Development and characterization of a microfluidic model of the tumour microenvironment
Open accessAbstract
The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening.
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Perfusion of DOX at 30 μM through the lateral microchannels significantly reduced the number of viable HCT-116 cancer cells in the hypoxic core.
“For instance, perfusion of DOX at a dose of 30 µM through the lateral microchannels significantly reduced the number of viable HCT-116 cancer cells in the hypoxic core.”
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 [36]
The Methods (Drug toxicity assays; page unavailable) confirm that 30 μM DOX was delivered through both lateral microchannels to HCT-116 cells. The Results (Drug penetration and evaluation of the impact of the microenvironment on drug responses; page unavailable) report significant cell killing near the channels, but much less killing farther away; they do not establish a significant reduction in viable cells specifically in the hypoxic core. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThere is a correlation between differences in the cytotoxic response of tumor cells and differences in the proliferative rate of cells within different regions of the tumor-on-chip.
“These experiments suggested a correlation between differences in the cytotoxic response of tumor cells and differences in the proliferative rate of cells within different regions of the tumor-on-chip.”
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 [36]
The device developed by Ayuso et al. enabled the establishment of clear oxygen gradients and hypoxic conditions and the study of anticancer drugs in cell populations under controlled oxygen gradients without spheroids.
“Due to its configuration, this device enabled the establishment of clear oxygen gradients and hypoxic conditions and the study of anticancer drugs in cell populations under controlled oxygen gradients, without resorting to the use of spheroids.”
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 [36]
Steep oxygen gradients were established within the middle chamber.
“Experiments using a fluorescent dye responsive to low oxygen concentrations further demonstrated the establishment of steep oxygen gradients within the middle chamber”
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 [36]
The configuration of the central chamber in Ayuso et al.'s device allowed the spontaneous generation of normoxic, hypoxic, and necrotic regions.
“Indeed, the configuration of the central chamber allowed the spontaneous generation of normoxic, hypoxic, and necrotic regions within the device.”
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 [36]
A necrotic core existed in the middle portion of the central chamber, suggesting the development of gradients of nutrients and oxygen.
“They demonstrated the existence of a necrotic core in the middle portion of the central chamber, suggesting the development of gradients of nutrients and oxygen”
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 [36]
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- Authors
- Ayuso, J. M., Virumbrales-Muñoz, M., Lacueva, A., Lanuza, P. M., Checa-Chavarria, E., Botella, P., Fernández, E., Doblare, M., Allison, S. J., Phillips, R. M., Pardo, J., Fernandez, L. J., & Ochoa, I.
- Affiliations
- Universidad de Zaragoza (ES)
- Universitat de Miguel Hernández d'Elx (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- University of Huddersfield (GB)
- Corresponding author
- Ochoa, Ignacio
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-10-31
- Volume
- 6
- Issue
- 1
- Pages
- 36086-36086
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5086897
- OpenAlex
- W2541191495
- Cited by
- 134
- References
- 36
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 16 · 2023: 19 · 2022: 18 · 2021: 23 · 2020: 12 · 2019: 11 · 2018: 12 · 2017: 7 · 2015: 1
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Huddersfield Repository (University of Huddersfield) (acceptedVersion)
- Huddersfield Research Portal (University of Huddersfield) (submittedVersion, cc-by)
- Zaguan (Universidad de Zaragoza) (submittedVersion, cc-by)
- 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, microfluidics, heterotypic cell interactions, oxygen gradients, glucose gradient, real-time monitoring, reactive oxygen species, apoptosis, cell proliferation, drug response, in vitro drug testing, cancer cell models
- MeSH terms
- Antineoplastic Agents, Cell Survival, Doxorubicin, Glucose, Humans, Killer Cells, Natural, Microscopy, Fluorescence, Oxygen, Apoptosis, Reactive Oxygen Species, Spheroids, Cellular, Cell Culture Techniques, Hydrogels, Microfluidics, HCT116 Cells, Cell Line, Tumor, Cell Proliferation, Time-Lapse Imaging, Tumor Microenvironment
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