Search Results (198)

Powder bed fusion (PBF) and directed energy deposition (DED) additive manufacturing use feedstock powders that contain metals associated with skin diseases. We performed a survey of surface contamination and limited task-based dermal exposure assessment (four employees) at a PBF and DED facility. Skin wipes of wrists for two employees in the PBF room had higher post-task levels of chromium, cobalt, molybdenum, and nickel. Personal clothing worn by PBF employees showed evidence of contamination with metals as did personal protective equipment (PPE). Microscopy analysis documented contamination of metals throughout most areas of the facility. Levels of metals on surfaces throughout the facility were (ng/cm²) <5.0–7247 (aluminum), <0.2–4899 (chromium), <background-6.0 (chromium VI), 0.03–468.1 (cobalt), 1.6–100.0 (copper), 32.9–19,000 (iron), 0.01–789.0 (molybdenum), 0.1–12,058 (nickel), 0.1–482.8 (titanium), and 0.07–9.3 (vanadium). Levels were significantly lower in administrative areas compared with the production area but generally did not differ among powder handling and non-powder handling rooms in production. The small number of participants in the dermal exposure assessment and uniqueness of the facility might limit generalizability of the results. At least for this facility, steps to lower skin contact with metals can include washing, consistent use of PPE, and increasing awareness of dermal hazards among workers. Approaches to reduce migration of metals throughout a facility can include using adhesive (“tacky”) mats and boot covers and frequent wet cleaning of floors, tools, handles, and high touch surfaces. Full article

Background: Erectile dysfunction (ED) and premature ejaculation (PE) are prevalent conditions affecting men’s sexual health, for which tadalafil and dapoxetine have shown promise in their treatment, respectively. Conventional oral dosage forms face limitations, including variable absorption and delayed onset of action. In this study, we developed electrospun nanofibers using polyvinylpyrrolidone for buccal drug delivery as an alternative dosage form to oral tablets. This route offers advantages such as easy administration, suitability for those with difficulty swallowing, particularly the elderly, and a rapid onset of action via the blood capillaries, which might improve bioavailability. Methods: PVP nanofibers loaded with tadalafil and dapoxetine were fabricated using a modified electrospinning procedure with the Spraybase system, where an 8% (w/v) PVP ethanol solution containing 1.5% dapoxetine and 0.5% tadalafil was electrospun under controlled conditions (800 µL/h flow rate, 15 cm distance, 0.55 mm needle, and 8–10 kV) to produce uniform fibers. Results: The morphology of the nanofibers was characterized using SEM, revealing smooth, uniform fibers with an average diameter of 218 ± 50 nm for drug-loaded nanofibers. This nanofibrous system also demonstrated ultra-rapid disintegration occurring within 4 ± 1 s and consistent drug loading and encapsulation efficiency for both drugs. The release profile showed a burst drug release after 15 min, which accounted for >45% for tadalafil and >50% for dapoxetine, followed by a sustained increment in the drug release that reached > 60% for tadalafil and >78% for dapoxetine after 30 min until a complete drug release (100%) for both drugs after 180 min. In vitro cytotoxicity studies on human dermal fibroblasts confirmed the safety of both medications, with cell viability exceeding 50%, at concentrations of 1.56 to 25 µg/mL for tadalafil and 4.69 to 9.38 µg/mL for dapoxetine after 24 and 48 h of incubation. Conclusions: These findings highlight the potential of PVP-based nanofibers as a novel buccal delivery system for the combined treatment of ED and PE. Full article

Botulinum toxin type A (BoNT/A) injection into the bladder wall is a milestone in the treatment of urinary incontinence in patients with neurogenic detrusor overactivity (NDOi) or overactive bladder syndrome (OABi) who are refractory to or unable to tolerate oral or transdermal therapies. However, the efficacy of BoNT/A is hampered by the low long-term adherence of patients to a treatment that requires repeated bladder injections under cystoscopy control. The discontinuation is particularly evident among incontinent patients with spontaneous voluntary voiding, regardless of whether the cause is NDOi or OABi, although clearly more marked among the latter group. In addition to the bother and pain associated with repeated cystoscopies, these patients show low tolerance to the high incidence of urinary tract infections (UTIs) and transient urinary retention, the two most common adverse events. Fewer injection points may render treatments less painful, apparently without reducing efficacy, but will not avoid the need for repeated cystoscopies, and no studies have demonstrated that such modification increases adherence. Eventually, accessing the bladder wall for BoNT/A administration via a transabdominal approach, under real-time ultrasound guidance, may overcome trans-urethral limitations, but the technique’s reproducibility remains unknown. An intensive investigation is ongoing to identify aids that facilitate the passage of the large, fragile BoNT/A molecule across the urothelium to reach the bladder nerves without injections. Electromotive Drug Administration (EMDA) of BoNT/A demonstrated efficacy and safety over a 6-year follow-up in NDOi patients at a single center, but the results were not reproduced at other institutions. The application of shock waves to the bladder using shock waves generated by Extracorporeal Shock Wave Lithotripsy (ESWL) machines to tear the urothelium and facilitate the passage of BoNT/A instilled in the bladder is ingenious, but the experience is very limited. Dimethyl sulfoxide, liposomes, and thermal-reversal hydrogel to deliver the toxin failed in pilot trials. BoNT/A in nano-formulations has high heat stability, resistance to pH changes, and to enzymatic degradation. Extended efficacy in dermal and intramuscular pilot applications is promising but needs to be replicated in the bladder. Full article

Cutaneous fibrosis is characterized by aberrant wound healing with excessive extracellular matrix deposition, sustained inflammation, and oxidative stress, while currently available therapies show limited efficacy and safety. A Dual Hyaluronic Acid Compound (DHC), consisting of high-molecular-weight, low-molecular-weight, and minimally cross-linked hyaluronic acid, has demonstrated regenerative and antioxidant properties, but its anti-fibrotic effects have not been fully explored. This study investigated the anti-fibrotic potential of DHC using a bleomycin-induced murine dermal fibrosis model and a UVB-irradiated ex vivo human skin model. In C57BL/6 mice, dermal fibrosis was induced by daily bleomycin injections for three weeks, followed by intradermal DHC administration. Histological and biomechanical analyses showed that DHC significantly reduced dermal thickness, collagen deposition, and skin hardness compared with untreated fibrotic controls. DHC decreased α-SMA expression and increased MMP1 levels, indicating attenuation of myofibroblast activation and enhanced matrix remodeling. It also reduced macrophage markers (CD68, CD163) and pro-inflammatory cytokines (IL-1β, TNF-α). Furthermore, DHC restored superoxide dismutase (SOD) and catalase (CAT) activity and upregulated NRF2, HO-1, and NQO1 expression in the in vivo model. Similarly, DHC upregulated SOD and CAT activity and reduced pro-inflammatory cytokines (IL-6, TNF-α) in the ex vivo human skin model. These findings suggest that DHC exerts multimodal anti-fibrotic effects through coordinated regulation of fibroblast activation, inflammation, and oxidative stress, supporting its potential as a therapeutic approach for cutaneous fibrosis. Full article

This study explored ultrastructural changes and the expression of oxidative stress-related genes and proteins in the laminar tissue of dairy cows with acute laminitis induced by oligofructose (OF) overload. Twelve clinically healthy, non-pregnant Chinese Holstein cows were randomly allocated into two groups: the OF-overload group (n = 6) and the control group (n = 6). 17 g/kg BW of oligofructose (OF) dissolved in 20 mL/kg BW of deionized water was provided to the OF-treated group, while the control group received 20 mL/kg BW of deionized water via a stomach tube. Laminar tissue samples were collected at 72 h post-OF administration. RT-qPCR revealed significantly increased Keap1 mRNA expression (p = 0.0097) and significantly decreased Nrf2 (p < 0.0001), Ho1 (p < 0.0001), and Nqo1 (p = 0.0101) mRNA expression in the OF group compared to the control group. Western blot analysis confirmed corresponding protein-level changes, with significantly increased Keap1 (p = 0.0062) and significantly decreased Nrf2 (p = 0.0008), Ho1 (p = 0.0297), and Nqo1 (p = 0.0004) in the OF group compared with the control group. Immunohistochemical analysis revealed significantly increased cytoplasmic Keap1 distribution (p = 0.0200) and significantly decreased nuclear Nrf2 localization (p = 0.0032) in the OF group than the control group. Ultrastructural examination revealed significant pathological changes in the OF group, including a reduced number of hemidesmosomes (p < 0.01), an increased distance from epidermal basal cells to the lamina densa (p < 0.01), thickened and damaged lamina densa with disorganized collagen fibers, and deformed basal cell nuclei with reduced chromatin relative to the control group. In conclusion, these findings demonstrate that OF-induced acute laminitis is associated with significant dysregulation of the Keap1-Nrf2 antioxidant pathway and severe ultrastructural damage to the dermal–epidermal interface, suggesting that oxidative stress contributes to laminar tissue injury in dairy cows. Full article

Background/Objectives: For successful wound management, dressings must be maintained in a moist environment to optimally enhance the microenvironment of the wound and efficiently deliver bioactive agents. Sodium humate has demonstrated potential wound-healing activity, although its topical delivery is still a challenge. This study aimed to develop and optimize polysaccharide-based dermal patches incorporating sodium-humate-loaded transferosomes and to assess their physicochemical and wound-healing properties. Methods: Transferosomes were obtained via thin-film hydration and prepared utilizing the Taguchi experimental design based on the impact of lipid content, lipid-to-surfactant ratio, and lipid-to-drug ratio on vesicle size, ζ-potential, and drug entrapment efficiency. The optimized transferosomes were loaded into alginate/HPMC composite dermal patches prepared through solvent evaporation. Results: The optimized transferosome formulation had an average size of 250.9 ± 2.3 nm, a ζ-potential of −3.57 ± 0.25, a high deformability of 93.01 ± 2.41%, and an effective drug-entrapment efficiency of 30.13 ± 1.04%. The use of transferosomes greatly affected patch thickness, moisture content, and surface morphology. A biphasic drug release profile of sodium humate was demonstrated via an in vitro release study, showing an initial burst followed by sustained drug release within 6 h. In vivo evaluation of transferosome-loaded patches showed that the formulations were able to effectively promote wound healing compared with the control. Conclusions: The developed transferosome-embedded alginate/HPMC dermal patches constitute a promising platform for the controlled topical administration of sodium humate and show promising enhancement of wound healing. Full article

Laurus nobilis hydrosol (HyLN), a water-soluble byproduct of essential oil extraction, containing beneficial antioxidants and antimicrobial compounds, was used as a sustainable ingredient in the development of a natural antioxidant-rich hydrogel formulation. Hydrogels were formulated using sodium hyaluronate and xanthan gum, natural ingredients with beneficial effects on the skin, while β-cyclodextrin (βCD) was added to enhance the stability of antioxidants in HyLN. Extensive rheological and textural analyses were employed to optimize the hydrogel formulation for dermal administration, while stability studies assessed the chemical and physical stability of developed formulations. A combination of sodium hyaluronate and xanthan gum provided several HyLN hydrogel formulations with tunable rheological and textural properties, presenting adequate physical and microbiological stability over 6 months of storage. The use of βCD failed to stabilize inherently unstable antioxidants in HyLN hydrogels, yet their residual antioxidant activity remained notable. An in vitro scratch test using a human keratinocyte cell line showed that the developed HyLN gel does not interfere with wound healing. HyLN hydrogels showed a pronounced occlusive effect in vitro, reaching up to 80% of that measured for Vaseline, which helps maintain skin hydration and appearance. Full article

Background: The heterogeneity of immune-related adverse events (irAEs) in real-world evidence highlights the need to identify patterns, knowledge gaps, and priorities for future research. Objectives: To assess in labels the expected irAEs associated with immune checkpoint inhibitors (ICIs) in lung cancer, melanoma, breast cancer, and colon cancer and evaluate their incidence, clinical characteristics, management, and outcomes in real-world studies. Methods: Medicine Agency data sources (Food and Drug Administration and European Medicines Agency) were assessed for labeled irAEs associated with ICIs, and a comprehensive literature review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for scoping review was performed by retrieving observational and target trial emulation studies conducted using data collected in administrative healthcare databases (AHDs) and in spontaneous reporting systems (SRSs) concerning the drugs and tumors of interest from PubMed. irAEs’ incidence, onset, management, and outcomes were retrieved. Results: ICI combination therapy increases irAE occurrence, and inter-agency differences emerged. From PubMed, 49 observational studies were included, 22 on SRSs and 27 on AHDs. The ICIs most frequently evaluated were pembrolizumab and nivolumab, and the irAEs most reported were “lower respiratory tract disorders (excluding obstruction and infection)” (SRSs) and “epidermal and dermal conditions” (AHDs) for both drugs. Missing information on survival analysis, therapy dechallenge and rechallenge, concomitant therapies, comorbidities, time to onset, and duration of irAEs were highlighted. Conclusions: This scoping review highlights the complex, multi-organ irAEs from ICIs, underlining the need for tailored monitoring and management based on both regulatory and real-world evidence. Full article

Alopecia profoundly impacts psychological well-being and quality of life, yet current therapeutic options such as minoxidil and finasteride exhibit limited efficacy. Fibroblast growth factor 7 (FGF-7), also known as keratinocyte growth factor (KGF), is a paracrine growth factor secreted by dermal papilla cells that specifically activates the epithelial receptor FGFR2b. Receptor engagement triggers multiple downstream signaling cascades, including the MAPK/ERK, PI3K/Akt, and Wnt/β-catenin pathways, promoting keratinocyte proliferation, stem cell activation, and the transition of hair follicles into the anagen phase. Both in vitro and in vivo animal studies consistently demonstrate that FGF-7 accelerates telogen-to-anagen transition and enhances follicular regeneration. FGF-7 acts synergistically with insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) to sustain nutrient delivery and cell proliferation. Human scalp studies further reveal a strong association between the FGF-7/FGFR2b signaling and follicular activity; however, clinical trials remain scarce. Topical application of FGF-7 has demonstrated an excellent safety profile, whereas systemic administration necessitates careful monitoring. Future directions include the development of engineering to extend the systemic half-life, advanced delivery systems, and gene or mRNA-based therapeutic approaches. Thus, the FGF-7/FGFR2b axis is a highly compelling molecular target for next-generation hair regeneration therapies. Full article

Cosmeceutical peptides (CPs), which modulate various biological activities, including skin regeneration and wound healing, have emerged as promising agents in skincare. In this study, we investigated the regenerative and wound healing potential of a short peptide, CP-02 (sequence CDARSDAR), using human dermal fibroblast cells (HDFs) in vitro and a zebrafish model in vivo. In HDFs, CP-02 treatment at concentrations of 50, 100, and 200 µg/mL significantly accelerated wound closure in a dose-dependent manner (p < 0.05) and upregulated the mRNA expression of CCND1, MYC, FGF2, EFG, and IL-8 at 12 h post-treatment. In amputated zebrafish larvae, exposure to CP-02 (5 µg/mL) for 72 h significantly increased fin regeneration, with a fin area of 3.5 mm² and fin-fold length of 0.2 mm, compared with those in controls (2 mm² and 0.07 mm, respectively). Intramuscular administration of CP-02 significantly improved the healing rates in wounded adult zebrafish to 58% and 76% on 12 and 16 days post wounding (dpw), respectively, compared with the vehicle (35% and 44%, respectively). Histological analysis (H&E staining) revealed reduced inflammatory cell infiltration, complete granulation, and re-epithelialization in the CP-02-treated tissues at 12 dpw. Furthermore, mRNA expression levels of tnf-α, il-1β, tgfb1, mmp9, mmp13, and timp2b were elevated in the CP-02 group at 4 dpw, whereas those of pro-fibrotic mediators, including acta2, ctgfb, cdh1, and col9a3 reduced in muscle tissue on 12 dpw. Collectively these findings demonstrate that CP-02 promotes effective, scar-reducing regeneration and wound healing, highlighting its strong potential as a therapeutic peptide for future skincare and cosmeceutical applications. Full article

Molecular hydrogen (H₂) exhibits anti-inflammatory and antioxidant properties. However, its role in ultraviolet B (UVB)-induced skin carcinogenesis remains unclear. Male HR-1 hairless mice received continuous H₂ (2% hydrogen gas inhalation plus hydrogen-rich water (HRW)) or control treatment (normal air plus dehydrogenated water) during chronic dorsal UVB exposure (270 mJ/cm², three times per week, 20 weeks), followed by a 10-week observation period. This protocol was replicated independently. H₂ exposure consistently delayed the onset of papilloma and reduced cumulative tumor counts in both series, whereas prolonged survival and delayed squamous cell carcinoma (SCC) development each reached statistical significance in only one of the two experimental series. The cyclobutane pyrimidine dimer (CPD) levels remained unchanged, indicating no reduction in DNA photolesions. H₂ exposure decreased epidermal T-cell infiltration, dermal IL-6 levels, and nuclear phosphorylated STAT3 levels. ERK and JNK phosphorylation levels were decreased. H₂ preserved the GSH/GSSG ratio following acute UVB exposure and reduced nuclear Nrf2 accumulation during chronic exposure. Epidermal thickness and proliferation markers (Ki-67 and PCNA) were decreased. These findings suggest that continuous H₂ administration attenuates inflammation-associated early UVB carcinogenesis through modulation of the IL-6/STAT3 and ERK/JNK pathways, supporting its use as a chemopreventive approach. Full article

Dermal drug delivery is a promising alternate route of drug administration, offering localized therapeutic effects, reduced systemic effects, and improved patient compliance. However, the skin’s intricate configuration, especially the stratum corneum (SC), presents formidable barriers, restricting drug permeation. This review summarizes biological, synthetic, and methodological models employed to study dermal absorption and permeability. Ex vivo human skin is a reference point, but limited availability and ethical constraints necessitate reliance on animal models, including porcine, rodent, rabbit, monkey, and even snake skin, each with unique advantages and drawbacks. Synthetic substitutes, e.g., reconstructed human epidermis and Strat-M^® membranes, provide reproducibility and economic practicality, though none fully mimic the barrier functions of human skin. Innovative analytical methods, including diffusion cells, skin-PAMPA, tape stripping, and advanced imaging techniques, enable quantitative, semi-quantitative, and qualitative insights into drug transport. Collectively, these tools support formulation optimization and aid regulatory bioequivalence assessments. However, challenges remain in correlating in vitro, ex vivo, and in vivo outcomes and in replicating the skin’s dynamic physiology. This review highlights current opportunities and limitations, emphasizing the need for more physiologically relevant models to advance safe, effective, and innovative dermal drug delivery systems. Full article

Natural deep eutectic solvents (NADES) have been extensively used for the extraction of a wide spectrum of plant materials. However, limited data about the in vivo toxicity of NADES extracts restrict their future practical application. In this study, we are aiming to assess the safety of a Sorbitol–lactic acid (3:1 mol./mol.; 30% water) NADES extract of Glycyrrhiza roots (GR) in mice. LC-MS/MS analysis revealed the presence of 17 metabolites, including phenolic acids, flavonoids, their glycosides, chalcones, terpene saponins, and coumarins. Interestingly, most of the identified compounds were found in higher amounts in NADES extract compared to water and EtOH extracts. No skin edema, inflammation, or erythema was observed in mice after topical application of NADES extract of GR and NADES at the doses of 50, 100, and 150 µL/mice in comparison with the control group. The calculated primary irritation index was about 0.45 both for NADES and NADES extract of GR only in high doses and falls into mild irritant categories. The individual Draize scores indicate that erythema was evident in the first three days and that all signs had disappeared by day five. No acute toxic signs or mortality of animals was observed in mice following oral administration of single doses of 4, 6, and 20 g/kg of NADES or NADES extract of GR. The NADES and extract seem to be safe at doses of up to 20 g/kg, and the LD50 was considered to be >20 g/kg. Our results open prospects for the use of NADES extract of GR for the development of transdermal and peroral formulations in the cosmetic, food, and pharmaceutical industries. Full article

Ultraviolet B (UV-B) radiation significantly contributes to skin photoaging, which is characterized by epidermal thickening, collagen degradation, wrinkle formation, barrier dysfunction, and oxidative stress. Nicotinamide mononucleotide (NMN), a key precursor of nicotinamide adenine dinucleotide, regulates cellular energy metabolism and antioxidant defense and demonstrates anti-aging effects in animal models. Here, we investigated the protective effects of oral NMN supplementation against UV-B-induced photoaging in SKH-1 hairless mice. Over a 10-week experimental period, oral NMN administration significantly alleviated epidermal hypertrophy, reduced wrinkle formation and skin surface roughness, improved hydration and elasticity, and restored transepidermal water loss to near-normal levels. Histological analyses revealed marked preservation of collagen fiber density and attenuation of dermal matrix degradation. Furthermore, NMN supplementation inhibited the phosphorylation of MAPK signaling components (ERK, JNK, and p38), suppressed pro-inflammatory cytokine (TNF-α and IL-6) and matrix-degrading enzyme (MMP-1) expression, and restored hyaluronan synthase (HAS-1 and HAS-2) expression. Additionally, NMN enhanced the systemic antioxidant defense, as indicated by the restored superoxide dismutase activity. Thus, NMN has multi-layered protective effects against UV-B–induced skin aging by modulating oxidative stress, inflammatory signaling, extracellular matrix remodeling, and hyaluronic acid metabolism. Full article

The Transdermal Drug Delivery System (TDDS) offers several benefits, such as enhanced patient adherence, controlled release, reduced gastric irritation, and the bypassing of the first-pass metabolism. However, not all drugs can be delivered through this route in effective doses. Biodegradable microneedles (BMn) are designed to improve TDDS. This review outlines various types of BMn and their fabrication methods. BMn are produced in different forms, including hollow, solid, dissolve, and hydrogel-forming versions, which have garnered significant attention. These innovative BMn do not contain drugs themselves but instead absorb interstitial fluid to create continuous channels between the dermal microcirculation and a drug-containing patch. Several types of BMn have been tested and approved by regulatory bodies. The use of BMn technology is rapidly growing in point-of-care applications, attracting significant interest from both researchers and healthcare providers. BMn-based Point-of-care (POC) devices have high efficacy for finding various analytes of clinical interests and transdermal drug administration in a minimally invasive manner owing to BMn’ micro-size sharp tips and ease of use. Porous BMn technology may have a very rising future in the case of a vaccine delivery system. Full article