Study of diffusive- and convective-transport mediated microtumor growth in a controlled microchamber
- 44 Downloads
In this paper, we report on using mass transport to control nutrition supply of colorectal cancer cells for developing a microtumor in a confined microchamber. To mimic the spatial heterogeneity of a tumor, two microfluidic configurations based on resistive circuits are designed. One has a convection-dominated microchamber to simulate the tumor region proximal to leaky blood vessels. The other has a diffusion-dominated microchamber to mimic the tumor core that lacks blood vessels and nutrient supply. Thus, the time for nutrition to fill the microchamber can vary from tens of minutes to several hours. Results show that cells cultured under a diffusive supply of nutrition have a high glycolytic rate and a nearly constant oxygen consumption rate. In contrast, cells cultured under convective supply of nutrition have a gradual increase of oxygen consumption rate with a low glycolytic rate. This suggests that cancer cells have distinct reactions under different mass transport and nutrition supply. Using these two microfluidic platforms to create different rate of nutrition supply, it is found that a continuous microtumor that almost fills the mm-size microchamber can be developed under a low-nutrient supply environment, but not for the convective condition. It also is demonstrated that microchannels can simulate the delivery of anti-cancer drugs to the microtumor under controlled mass-transport. This method provides a means to develop a larger scale microtumor in a lab-on-a-Chip system for post development and stimulations, and microchannels can be applied to control the physical and chemical environment for anti-cancer drug screening.
KeywordsTumor-on-a-Chip Mass transport Microfluidics Tumor metabolic Drug screening
This work was supported by the National Health Research Institutes, Taiwan (NHRI-EX106-10624EI) and the Ministry of Science and Technology, Taiwan (MOST 103-2221-E-002-161-MY2 & MOST 105-2221-E-002-230-MY3).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- S. Bersini, J.S. Jeon, G. Dubini, C. Arrigoni, S. Chung, J.L. Charest, M. Moretti, R.D. Kamm, A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials 35(8), 2454–2461 (2014). https://doi.org/10.1016/j.biomaterials.2013.11.050 CrossRefGoogle Scholar
- N. Hammad, M. Rosas-Lemus, S. Uribe-Carvajal, M. Rigoulet, A. Devin, The Crabtree and Warburg effects: Do metabolite-induced regulations participate in their induction? Biochim. Biophys. Acta, Rev. Bioenerg. 1857(8), 1139–1146 (2016). https://doi.org/10.1016/j.bbabio.2016.03.034 CrossRefGoogle Scholar
- K. Luongo, A. Holton, A. Kaushik, P. Spence, B. Ng, R. Deschenes, S. Sundaram, S. Bhansali, Microfluidic device for trapping and monitoring three dimensional multicell spheroids using electrical impedance spectroscopy. Biomicrofluidics 7, 034108 (2013). https://doi.org/10.1063/1.4809590 CrossRefGoogle Scholar
- Y. Nashimoto, T. Hayashi, I. Kunita, A. Nakamasu, Y.S. Torisawa, M. Nakayama, H. Takigawa-Imamura, H. Kotera, K. Nishiyama, T. Miura, R. Yokokawa, Integrating perfusable vascular networks with a three-dimensional tissue in a microfluidic device. Integr. Biol. 9, 506–518 (2017). https://doi.org/10.1039/C7IB00024C CrossRefGoogle Scholar
- D.T.T. Phan, X. Wang, B.M. Craver, A. Sobrino, D. Zhao, J.C. Chen, L.Y.N. Lee, S.C. George, A.P. Lee, C.C.W. Hughes, A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. Lab Chip 17(3), 511–520 (2017). https://doi.org/10.1039/c6lc01422d CrossRefGoogle Scholar
- K.J. Rakesh, Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 50(3 Suppl), 814s–819s (1990) http://cancerres.aacrjournals.org/content/50/3_Supplement/814s Google Scholar
- M. Singh, D.A. Close, S. Mukundan, P.A. Johnston, S. Sant, Production of uniform 3D microtumors in hydrogel microwell arrays for measurement of viability, morphology, and signaling pathway activation. Assay Drug Dev. Technol. 13(9), 570–583 (2015). https://doi.org/10.1089/adt.2015.662 CrossRefGoogle Scholar
- I.K. Zervantonakis, S.K. Hughes-Alford, J.L. Charest, J.S. Condeelis, F.B. Gertler, R.D. Kamm, Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc. Natl. Acad. Sci. U. S. A. 109(34), 13515–13520 (2012). https://doi.org/10.1073/pnas.1210182109 CrossRefGoogle Scholar