A cartridge based sensor array platform for multiple coagulation measurements from plasma.

This paper proposes a MEMS-based sensor array enabling multiple clot-time tests for plasma in one disposable microfluidic cartridge. The versatile LoC (Lab-on-Chip) platform technology is demonstrated here for real-time coagulation tests (activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)). The system has a reader unit and a disposable cartridge. The reader has no electrical connections to the cartridge. This enables simple and low-cost cartridge designs and avoids reliability problems associated with electrical connections. The cartridge consists of microfluidic channels and MEMS microcantilevers placed in each channel. The microcantilevers are made of electroplated nickel. They are actuated remotely using an external electro-coil and the read-out is also conducted remotely using a laser. The phase difference between the cantilever oscillation and the coil drive is monitored in real time. During coagulation, the viscosity of the blood plasma increases resulting in a change in the phase read-out. The proposed assay was tested on human and control plasma samples for PT and aPTT measurements. PT and aPTT measurements from control plasma samples are comparable with the manufacturer's datasheet and the commercial reference device. The measurement system has an overall 7.28% and 6.33% CV for PT and aPTT, respectively. For further implementation, the microfluidic channels of the cartridge were functionalized for PT and aPTT tests by drying specific reagents in each channel. Since simultaneous PT and aPTT measurements are needed in order to properly evaluate the coagulation system, one of the most prominent features of the proposed assay is enabling parallel measurement of different coagulation parameters. Additionally, the design of the cartridge and the read-out system as well as the obtained reproducible results with 10 μl of the plasma samples suggest an opportunity for a possible point-of-care application.

[1]  Libby G. Puckett,et al.  Magnetoelastic transducers for monitoring coagulation, clot inhibition, and fibrinolysis. , 2005, Biosensors & bioelectronics.

[2]  C. Hayward,et al.  Approaches to investigating common bleeding disorders: An evaluation of North American coagulation laboratory practices , 2012, American journal of hematology.

[3]  W. Marsden.  I and J , 2012 .

[4]  Junseok Chae,et al.  Real-Time Monitoring of Whole Blood Coagulation Using a Microfabricated Contour-Mode Film Bulk Acoustic Resonator , 2012, Journal of Microelectromechanical Systems.

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

[6]  Christiane Ziegler,et al.  Investigation of prothrombin time in human whole-blood samples with a quartz crystal biosensor. , 2010, Analytical chemistry.

[7]  Trai-Ming Yeh,et al.  Dengue virus nonstructural protein NS1 binds to prothrombin/thrombin and inhibits prothrombin activation. , 2012, The Journal of infection.

[8]  Anthony J. Killard,et al.  Coagulation monitoring devices: Past, present, and future at the point of care , 2013 .

[9]  Liviu Nicu,et al.  The Microcantilever: A Versatile Tool for Measuring the Rheological Properties of Complex Fluids , 2012, J. Sensors.

[10]  Michael V Sefton,et al.  Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. , 2004, Biomaterials.

[11]  G. Yaralioglu,et al.  LoC sensor array platform for real-time coagulation measurements , 2014, 2014 IEEE 27th International Conference on Micro Electro Mechanical Systems (MEMS).

[12]  V. Ng,et al.  Liver disease, coagulation testing, and hemostasis. , 2009, Clinics in laboratory medicine.

[13]  John E. Sader,et al.  Experimental validation of theoretical models for the frequency response of atomic force microscope cantilever beams immersed in fluids , 2000 .

[14]  J. Sader.  Frequency response of cantilever beams immersed in viscous fluids with applications to the atomic force microscope , 1998 .

[15]  Chien-Hsing Lu,et al.  Prothrombin time tests on a microfluidic disc analyzer , 2012 .

[16]  Anthony J. Killard,et al.  Measurement of the evolution of rigid and viscoelastic mass contributions from fibrin network formation during plasma coagulation using quartz crystal microbalance , 2014 .

[17]  Hakan Urey,et al.  MEMS based blood plasma viscosity sensor without electrical connections , 2013, 2013 IEEE SENSORS.

[18]  A. Maali,et al.  Hydrodynamics of oscillating atomic force microscopy cantilevers in viscous fluids , 2005 .

[19]  Siyang Zheng,et al.  Microfluidic device and system for point-of-care blood coagulation measurement based on electrical impedance sensing , 2013 .

[20]  Detection of human κ-opioid antibody using microresonators with integrated optical readout. , 2010, Biosensors & bioelectronics.

[21]  Jochen Lange,et al.  Preoperative fibrin monomer measurement allows risk stratification for high intraoperative blood loss in elective surgery , 2005, Thrombosis and Haemostasis.

[22]  Chunyan Yao,et al.  Detection of Fibrinogen and Coagulation Factor VIII in Plasma by a Quartz Crystal Microbalance Biosensor , 2013, Sensors.

[23]  Michael Spannagl,et al.  Monitoring of direct anticoagulants , 2011, Wiener Medizinische Wochenschrift.

[24]  J. Sader,et al.  Calibration of rectangular atomic force microscope cantilevers , 1999 .

[25]  Aaas News,et al.  Book Reviews , 1893, Buffalo Medical and Surgical Journal.

[26]  Dimitris Kouzoudis,et al.  Monitoring blood coagulation with magnetoelastic sensors. , 2003, Biosensors & bioelectronics.

[27]  C. Hofer,et al.  Coagulation Monitoring: Current Techniques and Clinical Use of Viscoelastic Point-of-Care Coagulation Devices , 2008, Anesthesia and analgesia.

[28]  Hakan Urey,et al.  Microcantilever based disposable viscosity sensor for serum and blood plasma measurements. , 2013, Methods.