Capturing and detection of MCF-7 breast cancer cells with a CMOS image sensor

Abstract This paper presents a CMOS image sensor with a 32 × 32 pixel array for cell capture, detection, and quantification. Pixels measuring 15 μm × 15 μm have a modified structure, suitable for post-CMOS electroless gold plating, which enables surface activation for cell capture without the need for any intermediate layer. This structure also increases the detection probability of captured cells, even when cells are much smaller than the pixel, owing to a special light mask implemented on pixels. Cells as small as 3 μm in diameter can be detected with this pixel structure. The proof of concept for surface activation of the gold coated sensor pixels was demonstrated by capturing and imaging MCF-7 breast cancer cells on the modified sensor surface. Accordingly, electroless gold coating of the Al pixels was achieved and the gold coated surface of the CMOS image sensor was activated with thiol-modified antibodies that can capture MCF-7 cells. Cells were then optically detected under green LED illumination.

[1]  D. Barrettino,et al.  Design considerations and recent advances in CMOS-based microsystems for point-of-care clinical diagnostics , 2006, 2006 IEEE International Symposium on Circuits and Systems.

[2]  Fredrik Nikolajeff,et al.  Bioactivated PDMS microchannel evaluated as sensor for human CD4+ cells—The concept of a point-of-care method for HIV monitoring , 2007 .

[3]  Tzuen-Rong J Tzeng,et al.  Electrokinetic focusing and filtration of cells in a serpentine microchannel. , 2009, Biomicrofluidics.

[4]  Mario Dagenais,et al.  Electroless remetallization of aluminum bond pads on CMOS driver chip for flip-chip attachment to vertical cavity surface emitting lasers (VCSEL's) , 1999 .

[5]  Mohamad Sawan,et al.  Dielectrophoresis-Based Integrated Lab-on-Chip for Nano and Micro-Particles Manipulation and Capacitive Detection , 2012, IEEE Transactions on Biomedical Circuits and Systems.

[6]  Steven W Graves,et al.  Analytical performance of an ultrasonic particle focusing flow cytometer. , 2007, Analytical chemistry.

[7]  Ali Khademhosseini,et al.  Integrating microfluidics and lensless imaging for point-of-care testing , 2009, 2009 IEEE 35th Annual Northeast Bioengineering Conference.

[8]  U. D Larsen,et al.  Microchip Coulter particle counter , 1997, Proceedings of International Solid State Sensors and Actuators Conference (Transducers '97).

[9]  Elinore M Mercer,et al.  Microfluidic sorting of mammalian cells by optical force switching , 2005, Nature Biotechnology.

[10]  T. Huang,et al.  Single-layer planar on-chip flow cytometer using microfluidic drifting based three-dimensional (3D) hydrodynamic focusing. , 2009, Lab on a chip.

[11]  Haluk Külah,et al.  MEMS biosensors for detection of methicillin resistant Staphylococcus aureus. , 2011, Biosensors & bioelectronics.

[12]  Derek K. Tseng,et al.  Lensfree holographic imaging for on-chip cytometry and diagnostics. , 2009, Lab on a chip.

[13]  T. Matsunaga,et al.  High-content analysis of single cells directly assembled on CMOS sensor based on color imaging. , 2010, Biosensors & bioelectronics.

[14]  Xudong Fan,et al.  Label Free Detection of CD4+ and CD8+ T Cells Using the Optofluidic Ring Resonator , 2010, Sensors.

[15]  Trevor F Peter,et al.  Effect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study , 2011, The Lancet.

[16]  Haluk Kulah,et al.  CMOS Cell Sensors for Point-of-Care Diagnostics , 2012, Sensors.

[17]  Cell detection using a CMOS image sensor with modified pixel structure suitable for bio-chemical surface activation , 2013, 2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS).

[18]  A. Ozcan,et al.  Ultra wide-field lens-free monitoring of cells on-chip. , 2008, Lab on a chip.

[19]  Yongjoo Kwon,et al.  Electroless Gold Plating on Aluminum Patterned Chips for CMOS-Based Sensor Applications , 2010 .

[20]  Joel P Golden,et al.  A hard microflow cytometer using groove-generated sheath flow for multiplexed bead and cell assays , 2010, Analytical and bioanalytical chemistry.

[21]  Gwo-Bin Lee,et al.  Optically induced flow cytometry for continuous microparticle counting and sorting. , 2008, Biosensors & bioelectronics.

[22]  Makoto Ishida,et al.  A sensor for blood cell counter using MEMS technology , 2002 .

[23]  David S Boyle,et al.  Emerging technologies for point-of-care CD4 T-lymphocyte counting. , 2012, Trends in biotechnology.

[24]  J. Greve,et al.  An Immunomagnetic Single-Platform Image Cytometer for Cell Enumeration Based on Antibody Specificity , 2007, Clinical and Vaccine Immunology.

[25]  Roberto Gambari,et al.  New trends in non-invasive prenatal diagnosis: applications of dielectrophoresis-based Lab-on-a-chip platforms to the identification and manipulation of rare cells. , 2008, International journal of molecular medicine.

[26]  Ebru Özgür,et al.  Dielectrophoresis: Applications and future outlook in point of care , 2013, Electrophoresis.

[27]  J. Chang,et al.  Simultaneous counting of two subsets of leukocytes using fluorescent silica nanoparticles in a sheathless microchip flow cytometer. , 2010, Lab on a chip.

[28]  S. Safe,et al.  Doxycycline Induces Expression of P Glycoprotein in MCF-7 Breast Carcinoma Cells , 2002, Antimicrobial Agents and Chemotherapy.

[29]  Sau Yin Chin,et al.  Microfluidic CD4+ T-cell counting device using chemiluminescence-based detection. , 2010, Analytical chemistry.