Extracellular vesicles secreted by bone marrow stem cells mediate angiogenesis for the treatment of diabetic ulcers: A systematic review and meta-analysis of preclinical studies.

Background: Diabetic ulcers (DUs) typically occur in patients with vascular diseases and diabetes. Extracellular vesicles secreted by bone marrow-derived stem cells (BMSC-EVs) represent a cell-free therapy that has emerged as a promising alternative for treating DU, especially due to significant advancements in the understanding of their role in promoting angiogenesis; however, their application in DU treatment remains in the preclinical stage, and their effectiveness is still uncertain. Therefore, we conducted this meta-analysis to evaluate the therapeutic efficacy of BMSC-EVs in treating DU and to expedite the clinical translation of BMSC-EV therapy for DU. Methods: We conducted a comprehensive search of PubMed, Cochrane Library, MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database, and our self-constructed database of Chinese Biomedical Literature up to May 2023 to identify preclinical studies related to the therapeutic use of extracellular vesicles secreted by bone marrow-derived stem cells for treating diabetic ulcers. Outcome measures included wound healing rate, neovascularization density, a-sma, and CD31. RevMan 5 software was employed for all statistical analyses. Results: In this meta-analysis, a total of 11 studies involving 103 animals were identified. The pooled analysis indicated that BMSC-EV treatment showed a superior wound healing rate compared to that of the control group (SMD = 1.06, 95% CI [0.52, 1.60], P = 0.0001). In the subgroup analysis, EV combined with new materials or drug therapy performed better than the sole injection of extracellular vesicles (SMD = 1.85, 95% CI [0.87, 2.82], P < 0.00001). BMSC-EV treatment also resulted in a higher number of neovascular structures compared to the control group(SMD = 5.80, 95% CI[0.89,10.71], P = 0.006). In the subgroup analysis, EV combined therapy showed a significant difference in the number of blood vessels compared to the sole injection of extracellular vesicles (SMD = 4.90, 95% CI[2.64,7.15], P < 0.00001). However, BMSCs-EV treatment did not demonstrate any statistically significant difference in the angiogenesis-related indicators CD31 and α-SMA compared to the control group (SMD = 1.61, 95% CI[-0.51,3.74], P = 0.14). Conclusion: According to the current meta-analysis, BMSC-EV therapy can enhance the healing of diabetic ulcers and promote wound angiogenesis, particularly when used in combination with novel dressings or other drugs, which further accelerates the healing process of diabetic ulcers. To establish the most effective parameters for EV treatment in diabetic ulcers, future research should promptly progress into clinical trials.

Quercetin and its derivatives for wound healing in rats/mice: Evidence from animal studies and insight into molecular mechanisms.

Aimed to clarify the effect of quercetin and its derivatives on wound healing in animal experiments. PubMed, Embase, Science Direct, Web of Science, SinoMed, Vip Journal Integration Platform, China National Knowledge Infrastructure and WanFang databases were searched for animal experiments investigating the effect of quercetin and its derivatives on wound healing to April 2023. The Review Manager 5.4 software was used to conduct meta-analysis. Eighteen studies were enrolled in this article. According to the SYRCLE's RoB tool assessment, these studies exposed relatively low methodological quality. It was shown that animals with cutaneous wound receiving quercetin had faster wound healing in wound closure (%) than the control group. Moreover, the difference in efficacy gradually emerged after third day (WMD = 7.13 [5.52, 8.74]), with a peak reached on the tenth day after wounding (WMD = 19.78 [17.82, 21.74]). Subgroup analysis revealed that quercetin for wound closure (%) was independent of the types of rats and mice, wound area and with or without diabetes. Clear conclusion was also shown regarding the external application of quercetin for wound healing (WMD = 17.77 [11.11, 24.43]). A significant reduction in the distribution of inflammatory cells occurred in the quercetin group. Quercetin could increase blood vessel density (WMD = 1.85 [0.68, -3.02]), fibroblast distribution and collagen fraction. Biochemical indicators, including IL-1ß, IL-10, TNF-α, TGF-ß, vascular endothelial growth factor (VEGF), hydroxyproline and alpha-smooth muscle actin (α-SMA), had the consistent results. Quercetin and its derivatives could promote the recovery of cutaneous wound in animals, through inhibiting inflammatory response and accelerating angiogenesis, proliferation of fibroblast and collagen deposition.

The Role of Contrast-Enhanced Ultrasound Plus Color Parametric Imaging in the Differential Diagnosis of Subpleural Pulmonary Lesions.

OBJECTIVES: To distinguish benign and malignant subpleural pulmonary lesions (SPLs) with contrast-enhanced ultrasound (CEUS) and color parametric imaging (CPI), and evaluate the role of CEUS plus CPI in the differential diagnosis of pathological types of SPLs. METHODS: One hundred and thirty-six patients underwent CEUS with a Logiq E9 XD Clear ultrasonic machine equipped with a 3.5- to 5.0-MHz C5-1 transducer in our center were enrolled in our study, including 27 cases of benign lesions and 109 cases of malignant lesions. The ultrasound contrast agent used in this study was SonoVue. CEUS images and CPI of all cases were reviewed and analyzed by the resident and staff radiologist groups separately. RESULTS: With CEUS alone, by both the two groups, the main enhancement pattern of benign SPLs was arborization (P < .001), while centripetal enhancement pattern occurred more frequently in malignant SPLs (P < .001). With CEUS plus CPI, by both the two groups, the main enhancement pattern of benign SPLs was arborization (P < .001), while those of malignant SPLs were centripetal (P < .001) and eccentric (P < .05). The diagnosis performance of CEUS plus CPI was significantly higher than that of CEUS alone in both the resident (area under the curve [AUC] = 0.857 vs 0.677, P < .001) and staff (AUC = 0.866 vs 0.681, P < .001) groups. Moreover, CPI offered remarkable inter-consistency improvements in the enhancement pattern determination between the two groups. CONCLUSION: The CEUS enhancement patterns would provide information of blood perfusion patterns in the differential diagnosis of benign and malignant SPLs. The diagnosis performance could be significantly improved by CEUS plus CPI compared with CEUS alone.

Effect of low-level laser therapy on orthodontic dental alignment: a systematic review and meta-analysis.

The aim of this study is to systematically summarize the available evidence regarding low-level laser therapy (LLLT) speed-up effect on dental alignment in comprehensive orthodontic treatment. An extensive electronic search was conducted in PubMed, ScienceDirect, Cochrane, Web of Science, and Scopus up to February 20, 2023. The Cochrane risk of bias tool and the Newcastle-Ottawa Quality Assessment Form were used by two authors independently to assess the risk of bias (RoB). Statistical analysis was performed by Review Manager 5.3. The eight eligible trials were reviewed and included in qualitative synthesis. Four studies reported the overall time of leveling and alignment (OLAT, days), enabling a synthesizing of the data. The meta-analysis results showed that LLLT significantly reduced the overall time of leveling and alignment compared to control group (MD=-30.36, 95% CI range -41.50 to -19.22, P<0.0001), with moderate heterogeneity (χ2=4.10, P=0.25, I2=27%). Based on the data available, statistically significant evidence with moderate risk of bias suggests that LLLT may have a positive effect on accelerating dental alignment. However, due to the differences in intervention strategy and evaluating method, the conclusions should be interpreted with caution.

Preclinical study of diabetic foot ulcers: From pathogenesis to vivo/vitro models and clinical therapeutic transformation.

Diabetic foot ulcer (DFU), a common intractable chronic complication of diabetes mellitus (DM), has a prevalence of up to 25%, with more than 17% of the affected patients at risk of amputation or even death. Vascular risk factors, including vascular stenosis or occlusion, dyslipidemia, impaired neurosensory and motor function, and skin infection caused by trauma, all increase the risk of DFU in patients with diabetes. Therefore, diabetic foot is not a single pathogenesis. Preclinical studies have contributed greatly to the pathogenesis determination and efficacy evaluation of DFU. Many therapeutic tools are currently being investigated using DFU animal models for effective clinical translation. However, preclinical animal models that completely mimic the pathogenesis of DFU remain unexplored. Therefore, in this review, the preparation methods and evaluation criteria of DFU animal models with three major pathological mechanisms: neuropathy, angiopathy and DFU infection were discussed in detail. And the advantages and disadvantages of various DFU animal models for clinical sign simulation. Furthermore, the current status of vitro models of DFU and some preclinical studies have been transformed into clinical treatment programs, such as medical dressings, growth factor therapy, 3D bioprinting and pre-vascularization, Traditional Chinese Medicine treatment. However, because of the complexity of the pathological mechanism of DFU, the clinical transformation of DFU model still faces many challenges. We need to further optimize the existing preclinical studies of DFU to provide an effective animal platform for the future study of pathophysiology and clinical treatment of DFU.

Study on the regulatory effect of Panax notoginseng saponins combined with bone mesenchymal stem cell transplantation on IRAK1/TRAF6-NF-κB pathway in patients with diabetic cutaneous ulcers.

Panax notoginseng saponins (PNSs) have been found as the major active ingredient of Panax notoginseng (Burkill) F.H.Chen (PN) leaves, which has the effect of reducing inflammatory response, facilitating fibroblast proliferation, as well as promoting angiogenesis. This study aimed to investigate the molecular basis of PNS combined with bone mesenchymal stem cells (BMSCs) for treating diabetic cutaneous ulcers (DCU) and its mechanism of action. METHODS: A total of 75 SD rats were selected to make diabetic cutaneous ulcers model. According random number table method, the rats were randomly divided into a control group, a DCU group, a BMSCs group, a PNS group and BMSCs + PNS group. Five groups of rats were given without treatment. After being treated for 7 days, the rats were anesthetized with pentobarbital, and granulation tissue was collected from the central point of the wound. They were used for pathological analysis, Western blot (WB) and polymerase chain reaction (PCR) assays. RESULTS: The wound healing area was the largest in the BMSCs + PNS group. HE staining results showed that the PNS + BMSCs group could promote the formation of new epidermis and reduce the infiltration of inflammatory cells. Immunohistochemistry (IHC) results showed that the PNS + BMSCs group could up-regulate the expression of Ki67 protein and cell proliferation. In addition, PNS combined with BMSCs up-regulated the expression of miR-146-5p and down-regulated the expression of IL-1ß, IL-6 and TNF-α, IRAK1, TRAF6 and p65 in the NF-κB signaling pathway (p < 0.05). CONCLUSIONS: PNS combined with bone mesenchymal stem cell transplantation up-regulated miR-146a-5p targeting and binding to IRAK1/TRAF6, inhibiting the activation of NF-κB pathway, which reduced the inflammatory response of DCU and facilitated the skin healing of DCU. Thus, this study provides a theoretical basis and a novel therapeutic option for the treatment of DFU with PNS combined with BMSCs.

Development and Characterization of Novel Orthodontic Adhesive Containing PCL-Gelatin-AgNPs Fibers.

Enamel demineralization around brackets is a relatively common complication of fixed orthodontic treatment, which seriously affects the aesthetics of teeth. In this study, a novel orthodontic adhesive containing polycaprolactone−gelatin−silver nanoparticles (PCL−gelatin−AgNPs) composite fibers was prepared to prevent enamel demineralization of orthodontic treatment. First, PCL−gelatin−AgNPs fibers film prepared by electrospinning was made into short fibers and added to traditional orthodontic adhesives (Transbond XT, 3M Unitek) in three different ratios to design a series of composite adhesives containing antibacterial materials. The antimicrobial performance of the control product and the three samples were then evaluated by bacterial live/dead staining, colony-forming unit (CFU) counts, tensile bond strength (TBS), and adhesive residue index (ARI) scores. The composite adhesives' antimicrobial properties increased with the increasing content of PCL−gelatin−AgNPs short fibers. The addition of complex antimicrobial fibers to 3M Transbond XT adhesive can significantly reduce the CFU of bacterial biofilms (p < 0.05). The bacterial survival rate on the surface of the specimen decreased with the increase of PCL−gelatin−AgNPs short fibers (p < 0.05). The TBS and ARI values (n = 10) indicated that adding PCL−gelatin−AgNPs short fibers had no significant adverse effect on adhesion. Therefore, adding PCL−gelatin−AgNPs short fibers makes it possible to fabricate orthodontic adhesives with strong antibacterial properties without compromising the bonding ability, which is essential for preventing enamel demineralization around the brackets.

Governance mechanisms for chronic disease diagnosis and treatment systems in the post-pandemic era.

"Re-visits and drug renewal" is difficult for chronic disease patients during COVID-19 and will continue in the post-pandemic era. To overcome this dilemma, the scenario of chronic disease diagnosis and treatment systems was set, and an evolutionary game model participated by four stakeholder groups including physical medical institutions, medical service platforms, intelligent medical device providers, and chronic disease patients, was established. Ten possible evolutionary stabilization strategies (ESSs) with their mandatory conditions were found based on Lyapunov's first method. Taking cardiovascular and cerebrovascular diseases, the top 1 prevalent chronic disease, as a specific case context, and resorting to the MATLAB simulation, it is confirmed that several dual ESSs and four unique ESS circumstances exist, respectively, and the evolution direction is determined by initial conditions, while the evolution speed is determined by the values of the conditions based on the quantitative relations of benefits, costs, etc. Accordingly, four governance mechanisms were proposed. By their adjustment, the conditions along with their values can be interfered, and then the chronic disease diagnosis and treatment systems can be guided toward the desired direction, that is, toward the direction of countermeasure against the pandemic, government guidance, global trends of medical industry development, social welfare, and lifestyle innovation. The dilemma of "Re-visits and drug renewal" actually reflects the uneven distribution problem of qualified medical resources and the poor impact resistance capability of social medical service systems under mass public emergency. Human lifestyle even the way of working all over the world will get a spiral upgrade after experiencing COVID-19, such as consumption, and meeting, while medical habits react not so rapidly, especially for mid or aged chronic disease patients. We believe that telemedicine empowered by intelligent medical devices can benefit them and will be a global trend, governments and the four key stakeholders should act according to the governance mechanisms suggested here simultaneously toward novel social medical ecosystems for the post-pandemic era.

Percutaneous ultrasound-guided radiofrequency ablation for patients with liver metastasis from pancreatic adenocarcinoma.

OBJECTIVE: To analyze the survival outcomes and prognostic factors of radiofrequency ablation (RFA) for pancreatic adenocarcinoma liver metastasis (PALM). METHODS: Between January 2010 and July 2021, 20 patients (13 males) with an average age of 58.9 ± 11.7 years who underwent RFA for PALM were included. The mean maximum diameter of PALMs was 2.6 ± 1.1 cm (1.0-6.0 cm). Survival curves were built using the Kaplan-Meier method and compared by the log-rank test. Multivariable analyses were performed by using the Cox proportional hazards model. RESULTS: Twenty patients with 29 PALMs underwent 23 RFA sessions. Technical efficacy was achieved in 28 PALMs (28/29, 96.6%). The mean overall survival (OS) after RFA was 14.6 months and the 1-, 2-year survival rates were 39.5%, 18.1%, respectively. With multivariate analysis, abnormal serum levels of CA199 (p = 0.023) and extrahepatic metastasis before RFA (p = 0.038) were identified as independent prognostic factors for OS in patients with PALM. Additionally, the mean progression-free survival (PFS) after RFA was 11.5 months and 1-, 2- year survival rates were 26.0%, 17.3%, respectively. With multivariate analysis, abnormal serum levels of CA199 (p = 0.016) and extrahepatic metastasis before RFA (p = 0.043) were also identified as independent prognostic factors for PFS in patients with PALM. CONCLUSION: RFA is a safe and effective treatment for patients with PALM, especially in patients with normal serum level of CA199 or the patients without extrahepatic metastases before RFA.

Constitutive Model Parameter Identification Based on Optimization Method and Formability Analysis for Ti6Al4V Alloy.

Titanium alloy is widely applied in aerospace, medical, shipping and other fields due to its high specific strength and low density. The purpose of this study was to analyze the formability of Ti6Al4V alloys at elevated temperatures. An accurate constitutive model is the basic condition for accurately simulating the plastic forming of materials, and it is an important basis for optimizing the parameters of the hot forging forming process. In this study, the optimization algorithm was used to accurately identify the high-temperature constitutive model parameters of Ti6Al4V titanium alloy, and the hot working diagram was established to optimize the hot forming process parameters. The optimal forming conditions of Ti6Al4V titanium alloy are given. Ti6Al4V alloy was subjected to high-temperature compression tests at 800-1000 °C and at strain rates of 0.01-5 s-1 on a Gleeble-1500D thermal/mechanical simulation machine. Each parameter of the Hansel-Spittel constitutive model was taken as an independent variable, and the accumulated error between the stress calculated by the constitutive model and the stress obtained by experimentation was used as an objective function. Based on response surface methodology, an inverse optimization method for identifying the parameters of the high-temperature constitutive model of Ti6Al4V alloy is proposed in this paper. An orthogonal test design was adopted to obtain sample point data, and a third-order response surface approximate model was established. The genetic algorithm (GA) was applied to reversely optimize the parameters of the constitutive model. To verify the accuracy of the optimized constitutive model, the average absolute relative error (AARE) and correlation coefficient (R) were used to evaluate the reliability of optimized constitutive model. The R value of the model was 0.999, and the AARE value was 0.048, respectively, indicating that the established high-temperature constitutive model for Ti6Al4V alloy has good calculation accuracy. The flow stress behavior of the material could be accurately delineated. Meanwhile, in order to study the formability of Ti6Al4V alloy, the hot processing map of the alloy, based on a dynamic material model, was established in this paper. The optimum hot working domains of the Ti6Al4V alloy were determined within 840-920 °C/0.01-0.049 s-1 and 940-980 °C/0.11-1.65 s-1; the hot processing map was verified in combination with the microstructure, and the fine and equiaxed grains and a large amount of ß phase could be found at 850 °C/0.01 s-1.