Biosensor system for actuating magnetic particles

The present invention relates to a biosensor system comprising a biosensor cartridge and a first biosensor magnetic assembly having two magnetic subunits for use with the biosensor cartridge, activating magnetic particles in the biosensor cartridge. Regarding the method.

Various analytical procedures for detecting specimens in test samples are known in the art.

For example, immunological tests use the mechanisms of the immune system in which antibodies and their respective antigens can bind to each other. This particular reaction mechanism is used to determine the presence or amount of antigen in a test sample. In particular, an antibody or antigen (specimen of interest) is labeled to measure the amount of interaction between the antibody and the antigen. Common labels are, for example, fluorescent and chemiluminescent molecules, colored particles (beads) or radioisotopes.

Recently, magnetic labels have been used in microfluidic analysis to detect the presence or amount of specimens. For example, using a magnetic label as a magnetic bead or a magnetic particle also named as a bead has several advantages. These magnetic particles can be actuated by applying a magnetic field to accelerate the analytical procedure. In addition, there are no magnetic background signals in biological tests that affect the detection of magnetic particles.

However, these analyzes using magnetic labels act to actuate the bound magnetic particles on antigens that are mobilized near the sensor surface of the sensor cartridge, and do not affect the quantitative measurement of those bound particles. Needs a means to shed the remaining unbound magnetic particles. So, for example, two magnets are placed on opposite sides of the sensor cartridge, the first magnet attracts the magnetic particles through the test sample towards the sensor surface, and as a result, the second magnet, It attracts unbound magnetic particles away from the sensor surface. In this configuration, the two magnets are mounted in a support structure, which mechanically moves the magnets toward or away from the sensor surface (see Non-Patent Document 1). ).

Such a method is very difficult, time consuming and requires a complex support structure for arranging the two magnets on opposite sides of the sensor cartridge. In addition, a first magnet located beneath the sensor cartridge controls the movement of the magnetic particles only in the direction perpendicular to the sensor surface, but in the horizontal direction, which is fundamentally parallel to the sensor surface. Do not control. Therefore, there may be regions in the cartridge where unbound magnetic particles have accumulated, next to regions where there may be few or too few magnetic particles bound to the antigen of interest. In addition, unbound particles in the peripheral region within the cartridge are not easily and as quickly attracted to the second magnet as the other particles, so these particles can remain in the cartridge. This can lead to unreliable test results.

Generally, the particles in the test sample go through several processes. For example, particles approach the sensor surface, bind to the sensor surface, and move away from the sensor surface. In conventional biosensor systems, magnetic particles near a magnet are typically actuated by a magnetic field and attracted towards the magnet. In this case, the quality and / or quantity of the signal received from the sensor surface next to the magnet is time dependent and therefore unreliable. This is because it not only represents the bound particles, but is also affected by the unbound magnetic particles in the distant part of the cartridge actuated by the magnetic field, which can move towards the sensor plane next to the magnet.

<p num="0008"><patcit num="1"><text>International Publication No. 2008/001266</text></patcit><patcit num="2"><text>International Publication No. 2008/107827</text></patcit><patcit num="3"><text>Special Table 2002-531811 Gazette</text></patcit></p>

<p num="0009"> One objective is to provide biosensor systems and methods for controlling the behavior of magnetic particles in cartridges and providing more reliable test results.</p>

<p num="0010"> The present invention is a biosensor system comprising a biosensor cartridge and a first biosensor magnet assembly for generating a magnetic field in a biosensor cartridge containing two magnetic subsystems, also referred to below as the first magnet assembly. Each of the two magnetic subsystems of its first biosensor magnet assembly has a core with a top surface separated by a gap, and the sensor surface contained by that biosensor cartridge is of that core. Placed on the top surface, the two subsystems are essentially parallel to the sensor plane to exert a force on the magnetic particles in the cartridge on the top surface between the first and second subsystems. It is adapted to generate a magnetic field with a wide range of magnetic lines of force. The term biosensor is used herein for biological substances and for all types of sensors suitable for detecting biological materials. The term top surface is used herein for a portion of a core at the top of the core near the sensor surface that has a different shape than the typical cylindrical shape of the core. Its top surface is aligned towards the sensor surface and its core is usually aligned vertically. When the sensor surface is placed between the cores, this means that its top surface is angled with respect to the core, which will be described in detail below. The top surface forms a profile of the magnetic field. The biosensor system is small, takes up little space, and allows flexible control of the movement of magnetic particles. In the biosensor system described, magnetic particles can move in several directions, especially left and right with respect to the figure. The biosensor system allows the sensor surface to wash away excess beads that are not bound to the asay without breaking the binding of the bound beads.</p><p num="0011"> Detailed examples of the present invention are described in the Dependent Section.</p><p num="0012"> In one example of a biosensor system, a second magnet assembly is placed on the sensor surface to exert a force on the magnetic particles in the cartridge. The second magnet assembly can be designed to resemble one of its two subunits. Its second magnet assembly supplies an additional magnetic field to exert a force on those beads and is controlled together with the two subunits by the control means driving the top coil. be able to.</p><p num="0013"> A first biosensor magnet assembly for generating a magnetic field is used in a biosensor system so that the spatial movement of magnetic particles in a biosensor cartridge can be controlled. By generating a magnetic field within the cartridge, the sample, usually the antigen or substance, contained in the test sample, labeled with magnetic particles and located in the vicinity of its first biosensor magnet assembly, is a mobilized antibody. Can be moved towards the sensor surface within the cartridge to couple to. Antibodies, antigen binding complexes, and magnetic particles that act as labels that are the samples to be tested are then determined whether the mere presence or amount of the sample in the test sample can be estimated. As such, it can be detected on its sensor surface. In another embodiment, due to changes in the magnetic field within the cartridge, magnetic particles present in the cartridge but far from the first biosensor magnet assembly are prevented from moving to the sensor surface. This further effect is shown in Figure 1, where different regions of the field lines are depicted. In the region indicated as B at the end of the cartridge, the magnetic particles or beads are oriented approximately perpendicular to their surface and are prevented from passing through due to the lines of magnetic force and corresponding forces that accumulate obstructions to the beads. In other words, domain walls are created between different regions in the cartridge.</p><p num="0014"> According to FIG. 1, a biosensor system including a biosensor cartridge and a first magnet assembly for generating a magnetic field within the biosensor cartridge is provided. In the biosensor cartridge, the lines of magnetic force are oriented to prevent the beads from passing through the edge of the sensor surface in one region B at the edge of the sensor surface of the cartridge.</p><p num="0015"> A biosensor cartridge is, for example, a container or reservoir for receiving a fluid test sample containing a sample such as an antigen of interest. Generally, the cartridge may have at least one planar substrate region, particularly a rectangular, circular or elliptical substrate area. The base area serves as a sensor surface on which the sample of interest can be analyzed by the detection procedure. Desirably, the cartridge or at least the planar substrate region of the cartridge is made of, for example, glass, cyclo-olefin polymer, polyethylene, polystyrene, polycarbonate, or polymethylmethacrylate, and of the test sample thereof. Enables optical analysis.</p><p num="0016"> Biosensor cartridges may contain or receive magnetic or magnetizable particles. "Magnetic" or "magnetizable" particles are affected by the application of a magnetic field and react magnetically. For example, these particles are attracted or repelled, or have a detectable magnetic susceptibility or induction. In a preferred embodiment, these particles are paramagnetic or superparamagnetic and may be made of a metal or metal oxide or a synthetic material such as ferrite such as magnetite. These particles may be beads or labels and are adapted to bind to target moieties such as antibodies and / or antigens. Such binding occurs directly or, for example, by a specific binding member, such as a protein captured by an antibody and / or a protein sandwiched between its particles and its antibody or antigen. In one embodiment of a biosensor cartridge, the antibody is passivated by a capture reagent on the sensor surface of the cartridge to provide a binding site for an antigen labeled with magnetic or magnetizable particles.</p><p num="0017"> In certain embodiments, at least one of its top surfaces may have an inclined portion, and different shapes can be designed as described below. In another example, at least one of its top surfaces has a flat portion at the top of the top surface spaced between 0.1 mm and 5 mm from the sensor surface.</p><p num="0018"> In certain embodiments, at least one of the magnetic subunits may be an electromagnetic subunit.</p><p num="0019"> The first magnet assembly of the biosensor system contains at least two magnetic subunits. In particular, those magnetic subunits may be electromagnetic subunits that include a coil with a magnetizable (magnetically reactive) core in each coil. The core may be made of ferromagnetic material. The first biosensor magnet assembly may be arranged such that one of the poles of each subunit is adjacent to the sensor surface on one of the sides of the biosensor cartridge. In one embodiment, the subunit basically has a cylindrical shape within the coil region, with two magnetic poles at the two ends of the cylinder (ie, the cylindrical base region and top surface). .. The subunit core may have a diameter between 0.01 mm and 0.5 mm, preferably between 0.02 mm and 2 mm, and its core height may be between 3 mm and 10 mm, preferably between 5 mm. May have a diameter of.</p><p num="0020"> In particular, the core of the magnetic subunit preferably has an upper surface that is located below the sensor surface of the cartridge, which may include flat and inclined portions. In a preferred embodiment, the planar portion is arranged parallel to the sensor surface of the cartridge.</p><p num="0021"> In certain embodiments, the magnetic field strength of each subunit can be changed separately by electrical control.</p><p num="0022"> The term "separately modifiable" means that the magnetic field of each subunit can be altered by electrical control independently of any modification of the magnetic fields of the other subunits. If the subunit includes an electromagnetic coil, as described above, the change in magnetic field strength of the subunit can be performed by changing the current flowing through the subunit coil. In this case, "electrical control" means controlling the current flowing through those coils.</p><p num="0023"> The biosensor system of the present invention allows in a biosensor cartridge to steer the movement of magnetic or magnetizable particles, such as beads such as labels, by the modifiable magnetic field of the first biosensor magnet assembly. .. Desirably, the particles can be steered to move directly to the sensor surface of the cartridge to save operating time. In addition, up-concentration of particles at specific locations on the sensor surface can be prevented by separately changing the magnetic field strength of the electromagnetic subsystem: by separate control of that subsystem, to the particles. The magnetic field gradient proportional to the acting force can be adjusted to move these particles horizontally, i.e. essentially parallel to the sensor plane, and / or essentially vertically, i.e. perpendicular to the sensor plane. ..</p><p num="0024"> In certain embodiments, the total analytical volume of the biosensor cartridge, i.e., the volume analyzed in the biosensor assembly, can be affected by the magnetic field generated by the subunit.</p><p num="0025"> The area or total volume of the sensor surface of the biosensor cartridge can be affected by the magnetic field of the subunit and / or the magnetic field can penetrate. The volume of the cartridge is its internal volume (excluding any inlet or outlet for filling the test sample) into which the test sample containing the sample can be inserted. The region of the sensor surface of the cartridge is generally, for example, the planar substrate region of the cartridge in which the antibody corresponding to the magnetic or magnetizable particles and / or antigen as an example in which the specimen is determined can be passivated. .. Advantageously, the biosensor cartridge is attached to the first biosensor magnet assembly so that the entire volume of the cartridge can be affected by and / or the magnetic field of the subunit can penetrate. They are placed next to each other. In this case, all magnetic or magnetizable particles in the cartridge are activated and geometric constraints within the cartridge can be avoided.</p><p num="0026"> In certain embodiments, the tilted portion of the magnetic subunit is 100 ° to 170 °, preferably 120 ° to 150 °, and even more preferably 130 ° to 140 °, with respect to the vertical plane of the sensor plane of the biosensor cartridge. Or it can be tilted 135 °.</p><p num="0027"> In one embodiment, the inclined portion is inclined toward the main axis of the core of the magnetic subunit. If the core basically has the outer shape of a right cylinder, its main axis is the height axis of the cylinder.</p><p num="0028"> In certain embodiments, each of its top surfaces may have planar portions spaced between 0.1 mm and 10 mm from the sensor surface.</p><p num="0029"> For example, the upper surface of the core of the magnetic subunit may have an inclined portion or may further have a flat portion. In this case, the flat portion may be arranged parallel to the sensor surface of the cartridge. The distance between the flat surface and the sensor surface may be 0.1 mm to 10 mm, more specifically 0.1 mm to 5 mm, and more specifically 0.1 mm to 3 mm. The close placement between the core and the sensor surface gives a high magnetic field density at that sensor surface and can therefore provide more reliable test results.</p><p num="0030"> According to the present invention, a method for operating magnetic particles in the biosensor system according to the biosensor system is claimed. In placing the biosensor cartridge adjacent to the first biosensor magnet assembly, the magnetic field generated by the first biosensor assembly moves towards its sensor surface and its sensor for reliable test results. The sensor surface in the cartridge can be affected to control the movement away from the surface.</p><p num="0031"> In certain embodiments, the first biosensor magnet assembly and biosensor cartridge used in the methods of the invention are part of the biosensor system described above.</p><p num="0032"> The method makes it possible to control the behavior of magnetic or magnetizable particles in biosensor cartridges to enable more reliable test results: those particles in the horizontal and / or vertical direction of the cartridge. The even distribution of is achieved and the remaining unbound particles far from the sensor surface are prevented from moving towards that sensor surface during the test procedure.</p><p num="0033"> In certain embodiments, the method may include changing the polarity of at least one magnetic subunit.</p><p num="0034"> For example, the system can have two different configurations, namely North-North configuration and North-South configuration, while South-South and South-North configurations are North-North and North-South configurations. And give the same pattern of magnetic field lines. In changing the polarity of at least one subunit, the direction of the force due to the magnetic field and the direction in which the magnetic particles in the cartridge are directed are opposite. Desirably, the force directed at the magnetic particle changes its sign by changing the polarity of at least one of its magnetic subunits.</p><p num="0035"> In certain embodiments, the first biosensor magnet assembly can generate a given gradient magnetic field in the biosensor cartridge in the direction parallel and / or perpendicular to the sensor plane.</p><p num="0036"> Desirably, the gradient magnetic field obtained in the biosensor cartridge is variable in the direction parallel and / or perpendicular to the sensor plane of the cartridge. In doing so, for example, the particles can be driven by their tilt to be placed in a predetermined area of the sensor surface in the biosensor cartridge so that the detection procedure is calibrated as desired.</p><p num="0037"> In certain embodiments, the tilted portion may be tilted 100 ° to 170 °, preferably 120 ° to 150 °, and even more preferably 130 ° to 140 ° or 135 ° with respect to the vertical plane of the sensor surface of the biosensor cartridge. ..</p><p num="0038"> In certain embodiments, each of the top surfaces may have planar portions spaced between 0.1 mm and 10 mm from the sensor surface.</p><p num="0039"> In particular, the subunit may be located in the substrate structure (particularly, the subunit region of the subunit is located in the substrate structure), preferably located in the ferromagnetic yoke. In one embodiment, the substrate structure may be part of a subunit. The substrate structure allows for easier handling of the first biosensor magnet assembly and may further avoid the geometric constraints that may arise if its subunits are not arranged in one plane. The ferromagnetic yoke as the substrate structure can enhance the magnetic field of the first biosensor magnet assembly by concentrating the magnetic field lines of the internal magnetic flux in the yoke and thus avoiding the loss. In particular, the substrate structure has a length and width between 0.01 mm and 10 mm, preferably less than 5 mm or 5 mm, and between 2 mm and 10 mm, preferably 4 mm high (ie, towards the biosensor cartridge). It may have the shape of a parallelepiped with a direction).</p><p num="0040"> In certain embodiments, the biosensor system of the present invention may further include control means adapted to switch or adjust the magnetic field strength of each subunit separately by electrical control. In particular, the control means may switch the direction of magnetization in the magnetic subunit. The control means may be advantageous for obtaining a predetermined gradient magnetic field in the biosensor cartridge. The magnetic field strength can be increased or decreased separately for each subunit by its control means, for example by increasing or decreasing the current in the subunit coil. Thus, a given gradient magnetic field is obtained in the biosensor cartridge, and the resulting gradient magnetic field can be easily modified by its control means at any time during the analytical procedure. In particular, the control means may be adapted to change its gradient magnetic field in directions parallel (horizontal) and / or perpendicular (perpendicular) to the sensor plane of the biosensor cartridge. The magnetic flux density in the cartridge can be variable by allowing the magnetic field strength to be adjusted separately for each subunit. Thus, the magnetic or magnetizable particles in the biosensor cartridge should move in a particular spatial direction, for example, in a horizontal direction (ie, parallel to or perpendicular to the sensor plane (ie, perpendicular to the sensor plane)). Thus, the diffusion of particles in the cartridge can be controlled by using control means for varying the magnetic field strength of the subunit, eg, accelerated or decelerated in each spatial direction. Can be done.</p><p num="0041"> In certain embodiments, the biosensor system of the present invention is an FTIR (Frustrated Total Internal Reflection) magnetic biosensor system. Due to the fact that light beams and magnetic fields generally do not interfere with each other, light detection methods for analyzing the presence and preferably quantity of a quantity of a sample of interest in a test sample are magnetic or magnetizable particles. It is advantageous when used as a marker. Therefore, external magnetic actuation may be very suitable for use with photodetection methods as it avoids sensor interference due to magnetic fields.</p><p num="0042"> These and other aspects of the invention will be clarified from the embodiments described below and will be described with reference to them.</p>

<figref num="1">FIG. 5 is a side sectional view showing a setting for a biosensor system in which two magnetic subunits are arranged under a cartridge according to one embodiment of the present invention.</figref><figref num="2">It is a mechanical drawing of the side surface of one magnetic subunit showing an exemplary size in mm for use in the present invention.</figref><figref num="3">It is a schematic diagram showing an example side of two magnetic subunits placed under a cartridge, another magnetic coil placed on the cartridge, lines of magnetic force aligned along the cartridge, and a sensor surface of the cartridge. The schematic magnetic particles in the vicinity are not represented to the exact scale, the figure.</figref><figref num="4">It is a diagram schematically showing a side of a biosensor system having another magnetic coil, an upper coil above a cartridge, a cartridge, and two subunits below the cartridge, the cartridge being each of the magnetic subunits. It is a figure which has a tip having a thin shape at one end.</figref><figref num="5">FIG. 4 is a schematic representation of a side view of a biosensor system similar to FIG. 4, having other magnetic coils, an upper coil above the cartridge, a cartridge, and two coils below the cartridge, the cartridge being a magnetic sub. It is a figure which has a thick shape at each end of a unit.</figref><figref num="6">It is a graph which shows the two curves of the angle of the magnetic field line with respect to the position on the sensor surface with respect to the thin-shaped tip according to FIG. 4 and the thick-shaped tip according to FIG. 5, as a broken line and a continuous line, respectively.</figref><figref num="7">It is a diagram schematically showing the top surface of two narrow tips of a magnetic subunit, the distribution of the magnetic field in the gap between the tips, and the optical window between the tips where the measurement is made.</figref><figref num="8">It is a schematic top view showing the distribution of the magnetic field in the wide gap between the two wide tips of the magnetic subunit, the optical window between the tips to be measured, as in FIG. 7.</figref>

<p num="0044"> FIG. 1 shows an embodiment of a biosensor system 1 comprising a first biosensor magnet assembly 10 with two electromagnetic subunits 20a and 20b, which is typically formed integrally with the subunits 20a, 20b. Can be placed on the subunit structure 23a and 23b. In one preferred embodiment, each subunit 20a, 20b comprises cores 22a, 22b inside coils 21a, 21b and the coils 21a, 21b. The magnetic field strength of each subunit 20a, 20b can be electrically controlled by changing the current flowing through the coils 21a, 21b. An example of magnetic field strength is up to 40 kA / m, and an example of gradient magnetic field is 2 * 107 A / m.²It extends to. Generally, the subunits 20a and 20b are located on one side of the biosensor cartridge 30 facing the magnetic subunits 20a and 20b. The biosensor cartridge 30 is shown in FIG. 1 as having a length dimension and a height h. When the board structures 23a, 23b are used, the cartridge 30 is adjacent to the subunits 20a and 20b so that the first magnet assembly 10 is located between the board structures 23a, 23b and the cartridge 30. To position. In certain embodiments, the substrate structures 23a, 23b may be a single yoke, as discussed above. In addition, the cartridge 30 may be arranged so that its volume can be affected and / or penetrated by the magnetic field of the first magnet assembly 10. In FIG. 1, the magnetic subunits 20a, 20b have a North-South configuration such that the magnetic field lines provide a pattern in the cartridge 30 as shown in FIG. 1 and can penetrate the sensor surface 31 in the cartridge 30. The sensor surface 31 of the cartridge 30 is useful for detecting a sample added to the cartridge 30. The cores 22a, 22b of subunits 20a, 20b include the top surfaces 24a, 24b located on top of those cores, also shown below as tips, the inclined portions 26a, 26b and, as depicted in FIG. It has flat portions 28a and 28b. The planar portions 28a, 28b are preferably located close to the cartridge 30 and / or parallel to the sensor surface 31 on the cartridge 30. After the magnetic field is generated in the cartridge 30 by the first biosensor magnet assembly 10, the field lines provide a pattern as shown in FIG. 1, and the field lines are perpendicular to the top surfaces 24a, 24b of the cores 22a, 22b. spread. For the purpose of clarity of the field line, the field line is drawn only in the area of the cartridge 30.</p><p num="0045"> According to an embodiment of the method of the present invention, the sensor surface 31 of the cartridge 30 is such that the magnetic field generated by the magnetic subunits 20a, 20b penetrates the volume of the cartridge 30, particularly the entire analytical volume analyzed by the biosensor asay. , Placed on top of the first magnet assembly in FIG. The tilted portions 26a, 26b of the top surfaces 24a, 24b of subunits 20a, 20b allow the behavior of magnetic or magnetizable particles present in or filled in the cartridge 30 to be controlled in detail.</p><p num="0046"> FIG. 2 shows a mechanical drawing of a particular magnetic subunit 20b for use in magnet assemblies 10 and 40 similar to FIG. In particular, the top surface 24b of the magnetic subunit 20b is drawn and further described. The same is true for subunit 20a located on the opposite side of subunit 20b, as described. As specified in FIG. 2, the dimensions of subunit 20b are shown in millimeters (mm). In the particular embodiment shown, the substrate structure 23b has a height of 4 mm. In particular, the height of the substrate structure 23b of subunit 20b may be between 2 mm and 10 mm, more preferably between 3 mm and 6 mm. In FIG. 2, the height of the core 22b is specified as 5 mm. In certain embodiments, the height of the core 22b may be between 3 mm and 10 mm, more preferably between 4 mm and 7 mm. The height of the tip 24b of subunit 20b is specified as approximately 1 mm. In certain embodiments, the height of the tip 24b may be between 0.5 mm and 3 mm, more preferably between 0.5 mm and 2 mm. The length of the flat portion of the top surface 24b of the core 22b is specified in FIG. 2 as being 1.7 mm. In certain embodiments, the length of the planar portion 28b may be between 1 mm and 3 mm, more preferably between 1.5 mm and 2 mm. The inclined portion 26b at the tip of the upper surface 24b is specified in FIG. 2 as being 135 °. In certain embodiments, the angle may be between 100 ° and 170 °, preferably between 120 ° and 150 °, and even more preferably between 130 ° and 140 °. The diameter of the cylindrical core 22b of subunit 20b is specified in FIG. 2 as being between 0.02 mm and 2 mm. In certain embodiments, the diameter of the core 22b is between 0.01 mm and 5 mm. The opposite end of the subunit structure 23b of subunit 20b is 0. Supplied with an offset with a height of 3 mm. In certain embodiments, the height of the offset is between 0.1 mm and 0.5 mm, preferably between 0.2 mm and 0.4 mm. The length of the substrate structure 23b of subunit 20b is specified in Figure 2 as being between 0.01 mm and 4.99 mm. In certain embodiments, the length and / or width of the substrate structure 23b is between 0.01 mm and 10 mm, preferably between 0.01 mm and 7 mm, or even more preferably less than 5 mm. These dimensions described are correspondingly similar for the magnetic subunit 20a.</p><p num="0047"> In certain embodiments, the magnet assemblies 10, 40 are essentially equal to the length of the biosensor cartridge 30. In this case, the magnetic field generated by subunits 20a, 20b can penetrate the entire volume of the cartridge 30. In doing so, the particles 2 can be controlled in each part of the cartridge 30 to obtain reliable test results.</p><p num="0048"> FIG. 3 shows a schematic side view of an example of two magnetic subunits 20a, 20b arranged under the cartridge 30 as in FIG. If the sensor surface 31 on the cartridge 30 above the magnetic subunits 20a, 20b has a greater distance to the tips 24a, 24b, a wider gap is typically used between the magnetic subunits 20a, 20b. The subunits 20a and 20b are spaced from each other by a gap 25. The gap 25 does not necessarily have to be filled with any material other than outside air so that the subunits 20a, 20b can move with respect to each other. In a further embodiment, the gap 25 may be filled with a dielectric material. The dielectric material may be a plastic molding material in which subunits 20a and 20b may be embedded so that the outer shape of each subunit 20a and 20b is not easily visible. In a preferred embodiment, only one or both of the polar surfaces of each subunit 20a, 20b is not coated with a dielectric material. The dielectric material may act as an insulator between the subunits, or the distance between the subunits 20a, 20b may be fixed so that the subunits 20a, 20b cannot move with respect to each other. .. Therefore, geometric restrictions can be further avoided. Normally, the gap 25 between the magnetic subunits 20a and 20b has the same unit size as the distance of the magnetic subunits 20a and 20b to the sensor surface 31. The coils 21a, 21b are schematically shown to further illustrate the described design and shape of the magnetic subunits 20a, 20b. Various combinations of polarities of the two magnetic subunits 20a, 20b may be used (North-South, North-North, South-South, South-North). Figure 3 sketches a configuration with opposite poles at the tips 24a and 24b. In this configuration, the lines of magnetic force between the poles of the two subunits 20a, 20b are cartridges in the region above the cartridge 30. It has a direction basically parallel to the sensor surface 31 of the di30 and the cartridge 30. This effect arises from one pole of the magnetic subunit 20a and is exemplary and schematically illustrated by the four lines of magnetic force projected onto the second pole of the opposite subunit 20b. The shape of the magnetic field generated by the magnet assemblies 10 and 40 resembles an arc. As a result, the lines of magnetic force penetrate the same volume in which the sample of the sample, such as saliva or blood, is dissolved, at different angles depending on the lateral position with respect to the magnetic subunits 20a, 20b of the cartridge 30. Another important feature of the magnetic field in this polar configuration is that it has a gradient magnetic field directed in the direction of the sensor surface 31, which causes the forces in the magnetic particles 2 to act towards the sensor surface 31.</p><p num="0049"> An additional magnetic assembly, also called the second magnet assembly 40, placed on top of the cartridge 30 is drawn in a schematic manner, as can be seen in FIG. The second magnet assembly 40 can be controlled separately by the biosensor system 1 and can be designed, for example, as a magnet assembly 40 with a coil or multiple magnetic subunits. The second magnet assembly 40 can be designed similar to one or both of the magnetic subunits 20a, 20b. In the case of a second magnet with a single core single coil architecture, in the region between the second magnet assembly 40 and the cartridge 30, the field lines are only activated in the second magnet assembly 40 and the two magnets. The magnetic field generated by the subsystems 20a, 20b is approximately perpendicular to the cartridge 30 when inactivated. The magnetic force generated by the second magnet assembly 40 affects the magnetic particles 2 and forces the magnetic particles 2 to move away from the cartridge 30. When the second magnet assembly 40 and the two subunits 20a and 20b are controlled in a coordinated manner by the control means 48, it is possible to exert a controlled force on the magnetic particle 2 in the fluid being analyzed with respect to the plane of FIG. become. For perfection, the control means 48 is taken out in a schematic way to drive the two subunits 20a, 20b and the second magnet assembly. The control means 48 switches on and off to control the magnetic field strength of the two subunits 20a and 20b and the second magnet assembly 40 according to its operating state. The operating state is, for example, a parallel cleaning state in which a force is applied in a direction basically parallel to the sensor surface 31 to wash away excess beads 2. Another operating state is the working state in which the beads 2 are dragged to the sensor surface 31 to establish a bond in the asay (hidden). The process of binding the beads 2 to the specimen and the antigen to the asay (hidden) is known and described in the prior art. By biosensor system 1 described , The binding process and the speed of this process are improved as the beads 2 approach the asay (hidden) faster than the magnetic force. The distance between the tips 24a, 24b of the two subunits 20a, 20b is selected with respect to the distance to the position where the magnetic beads 2 are driven, which is the area above the sensor surface 31 in the cartridge 30. The term actuation is known in the prior art and basically refers to the process of feeding the magnetic particles 2 to the ash (hidden) and binding the magnetic particles 2 and the specimen to the ash (hidden). Further, the described biosensor system 1 can also be applied to the biosensor cartridge 30 in which the measurement is made without binding the sample and the magnetic particle 2 to the ash (hidden).</p><p num="0050"> FIG. 4 schematically shows a side surface of a biosensor system 1 similar to FIG. 1 showing a constant example of top surfaces 24c, 24d, another example of top surfaces 24a, 24b is shown in FIG. ing. As shown in FIG. 3, the biosensor system 1 further includes a second magnet assembly 40 containing a core 42 and a coil 41 at the top of the biosensor system 1, which second magnet assembly 40 is shown in FIG. Is placed on the cartridge 30 with respect to the depiction of. The second magnet assembly 40 is located on the other side of the subunits 30 of subunits 20a, 20b, and the cartridge 30 including the sensor surface 31 is between the second magnet assembly 40 and the two subunits 20a, 20b. Located in. The two subunits 20a, 20b below the cartridge 30 are separated by a gap 25 in the region of the tips 24c, 24d of the magnetic subunits 20a, 20b. This means that the recesses are located between the tips 24a, 24b, which are usually formed integrally with the subunits 20a, 20b, as suggested in FIGS. 4 and 5. As described, the top surface or tips 24a, 24b, 24c, 24d are aligned in the direction towards the sensor surface 31. In the example of FIG. 2, the tips 24c, 24d have a shape that is described as thin, which means that the diameters of these exemplary tips 24c, 24d decrease in the direction away from the cores 23a, 23b. To do. In other words, the tips 24c and 24d taper toward the cartridge 30. The tips 24c, 24d in this example tilt toward each other, as seen in FIG. 4, which are near the cartridge 30, far from the cartridge 30, and of the subunit structures 23a, 23b of the subunits 20a, 20b. Brings a narrower gap 25 than near. In the example of FIG. 5, the tips 24a, 24b have a shape that is described as thick, which means that the diameters of these exemplary tips 24a, 24b are essentially constant in the direction away from the subunits 20a, 20b. This is Means that. The tips 24a and 24b in FIG. 5 have a shape similar to the tips 24a and 24b described in detail in FIG. The tips 24a and 24b extend in a direction basically perpendicular to the cores 23a and 23b as depicted in FIG. 5, and the end faces of the tips 24a and 24b far from the cores 23a and 23b face each other. This means that the width of the gap 25 between the tips 24a, 24b is constant in contrast to FIG. Both of the examples shown in FIGS. 4 and 5 result in a magnetic field characterized by the field lines depicted in a similar example of FIG. The results of different examples of tips 24a, 24b, 24c, 24d with respect to the profile of the generated magnetic field are described based on the curve in FIG.</p><p num="0051"> FIG. 6 shows two curves obtained in connection with the biosensor system 1, the x-axis showing the position x in mm along the sensor surface 31 of the cartridge 30. Its y-axis indicates the angle α of the field line. The angle α between the magnetic field line and the optical window is tan α = B._y/ B_xCan be calculated from B_xAnd B_yAre the lateral and vertical components of the magnetic flux density vector, respectively. FIG. 6 shows the dependence of the angle α on the lateral position at the bottom of the sample volume. The edges of the optical window 46 are drawn by vertical lines at -0.5 mm and +0.5 mm positions in FIG. It can be seen that the lines of magnetic force at the edge of the optical window 46 are tilted by about 30 °. Due to the symmetry of the magnetic field at equal current inputs into both coils 21a, 21b, the lines of magnetic force run horizontally in the center of the optical window 46 at the zero position. The dashed upper curve characterizes the angle α with respect to the shape of the narrow tips 24c, 24d, according to FIG. The lower continuous curve characterizes the angle α with respect to the shape of the thick tips 24a, 24b, according to FIG. The angle α formed by the magnetic field lines and the surface of the optical window 46 depends on the lateral position x on the horizontal line along the sensor surface 31. As shown by the curve, the angle α has a value of zero at the zero position. That is, at the center of the optical window 46, the lines of magnetic force are parallel to the sensor surface 31. The angle α increases almost continuously with increasing distance from the center at the zero position. The upper dashed curve runs steeper than the lower continuous curve, which has a stronger increase in its angle α at the narrow tips 24c and 24d according to FIG. 4 than at the thick tips 24a and 24b according to FIG. Means to have. The change in its shape leads to a decrease in the magnetic field angle α of about 7 ° at the edge of the optical window 46. The shapes of the tips 24a, 24b, 24c, and 24d affect the angle α of the field lines, and thus the exertion of force on the magnetic particle 2, as evidenced in FIG. As a result of the shape of the pole tips or tips 24a, 24b, 24c, 24d, the magnetic field distributions for the examples of magnetic subunits 20a, 20b according to FIGS. 4 and 5 are different.</p><p num="0052"> In the experiment, based on the magnetic subunits 20a, 20b according to FIG. 4 with thin tips 24c, 24d, the magnetic particles 2 form a chain while being attracted by the magnetic force, which is on the sensor surface 31 or the surface of the cartridge 30. Eventually adhered and the chain aligns according to the local direction of the magnetic lines of force. This effect has been identified as one of the causes of the non-uniform distribution of magnetic particles 2 on the sensor surface 31, which is not desirable as it can worsen accurate measurements.</p><p num="0053"> The biosensor system 1, which includes alternative shapes of thick tips 24a, 24b showing a flattened distribution of angle α, has a wider arc and avoids the formation of chains of magnetic particles 2, thus the distribution of magnetic particles. To improve.</p><p num="0054"> FIG. 7 shows a schematic top view of the two tips 24a, 24b of the magnetic subunits 20a, 20b facing each other. In this example, the distance between the tips 24a, 24b is selected to be about 1 mm. The width of the tips 24a and 24b is selected to be about 2 mm, which is described here as narrow. Both dimensions of the width of the tips 24a, 24b and the distance between the tips 24a, 24b can be selected differently. The distribution of the magnetic field is shown around the gap 25 and the tips 24a, 24b, while the field lines at the center of the gap 25 are basically parallel with respect to the end faces of the tips 24a, 24b. In FIG. 7, along the vertical line, in the direction far from the center of the gap 25 to the ends of the tips 24a, 24b, the magnetic field line is more curved in the direction around the tips 24a, 24b, and the center of the gap 25. Makes an increasing angle with the parallel lines of magnetic force in. In FIG. 7, a region centered on the gap 25 is plotted between the tips 24a and 24b, and the region is the optical window 46. As described above, one method of detecting the specimen present in the cartridge 30 is after a process of normal operation, which is a photodetection method. Other detection methods are also desirable. In the region of the optical window 46, the magnetic fields are aligned in such a way that they are essentially represented as parallel lines of magnetic force. Measurements of the biosensor system 1 are preferably made by the optical window 46, followed by the sensor 31, and the specimen is placed on the tips 24a, 24b in the optical window 46, as shown in FIGS. 3, 4, and 5. Will be done.</p><p num="0055"> FIG. 8 shows a schematic top view of the two tips 24a, 24b of the magnetic subunits 20a, 20b, similar to FIG. The configuration diagram shown in FIG. 8 is rotated 90 ° as compared to FIG. The tips 24a and 24b of the magnetic subunits 20a and 20b in FIG. 8 are wider than the tips 24a and 24b in FIG. 7 because they have a width of about 5 mm. The distance between the tips 24a and 24b in the gap 25 in the example of FIG. 7 is approximately the same as the corresponding distance of FIG. 8 and is selected as 1 mm. The distribution of the field lines between the tips 24a and 24b in the wide gap 25 in FIG. 8 is different from the narrow gap 25 in FIG. 7 as depicted. The lines of magnetic force are essentially parallel along a wide area within its wide gap 25, which area is at least the width of the tips 24a, 24b, about 5 mm in that given example. The optical window 46 in the gap 25 between the tips 24a, 24b is the area where the desired measurement of the biosensor system 1 is made. In FIG. 8, the optical window 46 can be shifted along a horizontal line without deteriorating the measurement result. This means that the sensor surface 31 of the cartridge 30 can be located not only in the center of the gap 25, but rather in the direction towards the ends of the tips 24a, 24b. This is because the magnetic field in the gap 25 is more uniform than in FIG. 7 due to structural changes in the tips 24a and 24b.</p><p num="0056"> The present invention has been described and described in detail in the figures and the aforementioned description, but such description and description should be considered exemplary or exemplary and non-limiting; the invention is therefore. , Not limited to the disclosed embodiments. Modifications of the disclosed embodiments can be understood and validated by those skilled in the art and those who practice the claimed invention from the study of the figures, the present disclosure, and the accompanying claims. In the claims, the term "contains" does not exclude other elements or steps, and the singular and numeric terms do not exclude plurals. A single processor or other unit may fulfill the functions of some of the items listed in the claims and descriptions of the present application (eg, the functions of the control means discussed above). The mere fact that certain measurements are listed in different dependent terms does not indicate that a combination of these measurements cannot be used in an advantageous way. No reference code in the claims should be considered as limiting its scope.</p><p num="0057"> Hereinafter, the means taught by the present application will be listed by way of example. (Appendix 1) Biosensor cartridge, A first biosensor magnet assembly for generating a first magnetic field in said biosensor cartridge, each having two magnetic subunits, each having a core with a top surface separated by a gap. Is a biosensor system with The sensor surface contained in the biosensor cartridge is arranged on the upper surface of the core, and the two magnetic subunits are attached to the magnetic particles in the cartridge between the first subunit and the second subunit. Adapted to generate the first magnetic field with a first line of magnetic force that is essentially parallel to the sensor surface to exert force. A second biosensor magnet assembly is placed on the sensor surface to generate a second magnetic field and exert a force on the magnetic particles in the cartridge. Further comprising a control means for independently controlling the second magnetic field by electrically driving the second biosensor magnet assembly and at least one of the two magnetic subunits. The control means includes a second magnetic force line in the direction perpendicular to the sensor surface in the second magnetic field, and the second magnetic force line is a domain wall that prevents the magnetic particles from translating in a direction parallel to the sensor surface. Act as, Biosensor system. (Appendix 2) The two magnetic subsystems and the second biosensor magnet assembly can generate a force acting in a direction toward the sensor surface and a force acting in a direction away from the sensor surface by electrical control of the control means. The biosensor system described in Appendix 1, which is arranged so that it can be used. (Appendix 3) At least one of the two magnetic subunits is an electromagnetic subunit, and the magnetic flux strength of each subunit can be changed separately by the electrical control of the control means, and the direction and / or magnitude of the force. The biosensor system described in Appendix 1, which is mutable. (Appendix 4) The biosensor system according to Appendix 2, wherein the entire analytical volume of the biosensor cartridge can be influenced by the magnetic field generated by the two magnetic subunits. (Appendix 5) The biosensor system according to Appendix 1, wherein the core having the upper surface has an inclined portion inclined by 100 ° to 170 ° with respect to the vertical line of the sensor surface of the biosensor cartridge. (Appendix 6) The biosensor system according to Appendix 1, wherein each of the top surfaces has a planar portion spaced between 0.1 mm and 5 mm from the sensor surface. (Appendix 7) A method of operating magnetic particles with the biosensor system described in Appendix 1. (Appendix 8) The magnetic field steers the movement of magnetic particles present in the first region of the biosensor cartridge close to the first biosensor magnet assembly and away from the first biosensor magnet assembly of the biosensor cartridge. The method according to Appendix 7, wherein the magnetic particles present in the two regions are prevented from moving into the first region. (Appendix 9) 7. The method of Appendix 7, comprising changing the polarity of at least one of the two magnetic subunits. (Appendix 10) The method of Appendix 7, wherein the first biosensor magnet assembly generates a predetermined gradient magnetic field in directions parallel and / or perpendicular to the sensor plane in the biosensor cartridge. (Appendix 11) The two magnetic subunits are directed from the first subunit to the second subunit, with lines of magnetic force directed from the second subunit to the first subunit to subsequently flush out unbound particles. The method described in Appendix 7, adapted to produce.</p>