Skin-on-a-Chip Device for Ex Vivo Monitoring of Transdermal Delivery of Drugs—Design, Fabrication, and Testing

To develop proper drug formulations and to optimize the delivery of their active ingredients through the dermal barrier, the Franz diffusion cell system is the most widely used in vitro/ex vivo technique. However, different providers and manufacturers make various types of this equipment (horizontal, vertical, static, flow-through, smaller and larger chambers, etc.) with high variability and not fully comparable and consistent data. Furthermore, a high amount of test drug formulations and large size of diffusion skin surface and membranes are important requirements for the application of these methods. The aim of our study was to develop a novel Microfluidic Diffusion Chamber device and compare it with the traditional techniques. Here the design, fabrication, and a pilot testing of a microfluidic skin-on-a chip device are described. Based on this chip, further developments can also be implemented for industrial purposes to assist the characterization and optimization of drug formulations, dermal pharmacokinetics, and pharmacodynamic studies. The advantages of our device, beside the low costs, are the small drug and skin consumption, low sample volumes, dynamic arrangement with continuous flow mimicking the dermal circulation, as well as rapid and reproducible results.

[1]  H. Pinkus Tape stripping in dermatological research. A review with emphasis on epidermal biology. , 1966, Giornale italiano di dermatolotia. Minerva dermatologica.

[2]  A. Loeffler,et al.  Opportunities for topical antimicrobial therapy: permeation of canine skin by fusidic acid , 2017, BMC Veterinary Research.

[3]  José Juan Escobar-Chávez,et al.  The tape-stripping technique as a method for drug quantification in skin. , 2008, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[4]  Amir Sanati-Nezhad,et al.  Skin Diseases Modeling using Combined Tissue Engineering and Microfluidic Technologies , 2016, Advanced healthcare materials.

[5]  T. Lindh,et al.  Workers' dermal exposure to UV-curable acrylates in the furniture and Parquet industry. , 2000, The Annals of occupational hygiene.

[6]  B. Michniak-Kohn,et al.  Effects of solvents and penetration enhancers on transdermal delivery of thymoquinone: permeability and skin deposition study , 2018, Drug delivery.

[7]  F. Erdő Microdialysis Techniques In Pharmacokinetic and Biomarker Studies. Past, Present and Future Directions. A Review. , 2015 .

[8]  J. Liaw,et al.  Evaluation of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) gels as a release vehicle for percutaneous fentanyl. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[9]  L. Nylander-French,et al.  A tape-stripping method for measuring dermal exposure to multifunctional acrylates. , 2000, The Annals of occupational hygiene.

[10]  José Juan Escobar-Chávez,et al.  Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations. , 2006, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[11]  A. El‐Kattan,et al.  Effect of formulation variables on the percutaneous permeation of ketoprofen from gel formulations. , 2000, Drug delivery.

[12]  P. Russo,et al.  Chemicals from textiles to skin: an in vitro permeation study of benzothiazole , 2018, Environmental Science and Pollution Research.

[13]  Andreas Dietzel,et al.  DynaMiTES – A dynamic cell culture platform for in vitro drug testing PART 1 – Engineering of microfluidic system and technical simulations , 2017, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[14]  I. Antal,et al.  Validation of an In vitro-in vivo Assay System for Evaluation of Transdermal Delivery of Caffeine , 2019, Drug Delivery Letters.

[15]  Leena A Nylander-French,et al.  Determination of keratin protein in a tape-stripped skin sample from jet fuel exposed skin. , 2004, The Annals of occupational hygiene.

[16]  José Juan Escobar-Chávez,et al.  In Vivo Skin Permeation of Sodium Naproxen Formulated in Pluronic F-127 Gels: Effect of Azone® and Transcutol® , 2005, Drug development and industrial pharmacy.

[17]  J. Hadgraft,et al.  Comparison of Franz cells and microdialysis for assessing salicylic acid penetration through human skin. , 2004, International journal of pharmaceutics.

[18]  D. Beebe,et al.  PDMS absorption of small molecules and consequences in microfluidic applications. , 2006, Lab on a chip.

[19]  M. Takada,et al.  Pluronic F-127 gels as a novel vehicle for rectal administration of indomethacin. , 1986, Chemical & pharmaceutical bulletin.

[20]  L. Barros,et al.  Mushroom ethanolic extracts as cosmeceuticals ingredients: Safety and ex vivo skin permeation studies. , 2019, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[21]  I. Oh,et al.  Effects of non-ionic surfactants as permeation enhancers towards piroxicam from the poloxamer gel through rat skins. , 2001, International journal of pharmaceutics.

[22]  J. Bouwstra,et al.  Barrier properties of an N/TERT-based human skin equivalent. , 2014, Tissue engineering. Part A.

[23]  H I Maibach,et al.  Stratum corneum adhesive tape stripping: influence of anatomical site, application pressure, duration and removal , 2004, The British journal of dermatology.

[24]  B. Michniak-Kohn,et al.  Strat‐M® synthetic membrane: Permeability comparison to human cadaver skin , 2018, International journal of pharmaceutics.

[25]  Samir D. Roy,et al.  Percutaneous absorption of nafarelin acetate, an LHRH analog, through human cadaver skin and monkey skin , 1994 .

[26]  C. Lehr,et al.  Interrelation of permeation and penetration parameters obtained from in vitro experiments with human skin and skin equivalents. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[27]  Andreas Dietzel,et al.  DynaMiTES – A dynamic cell culture platform for in vitro drug testing PART 2 – Ocular DynaMiTES for drug absorption studies of the anterior eye , 2017, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[28]  N. Zghoul,et al.  Reconstructed skin equivalents for assessing percutaneous drug absorption from pharmaceutical formulations. , 2001, ALTEX.

[29]  L. Bergers,et al.  Progress and Future Prospectives in Skin-on-Chip Development with Emphasis on the use of Different Cell Types and Technical Challenges , 2017, Stem Cell Reviews and Reports.

[30]  Sebastian Eggert,et al.  Skin-on-a-Chip: Transepithelial Electrical Resistance and Extracellular Acidification Measurements through an Automated Air-Liquid Interface , 2018, Genes.

[31]  R. Vaughan,et al.  3D In Vitro Model of a Functional Epidermal Permeability Barrier from Human Embryonic Stem Cells and Induced Pluripotent Stem Cells , 2014, Stem cell reports.

[32]  Y. Kalia,et al.  Passive skin penetration enhancement and its quantification in vitro. , 2001, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[33]  Shoji Takeuchi,et al.  Skin integrated with perfusable vascular channels on a chip. , 2017, Biomaterials.

[34]  Y. Y. Wang,et al.  In vitro and in vivo evaluations of topically applied capsaicin and nonivamide from hydrogels. , 2001, International journal of pharmaceutics.

[35]  E. Csányi,et al.  Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction , 2018, Drug design, development and therapy.

[36]  Dries Braeken,et al.  Current Strategies and Future Perspectives of Skin-on-a-Chip Platforms: Innovations, Technical Challenges and Commercial Outlook. , 2019, Current pharmaceutical design.

[37]  Monika Schäfer-Korting,et al.  Influence of Th2 Cytokines on the Cornified Envelope, Tight Junction Proteins, and ß-Defensins in Filaggrin-Deficient Skin Equivalents. , 2016, The Journal of investigative dermatology.

[38]  N. Nakamichi,et al.  Critical evaluation and methodological positioning of the transdermal microdialysis technique. A review. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[39]  Michael Schwartz,et al.  PDMS Compound Adsorption in Context , 2009, Journal of biomolecular screening.

[40]  Y. Kalia,et al.  Piroxicam delivery into human stratum corneum in vivo: iontophoresis versus passive diffusion. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[41]  van DrongelenVincent,et al.  Barrier properties of an N/TERT-based human skin equivalent. , 2014 .

[42]  Jia-You Fang,et al.  In vitro topical application and in vivo pharmacodynamic evaluation of nonivamide hydrogels using Wistar rat as an animal model. , 2002, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[43]  Leena A Nylander-French,et al.  Estimating dermal exposure to jet fuel (naphthalene) using adhesive tape strip samples. , 2004, The Annals of occupational hygiene.

[44]  D. Quintanar-Guerrero,et al.  Preparation of polymeric nanocapsules containing octyl methoxycinnamate by the emulsification-diffusion technique: penetration across the stratum corneum. , 2005, Journal of pharmaceutical sciences.