TW202127024A - Method of detecting biological sample - Google Patents

Abstract

A method of detecting a biological sample includes the following steps. A magnetic sensor chip is provided, wherein the magnetic sensor chip includes a substrate and a magnetic sensing layer located on the substrate. Probes are connected to the magnetic sensor chip. A sample solution including biological samples labeled with a first marker is provided on the magnetic sensor chip, so that the biological samples labeled with the first marker are hybridized with the probes. Magnetic beads labeled with a second marker is provided on the magnetic sensor chip, so that the magnetic beads labeled with the second marker are bound onto the biological samples labeled with the first marker. A signal sensed by the magnetic sensing layer is detected by a magnetic sensor.

Description

Detection methods of biological samples

The present invention relates to a detection method, and particularly relates to a detection method of a biological sample.

At present, the detection of biological samples is generally carried out using traditional optical detection techniques. However, the traditional optical detection technology has difficulty in optical identification of low-concentration biological samples, and is susceptible to background matrix interference when performing spectral identification, which results in a decrease in detection sensitivity. Therefore, the development of a detection technology and method that is not limited by optical identification is currently an important topic in this field.

The present invention provides a biological sample detection method, which can have better detection sensitivity (sensitivity).

The present invention provides a biological sample detection method, which includes the following steps. A magnetic sensing chip is provided, wherein the magnetic sensing chip includes a substrate and a magnetic sensing layer located on the substrate. Connect multiple probes to the magnetic sensor wafer. A sample solution containing a plurality of biological samples labeled with the first marker is provided on the magnetic sensing chip, so that the biological sample labeled with the first marker is hybridized with the probe. A plurality of magnetic beads marked with the second marker are provided on the magnetic sensing chip, so that the magnetic beads marked with the second marker are bonded to the biological sample marked with the first marker. A magnetic sensor is used to detect the signal sensed by the magnetic sensing layer.

According to an embodiment of the present invention, in the above biological sample detection method, the magnetic sensor is, for example, a tunnel magnetoresistance (TMR) sensor or a giant magnetoresistance (GMR) sensor. Device.

According to an embodiment of the present invention, in the above biological sample detection method, the probe is, for example, a nucleic acid probe.

According to an embodiment of the present invention, in the above biological sample detection method, the length of the nucleic acid probe is, for example, 20 monomer units to 40 monomer units (mer).

According to an embodiment of the present invention, in the above biological sample detection method, the probe may be located in the sensing area of the magnetic sensor chip.

According to an embodiment of the present invention, in the above biological sample detection method, the biological sample is, for example, a single strand of nucleic acid to be tested.

According to an embodiment of the present invention, in the above biological sample detection method, the length of the single strand of nucleic acid to be tested is, for example, 80 monomer units to 120 monomer units.

According to an embodiment of the present invention, in the above biological sample detection method, the preparation method of the biological sample labeled with the first marker may include the following steps. Provide double-stranded nucleic acid to be tested. The primer labeled with the first marker is used to perform amplication processing on the double-stranded nucleic acid to be tested to obtain a plurality of double-stranded nucleic acids to be tested labeled with the first marker. The double-stranded nucleic acid to be tested labeled with the first marker is denatured to obtain a sample solution of the single-stranded nucleic acid to be tested labeled with the first marker.

According to an embodiment of the present invention, in the above biological sample detection method, the amplification treatment of the double-stranded nucleic acid to be tested is, for example, polymerase chain reaction (PCR). The denaturation treatment is, for example, thermal decomposition.

According to an embodiment of the present invention, in the above biological sample detection method, the source of the biological sample may be the biological specimen to be tested. The biological sample to be tested is, for example, urine, saliva, serum, or plasma.

According to an embodiment of the present invention, in the above biological sample detection method, the first marker can be biotin, and the second marker can be Streptavidin.

According to an embodiment of the present invention, in the above biological sample detection method, the particle size of the magnetic beads is, for example, 0.2 μm to 2 μm.

According to an embodiment of the present invention, in the above-mentioned biological sample detection method, the material of the magnetic beads is, for example, ferroferric oxide (Fe ₃ O ₄ ).

According to an embodiment of the present invention, in the biological sample detection method described above, the detection performed by the magnetic sensor further includes quantitative analysis. Quantitative analysis can include the following steps. After performing the hybridization reaction and before bonding the magnetic beads to the biological sample, a magnetic sensor is used for measurement to obtain the first signal. After the magnetic beads are bonded to the biological sample, a magnetic sensor is used for measurement to obtain a second signal. The number of magnetic beads attached to the biological sample is calculated by the difference between the second signal and the first signal, so as to quantify the biological sample hybridized with the probe.

According to an embodiment of the present invention, in the above biological sample detection method, the first signal and the second signal are, for example, voltage signals. The voltage value of the second signal may be higher than the voltage value of the first signal.

According to an embodiment of the present invention, in the above biological sample detection method, the first signal and the second signal can be measured at room temperature.

According to an embodiment of the present invention, the above-mentioned biological sample detection method may further include the following steps. Before connecting multiple probes to the magnetic sensor wafer, the magnetic sensor wafer is subjected to surface modification treatment.

According to an embodiment of the present invention, in the above-mentioned biological sample detection method, the surface modification treatment is, for example, forming a silicon dioxide dielectric layer on a magnetic sensing wafer.

According to an embodiment of the present invention, the above-mentioned biological sample detection method may further include the following steps. After the hybridization reaction is performed, a washing treatment is performed to remove the biological sample that has not hybridized with the probe.

According to an embodiment of the present invention, the above-mentioned biological sample detection method may further include the following steps. After the magnetic beads are attached to the biological sample, a washing process is performed to remove the magnetic beads that are not attached to the biological sample.

Based on the above, in the biological sample detection method proposed in the present invention, when the magnetic sensor in the magnetic sensor chip is used for detection, since there is almost no magnetic substance in the biological sample, it will not be interfered by the matrix. In this way, when the magnetic sensor in the magnetic sensor chip is used to detect biological samples, it can have better detection sensitivity.

In order to make the above-mentioned features and advantages of the present invention more comprehensible, the following specific embodiments are described in detail in conjunction with the accompanying drawings.

Fig. 1 is a flowchart of a biological sample detection method according to an embodiment of the present invention. 2A to 2F are schematic diagrams of a biological sample detection process according to an embodiment of the present invention. Fig. 3 is a schematic diagram of a method for preparing a biological sample according to an embodiment of the present invention. Fig. 4 is a flow chart of quantitative analysis according to an embodiment of the present invention.

Please refer to FIG. 1 and FIG. 2A to perform step S100 to provide a magnetic sensor chip 100. The magnetic sensor chip 100 refers to a chip containing a magnetic sensor. In this embodiment, the magnetic sensing chip 100 includes a substrate 102 and a magnetic sensing layer 104 located on the substrate 102. The substrate 102 is, for example, a semiconductor substrate, such as a silicon substrate. The magnetic sensing layer 104 may be a magnetic tunnel junction (MTJ) structure. For example, the magnetic tunnel junction structure may be a sandwich structure including two upper and lower ferromagnetic metal layers (such as NiFe or CoFe) and an insulating layer (such as aluminum oxide or magnesium oxide) in between. The magnetic sensing layer 104 can be fabricated by a semiconductor process. In some embodiments, the magnetic sensor chip 100 may be a microfluidic chip, but the invention is not limited to this.

In addition, step S102 may be performed to perform a surface modification treatment on the magnetic induction wafer 100 to facilitate the connection of the probe to the magnetic induction wafer 100 in the subsequent manufacturing process. The surface modification treatment is, for example, to form a silicon dioxide dielectric layer 106 on the magnetic sensing wafer 100, but the invention is not limited to this. For example, the silicon dioxide dielectric layer 106 can be formed on the magnetic sensing layer 104. In other embodiments, the surface modification treatment may be to form a dielectric layer of other suitable materials on the magnetic sensing wafer 100.

Please refer to FIG. 1 and FIG. 2B to proceed to step S104 to connect a plurality of probes 108 on the magnetic sensor wafer 100. For example, the probe 108 can be connected to the silicon dioxide dielectric layer 106. In addition, the probe 108 may be located in the sensing area R of the magnetic sensing wafer 100. The sensing area R of the magnetic sensor chip 100 may be a well or a flow channel in the magnetic sensor chip 100. In this embodiment, the probe 108 is a nucleic acid probe as an example, but the present invention is not limited to this. In addition, the length of the nucleic acid probe is, for example, 20 to 40 monomer units, for example, about 20 to 25 monomer units, about 25 to 30 monomer units, about 30 to 35 monomer units, or about 35 to 40 monomer units. Monomer unit, but not limited to this. In an embodiment, the length of the nucleic acid probe may be 20 to 30 monomer units. The method of attaching the probe 108 to the magnetic sensitive wafer 100 is, for example, a chemical cross-linking method.

1 and 2C, proceed to step S106, provide a sample solution S1 containing a plurality of biological samples marked with the first marker 112 on the magnetic sensor chip 100, so that the biological sample marked with the first marker 112 The hybridization reaction with the probe 108 is performed. The source of the biological sample may be the biological specimen to be tested. The biological sample to be tested is, for example, urine, saliva, serum, or plasma. In the case where the source of the biological sample is the biological sample to be tested, the biological sample to be tested can be pre-processed, such as extraction processing or purification processing. The temperature range of the hybridization reaction is, for example, 45°C to 65°C, but the present invention is not limited to this. For example, the temperature range of the hybridization reaction may be about 45°C to 50°C, about 50°C to 55°C, about 55°C to 60°C, or about 60°C to 65°C, etc., but is not limited thereto. In one embodiment, the temperature range of the hybridization reaction may be about 55°C to 62°C, thereby shortening the reaction time. In some embodiments, the temperature range of the hybridization reaction may be about 50°C, about 55°C, or about 60°C.

In this embodiment, the biological sample is the single stranded nucleic acid 110a to be tested as an example, but the present invention is not limited to this. The length of the single-stranded nucleic acid 110a to be tested is, for example, 80 monomer units to 120 monomer units, for example, about 80 to 90 monomer units, about 90 to 100 monomer units, about 100 to 110 monomer units, or about 110 to about 110 monomer units. 120 monomer units, but not limited to this. In an embodiment, the length of the single-stranded nucleic acid 110a to be tested may be 90 monomer units to 110 monomer units. The first marker 112 may be biotin, but the present invention is not limited to it.

3, when the biological sample is the single-stranded nucleic acid 110a to be tested, the method for preparing the biological sample labeled with the first marker 112 may include the following steps, but the present invention is not limited thereto. Provide the double-stranded nucleic acid 110 to be tested. For example, the double-stranded nucleic acid 110 to be tested can be obtained by pre-processing the biological sample to be tested. The double-stranded nucleic acid to be tested 110 may include the single-stranded nucleic acid to be tested 110a and the single-stranded nucleic acid 110b. Next, the primer 114a labeled with the first marker 112 is used to perform the amplification processing 116 on the double-stranded nucleic acid 110 to be tested to obtain a plurality of double-stranded nucleic acids 110 labeled with the first marker 112. The amplification treatment of the double-stranded nucleic acid to be tested is, for example, polymerase chain reaction (PCR). In the amplification process 116, a pair of primer 114a and primer 114b can be used for amplification. Then, the test double-stranded nucleic acid 110 labeled with the first marker 112 is subjected to a denaturation treatment 118 to obtain a sample solution S1 of the test single-stranded nucleic acid 110a labeled with the first marker 112 (FIG. 2C ). In addition, the sample solution S1 may include a single-stranded nucleic acid 110b (not shown in FIG. 2C) in addition to the single-stranded nucleic acid 110a to be tested. That is, the double-stranded nucleic acid 110 to be tested can be subjected to the denaturation treatment 118 to form the single-stranded nucleic acid 110a and the single-stranded nucleic acid 110b to be tested labeled with the first marker 112. The denaturation treatment 118 is, for example, a pyrolysis treatment.

1 and 2D, step S108 may be performed, after the hybridization reaction is performed, a cleaning process is performed to remove the biological sample that has not hybridized with the probe 108 (for example, the single stranded nucleic acid 110a to be tested). For example, buffer S2 can be used to perform the above-mentioned cleaning process. The buffer S2 is, for example, a Tris (product name) buffer, but the present invention is not limited to this. The Tris buffer may contain Tris (hydroxymethyl)aminomethane (Tris), sodium chloride (NaCl), and Tween 20 (product name, manufactured by Sigma Aldrich). In one embodiment, the pH of the Tris buffer may be 7.6, and may include Tris at a concentration of 0.05M, NaCl at a concentration of 0.15M, and Tween 20 at 0.02%. In other embodiments, the cleaning process in step S108 may be omitted.

1 and 2E, step S110 is performed, a plurality of magnetic beads 122 marked with the second marker 120 are provided on the magnetic sensor chip 100, so that the magnetic beads 122 marked with the second marker 120 are bonded to the mark On the biological sample with the first marker 112 (for example, the single-stranded nucleic acid 110a to be tested). For example, the magnetic beads 122 marked with the second marker 120 can be prepared into a magnetic bead solution S3 in advance, and then the magnetic bead solution S3 is provided on the magnetic sensing chip 100. In addition, the magnetic beads 122 can be attached to a biological sample (for example, the single-stranded nucleic acid 110a to be tested) by the affinity between the second label 120 and the first label 112. In this embodiment, when the first marker 112 is biotin, the second marker 120 may be streptavidin, but the present invention is not limited to this. The preparation method of the magnetic beads 122 labeled with the second marker 120 is, for example, a chemical reduction method. The magnetic beads 122 may be hollow magnetic beads or solid magnetic beads. The particle size of the magnetic beads 122 is, for example, 0.2 μm to 2 μm. The material of the magnetic beads 122 is, for example, ferroferric oxide (Fe ₃ O ₄ ).

1 and 2F, step S112 may be performed. After the magnetic beads 122 are attached to the biological sample (e.g., the single-stranded nucleic acid 110a to be tested), a washing process is performed to remove the unattached biological sample (e.g., The magnetic beads 122 on the single stranded nucleic acid 110a) to be tested. For example, buffer S4 can be used to perform the above-mentioned cleaning process. The buffer S4 is, for example, a Tris buffer, but the present invention is not limited to this. The Tris buffer may contain Tris, NaCl, and Tween 20 (product name, manufactured by Sigma Aldrich). In one embodiment, the pH of the Tris buffer may be 7.6, and may include Tris at a concentration of 0.05 M, NaCl at a concentration of 0.15 M, and Tween 20 at 0.02%. In other embodiments, the cleaning process in step S112 may be omitted.

Please refer to FIG. 1, FIG. 2F and FIG. 4 to perform step S114 to detect the signal sensed by the magnetic sensing layer 104 with a magnetic sensor. The magnetic sensor is, for example, a tunneling magnetoresistance (TMR) sensor or a giant magnetoresistance (GMR) sensor. The detection performed by the magnetic sensor may further include quantitative analysis or qualitative analysis. That is, the biological sample detection method of this embodiment can be used for qualitative and quantitative detection of various diseases. In this embodiment, the detection performed by the magnetic sensor is explained by taking quantitative analysis as an example.

For example, quantitative analysis may include the following steps. First, step S1140 is performed. After the hybridization reaction is performed, and before the magnetic beads 122 are bonded to the biological sample (eg, the single-stranded nucleic acid 110a to be tested), the magnetic sensor is used for measurement to obtain the first signal. Then, step S1142 is performed, after the magnetic beads 122 are bonded to the biological sample (for example, the single stranded nucleic acid 110a to be tested), the magnetic sensor is used for measurement to obtain the second signal. Then, proceed to step S1144 to calculate the number of magnetic beads 122 attached to the biological sample (eg, single stranded nucleic acid 110a to be tested) based on the difference between the second signal and the first signal, so as to hybridize with the probe 108 The biological sample (for example, the single-stranded nucleic acid 110a to be tested) is quantified. The first signal and the second signal can be measured at room temperature to reduce the influence of temperature changes on the signal. The first signal and the second signal are, for example, voltage signals. In the case that the first signal and the second signal are voltage signals, the voltage value of the second signal when the magnetic beads 122 are bonded to the biological sample (for example, the single-stranded nucleic acid 110a to be tested) may be higher than that of the magnetic beads 122. The voltage value of the first signal when it is bonded to the biological sample (for example, the single stranded nucleic acid 110a to be tested). The measurement mode of the magnetic sensor can be a real time measurement mode. For example, the real-time measurement mode can continuously perform measurement during the period from step S106 to step S114.

In other embodiments, when a magnetic sensor is used for qualitative analysis, as long as the second signal is significantly different from the first signal, it can be determined to be a biological sample (such as a single strand of nucleic acid 110a to be tested) and The probe 108 hybridizes.

Based on the above embodiments, it can be known that in the biological sample detection method described above, when the magnetic sensor in the magnetic sensor chip 100 is used for detection, since there is almost no magnetic substance in the biological sample, it will not be interfered by the matrix. In this way, when the magnetic sensor in the magnetic sensor chip 100 is used to detect biological samples, better detection sensitivity can be achieved.

>Experimental example>

FIG. 5 is a diagram showing the relationship between the read signal and the time of an experimental example of the present invention.

Referring to FIG. 5, after the detection of the single-stranded nucleic acid (biological sample) labeled with biotin by the biological sample detection method of the above embodiment, the detection results obtained are described as follows.

At about 400 seconds, a single strand of nucleic acid to be tested labeled with biotin is added to the sensing area of the magnetic sensor chip for hybridization reaction with the nucleic acid probe in the sensing area. In about 700 seconds to about 1300 seconds, the temperature is raised to 56°C to 62°C, and the hybridization reaction is performed for 10 minutes (section A). By increasing the temperature to 56°C to 62°C, the hybridization reaction can be accelerated. In phase A, the signal will decrease due to the increase in temperature.

At about 1300 seconds, the temperature begins to drop to room temperature, at which time the signal will rise due to the decrease in temperature.

At about 1700 seconds, the sensing area is washed with Tris buffer, and the single strand of nucleic acid to be tested that has not hybridized with the nucleic acid probe is washed away from the sensing area (section B). The pH of the Tris buffer is 7.6, and it includes Tris at a concentration of 0.05M, NaCl at a concentration of 0.15M, and Tween 20 at 0.02%.

In about 2000 seconds, return to room temperature (for example, 28°C), and use the tunneling magnetoresistance (TMR) sensor of the magnetic sensor chip to measure the signal, and the signal at this time can be used as the initial signal of the measurement ( Section C).

At about 2200 seconds, add streptavidin-labeled magnetic beads, and react for 10 minutes at room temperature to make the streptavidin-labeled magnetic beads bind to the biotin-labeled single-stranded nucleic acid to be tested. And the magnetic signal reaction is generated by the magnetic beads (section D).

At about 2800 seconds, the sensing area is washed with Tris buffer, and the magnetic beads that are not attached to the single strand of nucleic acid to be tested are washed away from the sensing area. The pH of the Tris buffer is 7.6, and it includes Tris at a concentration of 0.05 M, NaCl at a concentration of 0.15 M, and Tween 20 at 0.02%. In addition, the signal measured by the tunneling magnetoresistance (TMR) sensor in this section (section E) is subtracted from the initial signal before the magnetic beads are added (section C), and the voltage difference ΔV (about 12.5 μV), and with this voltage difference, the number of single strands of nucleic acid to be tested hybridized with the nucleic acid probe in the sensing area can be calculated.

To sum up, in the biological sample detection method of the above embodiment, when the magnetic sensor in the magnetic sensor chip is used for detection, since there is almost no magnetic substance in the biological sample, it will not be interfered by the matrix. In this way, when the magnetic sensor in the magnetic sensor chip is used to detect biological samples, it can have better detection sensitivity.

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention. Anyone with ordinary knowledge in the relevant technical field can make some changes and modifications without departing from the spirit and scope of the present invention. The protection scope of the present invention shall be subject to those defined by the attached patent application scope.

100: Magnetic sensor chip 102: substrate 104: Magnetic sensing layer 106: silicon dioxide dielectric layer 108: Probe 110: Double-stranded nucleic acid to be tested 110a: Single strand of nucleic acid to be tested 110b: Single strand nucleic acid 112: first marker 114a, 114b: primer 116: Amplification processing 118: Denaturation treatment 120: second marker 122: magnetic beads R: Sensing area S1: sample solution S2, S4: buffer S3: Magnetic bead solution S100, S102, S104, S106, S108, S110, S112, S114, S1140, S1142, S1144: steps ΔV: Voltage difference

Fig. 1 is a flowchart of a biological sample detection method according to an embodiment of the present invention. 2A to 2F are schematic diagrams of a biological sample detection process according to an embodiment of the present invention. Fig. 3 is a schematic diagram of a method for preparing a biological sample according to an embodiment of the present invention. Fig. 4 is a flow chart of quantitative analysis according to an embodiment of the present invention. FIG. 5 is a diagram showing the relationship between the read signal and the time of an experimental example of the present invention.

S100, S102, S104, S106, S108, S110, S112, S114: steps

Claims (20)

A biological sample detection method, including: Providing a magnetic sensing chip, the magnetic sensing chip comprising a substrate and a magnetic sensing layer located on the substrate; Multiple probes are connected to the magnetic induction wafer; A sample solution containing a plurality of biological samples labeled with a first marker is provided on the magnetic sensing chip, so that the plurality of biological samples labeled with the first marker and the plurality of probes Hybridization (hybridization); The magnetic beads marked with a second marker are provided on the magnetic sensing chip, so that the plurality of magnetic beads marked with the second marker are bonded to the plurality of magnetic beads marked with the first marker. Biological samples; and A magnetic sensor is used to detect the signal sensed by the magnetic sensing layer. According to the biological sample detection method described in item 1 of the scope of patent application, the magnetic sensor includes a tunnel magnetoresistance sensor (Tunnel Magnetoresistance, TMR) or a giant magnetoresistance sensor (Giant Magnetoresistance, GMR) . The biological sample detection method according to the first item of the scope of patent application, wherein the plurality of probes include nucleic acid probes. According to the biological sample detection method described in item 3 of the scope of patent application, the length of the nucleic acid probe is from 20 monomer units to 40 monomer units (monomeric units, mers). According to the biological sample detection method described in item 1 of the scope of patent application, the plurality of probes are located in the sensing area of the magnetic sensor chip. The biological sample detection method according to the first item of the scope of patent application, wherein the plurality of biological samples include a single strand of nucleic acid to be tested. According to the method for detecting biological samples described in item 6 of the scope of patent application, the length of the single-stranded nucleic acid to be tested is 80 monomer units to 120 monomer units. The biological sample detection method according to the first item of the scope of patent application, wherein the preparation method of the plurality of biological samples marked with the first marker includes: Provide double-stranded nucleic acid to be tested; Using a primer labeled with the first marker to perform amplication processing on the double-stranded nucleic acid to be tested to obtain a plurality of double-stranded nucleic acids to be tested labeled with the first marker; and The plurality of double-stranded nucleic acids to be tested labeled with the first marker are subjected to denaturation treatment to obtain the sample liquid of the plurality of single-stranded nucleic acids to be tested labeled with the first marker. The method for detecting biological samples according to item 8 of the scope of patent application, wherein the amplification treatment of the double-stranded nucleic acid to be tested includes performing polymerase chain reaction (PCR), and the denaturation treatment includes high-temperature lysis Treatment (thermal decomposition). The biological sample detection method according to the first item of the scope of patent application, wherein the source of the biological sample includes a biological sample to be tested, and the biological sample to be tested includes urine, saliva, serum or plasma. The method for detecting a biological sample according to the first item of the scope of patent application, wherein the first marker includes biotin, and the second marker includes Streptavidin. According to the biological sample detection method described in item 1 of the scope of patent application, the particle size of the magnetic beads is 0.2 μm to 2 μm. According to the biological sample detection method described in item 1 of the scope of patent application, the material of the magnetic beads includes ferroferric oxide (Fe ₃ O ₄ ). As for the biological sample detection method described in item 1 of the scope of patent application, the detection performed by the magnetic sensor further includes quantitative analysis, and the quantitative analysis includes: After performing the hybridization reaction and before bonding the plurality of magnetic beads to the plurality of biological samples, perform measurement using the magnetic sensor to obtain a first signal; After the plurality of magnetic beads are bonded to the plurality of biological samples, the magnetic sensor is used for measurement to obtain a second signal; and The number of the plurality of magnetic beads attached to the plurality of biological samples is calculated by the difference between the second signal and the first signal, so as to compare all the magnetic beads that are hybridized with the plurality of probes. The multiple biological samples are quantified. The biological sample detection method according to claim 14, wherein the first signal and the second signal include voltage signals, and the voltage value of the second signal is higher than the voltage of the first signal value. According to the method for detecting biological samples as described in item 14 of the scope of patent application, the first signal and the second signal are measured at room temperature. The biological sample detection method as described in item 1 of the scope of patent application further includes: Before connecting the plurality of probes to the magnetic sensing wafer, the magnetic sensing wafer is subjected to surface modification treatment. According to the method for detecting biological samples according to the 17th patent application, the surface modification treatment includes forming a silicon dioxide dielectric layer on the magnetic sensing wafer. The biological sample detection method as described in item 1 of the scope of patent application further includes: After performing the hybridization reaction, a washing process is performed to remove the biological sample that has not hybridized with the plurality of probes. The biological sample detection method as described in item 1 of the scope of patent application further includes: After the plurality of magnetic beads are bonded to the plurality of biological samples, a washing process is performed to remove the magnetic beads that are not bonded to the plurality of biological samples.

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