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

The DOI matches its Crossref record; 228 of the 228 references it cites were found in a registry or an index; 15 of the 193 sources its claims cite were checked for support.

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

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

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

Overview

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TL;DR

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

Key findings

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

Methods

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

Limitations

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

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Registry

Crossref · 10.1038/s41378-021-00277-8

Cites

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Statistics

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Figures

Fig. 1 Schematic of the tumor-on-a-chip platform for modeling tumor cell tissue structure and functional units in vitro. Tumor-on-a-chip platforms can be generally prepared by photolithography and 3D bioprinting and applied in cancer biology and anticancer therapy research.
Fig. 1 Schematic of the tumor-on-a-chip platform for modeling tumor cell tissue structure and functional units in vitro. Tumor-on-a-chip platforms can be generally prepared by photolithography and 3D bioprinting and applied in cancer biology and anticancer therapy research.CC BY · PubMed Central
Fig. 2 Microfabrication techniques for tumor-on-a-chip. a, b Use of photolithography and soft lithography to fabricate a simple PDMS microfluidic culture device, conformally sealing it to a flat glass substrate. Adapted with permission136. Copyright 2013, RSC. c Use of microcontact printing to generate a protein pattern for cell culture. Adapted with permission144. Copyright 2000, Wiley.
Fig. 2 Microfabrication techniques for tumor-on-a-chip. a, b Use of photolithography and soft lithography to fabricate a simple PDMS microfluidic culture device, conformally sealing it to a flat glass substrate. Adapted with permission136. Copyright 2013, RSC. c Use of microcontact printing to generate a protein pattern for cell culture. Adapted with permission144. Copyright 2000, Wiley.CC BY · PubMed Central
Fig. 3 Bioprinting technology for tumor-on-a-chip fabrication. a Using 3D bioprinting to create microfluidic chips for 2D/3D microtissue culture. Adapted with permission130. Copyright 2017, American Institute of Physics. b 3D bioprinting was used to produce different patterns and complex 3D microstructures to model the TME. Adapted with permission158. Copyright 2019, Elsevier. c Using 3D bioprinting to fabricate heterogeneous tissues: 3D microwells were constructed to facilitate spheroid formation and vascularized tissue models. Adapted with permission159. Copyright 2016, Whioce Publishing Pte. Ltd.
Fig. 3 Bioprinting technology for tumor-on-a-chip fabrication. a Using 3D bioprinting to create microfluidic chips for 2D/3D microtissue culture. Adapted with permission130. Copyright 2017, American Institute of Physics. b 3D bioprinting was used to produce different patterns and complex 3D microstructures to model the TME. Adapted with permission158. Copyright 2019, Elsevier. c Using 3D bioprinting to fabricate heterogeneous tissues: 3D microwells were constructed to facilitate spheroid formation and vascularized tissue models. Adapted with permission159. Copyright 2016, Whioce Publishing Pte. Ltd.CC BY · PubMed Central
Fig. 4 Advanced tumor-on-a-chip models. a Microfluidic device for drug testing and flow cytometry analysis of tumor spheroids. I Two-layered microfluidic devices with different culture chamber geometries to prepare spheroids of different sizes for drug testing. II Microscopic cross-sectional views of microfluidic devices with different culture chamber geometries. Scale bar is 500 μm. Adapted with permission178. Copyright 2016, Springer Nature. b A microfluidic platform of perfusable microvascular beds to produce vascularized three-dimensional human microtissues. Adapted with permission182. Copyright 2016, Springer Nature. c A microfluidic metastasis chip platform for microvessel formation to analyze cancer angiogenesis and intravasation. I Schematic diagram of the microfluidic metastasis chip. II Microvessel formation. III Cancer angiogenesis. IV Cancer intravasation. Adapted with permission183. Copyright 2016, Springer Nature.
Fig. 4 Advanced tumor-on-a-chip models. a Microfluidic device for drug testing and flow cytometry analysis of tumor spheroids. I Two-layered microfluidic devices with different culture chamber geometries to prepare spheroids of different sizes for drug testing. II Microscopic cross-sectional views of microfluidic devices with different culture chamber geometries. Scale bar is 500 μm. Adapted with permission178. Copyright 2016, Springer Nature. b A microfluidic platform of perfusable microvascular beds to produce vascularized three-dimensional human microtissues. Adapted with permission182. Copyright 2016, Springer Nature. c A microfluidic metastasis chip platform for microvessel formation to analyze cancer angiogenesis and intravasation. I Schematic diagram of the microfluidic metastasis chip. II Microvessel formation. III Cancer angiogenesis. IV Cancer intravasation. Adapted with permission183. Copyright 2016, Springer Nature.CC BY · PubMed Central
Fig. 5 Some examples of lung-on-a-chip models. a Biologically inspired design of organ-level lung functions on a chip. I A lung mimic device with an alveolar–capillary barrier was fabricated using PDMS in combination with applying vacuum to the chambers. II Illustration diagram of the interaction of pulmonary alveoli with adjacent capillaries. III Fabrication of a microfluidic device with three parallel microchannels separated by a 10 μm-thick PDMS membrane. Scale bar, 200 μm. IV A PDMS etchant is used to selectively etch the membrane layers to form two large side chambers to which vacuum is applied to cause mechanical stretching. V Photos of an actual lung-on-a-chip microfluidic device viewed from above. Adapted with permission131. Copyright 2010, Science. b Human orthotopic lung cancer on-a-chip models. I Schematic diagram of a 2-channel microchannel chip coculturing NSCLC tumor cells and human lung microvascular endothelial cells to form a hollow vascular cavity. II Confocal fluorescence micrograph of a cross section of the two central cell-lined channels of an alveolar chip. Scale bar, 200 μm. III Immunofluorescence micrograph of an implanted cluster of GFP-labeled NSCLC cells (green) cultured in an airway chip at 1, 14, and 28 days after implantation. Scale bar, 100 μm. IV Quantification of NSCLC tumor cell densities when cultured for up to 1 month after implantation in the fully differentiated airway chip. Adapted with permission98. Copyright 2017, Elsevier. c A lung/liver-on-a-chip device for acute and chronic toxicity studies to predict the safety of inhaled compounds. I A schematic diagram of the lung/liver-on-a-chip platform. II The eight pictograms show the location of NHBE ALI tissues placed in the liver chamber and lung chamber for 28 days of culture. The flow control board was connected to the liquid storage board. III Representative histological sections of NHBE ALI tissues after 28 days of culture under static and dynamic conditions. IV Representative images of NHBE ALI tissues maintained under static or dynamic conditions for 28 days stained with β-tubulin 4 (green) and MUC5AC (yellow). Adapted with permission79. Copyright 2018, Royal Society of Chemistry.
Fig. 5 Some examples of lung-on-a-chip models. a Biologically inspired design of organ-level lung functions on a chip. I A lung mimic device with an alveolar–capillary barrier was fabricated using PDMS in combination with applying vacuum to the chambers. II Illustration diagram of the interaction of pulmonary alveoli with adjacent capillaries. III Fabrication of a microfluidic device with three parallel microchannels separated by a 10 μm-thick PDMS membrane. Scale bar, 200 μm. IV A PDMS etchant is used to selectively etch the membrane layers to form two large side chambers to which vacuum is applied to cause mechanical stretching. V Photos of an actual lung-on-a-chip microfluidic device viewed from above. Adapted with permission131. Copyright 2010, Science. b Human orthotopic lung cancer on-a-chip models. I Schematic diagram of a 2-channel microchannel chip coculturing NSCLC tumor cells and human lung microvascular endothelial cells to form a hollow vascular cavity. II Confocal fluorescence micrograph of a cross section of the two central cell-lined channels of an alveolar chip. Scale bar, 200 μm. III Immunofluorescence micrograph of an implanted cluster of GFP-labeled NSCLC cells (green) cultured in an airway chip at 1, 14, and 28 days after implantation. Scale bar, 100 μm. IV Quantification of NSCLC tumor cell densities when cultured for up to 1 month after implantation in the fully differentiated airway chip. Adapted with permission98. Copyright 2017, Elsevier. c A lung/liver-on-a-chip device for acute and chronic toxicity studies to predict the safety of inhaled compounds. I A schematic diagram of the lung/liver-on-a-chip platform. II The eight pictograms show the location of NHBE ALI tissues placed in the liver chamber and lung chamber for 28 days of culture. The flow control board was connected to the liquid storage board. III Representative histological sections of NHBE ALI tissues after 28 days of culture under static and dynamic conditions. IV Representative images of NHBE ALI tissues maintained under static or dynamic conditions for 28 days stained with β-tubulin 4 (green) and MUC5AC (yellow). Adapted with permission79. Copyright 2018, Royal Society of Chemistry.CC BY · PubMed Central
Fig. 6 Different types of tumor-on-a-chip platforms. a Schematics of the tumor-on-a-chip design for metastatic breast cancer research. The chip is made up of a top culture medium reservoir and a bottom cell growth chamber, separated by a dialysis membrane. Adapted with permission213. Copyright 2018, Wiley. b Microfluidic device-cultured BTSCs to study glioma. I A schematic diagram of the tumor chip platform, consisting of a cell/gel loading microchamber and two medium flow channels on both sides. II Representative images of microvessel formation at different time points over 6 days. III A whole chip scan showing interconnected microvessel network formation on day 4. Adapted with permission196. Copyright 2019, Wiley. c Biomimetic vascular microfluidic system on a human-on-leaf-chip for studying organ-specific pancreatic cancer metastasis. I Photograph of the assembled biomimetic vascular human-on-leaf-chip system. II Image of the chambers of interconnected biomimetic vascular networks in the chip filled with red ink. III Schematic diagram of the vascularization of liver and bone tissue in the biomimetic vascular system where PANC-1 cancer cells have metastasized. Adapted with permission217. Copyright 2020, Wiley.
Fig. 6 Different types of tumor-on-a-chip platforms. a Schematics of the tumor-on-a-chip design for metastatic breast cancer research. The chip is made up of a top culture medium reservoir and a bottom cell growth chamber, separated by a dialysis membrane. Adapted with permission213. Copyright 2018, Wiley. b Microfluidic device-cultured BTSCs to study glioma. I A schematic diagram of the tumor chip platform, consisting of a cell/gel loading microchamber and two medium flow channels on both sides. II Representative images of microvessel formation at different time points over 6 days. III A whole chip scan showing interconnected microvessel network formation on day 4. Adapted with permission196. Copyright 2019, Wiley. c Biomimetic vascular microfluidic system on a human-on-leaf-chip for studying organ-specific pancreatic cancer metastasis. I Photograph of the assembled biomimetic vascular human-on-leaf-chip system. II Image of the chambers of interconnected biomimetic vascular networks in the chip filled with red ink. III Schematic diagram of the vascularization of liver and bone tissue in the biomimetic vascular system where PANC-1 cancer cells have metastasized. Adapted with permission217. Copyright 2020, Wiley.CC BY · PubMed Central
Fig. 7 Applications of tumor-on-a-chip systems. a Based on the alveolar microenvironment, a lung organ chip was developed for lung cancer research. I Alveolar structure. II Schematic diagram of the preparation of the PLGA nanofiber membrane microfluidic chip by electrostatic spinning. III Schematic diagram of A549 cells cultured on chip. IV Schematic diagram of the coculture of A549 and HFL1 cells on a chip. V Schematic diagram of the coculture of A549, HFL1 and HUVECs on a chip. Adapted with permission80. Copyright 2018, The Royal Society of Chemistry. b Multiorgan system platforms for modeling tumor morphology and testing drug response. I 3D model device that aggregates liver cells and cancer cells for drug testing219. II Model of a multiorgan system on a plate for multithroughput. III HCT-116 cell activity was detected on the 3rd day of culture. Green: living cells; Red: dead cells. Scale bars: 500 µm9. Adapted with permission219 and 9. Copyright 2012, Biomaterials Publishing Group and Copyright 2018, The Royal Society of Chemistry, respectively. c Schematic of the cross-sectional view of the 3D stem cell differentiation assay using BMA-EDMA-based hydrogel patterning. Adapted with permission223. Copyright 2018, Wiley. d The design and biofabrication of a metastasis‐on‐a‐chip system for evaluating the metastatic preference of cancer cells. Adapted with permission117. Copyright 2019, American Chemical Society. e Design and preparation of a multiorgan microfluidic chip to mimic the in vivo microenvironment of lung cancer metastasis. The chip was made of PDMS, consisting of an upstream “lung organ” and three downstream “distant organs”. Different types of cells, including bronchial epithelial cells, stromal cells and cancer cells, were cocultured in the system, and some physical factors, such as air and pressure, were applied to the system to reconstitute the tissue-tissue interfaces and dynamic microenvironments. Adapted with permission225. Copyright 2016, American Chemical Society.
Fig. 7 Applications of tumor-on-a-chip systems. a Based on the alveolar microenvironment, a lung organ chip was developed for lung cancer research. I Alveolar structure. II Schematic diagram of the preparation of the PLGA nanofiber membrane microfluidic chip by electrostatic spinning. III Schematic diagram of A549 cells cultured on chip. IV Schematic diagram of the coculture of A549 and HFL1 cells on a chip. V Schematic diagram of the coculture of A549, HFL1 and HUVECs on a chip. Adapted with permission80. Copyright 2018, The Royal Society of Chemistry. b Multiorgan system platforms for modeling tumor morphology and testing drug response. I 3D model device that aggregates liver cells and cancer cells for drug testing219. II Model of a multiorgan system on a plate for multithroughput. III HCT-116 cell activity was detected on the 3rd day of culture. Green: living cells; Red: dead cells. Scale bars: 500 µm9. Adapted with permission219 and 9. Copyright 2012, Biomaterials Publishing Group and Copyright 2018, The Royal Society of Chemistry, respectively. c Schematic of the cross-sectional view of the 3D stem cell differentiation assay using BMA-EDMA-based hydrogel patterning. Adapted with permission223. Copyright 2018, Wiley. d The design and biofabrication of a metastasis‐on‐a‐chip system for evaluating the metastatic preference of cancer cells. Adapted with permission117. Copyright 2019, American Chemical Society. e Design and preparation of a multiorgan microfluidic chip to mimic the in vivo microenvironment of lung cancer metastasis. The chip was made of PDMS, consisting of an upstream “lung organ” and three downstream “distant organs”. Different types of cells, including bronchial epithelial cells, stromal cells and cancer cells, were cocultured in the system, and some physical factors, such as air and pressure, were applied to the system to reconstitute the tissue-tissue interfaces and dynamic microenvironments. Adapted with permission225. Copyright 2016, American Chemical Society.CC BY · PubMed Central
Fig. 8 Illustration of tumor-on-a-chip devices applied to drug screening. a The microdissected tumor/tissue samples (MDTs) were incubated in independent chambers of a microfluidics chip to assess one or several selected drug candidates. Some were treated with drugs, and the others were kept as nontreated controls. MDTs were labeled with viability dyes: CTG (live, green) and PI (dead, red). Adapted with permission121. Copyright 2016, The Royal Society of Chemistry. b A vascularized and perfused organ-on-a-chip platform for large-scale drug screening has been applied to some FDA-approved anticancer drug-blinded screenings, successfully identifying both antiangiogenesis and antitumor drugs. Adapted with permission86. Copyright 2017, The Royal Society of Chemistry. c Comparison diagram of the microfluidic chip models made by PMMA and PDMS. I The PMMA-PETE device with flat PETE membrane. II The PDMS-PETE device with wrinkled PETE membrane. III Confocal microscopic images of human lung adenocarcinoma cells cultured on PETE membrane in the PMMA and PDMS devices and stained with calcein. Adapted with permission164. Copyright 2019, The Royal Society of Chemistry. d The five-chamber reconfigurable multiorgan system platform used to evaluate the efficacy and off-target toxicity of anticancer drugs. I Computational fluid dynamics modeling. II Photograph of the multi-organ system. III Representative phase contrast images of Kasumi-1 and megakaryocytes growing inside the multi-organ system chamber on days in vitro (DIV) 1, 7, and 14. Adapted with permission230.
Fig. 8 Illustration of tumor-on-a-chip devices applied to drug screening. a The microdissected tumor/tissue samples (MDTs) were incubated in independent chambers of a microfluidics chip to assess one or several selected drug candidates. Some were treated with drugs, and the others were kept as nontreated controls. MDTs were labeled with viability dyes: CTG (live, green) and PI (dead, red). Adapted with permission121. Copyright 2016, The Royal Society of Chemistry. b A vascularized and perfused organ-on-a-chip platform for large-scale drug screening has been applied to some FDA-approved anticancer drug-blinded screenings, successfully identifying both antiangiogenesis and antitumor drugs. Adapted with permission86. Copyright 2017, The Royal Society of Chemistry. c Comparison diagram of the microfluidic chip models made by PMMA and PDMS. I The PMMA-PETE device with flat PETE membrane. II The PDMS-PETE device with wrinkled PETE membrane. III Confocal microscopic images of human lung adenocarcinoma cells cultured on PETE membrane in the PMMA and PDMS devices and stained with calcein. Adapted with permission164. Copyright 2019, The Royal Society of Chemistry. d The five-chamber reconfigurable multiorgan system platform used to evaluate the efficacy and off-target toxicity of anticancer drugs. I Computational fluid dynamics modeling. II Photograph of the multi-organ system. III Representative phase contrast images of Kasumi-1 and megakaryocytes growing inside the multi-organ system chamber on days in vitro (DIV) 1, 7, and 14. Adapted with permission230.CC BY · PubMed Central

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  • The paper relies on this without support.

    Oxygen tension is a key regulator of cellular behavior.

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    The tissue itself is composed of different cell types.

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

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

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

Cites

Research works printed but not linked: 7

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

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Metadata

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

About these checks

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

A language model drew the claims from the paper on 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (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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