ClotChip: A Microfluidic Dielectric Sensor for Point-of-Care Assessment of Hemostasis

Abstract

This paper describes the design, fabrication, and testing of a microfluidic sensor for dielectric spectroscopy (DS) of human whole blood during coagulation. The sensor, termed ClotChip, employs a three-dimensional (3D), parallel-plate, capacitive sensing structure with a floating electrode integrated into a microfluidic channel. Interfaced with an impedance analyzer, the ClotChip measures the complex relative dielectric permittivity, εr, of human whole blood in a frequency range of 40Hz to 100MHz. The temporal variation in the real part of the blood dielectric permittivity at 1MHz features a time to reach a permittivity peak, Tpeak, as well as a maximum change in permittivity after the peak, Δεr,max, as two distinct parameters of ClotChip readout. The ClotChip performance was benchmarked against rotational thromboelastometry (ROTEM) to evaluate the clinical utility of its readout parameters in capturing the clotting dynamics arising from coagulation factors and platelet activity. Tpeak exhibited a very strong positive correlation (r = 0.99, p < 0.0001) with the ROTEM clotting time (CT) parameter, whereas Δεr,max exhibited a strong positive correlation (r = 0.85, p < 0.001) with the ROTEM maximum clot firmness (MCF) parameter. This work demonstrates the ClotChip potential as a point-of-care (POC) platform to assess the complete hemostatic process using <10μL of human whole blood.

A novel, point‐of‐care, whole‐blood assay utilizing dielectric spectroscopy is sensitive to coagulation factor replacement therapy in haemophilia A patients

“…The ClotChip fabrication was based on a low‐cost, batch‐fabrication method of screen‐printing gold electrodes on polymethyl methacrylate (PMMA) plastic substrates. Detailed descriptions of the ClotChip operation and fabrication steps have been previously reported in Ref . Figure A shows a photograph of the fabricated ClotChip with dimensions of 26 mm × 9 mm × 3 mm and a total sample volume of 9 µL.…”

“…Dielectric measurements were performed over a frequency range of 10 kHz‐100 MHz at 10‐second intervals inside a thermostatic chamber at 37°C. As described previously, the dielectric properties of whole blood varied during the coagulation process, and a measurement frequency of 1 MHz was chosen to maximize the sensitivity to the coagulation process. Therefore, the ClotChip read‐out was taken as the temporal variation in the real part of blood dielectric permittivity at 1 MHz.…”

“…Therefore, the ClotChip read‐out was taken as the temporal variation in the real part of blood dielectric permittivity at 1 MHz. The ClotChip read‐out characteristically rose to a permittivity peak, and the time to reach this peak ( T peak ) was taken to be indicative of the coagulation time …”

“…We have recently reported on the development of ClotChip, a novel dielectric microsensor for rapid and comprehensive assessment of whole‐blood coagulation based on the electrical technique of dielectric spectroscopy . The ClotChip read‐out has been shown to be sensitive towards detecting non‐cellular (ie coagulation factor) and cellular (ie platelet) abnormalities in the haemostatic process, thereby allowing global haemostatic analysis in a miniaturized, portable measurement platform using miniscule blood sample volumes (<10 µL) …”

Carbon Nanotube Strain Sensor Based Hemoretractometer for Blood Coagulation Testing

“…Based on the same measurement principles as TEG, ROTEM, and Sonoclot, microengineered devices assessing viscoelasticity alteration during blood clotting using magnatoelastic transducer 4 , quartz crystal microbalance 5 , acoustic resonator 6 , ultrasound radiation 7 , laser speckle rheology 8 , cantilever beam oscillation 9 , dielectric sensor 10 , etc., have been reported. Using microtechnology, a few microscale devices have been specifically developed for platelet contractile force measurements down to the single cell level based on micropost array 11 , atomic force microscopy 12 , micropatterned fibrinogen array 13 , traction force microscopy 14 , etc.…”