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Cited by 2273D Printing in Biomedical ResearchMicrofluidic and Capillary Electrophoresis ApplicationsCancer Cells and Metastasis

Microfluidic modelling of the tumor microenvironment for anti-cancer drug development

Open access
Shang, Menglin, Soon, Ren Hao, Lim, Chwee Teck, Khoo, Bee Luan, Han, Jongyoon·2019·Lab on a Chip
DOI 10.1039/c8lc00970h
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Abstract

Cancer is the leading cause of death worldwide. The complex and disorganized tumor microenvironment makes it very difficult to treat this disease. The most common in vitro drug screening method now is based on 2D culture models which poorly represent actual tumors. Therefore, many 3D tumor models which are more physiologically relevant have been developed to conduct in vitro drug screening and alleviate this situation. Among all these models, the microfluidic tumor model has the unique advantage of recapitulating the tumor microenvironment in a comparatively easier and representative fashion. While there are many review papers available on the related topic of microfluidic tumor models, in this review we aim to focus more on the possibility of generating "clinically actionable information" from these microfluidic systems, besides scientific insight. Our topics cover the tumor microenvironment, conventional 2D and 3D cultures, animal models, and microfluidic tumor models, emphasizing their link to anti-cancer drug discovery and personalized medicine.

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Registry

Crossref · 10.1039/c8lc00970h

Cites

221 of 221 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

78 of 198 cited sources checked · 24 supported · 4 flagged · accuracy not yet measured

  • Interpretationcitation

    Adenosine played an important role in promoting tumor cell extravasation.

    “Through this, it was shown that adenosine played an important role in promoting tumor cells extravasation.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [98] 98. Jeon, J.S., et al., Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proceedings of the National Academy of Sciences, 2015. 112(1): p. 214-219. source

      The Results (p. 5) report that adding adenosine significantly reduced cancer cell extravasation, from 56.5% to 12.7%, rather than promoting it. The Fig. 3 caption (p. 6) confirms that extravasation decreased with adenosine. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    In a model where MDA-MB-231 suspension was flowed into a vascular network to model extravasation, blocking A3 adenosine receptors reduced the extravasation rate of cancer cells.

    “By blocking A3 adenosine receptors, cancer cells were observed to have a reduced extravasation rate.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [98] 98. Jeon, J.S., et al., Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proceedings of the National Academy of Sciences, 2015. 112(1): p. 214-219. source

      The Results (p. 5) report the opposite effect: blocking A3 adenosine receptors with PSB-10 significantly increased cancer cell extravasation in C2C12-containing matrices, from 8.2 ± 2.3% to 32.4 ± 7.7%. The Fig. 3 caption (p. 6) also states that extravasation increased with receptor blockade. (LLM, conf=0.95)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Steep pressure gradients at the tumor periphery favor tumor growth and metastasis.

    “The uniformly elevated IFP in tumor center is responsible for inhibiting drug delivery [172, 178, 186] while the steep pressure gradients at the periphery favors tumor growth and metastasis[154,[187][188][189][190].”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [154] source

      The Introduction (page unavailable) links elevated tumor pressure to outward interstitial flow, but does not identify steep gradients at the tumor periphery or show that they favor growth. More importantly, the Results and Discussion (page unavailable) report that, despite increasing cell speed, flow impaired the cells’ ability to spread to a distant site—the opposite of the claimed effect on metastasis. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [187] source

      The Introduction says pressure falls sharply at the tumor margin, creating fluid flow that transports molecules and cells facilitating angiogenesis and metastasis. The Mathematical model section says less steep gradients could potentially reduce lymphatic metastasis. The paper does not explicitly link the peripheral gradient to tumor growth, and presents its effect on metastasis as a proposed mechanism rather than an established outcome. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [188] source

      The Introduction says interstitial fluid pressure may stretch the tumor cortex and thereby promote proliferation; the Discussion reports that lowering pressure reduced proliferation in a xenograft model. The Discussion also describes pressure falling from the tumor core toward the cortex. Neither passage establishes that steep peripheral pressure gradients favor metastasis, and the growth finding concerns pressure-induced stretch rather than the gradient itself. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [189] source
    • cites [190] source

      The Results and the discussion on p. 2395 report that elevated pressure affected osteosarcoma-cell proliferation, with growth increasing in some cell lines and being suppressed in others. The paper does not show that steep pressure gradients at the tumor periphery favor growth, and it does not link those gradients to metastasis. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    The tumor microenvironment plays a key role in cancer metastasis.

    “Over the years, research has demonstrated that the tumor microenvironment plays a key role in this process [3,6,7].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [3] 3. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: The next generation. Cell, 2011. 144(5): p. 646-674. source
    • cites [6] 6. Kessenbrock, K., V. Plaks, and Z. Werb, Matrix Metalloproteinases: Regulators of the Tumor Microenvironment. Cell, 2010. 141(1): p. 52-67. source
    • cites [7] 7. Mantovani, A., et al., Cancer-related inflammation. Nature, 2008. 454(7203): p. 436-444. source
  • Premisecitation

    In direct co-culture, physical contact between cells allows for the study of adhesion molecules such as N-cadherins.

    “In the former, due to the physical contact between cells, this allows for the study of adhesion molecules such as Ncadherins [50].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] 50. De Wever, O. and M. Mareel, Role of tissue stroma in cancer cell invasion. The Journal of Pathology, 2003. 200(4): p. 429-447. source

      The sections “The normal epithelial ecosystem” and “The cancer ecosystem” describe co-culture systems and direct cell–cell contacts. “Molecular mechanisms of N-cadherin-mediated invasion and migration” links N-cadherin to cell–cell contact, but the paper does not say that direct co-culture is used to study adhesion molecules such as N-cadherin. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • May combine two claims. 55
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Premisecitation

    A separate co-culture system grows each cell type in a separate chamber and achieves cell-cell interaction by substance diffusion through culture media between chambers.

    “Instead of simultaneously culturing various cell types in the same chamber, a separate coculture system grows each cell type in a separate chamber and all the cell-cell interaction is achieved by substance diffusion through the culture media between individual culture chambers [131, 139-148] (Figure 4b).”
    Quote in the paperSubstantial claim7 of 10 sources checked
    • cites [131] 131. Byrne, M.B., et al., Methods to study the tumor microenvironment under controlled oxygen conditions. Trends Biotechnol, 2014. 32(11): p. 556-563. 210. Chang, C.W., et al., A polydimethylsiloxane-polycarbonate hybrid microfluidic device capable of generating perpendicular chemical and oxygen gradients for cell culture studies. Lab Chip, 2014. 14(19): p. 3762-72. 211. Wang, Z., et al., Investigation into the hypoxia-dependent cytotoxicity of anticancer drugs under oxygen gradient in a microfluidic device. Microfluidics and Nanofluidics, 2015. 19(6): p. 1271-1279. 212. Lin, X., et al., Oxyge source
    • cites [139] source
    • cites [140] source

      The Anticipated Results section (page unavailable) describes different cell types cultured in separate channels and paracrine interactions across a hydrogel. But it also reports cells migrating through the gel to interact with other cells, so it does not support the claim that all interaction occurs by diffusion through culture media. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [141] source
    • cites [142] source

      The Introduction says the two cell types were initially cultured in distinct compartments, but the barrier was then removed to create a region for migration and interaction. Results and Discussion reports physical contact between the cells. Thus, the paper contradicts the claim that all interaction occurred through substances diffusing in media between separate chambers. Page numbers were not supplied in our copy. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [143] source
    • cites [144] source

      The Experimental section describes culturing the two cell types in alternating gel channels, and the Conclusions say molecules can diffuse between adjacent channels. But the Conclusions also say cells can move across channel boundaries, and the Results report macrophages invading gels containing cancer cells. The paper therefore does not support the claim that all interaction occurs through diffusion in culture media. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [145] source
    • cites [146] source

      The device-fabrication and cell-observation passages describe four cell types grown in separate chambers, with channels allowing substances to diffuse between them. But the Cell morphological observations passage also reports a macrophage migrating through the matrigel toward bladder cancer cells, so the paper does not support the claim that all cell-cell interaction occurs by diffusion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [147] source

      The Introduction (Figure 1 description) shows tumor cells and immune cells initially placed in separate chambers, with chemoattractant signals guiding immune cells through connecting microchannels. But it also describes immune cells migrating toward tumor cells; the Introduction says they must firmly bind their targets. Thus, the claim that all interaction occurs through diffusion between chambers is not supported. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The tumor microenvironment induces tumor heterogeneity and promotes tumor growth.

    “Specifically, the tumor microenvironment has also been shown to induce tumor heterogeneity and promote the growth of a tumor itself [8,9].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] 8. Joyce, J.A. and J.W. Pollard, Microenvironmental regulation of metastasis. Nature Reviews Cancer, 2009. 9(4). source

      The passage beginning “Tumour–stroma interactions at the primary site” (page unavailable) says tumours exploit surrounding cells in processes that result in inappropriate growth. The passages do not say that the microenvironment induces tumour heterogeneity; describing tumours as complex mixtures of cell types does not establish that claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] 9. Lalonde, E., et al., Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. The Lancet Oncology, 2014. 15(13): p. 1521-1532. source

      The Discussion (page unavailable in our copy) reports that preclinical work supports hypoxia generating genomic instability and selecting genetically unstable clones, which supports a role for the microenvironment in tumour heterogeneity. It links hypoxia to metastatic capacity, but does not say that the microenvironment promotes growth of the tumour itself. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Tumor tissue explants use similar techniques and equipment as conventional cell culture, making it easy for researchers to adopt them.

    “As explants utilise similar techniques and equipment as those used in conventional cell culture work, this makes it easy for researchers to adopt tumor tissue explants in their research [36,37].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [36] 36. Hegerfeldt, Y., et al., Collective Cell Movement in Primary Melanoma Explants. Cancer Research, 2002. 62(7): p. 2125-2130.
    • cites [37] 37. Provenzano, P.P., et al., Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Medicine, 2006. 4(1): p. 38-38. source

      The Methods section, “Tumor explants and collagen gel culture” (page unavailable), describes culturing tumor explants with culture dishes, DMEM, antibiotics, and serum, supporting overlap with conventional cell culture. It does not compare the overall techniques or equipment with conventional culture or say that researchers can easily adopt explant methods. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Major molecular targets such as PTEN, BRAC1 or p53 have sequencing identities more similar to humans compared to mouse, indicating that a more accurate model can potentially be established.

    “Major molecular targets such as PTEN, BRAC1 or p53 have demonstrated sequencing identities that are more similar to humans as compared to those from a mouse, thereby indicating that a more accurate model can potentially be established [34].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] 34. Cekanova, M. and K. Rathore, Animal models and therapeutic molecular targets of cancer: utility and limitations. Drug Design, Development and Therapy, 2014. 8: p. 1911-1911. source

      The Companion animals section (page not available) says canine and feline cancer-related genes, including p53, are more similar to human genes than to mouse genes, and it names BRCA1 among homologous human and dog cancer-associated proteins. It supports the potential value of companion animals as cancer models, but the passages do not establish the specific comparison for PTEN or show that sequence similarity alone makes a model more accurate. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A missense mutation in the p53 transcription factor can be held accountable for tumor initiation, development, and growth in more than half of solid tumor cancers.

    “For instance, a missense mutation in the p53 transcription factor, which can be held accountable for tumor initiation, development, and growth in more than half of solid tumor cancers [32].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] 32. Aylon, Y. and M. Oren, New plays in the p53 theater. Current Opinion in Genetics & Development, 2011. 21(1): p. 86-92. source

      The Introduction (page unavailable) says p53 is mutated in approximately 50% of human cancers and describes its role in tumor prevention. The section on tumor cell invasion (page unavailable) says mutant p53 can promote cancer progression and metastasis. Neither passage establishes that the mutations are specifically missense mutations, that the figure exceeds half, or that it applies specifically to solid tumors. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Solid tumors are inherently heterogeneous and structurally complex.

    “As a result, solid tumors are inherently heterogeneous and structurally complex [18].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] 18. Chen, F., et al., New horizons in tumor microenvironment biology: challenges and opportunities. BMC Medicine, 2015. 13(1): p. 45-45. source

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

    Premisecitation

    Over the past two decades, many models have been created to mimic the tumor microenvironment and techniques involving small animal models or 2D in vitro cancer models have been developed for drug testing and screening.

    “Over the past two decades, many models have been created to mimic this microenvironment and various techniques involving small animal models or two-dimensional (2D) in vitro cancer models have been developed for drug testing and screening [34,35].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [34] 34. Cekanova, M. and K. Rathore, Animal models and therapeutic molecular targets of cancer: utility and limitations. Drug Design, Development and Therapy, 2014. 8: p. 1911-1911. source

      The Introduction describes three-dimensional and coculture models that mimic tumor–matrix interactions, alongside two-dimensional cancer cell models. The rodent xenograft section describes animal models used to test and develop cancer therapies. The copy does not establish the claimed two-decade timeframe, and it says two-dimensional cultures are isolated from the tumor microenvironment rather than mimicking it. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [35] 35. Ellem, S.J., E.M. De-Juan-Pardo, and G.P. Risbridger, In vitro modeling of the prostate cancer microenvironment. Advanced Drug Delivery Reviews, 2014. 79: p. 214-221. source

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

    Premisecitation

    The p53 protein acts as a tumor suppressor by inducing apoptosis when cellular mutations occur and initiating DNA repairs in healthy cells.

    “Briefly, the p53 protein acts as a tumor suppressor as it induces apoptosis when cellular mutations occur and initiate DNA repairs in healthy cells [32].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] 32. Aylon, Y. and M. Oren, New plays in the p53 theater. Current Opinion in Genetics & Development, 2011. 21(1): p. 86-92. source

      The Introduction says that stress activates p53, which facilitates DNA repair and can instigate apoptosis; it also describes p53’s role in tumor prevention. It does not specifically say that mutations trigger apoptosis or distinguish DNA repair in healthy cells from repair in other cells. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the hydrogel approach, the hydrogel works as a scaffold for the growth of an endothelial cell monolayer and also mimics the ECM for tumor spheroid formation.

    “In that approach, the hydrogel not only works as a scaffold for the growth of endothelial cells monolayer but also serves a function of mimicking the ECM for tumor spheroid formation.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [84] 84. Bai, J., et al., Identification of drugs as single agents or in combination to prevent carcinoma dissemination in a microfluidic 3D environment. Oncotarget, 2015. 6(34): p. 36603. source

      The Materials and Methods section says endothelial cells formed a monolayer on the collagen gel surface and that tumor aggregates were embedded in a second collagen gel region. But the Results say the aggregates were formed in non-adhesive microwells before being cultured in the device; the paper does not support saying the hydrogel was used for tumor spheroid formation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [85] 85. Riahi, R., et al., A microfluidic model for organ-specific extravasation of circulating tumor cells. Biomicrofluidics, 2014. 8(2): p. 024103. source

      The Results and Discussion (page unavailable) report that a Matrigel coating helped form a confluent endothelial monolayer. The Materials and Methods describe hydrogel used for chemokine delivery, but the paper does not describe using it to mimic ECM for tumor spheroid formation; it studies circulating tumor-cell extravasation instead. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    2D models cannot be used in the testing of drug efficacy because previous studies have shown that efficacy varies substantially between in vivo and 2D monoculture.

    “For instance, 2D models cannot be used in the testing of drug efficacy as previous studies have shown that the efficacy still varies quite substantially between in vivo as compared to 2D monoculture [52,53].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [52] 52. Horvath, P., et al., Screening out irrelevant cell-based models of disease. Nature Reviews Drug Discovery, 2016. 15(11): p. 751-769. source
    • cites [53] 53. Imamura, Y., et al., Comparison of 2D-and 3D-culture models as drug-testing platforms in breast cancer. Oncology reports, 2015. 33(4): p. 1837-1843. source

      The Introduction and Discussion say 2D cultures do not precisely simulate tumors in vivo and may overestimate anticancer activity. But the paper does not say 2D models cannot be used for drug-efficacy testing, and its Results compare 2D with 3D cultures rather than directly measuring a substantial efficacy difference between 2D cultures and in vivo tumors. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Suspension culture generally has high throughput but lacks the ability to control the size and uniformity of the spheroids formed.

    “Suspension culture generally has high throughput but lack the ability to control the size and uniformity of the spheroids formed [64,65].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [64] 64. Barrila, J., et al., Organotypic 3D cell culture models: using the rotating wall vessel to study host-pathogen interactions. Nature Reviews Microbiology, 2010. 8(11): p. 791-801. source
    • cites [65] 65. Sant, S. and P.A. Johnston, The production of 3D tumor spheroids for cancer drug discovery. Drug Discovery Today: Technologies, 2017. source

      The ‘Anchorage-independent tumor spheroids’ section says many methods produce aggregates with widely varying sizes and morphologies, supporting the uniformity concern. It does not support the claim that suspension culture generally has high throughput: it says some methods are labor-intensive and have been used only for small pilot screens. The ‘Ultra-low attachment microplates’ section also describes a method that is suitable for high-throughput screening and produces uniform-sized spheroids. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Conventional in vitro culture methods could generate a three-dimensional tumor structure that is more physiologically relevant than 2D models and more cost-efficient than animal models.

    “Conventional in vitro culture methods could also generate three-dimensional tumor structure which is more physiologically relevant than 2D models and more cost-efficient than animal models [57].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] 57. Asghar, W., et al., Engineering cancer microenvironments for in vitro 3-D tumor models. Materials Today, 2015. 18(10): p. 539-553. source

      The Introduction (page unavailable) says 3-D in vitro models can better recapitulate the natural tumor microenvironment and are relatively inexpensive compared with conventional methods, including animal models. But it describes 3-D models as an alternative to conventional 2-D in vitro culture, not as structures generated by conventional culture methods. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Hanging drop methods have high reliability and reproducibility but fluid volume is limited and the method is not good for long-term culture due to difficulty in refreshing the culture medium.

    “It has high reliability and reproducibility but fluid volume is limited and the method is not good for long-term culture due to difficulty in refreshing the culture medium [58,75].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [58] 58. Mehta, G., et al., Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. Journal of Controlled Release, 2012. 164(2): p. 192-204. source

      In ‘Challenge 1: Forming and maintaining spheroids of uniform size’ (page not provided), the paper says conventional hanging drops allow defined spheroid size but that changing medium is time-consuming, supporting the culture-maintenance concern. It describes 15–20 μl drops in a particular plate, not a general fluid-volume limit, and does not establish high reliability for hanging-drop methods generally. It also reports that an improved hanging-drop plate enables long-term culture, so the limitation needs to be qualified as applying to conventional methods. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [75] 75. Breslin, S. and L. O'Driscoll, Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today, 2013. 18(5-6): p. 240-9. source

  • May combine two claims.

    Premisecitation

    Fluid shear stress can prompt ovarian cancer cell dissemination, enrich cancer stem cell population, and enhance tumor chemoresistance to anti-cancer drugs.

    “It was found that fluid shear stress could prompt ovarian cancer cell dissemination, enrich cancer stem cell population as well as enhance tumor's chemoresistance to anti-cancer drugs.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Almost all current microfluidic devices incorporating fluid flow can generate a shear stress with physiologically relevant value and can demonstrate the impact of shear stress in cultured tumor cells in vitro.

    “Almost all current microfluidic devices incorporating fluid flow can generate a shear stress with physiologically relevant value and can demonstrate the impact of shear stress in cultured tumor cells in vitro [157-160].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [157] source

      The Introduction (page not available) says interstitial flow can exert shear stress and influence cell behavior, and the Discussion describes a microfluidic device that controls interstitial flow. But the paper does not establish that almost all flow-based microfluidic devices generate physiologically relevant shear stress. Its demonstrated application was vascular network formation using endothelial and stromal cells, not the effect of shear stress on cultured tumor cells. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [158] source

      The Introduction describes this paper’s microfluidic device operating at a physiological venular shear stress of approximately 1 dyn cm−2. The Discussion reports its use to study metastatic colon carcinoma cell adhesion under shear flow. This supports the device as an example, but the paper does not establish that almost all current microfluidic devices have these capabilities. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [159] source

      The Results and Discussions sections (pages not provided) describe one microfluidic platform that produces flow-induced shear stress and shows changes in cultured esophageal cancer cells. The paper does not establish that almost all current flow-based microfluidic devices do so, or that their shear-stress values are physiologically relevant. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [160] source

  • May combine two claims.

    Premisecitation

    High solid stress can increase drug resistance, influence tumor cell gene expression, compromise immune cells' ability to kill cancerous cells, turn macrophages to tumor-friendly cells, and thereby enhance the metastatic potential of cancer cells.

    “In addition to increasing drug resistance, a high SS could influence tumor cells' gene expression, comprise immune cells ability to kill cancerous cells or even turn macrophages to tumorfriendly cells, thereby enhancing the metastatic potential of cancer cells [180-184].”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [180] source
    • cites [181] source
    • cites [182] source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [183] source
    • cites [184] source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The pressure gradient in a microfluidic platform induces cell adhesion activation, cell polarization along flow direction, and migration towards regions with higher pressures.

    “The pressure gradient was found out to induce cell adhesion activation, cell polarization along flow direction and migration towards regions with higher pressures.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Most microfluidic oxygen control systems control oxygen levels in culture chambers and can be categorized into three groups: introducing oxygen scavenging chemicals, gas supply channels adjacent to the cell chamber, and oxygen impermeable materials.

    “Most of them control the oxygen levels in culture chambers and can be categorized into three groups; introducing oxygen scavenging chemicals [210, 211], gas supply channels adjacent to the cell chamber [212] and oxygen impermeable materials [213, 214].”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [210] source
    • cites [211] source
    • cites [212] source
    • cites [213] source
    • cites [214]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Abnormal solid stress is developed by the unregulated growth of tumorigenic cells and is transmitted by the extracellular matrix.

    “Abnormal SS is developed by the unregulated growth of tumorigenic cells and is transmitted by the extracellular matrix[179].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Hypoxic environment reduces cytotoxicity of many anticancer drugs, affects angiogenesis, promotes metastasis, and alters metabolic activity of cancer cells.

    “Hypoxic environment, on the other hand, is known to reduce cytotoxicity of many anticancer drugs, affect angiogenesis, promote metastasis and alter the metabolic activity of cancer cells [183,197].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [183] source
    • cites [197] source

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

    Premisecitation

    Cancer-associated fibroblasts may promote cancer cell invasion.

    “By using co-culture models, it was found that cancer-associated fibroblasts may promote cancer cell invasion [143].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Interpretationreasoning

    Different sub-populations of a tumor can respond differently to therapy, making it difficult for clinicians to treat cancer effectively.

    “Since different sub-populations of a tumor can respond differently to therapy, this makes it difficult for clinicians to treat cancer effectively.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    VEGF is expressed in varying quantities within a tumor.

    “Moreover, VEGF is expressed in varying quantities within a tumor.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    VEGF upregulation is only one pathway through which angiogenesis is induced.

    “It is important to note here that the upregulation of VEGF is only one of the pathways through which angiogenesis is induced.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cells in a tumor respond differently to cues and in the process create tumor heterogeneity.

    “Due to this difference, the cells in a tumor respond differently to these cues and in the process, creates tumor heterogeneity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Mouse models are highly popular with researchers; 65% of 949 oncology papers published in 2016 utilized a mouse tumor model.

    “Indeed, this has made mouse models highly popular with researchers (65% of 949 oncology papers published in 2016 utilized a mouse tumor model [42]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] 42. Gengenbacher, N., M. Singhal, and H.G. Augustin, Preclinical mouse solid tumour models. Nature Publishing Group, 2017. 17(12): p. 751-765. source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Researchers seek to build tumor models using methods with higher throughput and less batch-to-batch variation than the non-microfluidic models discussed.

    “It is for these reasons that researchers seek to build tumor models using methods which have a higher throughput and less batch-to-batch variation than those mentioned above.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Since a tumor explant is derived from the original patient sample, the tumor architecture is largely preserved, making this a representative model.

    “Moreover, since the tumor explant is derived from the original patient sample, the tumor architecture is largely preserved, making this a representative model.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Expression of oncogenes such as Ras or Myc inside tumor cells can induce angiogenesis.

    “Alternatively, through the expression of oncogenes such as such Ras or Myc inside tumor cells, angiogenesis can also be induced in a tumor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The discrepancy between animal models and clinical cancer trials may be attributed to lack of a standardized protocol for animal testing and to stress experienced in mice having a substantial impact on experimental results.

    “This discrepancy may be attributed to a variety of reasons ranging from the tangible, such as the lack of a standardized protocol for animal testing unlike in human trials [42], to the intangible such as how stress experienced in mice has been demonstrated to have a substantial impact on the experimental results [46].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] 42. Gengenbacher, N., M. Singhal, and H.G. Augustin, Preclinical mouse solid tumour models. Nature Publishing Group, 2017. 17(12): p. 751-765. source
    • cites [46] 46. Chesler, E.J., et al., Identification and ranking of genetic and laboratory environment factors influencing a behavioral trait, thermal nociception, via computational analysis of a large data archive. Neuroscience & Biobehavioral Reviews, 2002. 26(8): p. 907-923. source

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

    Premisecitation

    Cancer metastasis occurs through a series of mechanisms, most prominently the epithelial to mesenchymal transition (EMT).

    “For instance, cancer metastasis which is the leading cause of death in cancer patients occurs through a series of mechanisms (most prominently the epithelial to mesenchymal transition [EMT]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] 47. Thiery, J.P., et al., Epithelial-Mesenchymal Transitions in Development and Disease. Cell, 2009. 139(5): p. 871-890. source

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

    Interpretationreasoning

    Development of an in vitro model accurately representing in vivo TME would help researchers develop better drugs and could pave the way for clinicians to personalize cancer therapy.

    “Through the development of an in vitro model which can accurately represent the in vivo conditions of the tumor microenvironment, this would help not only researchers develop better drugs but could also pave the way for clinicians to personalize cancer therapy for individuals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    As VEGF expression promotes neo-vascularization, this results in a network of blood vessels within a tumor which cannot be replicated or predicted easily, making the tumor microenvironment highly complex.

    “As the expression of VEGF promotes neo-vascularization in tumors, this results in a network of blood vessels within a tumor which cannot be replicated or predicted easily, thereby making the tumor microenvironment highly complex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Animal-based models have underlying ethical issues and strict regulations restricting their use to specific purposes such as drug testing.

    “However, for all the benefits that an animal-based model confers, they still have underlying ethical issues and have very strict regulations regarding the use of them which restricts their use to only very specific purposes such as in a drug test.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Mice can tolerate higher drug concentrations than human patients, so questions about their effectiveness for drug tests remain even if a representative 3D model is created.

    “However, as mice can tolerate higher drug concentrations than human patients, questions about their effectiveness in using them for drug tests will remain even if a representative 3D model is to be created.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Tumor heterogeneity manifests chemically and biologically, giving rise to genetic and phenotypic variations seen in tumors.

    “However, this heterogeneity will manifest both chemically and biologically which will then give rise to genetic and phenotypic variations seen in tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Apart from malignant cells, the tumor microenvironment includes immune cell types, blood vessel cells (pericytes and adipocytes) and fibroblasts, each interacting and exhibiting dependencies on each other.

    “For instance, apart from the malignant cells, the tumor microenvironment also includes several different immune cell types, cells from blood vessels (pericytes and adipocytes) and fibroblasts, each interacting and exhibiting dependencies on each other.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Stiffening enhances cell growth and compromises cell-cell junction integrity, impeding lumen formation.

    “By doing so, cell growth is enhanced by stiffening and cell-cell junction integrity is compromised, impeding lumen formation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Scaffold-based culture has drawbacks of batch variance, limited throughput, and non-uniform spheroid size and distribution.

    “However, scaffold base culture also has drawbacks of batch variance, limited throughput, non-uniform spheroid size and distribution [63].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] 63. Breslin, S. and L. O'Driscoll, Three-dimensional cell culture: the missing link in drug discovery. Drug discovery today, 2013. 18(5): p. 240-249. source

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

    Premisecitation

    Many materials such as chitosan-alginate, collagen, Matrigel and Puramatrix hydrogel are capable of forming a scaffold structure.

    “Many different materials such as chitosan-alginate, collagen, Matrigel and Puramatrix hydrogel, were capable of forming such a scaffold structure [77][78][79][80][81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77][78][79][80][81]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Interpretationnone given

    An arguable advantage of scaffold-based culture is that the scaffold could mimic ECM and better recapitulate the in vivo microenvironment.

    “An arguable advantage of this approach is that the scaffold could mimic ECM and better recapitulate the in vivo microenvironment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    A microfluidic tumor-on-a-chip has the advantage of being cost-effective while maintaining high throughput.

    “It also has the advantage of being cost-effective while maintaining a high throughput.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Artificial blood vessels generated by growing cells on a vessel-like scaffold have relatively high mechanical strength and look like real blood vessels.

    “Although fabrication of the device is quite tedious, the artificial blood vessels generated by this method have relatively high mechanical strength and look like real blood vessels [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] 86. Wang, X.-Y., et al., An artificial blood vessel implanted three-dimensional microsystem for modeling transvascular migration of tumor cells. Lab on a Chip, 2015. 15(4): p. 1178-1187. source

  • May combine two claims.

    Premisecitation

    Growing cells on the inner surface of a cylindrical hydrogel channel can effectively build a circular endothelial cell tube, but the co-cultured cancer cells must be fixed in the hydrogel first before construction of the endothelial cellular tube can begin.

    “This method can effectively build a circular endothelial cell tube in a microfluidic device, but the co-cultured cancer cells must be fixed in the hydrogel first before construction of the endothelial cellular tube can begin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87][88][89][90][91]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Animal models have been used to recapitulate the human body environment, but this is a time-consuming and expensive approach.

    “On the other hand, although animal models have been used to recapitulate the human body environment, it is a time-consuming and expensive approach.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Although it is challenging to fully regenerate the in vivo microenvironment in a microfluidic system, researchers have been able to capture some key features in the tumor to recapitulate tumor growth and better predict drug response.

    “Although it can be very challenging to fully regenerate the in vivo microenvironment in a microfluidic system, researchers have been able to capture some key features in the tumor to recapitulate the process of tumor growth and use it to better predict drug response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    More complicated microfluidic devices achieve a closer representation of in vivo conditions albeit with lower throughput and becoming harder to operate.

    “The more complicated devices are, the closer a representative of in vivo conditions can be achieved albeit with a lower throughput and becoming harder to operate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Blood vessels developed in this type of device are cross-linked and perfusable, closely recapitulating in vivo blood flow conditions.

    “The blood vessels developed in this type of devices are cross-linked and perfusable, closely recapitulating the in vivo blood flow conditions [94][95][96][97]107].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94][95][96][97]107]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Development of a more comprehensive microfluidic tumor model with better-mimicked vasculature will allow in vitro fast screening of treatments that overcome abnormal vasculature and greatly contribute to the development of anti-cancer drugs.

    “As such, the development of a more comprehensive microfluidic tumor model with better-mimicked vasculature will allow in vitro fast screening of such treatment and greatly contribute to the development of anti-cancer drugs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The size of spheroids generated using the non-adherent surface method varies in a large range, but this problem can be overcome by using microarrays.

    “Although the size of spheroids generated using this method varies in a large range, this problem can be overcome by using microarrays instead [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] 66. Fennema, E., et al., Spheroid culture as a tool for creating 3D complex tissues. Trends in biotechnology, 2013. 31(2): p. 108-115. source

  • May combine two claims.

    Premisecitation

    The endothelial cell monolayer approach is very effective in applications where cylindrical vessel geometry is not essential, such as testing drugs that prevent cancer cell migration, because it is high throughput and simple to fabricate.

    “This monolayer approach is very effective in applications where cylindrical vessel geometry of blood vessels is not very essential to the study, such as in the testing of drugs which prevent cancer cell migration because this method is high throughput and simple to fabricate [106].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] 106. Ferrara, N. and R.S. Kerbel, Angiogenesis as a therapeutic target. Nature, 2005. 438(7070): p. 967-974. 122. Reymond, N., B.B. d'Agua, and A.J. Ridley, Crossing the endothelial barrier during metastasis. Nature Reviews Cancer, 2013. 13(12): p. 858-870. 123. Orimo, A., et al., Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 2005. 121(3): p. 335-348. 124. Polanska, U.M. and A. Orimo, Carcinoma-associated fibroblasts: Non-neoplastic tumour-promoting mesenchymal cells. Journal of cellular phys source

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

    Premisecitation

    Endothelial cells are a major component of blood vessels and play an important role in tumor angiogenesis.

    “Endothelial cells are one of the major components of blood vessels and play an important role in tumor angiogenesis [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] 121. Boucher, Y., L.T. Baxter, and R.K. Jain, Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer research, 1990. 50(15): p. 4478-4484. 186. Chauhan, V.P., et al., Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nature nanotechnology, 2012. 7(6): p. 383-388. 187. Jain, R.K., R.T. Tong, and L.L. Munn, Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer research,

  • May combine two claims.

    Premisecitation

    Interstitial shear stress can upregulate TGFβ and activate fibroblast contraction to stiffen the ECM.

    “Although this shear stress is very small when compared with the intravascular shear stress, it can still stimulate some oncogenic signaling pathways on cancer cells [150] as well as upregulate TGFβ and activate fibroblast contraction to stiffen the ECM [151].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] source

  • May combine two claims.

    Premisenone given

    In current microfluidic models culturing three-dimensional tumors, fluid only flows around tumor spheroids and the quantified shear stress value is the shear stress on the outer surface of the tumor.

    “In current microfluidic models culturing three-dimensional tumors, fluid only flows around tumor spheroids and the quantified shear stress value is the shear stress on the outer surface of the tumor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cancer-associated fibroblasts proliferate faster, produce more extracellular matrix, and secrete unique cytokines compared with normal fibroblasts.

    “Different from normal fibroblasts, cancer-associated fibroblasts proliferate faster, produce more extracellular matrix and secrete unique cytokine, which significantly enhances carcinogenesis [123, 124].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [123] 123. Somaweera, H., A. Ibraguimov, and D. Pappas, A review of chemical gradient systems for cell analysis. Anal Chim Acta, 2016. 907: p. 7-17. 194. source
    • cites [124] 124. Brennan, M.D., et al., Oxygen control with microfluidics. Lab Chip, 2014. 14(22): p. 4305-18. 195. Eccles, S.A., Targeting key steps in metastatic tumour progression. Current opinion in genetics & development, 2005. 15(1): p. 77-86. 196. source

  • May combine two claims.

    Premisecitation

    Elevated extracellular stresses enhance tumor cell proliferation and build up a transport barrier to drug delivery, greatly lowering the efficacy of anticancer drugs and therapies.

    “It enhances tumor cell proliferation and builds up a transport barrier to drug delivery, greatly lowering the efficacy of anticancer drugs and therapies.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [170] source
    • cites [171] source
    • cites [172]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [173]
    • cites [174]
    • cites [175]
    • cites [176]
    • cites [177] source
    • cites [178]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    This dynamic response is regulated by the β-catenin dependent Wnt signaling pathway.

    “This dynamic response was regulated by the β-catenin dependent Wnt signaling pathway [202].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] source

  • May combine two claims.

    Interpretationreasoning

    Mimicking static fluid pressure is key to understanding the role of IFP in drug resistance of tumor and whether it is necessary to be recapitulated in an in vitro drug screening platform.

    “Therefore, mimicking static fluid pressure is key to understanding the role of IFP in drug resistance of tumor and whether it is necessary to be recapitulated in an in vitro drug screening platform (Figure 4d).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A hypoxic environment can be easily incorporated into most existing systems by using a hypoxic incubator or a hypoxic workstation.

    “A hypoxic environment can be easily incorporated into most existing systems by using a hypoxic incubator or a hypoxic workstation [194].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] source

  • May combine two claims.

    Premisecitation

    Chemical and oxygen concentrations greatly affect cancer progression and therapeutic efficacy.

    “Many recent microfluidic devices were utilized to generate chemical or oxygen gradient in cancer research because chemical and oxygen concentrations have also been shown to greatly affect cancer progression and therapeutic efficacy [193,194].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [193] source
    • cites [194] source

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

    Interpretationnone given

    Current microfluidic tumor models have achieved much in showing the significance of incorporating the vascular system, co-culture with physiologically relevant cell types, and mimicking elevated interstitial fluid pressures as well as shear stresses.

    “As discussed, current microfluidic tumor models have achieved much in showing the significance of incorporating the vascular system, co-culture with physiologically relevant cell types and mimicking elevated interstitial fluid pressures as well as shear stresses.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The key to developing a successful microfluidic tumor model is to select and incorporate essential features that can facilitate better drug response prediction depending on the application.

    “Therefore, the key to developing a successful microfluidic tumor model is to select and incorporate essential features which can facilitate better drug response prediction depending on the application.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Large artificial blood vessels generated by planar or circular channels can reproduce a physiologically relevant multilayer structure comprising mainly endothelial cells, vascular smooth muscle, and connective tissue, but these vessels are often too big to be implanted in a vascularized tumor.

    “While large artificial blood vessels generated by planar or circular channels can reproduce a physiologically relevant multilayer structure, which comprises of mainly endothelial cells, vascular smooth muscle, and connective tissue, these vessels are often too big to be implanted in a vascularized tumor.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Although the artificial vascular network has similar dimensions to normal capillaries and allows coculture of multiple cell types, building a vascularized artificial tumor remains a big challenge.

    “On the other hand, although the artificial vascular network has similar dimensions to normal capillaries and allows coculture of multiple cell types, building a vascularized artificial tumor remains a big challenge.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Current approaches with an elevated pressure chamber do not have a blood vessel component and the magnitude of pressure is less than 10% of actual IFP in vivo.

    “For example, current approaches with an elevated pressure chamber do not have a blood vessel component and the magnitude of pressure is less than 10% of actual IPF in vivo [166][167][168][169].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166][167][168][169]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Some elements among the in vivo microenvironments such as IFP and shear stress have been mimicked in microfluidic devices, but their full functionality has not been reproduced yet.

    “Some elements among the in vivo microenvironments such as IFP and shear stress have been mimicked in microfluidic devices, but their full functionality has not been reproduced yet.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In patient-derived tumor tissue studies, nutrients and drugs are not delivered through the vascular network, which compromises the prediction of drug response in these models.

    “However, nutrients and drugs are not delivered through the vascular network in these studies, which compromise the prediction of drug response in these models.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The future generation of in vitro tumor models will need to use primary human cells integrated into in vivo conditions to generate predictions that are physiologically more relevant.

    “It is inevitable that the future generation of in vitro tumor models will need to use primary human cells with integrated into vivo conditions in order to generate predictions which are physiologically more relevant.”
    Quote in the paperNot a substantial claim
68 of 68

  • The paper relies on this without support.

    The deviation in animal models caused by non-human genetic material is impossible to overcome.

    “In addition, the deviation in animal models caused by non-human genetic material seems impossible to be overcome.”

  • The paper relies on this without support.

    Many different non-neoplastic cells exist in the tumor microenvironment and interact with tumor cells.

    “Many different non-neoplastic cells exist in the tumor microenvironment and interact with tumor cells.”

  • The paper relies on this without support.

    No more than 4 fluorescent dyes are usually used simultaneously on a single device due to cross-talking between fluorescent signals.

    “However, due to the concern of cross-talking between fluorescent signals, no more than 4 fluorescent dyes are usually used simultaneously on a single device.”

  • The paper relies on this without support.

    IFP is usually close to zero in normal tissue.

    “It is usually close to zero in normal tissue.”

  • The paper relies on this without support.

    There is usually a hypoxic core of solid tumors due to the abnormal vascular network and high cell density.

    “There is usually a hypoxic core of solid tumors due to the abnormal vascular network and high cell density.”

  • The paper relies on this without support.

    Commercially available cell lines are commonly used in co-culture models.

    “Commercially available cell lines are commonly used in co-culture models.”

  • The paper relies on this without support.

    Animal tests are much more easily approved than clinical testing on human subjects.

    “This is primarily because animal tests are much more easily approved than clinical testing on human subjects.”
7 of 7

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?

  • By incorporating organoids into a microfluidic device, organoids-on-a-chip inherit combined benefits of both microfluidics and 3D organoid models, providing a unique way to study tumor-stroma interactions and their systemic effects.

    “By incorporating organoids into a micro fl uidic device, organoids-ona-chip inherit the combined bene fi ts of both micro fl uidics and 3D organoid models, thus providing a unique way to study tumor -stroma interactions and their systemic effects [69,74 -76].”

    From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [75]

    The paper’s coculture discussion (section 4.2; page unavailable) describes microfluidic devices used to study interactions between cancer cells and fibroblasts, supporting the tumor–stroma portion. It does not establish that organoids-on-a-chip combine the benefits of microfluidics and 3D organoid models or enable study of systemic effects; the organoid mention found is in the References. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Tumor-on-chip systems are expected to increase the effective identification of new and better cancer therapies while minimizing non-specific toxicity.

    “These tumor-on-chip systems are expected to increase the effective identification of new and better cancer therapies while minimizing non-specific toxicity [13,14,15,16,17].”

    From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [16]

    The Introduction (page not provided) says physiologically relevant tumor models could help researchers develop better drugs, and section 4 says tumor-on-chip models can better predict drug response. Neither passage supports the additional expectation that these systems will minimize non-specific toxicity; searches for that term and for toxicity found no such statement in the paper’s discussion. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Tumor spheroids have been used as routine drug screening models to reduce drug development costs and unnecessary animal experiments.

    “Given their tumor‐like properties, tumor spheroids have been used as routine drug screening models to reduce drug development costs and unnecessary animal experiments.[ 49 ]”

    From 3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip (2023) · cites this paper as [49]

    Section 3.2, “Three-dimensional models” (page not given), describes spheroid-producing 3D cultures as more cost-efficient than animal models; the paper also discusses spheroid-based drug screening. Section 3, “Non-microfluidic tumor models” (page not given), raises ethical concerns about animal testing. Our copy does not establish that spheroids are routine screening models or that their use has reduced drug-development costs and unnecessary animal experiments. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Tumor-on-chip models hold promise as a cost-effective and higher-throughput resource for screening anticancer drugs.

    “Tumor-on-chip models based on these organ-on-chip systems can recreate human tumor microenvironments and now hold great promise as a new resource for cost-effective and higher-throughput screening of anticancer drugs [13,14,15,16,17] and powerful enablers of precision medicine [18].”

    From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [16]

  • Tumor-on-chip models can recreate human tumor microenvironments.

    “Tumor-on-chip models based on these organ-on-chip systems can recreate human tumor microenvironments and now hold great promise as a new resource for cost-effective and higher-throughput screening of anticancer drugs [13,14,15,16,17] and powerful enablers of precision medicine [18].”

    From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [16]

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.

  • Cancer is ranked both first and second as a cause of death

    Minor

    The abstract calls cancer the leading cause of death worldwide, while the introduction calls it the second leading cause globally.

  • Conflicting descriptions of where tumor hypoxia occurs

    Minor

    One section singles out cells near the tumor periphery as becoming hypoxic because they lack access to a blood vessel; a later section instead describes the tumor core as the usual hypoxic region.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 17

  1. WHO , Cancer , WHO , 2017
  2. Hegerfeldt, 2002, Cancer Res., 62, 2125
  3. N. Gengenbacher , M.Singhal and H. G.Augustin , Preclinical mouse solid tumour models , Nature Publishing Group , 2017 , vol. 17 12 , pp. 751–765
  4. Mak, 2014, Am. J. Transl. Res., 6, 114
  5. Breslin, 2013, Drug Discovery Today, 18, 240, 10.1016/j.drudis.2012.10.003 · DOI · Paper page
  6. Ahn, 2017, IEEE Trans. Nanotechnol., 1
  7. Khoo, 2016, Sci. Adv., 2, e1600274, 10.1126/sciadv.1600274 · DOI · Paper page
  8. Trietsch, 2013, Lab Chip, 13, 3548, 10.1039/c3lc50210d · DOI · Paper page
  9. Less, 1992, Cancer Res., 52, 6371
  10. Curti, 1993, Cancer Res., 53, 2204
  11. Gutmann, 1992, Cancer Res., 52, 1993
  12. Griffon-Etienne, 1999, Cancer Res., 59, 3776
  13. Leu, 2000, Cancer Res., 60, 4324
  14. Boucher, 1991, Cancer Res., 51, 6691
  15. Boucher, 1990, Cancer Res., 50, 4478
  16. Weigelt, 2005, Nat. Rev. Cancer, 5, 591, 10.1038/nrc1670 · DOI · Paper page
  17. Wang, 2015, Lab Chip, 15, 1445, 10.1039/C4LC01451K · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Shang, M., Soon, R. H., Lim, C. T., Khoo, B. L., & Han, J.
Affiliations
  • National University of Singapore (SG)
  • Singapore-MIT Alliance for Research and Technology (SG)
Corresponding author
  • Lim, Chwee Teck
  • Khoo, Bee Luan
  • Han, Jongyoon
ORCID
Venue
Lab on a Chip
Publisher
Royal Society of Chemistry (RSC)
Published
2019
Volume
19
Issue
3
Pages
369-386
ISSN
  • 1473-0189 (ISSN-L)
  • 1473-0197
DOI
10.1039/c8lc00970h
OpenAlex
W2907333863
Cited by
227
References
217
Citations by year
2026: 12 · 2025: 17 · 2024: 24 · 2023: 36 · 2022: 45 · 2021: 35 · 2020: 36 · 2019: 22
FWCI
2.79
Type
journal article
Language
en
Open access
Licence
rsc.li/journals-terms-of-use (am, 366 d)
Locations
  • Lab on a Chip (publishedVersion)
  • PubMed (publishedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
Funders
Mechanobiology Institute, Singapore
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 microenvironment, microfluidic tumor model, anticancer drug discovery, in vitro drug testing, 3D tumor models, 2D cell culture, animal models, personalized medicine
MeSH terms
Animals, Antineoplastic Agents, Drug Screening Assays, Antitumor, Humans, Lab-On-A-Chip Devices, Tumor Microenvironment

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

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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