Engineering and monitoring cellular barrier models

Yeste et al. Journal of Biological Engineering (2018) 12:18 https://doi.org/10.1186/s13036-018-0108-5 REVIEW Open Access Engineering and monitoring cellular barrier models Jose Yeste1,2* , Xavi Illa2,1, Mar Alvarez1 and Rosa Villa1,2 Abstract Epithelia and endothelia delineate tissue compartments and control their environments by regulating the passage of ions and solutes. This barrier function is essential for the development and maintenance of multicellular organisms, and its dysfunction is associated with numerous human diseases. Recent advances in biomaterials and microfabrication technologies have evolved in vitro approaches for modelling biological barriers. Current microphysiological systems have become more efficient and reliable in mimicking the cell microenvironment. Additionally, methods for the quantification of barrier permeability have long provided significant insight into their underlying mechanisms. In this review, we outline the current techniques to quantify the barrier function of engineered tissues, and we also give an overview of recent microphysiological systems of biological barriers that emulate the microenvironment and microarchitecture of native tissues. Keywords: Biological barriers, Cell barrier function, Microphysiological systems, Transepithelial electrical properties Background Physical barriers to separate different compartments are essential for the development and maintenance of multicellular organisms and are integral to numerous organs. Epithelia and endothelia form these vital barriers. They delineate tissue compartments and control their environments by regulating the passage of ions and solutes [1]. Some examples are renal tubule epithelium and blood capillaries. The physiological function of these biological barriers is diverse among tissues and responds to the particular needs of each organ, including the supply of nutrients, the absorption of ions, the secretion of waste, the protection against toxins, and the filtration of fluids. The deregulation of their essential function can lead to serious health complications. Numerous endothelia and epithelia dysfunctions are associated with prevalent human diseases such as hereditary diseases (e.g., hypomagnesemia), gastrointestinal tract diseases (e.g., Crohn’s disease), or viral infections (e.g., hepatitis C) [2–4]. Recent advances in microtechnologies and biomaterials have provided a new set of tools to construct relevant microphysiological systems (MPS) [5, 6]. These * Correspondence: 1 Institut de Microelectrònica de Barcelona, IMB-CNM (CSIC), 08193, Bellaterra, Barcelona, Spain 2 CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain engineered devices aim to recapitulate tissues- and organ-level functions and are promising constructs for disease modelling and drug development applications. Although cell cultures may not capture all of the complexity of the in vivo system, the barrier models being developed are enhancing our ability to more closely mimic the in vivo environment and therefore better predict cell behaviour in vivo. To date, this technology has led to the engineering of diverse systems for modelling human diseases [7] and also for mimicking biological barriers of the lung [8], kidney [9], and brain [10], among others. Since the major function of a cell barrier is to regulate and to separate two distinct physiological compartments, the strategy to build more relevant in vitro models usually lies in compartmentalization of different environments [11]. Most engineered cell barrier approaches utilize physical interfaces for such propose and to support cells (e.g., permeable membranes or gel-liquid interfaces). Besides compartmentalization, quantifying the permeability of barrier tissues is necessary to assess the state of the barriers and identify the factors contributing to barrier dysfunction. For example, in toxicology, the monitoring of the barrier integrity permits to evaluate the effects of toxic compounds; in disease modelling, to examine a barrier breakdown during a disease progression; or in drug development, to test the ability of new drugs to cross the © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yeste et al. Journal of Biological Engineering (2018) 12:18 barriers. In addition to tracer assays and immunocytochemistry, transepithelial electrical measurements—performed with extracellular electrodes in apical and basal sides—have been an essential methodology to quantify ion permeability and to elucidate important epithelial properties. These electrical measurements are non-invasive and yield information about the voltage, resistance, and current across the epithelium. Measuring these parameters under special conditions, it is possible to determine ion transepithelial transports and the electromotive forces generated by active transporters. Transepithelial electrical properties have also been widely used to determine ion selectivity, ion permeability, and electrophysiological characterization of epithelial tissues [12–14]. In this review, after introducing how epithelial and endothelial cells form functional barriers and describing some vital biological barriers of the human body, we outline the current techniques to quantify the barrier function of engineered tissues, focusing on permeability assays and transepithelial electrical measurements. Then, we give and overview of recent MPS for modelling biological barriers that emulate the cell microenvironment and microarchitecture of native tissues. Finally, we discuss the future perspectives in engineering and monitoring epithelial and endothelial barrier models. Page 2 of 19 Epithelial and endothelial tissues Epithelial and endothelial sheets are formed by cells that are attached together sealing the intercellular space and thus providing a physical barrier. This tissue configuration leads to two possible routes for solutes to cross the barrier: 1) the transcellular pathway in which ions and molecules pass through the cell membrane and 2) the paracellular pathway where solutes cross between cells (Fig. 1a). Ion and molecule movement along the paracellular route is passive and requires a driving force such as a concentration gradient, an electrical potential difference, a hydrostatic pressure, or an osmotic gradient. The combination of both chemical gradient and electric voltage leads to an electrochemical gradient whi (...truncated)