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Cited by 2463D Printing in Biomedical ResearchMicrofluidic and Capillary Electrophoresis ApplicationsCancer Cells and Metastasis

Tumor-on-a-chip: from bioinspired design to biomedical application

Open access
Liu, Xingxing, Fang, Jiaru, Huang, Shuang, Wu, Xiaoxue, Xie, Xi, Wang, Ji, Liu, Fanmao, Zhang, Meng +2 more·2021·Microsystems & Nanoengineering
DOI 10.1038/s41378-021-00277-8PMC PMC8433302
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Abstract

Cancer is one of the leading causes of human death, despite enormous efforts to explore cancer biology and develop anticancer therapies. The main challenges in cancer research are establishing an efficient tumor microenvironment in vitro and exploring efficient means for screening anticancer drugs to reveal the nature of cancer and develop treatments. The tumor microenvironment possesses human-specific biophysical and biochemical factors that are difficult to recapitulate in conventional in vitro planar cell models and in vivo animal models. Therefore, model limitations have hindered the translation of basic research findings to clinical applications. In this review, we introduce the recent progress in tumor-on-a-chip devices for cancer biology research, medicine assessment, and biomedical applications in detail. The emerging tumor-on-a-chip platforms integrating 3D cell culture, microfluidic technology, and tissue engineering have successfully mimicked the pivotal structural and functional characteristics of the in vivo tumor microenvironment. The recent advances in tumor-on-a-chip platforms for cancer biology studies and biomedical applications are detailed and analyzed in this review. This review should be valuable for further understanding the mechanisms of the tumor evolution process, screening anticancer drugs, and developing cancer therapies, and it addresses the challenges and potential opportunities in predicting drug screening and cancer treatment.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys tumor-on-a-chip platforms that combine microfluidics, 3D cell culture, and tissue engineering to better mimic the human tumor microenvironment for cancer biology and drug screening. It covers fabrication methods, materials, organ-specific tumor chip types, and applications, while outlining challenges for clinical and industrial translation.

Key findings

  • Conventional preclinical models have predictive limits: over 80% of anticancer drug candidates fail clinical screening due to weak efficacy or adverse events, and concordance between animal models and clinical trials averages barely 8%.
  • Tumor-on-a-chip systems can recreate key TME features such as 3D architecture, biochemical gradients, dynamic flow, cell–cell and cell–matrix interactions, and vascular structures; examples include lung, liver, brain, colorectal, breast, and pancreatic tumor chips.
  • Applications include modeling organ-level physiology, tumor morphology and drug response, cancer invasion/metastasis, and drug screening; multiorgan chips have been used to assess efficacy and off-target toxicity of anticancer therapeutics.
  • The review reports cancer burden figures: an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths in 2018; by 2040, worldwide cancer cases are projected to increase by 60%, with ~81% in developing countries. It also notes metastasis is responsible for more than 90% of cancer-related deaths and breast cancer bone metastases occur at ~70% frequency.

Methods

  • Narrative review of tumor-on-a-chip platforms, covering microfabrication techniques (photolithography, soft lithography, replica molding, microcontact printing, bioprinting), materials (PDMS, PMMA, gelatin/GelMA, bacterial cellulose paper, BME/Matrigel), and advanced models including organoids, spheroids, vascularized systems, and multiorgan chips.
  • The paper synthesizes prior studies across tumor types—lung, liver, brain, colorectal, breast, and pancreatic—and applications in cancer biology, drug screening, and metastasis modeling.
  • No primary experimental data, systematic search strategy, or meta-analysis is reported; the work is a review.

Limitations

  • The authors state that tumor chips still struggle to simulate complex signal regulation, especially endocrine and immune signals from nonadjacent organs.
  • The authors state challenges in industrial manufacture and data standardization, including the need for user-friendly systems and standardized data across laboratories.
  • The authors state that new biocompatible materials are needed because PDMS can adsorb hydrophobic compounds such as drugs and proteins, potentially reducing effective drug concentrations and causing experimental errors. As evident from the text, this is a review without original experimental validation or systematic review methodology.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41378-021-00277-8

Cites

228 of 228 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 193 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Conventional 2D cell monolayers and 3D cell culture models are unable to recapitulate the complex biochemical and biophysical factors of the tumor microenvironment in vivo because they lack the systemic nature of tumors, leading to weak predictive ability.

    “2D cell monolayers and three-dimensional cell culture models have been widely employed as initial screening models to provide a cost-efficient and simplified method to elucidate the mechanism of cancer biology or identify the efficacy and safety of a drug candidate14–16; however, they are unable to recapitulate complex biochemical and biophysical factors of the tumor microenvironment (TME) in vivo”
    Quote in the paperSubstantial claim0 of 8 sources checked
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  • Premisecitation

    Results of animal experiments cannot directly verify the toxicity and side effects of drugs in humans due to species differences.

    “One major reason for these issues is that the results of animal experiments cannot directly verify the toxicity and side effects of drugs in humans due to species differences12,13.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Sertkaya, A., Wong, H.-H., Jessup, A. & Beleche, T. Key cost drivers of pharmaceutical clinical trials in the United States. Clin. Trials 13, 117–126 (2016). source

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  • Premisecitation

    Microfluidic systems can link different organs-on-a-chip to potentially simulate the complexity of multiorgan drug metabolism and pharmacokinetics.

    “Furthermore, microfluidic systems can link different organs-on-a-chip to potentially simulate the complexity of multiorgan drug metabolism and pharmacokinetics9,47,50,68–71.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [9] Satoh, T. et al. A multi-throughput multi-organ-on-a-chip system on a plate formatted pneumatic pressure-driven medium circulation platform. Lab a Chip 18, 115–125 (2018). source

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    • cites [47] Zhang, Y. S., Zhang, Y.-N. & Zhang, W. Cancer-on-a-chip systems at the frontier of nanomedicine. Drug Discov. Today 22, 1392–1399 (2017). source

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    • cites [50] Ronaldson-Bouchard, K. & Vunjak-Novakovic, G. Organs-on-a-chip: a fast track for engineered human tissues in drug development. Cell Stem Cell 22, 310–324 (2018). source

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    • cites [68] Wang, Y. I. et al. Self-contained, low-cost Body-on-a-Chip systems for drug development. Exp. Biol. Med. 242, 1701–1713 (2017). source

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    • cites [69] Tsamandouras, N. et al. Integrated gut and liver microphysiological systems for quantitative in vitro pharmacokinetic studies. AAPS J. 19, 1499–1512 (2017). source

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    • cites [70] Skardal, A. et al. Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform. Sci. Rep. 7, 8837 (2017). source

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    • cites [71] Edington, C. D. et al. Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci. Rep. 8, 4530 (2018). source

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  • Premisecitation

    In vivo animal models possess limitations: species-specific differences between animals and humans cause differences in drug efficacy and toxicity tests in physiology and cell biology.

    “Species-specific differences between animals and humans cause differences in drug efficacy and toxicity tests in physiology and cell biology31–37.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [31] Engelman, R. & Kerr, W. G. Autoimmunity 433–441 (Springer, 2012). source

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    • cites [32] Kang, T. H. & Kim, H. J. Farewell to animal testing: innovations on human intestinal microphysiological systems. Micromachines 7, 107 (2016). source

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    • cites [33] Hintze, K. J. et al. Broad scope method for creating humanized animal models for animal health and disease research through antibiotic treatment and human fecal transfer. Gut Microbes 5, 183–191 (2014). source

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    • cites [34] Rongvaux, A. et al. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 32, 364–372 (2014). source

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    • cites [35] Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013). source

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    • cites [36] Rubin, E. H. & Gilliland, D. G. Drug development and clinical trials—the path to an approved cancer drug. Nat. Rev. Clin. Oncol. 9, 215 (2012). source

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    • cites [37] Zhou, Z. et al. The use of functionalized silk fibroin films as a platform for optical diffraction‐based sensing applications. Adv. Mater. 29, 1605471 (2017). source

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  • Interpretationreasoning

    3D models are able to better reflect the real tumor setting with a more natural response to different soluble factors present in the TME.

    “3D models are able to better reflect the real tumor setting with a more natural response to different soluble factors present in the TME.”
    Quote in the paperSubstantial claim
  • May combine two claims. 56
  • Classified as probably not a substantial claim. 24

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    Premisecitation

    Animal studies are hindered by animal expenses, low-throughput drug optimization and ethical controversy.

    “In addition, animal studies are hindered by animal expenses, low‐throughput drug optimization and ethical controversy31–35,38.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [31] Engelman, R. & Kerr, W. G. Autoimmunity 433–441 (Springer, 2012). source

      Not checked in the free run.

    • cites [32] Kang, T. H. & Kim, H. J. Farewell to animal testing: innovations on human intestinal microphysiological systems. Micromachines 7, 107 (2016). source

      Not checked in the free run.

    • cites [33] Hintze, K. J. et al. Broad scope method for creating humanized animal models for animal health and disease research through antibiotic treatment and human fecal transfer. Gut Microbes 5, 183–191 (2014). source

      Not checked in the free run.

    • cites [34] Rongvaux, A. et al. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 32, 364–372 (2014). source

      Not checked in the free run.

    • cites [35] Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013). source

      Not checked in the free run.

    • cites [38] Mak, I. W., Evaniew, N. & Ghert, M. Lost in translation: animal models and clinical trials in cancer treatment. Am. J. Transl. Res. 6, 114–118 (2014).

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    Premisecitation

    Organ-on-a-chip devices possess good performance and improved recapitulation of the native microenvironment, and they allow high-throughput tests with decreased cost, ethical advantages and enhanced reproducibility.

    “Organ-on-a-chip devices possess good performance and improved recapitulation of the native microenvironment, and they allow high‐throughput tests with decreased cost, ethical advantages and enhanced reproducibility47,55–57.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [47] Zhang, Y. S., Zhang, Y.-N. & Zhang, W. Cancer-on-a-chip systems at the frontier of nanomedicine. Drug Discov. Today 22, 1392–1399 (2017). source

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    • cites [55] Chan, C. Y. et al. Accelerating drug discovery via organs-on-chips. Lab a Chip 13, 4697–4710 (2013). source

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    • cites [56] Park, S. E., Georgescu, A. & Huh, D. Organoids-on-a-chip. Science 364, 960–965 (2019). source

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    • cites [57] Zhang, B., Korolj, A., Lai, B. F. L. & Radisic, M. Advances in organ-on-a-chip engineering. Nat. Rev. Mater. 3, 257–278 (2018). source

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  • May combine two claims.

    Interpretationreasoning

    In vivo tumors expand as three-dimensional multicellular masses, where inner cells have limited drug exposure, whereas cells grown in a monolayer are all well exposed to the drug.

    “The reason is that in these experiments, cells are grown in a monolayer, all well exposed to the drug, while in vivo tumors expand as three-dimensional multicellular masses, where inner cells have limited drug exposure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tumors possess a complicated microenvironment with a dense extracellular matrix, irregular vessels, assorted stromal, immune and inflammatory cells, cancer stem cells, and limited perfusion of nutrients.

    “Tumors possess a complicated microenvironment with a dense extracellular matrix (ECM), irregular vessels, assorted stromal, immune and inflammatory cells, cancer stem cells, and limited perfusion of nutrients109–112.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [109] Kim, J. Y. et al. 3D spherical microtissues and microfluidic technology for multi-tissue experiments and analysis. J. Biotechnol. 205, 24–35 (2015). source

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    • cites [110] Portillo-Lara, R. & Annabi, N. Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment. Lab a Chip 16, 4063–4081 (2016). source

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    • cites [111] Maley, C. C. et al. Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 17, 605–619 (2017). source

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    • cites [112] Fetah, K. L. et al. Cancer modeling-on-a-chip with future artificial intelligence integration. Small 15, 1901985 (2019). source

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    Premisecitation

    Organ chip microdevices are able to recapitulate organ-level responses to toxins, drugs, radiation, cigarette smoke, pathogens, and normal microorganisms, as well as the dependence on flow-circulating immune cells and organs to recruit specific in vitro inflammatory responses.

    “Crucially, these organ chip microdevices are able to recapitulate organ-level responses to toxins79,96,97, drugs86,98, radiation99, cigarette smoke100, pathogens96, and normal microorganisms96, as well as the dependence on flow-circulating immune cells and organs to recruit specific in vitro inflammatory responses101, which are very important for preclinical drug screening and disease modeling.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [79] Bovard, D. et al. A lung/liver-on-a-chip platform for acute and chronic toxicity studies. Lab a Chip 18, 3814–3829 (2018). source

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    • cites [96] Kim, H. J., Li, H., Collins, J. J. & Ingber, D. E. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc. Natl Acad. Sci. USA 113, E7–E15 (2016).

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    • cites [97] Ozkan, A., Ghousifam, N., Hoopes, P. J., Yankeelov, T. E. & Rylander, M. N. In vitro vascularized liver and tumor tissue microenvironments on a chip for dynamic determination of nanoparticle transport and toxicity. Biotechnol. Bioeng. 116, 1201–1219 (2019). source

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    • cites [98] Hassell, B. A. et al. Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Rep. 21, 508–516 (2017). source

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    • cites [99] Jalili-Firoozinezhad, S. et al. Modeling radiation injury-induced cell death and countermeasure drug responses in a human gut-on-a-chip. Cell Death Dis. 9, 223 (2018). source

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    • cites [100] Benam, K. H. et al. Matched-comparative modeling of normal and diseased human airway responses using a microengineered breathing lung chip. Cell Syst. 3, 456–466.e454 (2016). source

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    • cites [101] Huh, D. et al. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci. Transl. Med. 4, 159ra147 (2012). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many types of healthy and diseased tissues and organs have been constructed on microfluidic chips.

    “Currently, many types of healthy and diseased tissues and organs, including microvascular obstructions, cystic fibrosis models, heart72,73, kidney74–76, liver77–79, lung79,80, pancreas, brain81–86, skin87–89, eye90,91, intestine92, and neuropsychiatric disorder models93–95, have been constructed on microfluidic chips.”
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    • cites 72–95

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    Premisecitation

    Human lung adenocarcinoma cells cultured in the PMMA microfluidic device give more reliable results regarding the cytotoxicity of vincristine than human lung adenocarcinoma cells cultured in the PDMS device, because small molecules cannot permeate the PMMA material.

    “The results of drug testing demonstrated that human lung adenocarcinoma cells cultured in the PMMA microfluidic device give more reliable results regarding the cytotoxicity of vincristine than human lung adenocarcinoma cells cultured in the polydimethylsiloxane (PDMS) device. This is because the small molecules cannot permeate the PMMA material.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Nguyen, T. et al. Robust chemical bonding of PMMA microfluidic devices to porous PETE membranes for reliable cytotoxicity testing of drugs. Lab Chip 19, 3706–3713 (2019). source

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  • May combine two claims.

    Premisecitation

    Organoids derived from stem cells can be integrated into tumor chips, and because of the combination of the two technologies, organ-specific structures and gene expression signatures in vivo could be mimicked better than in either model alone.

    “Organoids derived from these stem cells can be integrated into tumor chips, and because of the combination of the two technologies, organ-specific structures and gene expression signatures in vivo could be mimicked better than in either model alone172.”
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    • cites [172] Kasendra, M. et al. Development of a primary human small intestine-on-a-chip using biopsy-derived organoids. Sci. Rep. 8, 2871 (2018). source

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  • May combine two claims.

    Premisecitation

    BME/Matrigel can enable 3D tumor culture and coculture of other cells, and researchers can adjust the microenvironment to be suitable for tumors by supplementing various factors on BME/Matrigel, which can better inform the mechanism of tumor growth.

    “BME/Matrigel can also enable 3D tumor culture and coculture of other cells, and researchers can adjust the microenvironment to be suitable for tumors by supplementing various factors on BME/Matrigel, which can better inform the mechanism of tumor growth169.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Benton, G., Arnaoutova, I., George, J., Kleinman, H. K. & Koblinski, J. Matrigel: From discovery and ECM mimicry to assays and models for cancer research. Adv. Drug Deliv. Rev. 79-80, 3–18 (2014). source

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    • Rests on an assumption: BME/Matrigel is a biomaterial with a composition similar to that of the early conservative basement membrane, which promotes the organization of different tissue types and microtissues of different species.
    • Rests on an assumption: Under similar conditions, tumor cells have high proliferation and are sometimes aggressive in BME/Matrigel, which can be used to evaluate the malignancy of tumors and explore tumor treatment methods.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Bioprinting technology has the potential to build miniaturized, multiorgan bionic pathophysiological models, accelerate the pace of research, and promote the application of technology in the medical field.

    “Hence, bioprinting technology has the potential to build miniaturized, multiorgan bionic pathophysiological models, accelerate the pace of research, and promote the application of technology in the medical field.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Tumor chips can simulate the 3D microstructure and microphysiological functions of in vivo human organs/tissues, providing a better understanding of the mechanisms of tumor growth and metastasis.

    “These tumor chips can simulate the 3D microstructure and microphysiological functions of in vivo human organs/tissues, providing a better understanding of the mechanisms of tumor growth and metastasis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Soft lithography fabrication technology has the ability to change the chemistry of the substrate surface, making it a promising low-cost method for manufacturing microfluidic chips.

    “It is worth mentioning that soft lithography fabrication technology has the ability to change the chemistry of the substrate surface, making it a promising low-cost method for manufacturing microfluidic chips.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Tumor models in vitro are usually under atmospheric oxygen conditions, which are not representative of the conditions in vivo, and therefore the results of these studies can be misleading.

    “In contrast to the tumor growth microenvironment in vivo, tumor models in vitro are usually under atmospheric oxygen conditions, which are not representative of the conditions in vivo. Therefore, the results of these studies can be misleading.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Oxygen tension is a key regulator of cellular behavior.

  • May combine two claims.

    Premisecitation

    Although many tumor chips have been successfully manufactured by photolithography or related processes, they still have shortcomings, such as the need for multiple masks and a multistep photolithography process, which makes the fabrication process time-consuming and costly.

    “Although many tumor chips have been successfully manufactured by photolithography or related manufacturing processes involving photolithography, they still have some shortcomings, such as the need for multiple masks and a multistep photolithography process, which makes the fabrication process time-consuming and costly.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Yang, Q., Lian, Q. & Xu, F. Perspective: fabrication of integrated organ-on-a-chip via bioprinting. Biomicrofluidics 11, 031301 (2017). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Gelatin is a collagen-derived natural biopolymer that is widely used in drug transport models and tissue engineering due to its cellular response characteristics and ability to deliver a wide range of biomolecules.

    “Gelatin is a collagen-derived natural biopolymer. Due to its cellular response characteristics and the ability to deliver a wide range of biomolecules, it is widely used in drug transport models and tissue engineering165.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Hoch, E., Hirth, T., Tovar, G. E. M. & Borchers, K. Chemical tailoring of gelatin to adjust its chemical and physical properties for functional bioprinting. J. Mater. Chem. B 1, 5675–5685 (2013). source

      Not checked in the free run.

    • Rests on an assumption: Gelatin can promote cell growth and polymerize with proteins, growth factor nucleotides, polysaccharides and other polyionic complexes, and has broad prospects for drug transport models due to controlled sustained and/or targeted release of bioactive molecules.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Multiorgan-on-a-chip systems that include the interactions of cell cocultures have shown great potential in screening anticancer drugs and cancer therapies.

    “Multiorgan-on-a-chip systems that include the interactions of cell cocultures have shown great potential in screening anticancer drugs and cancer therapies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Chips based on microfluidics can be designed to realize oxygen gradients with high spatial and temporal resolution, which can be used to simulate the physiological effects of oxygen on tumor progression and metastasis.

    “Chips based on microfluidics can be designed to realize oxygen gradients with high spatial and temporal resolution, which can be used to simulate the physiological effects of oxygen on tumor progression and metastasis127,128.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] Chen, Y.-A. et al. Generation of oxygen gradients in microfluidic devices for cell culture using spatially confined chemical reactions. Lab a Chip 11, 3626–3633 (2011). source

      Not checked in the free run.

    • cites [128] Brennan, M. D., Rexius-Hall, M. L., Elgass, L. J. & Eddington, D. T. Oxygen control with microfluidics. Lab a Chip 14, 4305–4318 (2014). source

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    Premisecitation

    A bioprinted blood vessel network can imitate these abnormalities, which could be further used to test and compare the behavior of healthy and abnormal blood vessels under different conditions and treatments.

    “A bioprinted blood vessel network can imitate these abnormalities, which could be further used to test and compare the behavior of healthy and abnormal blood vessels under different conditions and treatments162.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Knowlton, S. et al. Advancing cancer research using bioprinting for tumor-on-a-chip platforms. Int. J. Bioprint. 2, 3–8 (2016). source

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    • Rests on an assumption: Vascularization is very important to maintain tissue activities and can be used to separate different tissue compartments.

  • May combine two claims.

    Premisecitation

    Researchers have used bacterial cellulose paper equipment to make various microchannels and have successfully established 3D paper vascularized breast tumor models.

    “Researchers have used this paper equipment to make various microchannels and have successfully established 3D paper vascularized breast tumor models, resulting in the implementation of new materials for simple, low-cost models167,168.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Cheng, F. et al. Generation of cost-effective paper-based tissue models through matrix-assisted sacrificial 3D printing. Nano Lett. 19, 3603–3611 (2019). source

      Not checked in the free run.

    • cites [168] Gao, Q., He, Y., Fu, J. Z., Liu, A. & Ma, L. Coaxial nozzle-assisted 3D bioprinting with built-in microchannels for nutrients delivery. Biomaterials 61, 203–215 (2015). source

      Not checked in the free run.

    • Rests on an assumption: Bacterial cellulose has good biocompatibility and cost effects, and bacterial cellulose nanofibers can be processed and dried to form a stable paper device for building models.

  • May combine two claims.

    Premisecitation

    Tumor-on-a-chip can be used to simulate tumor growth and expansion, angiogenesis, and progression from early to advanced lesions involving epithelial-mesenchymal transition, tumor cell invasion and metastasis.

    “Tumor-on-a-chip can be used to simulate tumor growth and expansion, angiogenesis, and progression from early to advanced lesions involving epithelial–mesenchymal transition (EMT), tumor cell invasion and metastasis129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Sontheimer-Phelps, A., Hassell, B. A. & Ingber, D. E. Modelling cancer in microfluidic human organs-on-chips. Nat. Rev. Cancer 19, 65–81 (2019). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Photocrosslinked gelatin methacrylate (GelMA) hydrogels have been used in corneal tissue engineering, peripheral nerve regeneration and cartilage structure preparation.

    “In addition, photocrosslinked gelatin methacrylate (GelMA) hydrogels have been used in corneal tissue engineering, peripheral nerve regeneration and cartilage structure preparation166.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Echave, M. C. et al. Recent advances in gelatin-based therapeutics. Expert Opin. Biol. Ther. 19, 773–779 (2019). source

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  • May combine two claims.

    Premisecitation

    A 3D coculture model of tumor spheroids has been developed to study different in vitro cancer types, such as lung and salivary gland cancers, as well as invasion and extravasation, as cell migration leads to infiltration and extravasation events during metastasis.

    “A 3D coculture model of tumor spheroids has been developed to study different in vitro cancer types, such as lung and salivary gland cancers, as well as invasion and extravasation, as cell migration leads to infiltration and extravasation events during metastasis (Fig. 4)67,174.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] Rothbauer, M., Zirath, H. & Ertl, P. Recent advances in microfluidic technologies for cell-to-cell interaction studies. Lab Chip 18, 249–270 (2018). source

      Not checked in the free run.

    • cites [174] Swaminathan, S., Hamid, Q., Sun, W. & Clyne, A. M. Bioprinting of 3D breast epithelial spheroids for human cancer models. Biofabrication 11, 025003 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Tumor-on-a-chip platforms have the ability to recreate many cardinal TME features and show great promise as a novel technology for studying the mechanisms of tumor evolution, screening anticancer drugs and cancer therapies, and enabling precision medicine.

    “Ideally, tumor-on-a-chip platforms have the ability to recreate many cardinal TME features and show great promise as a novel technology for studying the mechanisms of tumor evolution, screening anticancer drugs and cancer therapies, and enabling precision medicine14,112,117–122.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [14] Tsai, H.-F., Trubelja, A., Shen, A. Q. & Bao, G. Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment. J. R. Soc. Interface 14, 20170137 (2017). source

      Not checked in the free run.

    • cites [112] Fetah, K. L. et al. Cancer modeling-on-a-chip with future artificial intelligence integration. Small 15, 1901985 (2019). source

      Not checked in the free run.

    • cites [117] Aleman, J. & Skardal, A. A multi-site metastasis-on-a-chip microphysiological system for assessing metastatic preference of cancer cells. Biotechnol. Bioeng. 116, 936–944, https://doi.org/10.1002/bit.26871 (2019). source

      Not checked in the free run.

    • cites [118] Han, B., Qu, C., Park, K., Konieczny, S. F. & Korc, M. Recapitulation of complex transport and action of drugs at the tumor microenvironment using tumor-microenvironment-on-chip. Cancer Lett. 380, 319–329 (2016). source

      Not checked in the free run.

    • cites [119] Kumar, V. & Varghese, S. Ex vivo tumor-on-a-chip platforms to study intercellular interactions within the tumor microenvironment. Adv. Healthc. Mater. 8, e1801198 (2019). source

      Not checked in the free run.

    • cites [120] Kennedy, R. et al. A patient tumour-on-a-chip system for personalised investigation of radiotherapy based treatment regimens. Sci. Rep. 9, 6327 (2019). source

      Not checked in the free run.

    • cites [121] Astolfi, M. et al. Micro-dissected tumor tissues on chip: an ex vivo method for drug testing and personalized therapy. Lab a Chip 16, 312–325 (2016). source

      Not checked in the free run.

    • cites [122] Shirure, V. S. et al. Tumor-on-a-chip platform to investigate progression and drug sensitivity in cell lines and patient-derived organoids. Lab a Chip 18, 3687–3702 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The microvascular system provides nutrition and removes waste products from the body.

    “The microvascular system plays an important role in the circulatory system, in which blood flows: the microvascular system provides nutrition and removes waste products from the body179.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Wang, X., Sun, Q. & Pei, J. Microfluidic-based 3D engineered microvascular networks and their applications in vascularized microtumor models. Micromachines 9, https://doi.org/10.3390/mi9100493 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    A variety of human-derived in vitro tumor-on-a-chip models have been developed for studying tumor progression characteristics such as growth, angiogenesis, metastasis, and drug response.

    “A variety of human-derived in vitro tumor-on-a-chip models have been developed for studying various characteristics associated with tumor progression, such as growth, angiogenesis, metastasis, and drug response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Tumor cell growth fills the alveolar space and reduces lung breathing movement.

    “As a result, researchers believe that tumor cell growth fills the alveolar space and reduces lung breathing movement, which results in positive feedback and promotes tumor cell growth and invasion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Hassell, B. A. et al. Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Rep. 21, 508–516 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Using μCCA systems as a coculture model with liver cells can be the best candidate to research drug resistance and metastasis of cancers.

    “Briefly, using μCCA systems as a coculture model with liver cells can be the best candidate to research drug resistance and metastasis of cancers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The transwell-based cell coculture model allows cells to be cultured in a small amount of liquid and is currently used for glioma research.

    “It allows cells to be cultured in a small amount of liquid and is currently used for glioma research195.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Saliba, J. et al. Development of microplatforms to mimic the in vivo architecture of CNS and PNS physiology and their diseases. Genes 9, https://doi.org/10.3390/genes9060285 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The tumor-on-a-chip system is usually composed of cells from a single organ, and its recombination ability is limited.

    “Since the tumor-on-a-chip system is usually composed of cells from a single organ, its recombination ability is limited.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The liver/lung-on-a-chip platform can evaluate the compound toxicity of drugs and provide new ideas for future drug development.

    “The liver/lung-on-a-chip platform can evaluate the compound toxicity of drugs and provide new ideas for future drug development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The microvascular system on a chip model can be used to describe the dynamics and heterogeneity of tumor cells in vivo and represents a new way to study specific tumors.

    “This model can be used to describe the dynamics and heterogeneity of tumor cells in vivo and represents a new way to study specific tumors (Fig. 6b)196.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Xiao, Y. et al. Ex vivo dynamics of human glioblastoma cells in a microvasculature‐on‐a‐chip system correlates with tumor heterogeneity and subtypes. Adv. Sci. 6, 1801531 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cell culture format (two-dimensional monolayer versus three-dimensional spheroid) and spheroid size play key roles in drug responses and show the advantages of connecting these two technologies in drug screening applications.

    “In addition, the cell culture format (two-dimensional monolayer versus three-dimensional spheroid) and spheroid size play key roles in drug responses and show the advantages of connecting these two technologies in drug screening applications.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Patra, B., Peng, C.-C., Liao, W.-H., Lee, C.-H. & Tung, Y.-C. Drug testing and flow cytometry analysis on a large number of uniform sized tumor spheroids using a microfluidic device. Sci. Rep. 6, 21061 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The blood vascular system can mimic the human colorectal-tumor microenvironment, reconstructing the physiological function of microvascular tissue.

    “The blood vascular system can mimic the human colorectal-tumor microenvironment, which reconstructs the physiological function of microvascular tissue209.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [209] Carvalho, M. R., Reis, R. L. & Oliveira, J. M. Dendrimer nanoparticles for colorectal cancer applications. J. Mater. Chem. B 8, 1128–1138 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytotoxicity assays can predict the direct toxicity of a drug or the indirect toxicity to the liver or other organs caused by the liver metabolites of the drug.

    “They can predict the direct toxicity of the drug itself or the indirect toxicity to the liver or other organs caused by the liver metabolites of the drug.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Kashaninejad, N. et al. Organ-tumor-on-a-chip for chemosensitivity assay: a critical review. Micromachines 7, 130 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CRC cells and HCoMECs respond to the incoming VEGF growth factor.

    “CRC cells, labeled in red, and HCoMECs, in yellow, respond to the incoming VEGF growth factor.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [210] Carvalho, M. R. et al. Colorectal tumor-on-a-chip system: a 3D tool for precision onco-nanomedicine. Sci. Adv. 5, eaaw1317 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A microfluidic platform recapitulated orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro.

    “Through the platform, researchers recapitulated orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro (Fig. 5b)98.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Hassell, B. A. et al. Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Rep. 21, 508–516 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The trend of the target gene can be used to analyze the gene expression level.

    “In addition, the trend of the target gene can be used to analyze the gene expression level.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Endothelial cells lining the microvasculature play a key gatekeeper role in avoiding colorectal cancer.

    “Endothelial cells lining in the microvasculature play a key gatekeeper role in avoiding colorectal cancer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Employing this device, researchers proved the relevance of tumor invasion and cell migration assays in breast cancer biology, showing good consistency in tumor invasion studies in in vivo xenograft models.

    “Employing this device, the researchers proved the relevance of tumor invasion and cell migration assays in breast cancer biology, showing good consistency in tumor invasion studies in in vivo xenograft models.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Sung, K. E. et al. Transition to invasion in breast cancer: a microfluidic in vitro model enables examination of spatial and temporal effects. Integr. Biol. 3, 439–450 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The glioma-related microfluidic device research will be helpful in developing glioma-related anticancer drugs and glial cell-based biosensors for glioma detection.

    “This research will be helpful in developing glioma-related anticancer drugs and for developing glial cell-based biosensors for glioma detection198.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Liu, W. et al. Assay of glioma cell responses to an anticancer drug in a cell-based microfluidic device. Microfluid. Nanofluid. 9, 717–725 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The liver tumor chip could provide a platform for liver cancer treatment.

    “The liver tumor chip could provide a platform for liver cancer treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There is a large difference in morphology between 2D and 3D cultures of breast tumor cells: in 2D culture, nonmalignant cells are morphologically similar to malignant cells; in 3D culture, nonmalignant breast tissue cells are polar and arranged in a tube, and malignant cells form spherical tissue.

    “There is a large difference in morphology between 2D and 3D cultures of breast tumor cells. In 2D culture, nonmalignant cells are morphologically similar to malignant cells. However, in 3D culture, nonmalignant breast tissue cells of are polar and arranged in a tube, and the malignant cells form spherical tissue.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [211] Lanz, H. L. et al. Therapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform. BMC Cancer 17, 709 (2017). source

      Not checked in the free run.

    • cites [212] Boyle, P. Triple-negative breast cancer: epidemiological considerations and recommendations. Ann. Oncol. 23, vi7–vi12 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 3 μm PLGA nanofiber membrane has good controlled porosity, molecular permeability and biocompatibility and can be used to simulate the alveolar respiratory membrane.

    “The 3 μm PLGA nanofiber membrane has good controlled porosity, molecular permeability and biocompatibility and can be used to simulate the alveolar respiratory membrane.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Yang, X. et al. Nanofiber membrane supported lung-on-a-chip microdevice for anti-cancer drug testing. Lab a Chip 18, 486–495 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Improved tumor modeling has great potential for studying the basic mechanisms of organ physiology and disease.

    “Improved tumor modeling has great potential for studying the basic mechanisms of organ physiology and disease.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The lung cancer model has a potential role in personalized treatment of lung tumors, other clinical treatments and tissue engineering.

    “It has a potential role in the personalized treatment of lung tumors, other clinical treatments and tissue engineering.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nguyen et al. used GLYMO to bond PMMA-PETE orbital etching film, which can be used in microfluidic devices that are not permeable to small molecules and can enable reliable cytotoxicity tests.

    “Nguyen et al. used (3-glycidyloxypropyl) trimethoxysilane to bond polymethyl methacrylate (PMMA) polyethylene terephthalate (PETE) orbital etching film (GLYMO), which can be used in microfluidic devices that are not permeable to small molecules and can enable reliable cytotoxicity tests, such as those for anticancer drugs (Fig. 8c)164.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Nguyen, T. et al. Robust chemical bonding of PMMA microfluidic devices to porous PETE membranes for reliable cytotoxicity testing of drugs. Lab Chip 19, 3706–3713 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This 2-organoid MOC model was one of the first in vitro models to simulate tumor cell metastasis, reproducing metastasis from a three-dimensional primary tissue to a three-dimensional target tissue.

    “This model was one of the first in vitro models to simulate tumor cell metastasis, reproducing metastasis from a three-dimensional primary tissue to a three-dimensional target tissue.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] Skardal, A., Devarasetty, M., Forsythe, S., Atala, A. & Soker, S. A reductionist metastasis‐on‐a‐chip platform for in vitro tumor progression modeling and drug screening. Biotechnol. Bioeng. 113, 2020–2032 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Compared with conventional in vitro planar cell models and in vivo animal models, tumor-on-a-chip systems can mimic the complexity of in vivo tumor masses, which are considered reliable for development of effective anticancer therapies.

    “Compared with conventional in vitro planar cell models and in vivo animal models, tumor-on-a-chip systems can mimic the complexity of in vivo tumor masses, which are considered to be reliable for the development of effective anticancer therapies.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Tumor-on-a-chip systems recapitulate in vivo tumors to improve anticancer drug screening strategies.

  • May combine two claims.

    Premisecitation

    Anti-imatinib does not affect liver vitality, and diclofenac reduces liver vitality by 30%.

    “Anti-imatinib does not affect liver vitality, and diclofenac reduces liver vitality by 30%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] McAleer, C. W. et al. Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. Sci. Transl. Med. 11, https://doi.org/10.1126/scitranslmed.aav1386 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The multiorgan chip system can be used for drug screening and for predicting preclinical target efficacy, metabolic conversion rate, and target off-target toxicity.

    “The multiorgan chip system can be used not only for drug screening but also for predicting preclinical target efficacy, metabolic conversion rate, and target off-target toxicity228.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Abaci, H. E. & Shuler, M. L. Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr. Biol. 7, 383–391 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The bonding strength between the two substrates is sufficient for culture exchange, and even at gauge pressure higher than 135 kPa, fluid can pass through the device without leakage.

    “The bonding strength between the two substrates is sufficient for culture exchange, and even at a gauge pressure higher than 135 kPa, the fluid can still pass through the device without leakage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Nguyen, T. et al. Robust chemical bonding of PMMA microfluidic devices to porous PETE membranes for reliable cytotoxicity testing of drugs. Lab Chip 19, 3706–3713 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This Toh platform integrates a 3D microenvironment that plays a key role in invasiveness of cancer cells, creating a model for antimigration and anti-invasive cancer drug testing that can be multiplexed for high-throughput analysis.

    “This platform integrates a 3D microenvironment that plays a key role in the invasiveness of cancer cells, creating an attractive model for antimigration and anti-invasive cancer drug testing that can be multiplexed for high-throughput analysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] Toh, Y.-C., Raja, A., Yu, H. & Van Noort, D. A 3D microfluidic model to recapitulate cancer cell migration and invasion. Bioengineering 5, 29 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    A large number of tumor-on-a-chip platforms have been designed and established, simulating tumors in the lung, liver, breast, and brain.

    “A large number of tumor-on-a-chip platforms have been designed and established, simulating tumors in the lung, liver, breast, and brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A bionic microsystem reconstructed the alveolar-capillary interface of the key function of the human lung and can produce a complex, integrated organ-level response to bacteria and inflammatory cytokines entering the alveolar space.

    “Earlier, Huh et al.131 used a bionic microsystem to reconstruct the alveolar–capillary interface of the key function of the human lung. This model can produce a complex, integrated organ-level response to bacteria and inflammatory cytokines entering the alveolar space.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Tumor-on-a-chip platforms are mainly applied to screen anticancer drugs and perform fundamental research on cancer metastasis to understand the biological basis of cancer.

    “They are mainly applied to screen anticancer drugs and perform fundamental research on cancer metastasis to understand the biological basis of cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Phan et al. created arrayed vascularized microtumors and used them for blind-hole screening.

    “Phan et al. created arrayed vascularized microtumors (VMTs) and used them for blind-hole screening (Fig. 8b)86.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Phan, D. T. et al. A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. Lab a Chip 17, 511–520 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tamoxifen reduces the activity of breast cancer cells only after producing metabolites but does not affect vulvar cancer cells.

    “Tamoxifen reduces the activity of breast cancer cells only after producing metabolites but does not affect vulvar cancer cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] McAleer, C. W. et al. Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. Sci. Transl. Med. 11, https://doi.org/10.1126/scitranslmed.aav1386 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Tumor-on-a-chip platforms can mimic the main in vivo TME features, exhibiting great promise as more realistic and accurate models for studying metastasis, distribution and mechanisms of tumor growth, as well as drug toxicity and therapeutic efficacy.

    “Tumor-on-a-chip platforms can mimic the main in vivo TME features, exhibiting great promise as more realistic and accurate models for studying the metastasis, distribution and mechanisms of tumor growth, as well as drug toxicity and therapeutic efficacy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tumor-on-a-chip systems recapitulate in vivo tumors to improve anticancer drug screening strategies.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    The key step in replicating functions at the organ level is to combine two or more different tissue types.

    “The key step in replicating the functions at the organ level is to combine two or more different tissue types.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: An organ is a hierarchical structure composed of two or more different tissues.

  • May combine two claims.

    Premisecitation

    Combined use of tamoxifen and verapamil produces nontargeted cardiac effects, manifested in reduced contractility, decreased beating frequency, and slower conduction speed but does not affect viability.

    “The combined use of tamoxifen and verapamil will produce nontargeted cardiac effects, which are manifested in reduced contractility, decreased beating frequency, and slower conduction speed but do not affect viability.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] McAleer, C. W. et al. Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. Sci. Transl. Med. 11, https://doi.org/10.1126/scitranslmed.aav1386 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Phan VMT platform can analyze small compound libraries, including FDA-approved compounds, and successfully identify antitumor drugs.

    “They can analyze small compound libraries, including FDA-approved compounds, and successfully identify antitumor drugs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Phan, D. T. et al. A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. Lab a Chip 17, 511–520 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These models show that cell-based in vitro culture systems can be used to evaluate target efficacy and target toxicity of parent drug and its metabolites and can improve efficiency of drug evaluation in preclinical studies.

    “These models show that cell-based in vitro culture systems can be used to evaluate the target efficacy and target toxicity of the parent drug and its metabolites and can improve the efficiency of drug evaluation in preclinical studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Compared with tumor cells cultured in traditional planar monoculture, tumor cells grown in channels have different morphologies and display different sensitivities to anticancer drugs.

    “Compared with tumor cells cultured in the traditional planar monoculture method, tumor cells grown in channels have different morphologies and display different sensitivities to anticancer drugs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [218] Vidi, P.-A. et al. Disease-on-a-chip: mimicry of tumor growth in mammary ducts. Lab a Chip 14, 172–177 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A pancreatic cancer model with a blood capillary structure is able to replicate cellular morphologies and reflect the death of endothelial cells during the metastasis process.

    “Nishiguchi et al. investigated a pancreatic cancer model with a blood capillary structure that is able to replicate cellular morphologies and reflect the death of endothelial cells during the metastasis process216.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] Nishiguchi, A. et al. In vitro 3D blood/lymph-vascularized human stromal tissues for preclinical assays of cancer metastasis. Biomaterials 179, 144–155 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Although tumor-on-a-chip platforms can mimic the in vivo TME and even establish a body-on-a-chip system through connections with organ-on-a-chip devices, it is difficult to simulate the various complex signal regulation responses of other nonadjacent organs in the human body to cancer, especially signals from the endocrine system or the immune system.

    “Although tumor-on-a-chip platforms can mimic the in vivo TME and even establish a body-on-a-chip system through connections with organ-on-a-chip devices, it is difficult to simulate the various complex signal regulation responses of other nonadjacent organs in the human body to cancer, especially signals from the endocrine system or the immune system.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationnone given

    Although tumor-on-a-chip platforms still face many challenges, they are promising platforms to facilitate the development of cancer therapies.

    “In conclusion, although tumor-on-a-chip platforms still face many challenges, they are promising platforms to facilitate the development of cancer therapies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    A variety of candidate materials have been developed, but these devices need to be optically transparent, easily moldable, mechanically adjustable, nonreactive and economical, limiting the available candidates.

    “A variety of candidate materials have been developed, but these devices need to be optically transparent, easily moldable, mechanically adjustable, nonreactive and economical, limiting the available candidates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    As an alternative to conventional preclinical models, tumor-on-a-chip platforms have the potential to improve many fields of basic research and drug development.

    “As an alternative to conventional preclinical models, tumor-on-a-chip platforms have the potential to improve many fields of basic research and drug development.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Tumor-on-a-chip systems are based on esoteric microfabrication technologies, and there is a great need to explore how to rationally design microfluidic devices for precise control of the physicochemical properties of the chips.

    “Tumor-on-a-chip systems are based on esoteric microfabrication technologies, and there is a great need to explore how to rationally design microfluidic devices for precise control of the physicochemical properties of the chips.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Not all researchers or users are proficient in microfabrication facilities and related expertise; therefore, it is important to develop user-friendly on-chip systems and standardize data from different laboratories.

    “Moreover, not all researchers or users are proficient in microfabrication facilities and the related expertise; therefore, it is important to develop user-friendly on-chip systems and simultaneously standardize the data from different laboratories so that researchers who are not experts can immediately use these emerging models for research and obtain meaningful data for clinical translation.”
    Quote in the paperNot a substantial claim
70 of 70

  • The paper relies on this without support.

    Oxygen tension is a key regulator of cellular behavior.

    “To create biomimetic 3D tumor models that better encapsulate pathologic processes, several important factors in the tumor microenvironment must be considered, including oxygen tension, which is a key regulator of cellular behavior.”

  • The paper relies on this without support.

    Vascularization is very important to maintain tissue activities and can be used to separate different tissue compartments.

    “Vascularization is very important to maintain tissue activities and can be used to separate different tissue compartments.”

  • The paper relies on this without support.

    The most widely used material for fabricating tumor-on-a-chip devices is polydimethylsiloxane (PDMS).

    “The most widely used material for fabricating tumor-on-a-chip devices is polydimethylsiloxane (PDMS).”

  • The paper relies on this without support.

    PDMS has advantages including optical transparency, breathability, biocompatibility, and flexibility, enabling continuous microscopic observation of tissue constructs for real-time evaluation of cell behavior and response to treatment.

    “The advantages of PDMS include optical transparency, breathability, biocompatibility, and flexibility, enabling the continuous microscopic observation of tissue constructs for real-time evaluation of cell behavior and response to treatment.”

  • The paper relies on this without support.

    In contrast to glass or plastic substrates, devices based on PDMS provide cells with a mechanical environment that is closer to the physical characteristics of soft tissues, possessing porosity and lower rigidity.

    “In contrast to glass or plastic substrates, devices based on PDMS provide cells with a mechanical environment that is closer to the physical characteristics of soft tissues, possessing porosity and lower rigidity.”

  • The paper relies on this without support.

    Gelatin can promote cell growth and polymerize with proteins, growth factor nucleotides, polysaccharides and other polyionic complexes, and has broad prospects for drug transport models due to controlled sustained and/or targeted release of bioactive molecules.

    “Gelatin cannot only promote cell growth but also polymerize with proteins, growth factor nucleotides, polysaccharides and other polyionic complexes. This material has broad prospects for drug transport models due to the controlled sustained and/or targeted release of bioactive molecules.”

  • The paper relies on this without support.

    Bacterial cellulose has good biocompatibility and cost effects, and bacterial cellulose nanofibers can be processed and dried to form a stable paper device for building models.

    “Bacterial cellulose has the comprehensive advantages of cellulose at the nanoscale and is derived from natural sources, which have good biocompatibility and cost effects. The bacterial cellulose nanofibers are processed and dried to form a stable paper device for building models.”

  • The paper relies on this without support.

    BME/Matrigel is a biomaterial with a composition similar to that of the early conservative basement membrane, which promotes the organization of different tissue types and microtissues of different species.

    “Basement membrane extract (BME/Matrigel) is a biomaterial with a composition similar to that of the early conservative basement membrane, which promotes the organization of different tissue types and microtissues of different species.”

  • The paper relies on this without support.

    Under similar conditions, tumor cells have high proliferation and are sometimes aggressive in BME/Matrigel, which can be used to evaluate the malignancy of tumors and explore tumor treatment methods.

    “Under similar conditions, tumor cells have high proliferation and are sometimes aggressive in BME/Matrigel, which can be used to evaluate the malignancy of tumors and explore tumor treatment methods.”

  • The paper relies on this without support.

    Tumor blood vessels have a great effect on the occurrence and development of tumors.

    “Tumor blood vessels have a great effect on the occurrence and development of tumors; therefore, the microfluidic technology of organ chips is also used to study the formation of tumor blood vessels.”

  • The paper relies on this without support.

    Lung cancer is one of the most common cancers and has a high fatality rate.

    “Lung cancer is one of the most common cancers and has a high fatality rate.”

  • The paper relies on this without support.

    Colorectal cancer is the second leading cause of cancer-related death due to the high incidence of cancer metastasis and the low cure rate of chemotherapy.

    “Colorectal cancer (CRC) is the second leading cause of cancer-related death due to the high incidence of cancer metastasis and the low cure rate of chemotherapy.”

  • The paper relies on this without support.

    In breast cancer, the frequency of bone metastases is approximately 70%.

    “In breast cancer, the frequency of bone metastases is ~70%.”

  • The paper relies on this without support.

    An organ is a hierarchical structure composed of two or more different tissues.

    “An organ is a hierarchical structure composed of two or more different tissues.”

  • The paper relies on this without support.

    The tissue itself is composed of different cell types.

    “In addition, the tissue itself is composed of different cell types.”

  • The paper relies on this without support.

    Tumor-on-a-chip systems recapitulate in vivo tumors to improve anticancer drug screening strategies.

    “It is fundamental that tumor-on-a-chip systems recapitulate in vivo tumors to improve anticancer drug screening strategies.”

  • The paper relies on this without support.

    Complex 3D organs are not well represented by monolayer cell models, the standard format for many drug screens.

    “Complex 3D organs are not well represented by monolayer cell models, the standard format for many drug screens.”

  • The paper relies on this without support.

    PDMS is the most widely used material to fabricate tumor-on-a-chip devices.

    “Polydimethylsiloxane (PDMS) is the most widely used material to fabricate tumor-on-a-chip devices; however, PDMS is known to easily adsorb hydrophobic compounds, such as drugs and proteins, which may reduce effective drug concentrations and activity and can cause experimental errors, limiting its application.”

  • The paper relies on this without support.

    PDMS easily adsorbs hydrophobic compounds, such as drugs and proteins, which may reduce effective drug concentrations and activity and can cause experimental errors.

    “Polydimethylsiloxane (PDMS) is the most widely used material to fabricate tumor-on-a-chip devices; however, PDMS is known to easily adsorb hydrophobic compounds, such as drugs and proteins, which may reduce effective drug concentrations and activity and can cause experimental errors, limiting its application.”

  • The paper relies on this without support.

    Most tumor-on-a-chip systems mimic tumors only in situ.

    “Currently, most tumor-on-a-chip systems mimic tumors only in situ; thus, the mechanism of tumor cell metastasis is still unclear, particularly the reasons for the initial activation of tumor cell growth and metastasis (such as specific signaling pathways) and the role of the microenvironment in regulating this phenomenon.”

  • The paper relies on this without support.

    The mechanism of tumor cell metastasis is still unclear, particularly the reasons for the initial activation of tumor cell growth and metastasis and the role of the microenvironment in regulating this phenomenon.

    “Currently, most tumor-on-a-chip systems mimic tumors only in situ; thus, the mechanism of tumor cell metastasis is still unclear, particularly the reasons for the initial activation of tumor cell growth and metastasis (such as specific signaling pathways) and the role of the microenvironment in regulating this phenomenon.”
21 of 21

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Depending on the presence and spatial distribution of cytotoxic T cells, tumors can be distinguished into two immunophenotypes: immunologically 'hot' and 'cold' tumors.

    “Depending on the presence and spatial distribution of these cytotoxic T cells, one can distinguish two immunophenotypes, namely, immunologically ‘hot’ and ‘cold’ tumors (Liu et al., 2021; Wang et al., 2023).”

    From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Liu et al., 2021

    The Introduction describes immune cells as part of the tumor microenvironment, but does not classify tumors by cytotoxic T-cell presence or spatial distribution. Searches for “hot” and “cold” tumors, cytotoxic T cells, and T-cell infiltration found no passage in our copy stating the claimed two-immunophenotype distinction. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Examples of immunologically 'cold' tumors include ovarian, prostate, pancreatic, glioma and some renal cell cancers, while 'hot' tumors are typically present in the liver, lung or bladder.

    “Examples of immunologically ‘cold’ tumors include ovarian, prostate, pancreatic, glioma and some renal cell cancers, while ‘hot’ tumors are typically present in the liver, lung or bladder (Liu et al., 2021; Huang et al., 2022; Wang et al., 2023).”

    From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Liu et al., 2021

    The Introduction discusses immune cells in the tumor microenvironment, and the Different types of tumor-on-a-chip section discusses glioma, lung, liver and pancreatic tumor models. Neither section classifies those cancers—or the other cancers named—as immunologically ‘cold’ or ‘hot.’ Searches for those classifications found no supporting passage in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • In immune excluded 'cold' tumors, cytotoxic T cells accumulate around the tumor but fail to efficiently infiltrate, whereas in immune-desert 'cold' tumors, tumor-specific CD8+ T cells are completely absent from the tumor and its periphery.

    “In fact, in immune excluded ‘cold’ tumors, cytotoxic T cells accumulate around the tumor but fail to efficiently infiltrate, whereas in immune-desert ‘cold’ tumors, tumor-specific CD8+ T cells are completely absent from the tumor and its periphery (Liu et al., 2021).”

    From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Liu et al., 2021

    The Introduction and the section on modeling cancer invasion and metastasis discuss tumor microenvironments and tumor-cell movement, but neither describes immune-excluded or immune-desert tumors. Searches for those terms and for CD8+ T-cell infiltration found no passage in our copy supporting the claimed distinction. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • Immunologically 'cold' tumors are characterized by the presence of immunosuppressive cell populations such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs).

    “Additionally, immunologically ‘cold’ tumors are characterized by the presence of immunosuppressive cell populations such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) (Hegde et al., 2016; Liu et al., 2021; Guha et al., 2022).”

    From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Liu et al., 2021

    The Introduction (page unavailable) says tumors contain assorted immune and inflammatory cells, but does not characterize immunologically ‘cold’ tumors or identify TAMs, MDSCs, and Tregs as their characteristic populations. Searches for ‘cold tumors,’ ‘macrophages,’ ‘regulatory T cells,’ and ‘immunosuppressive’ found no passage addressing that claim. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • Immunologically 'hot' tumors tend to be more responsive to ICI treatment, while immunologically 'cold' tumors rarely respond to ICI monotherapy due to the absence or exhaustion of TILs.

    “While immunologically ‘hot’ tumors tend to be more responsive to ICI treatment, immunologically ‘cold’ tumors rarely respond to ICI monotherapy due to the absence or exhaustion of TILs (Liu et al. (2021); Herbst et al. (2014).”

    From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Liu et al., 2021

    The Introduction discusses immune cells in the tumor microenvironment, but does not compare immunologically ‘hot’ and ‘cold’ tumors or their responses to checkpoint inhibitors. Searches for TILs, exhaustion, and ICI monotherapy found no passage in our copy addressing the claimed relationship; a checkpoint-immunotherapy study appears only in the References. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Brain-chip drug has two different names

    Minor

    For the brain tumor chip cited as reference 197, Table 1 lists pitavastatin, while the text says mepitastatin. Both passages pair the drug with irinotecan, indicating they describe the same experiment.

  • Duplicate reference has conflicting page ranges

    Minor

    References 159 and 162 give the same title, journal, volume, and year, but list different page ranges.

  • Figure 4b copyright year conflicts with its reference

    Minor

    The caption gives 2016 for reference 182, but the reference lists the work as published in 2019.

  • Figure 4c copyright year conflicts with its reference

    Minor

    The caption gives 2016 for reference 183, but the reference lists the work as published in 2014.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. Katt, M. E., Placone, A. L., Wong, A. D., Xu, Z. S. & Searson, P. C. In vitro tumor models: advantages, disadvantages, variables, and selecting the right platform. Front. Bioeng. Biotechnol. 4, 12 (2016). · DOI · Paper page
  2. Rothbauer, M., Zirath, H. & Ertl, P. Recent advances in microfluidic technologies for cell-to-cell interaction studies. Lab Chip 18, 249–270 (2018). · DOI · Paper page
  3. Hachey, S. J. & Hughes, C. C. Applications of tumor chip technology. Lab a Chip 18, 2893–2912 (2018). · DOI · Paper page
  4. Kumar, V. & Varghese, S. Ex vivo tumor-on-a-chip platforms to study intercellular interactions within the tumor microenvironment. Adv. Healthc. Mater. 8, 1801198 (2019). · DOI
  5. Knowlton, S. et al. Advancing cancer research using bioprinting for tumor-on-a-chip platforms. Int. J. Bioprint. 2, 3–8 (2016). · DOI
  6. Kashaninejad, N. et al. Organ-tumor-on-a-chip for chemosensitivity assay: a critical review. Micromachines 7, 130 (2016). · DOI · Paper page
  7. Fan, Y., Nguyen, D. T., Akay, Y., Xu, F. & Akay, M. Engineering a brain cancer chip for high-throughput drug screening. Sci. Rep. 6, 25062 (2016). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Liu, X., Fang, J., Huang, S., Wu, X., Xie, X., Wang, J., Liu, F., Zhang, M., Peng, Z., & Hu, N.
Affiliations
Sun Yat-sen University (CN)
Corresponding author
Hu, Ning
ORCID
Venue
Microsystems & Nanoengineering
Publisher
Springer Science and Business Media LLC
Published
2021-06-21
Volume
7
Issue
1
Pages
50-50
ISSN
2055-7434 (ISSN-L)
DOI
10.1038/s41378-021-00277-8
PMC
PMC8433302
OpenAlex
W3176320563
Semantic Scholar
2f5d9685d30e06242dbb6e60ba18bcba059f9a94
Cited by
246
References
228
Citations by year
2026: 46 · 2025: 53 · 2024: 57 · 2023: 41 · 2022: 44 · 2021: 5
FWCI
3.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Microsystems & Nanoengineering (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • the 100 Talents Program of Sun Yat-sen University
  • GuangDong Basic and Applied Basic Research Foundation of China
  • Open Fund of State Key Laboratory of Biocontrol at Sun Yat-sen University
  • National Natural Science Foundation of China (81770608)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
tumor-on-a-chip, tumor microenvironment, 3D cell culture, microfluidics, tissue engineering, anticancer drug screening, cancer therapy, in vitro tumor model, biomimetic design, drug repurposing

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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