Biomeasurement device

Abstract

A biological measurement device (10) comprises a stimulation device (12) comprising at least one stimulation electrode (102a, 102b) and a stimulation circuit. The stimulation circuit is configured to provide an electrical stimulation signal to the at least one stimulation electrode (102a, 102b) such that the at least one stimulation electrode (102a, 102b) generates a predetermined electrodynamic force field applied to the biological substance. The sensing device comprises at least one sensing electrode (202a, 202b) and a sensing circuit, the at least one sensing electrode (202a, 202b) being configured to sense the responsive electrodynamic force field and to provide a corresponding electrical response signal to the sensing circuit. The electrical stimulation signal includes a plurality of different pseudo-random binary sequences, each pseudo-random binary sequence having a length and a data rate that provide a predetermined electrodynamic force field having a frequency range that is different from those provided by the other pseudo-random binary sequences.

Description

[0001] This invention relates to a biological measurement device.

[0002] The analysis of the physical or chemical characteristics of biological particles has applications in disease diagnosis, research, and clinical trials of drugs. It is known to automate this analysis using measuring devices configured to simultaneously measure multiple parameters of the particles. Typically, the biological particles of interest are suspended in a fluid before being introduced into the measuring device, where they are stimulated, and the response to the stimulation is detected.

[0003] One example of such a measuring device utilizes impedance or dielectric spectroscopy to measure the characteristics of biological microparticles. Impedance spectroscopy, or dielectric spectroscopy, involves applying an electrodynamic field to a solution containing biological microparticles and measuring the field changes caused by the presence of the microparticles (e.g., field changes caused by the complex permittivity of the microparticles). Traditionally, impedance and dielectric spectroscopy devices utilize lock-in amplifiers to calculate the amplitude and phase shift of the signal caused by changes in the solution through the target region (such as the sudden appearance of cells). This means that, for each such lock-in amplifier, a typical measuring device can measure the impedance at a single frequency at a time.

[0004] For example, WO 2015 / 001355 proposes an apparatus for simultaneously measuring impedance at many frequencies to analyze many different characteristics of biological particles. However, there are significant challenges in achieving high bandwidth in such a measurement apparatus.

[0005] Improved biometric devices have been designed that overcome or substantially mitigate the aforementioned and / or other drawbacks associated with existing technologies.

[0006] According to a first aspect of the present invention, a biometric device is provided, the biometric device comprising: A stimulation device includes at least one stimulation electrode and a stimulation circuit configured to provide an electrical stimulation signal to the at least one stimulation electrode, causing the at least one stimulation electrode to generate a predetermined electrodynamic field applied to biological material. A sensing device includes at least one sensing electrode and a sensing circuit, wherein the at least one sensing electrode is configured to sense an electrodynamic field and provide a corresponding electrical response signal to the sensing circuit. The electrical stimulation signal comprises multiple different pseudo-random binary sequences, each with a length and data rate that provides a predetermined electrodynamic field, the frequency range of which differs from the frequency range provided by other pseudo-random binary sequences.

[0007] According to another aspect of the present invention, a biometric method is provided, the method comprising: An electrical stimulation signal is provided to at least one stimulating electrode, causing the at least one stimulating electrode to generate a predetermined electrodynamic field applied to biological material, and The system uses at least one sensing electrode to sense the response electrodynamic field and provides a corresponding electrical response signal to the sensing circuit. The electrical stimulation signal comprises multiple different pseudo-random binary sequences, each with a length and data rate that provides a predetermined electrodynamic field, the frequency range of which differs from the frequency range provided by other pseudo-random binary sequences.

[0008] This invention is advantageous because, compared to a single pseudo-random binary sequence (having a frequency range linearly proportional to its length), providing multiple different pseudo-random binary sequences with multiple different frequency ranges of a predetermined electrodynamic field enables a wider range of frequencies for a given sequence length and data rate. Therefore, compared to using a pseudo-random binary sequence with only one frequency range, this invention enables a greater bandwidth for biometric devices.

[0009] In particular, to realize a pseudo-random noise signal covering frequencies spanning several orders of magnitude of bandwidth using a single pseudo-random binary sequence, the sequence length must be extremely long, making it difficult to transmit to the host and requiring enormous computational resources for post-processing. Furthermore, the larger frequency bandwidth achieved by this invention enables a series of logarithmically distributed frequency measurements, rather than just linearly distributed measurements. This is advantageous because a series of linearly distributed frequency measurements would lead to overrepresentation at higher frequencies and underrepresentation at lower frequencies.

[0010] By using multiple different pseudo-random binary sequences, advantages can be provided in other devices that require broadband system response.

[0011] Therefore, according to another aspect of the present invention, a measuring device is provided, comprising: The stimulation device is configured to provide electrical stimulation signals. The sensing device provides a corresponding electrical response signal. The electrical stimulation signal comprises multiple different pseudo-random binary sequences, each with a length and data rate that provides a predetermined electrodynamic field, the frequency range of which differs from the frequency range provided by other pseudo-random binary sequences.

[0012] According to another aspect of the present invention, a measurement method is provided, the method comprising: Providing an electrical stimulation signal to at least one stimulating electrode, causing the at least one stimulating electrode to generate a predetermined electrodynamic field; and The system uses at least one sensing electrode to sense the response electrodynamic field and generate a corresponding electrical response signal. The electrical stimulation signal comprises multiple different pseudo-random binary sequences, each with a length and data rate that provides a predetermined electrodynamic field, the frequency range of which differs from the frequency range provided by other pseudo-random binary sequences.

[0013] The electrical stimulation signal (and therefore the predetermined electrodynamic field) may include a signal packet comprising multiple different pseudo-random binary sequences. One or more signal packets of the electrical stimulation signal (and therefore the predetermined electrodynamic field) may be applied to the material to be measured. In the case of applying more than one signal packet of the electrical stimulation signal (and therefore the predetermined electrodynamic field) to the material to be measured, the signal packets may be applied sequentially.

[0014] A predetermined electrodynamic field can be applied to the material to be measured, which may include liquid material or microparticles (e.g., biological microparticles) carried by liquid material. The measuring device may include a flow device or be adapted to work with a flow device that enables flow of the material to be measured relative to a stimulation device and a sensing device. At least one signal packet of an electrical stimulation signal (and therefore the predetermined electrodynamic field) can be applied to each microparticle to be measured or to each volume of the liquid material to be measured.

[0015] The present invention is particularly advantageous when used as a biometric device in Process Analytics Technology (PAT) because it enables continuous monitoring of cell cultures while they are located within a bioreactor, thus providing more reliable and / or more detailed data compared to existing monitoring systems.

[0016] The electrical stimulation signal may include three or more pseudo-random binary sequences, each pseudo-random binary sequence having a length and data rate that provide a predetermined electrodynamic field, the frequency range of which differs from the frequency range provided by the other pseudo-random binary sequences.

[0017] The measuring device can be configured to generate pseudo-random noise signals. These pseudo-random noise signals can be generated from pseudo-random binary sequences. The electrical stimulation signals provided by the stimulation circuit can include pseudo-random binary signals. The pseudo-random binary sequences are generated using deterministic algorithms. However, the pseudo-random binary sequences exhibit statistical behavior similar to truly random sequences. The pseudo-random binary sequences can be the longest possible sequences (i.e., the so-called "m-sequences"), which can be generated by linear feedback shift registers. When the binary sequence is generated by linear feedback shift registers, the output eventually repeats itself. For a given number of shift registers, the m-sequence is the longest potentially non-repeating sequence.

[0018] Therefore, pseudo-random noise signals can include m-sequences. m-sequences exhibit a fixed power spectral density over the desired operating bandwidth. Furthermore, m-sequences can be readily implemented using standard digital circuitry, making them suitable for implementation in integrated circuits (such as CMOS) fabricated using semiconductor manufacturing processes.

[0019] The stimulation circuit can operate to generate stimulation signals in the form of an m-sequence via a linear feedback shift register or other means within the scope of ordinary design skills of those skilled in the art. For example, the stimulation circuit may include a memory storing the m-sequence. Alternatively, the m-sequence may be provided by an external signal generator.

[0020] Multiple pseudo-random binary sequences can be m-sequences. Each m-sequence has a length of 2. n –1, where n This refers to the number of registers in the linear feedback shift register. Multiple pseudo-random binary sequences can have the same length or different lengths. The frequency range provided by each pseudo-random binary sequence can be determined by the length of each pseudo-random binary sequence, which is determined by the number of bits, and the bit rate of the electrical stimulation signal.

[0021] The frequency range of each pseudo-random binary sequence is determined by the binary signal obtainable using the length of the pseudo-random binary sequence and the bit rate of the electrical stimulation signal. The highest frequency in the frequency range can be an interleaved sequence of adjacent bits, with a frequency equal to half the bit rate. The lowest frequency can be a constant value over the entire length of the sequence, with a frequency equal to the bit rate divided by the sequence length. Multiple pseudo-random binary sequences can be generated using the same clock. However, the bit rates of the multiple pseudo-random binary sequences can differ because the bit period of the lower-frequency pseudo-random binary sequence is an integer multiple of the bit period of the higher-frequency pseudo-random binary sequence.

[0022] n The length of the register m- sequence is 2. n -1 bit. At the data rate f Down, n - Register m-sequence will provide f / 2 to f / (2 n–1) frequencies. For example, a 5-register m-sequence is 31 bits long. In an example provided for illustrative purposes, at a data rate of 950 MHz, a 5-register m-sequence would provide frequencies from 475 MHz to 30.65 MHz. In contrast, a 7-register m-sequence is 127 bits long. At a data rate of 50 MHz, a 7-register m-sequence would provide frequencies from 25 MHz to 393 kHz. Thus, a frequency range of 475 MHz to 393 kHz is provided using only 158 bits. By comparison, at a data rate of 950 MHz, an 11-register m-sequence of 2048 bits would be needed to provide frequencies from 475 MHz to 464 kHz, extending within the same order of magnitude as the example above, but requiring a length an order of magnitude larger than that required by the present invention.

[0023] Multiple pseudo-random binary sequences can include at least a low-frequency pseudo-random binary sequence and a high-frequency pseudo-random binary sequence.

[0024] Each pseudo-random binary sequence can provide a subframe within a frame of the electrical stimulation signal. Multiple pseudo-random binary sequences can be temporally separated by a period, which can be at least one m-sequence period.

[0025] The measuring device may include a processing device, which may include stimulation circuitry and / or sensing circuitry. The processing device and / or sensing circuitry may be configured to receive an electrical response signal and convert it into a digital form. Therefore, the processing device and / or sensing circuitry may have analog inputs and digital outputs, such that the output is a digital response signal.

[0026] Therefore, the processing device and / or sensing circuitry may include analog-to-digital converters and any signal conditioning circuitry that may be required (such as amplifiers and anti-aliasing filters). The processing device may be comprised of any suitable electronic device (such as separate analog-to-digital conversion circuitry, separate amplification circuitry, and separate filtering circuitry) or configurable integrated circuits (such as FPGAs) or specialized integrated circuits (such as application-specific integrated circuits, ASICs)) that include these circuits.

[0027] The digital response signal can have a frame size, which can have a predetermined length determined by the total number of bits in the frame, and the frame can accommodate digital response signals from multiple pseudo-random binary sequences. Therefore, digital response signals from the first pseudo-random binary sequence and the second pseudo-random binary sequence can constitute corresponding subframes of the digital response signal.

[0028] The same clock can be used to generate the electrical stimulation signal (which comprises multiple pseudo-random binary sequences) and the sampling rate of the processing device. This ensures that the electrical stimulation signal does not drift in time relative to the digital response signal. However, the sampling rate of the processing device can differ from the bit rate of the electrical stimulation signal, as discussed in more detail below. The sampling rate of the processing device and the bit rate of the electrical stimulation signal can also be represented based on the sampling period of the processing device and the bit period of the electrical stimulation signal.

[0029] The bit rate of the digital response signal can be equal to the bit rate of the electrical stimulation signal. The period of each bit of the digital response signal from a lower-frequency pseudo-random binary sequence can be an integer multiple of each bit of the digital response signal from a higher-frequency pseudo-random binary sequence.

[0030] The processing device can have a bandwidth sufficient to cover the frequency range being measured. However, the sampling rate of the processing device can still be lower than the bit rate of the electrical response signal, and therefore lower than the highest frequency of a higher-frequency pseudo-random binary sequence. Therefore, the sampling period of the processing device can be higher than the bit period of the electrical response signal. While a processing device with a sampling rate at least equal to the bit rate of the electrical response signal can be used, the resulting high data rate may be problematic.

[0031] By appropriately selecting the bit period of the electrical stimulation signal and the sampling period of the processing device, the processing device can be configured to sample the electrical response signal at a rate lower than the bit period, but this is done in multiple interleaved passes, which together provide a complete sample of the electrical response signal. This allows a processing device with a sampling rate lower than the bit rate of the electrical response signal to provide a digital response signal with a data rate higher than the sampling rate of the processing device.

[0032] In one particular embodiment, the processing device is configured with a sampling period equal to an integer multiple of the bit period of the electrical response signal minus an integer fraction of the bit period, and the processing device is configured to sample the electrical response signal in multiple interleaved passes.

[0033] With respect to a first aspect of the invention, this configuration can be used to sample higher frequency components (i.e., portions corresponding to higher frequency pseudo-random binary sequences) in the electrical response signal.

[0034] According to another aspect of the present invention, a biometric device is provided, the biometric device comprising: A stimulation device includes at least one stimulation electrode and a stimulation circuit configured to provide an electrical stimulation signal to the at least one stimulation electrode, causing the stimulation electrode to generate a predetermined electrodynamic field applied to biological material. A sensing device includes at least one sensing electrode and a sensing circuit, the at least one sensing electrode being configured to sense a response to an electrodynamic field and provide a corresponding electrical response signal having a bit period to the sensing circuit. The processing device is configured to receive an electrical response signal and convert the electrical response signal into a digital response signal. The processing device is configured with a sampling period equal to an integer multiple of the bit period of the electrical response signal plus or minus an integer fraction of the bit period, and the processing device is configured to sample the electrical response signal during multiple interleaving passes.

[0035] According to another aspect of the present invention, a biometric method is provided, the method comprising: An electrical stimulation signal is provided to at least one stimulating electrode, causing the at least one stimulating electrode to generate a predetermined electrodynamic field applied to biological material. The system senses the response electrodynamic field using at least one sensing electrode and generates a corresponding electrical response signal with a bit period. The electrical response signal is converted into a digital response signal using a processing device. The processing device is configured with a sampling period that is equal to an integer multiple of the bit period of the electrical response signal plus or minus an integer fraction of the bit period, and the electrical response signal is sampled in multiple interleaved passes.

[0036] An "integer fraction" is a fraction that is equal to the reciprocal of an integer.

[0037] The biometric apparatus according to this aspect of the invention is advantageous because the processing apparatus with a sampling rate lower than the bit rate of the electrical response signal can be configured to provide an effective sampling rate equal to or greater than the bit rate of the electrical response signal.

[0038] For example, in situations requiring a broadband system response, the use of this configuration can provide advantages in other devices. Therefore, according to another aspect of the invention, a measuring device is provided, comprising: The stimulation device is configured to provide electrical stimulation signals. The sensing device provides a corresponding electrical response signal with a bit period, and The processing device is configured to receive an electrical response signal and convert the electrical response signal into a digital response signal. The processing device is configured with a sampling period equal to an integer multiple of the bit period of the electrical response signal minus an integer fraction of the bit period, and the processing device is configured to sample the electrical response signal during multiple interleaving passes.

[0039] According to another aspect of the present invention, a measurement method is provided, the method comprising: An electrical stimulation signal is provided to at least one stimulation electrode, causing the at least one stimulation electrode to generate a predetermined electrodynamic field; The system senses the response electrodynamic field using at least one sensing electrode and generates a corresponding electrical response signal with a bit period. The electrical response signal is converted into a digital response signal using a processing device. The processing device is configured with a sampling period that is equal to an integer multiple of the bit period of the electrical response signal plus or minus an integer fraction of the bit period, and the electrical response signal is sampled in multiple interleaved passes.

[0040] For example, the processing device may be configured with a sampling period equal to the bit period of the electrical response signal multiplied by 1 / 2. n Subtract 1 / bit period n Furthermore, the processing device is configured to sample the electrical response signal during multiple interleaved passes. This configuration provides n The oversampling ratio is increased, thereby raising the highest frequency achievable by the device. n times.

[0041] When the electrical stimulation signal includes a first pseudo-random binary sequence having a length and data rate of a predetermined electrodynamic field having a first frequency range and the electrical stimulation signal includes a second pseudo-random binary sequence having a length and data rate of a predetermined electrodynamic field having a second different frequency range, this sampling configuration can be used to sample the higher frequency components (i.e., the portions corresponding to the higher frequency pseudo-random binary sequences) in the electrical response signal.

[0042] When sampling an electrical response signal for a low-frequency pseudo-random binary sequence, a lower sampling rate may be required than that used for a high-frequency pseudo-random binary sequence (e.g., low sampling rate). n A sampling rate of (times) can be achieved through undersampling (e.g., by discarding samples). n This can be achieved by averaging all samples except for one sample in a sample (or by averaging all samples). However, a preferred configuration is to discard only those samples that align with the transition points of the pseudo-random binary sequence, and then apply the remaining samples... n – One sample is averaged to provide the digital response signal.

[0043] According to another aspect of the present invention, a biometric device is provided, the biometric device comprising: A stimulation device includes at least one stimulation electrode and a stimulation circuit configured to provide an electrical stimulation signal to the at least one stimulation electrode, causing the stimulation electrode to generate a predetermined electrodynamic field applied to biological material. A sensing device includes at least one sensing electrode and a sensing circuit, the at least one sensing electrode being configured to sense a response to an electrodynamic field and provide a corresponding electrical response signal having a bit period to the sensing circuit. The processing device is configured to receive an electrical response signal and convert the electrical response signal into a digital response signal. The sampling rate of the processing device is greater than that of the lower frequency of the electrical response signal. n The processing unit is configured to discard samples aligned with the transition points of the pseudo-random binary sequence, and process the remaining samples... n – One sample is averaged to provide the digital response signal.

[0044] According to another aspect of the present invention, a biometric method is provided, the method comprising: An electrical stimulation signal is provided to at least one stimulating electrode, causing the at least one stimulating electrode to generate a predetermined electrodynamic field applied to biological material. The system senses the response electrodynamic field using at least one sensing electrode and generates a corresponding electrical response signal with a bit period. The electrical response signal is converted into a digital response signal using a processing device. The sampling rate of the processing device is a lower frequency of the electrical response signal. n Double, and discard samples aligned with the transition points of the pseudo-random binary sequence, and for the remaining n – One sample is averaged to provide the digital response signal.

[0045] The biometric apparatus according to this aspect of the invention is advantageous because the configuration improves the signal-to-noise ratio (SNR) of the digital response signal compared to discarding all but one of the n samples, while also avoiding the possibility of data skew at high frequencies caused by averaging every n samples without requiring computationally intensive adjustments.

[0046] In situations requiring a broadband system response, the use of this sampling configuration can offer advantages over other devices. Therefore, according to another aspect of the invention, a measuring device is provided, comprising: The stimulation device is configured to provide electrical stimulation signals. The sensing device provides a corresponding electrical response signal, and The processing device is configured to receive an electrical response signal and convert the electrical response signal into a digital response signal. The sampling rate of the processing device is a bit period of a lower frequency of the electrical response signal. n The processing unit is configured to discard samples aligned with the transition points of the pseudo-random binary sequence, and process the remaining samples... n– One sample is averaged to provide the digital response signal.

[0047] In cases where the electrical stimulation signal includes a first pseudo-random binary sequence having a length and data rate of a predetermined electrodynamic field having a first frequency range and the electrical stimulation signal includes a second pseudo-random binary sequence having a length and data rate of a predetermined electrodynamic field having a second different frequency range, this sampling configuration can be used to sample the lower frequency components (i.e., portions corresponding to the lower frequency pseudo-random binary sequence) in the electrical response signal.

[0048] Furthermore, when the sampling period of the processing device is equal to the bit period of the electrical response signal, the sampling rate that the processing device can be configured with is a fraction of the bit period of the electrical response signal. n times, of which n It is 2 or greater.

[0049] The digital response signal can be stored in memory (e.g., a single segment of memory). The digital response signal can be output at a data rate equal to the bit rate of the higher-frequency pseudo-random binary sequence in the electrical stimulation signal. The period of each bit of the digital response signal from the lower-frequency pseudo-random binary sequence can be an integer multiple of the period of each bit of the digital response signal from the higher-frequency pseudo-random binary sequence. Therefore, each bit of the digital response signal from the lower-frequency pseudo-random binary sequence can be configured to have a period equal to an integer multiple of the period of each bit of the digital response signal from the higher-frequency pseudo-random binary sequence.

[0050] The processing device and / or sensing circuitry may include a processor and may operate to decode a received output signal, which may be m-sequence encoded data.

[0051] The impulse response can be calculated by applying the Hadamard transform, such as the Fast Hadamard Transform. This enables rapid calculation of the impulse response. The Fast Hadamard Transform is given by the following formula:

[0052] Where Ψ' is the estimated output spectrum of the system under test, and m is the sequence order. H It is the Hadamard matrix. η It is the measured m-sequence encoded response, and ξ 1 and ξ 2 is the encoding and decoding matrix used to convert m-sequence data into the correct order for the Hadamard matrix. In one form, ξ 1 and ξ 2. They are equal to each other.

[0053] Alternatively, the analysis device can be configured to decode the received output signal, which may be m-sequence encoded data, for example, by cross-correlation. The analysis device can be composed of any suitable electronic device, such as a general-purpose computer (e.g., a personal computer (PC)).

[0054] The analysis device can also perform Fourier transforms (such as Fast Fourier Transform, FFT) on the decoded output signal, thereby providing frequency domain data. This frequency domain data can be displayed for user interpretation. The frequency domain data can be used to characterize biological cells in the analyte (e.g., for their size and composition), thereby determining the properties of specific cell types or distinguishing between different cell types.

[0055] This measuring device can operate to measure one or more biological cells held in a sample holder to determine the properties of one or more cells. It is known that this measuring device is configured as an integrated circuit (such as a CMOS integrated circuit). One known form of integrated circuit measuring device includes an electrode array. In its simplest form, the electrode array is one-dimensional, thus having a row of electrodes over which one or more cells flow or move. In more complex forms, the electrode array is two-dimensional, thus defining multiple parallel paths, thereby allowing for the simultaneous measurement of more biological cells. Regardless of the complexity of the electrode array, the electrodes in the array, together with a common electrode or another electrode in the array, the biological cells acting as dielectrics, and the fluid medium between these two electrodes, define a complex measurement capacitor (CM). Electrodes are typically cubic, and their working surfaces can be square or rectangular. Sensing and stimulating electrodes can be arranged such that their working surfaces are in a generally planar arrangement (i.e., in the same or parallel planes). Sensing and stimulating electrodes can be arranged side-by-side. The working surfaces of the electrodes can be flat. Sensing and stimulating electrodes can be disposed on exposed surfaces of a semiconductor and can be formed in integrated circuits (such as CMOS) fabricated using semiconductor manufacturing processes.

[0056] The measuring device further includes an output buffer for each measuring capacitor. The output signal is processed to determine one or more characteristics of the biological cell sensed by the measuring capacitor.

[0057] The measuring device may include or be adapted to work with a flow device that enables the flow of the test material (e.g., liquid material and bioparticles) relative to the stimulation device and the sensing device.

[0058] The stimulation device may include at least one pair of electrodes. The pair of electrodes may be positioned relative to each other and relative to the liquid material in the flow device to apply an electric field to the liquid material. One of the electrodes may be positioned on or toward one side of the liquid material (e.g., in a direction perpendicular to the flow direction of the liquid material). The other electrode may be positioned on or toward one side of the liquid material. The pair of electrodes may be positioned on substantially the same side of the liquid material or toward that side. The pair of electrodes may be positioned side-by-side. Such same-side positioning may be suitable when the particle stimulation device is included in a planar semiconductor integrated circuit (e.g., a CMOS integrated circuit).

[0059] In use, a liquid material sample (such as a biological sample) is introduced into a flow device configured to contain and facilitate the flow of the liquid material. The flow device can be configured to contain the liquid material in order to facilitate its flow. For example, the flow device can define an open channel that contains the liquid material and allows flow (e.g., when flow is generated by a pump). Alternatively or additionally, the flow device can be configured to drive its own flow. More specifically, the flow device can be configured to draw the liquid material through the flow device via capillary action.

[0060] The measuring device may include an integrated circuit formed using semiconductor fabrication processes, such as CMOS fabrication processes. The particles may be biological particles (e.g., cells or other structures including viruses, multicellular organisms, bacteria, and spores). Sensing particles can enable particle analysis, such as distinguishing between cell types.

[0061] The measuring device can be configured to measure quantities affected by the dielectric constant of the particles. The measuring device can also be configured to measure quantities affected by at least one of the true dielectric constant and the fictitious dielectric constant of the particles. The measured quantity can be a change in the applied electrodynamic field (i.e., the stimulus signal) caused by the presence of the particles.

[0062] Microparticles (such as cells) can interact with an applied electrodynamic field in a unique manner, thereby providing a measurable response. Therefore, this measuring device can be used to measure the characteristics of biological microparticles in liquid materials. Furthermore, different biological microparticles can interact with the applied electrodynamic field in different unique ways to provide correspondingly different responses. Therefore, this measuring device can be used to characterize biological microparticles. For example, this measuring device can be used to perform at least one of the following operations: distinguishing one type of cell from another; and determining cell characteristics, such as cell size or cell composition.

[0063] At least one stimulating electrode and at least one sensing electrode can be arranged for impedance or dielectric spectroscopy. At least one stimulating electrode and at least one sensing electrode can be arranged to form a capacitor, with the liquid material and any biological particles therein located in the electric field between the electrodes. With at least one stimulating electrode and at least one sensing electrode arranged such that their working surfaces are side-by-side in a generally planar arrangement, the liquid material and any biological particles therein can flow through the electrodes.

[0064] A pair of stimulating and sensing electrodes can be positioned relative to each other and relative to the liquid material in the flow device to sense an electric field (i.e., an electrical response signal) present in the liquid material. One of the electrodes can be positioned on or toward the side of the liquid material (e.g., in a direction perpendicular to the flow direction of the liquid material). The other electrode can also be positioned on or toward the side of the liquid material. The electrodes can be positioned on substantially the same side of the liquid material or toward that side. The electrodes can be positioned side-by-side. This same-side positioning may be suitable when the measuring device is included in a planar semiconductor integrated circuit (such as a CMOS integrated circuit).

[0065] The electrode may have dimensions substantially less than 100 micrometers, 50 micrometers, 30 micrometers, 20 micrometers, 15 micrometers, 10 micrometers, 5 micrometers, 3 micrometers, or 1 micrometer (e.g., at least one of width and height). Alternatively or additionally, the electrode may have dimensions substantially greater than 0.5 micrometers, 1 micrometer, 5 micrometers, 10 micrometers, 15 micrometers, 20 micrometers, 30 micrometers, or 50 micrometers.

[0066] The measuring device may include a plurality of spaced-apart sensing electrodes (e.g., a plurality of sensing electrode pairs), wherein each sensing electrode can operate to sense particles. Furthermore, the flow device may define a flow path along which the particles travel, and the measuring device may be configured such that the electrical response field of the particles is sensed by successive sensing electrodes (e.g., two sensing electrodes for differential measurement) as the particles travel along the flow path.

[0067] The sensing circuit can be configured to sense charge (such as charge that may be present on a sensing electrode). More specifically, the sensing circuit may include a capacitor that can operate to sense charge and convert the sensed charge into a voltage signal. The sensing circuit may include a high-impedance input to achieve the critical sensing signal. More specifically, the sensing circuit may include an impedance buffer (such as a field-effect transistor (FET)). The FET can provide a capacitive load, such as for the sensing electrode of the sensing device. Alternatively or additionally, the sensing circuit can provide one of a voltage signal and a current signal as an output signal.

[0068] Alternatively or additionally, the sensing circuit can be configured to amplify the input signal. For example, the sensing circuit can be configured to convert the charge present on the sensing electrode into a corresponding voltage and amplify the converted voltage; or to convert it into a corresponding current and amplify the converted current.

[0069] The measuring device can be configured to compare an electrical stimulation signal with an electrical response signal (e.g., an electrical response signal sensed by a sensing device). The comparison of the electrical stimulation signal and the electrical response signal may include cross-correlation between the two signals. The measuring device can operate to determine the time delay between the application of the electrical stimulation signal and the response provided by at least one particle in the liquid material. The measuring device can further operate to determine or at least estimate a transfer function for the at least one particle based on the time delay. The determined or estimated transfer function can then be used to characterize the at least one particle.

[0070] The predetermined electrodynamic field applied to the biological microparticles may include at least one corresponding frequency component. The sensing device may be configured to sense the frequency component included in the responsive electrodynamic field sensed by the microparticle sensing device, the frequency component being at least 1 kHz, 10 kHz, 50 kHz, 100 kHz, 250 kHz, 500 kHz, 1 MHz, 5 MHz, 10 MHz, 25 MHz, 50 MHz, 75 MHz, 100 MHz, 250 MHz, 500 MHz, 750 MHz, 1 GHz, 1.25 GHz, 1.5 GHz, 1.75 GHz, 2 GHz, 2.5 GHz, 2.75 GHz, or 5 GHz. More specifically, the frequency component may be between 10 kHz and 5 GHz. In some cases, at frequencies above 1 MHz, the measuring device may operate to characterize the interior of at least one microparticle (e.g., in the case where at least one microparticle is a biological cell). In some cases, frequencies above 1 kHz may be needed to characterize the microparticle for external features such as the size of a biological cell.

[0071] The sensing element of the measuring device may include an array of sensing electrodes (such as those described elsewhere in this document). The array may extend in the direction of flow of the liquid material provided by the flow device. Thus, as particles pass through the flow device, the particles can be sensed by a series of sensing electrodes.

[0072] Alternatively or additionally, the array can extend in a direction perpendicular to the direction in which the liquid material flows through the flow device. More specifically, the array can extend in both the flow direction and perpendicular to the flow direction, thus making it a two-dimensional array. The sensing electrode array enables simultaneous sensing operations.

[0073] The measuring device can operate and may also be configured to be label-free. Therefore, the biosensing device can operate on liquid materials without any labels, such as fluorescent dyes or microbeads.

[0074] The measuring device can operate and may also be configured to sense microbial samples. Therefore, the measuring device can be configured to measure particles (such as biological elements) with dimensions substantially smaller than 500 micrometers, 250 micrometers, 200 micrometers, 150 micrometers, 100 micrometers, 50 micrometers, 25 micrometers, 10 micrometers, 5 micrometers, 2 micrometers, 1 micrometer, 500 nanometers, 250 nanometers, 100 nanometers, 50 nanometers, 25 nanometers, 10 nanometers, or 5 nanometers. Alternatively or additionally, the measuring device can be configured to measure particles with dimensions substantially larger than 2 nanometers, 5 nanometers, 10 nanometers, 25 nanometers, 50 nanometers, 100 nanometers, 250 nanometers, 0.5 micrometers, 1 micrometer, 2 micrometers, 5 micrometers, 10 micrometers, 25 micrometers, 50 micrometers, 100 micrometers, 150 micrometers, 200 micrometers, or 250 micrometers.

[0075] The measuring device can be configured for particles of a specific size or a range of sizes, depending on the size of at least one of the stimulating and sensing devices (e.g., the size of at least one electrode). More specifically, the size of at least one of the stimulating and sensing devices can correspond to particles of a certain size or a range of sizes. Semiconductor fabrication processes can be planar semiconductor fabrication processes. Alternatively or additionally, semiconductor fabrication processes can be metal-oxide-semiconductor processes, such as CMOS processes. Alternatively or additionally, semiconductor fabrication processes can be submicron semiconductor fabrication processes, such as 0.18-micron CMOS processes and possibly high-voltage 0.18-micron CMOS processes.

[0076] Liquid materials can be substantially liquid (e.g., at room temperature). Therefore, liquid materials can include liquids that carry particles. More specifically, liquid materials can include charge carriers, such as salt molecules. For example, liquid materials can include phosphate-buffered saline (PBS).

[0077] The flow device can define a main channel through which liquid material flows during use. A sensing device can be disposed relative to the main channel to sense particles present in the main channel. The sensing device can be disposed on at least one of the first and second opposing sides of the liquid material flow. Thus, for example, components such as sensing electrodes of the sensing device can be disposed on one side of the liquid material flow. According to another example, components of the particle sensing device can be disposed on both sides of the liquid material flow.

[0078] The flow device may include a sample inlet configured to receive a sample of liquid material to be measured, for example by injection, and the sample inlet is in fluid communication with a main channel. The flow device may also include a sample outlet located at the end opposite the sample inlet, and the sample outlet is in fluid communication with the main channel. The sample outlet allows liquid material to flow out of the main channel.

[0079] The flow device may include at least one additional inlet disposed on the side of the sample inlet. More specifically, the flow device may include a first additional inlet and a second additional inlet, wherein the first inlet is laterally disposed on one side of the sample inlet, and the second inlet is laterally disposed on the opposite side of the sample inlet. At least one additional inlet may be in fluid communication with the main channel. In use, a sheath fluid (such as phosphate-buffered saline (PBS)) may be received by at least one additional inlet, thereby enabling the sheath fluid to flow in the main channel, with the sheath fluid flow located on the side of the liquid material flow. The sheath fluid flow can enable registration of the liquid material particles with the particle sensing device and can also help maintain the integrity of the liquid material flow as it passes through the flow device.

[0080] The flow device may be formed of glass and / or at least partially of a polymer, such as poly(methyl methacrylate) (PMMA). The length of the flow device may be substantially 25 mm, and the width may be substantially 10 mm. The stimulation and sensing device may be formed separately from the flow device. The stimulation and sensing device may be positioned relative to the flow device by attaching it to each other. The stimulation and sensing device and the flow device may be adhered together, for example, by a suitable chemical or physical bond, or may be mechanically attached to each other, for example, by a fastening device comprising a silicone liner layer, which may be releasable. Suitable chemical or physical bonds may include plasma bonding.

[0081] This biometric device can be configured to function as a flow cytometer. The device may further include a control unit. The control unit can be constructed from any suitable electronic device (such as a microprocessor or configurable electronic circuitry, such as a field-programmable gate array (FPGA)).

[0082] The measuring device may include a flow induction device (i.e., a pump) that operates to induce liquid material to flow through the flow device. Based on the output from the sensing device, the flow induction device can be controlled, for example, for the flow rate of the liquid material flowing through the flow device. A control device can operate to receive the output from the sensing device and, accordingly, provide an output to the flow induction device.

[0083] The sensing device described elsewhere in this document can operate to determine the flow rate of a liquid material flowing through a flow device, which is received by a control device. In cases where the sensing device includes multiple spaced-apart sensing electrodes (each capable of sensing particles), the flow rate can be determined based on the known spacing between the sensing electrodes and the time between the sensing electrodes sensing particles.

[0084] Alternatively or additionally, the characterization of at least one particle, as described elsewhere herein, can be compared to a predetermined standard, and the flow-inducing device can be controlled based on this comparison. For example, the characterization of at least one particle may include a confidence level value compared to a predetermined value. More specifically, if the confidence level value is lower than the predetermined value, the flow-inducing device may operate to reduce the flow rate of the liquid material, thereby achieving the improved characterization.

[0085] The processing device can provide an output signal (e.g., a digital output signal). The output signal can be stored in the memory of the measuring device. The measuring device may include an output for sending the output signal to an analysis device, which may or may not be integrated with the measuring device.

[0086] The analytical apparatus can be configured to measure particles included in a liquid material based on at least one output from a particle sensing device. For example, the analytical apparatus can operate to perform measurements based on an electric field measurement performed by the particle sensing device after analog-to-digital conversion. The density of particles included in the liquid material, the difference between one type of particle and another, and particle characteristics (such as regarding size or composition) can be determined. The analytical apparatus can be constructed from any suitable electronic device, such as a general-purpose computer (e.g., a personal computer (PC)), an embedded microprocessor, or configurable electronic circuitry (e.g., an FPGA).

[0087] The sensor chips can have orthogonal dimensions of less than 50 mm, less than 20 mm, or less than 10 mm (e.g., 5 mm × 5 mm). The sensor chips can be configured to be mounted within a bioreactor (e.g., from a microbial reactor to a large-scale bioreactor). Microbial reactors are particularly suitable for personalized medicine (e.g., where each patient may require small batches of medication).

[0088] Other features and advantages of the invention will become apparent from the following detailed description, which is given by way of example only and in conjunction with the accompanying drawings, wherein: Figure 1 This is a block diagram illustration of a biometric device according to one embodiment of the present invention; Figure 2 This is an illustration of a flow device as part of an implementation of a biometric device; Figure 3This is an illustration of an electrode array as part of an implementation of a biometric device; Figure 4 This is a circuit diagram of a stimulation device as part of an implementation of a biometric device; and Figure 5 This is a circuit diagram of a sensing device as part of an implementation of a biometric device.

[0089] Figure 1 A block diagram of a bioassay apparatus 10 according to the present invention is shown. The bioanalytical apparatus 10 includes a flow device 30, a stimulation device 12, a sensing device 13, a control and processing device 14, and an analysis device 16. The stimulation device 12 and the sensing device 13 receive an analytical stream in the form of phosphate-buffered saline (PBS) 18 (which constitutes a liquid material) via the flow device 30, in which biological cells (which constitute microparticles) are suspended. Because this method achieves sensing independent of the suspended material, alternatives to PBS can be used.

[0090] The flow of the analyte is guided by the flow device 30 through the stimulation device 12 and the sensing device 13, and is stimulated and sensed in the stimulation device 12 and the sensing device 13 before flowing out of the measuring device 10 20, as described in detail below.

[0091] The control and processing device 14 controls the stimulation device 12 to apply a stimulation signal to the analyte and processes the signal sensed by the sensing device 13. The processing includes amplification of the sensed signal, analog-to-digital conversion of the sensed signal, and storage of the converted sensed signal. Although Figure 1 Not shown, but the measuring device 10 further includes a pump that can operate to push or draw the analyte through the stimulation device 12 and the sensing device 13 via the flow device 30.

[0092] The analysis device 16 can operate to perform at least one analysis based on the stored converted sensing signal. The analysis includes: detecting the presence of biological cells in the analyte; counting the biological cells in the analyte; distinguishing between one type of biological cell and another; and determining the characteristics of the biological cells in the analyte (such as cell size or cell composition). The analysis device 16 can also operate to implement supervisory control of the control and processing device 14, for example, to modify the form of control of the biosensing device 12 performed by the control and processing device 14.

[0093] The control and processing unit 14 is composed of any suitable electronic device, such as a separate analog-to-digital converter, a separate amplifier circuit, and a separate electronic storage circuit, or a configurable integrated circuit (including digital circuits) such as a System-on-a-Chip (SOC) and an ASIC (including analog circuits). The analysis unit 16 is composed of any suitable electronic device, such as a general-purpose computer (e.g., a PC), an embedded microprocessor, or configurable electronic circuits (e.g., an FPGA). The control and processing unit 14 and the analysis unit 16 are configured separately from each other, for example as separate modules, or together in, for example, the same integrated circuit or the same general-purpose computer.

[0094] The flow device 30 receives the analyte 18 and enables the flow of the analyte before it flows out of the flow device 20. (Reference) Figure 2 The measuring device also includes a two-dimensional electrode array 32, which includes stimulation electrodes of the stimulation device 12 and sensing electrodes of the sensing device 13. The flow device 30 and the electrode array 32 are arranged relative to each other such that the electrode array 32 is located above the main channel of the flow device 30.

[0095] The control and processing device 14 is electrically coupled to the electrode array 32. The control and processing device 14 can operate to achieve biological cell stimulation, sensing, and actuation via the electrode array 32.

[0096] Figure 3 The arrangement of the electrode array is shown in more detail below.

[0097] The electrode array 32 and the control and processing device 14 are constructed using CMOS technology (e.g., 0.35-micron CMOS technology). Both the electrode array 32 and the control and processing device 14 are included in a CMOS ASIC. Each electrode in the array 32 is 18 microns × 18 microns in size, with a 2-micron gap between the electrodes, resulting in a center-to-center spacing of 20 microns. The electrodes are surrounded by a busbar that prevents capacitive coupling to silicon and is grounded.

[0098] The thickness and dielectric constant of the standard polyimide top layer in the ASIC are insufficient to provide adequate capacitance for proper bonding between electrode 32 and the analyte. Therefore, the fabrication process lacks a polyimide layer deposition step, resulting in the absence of a polyimide top layer. The hydrophilic nature of the silicon nitride layer maximizes exposure. However, the silicon nitride layer on the electrode can be removed, allowing the electrode to conduct with the analyte. As described above, the ASIC is positioned relative to the flow device 30 so that the electrode array 32 can bond with the analyte flowing through the flow device 30.

[0099] The ASIC control and processing unit 14 includes a binary-to-decimal decoder and memory for row and column addressing of the electrode array 32, as well as global configuration logic and bias circuitry for the sensor output signal path. The global configuration logic can function to implement memory reset and gating of control signals related to the global reset signal, ensuring that all control lines are energized in a known state.

[0100] The measuring device 10 further includes a printed circuit board (PCB) that supports an ASIC and provides electrical connections for ASIC-supporting circuitry. The circuitry included in the PCB includes a system-on-a-chip (SOC) configured to provide various digital functions, including the generation of stimulation signals, addressing of individual electrodes in the electrode array 32, and communication with a Universal Serial Bus (USB) module.

[0101] The SOC 44 can operate to generate stimulus signals in the form of m-sequences stored in memory and output one bit at a time. Specifically, in this embodiment, the stimulus signal consists of a higher-frequency m-sequence and a lower-frequency m-sequence, the higher-frequency m-sequence being generated by a linear feedback shift register with 5 registers, and the lower-frequency m-sequence being generated by a linear feedback shift register with 7 registers. Therefore, the higher-frequency m-sequence has a length of 31 bits, while the lower-frequency m-sequence has a length of 127 bits. The bit rate of the higher-frequency m-sequence of the stimulus signal is 950 Mbps, while the bit rate of the lower-frequency m-sequence is 50 Mbps.

[0102] The PCB includes an input signal conditioning circuit configured to receive a stimulus signal from a SOC or an external (not shown) signal generator and to perform programmable gain amplification of the voltage swing of the stimulus signal.

[0103] In addition, the PCB includes an output signal conditioning circuit that performs various functions, including fixed gain, low-distortion amplification of the sensed single-ended signal and subsequent programmable gain amplification or attenuation of these initially amplified signals under PC control.

[0104] The output signal conditioning circuit also includes an analog-to-digital converter.

[0105] The analog-to-digital converter (ADC) has a sampling rate of 200 MHz. The ADC is configured to sample the higher-frequency m-sequence of the stimulus signal in four interleaved passes, providing a sample length of 124 bits. Therefore, the theoretical bandwidth of this m-sequence measurement is 1.9 GHz to 30.65 MHz. Due to the x4 oversampling ratio, the flat region of this bandwidth only extends to 475 MHz (1 / 4 of the theoretical bandwidth), but higher frequency regions above this point can be reached through post-processing.

[0106] The analog-to-digital converter (ADC) is configured to sample the lower-frequency m-sequence of the stimulus signal at 200 MHz (four times the bit rate of the lower-frequency m-sequence of the stimulus signal). However, the ADC is configured to discard samples aligned with the transition points of the m-sequence and average the remaining three samples to provide a digital output.

[0107] Because the high-frequency and low-frequency components of the stimulus signal originate from the same source, the low-frequency stimulus signal must conform to the sampling method. In this case, each low-frequency sampling period (20 nanoseconds) consists of 4 analog-to-digital converter samples (5 nanoseconds each) and 19 high-frequency source samples (approximately 1.052 nanoseconds each); 19 * 1.052 nanoseconds = 20 nanoseconds.

[0108] To prevent significant contamination from one excitation mode to the next, a gap of at least one m-sequence period is maintained between the two captured portions.

[0109] In this particular implementation, the entire excitation packet, including both high-frequency and low-frequency signals, is stored in a single segment of memory. It is then streamed bit-by-bit at a high-frequency data rate (950 MHz in this example). The low-frequency signal is generated by padding (in this case, 7 bits) an m-sequence signal by a factor of 19, thus each bit lasts for 19 high-frequency cycles.

[0110] As described above, the PCB includes a USB module. The USB module enables communication with a PC running software that can then execute... Figure 1 The analysis device 16 in the PC performs the following functions. More specifically, the PC can operate to configure the ASIC 42 and the circuitry included in the PCB. Furthermore, the PC receives real-time sensing data or data blocks acquired from the SOC and stored locally.

[0111] The PC can work to decode the received m-sequence encoded data via cross-correlation to provide an impulse response. The PC can further work to perform a Fast Fourier Transform (FFT) on the decoded data, thus providing frequency domain data. This frequency domain data is then displayed for user interpretation. The frequency domain data enables the characterization of biological cells in the analyte (e.g., regarding their size and composition), thereby allowing the determination of properties of specific cell types or the differentiation of different cell types.

[0112] The PC can also be used to count biological cells present in the analyte and determine the density of cells present in the analyte based on the flow rate and volume of the flow device, displaying the count and density information to the user.

[0113] Figure 2 The details include Figure 2 The illustration shows the flow device 30 in the biosensing device. Figure 2 The flow device 30 is formed of glass and has a length of approximately 25 mm and a width of approximately 10 mm. The flow device 30 includes a main channel 34 through which the analytical material flows. An electrode array 32 is disposed above the main channel 34 such that the electrodes 32 engage with the analyte as the analytical material flows through the main channel.

[0114] As described above, the electrode array 32 is included in the CMOS ASIC. The CMOS ASIC and the flow device 30 are releasably attached to each other by a fastening device including a silicone pad layer, thereby achieving proper relative arrangement of the electrodes and the main channel.

[0115] The flow device 30 also includes a sample inlet 40 and a sample outlet 50. The sample inlet receives the analyte, for example, by injection, and the sample outlet is located at the end of the flow device opposite to the sample inlet 40. Both the sample inlet 40 and the sample outlet 50 are in fluid communication with the main channel 34. Furthermore, the flow device includes a first additional inlet 42 and a second additional inlet 44. The first additional inlet 42 is laterally disposed on one side of the sample inlet 40, while the second additional inlet 44 is laterally disposed on the other side of the sample inlet. Each of the first additional inlet 42 and the second additional inlet 44 is in fluid communication with the main channel 34.

[0116] In use, sheath fluid (such as phosphate-buffered saline (PBS)) is received by each of the first additional inlet 42 and the second additional inlet 44, thereby enabling sheath fluid flow in the main channel, which is located to the side of the analyte flow received at the sample inlet 40. Sheath fluid flow enables registration of the biological cells containing the analyte with the electrode array 32 and also helps maintain the integrity of the analyte flow as it passes through the main channel.

[0117] Stimulation and sensing include electric field stimulation and electric field sensing. Biological cells interact with the applied electric field, thereby interfering with it. Specific types of biological cells of different sizes interfere with the applied electric field in different ways. Furthermore, different types of biological cells interfere with the applied electric field in different ways. Therefore, interference-dependent electric field sensing can enable the detection of the presence of biological cells, the determination of the relative size of cells, and the differentiation of different cell types. Both electric field stimulation and electric field sensing can be performed within a CMOS ASIC of the form described above. More specifically, electrode array 32 is used for electric field stimulation and electric field sensing, wherein different groups of electrodes are used for stimulation and sensing.

[0118] Figure 3 A stimulation unit 100 configured for single-end operation is shown. Figure 3 The stimulation unit 100 includes a single electrode 102, which is included in the electrode array 32. A stimulation signal is applied to the stimulation electrode 102.

[0119] The stimulation unit 100 further includes a multiplexer 112 that implements one of two states selected according to the state selection bit 118. The stimulation unit 100 also includes a storage bit 114 for storing the state of the first state selection bit 118. The storage bit 114 is configured in static random access memory (SRAM).

[0120] Figure 3 The multiplexer in the code implements one of two states. To implement one of the two states, the electrode is addressed using the address-sensitive first state selection bit 118, and then the first state selection bit 118 is stored as storage bit 114.

[0121] In the first state, when the state selection bit 118 is zero, electrode 102 is connected to the common ground potential via a switch. In the second state, when the first state selection bit 118 is 1, electrode 102 is configured for stimulation, whereby the electrode receives stimulation input from signal bus 124. As described above, signal bus 124 is electrically connected to a portion of the control and processing device 14 that can operate to generate stimulation signals.

[0122] Each stimulation electrode 102 in the electrode array 32 includes Figure 4 The multiplexer and storage circuit shown are illustrated.

[0123] Figure 5 A sensing unit 200 configured for single-ended operation is shown. Figure 4 The sensing unit 200 includes a single electrode 202, which is included in the electrode array 32. The sensing unit 200 also includes an output buffer 215 and an output pin 230.

[0124] Electrode 202 is configured to sense an electrodynamic response field, and thus electrode 202 is connected to sensor output pin 230 via output buffer 215, which is addressed by a second state selection bit 225. As described above, sensor output pin 230 is electrically connected to a portion of control and processing circuitry 34 that is operational to process the sensed signal.

[0125] The stimulation electrode 102 and the sensing electrode 202 are arranged in a rectangular electrode array 32, which... Figure 3 The diagram is shown schematically.

[0126] Electrode array 32 includes two columns aligned with the flow of the analyte, wherein the first column consists of stimulating electrodes 102 and the second column consists of sensing electrodes 202. Rectangular electrode array 32 may include multiple pairs of two-column electrode arrangements laterally (e.g., an array of 32 columns and 8 rows), wherein stimulating electrodes 102 and sensing electrodes 202 are arranged alternately in rows, such as... Figure 3 As shown.

[0127] exist Figure 3 In this embodiment, the width of the main channel of the flow device 30 is sufficient to accommodate five columns of electrodes within the main channel, while the remaining electrodes of the array 32 are located outside the main channel of the flow device. In use, the activation electrodes are selected into columns (e.g., two columns), which are typically located at the center of the main channel of the flow device where laminar flow exists.

[0128] Configured for Figure 3 The electrodes are stimulating electrodes 102a and 102b and sensing electrodes 202a and 202b. Specifically, a stimulation signal is provided to the stimulating electrode 102a, and the same stimulation signal or a complementary signal of opposite polarity is provided to the stimulating electrode 102b. The stimulating electrode 102a forms a capacitor with the adjacent sensing electrode 202a, and the liquid material and any biological particles therein are located within the electric field between these electrodes 102a and 202a. Similarly, the stimulating electrode 102b forms a capacitor with the adjacent sensing electrode 202b, and the liquid material and any biological particles therein are located within the electric field between these electrodes 102b and 202b.

[0129] Differential measurement is performed by comparing (e.g., by subtraction) the output signals from the sensing circuit associated with sensing electrodes 202a and 202b. Specifically, the concentration and flow rate of the bioparticles are controlled such that each bioparticle in the flow passes sequentially through the first pair of electrodes 102a and 202a and the second pair of electrodes 102b and 202b. The differential measurement will be zero until the bioparticle passes through either the first pair of electrodes 102a and 202a or the second pair of electrodes 102b and 202b, at which point a differential signal will be output.

[0130] The distance between the first pair of electrodes 102a, 202a or the second pair of electrodes 102b, 202b is chosen to be large enough that the corresponding electric fields are separated, so that the biological particles are not detected by both pairs of electrodes at the same time.

[0131] Controlled according to at least one of the following Figure 1 The pump in the measuring device 10 measures the flow rate of the analyte through the measuring device 10 and the confidence level of the analyte flowing through the measuring device 10. When the flow rate of the analyte is further considered, the spacing between the electrode pairs in the array is known, and the travel time of the biological cells between the electrode pairs is determined by the control and processing device 14. Then, the control and processing device 14 can operate to determine the movement speed of the biological cells through the measuring device 10. The control and processing device 14 can then operate to control the pump based on the measured speed. For example, if the measured speed is lower than a predetermined value, the control and processing device 14 operates to increase the flow rate by controlling the pump. When further considering the characterization confidence level of the analyte, the control and processing device 14 can operate to characterize the biological cells and determine the confidence level of the characterization. The control and processing device 14 can further operate to compare the determined confidence level with a predetermined level, and then control the pump accordingly. If the determined confidence level is lower than the predetermined level, the control and processing device 14 can operate to reduce the flow rate by controlling the pump, thereby improving the characterization of the biological cells.

Claims

1. A biometric device, the biometric device comprising: A stimulation device includes at least one stimulation electrode and a stimulation circuit, the stimulation circuit being configured to provide an electrical stimulation signal to the at least one stimulation electrode, causing the at least one stimulation electrode to generate a predetermined electrodynamic field applied to biological material. A sensing device includes at least one sensing electrode and a sensing circuit, wherein the at least one sensing electrode is configured to sense a response to an applied electrodynamic field and provide a corresponding electrical response signal to the sensing circuit. The electrical stimulation signal comprises multiple different pseudo-random binary sequences, each pseudo-random binary sequence having a length and data rate that provide the predetermined electrodynamic field, and the frequency range of the predetermined electrodynamic field differs from the frequency range provided by other pseudo-random binary sequences.

2. The biomeasuring device according to claim 1, wherein, The electrical stimulation signal comprises three or more pseudo-random binary sequences, each pseudo-random binary sequence having a length and data rate that provide the predetermined electrodynamic field, the frequency range of which differs from the frequency range provided by other pseudo-random binary sequences.

3. The biomeasuring device according to claim 1 or 2, wherein, The electrical stimulation signal comprises a series of logarithmically distributed pseudo-random binary sequences.

4. The biomeasuring device according to any one of the preceding claims, wherein, The plurality of pseudo-random binary sequences are maximum-length sequences (m-sequences).

5. The biomeasuring device according to any one of the preceding claims, wherein, The electrical stimulation signal includes a signal packet, which includes the plurality of different pseudo-random binary sequences.

6. The biomeasuring device according to any one of the preceding claims, wherein, The multiple pseudo-random binary sequences have different sampling rates.

7. The biomeasuring device according to any one of the preceding claims, wherein, A clock is used for the plurality of pseudo-random binary sequences, the clock being the same for each of the pseudo-random binary sequences.

8. The biomeasuring device according to claim 7, wherein, The plurality of pseudo-random binary sequences include at least a low-frequency pseudo-random binary sequence and a high-frequency pseudo-random binary sequence, and the period of each bit of the low-frequency pseudo-random binary sequence is an integer multiple of the period of each bit of the high-frequency pseudo-random binary sequence.

9. The biometric device according to claim 8, wherein, The frequency range provided by the pseudo-random binary sequence is distributed across the global frequency range, and the period of each bit of the lower frequency pseudo-random binary sequence is an integer multiple of the period of each bit of the higher frequency pseudo-random binary sequence.

10. The biomeasuring device according to any one of the preceding claims, wherein, The plurality of pseudo-random binary sequences provide multiple subframes within the frames of the electrical stimulation signal.

11. The biomeasuring device according to claim 10, wherein, The subframes of the plurality of pseudo-random binary sequences are separated in time by a subframe separation period.

12. The biomeasuring device according to claim 11, wherein, The subframe separation period is at least one m-sequence period.

13. The biomeasuring device according to any one of the preceding claims, wherein, The measuring device includes a processing unit configured to receive an analog electrical response signal and convert the electrical response signal into a digital response signal.

14. The biomeasuring device according to claim 13, wherein, The bit rate of the digital response signal is equal to the bit rate of the electrical stimulation signal, and the period of each bit of the digital response signal from the lower frequency pseudo-random binary sequence is an integer multiple of the period of each bit of the digital response signal from the higher frequency pseudo-random binary sequence.

15. The biometric device according to claim 13 or 14, wherein, The higher frequency components of the electrical response signal have a higher frequency bit period, and the processing device is configured with a sampling period equal to an integer multiple of the higher frequency bit period minus an integer fraction of the higher frequency bit period, and the processing device is configured to sample the electrical response signal in multiple interleaved passes.

16. The biometric device according to claim 15, wherein, The processing device is configured with a sampling period, which is equal to the higher frequency bit period multiplied by a certain factor. n Subtract 1 / of the higher frequency bit period n .

17. The biomeasuring device according to any one of claims 13 to 16, wherein, The lower frequency components in the electrical response signal have lower frequency bit periods, and the sampling rate of the processing device is equal to the lower frequency bit periods. n The processing device is configured to discard samples aligned with the transition points of the pseudo-random binary sequence, and process the remaining samples... n – One sample is averaged to provide the digital response signal.

18. The biomeasuring device according to any one of claims 13 to 17, wherein, The digital response signal is stored in a single segment of the memory.

19. The biomeasuring device according to any one of claims 13 to 18, wherein, The digital response signal is output at a data rate equal to the bit rate of the pseudo-random binary sequence with higher frequency in the electrical stimulation signal.

20. The biomeasuring device according to any one of claims 13 to 19, wherein, The period of each bit of the digital response signal from a lower frequency pseudo-random binary sequence is an integer multiple of the period of each bit of the digital response signal from a higher frequency pseudo-random binary sequence.

21. A biometric device, the biometric device comprising: A stimulation device includes at least one stimulation electrode and a stimulation circuit, the stimulation circuit being configured to provide an electrical stimulation signal to the at least one stimulation electrode, causing the stimulation electrode to generate a predetermined electrodynamic field applied to biological material. A sensing device includes at least one sensing electrode and a sensing circuit, wherein the at least one sensing electrode is configured to sense a responsive electrodynamic field and provide a corresponding electrical response signal having a bit period to the sensing circuit. A processing device is configured to receive the electrical response signal and convert the electrical response signal into a digital response signal. The processing device is configured with a sampling period equal to an integer multiple of the bit period of the electrical response signal plus or minus an integer fraction of the bit period, and the processing device is configured to sample the electrical response signal in multiple interleaved passes.

22. A biometric device, the biometric device comprising: A stimulation device includes at least one stimulation electrode and a stimulation circuit, the stimulation circuit being configured to provide an electrical stimulation signal to the at least one stimulation electrode, causing the stimulation electrode to generate a predetermined electrodynamic field applied to biological material. A sensing device includes at least one sensing electrode and a sensing circuit, wherein the at least one sensing electrode is configured to sense a responsive electrodynamic field and provide a corresponding electrical response signal having a bit period to the sensing circuit. A processing device is configured to receive the electrical response signal and convert the electrical response signal into a digital response signal. The sampling rate of the processing device is a lower frequency of the electrical response signal. n The processing device is configured to discard samples aligned with the transition points of the pseudo-random binary sequence, and process the remaining samples... n – One sample is averaged to provide the digital response signal.

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