical translation in diabetic wound healing.