Microfluidics: circulating tumor cell and ctDNA

Sponsored by: NIH R01

Liquid biopsy as a diagnostic and prognostic tool. The information derived from liquid biopsy can be used for continuous monitoring of the patients, from initial screening to personalized treatment.

(a) Gold nanorods in a patient fluid sample with probe complimentary to ctDNA of interest. (b) ctDNA hybridization onto PNA on gold nanorod. (c) Resonant red shift in the absorbance through the sample upon ctDNA binding to the PNA probe at the gold nanorod surface, with the blue curve representing the resonance before binding, and the red curve after.

a Nanoparticle placement on a non-wrinkled surface. Particles are randomly distributed. b Particle flow on wrinkled surface showing lines of particles. c Cross section view. Most NPs are inside the nanowrinkles, but very few will attach to the top edges

Our research focuses on developing technologies that shorten time-to-diagnosis for bloodstream infections through rapid pathogen identification and characterization.

  • Paper microfluidic device for the detection of volatile biomarkers.
  • Following exposure to the gas-phase above a bacterial culture (E. coli), paper sensor undergoes colorimetric shift in assay regions, and QR code directs user to test result.
  • Micro-scale platform for bacterial capture and detection from a whole blood sample.
  • Following imummunomagnetic bacterial capture, this lab-on-a-chip platform integrates a novel contact-free cell lysis method, and detects bacterial DNA through a coupled nanoplasmonic sensing platform

Publications

T. J. Palinski, B. E. Vyhnalek, G. W. Hunter, A. Tadimety, and J. X. J. Zhang, “Mode Switching in a Metallic Photonic Crystal Slab,” in Conference on Lasers and Electro-Optics, OSA Technical Digest (Optical Society of America, 2020), paper JTh2F.9.

J. Molinski, A. Tadimety, A. Burklund, J.X.J. Zhang, Scalable Signature-Based Molecular Diagnostics Through On-chip Biomarker Profiling Coupled with Machine Learning, Ann. Biomed. Eng. (2020). doi:10.1007/s10439-020-02593-y.

C. Tymm, J. Zhou, A. Tadimety, A. Burklund, J.X.J. Zhang, Scalable COVID-19 Detection Enabled by Lab-on-Chip Biosensors, Cell. Mol. Bioeng. (2020). doi:10.1007/s12195-020-00642-z.

R.Zhang, B. Le, W. Xu, H. Wan, K. Guo, X. Sun, H. Su, L. Huang, J. Huang, T. Shen, T. Liao, Y. Liang, X.J. Zhang*, H. Dai*, Q. Kun*, “Magnetic ‘squashing’ of circulating tumor cells on plasmonic substrates for ultrasensitive NIR fluorescence detection”, Small Methods, in press. (*co-corresponding authors) (Cover Image), 2019

A.Bunklund, X.J. Zhang, Microfluidic platforms for pathogen isolation from whole blood–an emerging tool for bloodstream infection diagnosis, Annals of Biomedical Engineering, in press, 2019

A.Tadimety, Y. Zhang, K. Kready, T. J. Palinski, G. Tsongalis, X.J. Zhang, ”Design of Peptide Nucleic Acid Probes on Plasmonic Nanorods for Detection of Circulating Tumor DNA Point Mutations”, Biosensors and Bioelectronics, 2019, 130, 236-244.

A.Tadimety, K. Kready, T. J. Palinski, L. Zhang, Y. Zhang, H. T. Chorsi, X.J. Zhang, “Nanowrinkled thin films for nanorod assembly in microfluidics”, Microfluidics and Nanofluidics, 2019, 23, 17.

W.Shen, Y. Song, A. Burklund, B. Le, R. Zhang, L. Wang, Y. Xie, T. Shen, K. Qian, X.J. Zhang, “Combined Immunomagetic capture with ultrasensitive plasmonic detection of circulating tumor cells in blood”, Biomedical Microdevices, DOI: 10.1007/s10544-018-0333-1, 2018, 20, 99.

A.Tadimety, A. Closson, C. Li, Y. Song, T. Shen, X.J. Zhang, “Advances in Liquid Biopsy On-Chip for Cancer Management: Technologies, Biomarkers, and Clinical Analysis”, Critical Reviews in Clinical Laboratory Sciences, accepted, 55, 140-162, 2018.

N.J. Hao, X.J. Zhang, “Microfluidic Screening of Circulating Tumor Biomarkers towards Liquid Biopsy”, Separation & Purification Reviews (Taylor & Francis), 47, 19-48, 2018.

A.Tadimety, Y. Zhang, G.J. Tsongalis, X.J. Zhang, “Screening circulating nucleic acids of pancreatic ductal adenocarcinoma using a plasmonic nanosensor”, Journal of Molecular Diagnostics, 2017; 1050.

A.Tadimety, A. Syed, Y. Nie, C. Long, X.J. Zhang, “Liquid Biopsy on Chip: A Paradigm Shift Towards the Understanding of Cancer Metastasis”, Integrative Biology, 9: 22–49, 2017.

Y.Zhu, K. Kekalo, C. N. Dong, Y. Huang, F. Shubitidze, K. Krisword, I. Baker and X.J. Zhang, “Magnetic- nanoparticle-based immunoassays-on-Chip: materials synthesis, surface functionization and cancer cell screening”, Advanced Functional Materials,26: 3953–3972, 2016.

J.Wu, X. Wei, J. Gan, J. Lou, T. Shen, B. Liu, X.J. Zhang*, K. Qian*, “Multi-functional magnetic particles for combined circulating tumor cells isolation and cellular metabolism detection”, Advanced Functional Materials (*co-corresponding authors), 26: 4016–4025, 2016.

E.Ng, K. Chen, M. Hang, A. Syed, X.J. Zhang, “Multi-dimensional nanostructure for microfluidic screening of biomarkers: from molecular separation to cancer cell detection”, Annals of Biomedical Engineering, 44(4): 847–862, 2016.

K.Hoshino, H. Chung, C. Wu, K. Rajendran, Y. Huang, P. Chen, K. Sokolov, J. Kim, X.J. Zhang, “Immunofluorescence-assisted microfluidic single-cell quantitative reverse transcription polymerase chain reaction analysis of tumor cells in blood”, Journal of Circulating Biomarkers, 4:11, 2015 (This was the most popular research paper published in this journal in 2015.)

P.Chen, Y. Huang, G. Bhave, K. Hoshino, X.J. Zhang, “Inkjet-Print Micromagnet Array on Glass Slides for Immunomagnetic Enrichment of Circulating Tumor Cells”, Annals of Biomedical Engineering, 1–11, 2015.

P.Chen, Y-Y Huang, K. Hoshino and X.J. Zhang, “Microscale Magnetic Field Modulation for Enhanced Capture and Distribution of Rare Circulating Tumor Cells”, Scientific Reports, Nature Publishing Group, 5: 8745, doi:10.1038/srep08745, 2015.

Y.-Y. Huang, P. Chen, C.H. Wu, K. Hoshino, K. Sokolov, N. Lane, H. Liu, M. Huebschman, E. Frenkel, X.J. Zhang, “Screening and Molecular Analysis of Single Circulating Tumor Cells Using Micromagnet Array”, Scientific Reports, Nature Publishing Group, 5, 16047, 2015.

P.Chen, Y.-Y. Huang, K. Hoshino, C.-H. Wu, K.V. Sokolov, X.J. Zhang, “Multiscale immunomagnetic enrichment of circulating tumor cells: from tubes to microchips”, Lab on a Chip, 14: 446–458, 2014 (Critical Review).

Y.Song, Y. Huang, X. Liu, X.J. Zhang, M. Ferrari, L. Qin, “Point-of-care technologies for molecular diagnostics using a drop of blood”, Trends in Biotechnology, review for special issue on “Blood”, 32(3): 132–139, 2014 (invited review).

C.-H. Wu, Y.-Y. Huang, K. Hoshino, P. Chen, H. Liu, E.P. Frenkel, X.J. Zhang, K.V. Sokolov, “Versatile immunomagnetic nanocarrier platform for capturing cancer cells”, ACS Nano, 7(10): 8816–8823, 2013.

E.Ng, K. Hoshino, X.J. Zhang “Microfluidic Immunodetection of Cancer Cells via Site-Specific Microcontact Printing of Antibodies on Nanoporous Surface”, Methods, 63(3): 266–75, 2013.

Z.X. Wang, D. Fine, H. Wu, J. Schmulen, Y. Hu, B. Godin, X.J. Zhang, and X. Liu, “Ciliated micropillars for the microfluidic-based isolation of nanoscale lipid vesicles”, Lab on a Chip, 13: 2879–2882, 2013.

Y.Y. Huang, K. Hoshino, P. Chen, C. Wu, N. Lane, M. Huebschman, K. Sokolov, J.W. Uhr, E.P. Frenkel and X.J. Zhang, “Immunomagnetic Nanoscreening of Circulating Tumor Cells with a Motion Controlled Microfluidic System”, Biomedical Microdevices, 15(4): 673–81, 2013.

K.Hoshino, P. Cheng, Y. Huang and X.J. Zhang, “Computational analysis of immunomagnetic rare cell separation from a particulate blood flow”, Analytical Chemistry, 84: 4292 –4299, 2012.

J.Uhr, M. Huebschman, E.P. Frenkel, N. Lane, H. Liu, D. Rana, L. Cheng, A. Lin, G.A. Hughes, X.J. Zhang, and H. G. Garner, “Molecular Profiling of Individual Tumor Cells by Hyperspectral Microscopic Imaging”, Translational Research – The Journal of Laboratory and Clinical Medicine, 159: 366–375, 2012.

K.Hoshino, Y.Y. Huang, N. Lane, M. Huebschman, J.W. Uhr, E.P. Frenkel and X.J. Zhang, “Microchip based Immunomagnetic Detection of Circulating Tumor Cell”, Lab on Chip, 11: 3449–3457, 2011. (Among the top ten accessed articles of Lab on a Chip in the two consecutive months of August and September 2011.)

E.Ng, A. Gopal, K. Hoshino, X.J. Zhang, “Multicolor Microcontact Printing of Proteins on Nanoporous Surface for Patterned Immunoassay”, Applied Nanoscience, 1: 79–85, 2011.

Y.Hu, A. Gopal, K. Lin, Y. Peng, X.J. Zhang, M. Ferrari, “Microfluidic enrichment of small proteins from complex biological mixture on nanoporous silica chip”, Biomicrofluidics (joint-corresponding author), 5: 013410, 2011.

E.Blinka, K. Loeffler, Y. Hu, A. Gopal, K. Hoshino, M. Ferrari and X.J. Zhang, “Enhanced microcontact printing of proteins on nanoporous silica surface”, Nanotechnology, 21(41): 415302, 2010.

J.Fakhoury, J.C. Sisson, X.J. Zhang, “Microsystems for controlled genetic perturbation of live Drosophila embryos – RNA interference, Development Robustness and Drug Screening”, Journal of Microfluidics and Nanofluidics, 6: 200–313, 2009 (Invited Review Article).

X.J. Zhang, “Trapping the Nematode on micro-chip for the future of science”, HFSP Journal: Frontiers of Interdisciplinary Research in the Life Science, 1(4): 220–224, 2007. [This article has also been selected for the December 15, 2007 issue of Virtual Journal of Biological Physics Research (http://www.vjbio.org). The Virtual Journal, which is published by the American Physical Society and the American Institute of Physics in cooperation with numerous other societies and publishers, is an edited compilation of leading articles covering a focused area of frontier research.]

G.T. Dagani, K. Monzo, J.R. Fakhoury, C.-C. Chen, J. C. Sisson and X.J. Zhang, “Microfluidic self-assembly of live Drosophila embryos for versatile high-throughput analysis of embryonic morphogenesis”, Biomedical Microdevices, 9(5): 681–694, 2007.

D.N. Adamson, D. Mustafi, X.J. Zhang, B. Zheng and R. F. Ismagilov, “Production of arrays of chemically distinct nanolitre plugs via repeated splitting in microfluidic devices”, Lab on Chip, 6: 1178–1186, 2006.

C.C. Chen, S. Zappe, O. Sahin, X.J. Zhang, E. Furlong, M. Fish, M.P. Scott and O. Solgaard, “Design and Operation of a Microfluidic Sorter for Drosophila Embryos”, Sensors and Actuators: B Chemical, 102(1): 59–66, 2004.

R.W. Bernstein, X.J. Zhang, S. Zappe, M. Fish, M.P. Scott and O. Solgaard, “Characterization of Fluidic Microassembly For Immobilization and Positioning of Drosophila Embryos in 2D arrays”, Sensors and Actuators: A Physical, 114: 191–196, 2004.

Paper microfluidics for POC with computational power

A.Burklund, H. Hall, F. Franchina, J. Hill, X.J. Zhang, “Printable QR code paper microfluidic colorimetric assay for screening volatile biomarkers”, Biosensors and Bioelectronics, 2019, 128, 97-103.