Skin-on-a-Chip Technology for Testing Transdermal Drug Delivery-Starting Points and Recent Developments.

During the last decades, several technologies were developed for testing drug delivery through the dermal barrier. Investigation of drug penetration across the skin can be important in topical pharmaceutical formulations and also in cosmeto-science. The state-of- the-art in the field of skin diffusion measurements, different devices, and diffusion platforms used, are summarized in the introductory part of this review. Then the methodologies applied at Pázmány Péter Catholic University are shown in detail. The main testing platforms (Franz diffusion cells, skin-on-a-chip devices) and the major scientific projects (P-glycoprotein interaction in the skin; new skin equivalents for diffusion purposes) are also presented in one section. The main achievements of our research are briefly summarized: (1) new skin-on-a-chip microfluidic devices were validated as tools for drug penetration studies for the skin; (2) P-glycoprotein transport has an absorptive orientation in the skin; (3) skin samples cannot be used for transporter interaction studies after freezing and thawing; (4) penetration of hydrophilic model drugs is lower in aged than in young skin; (5) mechanical sensitization is needed for excised rodent and pig skins for drug absorption measurements. Our validated skin-on-a-chip platform is available for other research groups to use for testing and for utilizing it for different purposes.

Age-Related Inflammatory Balance Shift, Nasal Barrier Function, and Cerebro-Morphological Status in Healthy and Diseased Rodents.

Increased blood-brain barrier (BBB) permeability and extensive neuronal changes have been described earlier in both healthy and pathological aging like apolipoprotein B-100 (APOB-100) and amyloid precursor protein (APP)-presenilin-1 (PSEN1) transgenic mouse models. APOB-100 hypertriglyceridemic model is a useful tool to study the link between cerebrovascular pathology and neurodegeneration, while APP-PSEN1 humanized mouse is a model of Alzheimer's disease. The aim of the current study was to characterize the inflammatory changes in the brain with healthy aging and in neurodegeneration. Also, the cerebro-morphological and cognitive alterations have been investigated. The nose-to-brain delivery of a P-glycoprotein substrate model drug (quinidine) was monitored in the disease models and compared with the age-matched controls. Our results revealed an inflammatory balance shift in both the healthy aged and neurodegenerative models. In normal aging monocyte chemoattractant protein-1, stem cell factor and Rantes were highly upregulated indicating a stimulated leukocyte status. In APOB-100 mice, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), and interleukin-17A (IL-17A) were induced (vascular reaction), while in APP-PSEN1 mice resistin, IL-17A and GM-CSF were mostly upregulated. The nasal drug absorption was similar in the brain and blood indicating the molecular bypass of the BBB. The learning and memory tests showed no difference in the cognitive performance of healthy aged and young animals. Based on these results, it can be concluded that various markers of chronic inflammation are present in healthy aged and diseased animals. In APOB-100 mice, a cerebro-ventricular dilation can also be observed. For development of proper anti-aging and neuroprotective compounds, further studies focusing on the above inflammatory targets are suggested.

Development of Skin-On-A-Chip Platforms for Different Utilizations: Factors to Be Considered.

There is increasing interest in miniaturized technologies in diagnostics, therapeutic testing, and biomedicinal fundamental research. The same is true for the dermal studies in topical drug development, dermatological disease pathology testing, and cosmetic science. This review aims to collect the recent scientific literature and knowledge about the application of skin-on-a-chip technology in drug diffusion studies, in pharmacological and toxicological experiments, in wound healing, and in fields of cosmetic science (ageing or repair). The basic mathematical models are also presented in the article to predict physical phenomena, such as fluid movement, drug diffusion, and heat transfer taking place across the dermal layers in the chip using Computational Fluid Dynamics techniques. Soon, it can be envisioned that animal studies might be at least in part replaced with skin-on-a-chip technology leading to more reliable results close to study on humans. The new technology is a cost-effective alternative to traditional methods used in research institutes, university labs, and industry. With this article, the authors would like to call attention to a new investigational family of platforms to refresh the researchers' theranostics and preclinical, experimental toolbox.

Thieno[2,3-b]pyridines as negative allosteric modulators of metabotropic GluR5 receptors: hit-to-lead optimization.

An HTS campaign of our corporate compound library resulted in thieno[2,3-b]pyridines derivative hits with mGluR5 negative allosteric modulator effects. During the hit-to-lead development our objective was to improve affinity, and to keep the ligand efficiency values at an acceptable level. After different modifications of the linker resulted in a 2-sulfonyl-thieno[2,3-b]pyridines derivative, which fulfilled the lead criteria.