Control of Perfusable Microvascular Network Morphology Using a Multiculture Microfluidic System

Whisler, Jordan A.; Chen, Michelle B.; Kamm, Roger D.

doi:10.1089/ten.tec.2013.0370

Cited by 203 publications

(255 citation statements)

References 45 publications

(53 reference statements)

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“…In contrast to our results, recent in vitro vasculogenesis assays using spatially separated cocultures did not describe recruitment and direct contact of supporting cells with microvessels. 10,11 This might be due to the shorter experimental duration used in these studies. It is also possible that the primary cells used here are more migratory and physiologically relevant as compared to the lung fibroblasts reported earlier.…”

Section: Discussionmentioning

confidence: 97%

“…Yet another method exploited the natural microvessel formation of endothelial cells inside fibrin gel by providing appropriate growth factors and signals from fibroblasts. 10,11 These novel models mimic the cellular microenvironment much better than standard in vitro assays performed in static conditions. Endothelial cells attach to and modify a threedimensional (3D) meshwork to form perfusable microvessels and with the addition of perivascular cells or physiological interstitial flow further approach in vivo-like conditions.…”

Section: Introductionmentioning

confidence: 99%

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Primary Human Lung Pericytes Support and Stabilize In Vitro Perfusable Microvessels

Bichsel

Hall

Schmid

et al. 2015

Tissue Engineering Part A

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The formation of blood vessels is a complex tissue-specific process that plays a pivotal role during developmental processes, in wound healing, cancer progression, fibrosis, and other pathologies. To study vasculogenesis and vascular remodeling in the context of the lung, we developed an in vitro microvascular model that closely mimics the human lung microvasculature in terms of three-dimensional architecture, accessibility, functionality, and cell types. Human pericytes from the distal airway were isolated and characterized using flow cytometry. To assess their role in the generation of normal microvessels, lung pericytes were mixed in fibrin gel and seeded into well-defined microcompartments together with primary endothelial cells (human umbilical cord vein endothelial cells). Patent microvessels covering an area of 3.1 mm(2) formed within 3-5 days and were stable for up to 14 days. Soluble signals from the lung pericytes were necessary to establish perfusability, and pericytes migrated toward endothelial microvessels. Cell-cell communication in the form of adherens and tight junctions, as well as secretion of basement membrane were confirmed using transmission electron microscopy and immunocytochemistry on chip. Direct coculture of pericytes with endothelial cells decreased the microvascular permeability by one order of magnitude from 17.8×10(-6) to 2.0×10(-6) cm/s and led to vessels with significantly smaller and less variable diameter. Upon phenylephrine administration, vasoconstriction was observed in microvessels lined with pericytes, but not in endothelial microvessels only. Perfusable microvessels were also generated with human lung microvascular endothelial cells and lung pericytes. Human lung pericytes were thus shown to have a prominent influence on microvascular morphology, permeability, vasoconstriction, and long-term stability in an in vitro microvascular system. This biomimetic platform opens new possibilities to test functions and interactions of patient-derived cells in a physiologically relevant microvascular setting.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Primary Human Lung Pericytes Support and Stabilize In Vitro Perfusable Microvessels

Bichsel

Hall

Schmid

et al. 2015

Tissue Engineering Part A

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“…26 These self-organized, perfusable 3D mVNs were recently used to better understand extravasation events in tumor cell metastasis. 27 The in vitro microvascular network platform is a very useful tool for systematically studying transport of microparticles in real time, with increased physiological relevance compared to microuidics-based ow assays (similar to other bio-inspired experiments 4,28 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of colloidal microgels using oxygen-controlled flow lithography

Eral

Chen

et al. 2014

Soft Matter

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We report a synthesis approach based on stop-flow lithography (SFL) for fabricating colloidal microparticles with any arbitrary 2D-extruded shape. By modulating the degree of oxygen inhibition during synthesis, we achieved previously unattainable particle sizes. Brownian diffusion of colloidal discs in bulk suggests the out-of-plane dimension can be as small as 0.8 mm, which agrees with confocal microscopy measurements. We measured the hindered diffusion of microdiscs near a solid surface and compared our results to theoretical predictions. These colloidal particles can also flow through physiological microvascular networks formed by endothelial cells undergoing vasculogensis under minimal hydrostatic pressure ($5 mm H 2 O). This versatile platform creates future opportunities for on-chip parametric studies of particle geometry effects on particle passage properties, distribution and cellular interactions.

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“…Hydrogel-incorporating microfluidic devices have been developed to investigate the morphogenetic nature of blood vessels, angiogenesis (Chung et al 2009b;Shin et al 2011Shin et al , 2012 Jeong et al 2011a, b;Munn 2011), and vasculogenesis (Kim et al 2013;Whisler et al 2014;Chen et al 2013). Angiogenesis denotes the formation of new blood vessels from preexisting vessels, and vasculogenesis is the process that occurs when there are no preexisting vessels.…”

Section: D Angiogenesis Assaymentioning

confidence: 99%

Integrated Vascular Engineering: Vascularization of Reconstructed Tissue

Sudo

Chung²,

Shin

et al. 2016

Vascular Engineering

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In this chapter, we describe culture methods to construct microvascular networks as well as approaches to integrating capillary networks with 3D epithelial tissueengineered constructs. First, culture models of microvascular networks such as in vitro angiogenesis and vasculogenesis models are introduced. Using these culture models, the roles of endothelial cells (ECs), such as endothelial tip, stalk, and phalanx cells, are demonstrated. Additionally, regulatory factors, including both biochemical and biophysical factors, are discussed in the context of 3D capillary formation, including the process of vascular development, growth, and maturation. Next, we focus on the use of microfluidics technologies for investigating capillary morphogenesis. Examples of 3D capillary formation assays with growth factor gradients and different extracellular matrix materials are described. Cocultures of ECs and the other cell types in microfluidic devices are also introduced to show the potential of microfluidic vascular formation models. The vascularization of constructed tissues is discussed from the viewpoints of horizontal and vertical approaches for combining capillary structures and epithelial tissues in vitro. Finally, the concept of integrated vascular engineering and future perspectives are discussed. General Introduction for In Vitro Capillary FormationBlood vessels are tubular structures through which blood passes to provide oxygen and nutrients to individual cells within tissues and organs. Because oxygen and nutrients are the most important fundamental factors for vital activity, blood vessels are essential tissues in the body. The luminal surface of blood vessels is covered by endothelial cells (ECs). Thus, we need to understand how ECs form blood vessels for the development of vascular tissue engineering. In particular, in the context of tissue engineering for three-dimensional (3D) tissues and organs, construction of microvascular networks, rather than large blood vessels, has a high priority.There are two processes of microvessel formation in vivo, referred to as "angiogenesis" and "vasculogenesis" (Risau 1997). Angiogenesis is the formation of new capillaries branching from preexisting blood vessels. To investigate this angiogenic process, an in vitro 3D angiogenesis model has been developed. In this model, hydrogels, such as collagen gel and fibrin gel, are formed in a culture dish, and ECs are seeded on the surface of the 3D hydrogel scaffold. ECs grow on the gel surface and finally form a confluent monolayer. When the cells are cultured with no growth factors, they maintain a confluent monolayer, which is similar to the ECs covering the luminal surface of blood vessels in vivo (step 1, Fig. 16.1a). However, when ECs are cultured and supplemented with angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), some ECs penetrate into the underlying gel to form vascular sprouts, which is the beginning of vascular formation (step 2, Fig. 16.1a). T...

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Control of Perfusable Microvascular Network Morphology Using a Multiculture Microfluidic System

Cited by 203 publications

References 45 publications

Primary Human Lung Pericytes Support and Stabilize In Vitro Perfusable Microvessels

Primary Human Lung Pericytes Support and Stabilize In Vitro Perfusable Microvessels

Synthesis of colloidal microgels using oxygen-controlled flow lithography

Integrated Vascular Engineering: Vascularization of Reconstructed Tissue

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