CN114137191A

CN114137191A - Multifunctional Electrode Array System for Cell Biochemical Signal Detection and Regulation

Info

Publication number: CN114137191A
Application number: CN202111641063.1A
Authority: CN
Inventors: 刘彦; 闫鹏; 王国兴
Original assignee: Shanghai Jiao Tong University
Current assignee: Shanghai Jiao Tong University
Priority date: 2021-12-29
Filing date: 2021-12-29
Publication date: 2022-03-04
Anticipated expiration: 2041-12-29
Also published as: CN114137191B

Abstract

The invention relates to a multifunctional electrode array system for detecting and regulating cell biochemical signals, which comprises an NxN array module, a TDC counting module, an array power supply LDO module, an electrical stimulation generator, a row and column selection control module, a finite state machine and a digital control logic module, wherein the N x N array module is connected with the TDC counting module through the TDC counting module; the N multiplied by N array module is formed by combining N multiplied by N pixel units, is used for contacting with nerve cells and converting the collected analog signals into pulse width modulation signals (PWM waves); the TDC counting module is used for converting pulse width modulation signals (PWM waves) in the array into digital signals and transmitting the digital signals to the finite-state machine and the digital control logic module. By integrating four analog units with different functions in a front-end array and designing a corresponding system reading framework, the interference in pixels is eliminated, various ions are detected simultaneously, the complexity of chip functions is improved, the power consumption of a system is reduced, and a convenient detection platform is provided for biological detection.

Description

Multifunctional electrode array system for cell biochemical signal detection and regulation

Technical Field

The invention relates to the technical field of analog integrated circuits, in particular to a multifunctional electrode array system for detecting and regulating cell biochemical signals.

Background

The nerve cells are accompanied by complex electrical and chemical phenomena in the process of generating actions, and the acquisition of detailed nerve signals is helpful for further research on the nerve cells. Meanwhile, the nerve electrical stimulation regulation and control can give specific stimulation to nerve cells according to requirements, and the closed-loop system analysis of the nerve cells is realized by combining the sensing part. To realize an integrated sensing regulation system and meet the resolution of a cell level, a miniaturized sensing regulation platform is needed. The integrated circuit technology can realize the integration of a miniature complex system on a single chip by utilizing an advanced micro-nano processing technology, so the integrated circuit technology is widely applied to neuroscience, wherein a high-density, large-scale and multifunctional neuro-biochip integrating multiple functions into a whole can comprehensively acquire neural signals, meets the requirements under different application scenes, and has good development prospect.

The biochip based on integrated circuit has the following problems: 1. the functions are single, and multiple functions are integrated, so that the complexity and the design difficulty of the system are increased; 2. multiple functions cannot be in parallel. Due to mutual interference among different signal detection electrodes, bioelectric signals and chemical signals cannot be detected in parallel, and the dimension of the acquired signals is limited; 3. the spatial resolution is insufficient. The neuro-biochip with high spatial resolution can acquire action potential of a single neuron, which is beneficial to further analysis of neural signals, but when various functions are integrated together, the area of a single pixel unit is increased, and meanwhile, mutual interference is also increased; 4. the array scale is limited, large-scale arrays have higher data and require higher-performance system design; 5. the energy consumption is too large, the information is redundant, nerve cells are not attached to partial electrodes in the array, signals acquired by the partial electrodes are redundant, and the energy consumption of a circuit is wasted.

The development of biochips needs a large-scale detection array to collect more neuron signals at the same time to further analyze the cooperative work among nerves, but the expansion of the chip array scale causes the increase of the power consumption and data volume of the chip, and limits the further expansion of the scale.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a multifunctional chip for collecting nerve signals, which integrates the multifunctional, multi-modal and bidirectional interaction nerve multi-electrode chip for detecting nerve electrical signals, detecting nerve chemical signals, detecting optics and stimulating nerve electricity, solves the problems of multi-modal parallelism, resolution, scale and power consumption in an array chip, and improves the system integration level.

The technical solution of the invention is as follows:

the invention provides a multifunctional electrode array system for detecting and regulating cell biochemical signals, which is characterized by comprising an NxN array module, a TDC counting module, an array power supply LDO module, an electrical stimulation generator, a row and column selection control module, a finite state machine and a digital control logic module, wherein the N x N array module is connected with the TDC counting module through a network;

the N multiplied by N array module is formed by combining N multiplied by N pixel units, is used for contacting with nerve cells and converting the collected analog signals into pulse width modulation signals (PWM waves);

the TDC counting module is used for converting pulse width modulation signals (PWM waves) in the array into digital signals and transmitting the digital signals to the finite-state machine and the digital control logic module;

the array power supply LDO module is used for supplying power to the N multiplied by N array module;

the electrical stimulation generator is used for stimulating the electrical signals generated in the NxN array module, and selectively turning on a pixel stimulation switch through the row and column selection control module to stimulate a single point;

the row-column selection control module is used for regulating and controlling the working sequence of the N multiplied by N array module and the working state of a single pixel;

the finite state machine and the digital control logic module are used for receiving an external PC control signal, controlling the working state of the NxN array module according to the instruction content, completing each calibration in the system, converting a parallel digital signal sent by the TDC counting module into a serial signal and outputting the serial signal to the external PC.

The NxN array is a part of the chip which is directly contacted with nerve cells, is responsible for initially converting the collected analog signals into uniform pulse width modulation signals (PWM waves), and is mainly formed by regularly combining N x N pixel units. Each pixel unit consists of an electrical signal detection unit, three chemical signal detection units, a compensation unit, an optical detection unit and a stimulation unit, wherein the electrical signal detection unit acquires an electrical signal through an electrode and is used as the input of an amplifier, the front-end amplifier amplifies the electrical signal and compares the electrical signal with a triangular wave, and the magnitude of the electrical signal is converted into the pulse width of a square wave at the output end of a comparator; the chemical detection unit converts the concentration of chemical ions into the grid voltage of the MOS tube by using three different chemical sensitive films, reads the voltage and then compares the voltage, and converts the voltage into the pulse width of square waves; a compensation unit for eliminating the electrical interference in the chemical detection unit by using the interference compensation circuit; the optical detection unit detects the intensity of light by using a photosensitive diode, converts the light intensity into an electric signal, and converts the electric signal into the pulse width of a square wave through a reading circuit and a comparator; the stimulation unit uses electrical stimulation to output electrical stimulation signals to the nerve cells through the electrodes, and fixed-point stimulation on the nerve cells is achieved. In the whole array, the pixel units of the whole row are multiplexed by time division and share a TDC counting module.

The TDC counting module is mainly used for converting pulse width modulation signals (PWM waves) in the array into digital signals and sending the digital signals to a finite-state machine and a digital control logic, and the whole counter is divided into two parts: a coarse counter and a fine counter. The coarse counter is an asynchronous digital counter, counts the number of clocks when the pulse is high, and converts the pulse width into a high-bit digital signal. The fine counter can read the time difference between the edge of the pulse and the edge of the clock under the condition of not changing the clock frequency, thereby further improving the counting precision and generating a low-order digital signal. The coarse and fine counts together make up the complete digital signal.

The array power supply LDO mainly provides power for the whole array, solves the PVT problem of partial modules, and when the array scale is enlarged, the array power consumption is higher, and the LDO still provides enough current output capacity.

The electric stimulation generator is mainly used for generating the stimulation of electric signals in the array, the stimulation units of the whole array share one electric stimulation generator, and when the pixel units need stimulation, the switches for pixel stimulation are selectively turned on through row and column selection control to stimulate single points.

The row and column selection control regulates and controls the working sequence of the whole array and the working state of a single pixel, and in the aspect of signal reading, the row and column selection control module controls the time division multiplexing of the pixel units in the whole row and sends signals to the bus in turn; in the aspect of stimulation selection, the row and column selection control module can regulate and control the stimulation unit in a single pixel according to the address bit given by the digital system, and controls the on or off of the stimulation unit, so that the stimulation of a single potential is realized; in the edge detection loop, the row-column selection control module can turn off the pixel unit at the designated position according to the address bit stored in the digital system, so that the power consumption of the array and the TDC is saved.

The finite state machine and the digital control logic are responsible for regulating all logic within the system. And receiving a control signal sent by an external PC, controlling the working state of the array according to the instruction content, completing each calibration in the system, converting a parallel digital signal sent by the TDC counting module into a serial signal, and outputting the serial signal to the external PC. In addition, the digital module can also realize the function of edge detection, and a detection loop is mainly divided into four sub-modules: edge detection, position recording, stored data simplification and control signal generation. When the circuit works, the optical sensing units in the array transmit the intensity of light to the edge detection unit (12) in the digital module through signal flow, the edge detection unit detects the light intensity among different pixel units, judges which modules are positioned below nerve cells so as to determine the edge positions of the nerve cells, records position information in the position recording module, the stored data simplifying module deletes appointed position data of the memory according to address bits recorded in the position recording module, does not record the data at the position any more, reduces the data volume, and meanwhile, the control signal generating module closes the pixel units which are not positioned below the cells according to the address bits recorded in the position recording module so as to reduce the array power consumption. After the edge detection is completed, the address bits can be sent to the PC terminal, the edge of the nerve cell can be displayed, and the controllable stimulation unit can directly stimulate the nerve cell.

Compared with the prior art, the invention has the beneficial effects that:

the invention provides a multifunctional system chip integrating nerve electrical signal detection, neurochemical signal detection, optical detection and nerve electrical stimulation. The chip can simultaneously acquire electrical, chemical and optical signals, give out stimulation signals, eliminate electrical interference in the chemical signals, automatically adjust the opening and closing of the pixel units in the array according to an optical detection result, reduce power consumption and reduce redundant data, can be used for large-scale and multi-mode signal detection of living animals or isolated nerve tissues, acquires multi-dimensional nerve signals and realizes an on-chip experimental platform.

Drawings

FIG. 1 is an overall block diagram of the multifunctional chip for neural signal acquisition of the present invention

FIG. 2 is a block diagram of the structure of the pixel unit in the multifunctional chip for neural signal acquisition according to the present invention

FIG. 3 is an edge detection circuit in a multifunctional chip for neural signal acquisition according to the present invention

FIG. 4 is a circuit implementation diagram of a pixel unit in the multifunctional chip for neural signal acquisition according to the present invention

FIG. 5 is a circuit implementation diagram of a TDC counting module in the multifunctional chip for neural signal acquisition according to the present invention

FIG. 6 is a schematic diagram of the edge detection effect in the multifunctional chip for neural signal acquisition according to the present invention

Detailed Description

In order to make the objects, advantages, technical solutions and embodiments of the present invention more apparent, the present invention is further described in detail below with reference to examples and drawings, but the present invention should not be limited to the scope of protection.

The pixel units are the core of the whole array, each pixel unit can contact nerve cells to collect nerve signals, a large number of pixels form an N multiplied by N array 1, and output signals of the N multiplied by N array 1 are output to the TDC counting module 2 through a bus. Fig. 4 is a circuit implementation diagram of a pixel unit according to the present invention, which is a specific circuit implementation manner of the structural block diagram of the pixel unit shown in fig. 2. The single pixel includes: an electrical electrode 16, an electrical readout circuit 17, three types of chemical electrodes 18, a chemical readout circuit 19, a compensation circuit 20, a photosensitive device 21, an optical readout circuit 22, a stimulation electrode 23, a stimulation buffer 24 and a comparator 25. The electric electrode 16 and the electric reading circuit 17 form an electric signal detection unit 7, the three types of chemical electrodes 18 and the chemical reading circuit 19 form a chemical detection unit 8, the compensation circuit 20 is a compensation unit 9, the photosensitive device 21 and the optical reading circuit 22 form an optical detection unit 10, and the stimulation electrode 23 and the stimulation buffer 24 form a stimulation unit 11.

The electrical electrode 16 in the pixel can directly collect the nerve electrical signal, and the electrical signal is transmitted to the electrical readout circuit 17 for amplification; the three types of chemical electrodes 18 respectively collect three types of different ion concentrations through three types of ion sensitive membranes, and convert the chemical quantity into an electrical quantity, and the electrical quantity is amplified through a chemical readout circuit 19; the photosensitive device can acquire light intensity signals, the received signals are weaker for the photosensitive device below the cell, on the contrary, the light intensity of other positions is stronger, the photosensitive device generates corresponding electric quantity according to the light intensity, and the amplified signals are obtained through the optical reading circuit 22; the stimulating electrode 23 may deliver the stimulating current in the buffer 24 to the periphery of the nerve cell.

The circuit implementation of the pixel cell has a compact structure and the ability to read signals simultaneously. After the electrical, chemical and optical signals are converted into electrical quantities, the electrical quantities are buffered or amplified through a reading circuit, the amplified signals are compared with triangular waves through a comparator 25 through time division multiplexing control logic to obtain pulse width modulation PWM waves, and the PWM waves are finally transmitted to a bus under the control of a three-state gate. The front-end readout circuit should have a good signal-to-noise ratio, can amplify weak signals, can provide undistorted buffering for larger signals, and simultaneously provides sufficient driving capability for subsequent circuits. The comparator in the circuit has higher amplification factor and can provide quick pull-up and pull-down capability, and the pixel unit can be miniaturized and the pixel power consumption can be reduced by multiplexing the comparator. In addition, between the electrical and chemical circuits, there is a compensation circuit 20, which eliminates the forward electrical interference in chemistry by using the reverse electrical signal, obtains an undisturbed chemical signal, and realizes the simultaneous reading of the electrical and chemical signals. In the electrical stimulation part, a common stimulation signal is arranged in the nerve electrical stimulation bus, the signal is output to a buffer by controlling the on-off state of a transmission gate, the buffer provides enough driving capability, and a stimulation pulse is output to a solution to complete the stimulation of nerve cells. Through the control of the row-column selection control 5 and the digital control logic 6, signals of all pixels can be read out in an experiment, and the control of all stimulation units can be realized, so that the diversified requirements for researching nerve cells are met.

The TDC count module 2, as shown in fig. 5, includes an asynchronous counter (coarse counter), a delay line (fine counter), asynchronous control logic, and a hot code to binary. The TDC counting module 2 converts the pulse width output by the array into binary data and outputs the binary data to the finite-state machine and the digital control logic 6, and the combination of the coarse counter and the fine counter can further improve the counting precision under the condition of not changing the clock frequency. The asynchronous counter is built by using a D trigger, when the pulse is high, the rising edge of each clock can trigger the counter to increase by one, and the final counting result is the number of clocks contained in the pulse width to obtain high-bit data of digital output. The delay line can realize fine counting, and one clock period is averagely divided into 2ⁿAnd equally dividing, namely quantifying the distance between the rising edge and the falling edge of the pulse and the rising edge of the clock by using a small time period after the equally dividing, eliminating the time difference between the clock and the pulse, improving the measurement precision of the pulse width, and realizing a circuit by using an inverter chain to generate time delay and equally dividing the clock period. And the start, the end and the sign bit of the precise counting need to be regulated and controlled by asynchronous control logic, so that the accuracy of the precise counting is ensured. The hot code generated by the delay line is converted into binary number and output as the low-order data of digital output. The high, low and sign bits together form a digital code which is output by the counter to the finite state machine and digital control logic 6.

The array power supply LDO3 supplies power to the entire array, and in large-scale situations, the current of the entire array is large, and the LDO needs sufficient driving capability. The power tube in the circuit flows the current of the whole array, the size and the area need to be larger, and the power tube can keep a good working state under the condition that the pixel unit is partially turned off and is completely turned on.

The electrical stimulation generator 4 receives instructions from the finite state machine and the digital control logic 6 to generate a corresponding stimulation waveform. The specific implementation can use a digital-to-analog converter (DAC), the input end is a digital signal, the output is a stimulation waveform, and the higher the precision of the DAC is, the more accurate the stimulation waveform is. At the same time, the buffers in the in-pixel stimulation unit need to have sufficient bandwidth to reduce the distortion of the stimulation waveform.

The row and column selection control module 5 regulates and controls the working sequence of the whole array and the working state of a single pixel, and in the aspect of signal reading, the row and column selection control module controls the time division multiplexing of the pixel units in the whole row and sends signals to the bus in turn; in the aspect of stimulation selection, the row and column selection control module can regulate and control the stimulation unit in a single pixel according to the address bit given by the digital system, and controls the on or off of the stimulation unit, so that the stimulation of a single point location is realized; in the edge detection loop, the row-column selection control module can turn off the pixel unit at the designated position according to the address bit stored in the digital system, so that the power consumption of the array and the TDC is saved.

The finite state machine and digital control logic 6 is responsible for regulating all logic within the system. And receiving a control signal sent by an external PC, controlling the working state of the array according to the instruction content, completing each calibration in the system, converting parallel digital signals sent by the TDC coarse counter and the TDC fine counter 2 into serial signals, and outputting the serial signals to the external PC. In addition, the digital module can also implement the function of edge detection, and as shown in fig. 3, the digital module is a detection loop block diagram, and is mainly divided into four sub-modules: an edge detection unit 12, a position recording unit 13, a stored data reduction unit 14, and a control signal generation unit 15. When the circuit works, the optical sensing units in the array transmit the intensity of light to the edge detection unit 12 through signal flow, the edge detection unit 12 detects the intensity of light among different pixel units, and judges which modules are positioned below nerve cells, so that the edge position of the nerve cells is determined, and position information is recorded in the position recording unit 13; the memory data reduction unit 14 deletes the designated position data of the memory according to the address bit recorded in the position recording unit 13, and does not record the data at the position any more, reducing the data amount, and the control signal generation unit 15 closes the pixel unit not under the cell according to the address bit recorded in the position recording unit 13, reducing the array power consumption. After the edge detection is finished, the address bit is sent to the PC end, the edge of the nerve cell is displayed, and the stimulation unit is controlled to directly stimulate the nerve cell.

As shown in fig. 6, which is a schematic diagram of the edge detection effect of the present invention, nerve cells are covered on an N × N array 1, some pixel units are not covered by cells, the covered pixel units receive weak optical signals, the uncovered pixel units receive strong optical signals, all the signals are sent from the array to N × 1 TDC counting modules 2, TDCs transmit digital signals to a finite state machine and a digital control logic 6, an edge detection module 12 determines which pixel units are located at the edge of a cell according to the intensity of the received light, and stores the address bits of the pixel units in a position recording module 13, and the finite state machine and the digital control logic 6 close the pixel units located outside the cell according to the position recording module 13, thereby implementing the functions of edge detection and power consumption reduction. In addition, the finite state machine and the digital control logic 6 can also send out the address in the position recording module 13 for the reference of the experimenter.

The chip integrates multiple functions of nerve electrical signal detection, nerve chemical signal detection, optical detection and nerve electrical stimulation, and can be used for reaction analysis experiments of biological samples, neuroelectricity and chemical signal analysis experiments, brain-computer interface front-end chips, nerve biological cell positioning and nerve map drawing, cell culture and drug reaction.

The multifunctional electrode array system for detecting and regulating cell biochemical signals can be realized by using process platforms such as CMOS, SOI, TFT and the like.

Although particular embodiments of the present invention have been described above, it will be understood by those skilled in the art that these are by way of example only and that numerous changes or modifications may be made to these embodiments without departing from the spirit of the invention, the scope of which is therefore defined by the appended claims.

Claims

1. A multifunctional electrode array system for cell biochemical signal detection and regulation, characterized in that it comprises an N×N array module (1), a TDC counting module (2), an array power supply LDO module (3), an electrical stimulation module a generator (4), a row and column selection control module (5), a finite state machine and a digital control logic module (6);

The N×N array module (1), which is composed of N×N pixel units, is used to contact nerve cells and convert the collected analog signal into a pulse width modulation signal (PWM wave);

The TDC counting module (2) is used to convert the pulse width modulation signal (PWM wave) in the array into a digital signal, and transmit it to the finite state machine and the digital control logic module (6);

The array power supply LDO module (3) is used to supply power to the N×N array module (1);

The electrical stimulation generator (4) is used to stimulate the electrical signals generated in the N×N array module (1), and selectively turn on pixels through the row and column selection control module (5) Stimulation switch, to stimulate a single point;

The row and column selection control module (5) is used for regulating the working order of the N×N array module (1) and the working state of a single pixel;

The finite state machine and the digital control logic module (6) are used for receiving an external PC control signal, and according to the content of the instruction, controlling the working state of the N×N array module (1), completing each calibration in the system, and converting the TDC The parallel digital signals sent by the counting module (2) are converted into serial signals and output to an external PC.

2 . The multifunctional electrode array system for cell biochemical signal detection and regulation according to claim 1 , wherein the N×N array module (1) is formed by combining N×N pixel units. 3 . Each pixel unit includes an electrical signal detection unit (7), three chemical signal detection units (8), a compensation unit (9), an optical detection unit (10) and a stimulation unit (11);

The electrical signal detection unit (7) collects the electrical signal through the electrodes, as the input of the amplifier, the front-end amplifier amplifies the electrical signal, compares it with the triangular wave, and converts the magnitude of the electrical signal into a square wave at the output end of the comparator The chemical detection unit (8) converts the chemical ion concentration into the gate voltage of the MOS tube by using three different chemical sensitive films, reads the voltage for comparison, and also converts it into a square wave The described compensation unit (9) adopts the interference compensation circuit to eliminate the electrical interference in the chemical detection unit; the described optical detection unit (10) adopts the photosensitive diode to detect the intensity of light, and converts the light intensity into The electrical signal is converted into a pulse width of a square wave through a readout circuit and a comparator; the stimulation unit (11) uses electrical stimulation, and outputs the electrical stimulation signal to the nerve cells through electrodes to achieve fixed-point stimulation of the nerve cells.

3. a kind of multifunctional electrode array system for cell biochemical signal detection and regulation according to claim 1, is characterized in that, described TDC counting module (2) comprises rough count part, fine count part, asynchronous control Logic part and hot code to binary part;

The rough counting part is an asynchronous digital counter, which counts the number of clocks when the pulse is high, and converts the pulse width into a high-order digital signal for output.

The precise counting part is a delay line, and without changing the clock frequency, the time difference between the edge of the pulse and the edge of the clock is read out to generate a hot code;

The described hot code-to-binary part converts the hot code into a binary number and outputs it as a low-digit digital signal;

The asynchronous control logic part is used to control the start, end and sign bit of fine counting.

4. a kind of multifunctional electrode array system for cell biochemical signal detection and regulation according to claim 1, is characterized in that, described electrical stimulation generator (4) receives finite state machine and digital control logic module ( 6) The issued instruction generates the corresponding stimulation waveform.

5. A multifunctional electrode array system for cell biochemical signal detection and regulation according to claim 1, characterized in that, the row and column selection control module (5) in terms of signal reading, the row and column selection control module Controls the time-division multiplexing of the entire row of pixel units, and sends signals to the bus in turn; in terms of stimulus selection, the row and column selection control module regulates the stimulus units in a single pixel according to the address bits given by the digital system, and controls on or off to achieve Stimulation of a single point; in the edge detection loop, the row and column selection control module can turn off the pixel unit at the specified position according to the address bits saved by the digital system, saving the power consumption of the array and TDC.

6. A multifunctional electrode array system for cell biochemical signal detection and regulation according to claim 1, wherein the finite state machine and digital control logic (6) comprise an edge detection unit (12) , a position recording unit (13), a storage data reduction unit (14), a control signal generation unit (15); when the loop is working, the optical sensing unit in the array transmits the intensity of the light to the edge detection unit (12) through the signal flow ), the edge detection unit (12) detects the light intensity between different pixel units, and judges which modules are located below the nerve cells, thereby determining the edge position of the nerve cells, and recording the position information in the position recording unit (13), storing data The reduced module unit (14) deletes the specified location data of the memory according to the address bits recorded in the location recording unit (13), and stops recording, and the control signal generating unit (15) controls the signal generating unit (15) according to the address recorded in the location recording unit (13) bit, turn off the pixel unit that is not under the cell; after the edge detection is completed, the address bit is sent to the PC side, so that the edge of the nerve cell is displayed, and the stimulation unit is controlled to directly stimulate the nerve cell.