Poly-l-lactic acid microspheres delay aging of epidermal stem cells in rat skin.

Objective: Injectable skin fillers offer a wider range of options for cutaneous anti-aging and facial rejuvenation. PLLA microspheres are increasingly favored as degradable and long-lasting fillers. The present study focused solely on the effect of PLLA on dermal collagen, without investigating its impact on the epidermis. In this study, we investigated the effects of PLLA microspheres on epidermal stem cells (EpiSCs). Methods: Different concentrations of PLLA microspheres on epidermal stem cells (EpiSCs) in vitro through culture, and identification of primary rat EpiSCs. CCK-8 detection, apoptosis staining, flow cytometry, Transwell assay, wound healing assay, q-PCR analysis, and immunofluorescence staining were used to detect the effects of PLLA on EpiSCs. Furthermore, we observed the effect on the epidermis by injecting PLLA into the dermis of the rat skin in vivo. Results: PLLA microspheres promote cell proliferation and migration while delaying cell senescence and maintaining its stemness. In vitro, Intradermal injection of PLLA microspheres in the rat back skin resulted in delayed aging, as evidenced by histological and immunohistochemical staining of the skin at 2, 4, and 12 weeks of follow-up. Conclusion: This study showed the positive effects of PLLA on rat epidermis and EpiSCs, while providing novel insights into the anti-aging mechanism of PLLA.

Impact of the gut microbiome on skin fibrosis: a Mendelian randomization study.

Objective: Skin fibrosis is a lesion in the dermis causing to itching, pain, and psychological stress. The gut microbiome plays as an essential role in skin diseases developments. We conducted a Mendelian randomization study to determine the causal association between the gut microbiome and skin fibrosis. Methods: We retrieved valid instrumental variables from the genome-wide association study (GWAS) files of the gut microbiome (n = 18,340) conducted by the MiBioGen consortium. Skin fibrosis-associated data were downloaded from the GWAS Catalog. Subsequently, a two-sample Mendelian randomization (MR) analysis was performed to determine whether the gut microbiome was related to skin fibrosis. A reverse MR analysis was also performed on the bacterial traits which were causally associated with skin fibrosis in the forward MR analysis. In addition, we performed an MR-Pleiotropy Residual Sum and Outlier analysis to remove outliers and a sensitivity analysis to verify our results. Results: According to the inverse variance-weighted estimation, we identified that ten bacterial traits (Class Actinobacteria, Class Bacteroidia, family Bifidobacteriaceae, family Rikenellaceae, genus Lachnospiraceae (UCG004 group), genus Ruminococcaceae (UCG013 group), order Bacteroidales, order Bifidobacteriales, genus Peptococcus and genus Victivallis) were negatively correlated with skin fibrosis while five bacterial traits (genus Olsenella, genus Oscillospira, genus Turicibacter, genus Lachnospiraceae (NK4A136group), and genus Sellimonas) were positively correlated. No results were obtained from reverse MR analysis. No significant heterogeneity or horizontal pleiotropy was observed in MR analysis. Objective conclusion: There is a causal association between the gut microbiome and skin fibrosis, indicating the existence of a gut-skin axis. This provides a new breakthrough point for mechanistic and clinical studies of skin fibrosis.

PPAR-γ regulates the polarization of M2 macrophages to improve the microenvironment for autologous fat grafting.

The unpredictable survival rate of autologous fat grafting (AFG) seriously affects its clinical application. Improving the survival rate of AFG has become an unresolved issue in plastic surgery. Peroxisome proliferator-activated receptor-γ (PPAR-γ) regulates the adipogenic differentiation of adipocytes, but the functional mechanism in AFG remains unclear. In this study, we established an animal model of AFG and demonstrated the superior therapeutic effect of PPAR-γ regulation in the process of AFG. From day 3 after fat grafting, the PPAR-γ agonist rosiglitazone group consistently showed better adipose integrity, fewer oil cysts, and fibrosis. Massive macrophage infiltration was observed after 7 days. At the same time, M2 macrophages begin to appear. At day 14, M2 macrophages gradually became the dominant cell population, which suppressed inflammation and promoted revascularization and fat regeneration. In addition, transcriptome sequencing showed that the differentially expressed genes in the Rosiglitazone group were associated with the pathways of adipose regeneration, differentiation, and angiogenesis; these results provide new ideas for clinical treatment.

The Safety of Injections in the Infraorbital Region.

BACKGROUND:  Infraorbital filler injection is a commonly used minimally invasive cosmetic procedure on the face, which can cause vascular complications. OBJECTIVE:  In this study, we aimed to explore the anatomical structure of the infraorbital vasculature and to establish an accurate protocol for infraorbital filler injection. METHODS:  The vascular structure of the infraorbital region was evaluated in 84 hemifacial specimens using computed tomography. Four segments (P1-P4) and five sections (C1-C5) were considered. We recorded the number of identified arteries in each slice and at each location and the number of deep arteries. Furthermore, we also measured the infraorbital artery (IOA) distribution. RESULTS:  At P1-P4, the lowest number of arteries was detected in segment P4, with a 317/1727 (18.4%) and 65/338 (2.3%) probability of total and deep arterial identification, respectively. The probabilities of encountering an identified artery at the five designated locations (C1-C5) were 277/1727 (16%), 318/1727 (18.4%), 410/1727 (23.7%), 397/1727 (23%), and 325/1727 (18.8%), respectively. The probability of an IOA being identified at C2 was 68/84 (81%). CONCLUSION:  We described an effective filler injection technique in the infraorbital region to minimize the associated risks. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

S-Nitrosylation-mediated coupling of DJ-1 with PTEN induces PI3K/AKT/mTOR pathway-dependent keloid formation.

Background: Keloids are aberrant dermal wound healing characterized by invasive growth, extracellular matrix deposition, cytokine overexpression and easy recurrence. Many factors have been implicated as pathological causes of keloids, particularly hyperactive inflammation, tension alignment and genetic predisposition. S-Nitrosylation (SNO), a unique form of protein modification, is associated with the local inflammatory response but its function in excessive fibrosis and keloid formation remains unknown. We aimed to discover the association between protein SNO and keloid formation. Methods: Normal and keloid fibroblasts were isolated from collected normal skin and keloid tissues. The obtained fibroblasts were cultured in DMEM supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. The effects of DJ-1 on cell proliferation, apoptosis, migration and invasion, and on the expression of proteins were assayed. TurboID-based proximity labelling and liquid chromatography-mass spectrometry were conducted to explore the potential targets of DJ-1. Biotin-switch assays and transnitrosylation reactions were used to detect protein SNO. Quantitative data were compared by two-tailed Student's t test. Results: We found that DJ-1 served as an essential positive modulator to facilitate keloid cell proliferation, migration and invasion. A higher S-nitrosylated DJ-1 (SNO-DJ-1) level was observed in keloids, and the effect of DJ-1 on keloids was dependent on SNO of the Cys106 residue of the DJ-1 protein. SNO-DJ-1 was found to increase the level of phosphatase and tensin homolog (PTEN) S-nitrosylated at its Cys136 residue via transnitrosylation in keloids, thus diminishing the phosphatase activity of PTEN and activating the PI3K/AKT/mTOR pathway. Furthermore, Cys106-mutant DJ-1 is refractory to SNO and abrogates DJ-1-PTEN coupling and the SNO of the PTEN protein, thus repressing the PI3K/AKT/mTOR pathway and alleviating keloid formation. Importantly, the biological effect of DJ-1 in keloids is dependent on the SNO-DJ-1/SNO-PTEN/PI3K/AKT/mTOR axis. Conclusions: For the first time, this study demonstrated the effect of transnitrosylation from DJ-1 to PTEN on promoting keloid formation via the PI3K/AKT/mTOR signaling pathway, suggesting that SNO of DJ-1 may be a novel therapeutic target for keloid treatment.

Epidermal Stem Cell Derived Exosomes Alleviate Excessive Autophagy Induced Endothelial Cell Apoptosis by Delivering miR200b-3p to Diabetic Wounds.

The dysfunction of endothelial cells caused by hyperglycemia is observed as a decrease in neovascularization in diabetic wound healing. Studies have found that epidermal stem cells (EpiSCs) can promote the angiogenesis of full-thickness wounds. To further explain the therapeutic effect of EpiSCs, EpiSC-derived exosomes (EpiSC-EXOs) are considered the main substance contributing to stem cell effectivity. In our study, EpiSCs and EpiSC-EXOs were supplied to the dorsal wounds of db/db mice. Results showed that EpiSCs could colonize in the wound area and both EpiSCs and EpiSC-EXOs could accelerate diabetic wound healing by promoting angiogenesis. In vitro, persistent high glucose led to the malfunction and apoptosis of endothelial cells. The apoptosis induced by high glucose is due to excessive autophagy and was alleviated by EpiSC-EXOs. RNA sequencing of EpiSC-EXOs showed that miR200b-3p was enriched in EpiSC-EXOs and alleviated the apoptosis of endothelial cells. Synapse defective rho GTPase homolog 1 was identified the target of miR200b-3p and affected the phosphorylation of ERK to regulate intracellular autophagy and apoptosis. Furthermore, animal experiments validated the angiogenic effect of miR200b-3p. Collectively, our results verified the effect of EpiSC-EXOs on apoptosis caused by hyperglycemia in endothelial cells through the miR200b-3p/synapse defective rho GTPase homolog 1 /RAS/ERK/autophagy pathway, providing a theoretical basis for EpiSC in treating diabetic wounds.

GKT137831 in combination with adipose-derived stem cells alleviates high glucose-induced inflamm-aging and improves diabetic wound healing.

Adipose stem cells (ADSCs) have been proven to promote healing in diabetic wounds, which are one of the most serious chronic refractory wounds. However, reactive oxygen species (ROS) induced by high glucose (HG) lead to oxidative stress and aging in ADSCs, which limits the therapeutic effect of ADSCs. In this study, we investigated the role of GKT137831, a NOX1/4 inhibitor that can reduce ROS production, in protecting ADSCs from hyperglycemia and in diabetic wound healing. In vitro, ROS levels and NOX4 expression were increased after HG treatment of ADSCs, while the oxidative stress marker malondialdehyde (MDA) was increased, mitochondrial membrane potential (MMP) was decreased, inflammatory aging-related indicators such as p16, p21, MMP1, MMP3, IL6 and ß-GAL were increased, and migration was weakened. In vivo, we constructed a diabetic mouse wound model and found that the combination of ADSCs and GKT137831 synergistically promoted the 21-day wound healing rate, increased the expression of collagen and hydroxyproline, increased the number of blood vessels and the expression of CD31, and reduced the expression of IL6, MMP1, MMP3, and p21. These results suggest that GKT137831 could protect ADSCs from oxidative stress and aging induced by HG and enhance the therapeutic effect of ADSCs on diabetic wounds.

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)-1ß, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.

Melatonin influences the biological characteristics of keloid fibroblasts through the Erk and Smad signalling pathways.

Background: Keloids are abnormal fibrous hyperplasias that are difficult to treat. Melatonin can be used to inhibit the development of certain fibrotic diseases but has never been used to treat keloids. We aimed to discover the effects and mechanisms of melatonin in keloid fibroblasts (KFs). Methods: Flow cytometry, CCK-8 assays, western blotting, wound-healing assays, transwell assays, collagen gel contraction assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of melatonin in fibroblasts derived from normal skin, hypertrophic scars and keloids. The therapeutic potential of the combination of melatonin and 5-fluorouracil (5-FU) was investigated in KFs. Results: Melatonin significantly promoted cell apoptosis and inhibited cell proliferation, migration and invasion, contractile capability and collagen production in KFs. Further mechanistic studies demonstrated that melatonin could inhibit the cAMP/PKA/Erk and Smad pathways through the membrane receptor MT2 to alter the biological characteristics of KFs. Moreover, the combination of melatonin and 5-FU remarkably promoted cell apoptosis and inhibited cell migration and invasion, contractile capability and collagen production in KFs. Furthermore, 5-FU suppressed the phosphorylation of Akt, mTOR, Smad3 and Erk, and melatonin in combination with 5-FU markedly suppressed the activation of the Akt, Erk and Smad pathways. Conclusions: Collectively, melatonin may inhibit the Erk and Smad pathways through the membrane receptor MT2 to alter the cell functions of KFs, while combination with 5-FU could exert even more inhibitory effects in KFs through simultaneous suppression of multiple signalling pathways.

Single-stage transplantation combined with epidermal stem cells promotes the survival of tissue-engineered skin by inducing early angiogenesis.

BACKGROUND: The composite transplantation of a split-thickness skin graft (STSG) combined with an acellular dermal matrix (ADM) is a promising repair method for full-thickness skin defects. Due to delayed vascularization of the ADM, no currently available engineered skin tissue is able to permanently cover full-thickness skin defects via a single-stage procedure. Epidermal stem cells (EpSCs) have been found to promote angiogenesis in the wound bed. Whether EpSCs can induce early angiogenesis of dermal substitutes and promote the survival of single-stage tissue-engineered skin transplantation needs to be further studied. METHODS: In vitro, rat vascular endothelial cells (RVECs) were treated with the supernatant of EpSCs cultured in ADM and stimulated for 48 h. RVECs were analysed by RNA sequencing and tube formation assays. For the in vivo experiment, 75 rats were randomly divided into five groups: ADM, ADM + EpSCs (AE), STSG, ADM + STSG (AS), and ADM + STSG + EpSCs (ASE) groups. The quality of wound healing was estimated by general observation and H&E and Masson staining. The blood perfusion volume was evaluated using the LDPI system, and the expression of vascular markers was determined by immunohistochemistry (IHC). RESULTS: The active substances secreted by EpSCs cultured in ADM promoted angiogenesis, as shown by tube formation experiments and RNA-seq. EpSCs promoted epithelialization of the ADM and vascularization of the ADM implant. The ASE group showed significantly increased skin graft survival, reduced skin contraction, and an improved cosmetic appearance compared with the AS group and the STSG control group. CONCLUSIONS: In summary, our findings suggest that EpSCs promote the formation of new blood vessels in dermal substitutes and support one-step transplantation of tissue-engineered skin, and thereby provide new ideas for clinical application.

Transcriptome profiles of fatty acid metabolism-related genes and immune infiltrates identify hot tumors for immunotherapy in cutaneous melanoma.

Background: Immunotherapy with checkpoint inhibitors usually has a low response rate in some cutaneous melanoma (CM) cases due to its cold nature. Hence, identification of hot tumors is important to improve the immunotherapeutic efficacy and prognoses of CMs. Methods: Fatty acid (FA) metabolism-related genes were extracted from the Gene Set Enrichment Analysis and used in the non-negative matrix factorization (NMF), copy number variation frequency, tumor mutation burden (TMB), and immune-related analyses, such as immunophenoscore (IPS). We generate a risk model and a nomogram for predicting patient prognoses and predicted the potential drugs for therapies using the Connectivity Map. Moreover, the NMF and the risk model were validated in a cohort of cases in the GSE65904 and GSE54467. At last, immunohistochemistry (IHC) was used for further validation. Results: Based on the NMF of 11 FA metabolism-related DEGs, CM cases were stratified into two clusters. Cluster 2 cases had the characteristics of a hot tumor with higher immune infiltration levels, higher immune checkpoint (IC) molecules expression levels, higher TMB, and more sensitivity to immunotherapy and more potential immunotherapeutic drugs and were identified as hot tumors for immunotherapy. The risk model and nomogram displayed excellent predictor values. In addition, there were more small potential molecule drugs for therapies of CM patients, such as ambroxol. In immunohistochemistry (IHC), we could find that expression of PLA2G2D, ACOXL, and KMO was upregulated in CM tissues, while the expression of IL4I1, BBOX1, and CIDEA was reversed or not detected. Conclusion: The transcriptome profiles of FA metabolism-related genes were effective for distinguishing CM into hot-cold tumors. Our findings may be valuable for development of effective immunotherapy for CM patients and for proposing new therapy strategies.

Negative-Pressure Wound Therapy Improves Take Rate of Skin Graft in Irregular, High-Mobility Areas: A Randomized Controlled Trial.

BACKGROUND: Tie-over bolster dressing to secure a skin graft is associated with low graft take rates in irregular, high-mobility areas and suboptimal recipient wound beds. Negative-pressure wound therapy has become a well-established method to secure the graft, with a graft take rate of this method reported to be 96.7 percent. However, comparative efficacies between the two methods on irregular, high-mobility areas are yet to be determined. METHODS: Patients eligible for skin graft were randomly assigned to receive either negative-pressure wound therapy or tie-over bolster dressing between December of 2014 and December of 2015. The primary outcome was determined by the take rate of skin grafts between postoperative days 5 and 7. The secondary outcomes were dressing time and postoperative complications, including hematoma, seroma, infection, displacement, and necrosis. RESULTS: A total of 86 patients were assigned to receive either negative-pressure wound therapy ( n = 43) or tie-over bolster dressing ( n = 43) for skin graft treatment. Negative-pressure wound therapy significantly improved the take rate of grafts as compared with tie-over bolster dressing (97.2 versus 90.2 percent; p = 0.005). The improvements came from the grafts in irregular, high-mobility areas in the respective groups (97.6 versus 81.7 percent; p < 0.001). Negative-pressure wound therapy reduced skin graft displacement as a postoperative complication as compared with tie-over bolster dressing (one versus nine patients; p = 0.007). Dressing time using negative-pressure wound therapy was significantly shorter compared with tie-over bolster dressing (15.2 ± 4.2 versus 27.4 ± 4.3 minutes; p = 0.001). CONCLUSION: Negative-pressure wound therapy can improve the take rate of skin grafts in irregular, high-mobility areas and shorten the dressing time. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

Lycorine Inhibits Hypertrophic Scar Formation by Inducing ROS-Mediated Apoptosis.

Background: Hypertrophic scar (HS) is a fibrotic cutaneous disease with few effective therapies. Lycorine is a drug with pro-apoptotic ability and anti-fibrosis potential. This study aimed to test whether lycorine could trigger the apoptosis of hypertrophic scar fibroblasts (HSFs) to inhibit HS formation. Methods: The proapoptotic and anti-fibrosis effects of lycorine on the viability and apoptosis of human primary HSFs and their reactive oxygen species (ROS) production as well as a rabbit ear model of HS were determined by CCK-8, flow cytometry, Western blot, immunofluorescence, transwell migration, collagen gel contraction assays. Results: Lycorine treatment selectively decreased the viability of HSFs, and induced their apoptosis, but not normal fibroblasts (NFs). Lycorine treatment increased the relative levels of Bax and cleaved PARP expression, cytochrome C cytoplasm translocation, but decreased Bcl-2, caspase-3 and caspase-9 expression, the mitochondrial membrane potential (MMP) in HSFs. Lycorine inhibited the migration and contraction of HSFs, and reduced the expression of collagen I, collagen III and α-SMA. Mechanistically, lycorine treatment stimulated high levels of ROS production, leading to apoptosis of HSFs while treatment with NAC, a ROS inhibitor, significantly mitigated or abrogated the pro-apoptotic and antifibrotic activity of lycorine in HSFs. Moreover, lycorine treatment mitigated the severity of HS in rabbit ears by inducing fibroblast apoptosis. Conclusion: These results indicate that lycorine has a potent anti-fibrotic activity and is a potential drug for intervention of HS.

Clinical Studies on Platelet-Rich Plasma Therapy for Chronic Cutaneous Ulcers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Significance: Platelet-rich plasma (PRP) may be a potential drug for treatment of chronic refractory ulcers, which increase the risk of systemic infection and local canceration. However, the efficacy and safety of clinical application of PRP are still controversial. Thus, this study was aimed to assess the efficacy and safety of PRP in patients with chronic ulcers. Recent Advances: For this meta-analysis, Cochrane's Library, MEDLINE, EMBASE, PubMed, Web of Science, and CINAHL (Cumulate Index to Nursing and Allied Health Literature) databases were searched. Results were pooled using a random-effects model. The primary outcome was the proportion of completely healed chronic ulcers. Critical Issues: Seventeen randomized controlled trials were included. Compared with the control group, PRP significantly increased the fraction of healed ulcers (pooled risk ratio [RR] = 1.50; 95% confidence interval [CI] = 1.20 to 1.87; I2 = 47.8%). In autologous PRP (APRP) and homologous PRP (HPRP) subgroups, there were statistical differences between the control group versus treatment subgroup (pooled RR = 1.30, 95% CI = 1.10 to 1.54, I2 = 25.7%; pooled RR = 3.53, 95% CI = 1.94 to 6.43, I2 = 0.0%, respectively). In terms of percent of chronic ulcers area healed, there was a statistically significant difference between the PRP-treated group versus the control group (standard mean difference [SMD] = 1.37, 95% CI = 0.91 to 1.82, I2 = 22.1%). As for PRP safety, there existed a statistically significant difference between the APRP subgroup and the HPRP subgroup, respectively (pooled RR = 0.58; 95% CI = 0.35 to 0.98; I2 = 0.0%) and (pooled RR = 4.12; 95% CI = 1.55 to 10.96; I2 = 6.8%). Future Directions: Our findings shows that PRP may be a beneficial treatment of chronic skin ulcers and that APRP may be much safer than HPRP.

Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway.

We identified fermitin family member 2 (FERMT2, also known as kindlin-2) as a potential target in A375 cell line by siRNA library screening. Drugs that target mutant BRAF kinase lack durable efficacy in the treatment of melanoma because of acquired resistance, thus the identification of novel therapeutic targets is needed. Immunohistochemistry was used to identify kindlin-2 expression in melanoma samples. The interaction between kindlin-2 and Rac1 or p-Rac/Cdc42 guanine nucleotide exchange factor 6 (α-Pix) was investigated. Finally, the tumor suppressive role of kindlin-2 was validated in vitro and in vivo. Analysis of clinical samples and Oncomine data showed that higher levels of kindlin-2 predicted a more advanced T stage and M stage and facilitated metastasis and recurrence. Kindlin-2 knockdown significantly inhibited melanoma growth and migration, whereas kindlin-2 overexpression had the inverse effects. Further study showed that kindlin-2 could specifically bind to p-α-Pix(S13) and Rac1 to induce a switch from the inactive Rac1-GDP conformation to the active Rac1-GTP conformation and then stimulate the downstream MAPK pathway. Moreover, we revealed that a Rac1 inhibitor suppressed melanoma growth and metastasis and the combination of the Rac1 inhibitor and vemurafenib resulted in a better therapeutic outcome than monotherapy in melanoma with high kindlin-2 expression and BRAF mutation. Our results demonstrated that kindlin-2 promoted melanoma progression, which was attributed to specific binding to p-α-Pix(S13) and Rac1 to stimulate the downstream MAPK pathway. Thus, kindlin-2 could be a potential therapeutic target for treating melanoma.

Biomarker Prediction of Postoperative Healing of Diabetic Foot Ulcers: A Retrospective Observational Study of Serum Albumin.

PURPOSE: The purpose of this study was to investigate the relationship and to determine potential usefulness of serum albumin as a biomarker for predicting postoperative diabetic foot ulcer (DFU) healing. DESIGN: A retrospective study. SUBJECTS AND SETTING: The sample comprised 266 inpatients with type 2 diabetes receiving care in The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Among them, 174 had DFUs and underwent surgery for foot DFUs including amputation, skin grafting, and flap procedures. A comparison group consisted of 92 inpatients without a DFU or surgery. METHODS: The association between healing and preoperative albumin levels was analyzed via a logistic regression model and receiver operating characteristic (ROC) curve. RESULTS: The albumin value of patients with DFU grade 3 or more (3.23 ± 0.58 g/dL) was lower than that of patients with DFU grade 1-2 (3.58 ± 0.5 g/dL), and both were lower than that of the comparison group (3.89 ± 0.3 g/dL). Patients with a DFU with hypoalbuminemia (<3.5 g/dL) had a 2.5-fold higher risk of nonhealing at postoperative 28 days than patients with normal levels (odds ratio = 3.51; 95% confidence interval, 1.75-7.06; P < .001). For patients with a DFU overall, the ROC curve showed a preoperative albumin cutoff of 3.44 g/dL for DFU wound healing. CONCLUSIONS: For patients with a DFU undergoing surgery, preoperative serum albumin may be used as a biomarker for predicting postoperative healing.

Rat epidermal stem cells promote the angiogenesis of full-thickness wounds.

BACKGROUND: Full-thickness wounds severely affect patients' life quality and become challenging problems for clinicians. Stem cells have great prospects in the treatment of wounds. Our previous study confirmed that autologous basal cell suspension could promote wound healing, and epidermal stem cells (ESCs) were detected in the basal cell suspension. Herein, this study aimed to explore the effect of ESCs on full-thickness wounds. METHODS: Rat ESCs were isolated and expanded and then were transfected with lentivirus to stably express enhanced green fluorescent protein. The experimental rats were randomly divided into 2 groups: in the ESC group, the rat ESCs were sprayed on the full-thickness wounds of rats; in the control group, phosphate-buffered saline was sprayed the on the wounds. Next, wound healing and neovascularization were evaluated. Colonization, division, and differentiation of ESCs on the wound were analyzed by immunofluorescence. RESULTS: The rat ESCs colonized, divided, and proliferated in the wound. Additionally, rat ESCs around blood vessels differentiated into vascular endothelial cells and formed a lumen-like structure. Compared with the control group, the ESC group showed enhanced angiogenesis and accelerated wound healing. CONCLUSIONS: Our study confirmed that rat ESCs are safe and effective for treating full-thickness wounds. Additionally, under certain conditions, ESCs can differentiate into vascular endothelial cells to promote angiogenesis and wound healing.

Application of 3D Printed Models of Complex Hypertrophic Scars for Preoperative Evaluation and Surgical Planning.

BACKGROUND: Complex hypertrophic scar is a condition that causes multiple joint contractures and deformities after trauma or burn injuries. Three-dimensional (3D) printing technology provides a new evaluation method for this condition. The objective of this study was to print individualized 3D models of complex hypertrophic scars and to assess the accuracy of these models. METHODS: Twelve patients with complex hypertrophic scars were included in this study. Before surgery, each patient underwent a computed tomography (CT) scan to obtain cross-sectional information for 3D printing. Mimics software was used to process the CT data and create 3D printed models. The length, width, height, and volume measurements of the physical scars and 3D printed models were compared. Experienced surgeons used the 3D models to plan the operation and simulate the surgical procedure. The hypertrophic scar was completely removed for each patient and covered with skin autografts. The surgical time, bleeding, complications, and skin autograft take rate were recorded. All patients were followed up at 12 months. The surgeons, young doctors, medical students, and patients involved in the study completed questionnaires to assess the use of the 3D printed models. RESULTS: The 3D models of the hypertrophic scars were printed successfully. The length, width, height, and volume measurements were significantly smaller for the 3D printed models than for the physical hypertrophic scars. Based on preoperative simulations with the 3D printed models, the surgeries were performed successfully and each hypertrophic scar was completely removed. The surgery time was shortened and the bleeding was decreased. On postoperative day 7, there were two cases of subcutaneous hemorrhage, one case of infection and one case of necrosis. On postoperative day 12, the average take rate of the skin autografts was 97.75%. At the 12-month follow-up, all patients were satisfied with the appearance and function. CONCLUSION: Accurate 3D printed models can help surgeons plan and perform successful operations, help young doctors and medical students learn surgical methods, and enhance patient comprehension and confidence in their surgeons.

Efficacy and Safety of Platelet-Rich Plasma for Patients with Diabetic Ulcers: A Systematic Review and Meta-analysis.

Significance: Autologous platelet-rich plasma (PRP) has been suggested to be effective for wound healing. However, clinical evidence for its use in patients with diabetic ulcer remains inconsistent. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of PRP in patients with diabetic ulcer. Recent Advances: Relevant randomized controlled trials (RCTs) were identified via systematic search of PubMed, MEDLINE, EMBASE, the Cochrane Library, and Web of Knowledge databases. Results were pooled using a random-effects model. The primary outcome of the study was the healing rate of ulcers in patients with PRP, when compared with controls. Secondary outcomes included the percentage of ulcer area reduction, recurrence rate, and amputation rate. Critical Issues: Eight RCTs that involved 431 participants were included. Compared with controls, PRP was associated with a significantly increased ratio of complete ulcer healing (odds ratio [OR] = 3.77, 95% confidence interval [CI] = 1.91-7.45, I2 = 42.2%) and reduced areas of ulcers (standard mean difference = 0.86, 95% CI = 0.27-1.45, I2 = 0.0%). No differences were observed between patients allocated to PRP or controls, in terms of the outcomes of recurrence rate (OR = 3.32, 95% CI = 0.41-27.18, I2 = 66.3%) or amputation rate (OR = 0.15, 95% CI = 0.15-1.28). The results of the trial sequence analyses revealed that the cumulative Z-curve crossed both the traditional boundary (p = 0.05) and trial sequential monitoring boundary. Future Directions: Our findings suggest that PRP may improve ulcer healing without significant adverse effects for patients with diabetic ulcers.

Fibronectin precoating wound bed enhances the therapeutic effects of autologous epidermal basal cell suspension for full-thickness wounds by improving epidermal stem cells' utilization.

BACKGROUND: Autologous epidermal basal cell suspension therapy has been proven to be one of the most effective treatments for full-thickness wounds. However, we found there remain obvious defects that significantly confined the utilization and function of the epidermal basal cells (EBCs), especially the epidermal stem cells (ESCs) in it. This study investigated whether precoating fibronectin (FN) on the wound bed before spraying EBCs could overcome these defects and further explored its possible mechanisms. METHODS: In the in vitro study, EBCs were isolated from the donor skin of patients who needed skin grafting. Different concentrations of FN were used to precoat culture dishes before cell culture; the adherent efficiency, proliferation and migration ability of ESCs were analyzed and compared with traditional collagen IV precoating. In the in vivo study, Sprague-Dawley (SD) rats with full-thickness skin wounds were selected as full-thickness wounds' model. For the experiment groups, 20 µg/ml FN was precoated on the wound bed 10 min before EBC spray. The quality of wound healing was estimated by the residual wound area rate, wound healing time, and hematoxylin and eosin (H&E) staining. Expression of ESC markers, neovascular markers, inflammation markers, and collagen formation and degradation markers was elucidated by immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), and RT-qPCR analysis. RESULTS: The in vitro study showed that the dishes precoated with 20 µg/ml FN had a similar adherent efficiency and colony formation rate with collagen IV, but it could improve the proliferation and migration of ESCs significantly. Similarly, in the in vivo study, precoating FN on wound bed before EBC spray also significantly promote wound healing by improving ESCs' utilization efficiency, promoting angiogenesis, decreasing inflammations, and regulating collagen formation and degradation. CONCLUSION: FN precoating wound bed before EBC spray could significantly promote full-thickness wound healing by improving the utilization and function of the ESCs and further by promoting angiogenesis, decreasing inflammations, and regulating collagen formation and degradation.