Podiatrist intervention could reduce the incidence of foot ulcers in patients with diabetes: a hospital survey in China.

OBJECTIVE: This study aimed to evaluate the effectiveness of podiatrists in preventing diabetic foot ulcers (DFUs) in China. METHOD: The study was a prospective investigation. A total of 300 patients were enrolled from May 2016 to May 2018 in Handan Central Hospital, China. All patients who participated in this study had been diagnosed with type 2 diabetes, according to the International Classification of Diseases (ICD-10). All participants underwent our survey, which included basic patient data and information about DFUs. The patients were followed for one year, during which time they received appropriate intervention from podiatrists, including lifestyle guidance, callus resection, tinea grinding and ingrown nail correction. At the end of the year all the patients were surveyed again. The data before and after the year were statistically compared. RESULTS: The results showed that the incidence of DFUs in patients with diabetes was significantly decreased after one year of intervention from podiatrists (20.7% versus 6.7%, p<0.001). Additionally, there was a negative correlation between the number of intervention visits and the number of DFU occurrences (Spearman correlation coefficient: -0.496, p<0.001). Furthermore, we found that 68 patients with a history of DFUs or amputation had an obviously reduced incidence of DFUs after intervention by a podiatrist (89.7% versus 27.9%, p<0.001). We also investigated other foot risk factors in all participants, such as limb neuropathy (76.3%), lower extremity vascular disease (65.7%) and foot paralysis (43.7%). CONCLUSION: The results of this study help in understanding the situation of patients with diabetes in China and to prove that standardised podiatrist intervention has an important role in inhibiting the occurrence and development of DFUs.

Acellular dermal matrix for one-stage treatment of lower extremity full-thickness skin defect: a case series.

BACKGROUND: Self-repair of lower limb wounds has always been one of the research hotspots. Flaps and skin graft are the preferred treatment for lower extremity wound reconstruction. However, these treatments have many disadvantages, such as secondary damage, poor healing quality. In recent years, the use of acellular dermal matrix has emerged as an alternative treatment option for extremity ulcers. METHODS: This study aimed to explore whether acellular dermal matrix can be used as a single treatment to promote wound healing. 7 patients with lower extremities cutaneous deficiency exposing bone or tendon, were covered by Pelnac, which was an acellular dermal matrix product approved by China Food and Drug Administration. All the wound was treated by Pelnac without flaps and skin graft. The external dressing was changed every 10 days. RESULTS: After a maximum of 20 weeks, all the wounds were completely healed. During the 12 months follow-up period none of the patients developed skin wear on the treatment area. All patients maintained their postoperative ambulatory ability. All patients were satisfied with the appearance and feeling after wound healing. CONCLUSION: These findings may mean acellular dermal matrix is a novel method offering opportunity for treatment of lower extremities cutaneous deficiency exposing bone or tendon. It also has the potential to close wounds of all uninfected, non-ischemic, full-thickness cutaneous deficiency.

The risks and external effects of diabetic foot ulcer on diabetic patients: A hospital-based survey in Wuhan area, China.

Diabetic foot ulcer (DFU) is a common complication observed in diabetic patients and affects diabetic patients in multiple ways. Severe DFU even leads to amputation in many cases. Early detection and intervention of DFU in diabetic patients can significantly relieve the pain caused by the ulcer and also keep patients from losing limbs in severe cases. In this study, the risks of diabetic patients getting DFU were estimated through a hospital-based survey. This survey collected information from hospitalized diabetic patients in Wuhan City, Hubei Province, China, using a questionnaire. This investigation includes studies from two stages with 502 diabetic patients from 20 hospitals in Wuhan City. The results suggested that patients with a long history of diabetes are often associated with a high risk of DFU (χ2 = 11.428, p = 0.0007), smoking (χ2 = 8.386, p = 0.0007), diabetic complications (χ2 = 13.484, p < 0.0001), and especially patients with diabetic foot complications (χ2 = 57.6621, p < 0.0001). Foot lesions appeared to be important attributors to DFU since our data demonstrated close correlations between DFU and patients with calluses/corns (χ2 = 4.584, p = 0.0323), tinea pedis (χ2 = 4.030, p = 0.0447), and cracked skin (χ2 = 8.712, p = 0.0032). Only a small number of patients seek for the assistance from specialists, such as trimming toenails (3.4%), removing corn or calluses (1.4%) or treating wounds (11.78%), when they are suffering from foot problems. The findings of this study can potentially be utilized to develop an early DFU diagnostic method in diabetic patients and can provide objective evidence for suggesting that patients who are suffering from foot problems should seek professional help.

Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p.

Purpose: Diabetic wound is a highly prevalent and refractory disease. Extensive studies have confirmed that keratinocytes and macrophages play an important role in the process of wound healing. Additionally, exosomes are regarded as a vital intercellular communication tool. This study aimed to investigate the role of human keratinocyte-derived exosomal MALAT1 in the treatment of diabetic wound by influencing the biological function of macrophages. Methods: We mainly assessed the function of MALAT1 on the biological changes of macrophages, and the expression of MALAT1 in the keratinocyte-exosomes analyzed by quantitative real-time polymerase chain reaction (RT-qPCR). The downstream interaction between RNAs or proteins was assessed by mechanistic experiments. Besides, we evaluated the effects of human keratinocyte-derived exosomal MALAT1 on diabetic wound healing in vivo to verify in vitro results. Results: We demonstrated that human keratinocyte-derived exosomal MALAT1 enhanced the biological functions of high glucose-injured macrophages, including phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. Mechanistically, MALAT1 accelerated the expression of MFGE8 by competitively binding to miR-1914-3p, thereby affecting the function of macrophages and the signal axis of TGFB1/SMAD3, and finally promoting the healing of diabetic wounds. Human keratinocyte-derived exosomal MALAT1 might promote collagen deposition, ECM remodeling, and expression of MFGE8, VEGF, and CD31 but reduce the expression of TGFB and SMAD3 in an in vivo model of diabetic mice wounds, which accelerated diabetic wound healing and restored its function. Conclusion: The current study revealed that human keratinocyte-derived exosomal MALAT1 would suppress miR-1914-3p to activate MFGE8 and eventually promote wound healing by enhancing macrophage phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. It proposed that keratinocyte-derived exosomes might have the capacity to serve as a new method for the clinical treatment of diabetic wound.

Classification and prediction of spinal disease based on the SMOTE-RFE-XGBoost model.

Spinal diseases are killers that cause long-term disturbance to people with complex and diverse symptoms and may cause other conditions. At present, the diagnosis and treatment of the main diseases mainly depend on the professional level and clinical experience of doctors, which is a breakthrough problem in the field of medicine. This article proposes the SMOTE-RFE-XGBoost model, which takes the physical angle of human bone as the research index for feature selection and classification model construction to predict spinal diseases. The research process is as follows: two groups of people with normal and abnormal spine conditions are taken as the research objects of this article, and the synthetic minority oversampling technique (SMOTE) algorithm is used to address category imbalance. Three methods, least absolute shrinkage and selection operator (LASSO), tree-based feature selection, and recursive feature elimination (RFE), are used for feature selection. Logistic regression (LR), support vector machine (SVM), parsimonious Bayes, decision tree (DT), random forest (RF), gradient boosting tree (GBT), extreme gradient boosting (XGBoost), and ridge regression models are used to classify the samples, construct single classification models and combine classification models and rank the feature importance. According to the accuracy and mean square error (MSE) values, the SMOTE-RFE-XGBoost combined model has the best classification, with accuracy, MSE and F1 values of 97.56%, 0.1111 and 0.8696, respectively. The importance of four indicators, lumbar slippage, cervical tilt, pelvic radius and pelvic tilt, was higher.

Identification of the MALAT1/miR-106a-5p/ZNF148 feedback loop in regulating HaCaT cell proliferation, migration and apoptosis.

Aims: This study aims to investigate the function of positive feedback loops involving noncoding RNA in diabetic wound healing. Methods: We developed a mouse diabetic wound model to confirm that hyperglycemia can impair wound healing. We also used an in vitro keratinocyte model in high-glucose conditions to investigate the mechanism of delayed wound healing. Results: MALAT1 was decreased in diabetic mouse wound tissue and can promote keratinocyte biological functions. MALAT1 could bind to miR-106a-5p to modulate the expression of ZNF148, a target gene of miR-106a-5p. Surprisingly, ZNF148 bound to a region in the MALAT1 promoter to stimulate gene expression. Conclusion: ZNF148-activated MALAT1 increases ZNF148 expression by competitively binding miR-106a-3p, generating a positive feedback loop that enhances keratinocyte function.

Delayed wound repair is a leading cause of diabetic foot ulcers. However, the molecular mechanism underlying impaired wound healing in diabetes is unclear. In our study we found that a positive feedback loop consisting of MALAT1, miR-106a-5p and ZNF148 could promote chronic wound repair. In diabetic skin tissues, MALAT1 levels were lower, causing impairments in skin cell function. On a molecular level, MALAT1 can bind miR-106a-5p to increase ZNF148 levels. Surprisingly, ZNF148 can bind the promoter of MALAT1 to reverse the decline of MALAT1 levels in diabetic wounds. Our findings advance our understanding of chronic diabetic wounds and, more crucially, open new therapeutic possibilities for this disease.

Mechanisms of diabetic foot ulceration: A review.

Diabetic foot ulcers (DFUs) are associated with complex pathogenic factors and are considered a serious complication of diabetes. The potential mechanisms underlying DFUs have been increasingly investigated. Previous studies have focused on the three aspects of diabetic peripheral vascular disease, neuropathy, and wound infections. With advances in technology, researchers have been gradually conducting studies using immune cells, endothelial cells, keratinocytes, and fibroblasts, as they are involved in wound healing. It has been reported that the upregulation or downregulation of molecular signaling pathways is essential for the healing of DFUs. With a recent increase in the awareness of epigenetics, its regulatory role in wound healing has become a much sought-after trend in the treatment of DFUs. This review focuses on four aspects involved in the pathogenesis of DFUs: physiological and pathological mechanisms, cellular mechanisms, molecular signaling pathway mechanisms, and epigenetics. Given the challenge in the treatment of DFUs, we are hopeful that our review will provide new ideas for peers.

Multifunctional ADM hydrogel containing endothelial cell-exosomes for diabetic wound healing.

Non-healing wound, with limited treatment options, remains a prevalent complication of diabetes mellitus. The underlying causes wherein include oxidative stress injury, bacterial infection, cellular dysfunction, and persistent inflammation. Acellular Dermal Matrix (ADM), a wound dressing composed of natural extracellular matrix and abundant bioactive factors, has been successfully developed to treat various wounds, including burns and diabetic ulcers. Protocatechualdehyde (PA) & trivalent iron ion (Fe3+) complex (Fe3+@PA) exhibits potential antioxidant and antibacterial properties. In this study, we developed a dual hydrogel network by combining Fe3+@PA complex-modified ADM with light-cured gelatin (GelMA), supplemented with exosomes derived from human umbilical vein endothelial cells (HUVEC-Exos), to create an ADM composite hydrogel system (ADM-Fe3+@PA-Exos/GelMA) with antioxidant, antibacterial, and cell-promoting functions for diabetic wound treatment. Through in vitro experiments, we investigated the biosafety, antioxidant and antibacterial properties of ADM composite hydrogel. Furthermore, we examined the protective effects of ADM composite hydrogel on diabetic wound. The above experiments collectively demonstrate that our ADM-Fe3+@PA-Exos/GelMA hydrogel promotes diabetic wound healing by eliminating bacterial infection, reduced the reactive oxygen species (ROS) levels, protecting cells against oxidative stress damage, promotingcollagen deposition and angiogenesis, which provides a promising strategy to optimize ADM for diabetic wound treatment.

Exosomes from Adipose Stem Cells Promote Diabetic Wound Healing through the eHSP90/LRP1/AKT Axis.

Oxidative damage is a critical cause of diabetic wounds. Exosomes from various stem cells could promote wound repair. Here, we investigated the potential mechanism by which exosomes from adipose-derived stem cells (ADSC-EXOs) promote diabetic wound healing through the modulation of oxidative stress. We found that ADSC-EXOs could promote proliferation, migration, and angiogenesis in keratinocytes, fibroblasts, and endothelial cells. Furthermore, ADSC-EXOs reduced the reactive oxygen species (ROS) levels in these cells and protected them against hypoxic and oxidative stress damage. Finally, the local injection of ADSC-EXOs at wound sites significantly increased collagen deposition and neovascularization while reducing ROS levels and cell death; thus, it led to accelerated diabetic wound closure. The mechanism underlying ADSC-EXO functions involved heat-shock protein 90 (HSP90) expressed on the cell surface; these functions could be inhibited by an anti-HSP90 antibody. Exosomal HSP90 could bind to the low-density lipoprotein receptor-related protein 1 (LRP1) receptor on the recipient cell membrane, leading to activation of the downstream AKT signaling pathway. Knockdown of LRP1 and inhibition of the AKT signaling pathway by LY294002 in fibroblasts was sufficient to impair the beneficial effect of ADSC-EXOs. In summary, ADSC-EXOs significantly accelerated diabetic wound closure through an exosomal HSP90/LRP1/AKT signaling pathway.

Free Flap Reconstruction of Extremity Defects in Pediatric Patients.

BACKGROUND: Microsurgical reconstruction of extremity defects with free flaps has been carried out for many years. The aim of this retrospective study is to characterize free flap surgery on children of 1 to 7 years old by evaluating a series of 20 cases of free flap surgeries that have been performed in pediatric patients. METHODS: From February 2014 to January 2018, 20 patients, 10 boys and 10 girls aged from 1 to 7 years (average, 4.6 years), were engaged in this study. Several types of free flaps were used, including anterolateral thigh flaps (ALT), inferior ulnar collateral artery flap, latissimus dorsi flap, medial plantar flap, fibular osteocutaneous flap and hallux toenail flap. After operations, follow-up period was at least for 2 years and the average follow-up period was 48.5 months. The long-term outcomes were estimated by questionnaires derived from the American Academy of Orthopaedic Surgeons Pediatric Outcomes Data Collection Instrument (PODCI). RESULTS: A total of 21free-flap reconstructions were performed on 20patients, including 15 ALT, 3 composite flaps, and 3 other cutaneous flaps. The size of the tissue flap ranged from 1.5 to 280 cm2 (average, 74.1cm2). The diameter of the anastomosed artery of the flap ranged from 0.7 to 1.2 mm. Among the 21 flaps, 20 survived and the success rate was about 95 %. Contour adaption was achieved in all flaps. Fifteen children received a secondary operation for debulking or functional improvement. Secondary deformity was present in 3 children, among which ankle joint valgus was seen in two children and a flexion deformity of injured toe occurred in one child. The mean global functioning score of PODCI was 94 (ranging from 81 to 98, maximum 100). CONCLUSION: The success rate of free-flap surgery in pediatric patients was comparable to that achieved in adults. Post-operative caring for pediatric patients was easier than expected. For pediatric patients, the final outcomes were not varied remarkably from different types of free tissue transfer.

Pleiotropic Roles of CXCR4 in Wound Repair and Regeneration.

Wound healing is a multi-step process that includes multiple cellular events such as cell proliferation, cell adhesion, and chemotactic response as well as cell apoptosis. Accumulating studies have documented the significance of stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR4) signaling in wound repair and regeneration. However, the molecular mechanism of regeneration is not clear. This review describes various types of tissue regeneration that CXCR4 participates in and how the efficiency of regeneration is increased by CXCR4 overexpression. It emphasizes the pleiotropic effects of CXCR4 in regeneration. By delving into the specific molecular mechanisms of CXCR4, we hope to provide a theoretical basis for tissue engineering and future regenerative medicine.

Bone Marrow-Derived Mesenchymal Stem Cells Restored High-Fat-Fed Induced Hyperinsulinemia in Rats at Early Stage of Type 2 Diabetes Mellitus.

Numerous studies have proposed the transplantation of mesenchymal stem cells (MSCs) in the treatment of typical type 2 diabetes mellitus (T2DM). We aimed to find a new strategy with MSC therapy at an early stage of T2DM to efficiently prevent the progressive deterioration of organic dysfunction. Using the high-fat-fed hyperinsulinemia rat model, we found that before the onset of typical T2DM, bone marrow-derived MSCs (BM-MSCs) significantly attenuated rising insulin with decline in glucose as well as restored lipometabolic disorder and liver dysfunction. BM-MSCs also favored the histological structure recovery and proliferative capacity of pancreatic islet cells. More importantly, BM-MSC administration successfully reversed the abnormal expression of insulin resistance-related proteins including GLUT4, phosphorylated insulin receptor substrate 1, and protein kinase Akt and proinflammatory cytokines IL-6 and TNFα in liver. These findings suggested that MSCs transplantation during hyperinsulinemia could prevent most potential risks of T2DM for patients.

Skin Epidermis and Adnexa Regrowth Induced by Treatment With Artificial Dermal Template After Full-Thickness Skin Wound.

Full-thickness skin wounds are common accidents. Although healing can be achieved by treatments like autologous skin grafts, donor site morbidity is hardly evitable. In this article, we provide compelling evidence demonstrating that artificial dermal template (ADT)-treated wound healing is achieved by regrowth of skin epidermis as well as adnexa without skin grafts by use of rodent models. First, by fixating a chamber to the wound edge, we confirmed that wound healing was achieved by regeneration instead of contracture. We found highly proliferative cells in adnexa in the newly formed skin. In the distal edge of newly formed skin, we identified immature hair follicles at early developing stages, suggesting they were newly regenerated. Second, we observed that the Lgr5-positive hair follicle stem cells contributed to formation of new hair follicles through a lineage tracing model. Also, Lgr6-positive cells were enriched in distal edge of newly developed skin. Finally, WNT signaling pathway mediators were highly expressed in the new skin epidermis and adnexa, implying a potential role of WNT signaling during ADT treatment-stimulated skin regrowth. Taken together, our findings demonstrated that full skin regrowth can be induced by ADT treatment alone, thus arguing for its wide clinical application in skin wound treatment.

One-stage Pelnac Reconstruction in Full-thickness Skin Defects with Bone or Tendon Exposure.

Dermal regeneration template, such as Integra and Pelnac, was originally designed for treating large area burn injury by inducing regeneration of dermis. To date, it has been widely applied in various acute and chronic wound sites. The present study demonstrated that application of artificial dermis alone induced 1-stage wound healing for wounds with bone or tendon exposure that should usually be repaired by flap surgery. Eight patients who presented with skin defects with bone and/or tendon exposure were treated by 1-stage Pelnac approach. All wounds healed within 20 weeks without skin graft or flap surgery. The wound area was reconstructed by nearly normal skin structure and linear scar. In the case of scalp defect, evidence of hair follicle cell migration and regeneration during healing process was observed. Thereby, the 1-stage Pelnac reconstitution can be considered as a novel method for inducing regrowth of epidermis and hair follicles to cure large full-thickness skin defect with bone and tendon exposure in 1 stage.

Expression and Influence of Matrix Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 and Vascular Endothelial Growth Factor in Diabetic Foot Ulcers.

A high matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP9/TIMP1) ratio is associated with poor ulcer healing, yet how the ratio of MMP9/TIMP1 changes in diabetic foot ulcers (DFUs) with infection and how these changes may affect wound healing remain unclear. Therefore, the objective of this investigation was to explore relationships among the MMP9/TIMP1 ratio, infection, and DFUs. After being informed of the details of this study, 32 patients signed consent forms. Skin biopsies were performed for all patients. Wound tissues were obtained from all patients with wounds, and healthy skin samples were collected from patients without wounds during orthopedic surgery. Microbial cultures were obtained using the samples from diabetic patients with wounds. All patients were divided into 4 groups according to colony-forming units (CFUs) per gram of tissue (>1 × 106 or <1 × 106): group A (diabetic wounds with high quantities of bacteria), group B (diabetic wounds with low quantities of bacteria), group C (diabetic patients without wounds), and group D (nondiabetic patients with wounds). In addition, the biopsies were evaluated by both reverse transcription-quantitative polymerase chain reaction and Western blotting to assess the levels of MMP9, TIMP1, and vascular endothelial growth factor (VEGF). The results show that for both mRNA and protein, expression of MMP9 (fold change 1.14 ± 0.12 vs 0.60 ± 0.08 vs 0.39±0.09 vs 0.13 ± 0.06, P < .01) decreased, whereas that of TIMP1 (1.01 ± 0.09 vs 2.86 ± 0.85 vs 4.88 ± 0.83 vs 7.29 ± 1.55, P < .01) and VEGF (1.01 ± 0.22 vs 3.55 ± 0.97 vs 5.72 ± 0.55 vs 6.92 ± 1.55, P < .01) increased from group A to group D. These results suggest that an increase in the MMP9/TIMP1 ratio in infected DFUs may induce a decrease in VEGF expression.

A Modified Approach to Inducing Bone Marrow Stromal Cells to Differentiate into Cells with Mature Schwann Cell Phenotypes.

Marrow stromal cells (MSCs) can be induced to differentiate into Schwann-like cells under classical induction conditions. However, cells derived from this method are unstable, exhibiting a low neurotrophin expression level after the induction conditions are removed. In Schwann cell (SC) culture, progesterone (PROG) enhances neurotrophic synthesis and myelination, specifically regulating the expression of the myelin protein zero (P0)- and peripheral myelin protein 22 (PMP22)-encoding genes by acting in concert or in synergy with insulin and glucocorticoids (GLUCs). In the present study, we investigated whether combined PROG, GLUC, and insulin therapy induced MSCs to differentiate into modified SC-like cells with phenotypes similar to those of mature SCs. After being cultured for 2 weeks in modified differentiation medium, the modified SC-like cells showed increased expression of P0 and PMP22. In addition, morphological and phenotypic characterizations were conducted over a period of over 2 weeks, and functional characteristics persisted for more than 3 weeks after the induction reagents were withdrawn. The transplantation of green fluorescent protein-labeled, modified SC-like cells into transected sciatic nerves with a 10-mm gap significantly increased the proliferation of the original SCs and improved axon regeneration and myelination compared with original BM-SCs. Immunostaining for P0 revealed that more of the transplanted modified SC-like cells retained the phenotypic characteristics of SCs. Taken together, these results reveal that the combined application of PROG, GLUC, and insulin induces MSCs to differentiate into cells with phenotypic, molecular, and functional properties of mature SCs.