A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow

Kalchman, Johann; Fujioka, Satoko; Chung, Seok; Kikkawa, Yamato; Mitaka, Toshihiro; Kamm, Roger D.; Tanishita, Kazuo; Sudo, Ryo

doi:10.1007/s10404-012-1104-6

Cited by 36 publications

(26 citation statements)

References 25 publications

(31 reference statements)

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“…Researchers have already begun to explore the application of organs-on-chips as predictive phenotypic assay platforms for drug repositioning. For example, a microengineered model of liver cancer was used to investigate the anticancer effects of artemisinin, an antimalarial drug that is currently being considered for use as a cancer therapy 71 . In this model, human liver cancer cells self-assembled into 3D tumour structures and their invasive migration into neighbouring micropatterned 3D gel matrices was examined under physiological interstitial flow.…”

Section: Potential Uses In Drug Screeningmentioning

confidence: 99%

Organs-on-chips at the frontiers of drug discovery

Esch

Bahinski

Huh

2015

Nat Rev Drug Discov

966

733

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Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs — known as organs-on-chips — that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology.

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Section: Potential Uses In Drug Screeningmentioning

confidence: 99%

Organs-on-chips at the frontiers of drug discovery

Esch

Bahinski

Huh

2015

Nat Rev Drug Discov

966

733

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“…However, antiangiogenic responses were also observed in in vitro coculture models. Kalchman et al (2013) reported the coculture of HUVECs and HepG2, a hepatocellular carcinoma cell line. HUVECs and HepG2 cells were cultured in separate microfluidic channels.…”

Section: Remote Interaction Between Tumor Cells and Ecsmentioning

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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“…Early models used to study biochemical factors used cell migration through bulk gels in response to factors including EGF 80,81 , CXCL-12 (Ref. 81), hypoxia 82,83 , and serum concentration 84 . These models allowed the study of cancer cell migration in a 3D environment, which is known to occur via mechanisms different from those in a 2D environment 85,86 .…”

Section: Microfluidic Investigation Of Biochemical Signals In Cancer mentioning

confidence: 99%

A review of microfluidic approaches for investigating cancer extravasation during metastasis

et al. 2018

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Metastases, or migration of cancers, are common and severe cancer complications. Although the 5-year survival rates of primary tumors have greatly improved, those of metastasis remain below 30%, highlighting the importance of investigating specific mechanisms and therapeutic approaches for metastasis. Microfluidic devices have emerged as a powerful platform for drug target identification and drug response screening and allow incorporation of complex interactions in the metastatic microenvironment as well as manipulation of individual factors. In this work, we review microfluidic devices that have been developed to study cancer cell migration and extravasation in response to mechanical (section 'Microfluidic investigation of mechanical factors in cancer cell migration'), biochemical (section 'Microfluidic investigation of biochemical signals in cancer cell invasion'), and cellular (section 'Microfluidic metastasis-on-a-chip models for investigation of cancer extravasation') signals. We highlight the device characteristics, discuss the discoveries enabled by these devices, and offer perspectives on future directions for microfluidic investigations of cancer metastasis, with the ultimate aim of identifying the essential factors for a 'metastasis-on-a-chip' platform to pursue more efficacious treatment approaches for cancer metastasis.

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A three-dimensional microfluidic tumor cell migration assay to screen the effect of anti-migratory drugs and interstitial flow

Cited by 36 publications

References 25 publications

Organs-on-chips at the frontiers of drug discovery

Organs-on-chips at the frontiers of drug discovery

Integrated Vascular Engineering: Vascularization of Reconstructed Tissue

A review of microfluidic approaches for investigating cancer extravasation during metastasis

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