Impedance measurement monitoring blood coagulation
blood coagulation is a complex and dynamic physiological process. Blood will coagulate and stop bleeding in the injured place. In heart bypass surgery, blood will be transferred to the cardiopulmonary machine outside the patient, which is responsible for maintaining heart and lung functions. The performance stabilizer of cardiopulmonary products is operated by perfusion technical experts and is responsible for monitoring the correct parameters to ensure the effective use of anticoagulants and avoid blood coagulation of patients. Therefore, heparin, an anticoagulant drug, needs to be used during the operation, and then the reverse operation must be carried out quickly to prevent excessive bleeding. 1. In order to maintain a precise balance between coagulation and bleeding, the coagulation time of patients needs to be monitored every 30 ~ 60 minutes during the operation, and many times after the operation until the coagulation time of patients returns to normal. 2. At present, venous blood samples of patients can usually be collected in the ward, and the measured coagulation time value can be used to adjust anticoagulation therapy
ADI is a partner of the school of biomedical diagnostics (BDI) 3. BDI is a science, engineering and technology center funded by the Irish science foundation 4. It is a multidisciplinary research institution committed to developing the next generation of biomedical diagnostic equipment. In one of the BDI master plans, ADI is cooperating with the University of Dublin 5 and a global professional pharmaceutical and drug infusion company to develop a coagulation monitoring device for patient treatment in an intensive care environment. The system will provide fast and automatic information about patients' coagulation status, improve patients' safety, process and decision support level, so as to improve patients' treatment results
electronic measurement of blood coagulation
blood coagulation in human body is completed by the joint action of many cells and other active ingredients. The coagulation cascade describes the components of blood and how they participate in the formation of coagulation. With the activation of coagulation cascade, changes in molecular charge state and effective charge mobility are caused in the process of blood changing from non coagulation state to coagulation state. The final stage of the coagulation cascade involves two substances: thrombin and fibrinogen. Thrombin cuts off fibrinogen and forms filaments - they spontaneously converge. Coagulation completion time is defined as the time of fiber coagulation formation 6,7
by monitoring the whole impedance of the coagulation sample, the conductivity changes related to the formation of coagulation can be measured. In order to evaluate the performance of the instrument, the coagulation time determined according to the data should be compared with the "golden standard" of coagulation time measured clinically
use AD5933 for impedance measurement
ad59338 fully integrated single-chip impedance analysis device (Figure 1) is a high-precision impedance conversion system, which integrates a frequency generator and a 12 bit, 1 MSPs analog-to-digital converter (ADC). The frequency generator provides excitation voltage for the external complex impedance at a known frequency. The on-chip ADC samples the response signal (current) and performs discrete Fourier transform (DFT) operation processing through the on-board DSP engine. DFT algorithm returns the real part (R) and imaginary part (I) of the data word at each output frequency. Using these components, the impedance amplitude and relative phase corresponding to each frequency point can be easily calculated
Figure 1 The functional block diagram of impedance measurement system
ad5933 shows the fully integrated impedance measurement system. The local digital processing supports the complex impedance calculation of the test circuit. This system requires initial calibration: replace the measured impedance with a precision resistor, and calculate the scale coefficient of the later measurement. For the excitation frequency of 1 kHz ~ 100 kHz, AD5933 can measure the impedance between 100 Ω ~ 10 m Ω, and the system accuracy is 0.5%
the relationship between blood coagulation and impedance changes has been established for a long time. See references 9,10,11,12,13 for details. However, recently, integrated devices for complex impedance measurement have been introduced, which means that the instrument for measuring coagulation time can be miniaturized. It has significant advantages in energy saving, portability and instrument appearance, which is a key factor to be considered in intensive care equipment
for single power devices, such as AD5933, the center of signal swing is usually near the fixed DC bias value. In most impedance measurements, this is not a problem that needs to be seriously considered, but when the DC voltage exceeds a specific threshold, the water conducting medium will react electrochemically when it contacts the electrode, thereby changing the sample. In the current blood sample measurement project using AD5933, in order to prevent this electrolytic reaction, AC coupling is used for voltage excitation and current measurement, and the signal conditioning circuit shown in Figure 2 is used
Figure 2 AD5933
blood coagulation measurement system with output signal conditioning function
the interface between blood sample collection and measurement instrument is very critical. In this case, a specific microfluidic channel is designed to transmit blood samples to AD5933 measurement instrument circuit (Figure 3). The microfluidic device consists of three layers: the bottom layer includes two wire printed electrodes, which are connected with the input/output port pins of the AD5933 circuit. The microform polymer channel on the top layer includes two repositories, which are connected by microchannels. The microchannel or the connecting layer in the middle can contain chemical reagents to adjust the coagulation reaction. The top and bottom channels are bonded together with pressure-sensitive adhesive (PSA), and the blood sample in the repository will fill the microchannel. The microchannel contacts the printed electrode, so as to realize the interface with AD5933 circuit
Figure 3 Schematic diagram of impedance measurement system, which includes polymer microchannels of measured blood samples. The system allows the blood sample to interact with specific reagents that regulate coagulation, and creates an interface between the blood sample and the sample number n instrument that AD5933 test is definitely suitable for
measured impedance response
Figure 4 shows the comparison of impedance response curves of coagulated and non coagulated blood samples. The arrow in the figure indicates the determination of the coagulation time point of the blood sample
Figure 4 Impedance comparison between non coagulated (black) and coagulated (red) blood samples
the impedance response curve in Figure 5 shows that with the increase of heparin concentration in blood samples, the blood coagulation time also increases. The arrows in the figure indicate the coagulation time of different blood samples
Figure 5 Impedance comparison when coagulation time increases: from the shortest (blue) to the longest (black)
the coagulation time of a large number of clinical donated blood samples was measured through the system introduced above, and the coagulation time of blood samples was measured by using the clinical gold standard measurement system, and the two measurement results were correlated and compared (Fig. 6)
Figure 6 Correlation comparison between coagulation time measured by AD5933 measurement system and that measured by clinical gold standard,
for each blood sample, the number of measurements is n = 6
AD5933 single chip impedance analyzer has been successfully used to measure the changes of blood impedance during coagulation. Compared with existing commercial solutions, AD5933 has great advantages in flexibility, power consumption, size and so on for end users. Combining this integrated circuit technology with the latest technologies in other fields (such as microfluidics and sampling processing) can provide a powerful platform for the research and development of future medical devices
the relevant materials of this paper are based on the support of the Irish Science Foundation funded project (No. 05/ce3/b754). The author would like to thank Dermot Kenny, gerardene Meade, Sarah O'Neill and the molecular and cell therapy department of the Royal College of surgeons for their equipment and technical support, Nigel Kent for his work in microstructure, and Dr. Tony killard for his leadership of the coagulation monitoring research team of the College of physical diagnostics in Dublin City
1 Bowers, John and James J. ferguson “Use of the Activated Clotting Time in Anticoagulation Monitoring of Intravascular Procedures.” Texas Heart Institute Journal. 20 (4). 1993. 258–263.
2 Kost, geral through this kind of real use feedback D, J., ed. principles and practice of point of care testing Lippincott, Williams and Wilkins. 2002.
6 Guest, M.M. “Circulatory Effects of Blood Clotting, Fibrinolysis, and Related Hemostatic Processes.” Handbook of Physiology, Circulation III, American Physiological Society. Washington, DC. 1964.
7 Brummel-Siedins, K., T. Orfeo, Jenny N. Swords, S.J. Everse, and K.G. Mann. “Blood Coagulation and Fibrinolysis.” Chapter 21 in Wintrobe’s Clinical Hematology. 11th edition. Volume 1. M.M. Wintrobe and J.P. Greer, eds. Lippincott, Williams, and Wilkins. 2004.
8 ADI website: (Search) AD5933 (Go)
9 Ur, A. “Changes in the electrical impedance of blood during coagulation.” Nature 226. 1970a. 269–270.
10 ur, A. "dete, it doesn't mean that there is no thing rmination of blood negotiation using importance measurements." Biomedical Engineering 5 (7). 1970b. 342–345.
11 Ur, A. “Detection of clot retraction through changes of the electrical impedance of blood during coagulation.” American Journal of Clinical Pathology 56 (6). 1971. 713–717.
12 Ur, A. “Analysis and interpretation of the impedance blood coagulation curve.” American Journal of Clinical Pathology 67 (5). 1977. 470–476.
13 Theiss, W. and A. Ulmer. “Comparative and direct measurement of the electrical impedance in blood coagulation.” Thrombosis Research 13. 1978. 751–765.
about the author
helen Berney [rney@] is currently a research engineer in the medical products Department of ADI company, and joined ADI company in February 2006. She graduated from the City University of Dublin, Ireland, with a Bachelor of Science Degree in biotechnology, and then received a Ph.D. degree in silicon-based immune detection and diagnosis from cork University, Ireland. Helen used to work in the development of sensors and integrated systems in the biological application department of the national Microelectronics Research Center in cork. She was engaged in the development of microelectronics and nanotechnology in biomedical research and innovation during her work in the nanoscience and technology center of the University of Newcastle in the United Kingdom, and won the fahum scholarship
j.j. O'Riordan [iordan@] graduated from lemmeric University in 1984 with a Bachelor of engineering degree, and joined the test development department of ADI company in lemmeric, Ireland. He received a master's degree in computer systems from lemmeric University in 1998. He is committed to the development of test technology, developed test programs for the first microconverter product of ADI company, and developed test programs for high-resolution DAC Σ-Δ Converters, low leakage switches, and other products have developed test capabilities. Recently, J.J. has been committed to medical technology, designing and completing products such as coagulation monitor and blood glucose meter. In his spare time, J.J. also likes various sports, and is a life and professional coach certified by the international canoeing Federation. (end)