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      Microfluidic-Based 3D Engineered Microvascular Networks and Their Applications in Vascularized Microtumor Models

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          Abstract

          The microvasculature plays a critical role in human physiology and is closely associated to various human diseases. By combining advanced microfluidic-based techniques, the engineered 3D microvascular network model provides a precise and reproducible platform to study the microvasculature in vitro, which is an essential and primary component to engineer organ-on-chips and achieve greater biological relevance. In this review, we discuss current strategies to engineer microvessels in vitro, which can be broadly classified into endothelial cell lining-based methods, vasculogenesis and angiogenesis-based methods, and hybrid methods. By closely simulating relevant factors found in vivo such as biomechanical, biochemical, and biological microenvironment, it is possible to create more accurate organ-specific models, including both healthy and pathological vascularized microtissue with their respective vascular barrier properties. We further discuss the integration of tumor cells/spheroids into the engineered microvascular to model the vascularized microtumor tissue, and their potential application in the study of cancer metastasis and anti-cancer drug screening. Finally, we conclude with our commentaries on current progress and future perspective of on-chip vascularization techniques for fundamental and clinical/translational research.

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          Most cited references112

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          Molecular regulation of vessel maturation.

          The maturation of nascent vasculature, formed by vasculogenesis or angiogenesis, requires recruitment of mural cells, generation of an extracellular matrix and specialization of the vessel wall for structural support and regulation of vessel function. In addition, the vascular network must be organized so that all the parenchymal cells receive adequate nutrients. All of these processes are orchestrated by physical forces as well as by a constellation of ligands and receptors whose spatio-temporal patterns of expression and concentration are tightly regulated. Inappropriate levels of these physical forces or molecules produce an abnormal vasculature--a hallmark of various pathologies. Normalization of the abnormal vasculature can facilitate drug delivery to tumors and formation of a mature vasculature can help realize the promise of therapeutic angiogenesis and tissue engineering.
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            Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices.

            Culture of cells using various microfluidic devices is becoming more common within experimental cell biology. At the same time, a technological radiation of microfluidic cell culture device designs is currently in progress. Ultimately, the utility of microfluidic cell culture will be determined by its capacity to permit new insights into cellular function. Especially insights that would otherwise be difficult or impossible to obtain with macroscopic cell culture in traditional polystyrene dishes, flasks or well-plates. Many decades of heuristic optimization have gone into perfecting conventional cell culture devices and protocols. In comparison, even for the most commonly used microfluidic cell culture devices, such as those fabricated from polydimethylsiloxane (PDMS), collective understanding of the differences in cellular behavior between microfluidic and macroscopic culture is still developing. Moving in vitro culture from macroscopic culture to PDMS based devices can come with unforeseen challenges. Changes in device material, surface coating, cell number per unit surface area or per unit media volume may all affect the outcome of otherwise standard protocols. In this review, we outline some of the advantages and challenges that may accompany a transition from macroscopic to microfluidic cell culture. We focus on decisive factors that distinguish macroscopic from microfluidic cell culture to encourage a reconsideration of how macroscopic cell culture principles might apply to microfluidic cell culture.
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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

                Journal
                Micromachines (Basel)
                Micromachines (Basel)
                micromachines
                Micromachines
                MDPI
                2072-666X
                27 September 2018
                October 2018
                : 9
                : 10
                : 493
                Affiliations
                [1 ]Department of Micro/Nano Electronics, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; kizluy@ 123456sjtu.edu.cn (Q.S.); Peijianghua@ 123456sjtu.edu.cn (J.P.)
                [2 ]National Key Laboratory of Science and Technology on Micro/Nano Fabrication, Department of Micro/Nano Electronics, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
                [3 ]Key Laboratory for Thin Film and Microfabrication Technology (Ministry of Education), Department of Micro/Nano Electronics, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
                Author notes
                [* ]Correspondence: xlwang83@ 123456sjtu.edu.cn ; Tel.: +86-021-3420-6683
                Author information
                https://orcid.org/0000-0001-9510-4045
                Article
                micromachines-09-00493
                10.3390/mi9100493
                6215090
                30424426
                172e3020-cd47-4db2-a4f3-116e80f568fc
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 August 2018
                : 25 September 2018
                Categories
                Review

                microfluidics,vascularization,organ-on-a-chip,vascularized tumor model,tissue engineering

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