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      Small Force, Big Impact: Next Generation Organ-on-a-Chip Systems Incorporating Biomechanical Cues

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          Abstract

          Mechanobiology-on-a-chip is a growing field focusing on how mechanical inputs modulate physico-chemical output in microphysiological systems. It is well known that biomechanical cues trigger a variety of molecular events and adjustment of mechanical forces is therefore essential for mimicking in vivo physiologies in organ-on-a-chip technology. Biomechanical inputs in organ-on-a-chip systems can range from variations in extracellular matrix type and stiffness and applied shear stresses to active stretch/strain or compression forces using integrated flexible membranes. The main advantages of these organ-on-a-chip systems are therefore (a) the control over spatiotemporal organization of in vivo-like tissue architectures, (b) the ability to precisely control the amount, duration and intensity of the biomechanical stimuli, and (c) the capability of monitoring in real time the effects of applied mechanical forces on cell, tissue and organ functions. Consequently, over the last decade a variety of microfluidic devices have been introduced to recreate physiological microenvironments that also account for the influence of physical forces on biological functions. In this review we present recent advances in mechanobiological lab-on-a-chip systems and report on lessons learned from these current mechanobiological models. Additionally, future developments needed to engineer next-generation physiological and pathological organ-on-a-chip models are discussed.

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          Most cited references52

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          Capturing complex 3D tissue physiology in vitro.

          The emergence of tissue engineering raises new possibilities for the study of complex physiological and pathophysiological processes in vitro. Many tools are now available to create 3D tissue models in vitro, but the blueprints for what to make have been slower to arrive. We discuss here some of the 'design principles' for recreating the interwoven set of biochemical and mechanical cues in the cellular microenvironment, and the methods for implementing them. We emphasize applications that involve epithelial tissues for which 3D models could explain mechanisms of disease or aid in drug development.
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            Spheroid culture as a tool for creating 3D complex tissues.

            3D cell culture methods confer a high degree of clinical and biological relevance to in vitro models. This is specifically the case with the spheroid culture, where a small aggregate of cells grows free of foreign materials. In spheroid cultures, cells secrete the extracellular matrix (ECM) in which they reside, and they can interact with cells from their original microenvironment. The value of spheroid cultures is increasing quickly due to novel microfabricated platforms amenable to high-throughput screening (HTS) and advances in cell culture. Here, we review new possibilities that combine the strengths of spheroid culture with new microenvironment fabrication methods that allow for the creation of large numbers of highly reproducible, complex tissues. Copyright © 2013. Published by Elsevier Ltd.
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              Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation.

              A key aspect of cancer metastases is the tendency for specific cancer cells to home to defined subsets of secondary organs. Despite these known tendencies, the underlying mechanisms remain poorly understood. Here we develop a microfluidic 3D in vitro model to analyze organ-specific human breast cancer cell extravasation into bone- and muscle-mimicking microenvironments through a microvascular network concentrically wrapped with mural cells. Extravasation rates and microvasculature permeabilities were significantly different in the bone-mimicking microenvironment compared with unconditioned or myoblast containing matrices. Blocking breast cancer cell A3 adenosine receptors resulted in higher extravasation rates of cancer cells into the myoblast-containing matrices compared with untreated cells, suggesting a role for adenosine in reducing extravasation. These results demonstrate the efficacy of our model as a drug screening platform and a promising tool to investigate specific molecular pathways involved in cancer biology, with potential applications to personalized medicine.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                09 October 2018
                2018
                : 9
                : 1417
                Affiliations
                [1] 1Center for Translational Medicine, International Clinical Research Center, St. Anne’s University Hospital , Brno, Czechia
                [2] 2Faculty of Technical Chemistry, Institute of Applied Synthetic Chemistry and Institute of Chemical Technologies and Analytics, Vienna University of Technology , Vienna, Austria
                [3] 3AUVA Research Centre, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology , Vienna, Austria
                [4] 4Austrian Cluster for Tissue Regeneration , Vienna, Austria
                [5] 5Kompetenzzentrum für MechanoBiologie (INTERREG V-A Austria – Czech Republic Programme, ATCZ133) , Vienna, Austria
                [6] 6Competence Center for Mechanobiology (INTERREG V-A Austria – Czech Republic Programme, ATCZ133) , Brno, Czechia
                [7] 7Department of Biomaterials Science, Institute of Dentistry, University of Turku , Turku, Finland
                Author notes

                Edited by: Leonardo Alexandre Peyré-Tartaruga, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil

                Reviewed by: Khashayar Khoshmanesh, RMIT University, Australia; Irena Levitan, University of Illinois at Chicago, United States; T. Alexander Quinn, Dalhousie University, Canada

                *Correspondence: Giancarlo Forte, giancarlo.forte@ 123456fnusa.cz Peter Ertl, peter.ertl@ 123456tuwien.ac.at

                These authors have contributed equally to this work

                This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2018.01417
                6190857
                30356887
                933420d3-220a-43ef-bb38-406ce50cf768
                Copyright © 2018 Ergir, Bachmann, Redl, Forte and Ertl.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 April 2018
                : 18 September 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 70, Pages: 8, Words: 0
                Categories
                Physiology
                Mini Review

                Anatomy & Physiology
                microfluidics,mechanobiology,organ-on-a-chip,lab-on-a-chip,in vitro organ models,mechanical cell actuation

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