1 Introduction In 1988, a Brazilian scholar M. worked in the Research Group of the Department of Physics of the University of Paris, France. N. Baibich discovered the giant magnetoresistance (GMR) effect when studying the electronic transport properties of Fe/Cr magnetic superlattice thin films. That is, the resistivity of the material changes significantly with the magnetization state of the material. This discovery has attracted the attention of scientists in many countries. The basic research and applied research of the giant magnetoresistance effect and its materials have quickly become a hot issue. Since then, the research on the giant magnetoresistance effect has developed rapidly over the past 10 years, and basic research and applied research have gone hand-in-hand. This has become an international model for rapidly transforming basic research into commercial applications. At present, GMR materials have been commercially applied in magnetic sensors, computer read heads, magnetic random access memory and other fields.
The sensor made of GMR material is called a giant magneto-resistive sensor. It has the advantages of high sensitivity, wide detection range and resistance to harsh environments. It can utilize semiconductor exposure and etching processes to make the device integrated and miniaturized, and its cost performance is far Better than several other magnetic field sensors. This article reviews a new type of sensor, GMR biosensor, combining GMR sensor and biotechnology. The sensor is applied to the field of biological detection and is a sensor for detecting magnetic labeled biological samples. The sensor consists of three parts: immunomagnetic microsphere (IMB), high magnetic sensitivity GMR sensor and related readout circuit.
2 Immunomagnetic microspheres In 1979, John Ugelstad et al. successfully prepared a polystyrene microsphere with appropriate homogeneity and particle size. After being magnetized and linked with an antibody, it became an immunomagnetic cell with excellent separation effect. Tags - dynabeads. Since then, immunomagnetic labels have been widely used and have triggered a revolution in bioseparation technology. The characteristics of immunomagnetic labeling mainly include rapid separation, high efficiency, good reproducibility, simple operation, no expensive equipment, and no influence on biological characteristics and functions of the separated cells or other biological materials.
Immunomagnetic microspheres, or immunomagnetic markers, are magnetic microspheres with monoclonal antibodies on the surface. It is a new immunological technique that has become more popular at home and abroad in recent years. Based on immunology, it penetrates into various fields such as pathology, physiology, pharmacology, microbiology, biochemistry, and molecular genetics, and its application has been widely used. In particular, it has made tremendous progress in immunological detection, cell separation, and protein purification. Nowadays, there are many companies in the world that specialize in the production of magnetic marking products, such as the well-known Dynal, Nanomag, and Micromer companies. Domestically produced companies in this area include Ningbo Xinzhi Biotechnology Co., Ltd., Hangzhou Lianke Biotechnology Co., Ltd., and Shenzhen Nano Microbial Technology Co., Ltd. Figure 1 shows the magnetization curves of some immunomagnetic markers. Among them, Dynal's M-280 is the most commonly used immunomagnetic marker for GMR biosensor detection. It has a diameter of 2.8 μm and is superparamagnetic.
The basic principle of immunomagnetic labeling technology is as follows: Immunomagnetic labels can bind both active proteins (antibodies) and magnets. After a certain treatment, antibodies can be bound to magnetic labels to make them the carriers of antibodies. After the antibody on the label is bound to a specific antigenic substance, an antigen-antibody-magnetic labeling immune complex is formed. The functional group of immunomagnetic labeling mainly binds to proteins, but with the avidin-biotin system, immunomagnetic labels can also be combined with non-proteins, such as various DNA and RNA molecules. In order to make the immune magnetic marker play a greater role.
3 High-sensitivity GMR sensors At present, there are four main types of magnetically ordered materials with GMR effects, which are experimental and theoretical studies: multilayer film structures, spin valve structures, magnetic alloy particle structures, and particle-film composite structures. Each of the four structures has its own characteristics, and most of the GMR biosensors use multilayer membrane structures or spin valve structures.
In 1998, the US Naval Laboratory took the lead in proposing the use of the GMR effect and immunomagnetic labeling to implement a GMR fetal sensor. They tested the feasibility of the principle by measuring the DNA, antigen-antibody, donor and acceptor experiments, thus further proposed the Magnetic Tag Array Counter (BARC), and developed a DNA array chip. Figure 2 is a third-generation BARC array chip jointly designed by the US Navy Navy Lab and NVE Corporation. Its planar layout is shown in Figure 2(a). Figure 2(b) is a partial enlargement of Figure 2(a). The semiconductor process integrates a 64-channel GMR sensor on a silicon substrate. Each sensor consists of a magneto-resistive strip with a total length of 8 mm and a width of 1.6 μm that is distributed in a circular shape with a diameter of 200 μm (Figure 2(c)). The magnetoresistance value is 42kΩ, saturation magnetization and GMR effect (ΔR/R) are 30mT and 15%, respectively, and each sensor can perform a single detection. The sensor adopts a multi-layer film structure of a magnetic layer/a non-magnetic layer/a magnetic layer, and anti-parallel coupling between two magnetic layers separated by a non-magnetic layer.
In addition to the U.S. Naval Laboratory and NVE, Stanford University, the University of Bielefeld in Germany, and the University of Lisbon in Portugal also conducted research on GMR biosensors. In China, the Institute of Electrical Engineering of the Chinese Academy of Sciences, Tsinghua University, and University of Electronic Science and Technology have conducted research on GMR biosensors. Although they have made some progress, they lack the organic combination of biotechnology and are lagging behind.
GMR sensor detection process shown in Figure 3. First, a bio-probe for specific detection is generated on the surface of the sensor (Fig. 3(a)), and the test solution is then allowed to flow over the sensor surface. Specific target molecules in the test solution will be captured by the probe (Fig. 3(b)). ), Then add the immunomagnetic microspheres, and the immunomagnetic microspheres interact with the target molecule to complete the label (Figure 3(c)). In this case, extra magnetic immunomagnetic microspheres that do not participate in labeling need to be separated by an extra gradient magnetic field perpendicular to the sensor surface, which can reduce the background noise during detection, thereby improving the detection accuracy. Then, an additional alternating magnetic field is used to magnetize the magnetic mark, an additional alternating magnetic field generated by the magnetized magnetic mark causes a change in the sensor magnetoresistance, and by reading the change in the magnetic resistance, whether or not there is a target molecule in the test solution can be determined. The concentration of the target molecule in the test solution can be judged based on the magnitude of the change in the magnetoresistance.
4 signal detection circuit magnetoresistance changes need to be converted into electrical signals, there are two ways to achieve, one is the Wheatstone bridge structure, as shown in Figure 4 (a), the other is the use of IV conversion method, as shown in Figure 4 (b) shows.
Both output signals remove the background noise represented by the reference signal in the detection signal and then amplify it. However, the noise caused by the physical reasons of materials and devices cannot be completely eliminated. When the detection signal is very weak, since the signal-to-noise ratio is too low, the above circuit cannot read the signal. In this case, lock-in amplification must be used. Technology can read the signal. The detection process is shown in Figure 4(c). Phase-locked amplification technology is one of the effective methods for weak signal detection. It uses cross-correlation technology to amplify and detect signals in the signal under test that are synchronized with the reference signal.
The lock-in amplifier consists of three parts: the signal channel, the reference channel and the correlator (also called the phase detector). The function of the signal channel is to amplify the weak signal to a level high enough to drive the correlator, and it also has the suppression and filtering part. The function of interference and noise; Correlator is a unit circuit that completes the cross-correlation function calculation of the measured signal and the reference signal, and is composed of a multiplier and an integrator circuit; the reference channel provides a periodic signal with the same frequency as the measured signal.
At present, the signal detection of GMR biosensors is based on common general-purpose lock-in amplifiers on the market, and its full-scale sensitivity can reach the order of nV. However, most of them are modular test instruments, which are too large and expensive to be used. Marketization of products. For this reason, it is very necessary to design a GMR sensor chip and semiconductor technology with good compatibility, and it can be packaged together with the lock-in amplifier IC chip using MCM technology, which will greatly improve the practicality of the GMR biosensor, Popularity.
5 Conclusion In summary, the giant magnetoresistance biosensor integrated technology, semiconductor technology, magnetic thin film technology and weak signal detection technology in one, through the detection of immunomagnetic markers, can accurately determine the composition of the test solution and contained The concentration of ingredients, etc., is a successful extension of the GMR sensor in the field of biological detection. Because of its many advantages, such as high sensitivity, high resolution, low cost, miniaturization of equipment, and automation of measurement processes, it has great potential in life sciences, medicine, and defense, etc., and it has become integrated with the progress of semiconductor technology. And sensitivity will also have a further increase in greetings. However, at present, research on GMR biosensors is still at the basic stage at home and abroad, and there is still a certain distance from practical application.
The sensor made of GMR material is called a giant magneto-resistive sensor. It has the advantages of high sensitivity, wide detection range and resistance to harsh environments. It can utilize semiconductor exposure and etching processes to make the device integrated and miniaturized, and its cost performance is far Better than several other magnetic field sensors. This article reviews a new type of sensor, GMR biosensor, combining GMR sensor and biotechnology. The sensor is applied to the field of biological detection and is a sensor for detecting magnetic labeled biological samples. The sensor consists of three parts: immunomagnetic microsphere (IMB), high magnetic sensitivity GMR sensor and related readout circuit.
2 Immunomagnetic microspheres In 1979, John Ugelstad et al. successfully prepared a polystyrene microsphere with appropriate homogeneity and particle size. After being magnetized and linked with an antibody, it became an immunomagnetic cell with excellent separation effect. Tags - dynabeads. Since then, immunomagnetic labels have been widely used and have triggered a revolution in bioseparation technology. The characteristics of immunomagnetic labeling mainly include rapid separation, high efficiency, good reproducibility, simple operation, no expensive equipment, and no influence on biological characteristics and functions of the separated cells or other biological materials.
Immunomagnetic microspheres, or immunomagnetic markers, are magnetic microspheres with monoclonal antibodies on the surface. It is a new immunological technique that has become more popular at home and abroad in recent years. Based on immunology, it penetrates into various fields such as pathology, physiology, pharmacology, microbiology, biochemistry, and molecular genetics, and its application has been widely used. In particular, it has made tremendous progress in immunological detection, cell separation, and protein purification. Nowadays, there are many companies in the world that specialize in the production of magnetic marking products, such as the well-known Dynal, Nanomag, and Micromer companies. Domestically produced companies in this area include Ningbo Xinzhi Biotechnology Co., Ltd., Hangzhou Lianke Biotechnology Co., Ltd., and Shenzhen Nano Microbial Technology Co., Ltd. Figure 1 shows the magnetization curves of some immunomagnetic markers. Among them, Dynal's M-280 is the most commonly used immunomagnetic marker for GMR biosensor detection. It has a diameter of 2.8 μm and is superparamagnetic.
The basic principle of immunomagnetic labeling technology is as follows: Immunomagnetic labels can bind both active proteins (antibodies) and magnets. After a certain treatment, antibodies can be bound to magnetic labels to make them the carriers of antibodies. After the antibody on the label is bound to a specific antigenic substance, an antigen-antibody-magnetic labeling immune complex is formed. The functional group of immunomagnetic labeling mainly binds to proteins, but with the avidin-biotin system, immunomagnetic labels can also be combined with non-proteins, such as various DNA and RNA molecules. In order to make the immune magnetic marker play a greater role.
3 High-sensitivity GMR sensors At present, there are four main types of magnetically ordered materials with GMR effects, which are experimental and theoretical studies: multilayer film structures, spin valve structures, magnetic alloy particle structures, and particle-film composite structures. Each of the four structures has its own characteristics, and most of the GMR biosensors use multilayer membrane structures or spin valve structures.
In 1998, the US Naval Laboratory took the lead in proposing the use of the GMR effect and immunomagnetic labeling to implement a GMR fetal sensor. They tested the feasibility of the principle by measuring the DNA, antigen-antibody, donor and acceptor experiments, thus further proposed the Magnetic Tag Array Counter (BARC), and developed a DNA array chip. Figure 2 is a third-generation BARC array chip jointly designed by the US Navy Navy Lab and NVE Corporation. Its planar layout is shown in Figure 2(a). Figure 2(b) is a partial enlargement of Figure 2(a). The semiconductor process integrates a 64-channel GMR sensor on a silicon substrate. Each sensor consists of a magneto-resistive strip with a total length of 8 mm and a width of 1.6 μm that is distributed in a circular shape with a diameter of 200 μm (Figure 2(c)). The magnetoresistance value is 42kΩ, saturation magnetization and GMR effect (ΔR/R) are 30mT and 15%, respectively, and each sensor can perform a single detection. The sensor adopts a multi-layer film structure of a magnetic layer/a non-magnetic layer/a magnetic layer, and anti-parallel coupling between two magnetic layers separated by a non-magnetic layer.
In addition to the U.S. Naval Laboratory and NVE, Stanford University, the University of Bielefeld in Germany, and the University of Lisbon in Portugal also conducted research on GMR biosensors. In China, the Institute of Electrical Engineering of the Chinese Academy of Sciences, Tsinghua University, and University of Electronic Science and Technology have conducted research on GMR biosensors. Although they have made some progress, they lack the organic combination of biotechnology and are lagging behind.
GMR sensor detection process shown in Figure 3. First, a bio-probe for specific detection is generated on the surface of the sensor (Fig. 3(a)), and the test solution is then allowed to flow over the sensor surface. Specific target molecules in the test solution will be captured by the probe (Fig. 3(b)). ), Then add the immunomagnetic microspheres, and the immunomagnetic microspheres interact with the target molecule to complete the label (Figure 3(c)). In this case, extra magnetic immunomagnetic microspheres that do not participate in labeling need to be separated by an extra gradient magnetic field perpendicular to the sensor surface, which can reduce the background noise during detection, thereby improving the detection accuracy. Then, an additional alternating magnetic field is used to magnetize the magnetic mark, an additional alternating magnetic field generated by the magnetized magnetic mark causes a change in the sensor magnetoresistance, and by reading the change in the magnetic resistance, whether or not there is a target molecule in the test solution can be determined. The concentration of the target molecule in the test solution can be judged based on the magnitude of the change in the magnetoresistance.
4 signal detection circuit magnetoresistance changes need to be converted into electrical signals, there are two ways to achieve, one is the Wheatstone bridge structure, as shown in Figure 4 (a), the other is the use of IV conversion method, as shown in Figure 4 (b) shows.
Both output signals remove the background noise represented by the reference signal in the detection signal and then amplify it. However, the noise caused by the physical reasons of materials and devices cannot be completely eliminated. When the detection signal is very weak, since the signal-to-noise ratio is too low, the above circuit cannot read the signal. In this case, lock-in amplification must be used. Technology can read the signal. The detection process is shown in Figure 4(c). Phase-locked amplification technology is one of the effective methods for weak signal detection. It uses cross-correlation technology to amplify and detect signals in the signal under test that are synchronized with the reference signal.
The lock-in amplifier consists of three parts: the signal channel, the reference channel and the correlator (also called the phase detector). The function of the signal channel is to amplify the weak signal to a level high enough to drive the correlator, and it also has the suppression and filtering part. The function of interference and noise; Correlator is a unit circuit that completes the cross-correlation function calculation of the measured signal and the reference signal, and is composed of a multiplier and an integrator circuit; the reference channel provides a periodic signal with the same frequency as the measured signal.
At present, the signal detection of GMR biosensors is based on common general-purpose lock-in amplifiers on the market, and its full-scale sensitivity can reach the order of nV. However, most of them are modular test instruments, which are too large and expensive to be used. Marketization of products. For this reason, it is very necessary to design a GMR sensor chip and semiconductor technology with good compatibility, and it can be packaged together with the lock-in amplifier IC chip using MCM technology, which will greatly improve the practicality of the GMR biosensor, Popularity.
5 Conclusion In summary, the giant magnetoresistance biosensor integrated technology, semiconductor technology, magnetic thin film technology and weak signal detection technology in one, through the detection of immunomagnetic markers, can accurately determine the composition of the test solution and contained The concentration of ingredients, etc., is a successful extension of the GMR sensor in the field of biological detection. Because of its many advantages, such as high sensitivity, high resolution, low cost, miniaturization of equipment, and automation of measurement processes, it has great potential in life sciences, medicine, and defense, etc., and it has become integrated with the progress of semiconductor technology. And sensitivity will also have a further increase in greetings. However, at present, research on GMR biosensors is still at the basic stage at home and abroad, and there is still a certain distance from practical application.
Dry Roll Press Granulator Co., Ltd. , http://www.nspelletmill.com