A novel microfluidic device capable of maintaining functional thyroid carcinoma specimens ex vivo provides a new drug screening platform

Riley, Andrew; Green, Victoria; Cheah, Ramsah; McKenzie, Gordon; Karsai, Laszlo; England, James; Greenman, John

doi:10.1186/s12885-019-5465-z

Cited by 37 publications

(35 citation statements)

References 48 publications

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“…In this report we provide a detailed understanding of breast cancer cell behaviour when the cells were maintained as 3D tumouroids under fluid flow. Recently other fluidic systems have become available for example PhysioMimix (CN-Bio, UK); Mimitas (Leiden, Netherlands); these ‘off-the-shelf’ approaches augment bespoke systems developed in individual laboratories 47 , alongside this the emergence of ‘tumour-on-a-chip’ technology in which fluid flow is integral continues apace 48 . In these approaches it is important to ensure that the flow rates and shear forces delivered to the cancer cells are benchmarked against in vivo parameters.…”

Section: Discussionmentioning

confidence: 99%

Cancer cells grown in 3D under fluid flow exhibit an aggressive phenotype and reduced responsiveness to the anti-cancer treatment doxorubicin

Azimi

Loizidou

Dwek

2020

Sci Rep

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3D laboratory models of cancer are designed to recapitulate the biochemical and biophysical characteristics of the tumour microenvironment and aim to enable studies of cancer, and new therapeutic modalities, in a physiologically-relevant manner. We have developed an in vitro 3D model comprising a central high-density mass of breast cancer cells surrounded by collagen type-1 and we incorporated fluid flow and pressure. We noted significant changes in cancer cell behaviour using this system. MDA-MB231 and SKBR3 breast cancer cells grown in 3D downregulated the proliferative marker Ki67 (P < 0.05) and exhibited decreased response to the chemotherapeutic agent doxorubicin (DOX) (P < 0.01). Mesenchymal markers snail and MMP14 were upregulated in cancer cells maintained in 3D (P < 0.001), cadherin-11 was downregulated (P < 0.001) and HER2 increased (P < 0.05). Cells maintained in 3D under fluid flow exhibited a further reduction in response to DOX (P < 0.05); HER2 and Ki67 levels were also attenuated. Fluid flow and pressure was associated with reduced cell viability and decreased expression levels of vimentin. In summary, aggressive cancer cell behaviour and reduced drug responsiveness was observed when breast cancer cells were maintained in 3D under fluid flow and pressure. These observations are relevant for future developments of 3D in vitro cancer models and organ-on-a-chip initiatives.

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Section: Discussionmentioning

confidence: 99%

Cancer cells grown in 3D under fluid flow exhibit an aggressive phenotype and reduced responsiveness to the anti-cancer treatment doxorubicin

Azimi

Loizidou

Dwek

2020

Sci Rep

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“…The LDH cytotoxicity assay was performed using the Pierce LDH Cytotoxicity Assay Kit (Thermo Fisher) and carried out as per the manufacturer’s instructions and guidelines. This method has been previously applied to evaluate the cell viability of tumour tissue specimens cultured on a microfluidic platform 51 – 53 .…”

Section: Methodsmentioning

confidence: 99%

Characterising a PDMS based 3D cell culturing microfluidic platform for screening chemotherapeutic drug cytotoxic activity

Khot

Levenstein

Boer

et al. 2020

Sci Rep

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Three-dimensional (3D) spheroidal cell cultures are now recognised as better models of cancers as compared to traditional cell cultures. However, established 3D cell culturing protocols and techniques are time-consuming, manually laborious and often expensive due to the excessive consumption of reagents. Microfluidics allows for traditional laboratory-based biological experiments to be scaled down into miniature custom fabricated devices, where cost-effective experiments can be performed through the manipulation and flow of small volumes of fluid. In this study, we characterise a 3D cell culturing microfluidic device fabricated from a 3D printed master. HT29 cells were seeded into the device and 3D spheroids were generated and cultured through the perfusion of cell media. Spheroids were treated with 5-Fluorouracil for five days through continuous perfusion and cell viability was analysed on-chip at different time points using fluorescence microscopy and Lactate dehydrogenase (LDH) assay on the supernatant. Increasing cell death was observed in the HT29 spheroids over the five-day period. The 3D cell culturing microfluidic device described in this study, permits on-chip anti-cancer treatment and viability analysis, and forms the basis of an effective platform for the high-throughput screening of anti-cancer drugs in 3D tumour spheroids.

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“…FNA biopsies of lung adenocarcinomas from mouse PDX were successfully trapped and treated with staurosporine as a proof of principle. The Greenman group recently used a milled polyether ether ketone (PEEK) plastic microfluidic device to culture human thyroid tissue slices (malignant and benign) and demonstrated tissue viability for >4 days using various assessments 80 . These microfluidic models could potentially be used to determine the response of an individual tumor to various chemotherapy and radiation regimens in vitro, prior to exposing the patient to the therapy and its devastating side effects, as well as aiding in the development of drugs that better treat solid tumors 81 .…”

Section: In Vitro Studiesmentioning

confidence: 99%

Microfluidics for interrogating live intact tissues

et al. 2020

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The intricate microarchitecture of tissues – the “tissue microenvironment” – is a strong determinant of tissue function. Microfluidics offers an invaluable tool to precisely stimulate, manipulate, and analyze the tissue microenvironment in live tissues and engineer mass transport around and into small tissue volumes. Such control is critical in clinical studies, especially where tissue samples are scarce, in analytical sensors, where testing smaller amounts of analytes results in faster, more portable sensors, and in biological experiments, where accurate control of the cellular microenvironment is needed. Microfluidics also provides inexpensive multiplexing strategies to address the pressing need to test large quantities of drugs and reagents on a single biopsy specimen, increasing testing accuracy, relevance, and speed while reducing overall diagnostic cost. Here, we review the use of microfluidics to study the physiology and pathophysiology of intact live tissues at sub-millimeter scales. We categorize uses as either in vitro studies – where a piece of an organism must be excised and introduced into the microfluidic device – or in vivo studies – where whole organisms are small enough to be introduced into microchannels or where a microfluidic device is interfaced with a live tissue surface (e.g. the skin or inside an internal organ or tumor) that forms part of an animal larger than the device. These microfluidic systems promise to deliver functional measurements obtained directly on intact tissue – such as the response of tissue to drugs or the analysis of tissue secretions – that cannot be obtained otherwise.

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A novel microfluidic device capable of maintaining functional thyroid carcinoma specimens ex vivo provides a new drug screening platform

Cited by 37 publications

References 48 publications

Cancer cells grown in 3D under fluid flow exhibit an aggressive phenotype and reduced responsiveness to the anti-cancer treatment doxorubicin

Cancer cells grown in 3D under fluid flow exhibit an aggressive phenotype and reduced responsiveness to the anti-cancer treatment doxorubicin

Characterising a PDMS based 3D cell culturing microfluidic platform for screening chemotherapeutic drug cytotoxic activity

Microfluidics for interrogating live intact tissues

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