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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [139] source
• Partly supported

  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)

  cites [140] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [141] source
• Disputed

  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.

  cites [142] sourceExperimental — accuracy not yet measured
• Supported

  The Materials and Methods section (Design and fabrication of the bionic invasion chip) places lung cancer cells and fibroblasts in separate chambers and describes their co-culture as non-contacting. It says fibroblast-secreted molecules can cross between chambers and describes culture-medium flow carrying secretions through the device. (LLM, conf=0.92)

  cites [143] source
• Partly supported

  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)

  cites [144] sourceExperimental — accuracy not yet measured
• Supported

  Section 2.1 (page not provided) describes cells seeded into separate chambers without mixing. It states that diffusion ports allow soluble factors to pass between chambers while keeping the cell populations isolated, matching the cited description of indirect cell-cell interaction. (LLM, conf=0.91)

  cites [145] source
• Partly supported

  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)

  cites [146] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [147] sourceExperimental — accuracy not yet measured

In the paper

“Specifically, the tumor microenvironment has also been shown to induce tumor heterogeneity and promote the growth of a tumor itself [8,9].”

What the sources say

• Partly supported

  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)

  cites [8] 8. Joyce, J.A. and J.W. Pollard, Microenvironmental regulation of metastasis. Nature Reviews Cancer, 2009. 9(4). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [36] 36. Hegerfeldt, Y., et al., Collective Cell Movement in Primary Melanoma Explants. Cancer Research, 2002. 62(7): p. 2125-2130.
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“As a result, solid tumors are inherently heterogeneous and structurally complex [18].”

What the sources say

• Supported

  The Introduction describes tumors as three-dimensional structures involving diverse cells and discusses spatial and temporal heterogeneity. The Conclusions and future directions section explicitly calls the tumor microenvironment structurally complex, supporting the paraphrase about solid tumors. (LLM, conf=0.91)

  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

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Suspension culture generally has high throughput but lack the ability to control the size and uniformity of the spheroids formed [64,65].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  cites [65] 65. Sant, S. and P.A. Johnston, The production of 3D tumor spheroids for cancer drug discovery. Drug Discovery Today: Technologies, 2017. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Supported

  The Discussion says peritoneal ascitic flow contributes to ovarian cancer dissemination and may facilitate CSC enrichment. The Abstract reports increased CSC markers and resistance to cisplatin and paclitaxel in ovarian cancer cells grown under fluid shear stress compared with static conditions. (LLM, conf=0.92)

  cites [156] source

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [157] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [158] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [159] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [160] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [180] source
• ?Not checked — no full text of the sourcecites [181] source
• Partly supported

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

  cites [182] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [183] source
• Partly supported

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

  cites [184] sourceExperimental — accuracy not yet measured

In the paper

“The pressure gradient was found out to induce cell adhesion activation, cell polarization along flow direction and migration towards regions with higher pressures.”

What the sources say

• Supported

  The paper describes a microfluidic platform in which a pressure-driven interstitial flow produces adhesion activation and upstream cell polarization (p. 2). The Discussion (p. 5) reports migration upstream, toward maximum adhesion tension; upstream is toward the higher-pressure side of the flow. (LLM, conf=0.88)

  cites [168] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [210] source
• ?Not checked — no full text of the sourcecites [211] source
• Supported

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

  cites [212] source
• ?Not checked — no full text of the sourcecites [213] source
• ?Not matched

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

  cites [214]

In the paper

“Abnormal SS is developed by the unregulated growth of tumorigenic cells and is transmitted by the extracellular matrix[179].”

What the sources say

• Supported

  The Discussion (page not supplied) explains that cancer cells proliferate uncontrollably and that their expansion generates solid stress. It also says the resulting force is stored in deformations of other cells and the extracellular matrix, which links to cells. (LLM, conf=0.90)

  cites [179] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [183] source
• Supported

  The “Radiation and drug resistance” section says hypoxia can make tumor cells resistant to chemotherapy and describes mechanisms that reduce treatment effectiveness. The “Tumor microenvironment” section links hypoxia to new blood-vessel formation, the “Metastasis” section links it to increased spread, and the Conclusion states that hypoxia regulates metabolism. Together, these passages support the cited sentence’s broad paraphrase. (LLM, conf=0.92)

  cites [197] source

In the paper

“By using co-culture models, it was found that cancer-associated fibroblasts may promote cancer cell invasion [143].”

What the sources say

• Supported

  The Results section reports that secretions from a co-culture in which fibroblasts became cancer-associated fibroblasts induced invasion of A549 and SPCA-1 lung cancer cells; invasion was not observed with ordinary fibroblast secretions. This supports the citing sentence’s hedged claim based on a co-culture model. Page numbers were not supplied. (LLM, conf=0.93)

  cites [143] source

In the paper

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

In the paper

“Moreover, VEGF is expressed in varying quantities within a tumor.”

In the paper

“It is important to note here that the upregulation of VEGF is only one of the pathways through which angiogenesis is induced.”

In the paper

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

In the paper

“Indeed, this has made mouse models highly popular with researchers (65% of 949 oncology papers published in 2016 utilized a mouse tumor model [42]).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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]).”

What the sources say

• ?Not checked — no full text of the sourcecites [47] 47. Thiery, J.P., et al., Epithelial-Mesenchymal Transitions in Development and Disease. Cell, 2009. 139(5): p. 871-890. source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“By doing so, cell growth is enhanced by stiffening and cell-cell junction integrity is compromised, impeding lumen formation.”

In the paper

“However, scaffold base culture also has drawbacks of batch variance, limited throughput, non-uniform spheroid size and distribution [63].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [77][78][79][80][81]

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not matched

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

  cites [87][88][89][90][91]

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [94][95][96][97]107]

In the paper

“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.”

In the paper

“Although the size of spheroids generated using this method varies in a large range, this problem can be overcome by using microarrays instead [66].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Endothelial cells are one of the major components of blood vessels and play an important role in tumor angiogenesis [121].”

What the sources say

• ?Not checked — no full text of the sourcecites [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,

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [151] source

In the paper

“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 the paper

“Different from normal fibroblasts, cancer-associated fibroblasts proliferate faster, produce more extracellular matrix and secrete unique cytokine, which significantly enhances carcinogenesis [123, 124].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“It enhances tumor cell proliferation and builds up a transport barrier to drug delivery, greatly lowering the efficacy of anticancer drugs and therapies.”

What the sources say

• ?Not checked — no full text of the sourcecites [170] source
• ?Not checked — no full text of the sourcecites [171] source
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  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [172]
• ?Not checked — no full text of the sourcecites [173]
• ?Not checked — no full text of the sourcecites [174]
• ?Not checked — no full text of the sourcecites [175]
• ?Not checked — no full text of the sourcecites [176]
• ?Not checked — no full text of the sourcecites [177] source
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  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [178]

In the paper

“This dynamic response was regulated by the β-catenin dependent Wnt signaling pathway [202].”

What the sources say

• ?Not checked — no full text of the sourcecites [202] source

In the paper

“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).”

In the paper

“A hypoxic environment can be easily incorporated into most existing systems by using a hypoxic incubator or a hypoxic workstation [194].”

What the sources say

• ?Not checked — no full text of the sourcecites [194] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [193] source
• ?Not checked — no full text of the sourcecites [194] source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [166][167][168][169]

In the paper

“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.”

In the paper

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

In the paper

“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.”