A non-invasive multi-channel multi-parameter biological signal detection device and a method of using the same

Abstract

The application discloses a non-invasive multi-channel multi-parameter biological signal detection device and a use method thereof, relates to the technical field of biological sample signal collection, and comprises the following parts: a plurality of filter plates with different wave bands are uniformly arranged on an excitation filter plate switching device and a signal collection filter plate switching device, and a light source is arranged at one end of the excitation filter plate switching device; a detector is arranged at the light source of one end of the signal collection filter plate switching device; an excitation optical fiber bundle and a signal collection optical fiber bundle are arranged in opposite intervals; a plurality of detection heads are arranged between the excitation optical fiber bundle and the signal collection optical fiber bundle, the detection heads are arranged at one end of the excitation optical fiber bundle away from the excitation filter plate switching device, and a plurality of groups of the detection heads are arranged in the direction of a multi-well plate. The non-invasive multi-channel multi-parameter biological signal detection device and the use method thereof can solve the problems of low flux, low efficiency and single type of detected signals in the current biological signal detection field.

Description

Technical Field

[0001] This invention relates to the field of biological sample signal acquisition technology, and more specifically to a non-invasive multi-channel, multi-parameter biological signal detection device and its usage method. Background Technology

[0002] In biological experiments, biosignals generally refer to detectable physical or chemical information generated by organisms during their life activities, used to reflect physiological states, biochemical processes, or environmental responses. Based on their characteristics and detection methods, they are mainly divided into three categories: electrical signals (such as electroencephalograms), non-electrical signals (such as chemical hormones and fluorescence signals), and behavioral signals (such as movement trajectories). Molecular biology, cell biology, and microbiology have the highest requirements for sample sizes in the biological field. These disciplines typically use standard multiwell plates to perform different detections on biological samples to obtain different parameters. Different biosignals usually require different instruments or equipment for detection. Therefore, to detect multiple signals or different biosignal parameters, different equipment needs to be used in coordination, and the required sample size increases exponentially. This wastes a large amount of valuable biological experimental samples, hinders efficient detection, and, because different detections are performed separately, errors caused by individual sample differences are significant, resulting in poor control over experimental accuracy.

[0003] Traditional invasive methods (such as electrode implantation and blood sampling) can cause tissue damage, inflammatory responses, or the release of stress hormones, thereby interfering with the normal physiological state of experimental samples and affecting experimental results. Therefore, non-invasive signal acquisition is crucial to avoid affecting the normal biological activity of biological samples or the accuracy of signal acquisition during experiments. Furthermore, non-invasive methods support long-term, dynamic monitoring of the same object. For example, optical sensors can continuously track dissolved oxygen and pH values ​​in cell cultures by detecting fluorescence signals, avoiding data interruptions caused by sampling disruptions. This is essential for time-sensitive experiments studying biological development and disease progression.

[0004] In modern biological experiments, high-throughput signal acquisition is crucial because it acts like a "super accelerator" for biological research. It has completely transformed the inefficient traditional experimental model of "one sample at a time, all done manually," and instead, through automated and parallel processing of massive amounts of samples, it has greatly accelerated the process of scientific discovery and drug development. This is not only an improvement in efficiency, but also a fundamental shift in research paradigm from "single-point breakthrough" to "global exploration."

[0005] Therefore, how to provide a non-invasive, multi-channel, multi-parameter biosignal detection device and its usage method that can solve the problems of low throughput, low efficiency, and limited detection signal types in the current field of biosignal detection is an urgent problem that needs to be solved by those skilled in the art. Summary of the Invention

[0006] In view of this, the present invention provides a non-invasive multi-channel multi-parameter biosignal detection device and its usage method, aiming to solve one of the problems in the above-mentioned background technology, and can solve the problems of low throughput, low efficiency and single type of detected signal in the current biosignal detection field.

[0007] To achieve the above objectives, in one respect, the present invention discloses a non-invasive multi-channel, multi-parameter biosignal detection device, comprising: An excitation filter switching device is provided, wherein multiple filters of different wavelengths are evenly distributed on the excitation filter switching device, and a light source is provided at one end of the excitation filter switching device. A signal acquisition filter switching device is provided, wherein the signal acquisition filter switching device and the excitation filter switching device are arranged at intervals and corresponding to each other. Multiple filters with different wavelengths are evenly distributed on the signal acquisition filter switching device, and a detector is provided at one end of the signal acquisition filter switching device corresponding to the light source. An excitation fiber bundle and a signal acquisition fiber bundle are provided, which are arranged at a relative interval. The excitation fiber bundle is directed toward the end of the excitation filter switching device that is away from the light source, and the signal acquisition fiber bundle is directed toward the end of the signal acquisition filter switching device that is away from the detector. The detection head is provided in multiple ways, which are disposed between the excitation fiber bundle and the signal acquisition fiber bundle. The multiple detection heads are spaced apart along the axial direction of the excitation fiber bundle and the signal acquisition fiber bundle. The detection head is located at the end of the excitation fiber bundle away from the excitation filter switching device. The multiple sets of detection heads are arranged in the direction corresponding to the porous plate.

[0008] Furthermore, each of the detection heads includes a signal excitation probe and a signal acquisition probe, which are arranged at a relative interval. The signal acquisition probe is connected to the excitation fiber bundle via an optical fiber, and the signal acquisition probe is connected to the signal acquisition fiber bundle via an optical fiber.

[0009] Furthermore, the signal excitation probe and the signal acquisition probe are arranged at a relative angle of 90°.

[0010] Furthermore, the detector is configured as a surface signal acquisition device, which is equipped with a data transmission line and is connected to a host computer through the data transmission line.

[0011] Furthermore, a condenser array is provided at one end of the excitation fiber bundle near the signal acquisition filter switching device, and the number of condenser arrays corresponds one-to-one with the number of fiber bundles.

[0012] Furthermore, a collimating lens array is provided at one end of the signal acquisition fiber bundle near the excitation filter switching device.

[0013] Furthermore, both the excitation filter switching device and the signal acquisition filter switching device are configured as a circular rotary wheel structure or a long strip slider structure.

[0014] Furthermore, the light source is configured as a multi-wavelength light source, and a collimating lens is provided at one end of the light source facing the excitation filter switching device, with two collimating lenses arranged at a relative interval.

[0015] On the other hand, this invention discloses a biosignal detection method, based on the aforementioned non-invasive multi-channel multi-parameter biosignal detection device, specifically including the following steps: Step 1: Start the light source and detector, and ensure that the excitation fiber bundle is aligned with the signal acquisition fiber bundle, and that each detection head is aligned with the hole position of the multi-hole plate; Initialize the filter switching device, and place the excitation filter and the acquisition filter in their initial positions; Step 2: Add the biological samples into the multi-well plate according to the experimental design, select the excitation filter band and the acquisition filter band, and set the light source intensity, detector integration time, and acquisition frequency; Step 3: The collimated light emitted by the multi-wavelength light source is converted into light of the desired specific wavelength band by the excitation filter switching device. It then passes through the excitation fiber bundle with a condenser lens array at the front end to the excitation light end of multiple detection heads. After passing through the collimating lens, it is focused into a parallel beam and reaches the sample. The signal inside the sample generates a signal due to the action of the excitation light. After passing through the detection end of multiple detection heads and being focused by the condenser lens, it passes through the signal acquisition fiber bundle and approaches the collimating lens array of the detector. Finally, it passes through the signal collection filter switching device and reaches the detector. Step 4: The detector converts the optical signal into an electrical signal using a photoelectric converter. Each converter corresponds to a detection head signal, and the electrical signal is transmitted to the host computer in real time through a data transmission line.

[0016] As can be seen from the above technical solution, compared with the prior art, the present invention discloses a non-invasive multi-channel multi-parameter biosignal detection device and its usage method, with the following beneficial effects: The tests that can be performed include, but are not limited to, turbidity detection, FL, TRF, Luminescence, FRET, and BRET detection. Multi-parameter signal acquisition is achieved through a special optical path design and a combination of replaceable filters. It can acquire scattered light signals, fluorescence signals of different wavelengths emitted by excitation light of different wavelengths, time-resolved fluorescence signals, and luminescence signals, thus realizing multi-parameter signal acquisition. Multiple detection heads simultaneously acquire and detect signals, enabling massive sample processing capabilities: traditional methods rely on manual operation, which is inefficient and prone to errors; high-throughput methods can achieve parallel processing, for example: drug screening: hundreds of thousands of compounds can be detected daily, more than 100 times faster than traditional methods (this invention can be used for tests such as FL, TRF, Luminescence, FRET, and BRET in drug screening applications); gene sequencing: high-throughput sequencing (NGS) can complete whole-genome analysis in hours, while traditional Sanger sequencing takes weeks (this invention can be used for tests such as FL and FRET in sequencing); in synthetic biology, automated high-throughput platforms reduce the positive clone screening cycle from weeks to 1-2 days, significantly accelerating strain optimization (this invention can be used for tests such as turbidity, OD, FL, and Luminescence); furthermore, high-throughput testing can analyze patient genomic and metabolomics data, identify disease biomarkers, and provide a basis for personalized treatment; Current high-throughput biological experiments are mostly conducted using multi-well plates, such as high-throughput drug discovery and target screening. This invention, due to its small and simple detection head, is very suitable for multiple arrangements, meeting the requirements of rapid signal acquisition in multi-well plates. Because multiple samples are detected simultaneously using light emitted from a single light source, this method achieves high throughput while reducing differences in detection results caused by varying energy levels from different light sources, compared to methods using light source arrays. Furthermore, it reduces differences in detection results caused by inconsistent energy levels due to time asynchrony, compared to methods requiring multiple illuminations from the same probe. This improves detection accuracy. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0018] Figure 1 A schematic diagram of the structure of a non-invasive multi-channel multi-parameter biosignal detection device provided by the present invention; Figure 2This is a schematic diagram of the structure of a non-invasive, multi-channel, multi-parameter biosignal detection device provided by the present invention.

[0019] Figure 3 A schematic diagram of the structure of a non-invasive multi-channel multi-parameter biosignal detection device provided by the present invention (another perspective); Figure 4 A schematic diagram of the structure of a non-invasive multi-channel multi-parameter biosignal detection device provided by the present invention (another perspective); Figure 5 Detailed diagrams of the detector array and excitation fiber bundle array provided by this invention; Figure 6 A schematic diagram of the internal structure of the detector provided by the present invention; Figure 7 This is a schematic diagram of the internal structure of the light source provided by the present invention.

[0020] Wherein: 1 is the excitation filter switching device; 2 is the light source; 21 is the collimating lens; 3 is the signal acquisition filter switching device; 4 is the detector; 41 is the data transmission line; 5 is the excitation fiber bundle; 51 is the condenser lens array; 6 is the signal acquisition fiber bundle; 61 is the collimating lens array; 7 is the detection head; 71 is the signal excitation probe; 72 is the signal acquisition probe; 73 is the optical fiber; 8 is the filter; 9 is the porous plate. Detailed Implementation

[0021] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] See Figure 1-7 This invention discloses a non-invasive multi-channel, multi-parameter biosignal detection device, comprising: Excitation filter switching device 1, multiple filters 8 of different wavelengths are evenly distributed on the excitation filter switching device 1, and a light source 2 is provided at one end of the excitation filter switching device 1. The signal acquisition filter switching device 3 is arranged at intervals with the excitation filter switching device 1. The signal acquisition filter switching device 3 is equipped with multiple filters 8 of different wavelengths. One end of the signal acquisition filter switching device 3 is equipped with a detector 4 corresponding to the light source 2. By setting filters 8 of different wavelengths and switching filters 8, the light emitted by the light source 2 is filtered so that the light of the required specific wavelength reaches the excitation fiber bundle 5 with the condenser array 51 at the front end, and the light of the required specific wavelength reaches the detector 4. Excitation fiber bundle 5 and signal acquisition fiber bundle 6 are arranged at a relative interval. Excitation fiber bundle 5 is directed toward the end of excitation filter switching device 1 away from light source 2, and signal acquisition fiber bundle 6 is directed toward the end of signal acquisition filter switching device 3 away from detector 4. Multiple detection heads 7 are arranged between the excitation fiber bundle 5 and the signal acquisition fiber bundle 6. The multiple detection heads 7 are spaced apart along the axial direction of the excitation fiber bundle 5 and the signal acquisition fiber bundle 6. The detection heads 7 are located at the end of the excitation fiber bundle 5 away from the excitation filter switching device 1. The multiple sets of detection heads 7 are arranged in the direction corresponding to the porous plate 9. The number of detection heads 7 is equal to the number of excitation fiber bundles 5 and the number of signal acquisition fiber bundles 6. The porous plate 9 is specifically a 96-well plate.

[0023] In this embodiment, each detection head 7 includes a signal excitation probe 71 and a signal acquisition probe 72, which are spaced apart from each other. The signal acquisition probe 72 is connected to the excitation fiber bundle 5 via an optical fiber and to the signal acquisition fiber bundle 6 via an optical fiber 73. The signal excitation probe 71 and the signal acquisition probe 72 transmit signals through the optical fiber 73. The purpose of the signal acquisition probe 72 is to collect the signals emitted by the sample, and a focusing lens is provided at the front end to improve efficiency.

[0024] In this embodiment, the signal excitation probe 71 and the signal acquisition probe 72 are arranged at a 90° angle relative to each other; because 96-well plates (8 rows) are commonly used in biological experiments. The sample container is made of 12 columns, so 8 detection heads 7 are set up in parallel, with the signal excitation probe 71 and the signal acquisition probe 72 at a relative angle of 90°.

[0025] In this embodiment, detector 4 is configured as a surface acquisition signal device, which is equipped with a data transmission line and is connected to a host computer via the data transmission line. The host computer serves as the control terminal. The purpose of the surface acquisition signal device (CCD / CMOS) is to convert the signals acquired by the signal acquisition probe 72 into electrical signals and transmit them to the host computer via the data transmission line for further signal processing. Since multiple signal acquisition probes 72 are configured and the collimating lens array of the signal acquisition fiber bundle 6 is arranged in an orderly manner, the surface acquisition signal device can process multiple signals by circling the corresponding ROI regions in the image. Detector 4 can also be configured as an array of photoelectric converters (PD / PIN / APD / PMT, etc.). The photoelectric converters of the point acquisition device can be arranged in an array, with the arrangement corresponding one-to-one with the collimating lens array of the signal acquisition fiber bundle 6. Thus, each photoelectric converter corresponds to the signal of one signal acquisition probe 72 (or one sample).

[0026] In this embodiment, a condenser array 51 is provided at one end of the excitation fiber bundle 5 near the signal acquisition filter switching device 3. The number of condensers corresponds one-to-one with the fiber, so as to uniformly transmit the light from the light source 2 to all the detection heads 7.

[0027] In this embodiment, a collimating lens array is provided at one end of the signal acquisition fiber bundle 6 near the excitation filter switching device 1.

[0028] In this embodiment, both the excitation filter switching device 1 and the signal acquisition filter switching device 3 are configured as a circular rotary wheel structure or a long strip slider structure.

[0029] In this embodiment, the light source 2 is configured as a multi-wavelength light source 2, and a collimating lens 21 is provided at one end of the light source 2 facing the excitation filter switching device 1. Two collimating lenses 21 are arranged at intervals. The light source 2 is preferably a xenon lamp light source 2. By setting the collimating lens 21, the divergent light emitted by the light source 2 is focused and collimated into parallel light.

[0030] On the other hand, this invention discloses a biosignal detection method, based on the aforementioned non-invasive multi-channel multi-parameter biosignal detection device, specifically including the following steps: Step 1: Start the light source 2 and detector 4, and ensure that the excitation fiber bundle 5 is aligned with the signal acquisition fiber bundle 6, and that each detection head 7 is aligned with the hole position of the multi-hole plate 9; Initialize the filter 8 switching device, and place the excitation filter 8 and the acquisition filter 8 in the initial position; Step 2: Add the biological sample into the multi-well plate 9 according to the experimental design, select the excitation filter band 8 and the acquisition filter band 8, and set the intensity of the light source 2, the integration time of the detector 4, and the acquisition frequency; Step 3: The collimated light emitted by the multi-wavelength light source 2 is converted into light of the desired specific wavelength band by the excitation filter switching device 1. It then passes through the excitation fiber bundle 5 with the condenser array 51 at the front end and reaches the excitation light end of the multiple detection heads 7. After passing through the collimating lens, it is focused into a parallel beam and reaches the sample. The signal inside the sample generates a signal due to the action of the excitation light. After passing through the detection end of the multiple detection heads 7 and being focused by the condenser, it passes through the signal acquisition fiber bundle 6 and approaches the collimating lens array of the detector 4. Finally, it passes through the signal collection filter switching device 8 and reaches the detector 4. Step 4: Detector 4 converts the optical signal into an electrical signal using a photoelectric converter array. Each converter corresponds to a signal from detector head 7, and the electrical signal is transmitted to the host computer in real time via a data transmission line.

[0031] In addition, in this embodiment, the multi-parameter detection is implemented as follows: 1. Turbidity Detection: The filter 8 at the light source 2 end is selected as 600nm or 860nm, and the filter 8 at the detector 4 end is selected as empty (i.e., without filter 8). When the light source 2 emits light, the detector 4 detects the signal. The detected signal is converted into NTU through the signal calculation formula or converted into OD value through the correspondence between NTU and OD, or used for subsequent calculations. Furthermore, in order to obtain the change process of sample turbidity, an experimental scheme of time-series detection or kinetic detection can be designed. Detection is performed once at a certain time interval to obtain the data at this time point. After multiple detections, the data is plotted into a graph with a time axis. The graph can intuitively show the change process of turbidity over time, intuitively reflect the growth curve of microorganisms or the killing curve of drugs, and thus obtain data such as EC50. 2. Fluorescence (FL) Detection: Multiple fluorescence detection methods are possible. The desired excitation band is selected by filter 8 at the light source 2, and the corresponding emission band is selected by filter 8 at the detector 4. When the light source 2 emits light, the detector 4 detects the signal. The detected signal is converted into relative fluorescence intensity using a signal calculation formula, or used for subsequent calculations. Furthermore, to obtain the change process of sample fluorescence intensity, experimental schemes for time-series detection or kinetic detection can be designed. Detection is performed once at intervals to obtain data at each time point. After multiple detections, the data is plotted into a graph with a time axis. The graph can visually show the change process of fluorescence intensity over time, and can intuitively reflect changes in cell oxygen consumption over time, changes in gene expression over time, enzyme kinetics, and other data. 3. Fluorescence Resonance Energy Transfer (FRET) Detection: Two detections are performed to obtain one set of data. Assuming target molecule a is the donor and b is the acceptor, the detection aims to determine whether target molecules a and b interact. First detection: Filter 8 at end 2 of the light source selects the desired excitation band, and filter 8A at end 4 of the detector selects the filter corresponding to the emission light of target molecule a. When light source 2 emits light, detector 4 detects the signal, and the detected signal is converted into relative fluorescence intensity A1 using a signal calculation formula. Second detection: Filter 8 at end 2 of the light source selects the desired excitation band, and filter 8B at end 4 of the detector selects the filter corresponding to the emission light of target molecule b. When light source 2 emits light, detector 4 detects the signal, and the detected signal is converted into relative fluorescence intensity B1 using a signal calculation formula. Due to the donor emission spectrum... By overlapping with the receptor absorption spectrum, the relative intensities of A1 and B1 can be used to determine whether two target molecules in the sample interact through fluorescence resonance energy transfer. When only A1 is detected and B1 is not detected, it indicates that the target molecules do not interact. When only B1 is detected and A1 is not detected, it indicates that all target molecules interact. When both signals are present, analyzing the ratio of A1 to B1 can determine how many target molecules have interacted. Furthermore, to obtain the changing process of the interaction between target molecules a and b, time-series detection or kinetic detection experimental schemes can be designed to perform two detections at intervals, obtain data at these time points, and plot the data into a graph. After multiple detections, the changing process of the interaction can be visually observed through the graph. 4. Time-Resolved Fluorescence (TRF) Detection: The desired excitation band is selected by filter 8 at the light source 2, and the corresponding emission band is selected by filter 8 at the detector 4. When the light source 2 emits light, the detector 4 does not detect the signal. After a certain period of time (microseconds or milliseconds, adjustable by software) after the light source 2 is turned off, the signal is detected again. The detected signal is converted into relative fluorescence intensity using a signal calculation formula. At this time, the fluorescence signal can completely avoid interference from the signal of the light source 2. Similarly, kinetic detection can also be performed to obtain more data. 5. Luminescence detection: With light source 2 off, the detector 4 selects the corresponding wavelength filter 8 or leaves it blank. After the sample is placed, the detector 4 is turned on for a period of time (integration time, on the order of seconds) to detect the signal. The detected signal is converted into relative luminescence intensity through a signal calculation formula, or used for subsequent calculations. Similarly, kinetic detection can also be performed to obtain more data. 6. Brilliant Resonance Energy Transfer (BRET) Detection: After the sample is placed, two detections are performed to obtain initial data. Assuming target molecule c is the donor and d is the acceptor, the detection aims to determine whether target molecules c and d interact without turning on light source 2. First detection: Filter 8 at detector 4 is selected to correspond to the emission light of target molecule c via filter 8C. The detected signal is converted to relative luminous intensity C1 using a signal calculation formula. Second detection: Filter 8 at detector 4 is selected to correspond to the emission light of target molecule d via filter 8D. The detected signal is converted to relative luminous intensity D1 using a signal calculation formula. Since the donor emission spectrum overlaps with the acceptor absorption spectrum, the relative intensities of C1 and D1 can be used to determine whether the two target molecules in the sample interact through BRET. When only C1 is detected and D1 is not, it indicates that the target molecules do not interact. When only D1 is detected and C1 is not, it indicates that all target molecules interact. When both signals are present, analyzing the ratio of C1 to D1 can determine how many target molecules interact. Similarly, kinetic detection can be performed to obtain more data.

[0032] Specific implementation case 1: This invention is used for simultaneous monitoring of microbial growth curves and fluorescence monitoring of microbial metabolites. In today's scientific and industrial communities, synthetic biology is considered the "third revolution in life sciences and technology" after the discovery of the DNA double helix structure and the Human Genome Project. Its core lies in providing a new path to solving global challenges through the engineering design and modification of living systems. Synthetic biology, through an iterative research paradigm of "design-build-test-learn," has achieved a transformation from the traditional "investigation of things to gain knowledge" to "building things to gain knowledge." This engineering method not only subverts traditional life science research strategies but also opens up a new culture for understanding the essence of life. By modifying living organisms through engineering methods, synthetic biology possesses both scientific unknowns and engineering reproducibility. In the design-build-test research paradigm, how to study microbial metabolism and screen useful microbial strains more efficiently is a current hot topic. Two approaches are to study microbial growth curves and microbial metabolites; however, no device yet can simultaneously detect microbial growth curves and microbial metabolites in real time with high throughput. The detection device designed using this invention employs a 96-well plate as a high-throughput microbial detection carrier. This device can detect ≥1 96-well plate at a time. The core of this detection device is the four detectors of this invention. These four detectors are placed in a suitable position below the 96-well plate, and the detection parameters, required wavelengths, and detection intervals are set. Taking the synthesis of artemisinin by *E. coli* and the high-throughput screening of favorable culture media as an example, the promoter of artemisinin response is coupled with the green fluorescent protein (GFP) gene to construct a reporter system. When artemisinin accumulates in *E. coli*, it activates the promoter, thereby driving GFP expression and generating a fluorescent signal. But what culture medium ratio best reflects the growth trend of *E. coli* and the optimal performance of its metabolites? To screen for the optimal culture medium, multiple culture medium formulations and ratios can be preset. The same E. coli is inoculated into 96-well plates, and the instrument is set to detect once every 1 hour. The parameters for each detection are turbidity (excitation filter 8 is set to 680nm, emission filter 8 is set to empty) and fluorescence intensity (excitation filter 8 is set to 480nm, emission filter 8 is set to 520nm). Appropriate shaking and temperature are also set. A total of 24 detections are performed (in fact, detector 4 performs 2 acquisitions for each detection, obtaining 2 parameters in turbidity mode and fluorescence mode respectively). Two curves are obtained with time as the X-axis, with turbidity (representing the growth curve) and relative fluorescence intensity (representing the expression level of the metabolite artemisinic acid) as the graph. Based on the precise correlation between growth status and metabolic activity, the appropriate culture medium is found. Based on this, the induction time and culture medium composition are optimized, which increases the yield of artemisinic acid by about 30%.

[0033] In specific implementation case 2, this invention is applied to high-throughput rapid screening of anti-tumor drugs. Taking the detection of drug molecule binding to target site as an example, when biomolecular interactions bring the donor (such as europium cavitary compounds) and receptor (such as XL665 or d2) close together, the donor is excited, energy is transferred to the receptor, and a specific fluorescence signal (such as 665nm emission) is generated. This signal is proportional to the binding rate. Utilizing the long fluorescence lifetime (milliseconds) of lanthanide elements (such as europium), background interference is eliminated and binding activity is directly quantified through delayed detection. The detection device designed using this invention employs a 96-well plate as a high-throughput microbial detection carrier. This device can detect ≥1 96-well plate at a time. The core of this detection device is the four detectors of this invention. The device uses time-resolved fluorescence (TRF) detection. The four detectors are placed in a suitable position below the 96-well plate, and the detection parameters are set. The required wavelength and detection interval are set as follows: The excitation filter is selected at 337nm; the emission light is selected twice; detector 4 performs two detections, with emission filters selected at 620nm and 665nm respectively. Both detections are performed approximately 40µs after the excitation light is turned off to eliminate background fluorescence interference. The results of the two detections for each sample are analyzed using a ratio method (e.g., 665nm / 620nm signal). The ratios of all samples are measured at once, and the optimal molecule or dose for each sample is directly selected based on the ratio. Compared to the current mainstream method of using a multi-functional microplate reader to detect samples one by one, this detection efficiency is at least several times higher. Furthermore, the consistency of light source 2 is excellent, eliminating errors caused by light source 2 being turned on at different times (even the most advanced microplate reader has an average energy error of about 2% after 200 light source activations).

[0034] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on its differences from other embodiments. Similar or identical parts between embodiments can be referred to interchangeably. For the apparatus disclosed in the embodiments, since they correspond to the methods disclosed in the embodiments, the description is relatively simple; relevant parts can be referred to the method section.

[0035] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A non-invasive multi-channel multi-parameter biological signal detecting device provided on a multi-well plate for detecting a biological sample in the multi-well plate, characterized in that, include: An excitation filter switching device is provided, wherein multiple filters of different wavelengths are evenly distributed on the excitation filter switching device, and a light source is provided at one end of the excitation filter switching device. A signal acquisition filter switching device is provided, wherein the signal acquisition filter switching device and the excitation filter switching device are arranged at intervals and corresponding to each other. Multiple filters with different wavelengths are evenly distributed on the signal acquisition filter switching device, and a detector is provided at one end of the signal acquisition filter switching device corresponding to the light source. An excitation fiber bundle and a signal acquisition fiber bundle are provided, which are arranged at a relative interval. The excitation fiber bundle is directed toward the end of the excitation filter switching device that is away from the light source, and the signal acquisition fiber bundle is directed toward the end of the signal acquisition filter switching device that is away from the detector. The detection head is provided in multiple ways, which are disposed between the excitation fiber bundle and the signal acquisition fiber bundle. The multiple detection heads are spaced apart along the axial direction of the excitation fiber bundle and the signal acquisition fiber bundle. The detection head is located at the end of the excitation fiber bundle away from the excitation filter switching device. The multiple sets of detection heads are arranged in the direction corresponding to the porous plate.

2. The non-invasive multi-channel multi-parameter bio-signal detection apparatus according to claim 1, wherein, Each of the detection heads includes a signal excitation probe and a signal acquisition probe, which are arranged at a relative interval. The signal acquisition probe is connected to the excitation fiber bundle via an optical fiber, and the signal acquisition probe is connected to the signal acquisition fiber bundle via an optical fiber.

3. The non-invasive multi-channel multi-parameter biosignal detection device according to claim 2, characterized in that, The signal excitation probe and the signal acquisition probe are arranged at a relative angle of 90°.

4. The non-invasive multi-channel multi-parameter biosignal detection device according to claim 1, characterized in that, The detector is configured as a surface signal acquisition device, which is equipped with a data transmission line and is connected to a host computer through the data transmission line.

5. A non-invasive multi-channel multi-parameter biosignal detection device according to claim 1, characterized in that, The excitation fiber bundle is provided with a condenser array at one end near the signal acquisition filter switching device, and the number of condensers corresponds one-to-one with the number of fibers.

6. The non-invasive multi-channel multi-parameter biosignal detection device according to claim 1, characterized in that, The signal acquisition fiber bundle is equipped with a collimating lens array at one end near the excitation filter switching device.

7. A non-invasive multi-channel multi-parameter biosignal detection device according to claim 1, characterized in that, Both the excitation filter switching device and the signal acquisition filter switching device are configured as a circular rotary wheel structure or a long strip slider structure.

8. A non-invasive multi-channel multi-parameter biosignal detection device according to claim 1, characterized in that, The light source is configured as a multi-wavelength light source, and a collimating lens is provided at one end of the light source facing the excitation filter switching device. Two collimating lenses are arranged at a distance from each other.

9. A method for detecting biosignals, using a non-invasive multi-channel, multi-parameter biosignal detection device as described in any one of claims 1-8, characterized in that, Specifically, the following steps are included: Step 1: Start the light source and detector, and ensure that the excitation fiber bundle is aligned with the signal acquisition fiber bundle, and that each detection head is aligned with the hole position of the multi-hole plate; Initialize the filter switching device, and place the excitation filter and the acquisition filter in their initial positions; Step 2: Add the biological samples into the multi-well plate according to the experimental design, select the excitation filter band and the acquisition filter band, and set the light source intensity, detector integration time, and acquisition frequency; Step 3: The collimated light emitted by the multi-wavelength light source is converted into light of the desired specific wavelength band by the excitation filter switching device. It then passes through the excitation fiber bundle with a condenser lens array at the front end to the excitation light end of multiple detection heads. After passing through the collimating lens, it is focused into a parallel beam and reaches the sample. The signal inside the sample generates a signal due to the action of the excitation light. After passing through the detection end of multiple detection heads and being focused by the condenser lens, it passes through the signal acquisition fiber bundle and approaches the collimating lens array of the detector. Finally, it passes through the signal collection filter switching device and reaches the detector. Step 4: The detector converts the optical signal into an electrical signal using a photoelectric converter. Each converter corresponds to a detection head signal, and the electrical signal is transmitted to the host computer in real time through a data transmission line.

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