Millions of patients worldwide are receiving anticoagulant therapy to treat hypercoagulable diseases. While standard testing is still performed in the central laboratory, point-of-care (POC) diagnostics are being developed due to the increasing number of patients requiring long-term anticoagulation and with a need for more personalized and targeted therapy. Many POC devices on the market focus on clot measurement, a technique which is limited in terms of variability, highlighting the need for more reliable assays of anticoagulant status. The anti-Xa assay, a factor specific optical assay, was developed to measure the extent to which exogenous factor Xa (FXa) is inhibited by heparinantithrombin complexes. We have developed a novel microfluidic device and assay for monitoring the effect of heparin anticoagulant therapy at the point-of-care. The assay which was also developed in our institute is based on the anti-Xa assay principle but uses fluorescence as the method of detection. Our device is a disposable laminate microfluidic strip, fabricated from the cyclic polyolefin (COP), Zeonor®, which is extremely suitable for application to fluorescent device platforms. We present data on the execution of the anti-Xa assay in this microfluidic format, demonstrating that the assay can be used to measure heparin in human plasma samples from 0 to 0.8 U/ml, with average assay reproducibility of 8% and a rapid result obtained within 60 seconds. Results indicate that with further development, the fluorogenic anti-Xa assay and device could become a successful method for monitoring anticoagulant therapy.
This paper investigates the use of electrical conductivity monitoring in silicon-based capillaries and the inherent problems therein. In comparison to reference glass devices, the conductance waveforms from the silicon devices were significantly distorted. This has been shown to be due to the profiles of the ends of the capillaries where single-sided etching was employed, and the silicon dioxide capacitance. Double-sided processing provides a solution to tapering of channel inlets, by reducing the time that the front side is exposed to the KOH solution. Models are developed for the devices, which identify degradation of the oxide isolation as another source of distortion. Matching of the experimental and simulated characteristics enables an estimation of the capacitance between the silicon and the bulk solution. Silicon nitride layers are shown to provide more effective isolation and greatly reduce the distortion observed during conductivity monitoring.
This paper investigates modeling of the conductance of liquid in a microchannel, using SPICE. When more than one liquid is present, conductance monitoring is an effective technique to measure electroosmotic flow rates. In micromachined silicon capillaries, the technique is hampered by the capacitance that exists between the bulk fluid and the silicon substrate, and leakage currents due to the thin insulating oxide layer. A SPICE model is used to simulate conductance waveforms, by using MOS transistors to model the time dependant resistance of the channel. The simulation results are used to determine the capacitance and explain the conductance waveforms measured for micromachined silicon channels.
This paper investigates methods of flow rate quantification in micro- fluidic devices, using electrodes to measure the conductivity of solution. Conductivity changes occur when liquid flow causes movement of the boundary between two solutions of differing conductivity. The fabrication technology for the micromachined silicon structures is based on anisotropic etching and anodic bonding to glass. The silicon processing is simplified by using a single-mask process, whereby 9 - 15 mm long, 50 - 100 micrometers wide capillaries and access through-holes are created with a single etch step. Thin film gold electrodes patterned on the glass provide contact with the liquid in the capillary. The current monitoring method, used in capillary electrophoresis, is employed to determine conductance-time waveforms during electroosmotic pumping. The waveforms for silicon based devices are distorted due to oxide capacitance and the profiles of the ends of the channel. The transitions are much more linear for reference devices formed using standard glass capillary tubing. Electrical models are developed for the devices and these are used to determine flow velocities and hence volume flow rates of liquid.
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