Looking to the Future of Organs-on-Chip

Greenman, John

doi:10.4155/fsoa-2017-0040

Cited by 6 publications

(6 citation statements)

References 14 publications

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“…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. Concordance studies with different 3D cancer model systems under flow are now an important aim, the realisation of this will enable standardisation and adoption into the pharmaceutical drug development pipeline and is expected will result in reductions in the use of in vivo model systems 49 – 51 .…”

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 CCLE was found to have a preponderance of mutations in cell-cycle related genes. As well as the potential for selection pressures to be causative of these differences, in this comparison it should also be appreciated that PDX models and TCGA represent naive tumor populations, whereas the CCLE consists of many models from later stage disease that have previously been exposed to therapies, compromising the comparison It should also be noted that a new generation of cell line models are being created directly from patients and PDX models both in 2D and three-dimensional (3D) with multiple layers of complexity by many groups [ 26 , 76 , 77 ]; only time will tell how this new generation of cell lines or model systems such as organ-on-a-chip [ 78 ] represent the patient population as compared to PDXs, and if using PDX models in vivo will be surpassed in high-throughput studies with the relative ease and cost factors of in vitro experiments.…”

Section: Fidelity and Stability Of Pdx Modelsmentioning

confidence: 99%

Using PDX for Preclinical Cancer Drug Discovery: The Evolving Field

Williams

2018

JCM

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The ability to create patient derived xenografts (PDXs) has evolved considerably from the breakthrough of the development of immune compromised mice. How researchers in drug discovery have utilized PDX of certain cancer types has also changed from traditionally selecting a few models to profile a drug, to opting to assess inter-tumor response heterogeneity by screening across a broad range of tumor models, and subsequently to enable clinical stratification strategies. As with all models and methodologies, imperfections with this approach are apparent, and our understanding of the fidelity of these models continues to expand. To date though, they are still viewed as one of the most faithful modeling systems in oncology. Currently, there are many efforts ongoing to increase the utility and translatability of PDXs, including introducing a human immune component to enable immunotherapy studies.

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“…Standardization guidelines currently do not exist, and different platforms exhibit various data collection endpoints, which makes platform-to-platform comparison a challenging task. As MPS platforms move beyond the prototype stage developed primarily to suit a proof of concept, the growing interest for practical applications is giving rise to scaled-up production and commercially available platforms, which are now finding their niche for both academic and industrial research (Greenman, 2017). Overall, MPS platforms comprise a chip encasing a microcirculation pathway that leads to a growth chamber populated with cells.…”

Section: Mps Models and The Enhancement Of In Vitro Phenotypesmentioning

confidence: 99%

“…Standardization of MPS models would make the applications of these platforms more translatable and concerted efforts of different institutions, such as the National Institutes of Health and regulatory agencies, are considering the feasibility, applications, and prospective uses of MPS platforms in drug development (Marx et al, 2016;Ewart et al, 2017;Greenman, 2017). This could lead to guidelines governing the use of MPS models when this technology is still maturing, and drug transporter studies can positively benefit from such an approach.…”

Section: Limitations Challenges and Opportunities Of Mps Applicatiomentioning

confidence: 99%

Perspective on the Application of Microphysiological Systems to Drug Transporter Studies

Caetano-Pinto

Stahl

2018

Drug Metabolism and Disposition

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Transmembrane flux of a drug within a tissue or organ frequently involves a complex system of transporters from multiple families that have redundant and overlapping specificities. Current in vitro systems poorly represent physiology, with reduced expression and activity of drug transporter proteins; therefore, novel models that recapitulate the complexity and interplay among various transporters are needed. The development of microphysiological systems that bring simulated physiologic conditions to in vitro cell culture models has enormous potential to better reproduce the morphology and transport activity across several organ models, especially in tissues such as the liver, kidney, intestine, or the blood-brain barrier, in which drug transporters play a key role. The prospect of improving the in vitro function of organ models highly prolific in drug transporters holds the promise of implementing novel tools to study these mechanisms with far more representative biology than before. In this short review, we exemplify recent developments in the characterization of perfused microphysiological systems involving the activity of drug transporters. Furthermore, we analyze the challenges and opportunities for the implementation of such systems in the study of transporter-mediated drug disposition and the generation of clinically relevant physiology-based in silico models incorporating relevant drug transport activity.

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Looking to the Future of Organs-on-Chip

Cited by 6 publications

References 14 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

Using PDX for Preclinical Cancer Drug Discovery: The Evolving Field

Perspective on the Application of Microphysiological Systems to Drug Transporter Studies

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