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      Recapitulating the Vasculature Using Organ-On-Chip Technology

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          Abstract

          The development of Vasculature-on-Chip has progressed rapidly over the last decade and recently, a wealth of fabrication possibilities has emerged that can be used for engineering vessels on a chip. All these fabrication methods have their own advantages and disadvantages but, more importantly, the capability of recapitulating the in vivo vasculature differs greatly between them. The first part of this review discusses the biological background of the in vivo vasculature and all the associated processes. We then evaluate the biological relevance of different fabrication methods proposed for Vasculature-on-Chip, we indicate their possibilities and limitations, and we assess which fabrication methods are capable of recapitulating the intrinsic complexity of the vasculature. This review illustrates the complexity involved in developing in vitro vasculature and provides an overview of fabrication methods for Vasculature-on-Chip in relation to the biological relevance of such methods.

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          Most cited references73

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          Vascular-specific growth factors and blood vessel formation.

          A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
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            Three-dimensional bioprinting of thick vascularized tissues.

            The advancement of tissue and, ultimately, organ engineering requires the ability to pattern human tissues composed of cells, extracellular matrix, and vasculature with controlled microenvironments that can be sustained over prolonged time periods. To date, bioprinting methods have yielded thin tissues that only survive for short durations. To improve their physiological relevance, we report a method for bioprinting 3D cell-laden, vascularized tissues that exceed 1 cm in thickness and can be perfused on chip for long time periods (>6 wk). Specifically, we integrate parenchyma, stroma, and endothelium into a single thick tissue by coprinting multiple inks composed of human mesenchymal stem cells (hMSCs) and human neonatal dermal fibroblasts (hNDFs) within a customized extracellular matrix alongside embedded vasculature, which is subsequently lined with human umbilical vein endothelial cells (HUVECs). These thick vascularized tissues are actively perfused with growth factors to differentiate hMSCs toward an osteogenic lineage in situ. This longitudinal study of emergent biological phenomena in complex microenvironments represents a foundational step in human tissue generation.
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              Engineering of functional, perfusable 3D microvascular networks on a chip.

              Generating perfusable 3D microvessels in vitro is an important goal for tissue engineering, as well as for reliable modelling of blood vessel function. To date, in vitro blood vessel models have not been able to accurately reproduce the dynamics and responses of endothelial cells to grow perfusable and functional 3D vascular networks. Here we describe a microfluidic-based platform whereby we model natural cellular programs found during normal development and angiogenesis to form perfusable networks of intact 3D microvessels as well as tumor vasculatures based on the spatially controlled co-culture of endothelial cells with stromal fibroblasts, pericytes or cancer cells. The microvessels possess the characteristic morphological and biochemical markers of in vivo blood vessels, and exhibit strong barrier function and long-term stability. An open, unobstructed microvasculature allows the delivery of nutrients, chemical compounds, biomolecules and cell suspensions, as well as flow-induced mechanical stimuli into the luminal space of the endothelium, and exhibits faithful responses to physiological shear stress as demonstrated by cytoskeleton rearrangement and increased nitric oxide synthesis. This simple and versatile platform provides a wide range of applications in vascular physiology studies as well as in developing vascularized organ-on-a-chip and human disease models for pharmaceutical screening.
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                Author and article information

                Journal
                Bioengineering (Basel)
                Bioengineering (Basel)
                bioengineering
                Bioengineering
                MDPI
                2306-5354
                18 February 2020
                March 2020
                : 7
                : 1
                : 17
                Affiliations
                [1 ]Microsystems, Department of Mechanical Engineering, Eindhoven University of Technology, 5600MB Eindhoven, The Netherlands; a.m.a.o.pollet@ 123456tue.nl
                [2 ]Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600MB Eindhoven, The Netherlands
                Author notes
                Author information
                https://orcid.org/0000-0002-9571-2902
                https://orcid.org/0000-0002-5923-4456
                Article
                bioengineering-07-00017
                10.3390/bioengineering7010017
                7175276
                32085464
                7dca9ed5-dad6-44be-a552-526b0a344378
                © 2020 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
                : 20 January 2020
                : 15 February 2020
                Categories
                Review

                vasculature,organ-on-chip,microfabrication,microfluidics,angiogenesis,vasculogenesis

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