Stratum Corneum Research Articles

Transdermal Drug Delivery Systems: Different Generations and Dermatokinetic Assessment of Drug Concentration in Skin.

Transdermal drug delivery systems (TDDS) are a highly appealing and innovative method of administering drugs through the skin, as it enables the drugs to achieve systemic effects. A TDDS offers patient convenience, avoids first-pass hepatic metabolism, enables local targeting, and reduces the toxic effect of drug. This review details several generations of TDDS and the advancements made in their development to address the constraints associated with skin delivery systems. Transdermal delivery methods of the first generation have been consistently growing in their clinical application for administering small, lipophilic, low-dose drugs. Second-generation TDDS, utilizing chemical enhancers and iontophoresis, have led to the development of clinical products. Third-generation delivery systems employ microneedles, thermal ablation, and electroporation to specifically target the stratum corneum, which is the skin's barrier layer. Dermatokinetics is the study of the movement of drugs and formulations applied to the skin over a period of time. It provides important information regarding the rate and extent to which drugs penetrate skin layers. Several dermatokinetic techniques, including tape stripping, microdialysis, and laser scanning microscopy, have been used to study the intricate barrier properties and clearance mechanisms of the skin. This understanding is essential for developing and improving effective TDDS.

Unveiling the Metabolomic Profile of Oily Sensitive Skin: A Non-Invasive Approach

Skin barrier impairment is becoming increasingly common due to changes in lifestyle and modern living environments. Oily sensitive skin (OSS) is a condition that is characterized by an impaired skin barrier. Thus, examining the differences between OSS and healthy skin will enable a more objective evaluation of the characteristics of OSS and facilitate investigations of potential treatments. Initially, a self-assessment questionnaire was used to identify patients with OSS. Biophysical measurements and LAST scores were used to determine whether skin barrier function was impaired. Epidermal biophysical properties, including skin hydration, transepidermal water loss (TEWL), sebum content, erythema index (EI), and a* value, were measured with noninvasive instruments. We subsequently devised a noninvasive D-square sampling technique to identify changes in the skin metabolome in conjunction with an untargeted metabolomics analysis with an Orbitrap Q ExactiveTM series mass spectrometer. In the stratum corneum of 47 subjects, 516 skin metabolites were identified. In subjects with OSS, there was an increase in the abundance of 15 metabolites and a decrease in the abundance of 48 metabolites. The participants with OSS were found to have the greatest disruptions in sphingolipid and amino acid metabolism. The results revealed that an impaired skin barrier is present in patients with OSS and offers a molecular target for screening for skin barrier damage.

A Self-Assembled Transdermal Nanomedicines Incorporating Pendant Disulfides for Non-Invasive, Synergistic Treatment of Melanoma.

Transdermal drug delivery system (TDDS) offers lower systemic toxicity and good patient compliance, making it a promising treatment option for skin-related cancers. However, physiological barriers in the skin frequently impede the therapeutic efficiency of TDDS. To address this, a unique self-assembled TDDS that incorporates disulfide pendant groups (termed Sup-TDDS) is presented. It is formulated with dithiolane-containing lipoic acid (LA), photosensitizers Ce6, and chemotherapeutic agents trametinib. Pendant disulfide moieties on Sup-TDDS facilitate thiol-disulfide exchange reactions with exofacial thiols on cell surfaces, thus enhancing stratum corneum penetration. In contrast to intravenous injection, topical administration of Sup-TDDS can penetrate deeper into the skin (> 500 µm) and promote drug accumulation in subcutaneous tumors. In a B16F10-bearing mouse model, Sup-TDDS treatment demonstrates significant anti-tumor effects in primary and recurrent melanoma, benefiting from the synergistic effects of Ce6 and trametinib. These results underscore that Sup-TDDS's transdermal properties allow non-invasive melanoma therapy, implying the potential of nanodrugs containing pendant disulfides for transdermal treatment of skin illnesses.

Flexible yet Durable Microneedle Electrodes Based on Nanowire-Embedded Polyimide for Precise Wearable Electrophysiological Monitoring.

A precise recording of electrophysiological signals requires high-performance flexible bioelectrodes to build a robust skin interface. The past decade has witnessed encouraging progress in the development of elastomeric electrodes for wearable electrophysiological monitoring; however, it remains challenging to achieve excellent flexibility, conformal contact, and high durability simultaneously. Herein, we report on an effective method to fabricate flexible yet durable microneedle electrodes (MEs) based on vertically aligned gold nanowires (Au NWs) embedded polyimide (PI), which meet the above three design requirements. The Au NWs embedded PI MEs could build conformal contact with human skin and maintain electrical stability with minimal contact impedance by effectively penetrating the stratum corneum of the skin. In comparison studies, we found our MEs outperformed conventional gel or elastomeric soft electrodes. We further integrated the vertical Au-NW MEs into a wearable healthcare system and achieved wireless real-time recordings of electromyography (EMG) and electrocardiography (ECG) with high signal-to-noise ratios (SNRs) and low motion artifacts. Our fabrication strategy opens a new route to improve the durability and reliability of emerging nanomaterial-based soft bioelectrodes for long-term wearable healthcare applications.

Optimization, Formulation, and Ex vivo Evaluation of Solid Lipid Nanoparticles for Transdermal Delivery of Diltiazem Hydrochloride.

Cardiac arrhythmia, is a medical condition that reduces the heart's efficiency in pumping blood, and can be fatal, requires long-term management with conventional drugs, despite their limited efficacy. Diltiazem hydrochloride, chosen as a model drug, has a short biological half-life and extensive metabolism. Administering drug through skin is challenging, particularly due to the penetration via stratum corneum. However, solid lipid nanoparticles as a particulate carrier system can enhance its permeation and bioavailability. The study aimed to develop a matrix type transdermal patch with diltiazem hydrochloride encapsulated in solid lipid nanoparticles Methods: The study used the solvent diffusion technique to prepare SLNs by mixing the drug and solid lipid in an organic phase at 80°C, then slowly adding it to an aqueous phase with continuous stirring for 45 minutes. The resulting nanodispersion was freeze-dried and analyzed for morphological studies, encapsulation efficiency & drug content. A patch was formulated using solvent evaporation technique, incorporating HPMC E50 (2% w/v), propylene glycol, and ethanolic oleic acid (1.5% v/v). SLNs loaded with diltiazem hydrochloride taken equivalent to diltiazem hydrochloride dose in the transdermal patch. The patch was then evaluated for In vitro and skin permeation studies. The result showed a positive correlation between lipid concentration and particle size. Probe sonication and homogenization increased particle size, while stirring speed reduced it. SEM and TEM images confirmed spherical particles with a size of 488.1±4.01nm and an entrapment efficiency of 55.03±1.99%. Drug release studies demonstrated 70.7% drug release from lipid matrix over 24 hrs. The formulated patch with uniform SLN distribution, had a drug content 89.37 ± 0.04% with a surface pH of 6.1 ± 0.53, close to skin pH. The uniformity of content in 3x3 patch estimated to be 14.587 ± 1.404 mg, close to the theoretical content 16.318 ± 1.08 mg, confirmed homogenous distribution of diltiazem hydrochloride SLNs throughout the patch diameter. Cumulative amount released from patch formulation at pH 5.6 and pH 7.4 was 518.1414μg/cm2 and 404.4466 μg/cm2. Synergistic flux enhancement was observed with oleic acid propylene glycol blend. Ex vivo study of the patch showed steady-state flux of 6.9 μg/cm2/hr, permeability coefficient 0.00362 cm/hr, diffusion coefficient 0.000103 cm/hr, cumulative drug permeation (Dmax) 814.885 μg after 24 hrs, and followed a Higuchi-matrix release model. The developed patch possessed improved bioavailability with reduced dosing and enhanced patient compliance.

Invasomes: An Artificial Vesicle Nanocarrier to Enhance Transdermal Drug Delivery

Abstract: The greatest and most noticeable organ in the body is the skin. The stratum corneum, or top layer of skin, acts as a vital barrier to prevent skin penetration for many drugs. To over-come this barrier, numerous nanocarrier frameworks have been developed, which are important for the functioning of active agents. Vascular systems known as invasomes contain low levels of ethanol as well as terpenes or terpene combinations, which have a higher skin penetration rate and function as potential carriers. Improved drug delivery via the skin using a carrier that can pene-trate these barriers presents a wide range of difficulties and possibilities for further study and the creation of new and better treatment options. The main objective of an invasome-based delivery system is to significantly improve patient compliance and therapeutic value, in addition to bol-stering the safety and efficacy of the drug. This article gives a summary of the synthesis process, invasome characterizations, penetration mechanisms, and applications. This review paper also in-cludes phospholipids and their classification. Phospholipids are present in the cell membrane and provide ceramide, a bioactive molecule that moisturizes skin and protects against environmental damage in transdermal drug delivery systems. Pharmaceutical studies demonstrate that many drug molecules have less solubility, stability, bioavailability, and penetrating power. Invasomes repre-sent a novel dosage form with promising properties for enhancing transdermal drug delivery.

Mechanistic insight into heat enhanced permeation of diclofenac and piroxicam in combination with chemical penetration enhancers across skin

The topical application of heat offers considerable potential for enhancing the delivery of non-steroidal anti-inflammatory drugs across the skin barrier. A better understanding of the mechanisms underpinning the improved skin permeation and how heat can be best used to work with complementary enhancement strategies would help to realise this potential. In this study the effect of heat on the permeation of diclofenac and piroxicam across different membranes, including human skin was investigated along with use of complementary enhancement strategies including selection of formulation pH, drug salt form and inclusion of chemical penetration enhancers. Heat alone improved drug delivery across human skin for both drugs, with larger increases for piroxicam. This increase was produced by improvements in drug release, molecular diffusivity and partitioning into the stratum corneum. In combination with chemical penetration enhancers, heat synergistically increased the skin permeation of diclofenac and piroxicam up to 13 and 40-fold respectively, with the increase in permeation being ascribed primarily to improvements in drug and enhancer partitioning into the stratum corneum. An Arrhenius plot of diclofenac permeation across skin was linear indicating that the orthorhombic to hexagonal stratum corneum lipid packing transition did not have a significant effect on skin permeation in response to heat.

Autophagy-Mediated Cellular Remodeling during Terminal Differentiation of Keratinocytes in the Epidermis and Skin Appendages.

The epidermis of the skin and skin appendages, such as nails, hair and sebaceous glands, depend on a balance of cell proliferation and terminal differentiation in order to fulfill their functions at the interface of the body and the environment. The differentiation of epithelial cells of the skin, commonly referred to as keratinocytes, involves major remodeling processes that generate metabolically inactive cell remnants serving as building blocks of the epidermal stratum corneum, nail plates and hair shafts. Only sebaceous gland differentiation results in cell disintegration and holocrine secretion. A series of studies performed in the past decade have revealed that the lysosome-dependent intracellular degradation mechanism of autophagy is active during keratinocyte differentiation, and the blockade of autophagy significantly alters the properties of the differentiation products. Here, we present a model for the autophagy-mediated degradation of organelles and cytosolic proteins as an important contributor to cellular remodeling in keratinocyte differentiation. The roles of autophagy are discussed in comparison to alternative intracellular degradation mechanisms and in the context of programmed cell death as an integral end point of epithelial differentiation.

Clinical vs. chronological skin age: exploring determinants and stratum corneum protein markers of differential skin ageing in 351 healthy women

Apparent skin age can be determined by several clinical measurements and may differ from chronological age, hence defining age acceleration/deceleration (Age A/D). Using data from 360 women with dermatological scoring of 21 clinical signs, we defined 3 well-separated co-occurring classes capturing the dryness, the elasticity and the oily nature of the skin. We related the risk of each clinical signs to the stratum corneum levels of 5 pre-selected proteins, we identified specific chronological age-adjusted signatures of each clinical sign. Using variable selection approaches, we identified 6 (of the 21) clinical signs which were jointly predictive of chronological age and used to define the clinical skin age, and subsequently age A/D. Applying univariate and multivariate approaches we found that stratum corneum levels of insulin degrading enzyme (IDE) was protective against (β = − 1.74, p = 3.3 × 10−6; selection proportion > 90%) accelerated skin ageing. In conclusion, our results support the fact that molecular markers found in the stratum corneum could predict skin ageing acceleration/deceleration.

The Design Features, Quality by Design Approach, Characterization, Therapeutic Applications, and Clinical Considerations of Transdermal Drug Delivery Systems—A Comprehensive Review

Transdermal drug delivery systems (TDDSs) are designed to administer a consistent and effective dose of an active pharmaceutical ingredient (API) through the patient’s skin. These pharmaceutical preparations are self-contained, discrete dosage forms designed to be placed topically on intact skin to release the active component at a controlled rate by penetrating the skin barriers. The API provides the continuous and prolonged administration of a substance at a consistent rate. TDDSs, or transdermal drug delivery systems, have gained significant attention as a non-invasive method of administering APIs to vulnerable patient populations, such as pediatric and geriatric patients. This approach is considered easy to administer and helps overcome the bioavailability issues associated with conventional drug delivery, which can be hindered by poor absorption and metabolism. A TDDS has various advantages compared to conventional methods of drug administration. It is less intrusive, more patient-friendly, and can circumvent first pass metabolism, as well as the corrosive acidic environment of the stomach, that happens when drugs are taken orally. Various approaches have been developed to enhance the transdermal permeability of different medicinal compounds. Recent improvements in TDDSs have enabled the accurate administration of APIs to their target sites by enhancing their penetration through the stratum corneum (SC), hence boosting the bioavailability of drugs throughout the body. Popular physical penetration augmentation methods covered in this review article include thermophoresis, iontophoresis, magnetophoresis, sonophoresis, needle-free injections, and microneedles. This review seeks to provide a concise overview of several methods employed in the production of TDDSs, as well as their evaluation, therapeutic uses, clinical considerations, and the current advancements intended to enhance the transdermal administration of drugs. These advancements have resulted in the development of intelligent, biodegradable, and highly efficient TDDSs.

Comparative Analysis of the Intrinsic Disorder Within the Layers of the Human Cornea.

The human cornea is essential for vision, providing structural integrity and refractive power to the eye. Recent advancements have deepened our understanding of the corneal molecular composition, yet the role of intrinsically disordered proteins within the cornea is unexplored. We analyzed 3,250 corneal proteins identified by Dyrlund et al, focusing on the epithelium, stroma, and endothelium layers. We performed a bioinformatics analysis to characterize the amino acid composition, the propensity for intrinsic protein disorder, and the distribution of protein types in 3 corneal layer proteome. Our study demonstrates that each corneal layer exhibited unique patterns in amino acid composition related to protein disorder. Order-promoting amino acids were generally depleted except for leucine, whereas disorder-promoting amino acids like arginine and glutamic acid were enriched across all layers. Significant variations were observed in the levels of intrinsic disorder among the different corneal layers, with substantial proportions of highly disordered proteins present in each. Analysis of protein class type in each layers revealed that no significant differences were detected in the distribution of protein classifications across the layers, suggesting a consistent population of the protein types across all corneal layers. Our findings reveal a sophisticated landscape of protein structures where intrinsic disorder varies across layers, suggesting an adaptation of the corneal proteome to the unique physiological demands of each layer. These structural variations may reflect the intricate requirements for corneal transparency, biomechanical stability, and environmental responsiveness.

Development and evaluation of nanostructured systems for cutaneous delivery of H2S-releasing corticosteroids for skin inflammatory diseases

Psoriasis is an immune-mediated chronic inflammatory disease that causes major psychosocial impact. Topical corticosteroids represent the standard pharmacological treatment for mild-to-moderate disease, but their local and systemic adverse effects reinforce the need for treatment innovations. Here we developed lamellar phase-based formulations for topical delivery of a hybrid dexamethasone and hydrogen sulfide (H2S) donor molecule (Dexa-TBZ), aiming to potentiate the effects of the glucocorticoid with H2S. They offer the possibility to obtain precursor formulations free of water that originate lamellar phases upon water addition, preventing drug hydrolysis during storage. Two groups of formulations were developed varying the surfactants and oil phase types and content. Systems containing 20 and 70 % of water formed, respectively, bulk lamellar phase and a more fluid formulation consisting of dispersed droplets (< 1000 nm) stabilized by lamellar phase. Both presented pseudoplastic behavior. Dexa-TBZ was incorporated at 1 %, remaining stable for 8 h. Drug content decreased to ∼80 % after 1 week in precursor formulations free of water, but remained stable after that. Without causing changes to the cutaneous barrier function ex vivo or to the histological structure of the skin in vivo, the formulation containing phosphatidylcholine as surfactant and 70 % of water promoted 1.8- and 2.7-fold increases in Dexa-TBZ penetration in the stratum corneum and epidermis+dermis, respectively, compared to a control solution, demonstrating their potential applicability as topical delivery systems.

Antiaging synergistic effect in noninvasive transdermal delivery of peptide loaded liposomes by low energy/frequency radiofrequency

Low energy/frequency radiofrequency (LRF) combined with the transdermal delivery of liposome (L) encapsulated antiaging peptides technology is a remarkable, newly developed physical noninvasive transdermal penetration technique; it is considered a highly efficient, comprehensive and safe technology. In this study, our objective was to evaluate the physical and chemical mechanisms underlying the efficacy of this innovative technique involving a combination of LRF and L, termed LLRF, that exerts a synergistic anti-aging effect on human skin, via an animal experiment. Physical and chemical analyses indicated that a relatively stable liposome with a uniform nano-size, which was formed, possessed good transdermal permeability that was 2.74 folds higher than that of the free peptide (F). LLRF exhibited a higher transdermal permeation performance that was of 3.65 folds higher than that of the free one, which was substantiated via confocal laser scanning fluorescence microscopy. The mouse UVB photoaging model trial confirmed that the LLRF technology exerted a significant synergistic effect compared to liposome technology, or free peptide, by downregulating inflammatory factors (IL-6, TNF-α), inhibiting the mRNA and protein expression of matrix metalloproteinases (MMP1, MMP3), promoting the mRNA and protein expression of related collagens (Procollagen, Col1α1 and Col3α1), and repairing the stratum corneum barrier function, as evidenced by trans-epidermal water loss (TEWL), skin cuticle hydration (SCH), and decreased expression of β-gal, an aging marker. These findings indicated that photoaging skin can be effectively and comprehensively rejuvenated, and that even photodamage can be reversed, thereby restoring the original physiological characteristics of healthy skin. Clinical tests have confirmed that although liposome technology is an effective antiaging method which helps exert tightening and anti-wrinkle effects on human skin, LLRF is an even more effective anti-aging technique. This study reveals a highly effective technique involving a combination physical and chemical therapy that may be utilized for antiaging purposes as well as repairing lightly damaged skin, and can be made readily available in the future.

A finasteride patch for the treatment of androgenetic alopecia: A study of promoting permeability strategy using synthetic novel O-acylmenthols combined with ion-pair

Currently, finasteride (FIN) is approved to treat androgenetic alopecia only orally, and the application of FIN in transdermal drug delivery system (TDDS) has introduced a new approach for treating the disease. This study was aimed to develop a FIN transdermal patch for the treatment of androgenetic alopecia（AGA） by combing ion-pair and O-acylmenthols (AM) as chemical permeation enhancers (CPEs). The formulation of patch was optimized though single-factor investigation and Box-Behnken design. The pharmacokinetics and androgenetic alopecia pharmacodynamics of the patch were evaluated. Additionally, the permeability enhancement mechanisms of ion-pair and AMs were explored at both the patch and skin levels. The effects of ion-pair and AMs on the patch were characterized by rheology study, FTIR, and molecular docking, and the effects on the skin were assessed through ATR-FTIR, Raman study, DSC, CLSM and molecular dynamics. The finalized formulation of FIN patches was consisted of 5 % (w/w) synthetic FIN-CA (Citric Acid), 6 % MT-C6 as CPEs, 25-AAOH as a pressure-sensitive adhesive (PSA), with a patch thickness of 80 ± 5 μm. The final Q24 h is 78.22 ± 5.18 μg/cm2. Based on the high FIN permeability, the pharmacokinetic analysis revealed that the FIN patch group exhibited a slower absorption rate (tmax = 7.3 ± 2.7 h), lower peak plasma concentration and slower metabolic rate (t1/2 = 6.2 ± 0.8 h, MRT0-t = 26.0 ± 7.8 h) compared to the oral group. Moreover, the FIN patch also demonstrated the same effect as the oral group in promoting hair growth in AGA mice. The results indicated that both FIN-CA and AMs could enhance the fluidity of the PSA and weaken the interaction between FIN-CA and PSA, thereby promoting the release of the FIN from the patch. The interaction sites on the skin for ion-pair and the four AMs were found in the stratum corneum (SC) of the skin, disrupting the tight arrangement of stratum corneum lipids. This study serves as a reference for the multi-pathway administration of FIN and the combination of ion-pair with AMs to enhance drug permeation.

The penetration efficiency of a dissolved model drug into hair follicles depends on the concentration of added nanoparticles.

Hair follicles have recently emerged as promising drug delivery targets and gates for skin penetration. The so-called ratchet effect, which is based on an interaction between the hair shaft surface, the intrafollicular stratum corneum and nanoparticles, has proven to be very effective for the transport of active ingredients. Especially the nanoparticle-assisted decolonization of hair follicles constitutes an interesting new area of application. In a recently published work it was shown that small molecules as well as macromolecules solved in an outer phase of a formulation can be transported into the deeper parts of the hair follicles by adding nanoparticles to the formulation. In this case the nanoparticles constitute an entity independent of the drug and the transport is hypothesized to be based on an adhesion effect. In the present work, we focused on the impact of the particle concentration in the formulation on the transport efficiency of the model drug fluorescein sodium into hair follicles utilizing an ex vivo porcine skin model. It was observed that a particle concentration of 4% significantly enhances the transport efficiency of fluorescein as compared to 2% particle concentration. Doubling the concentration to 8% did not significantly increase the penetration depth. The effect evolved more efficiently when using 4Hz circular motion massage as compared to 100Hz oscillating massage. These results deliver interesting information on the optimal formulation as well as application parameters for a future application in clinical studies for e.g. skin antisepsis purposes.

Performance, ruminal and fecal microbiome of lambs fed diets supplemented with probiotics.

The present study aimed to investigate the impact of adding two doses of a commercial probiotic on productive performance, ruminal and fecal microbiome in growing lambs. Forty-two Texel or Ile de France crossbred lambs aged 86.9 ± 8.0days (body weight: 27.4 ± 3.7kg) were distributed into three groups: basal diet without probiotic supplementation (CG); basal diet + 1g/animal/day of probiotic (GP1) and basal diet + 5g/animal/day of probiotic (GP5). The experimental period was 84days. The weight was evaluated weekly and dry matter intake (DMI) and leftovers were measured daily. At the end of the experiment, lambs were slaughtered. Feces and rumen fluid were collected for microbiome analysis and rumen fragments for histological evaluation. The use of probiotics did not affect weight gain, but GP1 showed a higher silage and DMI intake than CG (p < 0.001). The CG had a greater thickness of keratinized epithelium and stratum corneum (< 0.001) than GP1 and GP5, and greater total papilla width (p = 0.039) than GP1. There was no difference in the general abundance in the rumen and fecal microbiomes. GP5 had a higher proportion of Azoarcus and Dialister taxa in the rumen fluid (p = 0.012 and p = 0.017, respectively) and higher proportion of Treponema and Fibrobacter taxa in the fecal microbiome (p = 0.015 and p = 0.026, respectively), whereas CG had a higher proportion of Anaeroplasma than the other groups (p = 0.032). These results demonstrated the benefits of probiotics for ruminal epithelium protection and microbial diversity. However, there was no effect on performance parameters.

Optimisation and Characterisation of Improved Nanoemulsion Formulations Containing Ceramide 3

AbstractCeramide3 (Cer3) is one of the important components of stratum corneum (SC) lipids with good moisturizing and repairing properties. However, it suffers from (a) poor solubility, (b) easy crystallization and precipitation, and (c) strong polarity and difficulty in transdermal application. This study aimed to load Cer3 into nanoemulsions (NEs) to overcome these mentioned defects. The optimized NEs formulation was prepared by high pressure homogenization method and characterized by several methods. The optimized ceramide3 nanoemulsions (Cer3‐NEs) exhibited a good physico‐chemical stability over 3 months under different conditions, with droplet size of 103.1 nm, PDI of 0.178, zeta potential of −39.09 mV, pH of 6.20 and encapsulation efficiency of 96.39 %. Turbiscan results showed that formulations containing Cer3‐NEs have better stability than those containing free Cer3. The dermal delivery ability of Cer3‐NEs was assessed by Franz diffusion and confocal Raman spectroscopy (CRM). In vitro and in vivo penetration studies showed that Cer3‐NEs serum have almost 2–3 times higher retention in the skin and permeation in the receptor solution compared to serum with free Cer3. The findings show NE is a promising carrier of Cer3 for topical administration in the treatment of dryness and barrier damage due to higher stability and better skin permeability.

Comprehensive combined analysis of physician-initiated phase II and III clinical trials on a cultured human corneal endothelial cell product for treating bullous keratopathy.

To evaluate the efficacy and safety of a cultured human corneal endothelial cell (cHCEC) product in eyes with bullous keratopathy (BK). Combined analysis of multicenter phase II and III clinical trials. This analysis involved 15 BK eyes in the phase II trial and 12 BK eyes in the phase III trial that underwent cHCEC transplant therapy. Safety was assessed in all the cases. Efficacy was assessed in 17 cases with exclusion of the low- and medium-dose groups in the phase II trial. The primary endpoint was a corneal endothelial cell density of 1000 cells/mm2 or more at 24 weeks post-transplant, which was attained in 94.1% of the eyes (16 of 17), with a 95% CI of 71.3-99.9%. Additionally, 82.4% of the eyes (14 of 17) met the secondary endpoint of reduction in corneal thickness to less than 630 µm without corneal epithelial edema within the same time frame, with a 95% CI of 56.6-96.2%. The mean decrease in corneal thickness from baseline to 24 weeks post-transplant was -187.4 µm (95% CI, -240.2 µm to -134.5 µm). Furthermore, all the eyes exhibited improvement in best-corrected visual acuity from baseline to 24 weeks post-transplant (95% CI, 80.5-100.0%). By 24 weeks post-transplant, 88.9% of the patients (24 of 27) had experienced adverse events, which were mostly local, mild, and transient. The cHCEC product of this study reconstitutes the corneal endothelial layer with high cellular density and restores corneal thickness and improves visual acuity.

Natural Skin Care Regimen Improves Clinical Parameters and Quality of Life in Children with Atopic Dermatitis

Background: Atopic dermatitis (AD) is a prevalent, chronic inflammatory skin disorder, characterized by xerosis, itching and recurrent eczematous lesions. The condition also has major psychosocial implications for patients and their families. A daily skincare regimen of gentle cleansing and moisturization is an important part of atopic dermatitis therapy. Objective: This study evaluated the tolerability and efficacy of a nature-based shampoo/wash and moisturizer in children with mild to moderate atopic dermatitis Methods: This open-label study involved 23 children (6 months – 13 years) with atopic dermatitis. A daily skin care regimen of nature-based shampoo/wash and moisturizer was used for 4 weeks. The primary endpoint was tolerability assessed through clinical grading of erythema, dryness and roughness. The study pediatrician graded the eczema condition using the Eczema Area and Severity Index (EASI), and assessments of stratum corneum hydration and transepidermal water loss were performed before and after treatment. Parent/guardian completed two validated quality of life questionnaires. Results: Twenty children completed the study. Clinical evaluations showed significant improvement in subjects’ atopic disease with daily use of nature-based regimen. Significant reduction in dryness and roughness was observed, indicating that both products were well-tolerated. Moisture content and transepidermal water loss measurements showed directional improvements in skin barrier function. Parent/guardian reported significant improvements in quality-of-life assessments. Conclusions: The study demonstrated that nature-based skin care regimen was well tolerated and improved quality of life and skin condition in children with atopic dermatitis and can be used either alone or in adjunction with traditional treatment for disease control.

Molecular dynamics simulations of lipid composition and its impact on structural and dynamic properties of skin membrane

The stratum corneum (SC) plays the most important role in the absorption of topical and transdermal drugs. In this study, we developed a multi-layered SC model using coarse-grained molecular dynamics (CGMD) simulations of ceramides, cholesterol, and fatty acids in equimolar proportions, starting from two different initial configurations. In the first approach, all ceramide molecules were initially in the hairpin conformation, and the membrane bilayers were pre-formed. In the second approach, ceramide molecules were introduced in either the hairpin or splayed conformation, with the lipid molecules randomly oriented at the start of the simulation. The aim was to evaluate the effects of lipid chain length on the structural and dynamic properties of SC. By incorporating ceramides and fatty acids of different chain lengths, we simulated the SC membrane in healthy and diseased states. We calculated key structural properties including the thickness, normalized lipid area, lipid tail order parameters, and spatial ordering of the lipids from each system. The results showed that systems with higher ordering and structural integrity contained an equimolar ratio of ceramides (chain length of 24 carbon atoms), fatty acids with chain lengths ≥ of 20 carbon atoms, and cholesterol. In these systems, strong apolar interactions between the ceramide and fatty acid long acyl chains restricted the mobility of the lipid molecules, thereby maintaining a compact lipid headgroup region and high order in the lipid tail region. The simulations also revealed distinct flip-flop mechanisms for cholesterol and fatty acid within the multi-layered membrane. Cholesterol is mostly diffused through the tail-tail interface region of the membrane and could flip-flop in the same bilayer. In contrast, fatty acids flip-flopped between adjacent leaflets of two bilayers in which the tails crossed the thinner headgroup region of the membrane. To conclude, our SC model provides mechanistic insights into lipid mobility and is flexible in its design and composition of different lipids, enabling studies of varying skin conditions.