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Modelling Biological Barriers to Study Molecular Trafficking In Vitro: Advances and Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 12847

Special Issue Editors

Department of Neurosciences, Biomedicine and Movement Sciences, Anatomy and Histology Section, University of Verona, 37134 Verona, Italy
Interests: nanomaterials; nanoparticles formulation and characterization; drug delivery; cell culture; tissue engineering; biomaterilas; molecular biology; biological barriers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Understanding molecular traffic thought biological barriers is crucial for basic and applied research in several fields such as pharmaceutics, nanotechnology, pathology, physiology, toxicology, cosmetics, and food science. In recent years, a variety of in vitro models of biological barriers have been developed: the conventional two-dimensional cell monocultures have been complemented by three-dimensional co-cultures and organoids; to better mimic the barrier structure, bioengineered materials have been used to build matrices and scaffolds as a support for the cultured cells; bioreactors and microfluidics have made it possible to simulate the complex physiological dynamics that occurs in vivo. These models have proved to be standardized, reliable, fast, cost effective and ethically preferable, and allowed investigating how molecules may move through several types of barriers, such as the skin, cornea, intestinal mucosa, airway epithelium, renal epithelium, blood–brain and blood–placental barrier, and others.

This Special Issue is aimed at illustrating the great contribution of in vitro biological barriers to the knowledge of the trans-barrier molecular trafficking in vivo, as well as at presenting novel biological barrier models designed for permeability studies. All related deep molecular research is welcome and in vivo verification experiments are highly encouraged.

We invite researchers of all the relevant fields—bioengineering, biology, biotechnology, chemistry, pharmacology, biophysics, etc.—to present their results and commentaries by contributing original research articles or review papers.  

Prof. Manuela Malatesta
Dr. Flavia Carton
Guest Editors

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Keywords

  • barrier permeability
  • cell culture
  • biomaterials
  • bioreactor
  • microfluidics

Published Papers (5 papers)

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Research

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26 pages, 14853 KiB  
Article
An Innovative Fluid Dynamic System to Model Inflammation in Human Skin Explants
Int. J. Mol. Sci. 2023, 24(7), 6284; https://doi.org/10.3390/ijms24076284 - 27 Mar 2023
Cited by 2 | Viewed by 1344
Abstract
Skin is a major administration route for drugs, and all transdermal formulations must be tested for their capability to overcome the cutaneous barrier. Therefore, developing highly reliable skin models is crucial for preclinical studies. The current in vitro models are unable to replicate [...] Read more.
Skin is a major administration route for drugs, and all transdermal formulations must be tested for their capability to overcome the cutaneous barrier. Therefore, developing highly reliable skin models is crucial for preclinical studies. The current in vitro models are unable to replicate the living skin in all its complexity; thus, to date, excised human skin is considered the gold standard for in vitro permeation studies. However, skin explants have a limited life span. In an attempt to overcome this problem, we used an innovative bioreactor that allowed us to achieve good structural and functional preservation in vitro of explanted human skin for up to 72 h. This device was then used to set up an in vitro inflammatory model by applying two distinct agents mimicking either exogenous or endogenous stimuli: i.e., dithranol, inducing the contact dermatitis phenotype, and the substance P, mimicking neurogenic inflammation. Our in vitro system proved to reproduce inflammatory events observed in vivo, such as vasodilation, increased number of macrophages and mast cells, and increased cytokine secretion. This bioreactor-based system may therefore be suitably and reliably used to simulate in vitro human skin inflammation and may be foreseen as a promising tool to test the efficacy of drugs and cosmetics. Full article
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21 pages, 3729 KiB  
Article
The Cultivation Modality and Barrier Maturity Modulate the Toxicity of Industrial Zinc Oxide and Titanium Dioxide Nanoparticles on Nasal, Buccal, Bronchial, and Alveolar Mucosa Cell-Derived Barrier Models
Int. J. Mol. Sci. 2023, 24(6), 5634; https://doi.org/10.3390/ijms24065634 - 15 Mar 2023
Viewed by 1395
Abstract
As common industrial by-products, airborne engineered nanomaterials are considered important environmental toxins to monitor due to their potential health risks to humans and animals. The main uptake routes of airborne nanoparticles are nasal and/or oral inhalation, which are known to enable the transfer [...] Read more.
As common industrial by-products, airborne engineered nanomaterials are considered important environmental toxins to monitor due to their potential health risks to humans and animals. The main uptake routes of airborne nanoparticles are nasal and/or oral inhalation, which are known to enable the transfer of nanomaterials into the bloodstream resulting in the rapid distribution throughout the human body. Consequently, mucosal barriers present in the nose, buccal, and lung have been identified and intensively studied as the key tissue barrier to nanoparticle translocation. Despite decades of research, surprisingly little is known about the differences among various mucosa tissue types to tolerate nanoparticle exposures. One limitation in comparing nanotoxicological data sets can be linked to a lack of harmonization and standardization of cell-based assays, where (a) different cultivation conditions such as an air-liquid interface or submerged cultures, (b) varying barrier maturity, and (c) diverse media substitutes have been used. The current comparative nanotoxicological study, therefore, aims at analyzing the toxic effects of nanomaterials on four human mucosa barrier models including nasal (RPMI2650), buccal (TR146), alveolar (A549), and bronchial (Calu-3) mucosal cell lines to better understand the modulating effects of tissue maturity, cultivation conditions, and tissue type using standard transwell cultivations at liquid-liquid and air-liquid interfaces. Overall, cell size, confluency, tight junction localization, and cell viability as well as barrier formation using 50% and 100% confluency was monitored using trans-epithelial-electrical resistance (TEER) measurements and resazurin-based Presto Blue assays of immature (e.g., 5 days) and mature (e.g., 22 days) cultures in the presence and absence of corticosteroids such as hydrocortisone. Results of our study show that cellular viability in response to increasing nanoparticle exposure scenarios is highly compound and cell-type specific (TR146 6 ± 0.7% at 2 mM ZnO (ZnO) vs. ~90% at 2 mM TiO2 (TiO2) for 24 h; Calu3 93.9 ± 4.21% at 2 mM ZnO vs. ~100% at 2 mM TiO2). Nanoparticle-induced cytotoxic effects under air-liquid cultivation conditions declined in RPMI2650, A549, TR146, and Calu-3 cells (~0.7 to ~0.2-fold), with increasing 50 to 100% barrier maturity under the influence of ZnO (2 mM). Cell viability in early and late mucosa barriers where hardly influenced by TiO2 as well as most cell types did not fall below 77% viability when added to Individual ALI cultures. Fully maturated bronchial mucosal cell barrier models cultivated under ALI conditions showed less tolerance to acute ZnO nanoparticle exposures (~50% remaining viability at 2 mM ZnO for 24 h) than the similarly treated but more robust nasal (~74%), buccal (~73%), and alveolar (~82%) cell-based models. Full article
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21 pages, 4030 KiB  
Article
Ethosomal Gel for Topical Administration of Dimethyl Fumarate in the Treatment of HSV-1 Infections
Int. J. Mol. Sci. 2023, 24(4), 4133; https://doi.org/10.3390/ijms24044133 - 18 Feb 2023
Cited by 4 | Viewed by 2045
Abstract
The infections caused by the HSV-1 virus induce lesions on the lips, mouth, face, and eye. In this study, an ethosome gel loaded with dimethyl fumarate was investigated as a possible approach to treat HSV-1 infections. A formulative study was conducted, evaluating the [...] Read more.
The infections caused by the HSV-1 virus induce lesions on the lips, mouth, face, and eye. In this study, an ethosome gel loaded with dimethyl fumarate was investigated as a possible approach to treat HSV-1 infections. A formulative study was conducted, evaluating the effect of drug concentration on size distribution and dimensional stability of ethosomes by photon correlation spectroscopy. Ethosome morphology was investigated by cryogenic transmission electron microscopy, while the interaction between dimethyl fumarate and vesicles, and the drug entrapment capacity were respectively evaluated by FTIR and HPLC. To favor the topical application of ethosomes on mucosa and skin, different semisolid forms, based on xanthan gum or poloxamer 407, were designed and compared for spreadability and leakage. Dimethyl fumarate release and diffusion kinetics were evaluated in vitro by Franz cells. The antiviral activity against HSV-1 was tested by plaque reduction assay in Vero and HRPE monolayer cells, while skin irritation effect was evaluated by patch test on 20 healthy volunteers. The lower drug concentration was selected, resulting in smaller and longer stable vesicles, mainly characterized by a multilamellar organization. Dimethyl fumarate entrapment in ethosome was 91% w/w, suggesting an almost total recovery of the drug in the lipid phase. Xanthan gum 0.5%, selected to thicken the ethosome dispersion, allowed to control drug release and diffusion. The antiviral effect of dimethyl fumarate loaded in ethosome gel was demonstrated by a reduction in viral growth both 1 h and 4 h post-infection. Moreover, the patch test demonstrated the safety of the ethosomal gel applied on the skin. Full article
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Review

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33 pages, 752 KiB  
Review
Complexification of In Vitro Models of Intestinal Barriers, A True Challenge for a More Accurate Alternative Approach
Int. J. Mol. Sci. 2023, 24(4), 3595; https://doi.org/10.3390/ijms24043595 - 10 Feb 2023
Cited by 2 | Viewed by 4751
Abstract
The use of cell models is common to mimic cellular and molecular events in interaction with their environment. In the case of the gut, the existing models are of particular interest to evaluate food, toxicants, or drug effects on the mucosa. To have [...] Read more.
The use of cell models is common to mimic cellular and molecular events in interaction with their environment. In the case of the gut, the existing models are of particular interest to evaluate food, toxicants, or drug effects on the mucosa. To have the most accurate model, cell diversity and the complexity of the interactions must be considered. Existing models range from single-cell cultures of absorptive cells to more complex combinations of two or more cell types. This work describes the existing solutions and the challenges that remain to be solved. Full article
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20 pages, 2595 KiB  
Review
In Vitro Models of Biological Barriers for Nanomedical Research
Int. J. Mol. Sci. 2022, 23(16), 8910; https://doi.org/10.3390/ijms23168910 - 10 Aug 2022
Cited by 14 | Viewed by 2205
Abstract
Nanoconstructs developed for biomedical purposes must overcome diverse biological barriers before reaching the target where playing their therapeutic or diagnostic function. In vivo models are very complex and unsuitable to distinguish the roles plaid by the multiple biological barriers on nanoparticle biodistribution and [...] Read more.
Nanoconstructs developed for biomedical purposes must overcome diverse biological barriers before reaching the target where playing their therapeutic or diagnostic function. In vivo models are very complex and unsuitable to distinguish the roles plaid by the multiple biological barriers on nanoparticle biodistribution and effect; in addition, they are costly, time-consuming and subject to strict ethical regulation. For these reasons, simplified in vitro models are preferred, at least for the earlier phases of the nanoconstruct development. Many in vitro models have therefore been set up. Each model has its own pros and cons: conventional 2D cell cultures are simple and cost-effective, but the information remains limited to single cells; cell monolayers allow the formation of cell–cell junctions and the assessment of nanoparticle translocation across structured barriers but they lack three-dimensionality; 3D cell culture systems are more appropriate to test in vitro nanoparticle biodistribution but they are static; finally, bioreactors and microfluidic devices can mimicking the physiological flow occurring in vivo thus providing in vitro biological barrier models suitable to reliably assess nanoparticles relocation. In this evolving context, the present review provides an overview of the most representative and performing in vitro models of biological barriers set up for nanomedical research. Full article
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