CN113076003B - Implantable probe and its preparation method, control circuit, control system - Google Patents

Abstract

The application belongs to the technical field of bioengineering and relates to an implantable probe, a preparation method of the implantable probe, a control circuit and a control system, wherein the implantable probe comprises an optical exciter and a flexible probe body; the optical exciter is integrated on the flexible probe body and used for exciting a fluorescence signal reflecting the neural activity or activating the neural activity through illumination; at least one side of the flexible probe body is provided with a heat conduction material, and the heat conduction material is used for dissipating heat of devices on the flexible probe body. Therefore, flexible probe has been used to this application to for flexible probe has set up and has carried out radiating heat conduction material for device on the flexible probe, so, this application can realize improving the mechanical mismatch problem of implanted probe and brain tissue, reduces the appearance rate of biological tissue inflammation, in addition, can also promote implanted probe heat dispersion, thereby can promote biocompatibility.

Description

Implantable probe and its preparation method, control circuit, control system

technical field

The present application relates to the technical field of bioengineering, in particular to an implantable probe, a preparation method of the implantable probe, a control circuit and a control system.

Background technique

Brain-Computer Interface (BCI) is a non-muscular communication channel established between the brain and external devices, which realizes the communication between the brain's intentions and the external environment. As a new way of human-computer interaction, BCI provides a new idea for the brain control of equipment, has become a research hotspot in the field of intelligent robots, and has built a bridge combining "human brain biological intelligence" and "artificial intelligence". With the integration of BCI technology and robot automatic control technology, a new technology - brain-controlled robot technology has emerged.

From the perspective of the control object, in the process of the development of the brain-computer interface, the communication between the brain and the mechanical arm, the human brain and the biological brain, and the human brain and the human brain also appeared in the existing technology. Most of these systems collect and regulate the brain wave (EEG) signals of the human brain, which are non-invasive and cause little damage to the human brain of the experimental subjects, but it is difficult to obtain information with high spatial resolution. So far, the most notable achievements of brain-computer interface technology have come from invasive brain-computer interfaces for animals and humans, such as high-precision control of two-dimensional cursors, real-time control of prosthetic arms and grippers, and so on. In addition, the two main strategies used in the construction of invasive BCIs are operant conditioning and cluster decoding methods. In the former method, the BCI is completely controlled by neuron self-adaptation. In one method, statistical techniques are used to learn the mapping relationship between neuron activity and control parameters, but these are often applied to one-way BCI, while the typical way of two-way BCI is to collect and extract information while using electronic Stimulation provides information to other neurons so that the brain no longer relies on the body for perception and action. Other typical collection/stimulation methods, such as optogenetics, have high spatial resolution when building a high-performance two-way brain-computer interface. Rate and other characteristics are more advantageous. From the perspective of neural information collection, the existing technologies include invasive two-photon imaging, microcortical EEG, etc., and non-invasive EEG, magnetoencephalography, functional magnetic resonance imaging, functional near-infrared imaging, Positron emission tomography, etc. From the perspective of neural information processing, neural information can still be perceived and utilized by the nervous system after passing through the artificially set transfer function. Certain neuronal networks in , are highly plastic, using their inputs to shape their properties and achieve sensory amplification.

At present, the above-mentioned invasive brain-computer interface usually includes implantable probes, but most of the traditional implantable probes are rigid probes (such as silicon-based probes, glass-based probes, etc.), and due to rigidity The hardness characteristics of the probe make the mechanical mismatch between the rigid probe and the brain tissue serious, which easily leads to inflammation of the biological tissue. Therefore, the biocompatibility is relatively low. In addition, the traditional invasive brain-computer interface includes implantable probes Electrical devices such as LEDs are usually installed on the LED. Therefore, these electrical devices will generate heat during operation, and there will be a phenomenon of local accumulation of heat, which will easily lead to adverse reactions of organisms. Therefore, those skilled in the art have been seeking solutions to the above problems.

The foregoing description is provided to provide general background information and does not necessarily constitute prior art.

Contents of the invention

The technical problem to be solved in this application is to provide implantable probes, preparation methods of implantable probes, control circuits and control systems for the defects of the above-mentioned prior art, so as to improve the connection between implantable probes and the brain. The mechanical mismatch of the tissue and the improvement of the heat dissipation performance of the implanted probe.

This application is implemented like this:

The first aspect of the present application provides an implantable probe, including an optical exciter and a flexible probe body; the optical exciter is integrated in the flexible probe body, and is used to excite fluorescent signals reflecting neural activity or activate neural activity through light; At least one side of the flexible probe body is provided with a heat-conducting material, and the heat-conducting material is used for dissipating heat from devices on the flexible probe body.

Optionally, the optical exciter includes one of micro LEDs and micro laser diodes.

Optionally, the micro LEDs are InGaN based LEDs.

Optionally, an optical filter is integrated on the optical exciter, and the optical filter is made of silicon dioxide.

Optionally, the flexible probe body is flat and has two opposite sides; both sides of the flexible probe body are provided with a heat conducting layer formed of a heat conducting material.

Optionally, the thermally conductive material includes one of thermally conductive metal materials and thermally conductive non-metallic materials.

Optionally, a detector is also included, and the detector is integrated into the flexible probe body.

Optionally, the detector is a miniature InGaP-based detector.

Optionally, a dye filter is integrated on the miniature InGaP-based detector.

The second aspect of the present application provides a method for preparing an implantable probe, including: depositing a thermally conductive material on at least one side of a flexible substrate to obtain a target flexible substrate; placing an optical exciter on the target flexible substrate; The target flexible substrate provided with the optical exciter is processed to make an implantable probe, wherein the processing includes at least one of photolithography, metal deposition, laser cutting, and packaging, and the implantable probe includes Optical exciter and flexible probe body.

Optionally, the step of depositing a thermally conductive material on at least one side of the flexible substrate to obtain the target flexible substrate includes: depositing a thermally conductive material on opposite two sides of the flexible substrate respectively, so that A thermally conductive layer is respectively formed on the substrate to obtain a target flexible substrate.

Optionally, after the step of arranging the optical exciter on the target flexible substrate, the method includes: performing a filter forming process using silicon dioxide for the optical exciter, so as to form an optical filter on the optical exciter.

Optionally, the flexible substrate includes one of a PI substrate, a PT substrate, and a PTMS substrate.

Optionally, arranging the optical exciter in the target flexible substrate includes: arranging the optical exciter and the detector on the target flexible substrate using PDMS stamp transfer technology.

Optionally, after the step of disposing the optical exciter and detector on the target flexible substrate using the PDMS stamp transfer technique, it includes: doping the photoresist with dye to obtain a dye photoresist; using dye photoresist for the detector The resist is subjected to a filter forming process to form a dye filter on the detector, wherein the filter forming process is at least one of spin coating, photolithography, and hardening.

The third aspect of the present application provides a control circuit, including a power supply module, a communication module, and a control module; the power supply module is connected to the control module for supplying power to the control module; the communication module is connected to the control module for receiving regulation information or sending The collected data and/or regulation information of the implanted probe; the control module is connected with the implanted probe as described above, and is used to control the operation of the optical exciter and/or detector in the implanted probe.

Optionally, the control module includes a main control chip and an excitation light control chip; the main control chip is connected to the optical exciter through the excitation light control chip, and is used to control the excitation light parameters of the optical exciter through the excitation light control chip, and to excite The light parameters include any one or more of excitation light intensity, duty cycle, period, and luminescence duration.

Optionally, the control module further includes a work indicator; the work indicator shares anode or cathode with the optical exciter, and is used to indicate the working state of the optical exciter.

Optionally, the main control chip is connected to the detector, and is used to receive the neural activity information collected by the detector to process and control the neural activity information to obtain regulatory information.

Optionally, the control module also includes a signal optimization unit; the signal optimization unit includes a filtering subunit and a signal amplification subunit; the filtering subunit is connected between the signal amplification subunit and the detector, and is used for neural activity information collected by the detector After filtering, the filtered neural activity information is transmitted to the signal amplification subunit; the signal amplification subunit is connected to the main control chip, and is used to perform signal amplification processing on the filtered neural activity information to obtain the final neural activity information, and the final The neural activity information is transmitted to the main control chip.

Optionally, the signal amplifying unit includes a transimpedance amplifier; the transimpedance amplifier is connected with the filter subunit and the main control chip, and is used to perform signal amplification processing on the filtered neural activity information to obtain the final neural activity information, and convert the final neural activity information The activity information is transmitted to the main control chip.

Optionally, the signal amplifying unit includes a transimpedance amplifier and a buffer stage; the transimpedance amplifier includes a positive input terminal, a negative input terminal, an output terminal and a potential protection terminal, wherein the negative input terminal of the transimpedance amplifier is connected to the negative pole of the detector, and the transimpedance amplifier The positive input end of the impedance amplifier is connected to the positive electrode of the detector, and the output end of the transimpedance amplifier is connected to the I/O port of the main control chip; the buffer stage includes a positive input end, a negative input end and an output end, wherein the output of the buffer stage The terminal is connected to the negative input terminal of the buffer stage, the positive input terminal of the buffer stage is connected to the positive input terminal of the transimpedance amplifier, and the output terminal of the buffer stage is connected to the potential protection terminal of the transimpedance amplifier to form a potential near the negative input terminal of the transimpedance amplifier protection, constituting the filtering subunit.

Optionally, the model of the main control chip is nRF24LE1; the model of the excitation light control chip is ZLED7012; the model of the transimpedance amplifier is LMP7721; the model of the buffer stage is ADA4505.

Optionally, the communication module is a wireless communication module or a wired communication module.

The fourth aspect of the present application provides a control system, including an acquisition module and a reproduction module; the acquisition module includes the above-described implantable probe and the above-described control circuit; wherein, the implantable probe of the acquisition module The optical exciter on the sensor is used to excite the fluorescent signal reflecting the neural activity, and the detector on the implanted probe of the acquisition module is used to collect the fluorescent signal to obtain the neural activity information; wherein, the control circuit of the acquisition module is used to receive the neural activity information, And process and control the neural activity information to obtain regulatory information; the reproduction module includes the implantable probe as described above and the control circuit as described above; wherein, the control circuit of the reproduction module is used to receive the control of the acquisition module The control information sent by the circuit is used to drive the optical exciter in the implanted probe of the reproduction module according to the control information, so as to activate the brain region optogenetically.

The implantable probe, the preparation method of the implantable probe, the control circuit and the control system provided by the application, wherein the implantable probe includes an optical exciter and a flexible probe body; the optical exciter is integrated in the flexible probe The needle body is used to excite fluorescent signals reflecting nerve activity or to activate nerve activity through light; at least one side of the flexible probe body is provided with a heat-conducting material, and the heat-conducting material is used to dissipate heat from devices on the flexible probe body. Therefore, this application uses a flexible probe, and provides a thermally conductive material for the flexible probe to dissipate heat for the device on the flexible probe, so this application can improve the mechanical mismatch between the implanted probe and the brain tissue , reduce the occurrence rate of biological tissue inflammation, in addition, it can also improve the heat dissipation performance of the implanted probe, thereby improving the biocompatibility.

In order to make the above and other objects, features and advantages of the present application more comprehensible, preferred embodiments will be described in detail below together with the accompanying drawings.

Description of drawings

FIG. 1 is a schematic structural diagram of an implantable probe provided in the first embodiment of the present application;

Fig. 2 is the transmission spectrum of the optical filter provided by the application;

Fig. 3 is the emission spectrum contrast figure that the application provides;

Fig. 4 is a schematic structural diagram of the implantable probe provided in the second embodiment of the present application;

FIG. 5 is a transmission spectrum diagram of the dye filter provided in the second embodiment of the present application;

Fig. 6 is the external quantum efficiency spectrogram and the emission spectrogram of LED and GCaMP6 of the detector with dye filter that the second embodiment of the present application provides;

Fig. 7 is an I-V curve diagram of the detector provided by the second embodiment of the present application under different illuminations;

Fig. 8 is the graph that the electric current changes with the calcein concentration during the test provided by the second embodiment of the present application;

Fig. 9 is a graph showing the relative optical signal intensity as a function of the molar concentration of calcium ions in calcein provided by the second embodiment of the present application;

Fig. 10 is a curve diagram of changes in detection current under different light intensities provided by the second embodiment of the present application;

Fig. 11 is a schematic flow chart of the preparation method of the implantable probe provided in the third embodiment of the present application;

FIG. 12 is a schematic diagram of the first structure of the control circuit provided by the fourth embodiment of the present application;

FIG. 13 is a second structural schematic diagram of the control circuit provided by the fourth embodiment of the present application;

FIG. 14 is a third structural schematic diagram of the control circuit provided by the fourth embodiment of the present application;

FIG. 15 is a fourth structural schematic diagram of the control circuit provided by the fourth embodiment of the present application;

Fig. 16 is a schematic structural diagram of the control system provided by the fifth embodiment of the present application;

Fig. 17 is a schematic diagram of an application scenario provided by the fifth embodiment of the present application.

detailed description

In order to make the purpose, technical solution and advantages of the present application clearer, the present application will be further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the described embodiments are only some of the embodiments of the present application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the scope of protection of this application.

Although the application uses first, second, etc. terms to describe various components (eg, ports, etc.), these components should not be limited by these terms. These terms are only used to distinguish one component from another. Unless otherwise defined, all terms (including technical terms and scientific terms) used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

The embodiments of the present application will be described in further detail below in conjunction with the accompanying drawings.

First embodiment:

Fig. 1 is a schematic structural diagram of an implantable probe provided in the first embodiment of the present application. Fig. 2 is the transmission spectrum of the optical filter provided by the present application. Fig. 3 is a comparison chart of emission spectra provided by the present application. In order to clearly describe the implantable probe A1 provided in the first embodiment of the present application, please refer to FIG. 1 to FIG. 3 .

The first embodiment of the present application provides an implantable probe A1, including an optical exciter 102 and a flexible probe body 101; the optical exciter 102 is integrated in the flexible probe body 101, and is used to excite fluorescent signals or Nerve activity is activated by light; at least one side of the flexible probe body 101 is provided with a heat-conducting material (not shown in FIG. 1 ), and the heat-conducting material is used to dissipate heat from devices on the flexible probe body 101 .

In an optional implementation manner, the preparation method of the implanted probe A1 provided in this embodiment may include: depositing a thermally conductive material on at least one side of the flexible substrate to obtain a target flexible substrate; setting the optical exciter 102 on the target flexible substrate; the implantable probe A1 is made by processing the target flexible substrate provided with the optical exciter 102, wherein the processing includes photolithography, metal deposition, laser cutting, packaging At least one, the implantable probe A1 includes an optical exciter 102 and a flexible probe body 101 . For example, copper is deposited on both sides of the flexible PI substrate to obtain the target flexible substrate (wherein, the thickness of the target flexible substrate is, for example, 18um copper/25umPI substrate/18um copper), and the optical exciter is transferred by means of PDMS stamp transfer technology. 102 (size, for example, 125um*185um*7um) is disposed on the target substrate, and then processed (for example, at least one of photolithography, metal deposition, laser cutting and packaging, etc.) to obtain implantable probes A1 (size, for example, about 420um in width/about 140um in thickness/about 5mm in length).

In an optional implementation manner, the optical exciter 102 may include, but is not limited to, one of micro LEDs and micro laser diodes. Specifically, the optical exciter 102 can stimulate the brain as a switching mode after the implantable probe A1 is implanted in the biological brain area.

In an alternative embodiment, the micro-LEDs may be InGaN-based LEDs. Therefore, the present embodiment uses InGaN-based LEDs to ensure good monochromatic light emission.

In an optional implementation, the optical exciter 102 can be integrated with a filter 103, for example, a filter 103 is integrated on a traditional micro-LED. Therefore, in actual operation, a filter 103 can be provided for it to further improve monochromatic light emission, or no filter 103 can be provided for it. Optionally, the optical filter 103 may be made of silicon dioxide or other materials.

In an alternative embodiment, referring to FIG. 2 , the optical exciter 102 integrated with the optical filter 103 can optimize its transmittance (transmittance > 85%) for light with a wavelength between 420 nm and 490 nm. Referring to Fig. 3, taking the micro LED as an example, compared with the micro LED without the integrated filter 103, the monochromaticity of the micro LED integrated with the filter 103 has been improved to a certain extent, and the stray light with a wavelength of 500nm in the green light region The attenuation is obvious.

In an optional embodiment, the flexible probe body 101 may be flat and have two opposite sides; both sides of the flexible probe body 101 may be provided with a heat conducting layer formed of a heat conducting material. Therefore, the double-sided heat conduction layer in this embodiment can greatly improve the heat dissipation of the device without affecting the mechanical properties of the probe (for example, greatly improve the heat dissipation performance of the optical exciter 102 that generates more heat during operation) .

In an optional implementation manner, the thermally conductive material may include one of thermally conductive metal materials and thermally conductive non-metallic materials. Among them, heat-conducting metal materials, such as copper, silver, aluminum and so on. Among them, thermally conductive non-metallic materials, such as graphite, diamond, boron nitride, silicon dioxide and so on.

In an optional implementation, the implantable probe A1 provided in this embodiment can form a reappearance module with the control circuit. Preferably, the control circuit of the reappearance module is used to drive the implantable probe A1 of the reappearance module according to the control information. Optical exciter 102 in probe A1 to perform optogenetic activation of brain regions. In addition, the implantable probe A1 including the optical exciter 102 provided in this embodiment can cooperate with the control circuit and the implantable probe A1 including the detector to form an acquisition module, wherein the implantable probe A1 including the optical exciter 102 The probe A1 can be used to excite the fluorescent signal reflecting the neural activity, the implanted probe A1 including the detector can be used to collect the fluorescent signal to obtain the neural activity information, and the control circuit can be used to receive the neural activity information, and to monitor the neural activity Information is processed and controlled to obtain regulatory information.

In an optional embodiment, the implantable probe A1 and the control circuit provided by this embodiment form a reproduction module, wherein the implantable probe A1 directly contacts with neurons in the brain as a front end to realize photoelectric signal regulation, Among them, the control circuit realizes signal processing and conversion and wireless communication functions.

An implantable probe A1 provided in the first embodiment of the present application includes an optical exciter 102 and a flexible probe body 101; the optical exciter 102 is integrated in the flexible probe body 101 to excite fluorescent signals or Nerve activity is activated by light; at least one side of the flexible probe body 101 is provided with a heat-conducting material, and the heat-conducting material is used to dissipate heat from devices on the flexible probe body 101 . Therefore, the implantable probe A1 provided in the first embodiment of the present application uses a flexible probe, and the flexible probe is provided with a thermally conductive material for dissipating heat from the devices on the flexible probe. Therefore, the first embodiment of the present application An implantable probe A1 provided in this example can improve the mechanical mismatch between the implantable probe A1 and the brain tissue, reduce the incidence of biological tissue inflammation, and also improve the heat dissipation performance of the implantable probe A1. Thereby, biocompatibility can be improved.

Second embodiment:

Fig. 4 is a schematic structural diagram of the implantable probe provided in the second embodiment of the present application. Fig. 5 is a transmission spectrum diagram of the dye filter provided in the second embodiment of the present application. Fig. 6 is the external quantum efficiency spectrum diagram of the detector with dye filter provided in the second embodiment of the present application and the emission spectrum diagrams of LED and GCaMP6. Fig. 7 is an I-V curve diagram of the detector provided by the second embodiment of the present application under different illuminations. Fig. 8 is a graph showing the variation of current with the concentration of calcein during the test provided by the second embodiment of the present application.

Fig. 9 is a graph showing the relative optical signal intensity as a function of the molar concentration of calcium ions in calcein provided by the second embodiment of the present application. FIG. 10 is a graph showing changes in detection current under different light intensities provided by the second embodiment of the present application. In order to clearly describe the implantable probe A2 provided by the second embodiment of the present application, please refer to FIG. 2 , FIG. 3 , FIG. 4 , FIG. 5 , FIG. 6 , FIG. 7 , FIG. 8 , FIG. 9 and FIG. 10 .

The second embodiment of the present application provides an implantable probe A2, including a detector 204, an optical exciter 202, and a flexible probe body 201; the optical exciter 202 is integrated in the flexible probe body 201, and is used to excite and reflect neural activity. the fluorescent signal; the detector 204 is integrated in the flexible probe body 201, and is used to collect the fluorescent signal to obtain nerve activity information and transmit it to the control circuit; at least one side of the flexible probe body 201 is provided with a thermally conductive material (not shown in FIG. 4 ), the thermally conductive material is used to dissipate heat from the devices on the flexible probe body 201 .

In an optional implementation manner, the optical exciter 202 may include, but is not limited to, one of micro LEDs and micro laser diodes. Specifically, the optical exciter 202 can stimulate the brain as a conversion mode after the implantable probe A2 is implanted in the biological brain area.

In an alternative embodiment, the micro-LEDs may be InGaN-based LEDs. Therefore, the present embodiment uses InGaN-based LEDs to ensure good monochromatic light emission.

In an optional embodiment, the optical exciter 202 can be integrated with a filter 203, for example, a filter 203 is integrated on a traditional micro-LED. It is worth mentioning that due to the monochromaticity of the InGaN-based LED itself Better, so in actual operation, a filter 203 can be provided for it to further improve monochromatic light emission, or no filter 203 can be provided for it. Optionally, the optical filter 203 may be made of silicon dioxide or other materials.

In an alternative embodiment, referring to FIG. 2 , the optical exciter 202 integrated with the optical filter 203 can optimize its transmittance (transmittance > 85%) for light with a wavelength between 420 nm and 490 nm. Referring to Fig. 3, taking the micro-LED as an example, compared with the micro-LED without the integrated filter 203, the monochromaticity of the micro-LED integrated with the filter 203 has been improved to a certain extent, and the stray light with a wavelength of 500nm in the green light region The attenuation is obvious.

In an optional embodiment, the flexible probe body 201 may be flat and have two opposite sides; both sides of the flexible probe body 201 may be provided with a heat conducting layer formed of a heat conducting material. Therefore, the double-sided heat conduction layer in this embodiment can greatly improve the heat dissipation of the device without affecting the mechanical properties of the probe (for example, greatly improve the heat dissipation performance of the optical exciter 202 that generates more heat during operation) .

In an optional implementation manner, the thermally conductive material may include one of thermally conductive metal materials and thermally conductive non-metallic materials. Among them, heat-conducting metal materials, such as copper, silver, aluminum and so on. Among them, thermally conductive non-metallic materials, such as graphite, diamond, boron nitride, silicon dioxide and so on.

In an optional implementation manner, the method for preparing the implantable probe A2 provided in this embodiment may include: depositing a thermally conductive material on at least one side of a flexible substrate to obtain a target flexible substrate; The exciter 202 is arranged on the target flexible substrate; the implantable probe A2 is made by processing the target flexible substrate provided with the optical exciter 202, wherein the processing includes photolithography, metal deposition, laser cutting , at least one of packages, the implantable probe A2 includes a detector 204 , an optical exciter 202 and a flexible probe body 201 . For example, copper is deposited on both sides of the flexible PI substrate to obtain the target flexible substrate (wherein, the thickness of the target flexible substrate, such as 18um copper/25umPI substrate/18um copper), the detector 204 is transferred by PDMS seal (dimensions such as 195um*140um*3.5um) and optical exciter 202 (dimensions such as 125um*185um*7um) are set on the target substrate, and then processing (such as photolithography, metal deposition, laser cutting packaging etc.) to obtain the implantable probe A2 (dimensions such as about 420um in width/about 140um in thickness/about 5mm in length).

In an optional embodiment, the detector 204 may be a miniature InGaP-based detector 204 , or other conventional detectors 204 .

In an optional embodiment, a dye filter 205 is integrated on the miniature InGaP-based detector 204 . Wherein, the dye filter 205 can reduce the interference of the blue LED to the detector 204, and the detector 204 integrated with the dye filter 205 can produce a better response to different light intensities. Wherein, the transmission spectrum of the dye filter 205 can refer to FIG. 5 .

In an optional embodiment, the external quantum efficiency spectrum of the detector 204 with the dye filter 205 , the emission spectrum of the blue LED and GCaMP6 can be referred to FIG. 6 .

In an optional embodiment, the current I-voltage V curves of the detector 204 under different illuminations can refer to Figure 7 (dark, 15.93 μW/mm2, 28.85 μW/mm2, 40.32 μW/mm2, independent ).

In an optional implementation manner, the implantable probe A2 provided in this embodiment can form an acquisition module or a reproduction module together with a control circuit. Preferably, when it is an acquisition module, the optical exciter 202 of the implantable probe A2 can be used to excite the fluorescent signal reflecting the nerve activity, and the detector 204 of the implantable probe A2 can be used to collect the fluorescent signal to obtain the neural activity. For activity information, the control circuit can be used to receive neural activity information, and process and control the neural activity information to obtain regulatory information; when it is a reproduction module, the control circuit is used to drive the optical sensor of the implantable probe A2 according to the regulatory information. The exciter 202 is used to activate the brain region by optogenetics. At this time, the detector 204 of the implanted probe A2 may not work.

In an optional embodiment, the optical exciter 202 of the implanted probe A2 excites a fluorescent signal reflecting neural activity, which is actually a fluorescent reaction of calcein in the brain tissue. The current of the photoelectric signal collected by the detector 204 of the implanted probe A2 is related to the concentration of calcein. The curves of the current changing with the concentration of calcein in different simulated brain tissues are shown in Figure 8. It can be seen that when the concentration of calcein is 0 μM, 100 μM, 200 μM, and 250 μM, the photocurrent collected by the micro-detector is 0, 60nA, 90nA, 160nA, the photocurrent changes linearly with the concentration of calcein, and the current value can be used to reflect the concentration of calcein.

In an optional embodiment, the relative optical signal intensity varies with the molar concentration of calcium ions in calcein when there is no dye filter, as can be seen in Figure 9. It can be seen that when the calcium ions in calcein are not saturated, the light intensity As the molar concentration of calcium ions rises, it reaches saturation at 0.8, and the detector 204 with the dye filter slope has higher detection sensitivity to light intensity.

In an optional embodiment, the control circuit connected to the implanted probe A2 tests the current of the detector 204 in real time under different light intensities, as shown in FIG. 10 . It can be seen that as the light intensity increases, the detector The photocurrent detected by 204 rises in real time, which can realize real-time detection of fluorescence intensity.

In an optional embodiment, the implantable probe A2 and the control circuit provided by this embodiment form an acquisition module or a reproduction module, wherein the implantable probe A2 directly contacts with neurons in the brain as a front end to realize photoelectric Signal photoelectric signal acquisition or regulation, wherein, the control circuit realizes signal processing and conversion and wireless communication functions.

An implantable probe A2 provided in the second embodiment of the present application includes a detector 204, an optical exciter 202, and a flexible probe body 201; the optical exciter 202 is integrated in the flexible probe body 201, and is used to excite and reflect neural activity. the fluorescent signal; the detector 204 is integrated in the flexible probe body 201, and is used to collect the fluorescent signal to obtain nerve activity information and transmit it to the control circuit; at least one side of the flexible probe body 201 is provided with a heat-conducting material, which is used for flexible The devices on the probe body 201 dissipate heat. Therefore, an implantable probe A2 provided in the second embodiment of the present application uses a flexible probe, and the flexible probe is provided with a thermally conductive material for dissipating heat from the device on the flexible probe. Therefore, the second embodiment of the present application An implantable probe A2 provided in this example can improve the mechanical mismatch between the implantable probe A2 and brain tissue, reduce the incidence of biological tissue inflammation, and also improve the heat dissipation performance of the implantable probe A2. Thereby, biocompatibility can be improved.

Third embodiment:

Fig. 11 is a schematic flowchart of a method for preparing an implantable probe provided in the third embodiment of the present application. In order to clearly describe the preparation method of the implantable probe provided in the third embodiment of the present application, please refer to FIG. 11 .

The third embodiment of the present application provides a method for preparing an implantable probe, including:

S11: Deposit a thermally conductive material on at least one side of the flexible substrate to obtain a target flexible substrate.

In an optional embodiment, step S11: depositing a thermally conductive material on at least one side of the flexible substrate to obtain the target flexible substrate may include: respectively depositing a thermally conductive material on two opposite sides of the flexible substrate to obtain the target flexible substrate. A heat conduction layer is respectively formed on two opposite surfaces of the substrate to obtain a target flexible substrate.

In an optional implementation manner, the flexible substrate may include one of a PI substrate, a PT substrate, and a PTMS substrate.

In an optional implementation manner, the thermally conductive material may include one of thermally conductive metal materials and thermally conductive non-metallic materials. Among them, heat-conducting metal materials, such as copper, silver, aluminum and so on. Among them, thermally conductive non-metallic materials, such as graphite, diamond, boron nitride, silicon dioxide and so on.

In an optional embodiment, thermally conductive materials are respectively deposited on opposite sides of the flexible substrate to respectively form a thermally conductive layer on the opposite sides of the flexible substrate to obtain the target flexible substrate, for example, on a flexible PI substrate Copper is deposited on both sides to obtain the target flexible substrate (wherein, the thickness of the target flexible substrate is, for example, 18um copper/25um PI substrate/18um copper).

S12: disposing the optical exciter on the target flexible substrate.

In an optional implementation manner, the optical exciter may include, but is not limited to, one of micro LEDs and micro laser diodes. Specifically, the optical exciter can be used as a switching mode to stimulate the brain after the implantable probe is implanted in the biological brain area.

In an alternative embodiment, the micro-LEDs may be InGaN-based LEDs.

In an optional implementation manner, step S12: after the step of arranging the optical exciter on the target flexible substrate, may include: performing an optical filter formation process using silicon dioxide for the optical exciter to form a filter on the optical exciter. light sheet. Specifically, the optical exciter integrated with a filter can optimize its transmittance (transmittance > 85%) for light with a wavelength between 420nm and 490nm. Taking micro-LEDs as an example, compared with micro-LEDs without integrated filters, the monochromaticity of micro-LEDs integrated with filters has been improved to a certain extent, and the stray light attenuation in the green light region with a wavelength of 500nm is obvious.

In other optional implementation manners, step S12: arranging the optical exciter in the target flexible substrate may include: arranging the optical exciter and the detector on the target flexible substrate using PDMS stamp transfer technology. For example, detectors (eg, 195um*140um*3.5um in size) and optical exciters (eg, 125um*185um*7um in size) are disposed on the target substrate by PDMS stamp transfer technology.

In other optional implementation manners, the detector may be a miniature InGaP-based detector, or other traditional detectors.

In other optional embodiments, after the step of disposing the optical exciter and the detector on the target flexible substrate using PDMS stamp transfer technology, it may include: doping dyes in the photoresist to obtain a dye photoresist; The detector uses a dye photoresist to perform a filter forming process to form a dye filter on the detector, wherein the filter forming process is at least one of spin coating, photolithography, and film hardening. Specifically, the dye filter can reduce the interference of the blue LED to the detector, and the detector integrated with the dye filter can produce better response to different light intensities.

S13: Processing the target flexible substrate provided with an optical exciter to make an implantable probe, wherein the processing includes at least one of photolithography, metal deposition, laser cutting, packaging, implantation The type probe includes an optical exciter and a flexible probe body.

In other optional embodiments, step S13: processing the target flexible substrate provided with an optical exciter to make an implantable probe may include: The target flexible substrate is processed to make an implantable probe, wherein the implantable probe includes a detector, an optical exciter and a flexible probe body (such as the implantable probe described in the second embodiment ). For example, after the detector (for example, 195um*140um*3.5um in size) and the optical exciter (for example, 125um*185um*7um in size) are arranged on the target substrate, processing (for example, photolithography, metal deposition , laser cutting package, etc.) to obtain implantable probes (dimensions such as about 420um in width/about 140um in thickness/about 5mm in length).

A method for preparing an implantable probe provided in the third embodiment of the present application includes: S11: depositing a thermally conductive material on at least one side of a flexible substrate to obtain a target flexible substrate; S12: disposing an optical exciter on the target flexible substrate Substrate; S13: Processing the target flexible substrate provided with an optical exciter to make an implantable probe, wherein the processing includes at least one of photolithography, metal deposition, laser cutting, and packaging , the implantable probe includes an optical exciter and a flexible probe body. Therefore, the preparation method of the implantable probe provided in the third embodiment of the present application can obtain a flexible implantable probe integrated with an optical exciter by performing processes such as photolithography, metal deposition, laser cutting and packaging on the flexible substrate. Needle (implantable probe as described in the first embodiment) or flexible implantable probe integrated with detector, optical exciter (implantable probe as described in the second embodiment), therefore, using The implantable probe obtained by the preparation method of the implantable probe provided in this example can improve the mechanical mismatch between the implantable probe and the brain tissue, reduce the occurrence rate of biological tissue inflammation, and also improve the The heat dissipation performance of the implanted probe can improve biocompatibility.

Fourth embodiment:

FIG. 12 is a schematic diagram of the first structure of the control circuit provided by the fourth embodiment of the present application. FIG. 13 is a second structural schematic diagram of the control circuit provided by the fourth embodiment of the present application. FIG. 14 is a third structural schematic diagram of the control circuit provided by the fourth embodiment of the present application. FIG. 15 is a fourth structural schematic diagram of the control circuit provided by the fourth embodiment of the present application. In order to clearly describe the control circuit provided by the fourth embodiment of the present application, please refer to FIG. 1 to FIG. 15 .

Referring to FIG. 12 or FIG. 13 , the fourth embodiment of the present application provides a control circuit, including a power supply module M1, a communication module M2, and a control module M3; the power supply module M1 is connected to the control module M3 for supplying power to the control module M3; The communication module M2 is connected with the control module M3, and is used to receive regulation information or send the data collected and/or regulation information of the implantable probe as described in the first embodiment or the second embodiment; the control module M3 is connected with the first The implantable probe described in the embodiment or the second embodiment is connected to control the operation of the optical exciter and/or the optical detector in the implantable probe.

In an optional implementation manner, the power supply module M1 may include a power supply battery S1 and a filter capacitor C1. Wherein, the negative pole of the power supply battery S1 is grounded, and the positive pole of the power supply battery S1 is connected to the control module M3, wherein the filter capacitor C1 is connected in parallel with the power supply battery S1 to implement battery filtering.

In an optional implementation manner, the communication module M2 is a wireless communication module or a wired communication module. Wherein, the wireless communication module may include a communication antenna.

In an optional implementation manner, the wireless communication module may implement communication in a 2.4GHz wireless manner.

In an optional implementation, the control module M3 may include a main control chip IC1 and an excitation light control chip IC2; the main control chip IC1 is connected to the optical exciter through the excitation light control chip IC2, and is used to control the optical excitation through the excitation light control chip IC2. The excitation light parameters of the exciter are controlled, and the excitation light parameters include any one or more of excitation light intensity, duty cycle, period, and luminescence time.

In an optional implementation, the model of the main control chip IC1 is nRF24LE1; the model of the excitation light control chip IC2 is ZLED7012;

In an optional implementation manner, both the main control chip IC1 and the excitation light control chip IC2 are connected to the positive pole of the power supply battery S1 in the power supply module M1.

In an optional embodiment, the control module M3 further includes a working indicator D1; the working indicator D1 shares anode or cathode with the optical exciter, and is used to indicate the working state of the optical exciter. In this embodiment, the working indicator D1 and the optical exciter preferably have a common anode.

In an optional embodiment, the working indicator D1 can be obtained by covering a light-emitting device with a fluorescent film of a specific color. Among them, the fluorescent film of a specific color can choose a fluorescent film of a color that is not sensitive to the biological object to be tested. For example, the biological object to be tested is a mouse, and the mouse is sensitive to blue light, but not to red light, so red fluorescent film is selected. The film covers the light emitting device to obtain a red light working indicator D1. Among them, a light-emitting device is covered with a fluorescent film of a specific color, for example, a red fluorescent film is used to cover a commercial 0402-packaged blue LED to indicate the working status of the optical exciter after implantation. It can be known from the information of the excitation light control chip IC2 of ZLED7012 , the working current of the channels controlled by the constant current is the same, and when the commercial blue light LED and the implanted optical exciter (such as micro LED) have the same working mode, the indication function can be effectively realized.

In an optional embodiment, specifically, the optical exciter is implanted into the brain of the biological subject to be tested. When the stimulated brain area is relatively shallow, the optical exciter can be observed to light up from outside the brain, but when the stimulated brain area When the area is deep, it is difficult to directly observe whether the optical exciter is on or not from outside the brain. For example, the mouse is in an active state during the actual behavioral test. The existence of the working indicator D1 facilitates the recording of the working status of the implanted optical exciter. , and because the system is worn on the head of the mouse during the experiment, the blue light indicator may affect the vision of the mouse, and the mouse is not sensitive to red light, so the red light working indicator obtained by covering the light-emitting device with a red fluorescent film is selected D1, which converts the blue light of the blue LED into red light, has little effect on mice while indicating the working status of the implanted optical exciter.

In an optional implementation manner, referring to FIG. 12 , when the control module M3 is connected to the implantable probe described in the first embodiment, it is used to drive the optical exciter 102 in the implantable probe according to regulation information, To perform optogenetic activation on brain regions; see FIG. 13 , when the control module M3 is connected to the implanted probe described in the second embodiment, it is used to control the optical exciter 202 to excite fluorescent signals reflecting neural activity in real time, And receive the nerve activity information obtained after the detector 204 collects the fluorescent signal in real time, so as to process and control the nerve activity information to obtain regulation information, or to drive the optical exciter 202 in the implanted probe according to the regulation information, to Optogenetic activation of brain regions.

In an optional implementation, when the control module M3 is connected to the implantable probe described in the second embodiment, the main control chip IC1 is connected to the detector of the implantable probe, and is used to receive the data collected by the detector. Neural activity information is processed and controlled to obtain regulatory information.

In an optional embodiment, the control module M3 also includes a signal optimization unit; the signal optimization unit includes a filtering subunit L3 and a signal amplification subunit; the filtering subunit L3 is connected between the signal amplification subunit and the detector for After the neural activity information collected by the detector is filtered, the filtered neural activity information is transmitted to the signal amplification subunit; the signal amplification subunit is connected to the main control chip IC1, and is used to perform signal amplification processing on the filtered neural activity information to obtain The final neural activity information is transmitted to the main control chip IC1.

Referring to Fig. 13, in an optional implementation manner, the signal amplifying unit may include a transimpedance amplifier L1; the transimpedance amplifier L1 is connected with the filter subunit L3 and the main control chip IC1, and is used for signal amplification of the filtered neural activity information Process to obtain the final neural activity information, and transmit the final neural activity information to the main control chip IC1. For example, in this embodiment, the nerve activity information (such as photoelectric signal) collected by the detector is transmitted to the transimpedance amplifier L1 through the filtering subunit L3 (such as a capacitor-resistance low-pass filter) to obtain the final nerve activity information obtained after single-stage amplification processing. Activity information, so that the final neural activity information is transmitted to the main control chip IC1 for analog-to-digital conversion, digital filtering, feature extraction and other processing and control to obtain regulatory information.

In an optional implementation manner, the model of the transimpedance amplifier L1 may be LMP7721.

Referring to FIG. 14 , in another optional implementation manner, the signal optimization unit may include a transimpedance amplifier L1 and a buffer stage L2. Wherein, the transimpedance amplifier L1 includes a positive input terminal, a negative input terminal, an output terminal and a potential protection terminal (not shown in FIG. 14 ), wherein the negative input terminal of the transimpedance amplifier L1 is connected to the negative pole of the detector, and the transimpedance amplifier L1 The positive input terminal is connected to the positive terminal of the detector, and the output terminal of the transimpedance amplifier L1 is connected to the I/O port of the main control chip IC1. Wherein, the buffer stage L2 includes a positive input terminal, a negative input terminal and an output terminal, wherein the output terminal of the buffer stage L2 is connected to the negative input terminal of the buffer stage L2 (not shown in FIG. 14 ), and the positive input terminal of the buffer stage L2 is connected to The positive input terminal of the transimpedance amplifier L1, the output terminal of the buffer stage L2 is connected to the potential protection terminal (not shown in Figure 14) of the transimpedance amplifier L1 to form a potential protection near the negative input terminal of the transimpedance amplifier L1, forming a filter subunit. Therefore, in this embodiment, the filtered neural activity information can be transmitted to the transimpedance amplifier L1 and the buffer stage L2 to obtain the final neural activity information, and the final neural activity information can be transmitted to the main control chip IC1. For example, in this embodiment, the nerve activity information (such as photoelectric signal) collected by the detector is transmitted to the transimpedance amplifier L1 and the buffer stage L2 through the filtering subunit L3 (such as a low-pass filter of capacitance and resistance) to obtain the final nerve activity information after amplifying and processing. Activity information, so that the final neural activity information is transmitted to the main control chip IC1 for analog-to-digital conversion, digital filtering, feature extraction and other processing and control to obtain regulatory information.

In another optional implementation manner, the model of the buffer stage L2 in FIG. 14 may be ADA4505+1.

Referring to Fig. 15, in other optional implementation manners, the signal optimization unit may include a transimpedance amplifier L1, a buffer stage L2, and an amplification subunit L2'. Among them, the model of the transimpedance amplifier L1 is LMP7721; the models of the buffer stage L2 and the amplifier subunit L2' can both be ADA4505-2. Specifically, the buffer stage L2 is built by an amplifier model ADA4505-2 to form a potential protection at the photoelectric signal acquisition end to reduce the influence of noise signals on weak photoelectric signals.

This embodiment can realize the detection under different fluorescence intensities in the in vitro simulated brain tissue test, but in the biological in vivo experiment (that is, collecting the fluorescent signal from the biological brain), due to the complexity of the signal in the brain and the existence of individual differences, it needs to be based on According to the test results, adjust the magnification of the operational amplifier network and adjust the filter structure according to the actual noise. At this time, in addition to using the above model to build the buffer stage L2 for the ADA4505-2 amplifier to reduce noise and form an input protection potential, another model ADA4505-2 can also be used. An amplifier is cascaded with the transimpedance amplifier LMP7721 as the amplifying sub-unit L2' to form a multi-stage structure to further increase the gain of the amplifying unit. It should be understood that a single stage (or multiple stages) can be constructed according to the intensity of fluorescent signals in the brains of different organisms in actual experiments.

In another optional implementation manner, the filtering subunit L3 can implement a preliminary low-pass filtering process of the signal, and it can be composed of a common resistor-capacitor structure.

In an optional implementation manner, the control circuit may be connected to the implantable probe provided in the first embodiment or the second embodiment through an FPC interface connected from the bottom to the top.

A control circuit provided in the fourth embodiment of the present application includes a power supply module M1, a communication module M2, and a control module M3; the power supply module M1 is connected to the control module M3 for supplying power to the control module M3; the communication module M2 and the control module M3 connected, used to receive control information or send the data collected and/or control information of the implantable probe as described in the first embodiment or the second embodiment; the control module M3 and the control module M3 described in the first embodiment or the second embodiment The described implantable probe is connected to control the operation of the optical exciter and/or detector in the implanted probe. Therefore, the control circuit provided in this embodiment can realize the conversion of neural activity information and regulatory information, and control the optical exciter to excite the fluorescent signal reflecting neural activity in real time, and receive the neural activity information obtained after the detector collects the fluorescent signal in real time, In this way, the neural activity information is processed and controlled to obtain regulatory information, or used to drive the optical exciter in the implanted probe according to the regulatory information to activate optogenetic brain regions. Furthermore, this embodiment provides a convenient control method for the implantable probe described in the first embodiment or the second embodiment.

Fifth embodiment:

Fig. 16 is a schematic structural diagram of a control system provided by a fifth embodiment of the present application. Fig. 17 is a schematic diagram of an application scenario provided by the fifth embodiment of the present application. In order to clearly describe what is provided by the fifth embodiment of the present application, please refer to FIG. 16 and FIG. 17 .

Referring to FIG. 16 , the fifth aspect of the present application provides a control system, including a collection module K1 and a reproduction module K2 .

Wherein, the collection module K1 includes the implantable probe as described in the second embodiment and the control circuit as described in the fourth embodiment.

In an optional embodiment, the implantable probe included in the acquisition module K1 includes at least a detector, an optical exciter, and a flexible probe body; the optical exciter is integrated in the flexible probe body, and is used to excite fluorescent light reflecting neural activity. signal; the detector is integrated in the flexible probe body, and is used to collect fluorescent signals to obtain nerve activity information and transmit them to the control circuit; at least one side of the flexible probe body is provided with a thermally conductive material, which is used to The device dissipates heat.

In an optional implementation manner, the implantable probe in the acquisition module K1 can be connected to the control circuit K103 of the acquisition module K1 through an FPC interface connected from the bottom to the top.

Among them, the optical exciter K101 on the implanted probe of the acquisition module K1 is used to excite the fluorescent signal reflecting the neural activity, and the detector K102 on the implanted probe of the acquisition module K1 is used to collect the fluorescent signal to obtain the neural activity information.

In an optional embodiment, the optical exciter K101 in the collection module K1 can excite the green fluorescent signal reflecting the calcium ion concentration in real time when working, and the more intense the neuron activity in the corresponding brain area of the biological individual, the more the number of activated neurons In the case of , the greater the intensity of the green fluorescent signal detected by the detector K102 in the acquisition module K1, the detector K102 in the acquisition module K1 realizes the detection of the neural activity information of the corresponding brain area of the biological individual by collecting the change of the green fluorescence intensity in real time .

In an optional embodiment, at the brain area where the flexible probe tip of the acquisition module K1 is implanted, the activation degree of neurons can be reflected by the intensity of the fluorescent signal, and the neurons in the corresponding brain area are subjected to GCaMP green fluorescent calcium through genetic means. Indicator protein expression is achieved.

Wherein, the control circuit K103 of the acquisition module K1 is used to receive neural activity information, and process and control the neural activity information to obtain regulatory information.

In an optional implementation manner, the control circuit K103 of the acquisition module K1 may include: a power supply module, a communication module, and a control module; the power supply module is connected to the control module for supplying power to the control module; the communication module is connected to the control module for Send regulation information; the control module is connected with the implantable probe as described in the second embodiment, and is used to control the optical exciter in the implantable probe to excite the fluorescent signal reflecting neural activity, and at the same time control the implantable probe The detector in the needle collects fluorescent signals to obtain neural activity information, so as to process and control the neural activity information to obtain regulatory information.

In an optional implementation manner, the processing control includes at least one of analog-to-digital conversion, filtering, signal amplification, and signal conversion. Among them, the signal conversion includes classifying by means of support vector machine and converting it into frequency-carrying control information through a specific transfer function, and the frequency-carrying control information includes TTL pulse signal.

Wherein, the reproducing module K2 includes the implantable probe as described in the first embodiment or the second embodiment and the control circuit as described above.

In an optional embodiment, the implantable probe included in the reproduction module K2 includes at least: an optical exciter and a flexible probe body; the optical exciter is integrated in the flexible probe body for activating nerve activity by light; the flexible At least one side of the probe body is provided with a thermally conductive material, which is used to dissipate heat from devices on the flexible probe body.

Among them, the control circuit of the reproduction module K2 is used to receive the control information sent by the control circuit K103 of the acquisition module K1, and drive the optical exciter K201 in the implantable probe of the reproduction module K2 according to the control information, so as to control the brain area. Perform optogenetic activation. When the reproduction module K2 includes the detector K202, the detector K202 in the implantable probe of the reproduction module K2 may not work to realize the optogenetic stimulation function required for reproduction. When the reproducing module K2 includes a detector K202, the reproducing module K2 can be transformed into an acquisition module K1.

In an optional embodiment, the control circuit of the reproduction module K2 includes a power supply module, a communication module and a control module; the power supply module is connected to the control module for supplying power to the control module; the communication module is connected to the control module for receiving control Information; the control module is connected with the implantable probe as described in the first embodiment or the second embodiment, and is used to drive the optical exciter in the implantable probe to activate the brain region by optogenetics.

In an optional implementation manner, both the control circuit K203 of the reproduction module K2 and the control circuit K103 of the collection module K1 may include a wireless communication module, for example, communicate via 2.4GHz wireless.

In an optional embodiment, the control circuit K203 of the reproduction module K2 drives the optical exciter K201 (such as a blue LED) of the reproduction module K2 with light pulses to realize the optogenetic activation of the neural activity of the corresponding brain region of the biological individual.

In an optional embodiment, at the brain region where the tip of the flexible probe of the recurrence module K2 is implanted, the neurons can be activated by light of a specific wavelength, and the neurons in the corresponding brain region are treated with ChR2 photosensitive channel protein by genetic means. expression realized.

In an optional embodiment, based on the above-mentioned inventive concept, taking mice as an example of the experimental object, the following experimental structure can be obtained: Referring to Figure 17, the mouse is selected as the experimental organism individual, and the brain area is selected as the area involved in the predation behavior loop. In the LH brain area, the specific experimental test is that when the mouse carrying the acquisition module K1 preys on crickets spontaneously, the neurons in the LH brain area are activated, and the control system recognizes the occurrence of predation behavior, and transmits the control information to the reproduction module K2 through wireless communication. The mice of this reproduction module K2 passively produce the behavior of preying on crickets in real time.

The fifth aspect of the present application provides a control system, including an acquisition module K1 and a reproduction module K2; the acquisition module K1 includes the implantable probe as described in the second embodiment and the control circuit as described in the fourth embodiment ; Wherein, the optical exciter on the implanted probe of the collection module K1 is used to excite the fluorescent signal reflecting neural activity, and the detector on the implanted probe of the collection module K1 is used to collect the fluorescent signal to obtain neural activity information; where , the control circuit of the acquisition module K1 is used to receive neural activity information, and process and control the neural activity information to obtain regulatory information; the reproduction module K2 includes the implantable probe described in the first embodiment or the second embodiment And the control circuit as described above; wherein, the control circuit of the reproduction module K2 is used to receive the regulation information sent by the control circuit of the acquisition module K1, and drive the optical excitation in the implantable probe of the reproduction module K2 according to the regulation information for optogenetic activation of brain regions. Therefore, this embodiment can realize brain-to-brain nerve information regulation and communication, collect the nerve activity information in the brain through the acquisition module K1, obtain the regulation information through specific transfer function transformation, and drive the reproduction module K2 to generate corresponding nerve activity in the brain , wherein the neural activity information is reflected by the fluorescence intensity emitted by the neurons expressing the GCaMP fluorescent calcium indicator protein, and the neural activity reproduction is realized by the light activation of the neurons expressing the ChR2 photosensitive channel protein. In this embodiment, both the acquisition module K1 and the reproduction module K2 are composed of an implantable probe and a control circuit. The implantable probe is used as a front end to directly contact with neurons in the brain to realize photoelectric signal acquisition or regulation, and the control circuit realizes Signal processing and conversion and wireless communication functions. In addition, in this embodiment, the implanted probe has good biocompatibility and photoelectric properties, and has the ability to perform optogenetic stimulation and fluorescence detection of biological indicators in the brain; the control circuit needs to have weak signal processing conversion, The ability to simulate the front-end driver can meet the transmission rate requirements of wireless data communication in different scenarios.

Based on the above embodiments, the present application can realize real-time wireless information communication between brain and brain, through optogenetics technology and fluorescence detection technology, using miniature implantable probes to achieve information with higher spatial resolution and time resolution The process of acquisition and information regulation provides solutions for the research of neural circuits and the treatment of sensory damage diseases. Furthermore, this application can directly realize the communication between the brain-brain interface, realize the collection of neural information and the reproduction of neural activity, from the perspective of neural information processing, the characteristic information of neural information transmission is preserved to a large extent, and other The more complex mapping relationship construction process in the brain-interface. The method of optogenetics and calcium ion fluorescence intensity detection enables signal acquisition/stimulation to have higher spatial resolution and nerve cell specificity, and is more sensitive than systems using electrical signal detection and electrical stimulation. The control system is realized by wireless control circuit and miniature implantable probe, which is small in size and light in weight, can communicate in real time, and is more portable than functional magnetic resonance imaging.

The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.

It should be noted that, in this document, the term "comprising", "comprising" or any other variation thereof is intended to cover a non-exclusive inclusion, such that a process, method, article, element or device comprising a series of elements includes not only those elements, but also other elements not expressly listed, or elements inherent in such a process, method, article, element, or device. Without further limitations, an element defined by the phrase "comprising a..." does not exclude the existence of other identical elements in the process, method, article, element or device that includes the element. In addition, the present application Components, features, and elements with the same name in different embodiments may have the same meaning, or may have different meanings, and the specific meaning shall be determined based on the explanation in the specific embodiment or further combined with the context in the specific embodiment.

It should be understood that although the terms first, second, third, etc. may be used herein to describe various devices, information, etc., these devices, information, etc. should not be limited to these terms. These terms are only used to distinguish devices, information, etc. of the same type from each other. Depending on the context, the word "if" as used herein may be interpreted as "at" or "when" or "in response to a determination". Furthermore, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context indicates otherwise. It should be further understood that the terms "comprising", "comprising" indicate the presence of stated features, steps, operations, elements, components, items, species, and/or groups, but do not exclude one or more other features, steps, operations, The existence, occurrence or addition of an element, component, item, species, and/or group. The terms "or" and "and/or" as used herein are to be construed as inclusive, or to mean either one or any combination. Thus, "A, B or C" or "A, B and/or C" means "any of the following: A; B; C; A and B; A and C; B and C; A, B and C" . Exceptions to this definition will only arise when combinations of elements, functions, steps or operations are inherently mutually exclusive in some way.

The above are only preferred embodiments of the application, and are not intended to limit the application. Any modification, equivalent replacement or improvement made within the spirit and principles of the application shall be included in the protection scope of the application. Inside.

Claims (20)

1. An implantable probe comprising an optical exciter, a flexible probe body and a probe;

the optical exciter is integrated on the flexible probe body and used for exciting a fluorescence signal reflecting the neural activity or activating the neural activity through illumination;

at least one surface of the flexible probe body is provided with a heat conduction material, and the heat conduction material is used for dissipating heat of devices on the flexible probe body;

the detector is integrated with the flexible probe body, is a micro InGaP-based detector and is used for collecting fluorescence signals to obtain nerve activity information and transmitting the nerve activity information to the control circuit;

and a dye filter is integrated on the micro InGaP-based detector.

2. The implantable probe of claim 1, wherein the optical exciter comprises one of a micro LED, a micro laser diode.

3. The implantable probe of claim 2, wherein the micro LED is an InGaN-based LED.

4. The implantable probe of claim 2, wherein the optical energizer has integrated thereon a filter made of silicon dioxide.

5. The implantable probe of claim 1, wherein the flexible probe body is flat and has two opposing sides;

and two side surfaces of the flexible probe body are provided with heat conduction layers formed by the heat conduction materials.

6. The implantable probe of claim 1, wherein the thermally conductive material comprises one of a thermally conductive metallic material, a thermally conductive non-metallic material.

7. A method of making an implantable probe, comprising:

depositing a thermally conductive material on at least one side of a flexible substrate to obtain a target flexible substrate;

disposing an optical exciter and detector on the target flexible substrate;

processing the target flexible substrate provided with the optical exciter and the detector to manufacture the implanted probe, wherein the processing comprises at least one of photoetching, metal deposition, laser cutting and packaging, the implanted probe comprises the optical exciter, a flexible probe body and a detector, and the detector is a micro InGaP-based detector and is used for collecting fluorescence signals to obtain nerve activity information and transmitting the nerve activity information to a control circuit;

wherein the step of disposing an optical exciter and detector on the target flexible substrate is followed by:

performing a filter formation process using silicon dioxide for the optical exciter to form a filter on the optical exciter;

doping a dye into the photoresist to obtain a dye photoresist;

and performing a filter forming process on the detector by using the dye photoresist to form a dye filter on the detector, wherein the filter forming process comprises at least one of spin coating, photoetching and hardening.

8. The method of claim 7, wherein the step of depositing a thermally conductive material on at least one side of the flexible substrate to obtain the target flexible substrate comprises:

depositing the heat conduction materials on two opposite sides of the flexible substrate respectively to form heat conduction layers on the two opposite sides of the flexible substrate respectively to obtain the target flexible substrate.

9. The method of making an implantable probe of claim 7, wherein the flexible substrate comprises one of a PI substrate, a PT substrate, and a PTMS substrate.

10. The method of making an implantable probe according to any one of claims 7 to 9, wherein the step of disposing an optical exciter and detector on the target flexible substrate comprises:

and arranging the optical exciter and the detector on the target flexible substrate by using a PDMS stamp transfer technology.

11. A control circuit is characterized by comprising a power supply module, a communication module and a control module;

the power supply module is connected with the control module and used for supplying power to the control module;

the communication module is connected with the control module and is used for receiving regulation information and transmitting acquisition data of the implantable probe of any one of claims 1-6 and/or the regulation information;

the control module is coupled to the implantable probe of any one of claims 1-6 for controlling operation of the optical actuator and/or detector in the implantable probe.

12. The control circuit of claim 11, wherein the control module comprises a main control chip and an excitation light control chip;

the main control chip is connected with the optical exciter through the excitation light control chip and is used for controlling excitation light parameters of the optical exciter through the excitation light control chip, and the excitation light parameters comprise any one or more of excitation light intensity, duty ratio, period and light emitting duration.

13. The control circuit of claim 12, wherein the control module further comprises an operation indicator;

the working indicator is in common anode or cathode with the optical exciter and is used for indicating the working state of the optical exciter.

14. The control circuit of claim 12, wherein the main control chip is connected to the detector, and configured to receive the neural activity information collected by the detector, so as to process and control the neural activity information to obtain the regulation information.

15. The control circuit of claim 14, wherein the control module further comprises a signal optimization unit;

the signal optimization unit comprises a filtering subunit and a signal amplification subunit;

the filtering subunit is connected between the signal amplifying subunit and the detector, and is configured to filter the neural activity information acquired by the detector and transmit the filtered neural activity information to the signal amplifying subunit;

the signal amplification subunit is connected with the main control chip and is used for performing signal amplification processing on the filtered neural activity information to obtain final neural activity information and transmitting the final neural activity information to the main control chip.

16. The control circuit of claim 15, wherein the signal amplification subunit comprises a transimpedance amplifier;

the transimpedance amplifier is connected with the filtering subunit and the main control chip and is used for performing signal amplification processing on the filtered neural activity information to obtain final neural activity information and transmitting the final neural activity information to the main control chip.

17. The control circuit of claim 15, wherein the signal amplification subunit comprises a transimpedance amplifier and a buffer stage;

the transimpedance amplifier comprises a positive input end, a negative input end, an output end and a potential protection end, wherein the negative input end of the transimpedance amplifier is connected with the negative electrode of the detector, the positive input end of the transimpedance amplifier is connected with the positive electrode of the detector, and the output end of the transimpedance amplifier is connected with an I/O port of the main control chip;

the buffer stage comprises a positive input end, a negative input end and an output end, wherein the output end of the buffer stage is connected with the negative input end of the buffer stage, the positive input end of the buffer stage is connected with the positive input end of the transimpedance amplifier, the output end of the buffer stage is connected with the potential protection end of the transimpedance amplifier, so that potential protection is formed near the negative input end of the transimpedance amplifier to form the filtering subunit.

18. The control circuit of claim 17,

the model of the main control chip is nRF24LE1;

the type of the excitation light control chip is ZLED7012;

the type of the transimpedance amplifier is LMP7721;

the buffer stage is model ADA4505.

19. The control circuit of claim 11, wherein the communication module is a wireless communication module or a wired communication module.

20. A control system is characterized by comprising an acquisition module and a reproduction module;

the acquisition module comprises the implantable probe of any one of claims 1-6 and the control circuit of any one of claims 11-18;

the optical exciter on the implanted probe of the acquisition module is used for exciting a fluorescence signal reflecting nerve activity, and the detector on the implanted probe of the acquisition module is used for acquiring the fluorescence signal to acquire nerve activity information;

the control circuit of the acquisition module is used for receiving the neural activity information and processing and controlling the neural activity information to obtain the regulation and control information;

the recurrence module comprises the implantable probe of any one of claims 1-6 and the control circuit of any one of claims 11-13;

the control circuit of the recurrence module is used for receiving the regulation and control information sent by the control circuit of the acquisition module and driving an optical exciter in an implanted probe of the recurrence module according to the regulation and control information so as to carry out optogenetic activation on a brain region.

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