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Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 23442

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Special Issue Editors

Prof. Dr. Stephan Reichl

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Guest Editor

Institute of Pharmaceutical Technology and Biopharmaceutics, Technische Universität Braunschweig, 38106 Braunschweig, Germany
Interests: drug absorption; 3D in vitro models of drug-absorption barriers; organ on chip; tissue engineering; ophthalmic drugs; tight junction modulators
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Andreas Dietzel

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Guest Editor

Institute of Microtechnology, Technische Universität Braunschweig, 38106 Braunschweig, Germany
Interests: lab on chip; biosensors; organ on chip; MEMS; femtosecond laser manufacturing; mechatronics; sensors on foil; micro actuators

Special Issue Information

Dear Colleagues,

In the development of new drugs or drug delivery systems as well as in the evaluation of bioavailability and bioequivalence, studies on drug absorption and distribution are essential. In the sense of the 3R concept and in the effort to implement studies on human models, numerous approaches for cell culture-based models of epithelial and endothelial barriers as alternative methods for animal experiments have already been established in the last two decades. In particular, modern methods of tissue engineering and, more recently, organ-on-chip technology enabled by micro- and nanofabrication have led to even more significant models of drug transport barriers in the human body. This Special Issue is, therefore, intended to present the broad diversity of research as well as the progress made in this field. We would like to encourage scientists from academia and industry to submit their latest results that can be attributed to this major topic. In this way, we hope to present a wide variety of high-quality articles that demonstrate the enormous potential of these technologies for drug discovery. In addition to the pure collection of research results, however, we will also be pleased if this Special Issue helps to promote scientific exchange in this field and further strengthen the scientific network.

Prof. Dr. Stephan Reichl
Prof. Dr. Andreas Dietzel
Guest Editors

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Keywords

tissue engineering
organ-on-chip
epithelial and endothelial barriers
in vitro models
drug absorption/drug transport
biopharmaceutics/pharmacokinetics
bioavailability/bioequivalence
integrated sensors
biomimetic microfluidics
alternative to animal testing/3R concept

Published Papers (6 papers)

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Research

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17 pages, 3384 KiB

Open AccessArticle

Mimicking the Intestinal Host–Pathogen Interactions in a 3D In Vitro Model: The Role of the Mucus Layer

by María García-Díaz, Maria del Mar Cendra, Raquel Alonso-Roman, María Urdániz, Eduard Torrents and Elena Martínez

Pharmaceutics 2022, 14(8), 1552; https://doi.org/10.3390/pharmaceutics14081552 - 26 Jul 2022

Cited by 9 | Viewed by 2773

Abstract

The intestinal mucus lines the luminal surface of the intestinal epithelium. This mucus is a dynamic semipermeable barrier and one of the first-line defense mechanisms against the outside environment, protecting the body against chemical, mechanical, or biological external insults. At the same time, the intestinal mucus accommodates the resident microbiota, providing nutrients and attachment sites, and therefore playing an essential role in the host–pathogen interactions and gut homeostasis. Underneath this mucus layer, the intestinal epithelium is organized into finger-like protrusions called villi and invaginations called crypts. This characteristic 3D architecture is known to influence the epithelial cell differentiation and function. However, when modelling in vitro the intestinal host–pathogen interactions, these two essential features, the intestinal mucus and the 3D topography are often not represented, thus limiting the relevance of the models. Here we present an in vitro model that mimics the small intestinal mucosa and its interactions with intestinal pathogens in a relevant manner, containing the secreted mucus layer and the epithelial barrier in a 3D villus-like hydrogel scaffold. This 3D architecture significantly enhanced the secretion of mucus. In infection with the pathogenic adherent invasive E. coli strain LF82, characteristic of Crohn’s disease, we observed that this secreted mucus promoted the adhesion of the pathogen and at the same time had a protective effect upon its invasion. This pathogenic strain was able to survive inside the epithelial cells and trigger an inflammatory response that was milder when a thick mucus layer was present. Thus, we demonstrated that our model faithfully mimics the key features of the intestinal mucosa necessary to study the interactions with intestinal pathogens. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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16 pages, 1784 KiB

Open AccessArticle

Proof-of-Concept Organ-on-Chip Study: Topical Cinnamaldehyde Exposure of Reconstructed Human Skin with Integrated Neopapillae Cultured under Dynamic Flow

by Irit Vahav, Maria Thon, Lenie J. van den Broek, Sander W. Spiekstra, Beren Atac, Gerd Lindner, Katharina Schimek, Uwe Marx and Susan Gibbs

Pharmaceutics 2022, 14(8), 1529; https://doi.org/10.3390/pharmaceutics14081529 - 22 Jul 2022

Cited by 7 | Viewed by 2920

Abstract

Pharmaceutical and personal care industries require human representative models for testing to ensure the safety of their products. A major route of penetration into our body after substance exposure is via the skin. Our aim was to generate robust culture conditions for a next generation human skin-on-chip model containing neopapillae and to establish proof-of-concept testing with the sensitizer, cinnamaldehyde. Reconstructed human skin consisting of a stratified and differentiated epidermis on a fibroblast populated hydrogel containing neopapillae spheroids (RhS-NP), were cultured air-exposed and under dynamic flow for 10 days. The robustness of three independent experiments, each with up to 21 intra-experiment replicates, was investigated. The epidermis was seen to invaginate into the hydrogel towards the neopapille spheroids. Daily measurements of lactate dehydrogenase (LDH) and glucose levels within the culture medium demonstrated high viability and stable metabolic activity throughout the culture period in all three independent experiments and in the replicates within an experiment. Topical cinnamaldehyde exposure to RhS-NP resulted in dose-dependent cytotoxicity (increased LDH release) and elevated cytokine secretion of contact sensitizer specific IL-18, pro-inflammatory IL-1β, inflammatory IL-23 and IFN-γ, as well as anti-inflammatory IL-10 and IL-12p70. This study demonstrates the robustness and feasibility of complex next generation skin models for investigating skin immunotoxicity. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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19 pages, 4198 KiB

Open AccessArticle

Tissue Barrier-on-Chip: A Technology for Reproducible Practice in Drug Testing

by Eugen V. Koch, Verena Ledwig, Sebastian Bendas, Stephan Reichl and Andreas Dietzel

Pharmaceutics 2022, 14(7), 1451; https://doi.org/10.3390/pharmaceutics14071451 - 12 Jul 2022

Cited by 9 | Viewed by 2365

Abstract

One key application of organ-on-chip systems is the examination of drug transport and absorption through native cell barriers such the blood–brain barrier. To overcome previous hurdles related to the transferability of existing static cell cultivation protocols and polydimethylsiloxane (PDMS) as the construction material, a chip platform with key innovations for practical use in drug-permeation testing is presented. First, the design allows for the transfer of barrier-forming tissue into the microfluidic system after cells have been seeded on porous polymer or Si3N4 membranes. From this, we can follow highly reproducible models and cultivation protocols established for static drug testing, from coating the membrane to seeding the cells and cell analysis. Second, the perfusion system is a microscopable glass chip with two fluid compartments with transparent embedded electrodes separated by the membrane. The reversible closure in a clamping adapter requires only a very thin PDMS sealing with negligible liquid contact, thereby eliminating well-known disadvantages of PDMS, such as its limited usability in the quantitative measurements of hydrophobic drug molecule concentrations. Equipped with tissue transfer capabilities, perfusion chamber inertness and air bubble trapping, and supplemented with automated fluid control, the presented system is a promising platform for studying established in vitro models of tissue barriers under reproducible microfluidic perfusion conditions. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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Graphical abstract

22 pages, 5814 KiB

Open AccessEditor’s ChoiceArticle

Electrospun Scaffolds as Cell Culture Substrates for the Cultivation of an In Vitro Blood–Brain Barrier Model Using Human Induced Pluripotent Stem Cells

by Felix Rohde, Karin Danz, Nathalie Jung, Sylvia Wagner and Maike Windbergs

Pharmaceutics 2022, 14(6), 1308; https://doi.org/10.3390/pharmaceutics14061308 - 20 Jun 2022

Cited by 8 | Viewed by 2959

Abstract

The human blood–brain barrier (BBB) represents the interface of microvasculature and the central nervous system, regulating the transport of nutrients and protecting the brain from external threats. To gain a deeper understanding of (patho)physiological processes affecting the BBB, sophisticated models mimicking the in vivo situation are required. Currently, most in vitro models are cultivated on stiff, semipermeable, and non-biodegradable Transwell^® membrane inserts, not adequately mimicking the complexity of the extracellular environment of the native human BBB. To overcome these disadvantages, we developed three-dimensional electrospun scaffolds resembling the natural structure of the human extracellular matrix. The polymer fibers of the scaffold imitate collagen fibrils of the human basement membrane, exhibiting excellent wettability and biomechanical properties, thus facilitating cell adhesion, proliferation, and migration. Cultivation of human induced pluripotent stem cells (hiPSCs) on these scaffolds enabled the development of a physiological BBB phenotype monitored via the formation of tight junctions and validated by the paracellular permeability of sodium fluorescein, further accentuating the non-linearity of TEER and barrier permeability. The novel in vitro model of the BBB forms a tight endothelial barrier, offering a platform to study barrier functions in a (patho)physiologically relevant context. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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Graphical abstract

18 pages, 4175 KiB

Open AccessArticle

Experimental Comparison of Primary and hiPS-Based In Vitro Blood–Brain Barrier Models for Pharmacological Research

by Karin Danz, Tara Höcherl, Sascha Lars Wien, Lena Wien, Hagen von Briesen and Sylvia Wagner

Pharmaceutics 2022, 14(4), 737; https://doi.org/10.3390/pharmaceutics14040737 - 29 Mar 2022

Cited by 2 | Viewed by 2414

Abstract

In vitro model systems of the blood–brain barrier (BBB) play an essential role in pharmacological research, specifically during the development and preclinical evaluation of new drug candidates. Within the past decade, the trend in research and further development has moved away from models based on primary cells of animal origin towards differentiated models derived from human induced pluripotent stem cells (hiPSs). However, this logical progression towards human model systems from renewable cell sources opens up questions about the transferability of results generated in the primary cell models. In this study, we have evaluated both models with identical experimental parameters and achieved a directly comparable characterisation showing no significant differences in protein expression or permeability even though the achieved transendothelial electrical resistance (TEER) values showed significant differences. In the course of this investigation, we also determined a significant deviation of both model systems from the in vivo BBB circumstances, specifically concerning the presence or absence of serum proteins in the culture media. Thus, we have further evaluated both systems when confronted with an in vivo-like distribution of serum and found a notable improvement in the differential permeability of hydrophilic and lipophilic compounds in the hiPS-derived BBB model. We then transferred this model into a microfluidic setup while maintaining the differential serum distribution and evaluated the permeability coefficients, which showed good comparability with values in the literature. Therefore, we have developed a microfluidic hiPS-based BBB model with characteristics comparable to the established primary cell-based model. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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Review

Jump to: Research

30 pages, 3889 KiB

Open AccessReview

Skin-on-a-Chip Technology: Microengineering Physiologically Relevant In Vitro Skin Models

by Patrícia Zoio and Abel Oliva

Pharmaceutics 2022, 14(3), 682; https://doi.org/10.3390/pharmaceutics14030682 - 21 Mar 2022

Cited by 16 | Viewed by 9009

Abstract

The increased demand for physiologically relevant in vitro human skin models for testing pharmaceutical drugs has led to significant advancements in skin engineering. One of the most promising approaches is the use of in vitro microfluidic systems to generate advanced skin models, commonly known as skin-on-a-chip (SoC) devices. These devices allow the simulation of key mechanical, functional and structural features of the human skin, better mimicking the native microenvironment. Importantly, contrary to conventional cell culture techniques, SoC devices can perfuse the skin tissue, either by the inclusion of perfusable lumens or by the use of microfluidic channels acting as engineered vasculature. Moreover, integrating sensors on the SoC device allows real-time, non-destructive monitoring of skin function and the effect of topically and systemically applied drugs. In this Review, the major challenges and key prerequisites for the creation of physiologically relevant SoC devices for drug testing are considered. Technical (e.g., SoC fabrication and sensor integration) and biological (e.g., cell sourcing and scaffold materials) aspects are discussed. Recent advancements in SoC devices are here presented, and their main achievements and drawbacks are compared and discussed. Finally, this review highlights the current challenges that need to be overcome for the clinical translation of SoC devices. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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