Simultaneous or Sequential Orthogonal Gradient Formation in a 3D Cell Culture Microfluidic Platform
Open accessAbstract
Biochemical gradients are ubiquitous in biology. At the tissue level, they dictate differentiation patterning or cell migration. Recapitulating in vitro the complexity of such concentration profiles with great spatial and dynamic control is crucial in order to understand the underlying mechanisms of biological phenomena. Here, a microfluidic design capable of generating diffusion‐driven, simultaneous or sequential, orthogonal linear concentration gradients in a 3D cell‐embedded scaffold is described. Formation and stability of the orthogonal gradients are demonstrated by computational and fluorescent dextran‐based characterizations. Then, system utility is explored in two biological systems. First, stem cells are subjected to orthogonal gradients of morphogens in order to mimic the localized differentiation of motor neurons in the neural tube. Similarly to in vivo, motor neurons preferentially differentiate in regions of high concentration of retinoic acid and smoothened agonist (acting as sonic hedgehog), in a concentration‐dependent fashion. Then, a rotating gradient is applied to HT1080 cancer cells and the change in migration direction is investigated as the cells adapt to a new chemical environment. The response time of ≈4 h is reported. These two examples demonstrate the versatility of this new design that can also prove useful in many applications including tissue engineering and drug screening.
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Different types of cancer cells may react differently to the same chemical stimuli.
“By observing cell behavior in these devices, it was found that different types of cancer cells may react differently to the same chemical stimuli.”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [199]
Section 2.3 reports that HT1080 cancer cells responded to a chemical gradient, supporting the claim that cancer cells can react to chemical stimuli. It does not show different cancer cell types responding differently to the same stimulus: its comparison with MDA-MB-231 cells concerns interstitial flow, a different cue. (LLM, conf=0.83)
Experimental — accuracy not yet measuredImmune cells can both enhance and inhibit malignant cell proliferation, migration, and metastasis.
“Immune cells were shown to both enhance and inhibit malignant cells proliferation, migration, and metastasis [125-128].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [127]
Section 2.3 discusses cancer-cell migration in the metastatic cascade and responses to chemical gradients, but does not address immune cells enhancing or inhibiting malignant-cell proliferation, migration, or metastasis. Searches for immune-cell effects and tumor proliferation found no passage supporting the attributed point; no page number was provided in our copy. (LLM, conf=0.76)
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References 65 · Cited by 100
Research works printed but not linked: 3
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- Authors
- Uzel, S. G. M., Amadi, O. C., Pearl, T. M., Lee, R. T., So, P. T. C., & Kamm, R. D.
- Affiliations
- Massachusetts Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Kamm, Roger D.
- Venue
- Small
- Publisher
- Wiley
- Published
- 2015-11-30
- Volume
- 12
- Issue
- 5
- Pages
- 612-622
- ISSN
- 1613-6810 (ISSN-L)
- 1613-6829
- PMC
- PMC4752442
- OpenAlex
- W2181487307
- Cited by
- 100
- References
- 65
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 10 · 2021: 7 · 2020: 20 · 2019: 13 · 2018: 9 · 2017: 11 · 2016: 8
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Small (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- National Science Foundation Science and Technology Center for Emergent Behaviors of Integrated Cellular Systems (CBET-0939511)
- NIH NRSA/UNCF Merck
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- microfluidic gradient generator, 3D cell culture, stem cell differentiation, motor neuron differentiation, retinoic acid, Sonic hedgehog, Smoothened agonist, cell migration, fluorescent dextran, tissue engineering, drug screening
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Chemotaxis, Cyclohexylamines, Equipment Design, Humans, Motor Neurons, Thiophenes, Time Factors, Tretinoin, Cell Culture Techniques, Hydrogel, Polyethylene Glycol Dimethacrylate, Microfluidic Analytical Techniques, Mice, Neural Tube
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