Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments

doi:10.1088/1674-1056/ac381c

中国物理B ›› 2022, Vol. 31 ›› Issue (2): 28703-028703.doi: 10.1088/1674-1056/ac381c

Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments

Guoqiang Li(李国强)^1,†, Yanping Liu(刘艳平)^1,†, Jingru Yao(姚静如)¹, Kena Song(宋克纳)², Gao Wang(王高)¹, Lianjie Zhou(周连杰)¹, Guo Chen(陈果)¹, and Liyu Liu(刘雳宇)^1,‡

1 Chongqing Key Laboratory of Soft Condensed Matter Physics and Smart Materials, College of Physics, Chongqing University, Chongqing 401331, China;
2 College of Medical Technology and Engineering, Henan University of Science and Technology, Henan 471023, China

收稿日期:2021-09-22 修回日期:2021-10-21 接受日期:2021-11-10 出版日期:2022-01-13 发布日期:2022-01-18
通讯作者: Liyu Liu E-mail:lyliu@cqu.edu.cn
基金资助:
Project supported by the National Natural Science Foundation of China (Grant Nos. 11974066 and 12174041), the Fundamental and Advanced Research Program of Chongqing, China (Grant No. cstc2019jcyj-msxmX0477), the Capital Health Development Research Project (Grant No. 2020-2-2072), the Key Specialized Research and Development Breakthrough of Henan Province, China (Grant No. 212102310887), and the Key Scientific Research Projects of Colleges and Universities of Henan Province, China (Grant No. 21A416005). In addition, we would like to thank Miss Qin Deng at the Analytical and Testing Center of Chongqing University for her assistance with the confocal imaging.

Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments

1 Chongqing Key Laboratory of Soft Condensed Matter Physics and Smart Materials, College of Physics, Chongqing University, Chongqing 401331, China;
2 College of Medical Technology and Engineering, Henan University of Science and Technology, Henan 471023, China

Received:2021-09-22 Revised:2021-10-21 Accepted:2021-11-10 Online:2022-01-13 Published:2022-01-18
Contact: Liyu Liu E-mail:lyliu@cqu.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China (Grant Nos. 11974066 and 12174041), the Fundamental and Advanced Research Program of Chongqing, China (Grant No. cstc2019jcyj-msxmX0477), the Capital Health Development Research Project (Grant No. 2020-2-2072), the Key Specialized Research and Development Breakthrough of Henan Province, China (Grant No. 212102310887), and the Key Scientific Research Projects of Colleges and Universities of Henan Province, China (Grant No. 21A416005). In addition, we would like to thank Miss Qin Deng at the Analytical and Testing Center of Chongqing University for her assistance with the confocal imaging.

摘要/Abstract

摘要： The in vivo tumor microenvironment is a complex niche that includes heterogeneous physical structures, unique biochemical gradients and multiple cell interactions. Its high-fidelity in vitro reconstruction is of fundamental importance to improve current understandings of cell behavior, efficacy predictions and drug safety. In this study, we have developed a high-throughput biochip with hundreds of composite extracellular matrix (ECM) microchambers to co-culture invasive breast cancer cells (MDA-MB-231-RFP) and normal breast epithelial cells (MCF-10A-GFP). The composite ECM is composed of type I collagen and Matrigel which provides a heterogeneous microenvironment that is similar to that of in vivo cell growth. Additionally, the growth factors and drug gradients that involve human epidermal growth factor (EGF), discoidin domain receptor 1 (DDR1) inhibitor 7rh and matrix metalloproteinase inhibitor batimastat allow for the mimicking of the complex in vivo biochemical microenvironment to investigate their effect on the spatial-temporal dynamics of cell growth. Our results demonstrate that the MDA-MB-231-RFP cells and MCF-10A-GFP cells exhibit different spatial proliferation behaviors under the combination of growth factors and drugs. Basing on the experimental data, we have also developed a cellular automata (CA) model that incorporated drug diffusion to describe the experimental phenomenon, as well as employed Shannon entropy (SE) to explore the effect of the drug diffusion coefficient on the spatial-temporal dynamics of cell growth. The results indicate that the uniform cell growth is related to the drug diffusion coefficient, which reveals that the pore size of the ECM plays a key role in the formation of complex biochemical gradients. Therefore, our integrated, biomimetic and high-throughput co-culture platforms, as well as the computational model can be used as an effective tool for investigating cancer pathogenesis and drug development.

关键词: microfluidic, high-throughput, biochemical gradient, cancer

Abstract: The in vivo tumor microenvironment is a complex niche that includes heterogeneous physical structures, unique biochemical gradients and multiple cell interactions. Its high-fidelity in vitro reconstruction is of fundamental importance to improve current understandings of cell behavior, efficacy predictions and drug safety. In this study, we have developed a high-throughput biochip with hundreds of composite extracellular matrix (ECM) microchambers to co-culture invasive breast cancer cells (MDA-MB-231-RFP) and normal breast epithelial cells (MCF-10A-GFP). The composite ECM is composed of type I collagen and Matrigel which provides a heterogeneous microenvironment that is similar to that of in vivo cell growth. Additionally, the growth factors and drug gradients that involve human epidermal growth factor (EGF), discoidin domain receptor 1 (DDR1) inhibitor 7rh and matrix metalloproteinase inhibitor batimastat allow for the mimicking of the complex in vivo biochemical microenvironment to investigate their effect on the spatial-temporal dynamics of cell growth. Our results demonstrate that the MDA-MB-231-RFP cells and MCF-10A-GFP cells exhibit different spatial proliferation behaviors under the combination of growth factors and drugs. Basing on the experimental data, we have also developed a cellular automata (CA) model that incorporated drug diffusion to describe the experimental phenomenon, as well as employed Shannon entropy (SE) to explore the effect of the drug diffusion coefficient on the spatial-temporal dynamics of cell growth. The results indicate that the uniform cell growth is related to the drug diffusion coefficient, which reveals that the pore size of the ECM plays a key role in the formation of complex biochemical gradients. Therefore, our integrated, biomimetic and high-throughput co-culture platforms, as well as the computational model can be used as an effective tool for investigating cancer pathogenesis and drug development.

Key words: microfluidic, high-throughput, biochemical gradient, cancer

中图分类号: (Cells on a chip)

87.85.dh

87.80.-y (Biophysical techniques (research methods)) 87.18.Gh (Cell-cell communication; collective behavior of motile cells) 87.50.cf (Biophysical mechanisms of interaction)

Guoqiang Li(李国强), Yanping Liu(刘艳平), Jingru Yao(姚静如), Kena Song(宋克纳), Gao Wang(王高), Lianjie Zhou(周连杰), Guo Chen(陈果), and Liyu Liu(刘雳宇). Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments[J]. 中国物理B, 2022, 31(2): 28703-028703.

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Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments

Biophysical model for high-throughput tumor and epithelial cell co-culture in complex biochemical microenvironments

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