3D printed microfluidic chip for multiple anticancer drug combinations

Abstract Multi-drug combinations therapy is a promising method in the fight against cancer cells. Multi-drug combinations cannot be practically elucidated using conventional devices owing to structural limitations or operational complexity. 3D printing has recently attracted attention as a way to fabricate complicated and interconnected microfluidic channels, which is of design flexibility. Here, an easy-to-use, high-throughput, multi-drug combinations 3D printed microfluidic chips were brought forward. 36 discrete concentration combinations have been generated by repeated splitting-and-mixing of four inlet drugs in interconnected network channels, which are used to determine the optimal concentration of inhibition of cancer cells survival. We evaluate the potential to advance multi-drug combinations efficiency by optimizing the geometric parameters of tree-shaped branch unit, as well as the chip performance by dye visualization. The microfluidic chip was further applied to study multi-drug combinations responses, and the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay was employed to test the cytotoxic effect of four drugs combinations on A549. The experiment results demonstrated clinically relevant antagonistic, synergistic interactions between the four different antitumor drugs. Moreover, this chip has outstanding features, e.g., more compact structure, more accurate combination of concentrations, greater space for scalability. As such, it will be an effective multi-drug combinations screening platform for applications in biomedical research and clinical medicine.

[1]  Jie Lu,et al.  In Vivo Evolution of Tumor-Derived Endothelial Cells , 2012, PloS one.

[2]  Michael R Green,et al.  Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A , 2014, Proceedings of the National Academy of Sciences.

[3]  J. Trzcińska-Danielewicz,et al.  Synergy of BID with doxorubicin in the killing of cancer cells , 2015, Oncology reports.

[4]  Yu-Chong Tai,et al.  A 3-D microfluidic combinatorial cell array , 2011, Biomedical microdevices.

[5]  Xiuqing Gong,et al.  Wax-bonding 3D microfluidic chips. , 2010, Lab on a chip.

[6]  G. Whitesides,et al.  Generation of Solution and Surface Gradients Using Microfluidic Systems , 2000 .

[7]  M. Chudy,et al.  A microfluidic system to study the cytotoxic effect of drugs: the combined effect of celecoxib and 5-fluorouracil on normal and cancer cells , 2013, Microchimica Acta.

[8]  Liu Jian.  Effects of several commonly used chemotherapeutic drugs on expression of human lung cell carcinoma livin gene , 2011 .

[9]  Chengpeng Chen,et al.  3D-printed Microfluidic Devices: Fabrication, Advantages and Limitations-a Mini Review. , 2016, Analytical methods : advancing methods and applications.

[10]  Tobias Bollenbach,et al.  Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution. , 2015, Current opinion in microbiology.

[11]  Q S Zheng,et al.  Analysis of drug interactions in combined drug therapy by reflection method. , 2000, Acta pharmacologica Sinica.

[12]  A. Folch,et al.  A multi-purpose microfluidic perfusion system with combinatorial choice of inputs, mixtures, gradient patterns, and flow rates. , 2009, Lab on a chip.

[13]  Albert Folch,et al.  The upcoming 3D-printing revolution in microfluidics. , 2016, Lab on a chip.

[14]  Liangfang Zhang,et al.  Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. , 2012, Biochemical pharmacology.

[15]  Q S Zheng,et al.  Analysis of multidrug effects by parameter method. , 1998, Zhongguo yao li xue bao = Acta pharmacologica Sinica.

[16]  Kwok-Kin Wong,et al.  Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. , 2011, Cancer cell.

[17]  Jian-Hua Wang,et al.  A radial microfluidic concentration gradient generator with high-density channels for cell apoptosis assay. , 2011, Lab on a chip.

[18]  Jun Miao,et al.  Arbitrarily Accessible 3D Microfluidic Device for Combinatorial High-Throughput Drug Screening , 2016, Sensors.

[19]  S. Sugiura,et al.  Generation of arbitrary monotonic concentration profiles by a serial dilution microfluidic network composed of microchannels with a high fluidic-resistance ratio. , 2009, Lab on a chip.

[20]  Fang Liu,et al.  Comparison of Efficacy and Toxicity of Traditional Chinese Medicine (TCM) Herbal Mixture LQ and Conventional Chemotherapy on Lung Cancer Metastasis and Survival in Mouse Models , 2014, PloS one.

[21]  L Norberg,et al.  Anaesthetic effects of flurazepam alone and in combination with thiopental or hexobarbital evaluated with an EEG-threshold method in male rats. , 1988, Archives internationales de pharmacodynamie et de therapie.

[22]  Van M. Savage,et al.  Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs , 2016, Journal of The Royal Society Interface.

[23]  Rafał Walczak,et al.  Inkjet 3D printing of microfluidic structures—on the selection of the printer towards printing your own microfluidic chips , 2015 .

[24]  Yanan Du,et al.  A ready-to-use, versatile, multiplex-able three-dimensional scaffold-based immunoassay chip for high throughput hepatotoxicity evaluation. , 2015, Lab on a chip.

[25]  B. Lin,et al.  Cell-based high content screening using an integrated microfluidic device. , 2007, Lab on a chip.

[26]  Wei-Xue Tang,et al.  Interaction between cisplatin, 5-fluorouracil and vincristine on human hepatoma cell line (7721). , 1998, World journal of gastroenterology.

[27]  Dana M Spence,et al.  Recent Advances in Analytical Chemistry by 3D Printing. , 2017, Analytical chemistry.

[28]  Michal Chudy,et al.  PDMS/glass microfluidic cell culture system for cytotoxicity tests and cells passage , 2010 .

[29]  Sidra Waheed,et al.  3D printed microfluidic devices: enablers and barriers. , 2016, Lab on a chip.

[30]  Kit S Lam,et al.  Microfluidic-Enabled Print-to-Screen Platform for High-Throughput Screening of Combinatorial Chemotherapy. , 2015, Analytical chemistry.

[31]  Liwei Lin,et al.  3D printed three-flow microfluidic concentration gradient generator for clinical E. Coli-antibiotic drug screening , 2017, 2017 IEEE 30th International Conference on Micro Electro Mechanical Systems (MEMS).

[32]  Chee Meng Benjamin Ho,et al.  3D printed microfluidics for biological applications. , 2015, Lab on a chip.

[33]  G. Whitesides,et al.  Generation of Gradients Having Complex Shapes Using Microfluidic Networks , 2001 .

[34]  Gurusamy Mariappan,et al.  Abstract 3325: Combination of DNMT and HDAC inhibitors reprogram cancer stem cell signaling to overcome drug resistance , 2016 .

[35]  Rui Liu,et al.  Potentiation of paclitaxel activity by curcumin in human breast cancer cell by modulating apoptosis and inhibiting EGFR signaling , 2014, Archives of pharmacal research.

[36]  Bethany C Gross,et al.  Evaluation of 3D printing and its potential impact on biotechnology and the chemical sciences. , 2014, Analytical chemistry.

[37]  Kwangmi Kim,et al.  Microfluidic System Based High Throughput Drug Screening System for Curcumin/TRAIL Combinational Chemotherapy in Human Prostate Cancer PC3 Cells , 2014, Biomolecules & therapeutics.

[38]  A. Khademhosseini,et al.  An integrated microfluidic device for two-dimensional combinatorial dilution. , 2011, Lab on a chip.

[39]  G. Whitesides.  The origins and the future of microfluidics , 2006, Nature.

[40]  Tae Hyeon Kim,et al.  Analysis of 3D multi‐layer microfluidic gradient generator , 2017, Electrophoresis.

[41]  A. Jayaraman,et al.  A programmable microfluidic cell array for combinatorial drug screening. , 2012, Lab on a chip.

[42]  R D Sochol,et al.  3D printed microfluidic circuitry via multijet-based additive manufacturing. , 2016, Lab on a chip.

[43]  Ernst J. Wolvetang,et al.  Microbioreactor Arrays for Full Factorial Screening of Exogenous and Paracrine Factors in Human Embryonic Stem Cell Differentiation , 2012, PloS one.

[44]  A. Jayaraman,et al.  Microfluidic geometric metering-based multi-reagent mixture generator for robust live cell screening array , 2014, Biomedical Microdevices.

[45]  Donald Wlodkowic,et al.  Three-dimensional printed millifluidic devices for zebrafish embryo tests. , 2015, Biomicrofluidics.