Industrializable approach for preparing hydrogel microneedles and their application in melanoma treatment.

Microneedles (MNs) technology has been studied in transdermal drug delivery for more than 20 years with hundreds of clinical trials conducted. However, there are currently no commercially available MNs in medicine due to challenges in materials safety, cost-effective fabrication, and large-scale manufacturing. Herein, an approach for rapid and green fabrication of hydrogel microneedles (HMNs) based on infrared irradiation process was proposed for the first time. The optimized formulation consisted of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), which acted as cross-linked materials and pore-forming agents, respectively. The manufacturing method involved placing MNs patches under infrared irradiation at 70 °C for 2 min and annealing to obtain HMNs with excellent swelling behavior, mechanical strength, and biocompatibility. When model drugs azelaic acid (AZA) and matrine (MAT) were loaded into HMNs systems, the chemical stability of MAT was significantly improved. Ex vivo transdermal delivery experiments indicated that HMNs could achieve synchronous release of AZA and MAT, and the 24-hour percutaneous permeability rates of both drugs were 73.09 ± 0.48 % and 71.56 ± 1.23 %, respectively. In-vivo pharmacokinetic studies, HMNs administration presented dose-dependent stable blood drug concentrations for both drugs. Additionally, prominent anti-tumor efficacy and biosecurity were observed in the drug-loaded HMNs group in the pharmacodynamic evaluation. In summary, the efficient, convenient, and low-cost fabrication method based on infrared irradiation offers the possibility of mass production of drug-loaded HMNs, showing potential for industrial manufacturing development.

Exploring causal correlations between inflammatory cytokines and varicose veins: A Mendelian randomization analysis.

This study aimed to investigate the causal relationship between inflammatory cytokines and the risk of varicose veins. The data were sourced from genome-wide association studies (GWAS) of European individuals. Multiple Mendelian randomization (MR) methods were used to evaluate the association between inflammatory cytokines and varicose veins. The study found significant associations between elevated levels of certain inflammatory biomarkers (e.g., CASP-8, Vascular endothelial growth factor A levels (VEGF_A)) and an increased risk of varicose veins, while others (e.g., 4EBP1, MMP-10) showed a protective effect. The MR-Egger Intercept and heterogeneity tests indicated no significant pleiotropy or heterogeneity. This comprehensive MR analysis identifies several cytokines as potential contributors to the pathogenesis of varicose veins, offering insights into novel therapeutic targets. Our findings underscore the importance of inflammation in varicose veins and suggest that targeting specific cytokines could be a promising strategy for the treatment and prevention of varicose veins.

Potential Causal Association between Depression and Oral Diseases: A Mendelian Randomization Study.

BACKGROUND: Globally, oral diseases are common, pose an economic burden, and significantly decline the quality of life of affected individuals. Recently, researchers have substantially highlighted the effect of depression on oral disease incidence and development. In this study, we elucidated the correlation between depression and oral diseases. METHODS: Using two-sample Mendelian randomization (MR), the association between depression and the risk of 17 oral diseases was evaluated. Three methods were used to perform MR analysis: the inverse variance-weighted, weighted median, and MR-Egger methods. Furthermore, Cochran's Q test, MR-Egger intercept test, MR Pleiotropy RESidual Sum and Outlier test, and leave-one-out analysis were performed to analyze sensitivity. RESULTS: After implementing multiple test corrections, we observed that genetic susceptibility to depression was associated with an increased risk of mouth ulcers, toothache, loose teeth, bleeding gums, painful gums, chronic periodontitis, chronic tonsil and adenoid diseases, peritonsillar abscess, and excessive tooth attrition. However, a causal relationship between depression and other oral diseases was not observed. Sensitivity analysis confirmed the robustness of the results. CONCLUSIONS: We confirmed the causal relationship between depression and several oral diseases, thereby providing a novel viewpoint on the prevention and treatment of oral diseases. Our findings suggest the integration of depression control into routine clinical care to enhance the effectiveness of oral disease treatment.

Clinical Development and Evaluation of a Multi-Component Dissolving Microneedle Patch for Skin Pigmentation Disorders.

Excessive melanin deposition in the skin leads to various skin pigmentation diseases, such as chloasma and age spots. The deposition is induced by several factors, including tyrosinase activities and ultraviolet-induced oxidative stress. Herein, we propose a multi-component, multi-pathway drug combination, with glabridin, 3-O-ethyl-L-ascorbic acid, and tranexamic acid employed as, respectively, a tyrosinase inhibitor, an antioxidant, and a melanin transmission inhibitor. Considering the poor skin permeability associated with topical application, dissolving microneedles (MNs) prepared with hyaluronic acid/poly(vinyl alcohol)/poly(vinylpyrrolidone) were developed to load the drug combination. The drug-loaded microneedles (DMNs) presented outstanding skin insertion, dissolution, and drug delivery properties. In vitro experiments confirmed that DMNs loaded with active ingredients had significant antioxidant and inhibitory effects on tyrosinase activity. Furthermore, the production of melanin both in melanoma cells (B16-F10) and in zebrafish was directly reduced after using DMNs. Clinical studies demonstrated the DMNs' safety and showed that they have the ability to effectively reduce chloasma and age spots. This study indicated that a complex DMN based on a multifunctional combination is a valuable depigmentation product worthy of clinical application.

Thermal stability of exenatide encapsulated in stratified dissolving microneedles during storage.

As low-temperature storage and transportation of peptides require high costs, improving the dosage form of peptides can reduce costs. We developed a thermostable and fast-releasing stratified dissolving microneedle (SDMN) system for delivering exenatide (EXT) to patients with type 2 diabetes. Among the tested polymers, dextran and polyvinyl alcohol (PVA) were the best at stabilizing EXT under high-temperature storage for 9 weeks. The two polymers possess a relatively high glass transition temperature (Tg) and weak hydrogen bonding between PVA and EXT. Additionally, zinc sulfate (ZnSO4) had a stabilizing effect on EXT among the selected stabilizers, suggesting that EXT formed a dimer after coordination with zinc ions (Zn2+). In addition, the denaturation temperature (Tm) of EXT was increased by adding ZnSO4, thus stabilizing EXT. Accordingly, SDMNs consisting of a tip layer (dextran encapsulating the Zn2+-EXT complex) and a base layer (PVA) were fabricated. Within 2 min of implantation, the EXT loaded on the patch was quickly released into the skin. Transdermal pharmacokinetics studies showed that manufactured SDMNs generated comparable efficacy to subcutaneous injection. Significantly, the remaining EXT amount was not significantly different under storage at 40 °C and -20 °C for 3 months, supporting that the SDMN system had excellent delivery efficiency and stability, thus reducing the dependence on the cold chain.

Design and Evaluation of Complex Polypeptide-Loaded Dissolving Microneedles for Improving Facial Wrinkles in Different Areas.

Wrinkles are one of the most intuitive manifestations of skin aging. Complex polypeptide-loaded dissolving microneedles (CP-DMNs) for facial wrinkles in different areas have been developed and evaluated for the first time. In optimizing formulations, we compared the differences in CP-DMNs heights on skin insertion depth and skin repair and healing. Furthermore, systemic safety experiments were carried out to provide a reference for clinical application. On this basis, an 84-day efficacy assessment based on the improvement of facial wrinkles in different areas and a comparison between CP-DMNs vs. placebo was performed on 30 healthy subjects. As a result, DMNs with a height of 300 µm presented sufficient strength to pierce the stratum corneum with minimized skin damage. In addition, CP-DMNs possessed excellent biological safety and skin compatibility for clinical application. Compared with placebo, CP-DMNs exhibited obvious improvements in wrinkles distributed in the corners of eyes, under-eyes, and nasolabial folds. Furthermore, after using CP-DMNs for 84 days, facial wrinkles in five different areas were smoothed. In short, the complex polypeptides showed apparent anti-wrinkle efficacy with the aid of DMNs technology, and CP-DMNs seemed to work better on deeper wrinkles, such as frown lines and nasolabial folds.