A microfluidic device integrating dual CMOS polysilicon nanowire sensors for on-chip whole blood processing and simultaneous detection of multiple analytes.

The hemoglobin-A1c test, measuring the ratio of glycated hemoglobin (HbA1c) to hemoglobin (Hb) levels, has been a standard assay in diabetes diagnosis that removes the day-to-day glucose level variation. Currently, the HbA1c test is restricted to hospitals and central laboratories due to the laborious, time-consuming whole blood processing and bulky instruments. In this paper, we have developed a microfluidic device integrating dual CMOS polysilicon nanowire sensors (MINS) for on-chip whole blood processing and simultaneous detection of multiple analytes. The micromachined polymethylmethacrylate (PMMA) microfluidic device consisted of a serpentine microchannel with multiple dam structures designed for non-lysed cells or debris trapping, uniform plasma/buffer mixing and dilution. The CMOS-fabricated polysilicon nanowire sensors integrated with the microfluidic device were designed for the simultaneous, label-free electrical detection of multiple analytes. Our study first measured the Hb and HbA1c levels in 11 clinical samples via these nanowire sensors. The results were compared with those of standard Hb and HbA1c measurement methods (Hb: the sodium lauryl sulfate hemoglobin detection method; HbA1c: cation-exchange high-performance liquid chromatography) and showed comparable outcomes. Finally, we successfully demonstrated the efficacy of the MINS device's on-chip whole blood processing followed by simultaneous Hb and HbA1c measurement in a clinical sample. Compared to current Hb and HbA1c sensing instruments, the MINS platform is compact and can simultaneously detect two analytes with only 5 μL of whole blood, which corresponds to a 300-fold blood volume reduction. The total assay time, including the in situ sample processing and analyte detection, was just 30 minutes. Based on its on-chip whole blood processing and simultaneous multiple analyte detection functionalities with a lower sample volume requirement and shorter process time, the MINS device can be effectively applied to real-time diabetes diagnostics and monitoring in point-of-care settings.

[1]  Daniel R. Sabatino,et al.  Boundary Layer Influence on the Unsteady Horseshoe Vortex Flow and Surface Heat Transfer , 2007 .

[2]  A. Undar,et al.  A microfluidic device for continuous, real time blood plasma separation. , 2006, Lab on a chip.

[3]  Hsin I. Lin,et al.  Measurement of glycated hemoglobin levels using an integrated microfluidic system , 2015 .

[4]  C-T Lin,et al.  A CMOS wireless biomolecular sensing system-on-chip based on polysilicon nanowire technology. , 2013, Lab on a chip.

[5]  F. Sotiropoulos,et al.  Reynolds Number Effects on the Coherent Dynamics of the Turbulent Horseshoe Vortex System , 2011 .

[6]  Chong H Ahn,et al.  An on-chip whole blood/plasma separator with bead-packed microchannel on COC polymer , 2010, Biomedical microdevices.

[7]  Mehmet Toner,et al.  Blood-on-a-chip. , 2005, Annual review of biomedical engineering.

[8]  M.A. Alam,et al.  Design Considerations of Silicon Nanowire Biosensors , 2007, IEEE Transactions on Electron Devices.

[9]  Václav Kašička,et al.  Analysis of glycated hemoglobin A1c by capillary electrophoresis and capillary isoelectric focusing. , 2011, Analytical biochemistry.

[10]  C. Kilo,et al.  Hemoglobin AIc as an indicator of the degree of glucose intolerance in diabetes , 1976, Diabetes.

[11]  Luke P. Lee,et al.  Stand-alone self-powered integrated microfluidic blood analysis system (SIMBAS). , 2011, Lab on a chip.

[12]  Han Wei Hou,et al.  Microfluidic Devices for Blood Fractionation , 2011, Micromachines.

[13]  Shanhong Xia,et al.  A field effect transistor (FET)-based immunosensor for detection of HbA1c and Hb , 2011, Biomedical microdevices.

[14]  Ajay Agarwal,et al.  Label-free electrical detection of cardiac biomarker with complementary metal-oxide semiconductor-compatible silicon nanowire sensor arrays. , 2009, Analytical chemistry.

[15]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[16]  Boyd,et al.  Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. , 2002, Clinical chemistry.

[17]  T. Crowley,et al.  Isolation of plasma from whole blood using planar microfilters for lab-on-a-chip applications. , 2005, Lab on a chip.

[18]  Ling-Sheng Jang,et al.  Detection of glycated hemoglobin (HbA1c) based on impedance measurement with parallel electrodes integrated into a microfluidic device , 2012 .

[19]  Sung Yang,et al.  A microfluidic device for continuous white blood cell separation and lysis from whole blood. , 2010, Artificial organs.

[20]  J. Shaw,et al.  International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes , 2009, Diabetes Care.

[21]  E. Sollier,et al.  Fast and continuous plasma extraction from whole human blood based on expanding cell-free layer devices , 2010, Biomedical microdevices.

[22]  W. Marsden.  I and J , 2012 .

[23]  Lidan You,et al.  Effect of nanowire number, diameter, and doping density on nano-FET biosensor sensitivity. , 2011, ACS nano.

[24]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[25]  Jing‐Juan Xu,et al.  Gold nanoparticles-coated magnetic microspheres as affinity matrix for detection of hemoglobin A1c in blood by microfluidic immunoassay. , 2011, Biosensors & bioelectronics.

[26]  R. Stephenson.  A and V , 1962, The British journal of ophthalmology.

[27]  Ratio of HbA1c to hemoglobin on ring-shaped interdigital electrode arrays based on impedance measurement , 2014 .

[28]  V. Vandelinder,et al.  Separation of plasma from whole human blood in a continuous cross-flow in a molded microfluidic device. , 2006, Analytical chemistry.

[29]  K. Oh,et al.  Phaseguide-assisted blood separation microfluidic device for point-of-care applications. , 2015, Biomicrofluidics.

[30]  Sungyoung Choi,et al.  Smart Pipette and Microfluidic Pipette Tip for Blood Plasma Separation. , 2016, Small.

[31]  T. Chou,et al.  Integrated microfluidic system for electrochemical sensing of glycosylated hemoglobin , 2009, 2009 IEEE 3rd International Conference on Nano/Molecular Medicine and Engineering.