CN111938632B - Intra-brain signal acquisition device, preparation method thereof and brain-computer interface - Google Patents
Intra-brain signal acquisition device, preparation method thereof and brain-computer interface Download PDFInfo
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Abstract
The application relates to an intra-brain signal acquisition device, a preparation method thereof and a brain-computer interface, wherein the intra-brain signal acquisition device comprises a biological silk protein substrate; a brain electrode on the biological silk protein substrate; the brain electrode is used for collecting brain electrical signals; a first biological silk protein insulating layer located on the brain electrode; an intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure; and the biological silk protein packaging layer is positioned on the intracranial information acquisition layer. The brain signal acquisition device has the advantages of multifunction, implantation, in vivo degradation, long-term in vivo stable recording, high space-time resolution and the like, and not only can acquire brain electrical signals, but also can acquire intracranial information, thereby being capable of monitoring intracranial hemorrhage, intracranial infection and the like in real time.
Description
Technical Field
The application relates to the field of brain function detection, in particular to an intra-brain signal acquisition device, a preparation method thereof and a brain-computer interface.
Background
In the nervous system, a large number of neurons continuously generate and transmit electrophysiological signals to achieve signal communication between the neurons and different areas of the brain. The brain signal acquisition and recording is an indispensable research means in basic brain science and brain disease analysis and diagnosis, and the high-performance brain signal acquisition technology is not only beneficial to decoding the working principle of the brain, but also promotes a series of high-precision technological development based on the brain signal acquisition and recording, such as brain-computer interface research, nerve regulation technology and the like. In the last decade, the advent of several different kinds of neural electrode technology, which are capable of more accurate, detailed and long-term recording of the activity of neuronal populations, has been driven by national and international policy initiatives and the maturation of silicon-based electronics industry manufacturing technologies.
Brain electrodes are generally classified into non-invasive, semi-invasive and invasive according to the difference between the implantation site and the information acquisition mode, the non-invasive scalp brain electrode (acquiring EEG signals) is directly attached to the scalp without surgery, but the acquired signals are inaccurate due to the attenuation of the skull obstruction; the semi-invasive cortical brain electrode (for collecting ECoG signals) is attached to the cortex, and the brain electrical signal is accurate; invasive deep electrodes (acquiring LFP, spikes signals) are directly implanted into deep brain, and the spatial distance closer to target neurons enables the deep brain to have higher spatial resolution, detection accuracy and signal-to-noise ratio. It can be seen that, by minimally invasive implantation, an implanted deep electrode with long-term in-vivo safety and high-throughput electroencephalogram signal acquisition is gradually becoming one of the mainstream technologies of future brain science research.
Currently, the history of the development of implantable deep electrodes has also undergone iterative updates of materials and continual advances in performance. The earliest implanted electrode capable of recording brain activities for a long time is made of insulated microfilaments, and the used materials are heavy metals such as tungsten, nickel-chromium, platinum-iridium alloy and the like which have good biocompatibility and are not easy to corrode, so that the requirement of long-term use is met. Compared with the metal electrode, the silicon-based microelectrode represented by the Michigan electrode and the Utah electrode has better biocompatibility and good mechanical property, thereby having wider clinical and research application. The Michigan electrode is an electrode manufactured based on a silicon plane, a plurality of nerve recording sites are arranged on the surface of a single-handle electrode, a formed high-density electrode array can record a large number of electroencephalogram signals at the same time, and electroencephalogram recording in a three-dimensional space can be realized. The Utah electrode is manufactured based on a Micro-Electro-MECHANICALSYSTEM, MEMS (Micro-Electro-MECHANICALSYSTEM, MEMS) processing technology, a recording point electrode array is arranged at the tip, the characteristics of high density, high flux, small volume and the like are achieved, and the discharge signals of tens or hundreds of neurons can be collected at the same time, so that the requirements of most neurophysiologic experiments are met. Utah electrodes are approved by the U.S. Food and Drug Administration (FDA) for in vivo recording studies for human brain signal recording, for effective chronic in vivo recording times of up to 3 months or more, because of excellent biocompatibility and in vivo safety.
On the one hand, the two electrodes are hard and inflexible electroencephalogram recording and monitoring electrodes, and after the electrodes are implanted into brain tissues through surgery, relative micro-movement occurs between the electrodes and the brain tissues and inflammatory reaction is caused due to the difference of size and mechanical properties, so that long-term in-vivo stable reading of nerve electrophysiological signals is difficult to realize. On the other hand, the surface furrows of primate cerebral cortex are dense, so that the plane electrode can not be used for measuring signals in a large range, and can only be used for measuring the brain electrical nerve signals in a micro-area.
In addition, for the cortical brain electrode which is used for craniotomy and is not degradable, the craniotomy with great trauma is usually required to be carried out firstly when the craniotomy is used, and the brain electrode is also required to be removed and the wound is sutured when the monitoring task is completed. However, for some patients who need to monitor cortex brain electrical signals for a long period of time, it is necessary to keep brain electrodes in the brain and suture them, and at the same time, observe the brain electrical signals for a long period of time, and remove the electrodes after the recovery by secondary craniotomy, which increases the pain of the patient to some extent. Brain electrodes have evolved to date, undergoing a re-invasive craniotomy type nondegradable brain electrode, a re-invasive and degradable brain electrode, and a minimally invasive implantable and nondegradable brain electrode. Minimally invasive implantable and long-term monitoring of non-degradable nerve electrodes reported in the prior literature still remains to be improved in terms of: 1) Most of the currently reported electroencephalogram signal acquisition tools have single functions or have related functions but poor integration, and cannot synchronously measure physiological and medical information such as intracranial pressure and intracranial Wen Dengchong in real time; 2) For some applications, although the pain suffered by the patient during craniotomy is relieved by implanting the intracranial nerve electrodes through a new minimally invasive surgery, the related electrodes still need to be eliminated through a secondary surgery after the electrode monitoring task is completed, and the related electrodes need to be subjected to re-injury.
Disclosure of Invention
The embodiment of the application provides an electroencephalogram signal acquisition device, a preparation method thereof and a brain-computer interface, which have the advantages of multifunction, implantation, degradability, long-term in-vivo stable recording and the like, and solve the problems that the electroencephalogram signal acquisition device in the prior art has single function, cannot record in-vivo stable for a long time and the like.
In one aspect, an embodiment of the present application provides an intra-brain signal acquisition device, including:
A biological silk protein substrate;
A brain electrode on the biological silk protein substrate; the brain electrode is used for collecting brain electrical signals;
A first biological silk protein insulating layer located on the brain electrode;
An intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure;
And the biological silk protein packaging layer is positioned on the intracranial information acquisition layer.
Optionally, the biological silk protein packaging layer is doped with a specific sensitive enzyme and is used for being automatically degraded when an external trigger signal is received.
Optionally, the brain electrode is used for attaching to the surface of the cerebral cortex to collect brain electrical signals; or; the brain electrode is used for deep into the cerebral cortex to collect brain electrical signals.
Optionally, the intracranial information acquisition layer comprises a thermistor and a piezoresistor, the thermistor is used for acquiring intracranial temperature, and the piezoresistor is used for acquiring intracranial pressure;
A second biological silk protein insulating layer is arranged between the thermistor and the piezoresistor.
Optionally, the thermistor material, the brain electrode material and the piezoresistor material are all in-vivo degradable metal conductive materials.
Optionally, the sum of the thickness of the biological silk protein substrate, the thickness of the brain electrode, the thickness of the first biological silk protein insulating layer, the thickness of the intracranial information acquisition layer and the thickness of the biological silk protein packaging layer is less than or equal to 20 micrometers.
Optionally, the material of the biological silk protein substrate or the material of the first biological silk protein insulating layer or the material of the biological silk protein packaging layer is in vivo degradable fibroin.
In another aspect, an embodiment of the present application provides a method for preparing an intra-brain signal acquisition device, including:
Obtaining a silicon substrate;
forming a sacrificial layer on a silicon substrate;
forming a biological silk protein substrate on the sacrificial layer;
forming a brain electrode on a biological silk protein substrate; the brain electrode is used for collecting brain electrical signals;
forming a first biological silk protein insulating layer on the brain electrode;
Forming an intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure;
Forming a biological silk protein packaging layer on the intracranial information acquisition layer;
releasing the sacrificial layer to obtain the brain signal acquisition device.
Optionally, a specific sensitive enzyme is incorporated into the biological silk protein encapsulation layer.
Optionally, the intracranial information acquisition layer comprises a thermistor and a piezoresistor, the thermistor is used for acquiring intracranial temperature, and the piezoresistor is used for acquiring intracranial pressure;
Forming an intracranial information acquisition layer on the first biological silk protein insulating layer, comprising:
growing a thermistor on the first biological silk protein insulating layer through a metal process;
forming a second biological silk protein insulating layer on the surface of the thermistor;
And forming the piezoresistor on the surface of the second biological silk protein insulating layer through a photoetching metal process.
Optionally, the material of the biological silk protein substrate is silk protein;
After forming the sacrificial layer on the silicon substrate, before forming the biogenic silk protein base on the sacrificial layer, comprising:
Obtaining a fibroin substrate;
Obtaining a fibroin substrate, comprising:
Cutting silkworm cocoons, placing the cut silkworm cocoons into a sodium carbonate solution, heating and stirring the cut silkworm cocoons, and degumming the cut silkworm cocoons to form silk;
Placing silk in ultrapure water, stirring, washing, kneading, repeating for several times, and drying;
Immersing the dried silk in a lithium bromide solution, and preserving heat for a certain time to obtain a mixed solution of fibroin and lithium bromide;
filling the mixed solution of fibroin and lithium bromide into a dialysis bag, and placing the dialysis bag into ultrapure water for dialysis;
After dialysis, carrying out centrifugal separation on the solution in the dialysis bag, and collecting supernatant to obtain fibroin solution;
And (3) solidifying and drying the fibroin solution to obtain the fibroin substrate.
On the other hand, the embodiment of the application provides a brain-computer interface, which comprises the brain-computer signal acquisition device, a flat cable and an external connector; one end of the flat cable is connected with the brain signal acquisition device, and the other end of the flat cable is connected with an external connector; and the external connector is used for being connected with an external brain signal output circuit.
The brain-computer interface and the preparation method thereof have the following beneficial effects:
the brain signal acquisition device comprises a biological silk protein substrate; a brain electrode on the biological silk protein substrate; the brain electrode is used for collecting brain electrical signals; a first biological silk protein insulating layer located on the brain electrode; an intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure; and the biological silk protein packaging layer is positioned on the intracranial information acquisition layer. The brain signal acquisition device has the advantages of multifunction, implantation, in vivo degradation, long-term in vivo stable recording, high space-time resolution and the like, and not only can acquire brain electrical signals, but also can acquire intracranial information, thereby being capable of monitoring intracranial hemorrhage, intracranial infection and the like in real time.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for the description of the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a schematic structural diagram of an intra-brain signal acquisition device according to an embodiment of the present application;
Fig. 2 is a schematic structural diagram of an intra-brain signal acquisition device according to an embodiment of the present application;
FIG. 3 is a schematic flow chart of a method for preparing an intra-brain signal acquisition device according to an embodiment of the present application;
FIGS. 4a to 4j are schematic diagrams of a preparation process of an intra-brain signal acquisition device according to an embodiment of the present application;
FIG. 5 is a schematic diagram of a brain-computer interface according to an embodiment of the present application;
Fig. 6 is a schematic structural diagram of an intra-brain signal acquisition device according to an embodiment of the present application;
Fig. 7 is a schematic diagram of an application structure of a brain-computer interface according to an embodiment of the present application.
Detailed Description
The following description of the embodiments of the present application will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
It should be noted that the terms "first," "second," and the like in the description and the claims of the present application and the above figures are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used may be interchanged where appropriate such that the embodiments of the application described herein may be implemented in sequences other than those illustrated or otherwise described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or server that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed or inherent to such process, method, article, or apparatus, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
Based on the problems in the prior art mentioned in the background art, the embodiment of the application provides a multifunctional implantable degradable brain-in signal acquisition device, a preparation method thereof and a brain-computer interface, utilizes transient electronic correlation technology to develop the degradable brain-in signal acquisition device integrating an electroencephalogram signal acquisition unit, an intracranial temperature sensing unit and an intracranial pressure sensing unit, and can realize minimally invasive implantation by selecting proper materials and a substrate structure with reasonable design.
Referring to fig. 1, fig. 1 is a schematic structural diagram of an intra-brain signal acquisition device according to an embodiment of the present application, where the intra-brain signal acquisition device includes:
A biological silk fibroin substrate 101;
A brain electrode 102 located on the biogenic silk fibroin base 101; the brain electrode 102 is used for collecting brain electrical signals;
a first biological silk protein insulating layer 103 on the brain electrode 102;
An intracranial information acquisition layer 104 on the first biological silk protein insulating layer 103; the intracranial information acquisition layer 104 is used for acquiring intracranial temperature and intracranial pressure;
A biological silk protein encapsulation layer 105 located on the intracranial information acquisition layer 104.
The brain signal acquisition device provided by the embodiment of the application not only can acquire brain signals through the brain electrode 102, but also can monitor the problems of intracranial hemorrhage, intracranial infection and the like in real time through the intracranial information acquisition layer 104, and solves the problem of single function of the existing brain signal acquisition device; secondly, the brain electrode 102 is embedded into the brain through a minimally invasive implantation brain signal acquisition device, and compared with the traditional brain electrode, the brain electrode has high space-time resolution, so that the requirements on the quality of brain electrical signals in practical application can be met; in addition, due to the biological silk protein packaging layer 105 prepared by taking the biological silk protein with a relatively good biocompatibility and a degradable material as a base material, on one hand, the brain electrode 102 can be protected to perform long-term stable work; on the other hand, because the biological silk protein can be automatically degraded in the organism, the patient does not need to undergo secondary operation to be eliminated after the acquisition task of the signal acquisition device in the brain is completed, thereby avoiding secondary injury.
The brain signal acquisition device provided by the embodiment of the application not only can analyze the acquired intracranial information to carry out brain disease related diagnosis, but also can be used for timely treatment of related brain diseases such as epilepsy by carrying medicines in a biological material substrate.
In an alternative embodiment, the bio-silk protein encapsulation layer 105 incorporates a specific sensitive enzyme. When an external trigger signal is received, the biological silk protein packaging layer 105 can be automatically degraded, so that controllable trigger degradation of the signal acquisition device in the brain can be realized.
In an alternative way, the brain electrode 102 is used to acquire brain electrical signals deep into the cerebral cortex, in this case invasive brain electrodes, capable of acquiring LFP, spikes signals.
Specifically, the brain electrode 102 can be a flexible implanted brain electrode, and the flexible implanted brain electrode can solve the problem of co-adhesion with cerebral cortex tissues, so that high-precision acquisition of three-dimensional and large-range brain electrical nerve signals is realized.
In another alternative, the brain electrode 102 is used to collect brain electrical signals attached to the surface of the cerebral cortex, which is a semi-invasive brain electrode in this case, and can collect ECoG signals.
In the embodiment of the application, the micro-nano processing technology, the integrated MEMS technology and the transient soluble processing technology are adopted to integrate the brain electrode 102 and the intracranial information acquisition layer 104 to the brain signal acquisition device, so that the integrated monitoring of brain signal monitoring, intracranial pressure and intracranial temperature remote sensing can be realized, and the problem of single function of the traditional brain signal acquisition device is solved.
In an alternative, as shown in fig. 2, the intracranial information collection layer 104 includes a thermistor 1041 and a piezoresistor 1042, the thermistor 1041 is used for collecting intracranial temperature, and the piezoresistor 1042 is used for collecting intracranial pressure; a second biological silk protein insulating layer 1043 is arranged between the thermistor 1041 and the piezoresistor 1042.
In an alternative, the material of the thermistor 1041, the material of the brain electrode 102 and the material of the piezoresistor 1042 are all metal conductive materials degradable in vivo.
In particular, the in vivo degradable metallic conductive material may be iron or magnesium.
In the embodiment of the application, the biological silk protein substrate 101, the first biological silk protein insulating layer 103 and the biological silk protein packaging layer 105 are all made of degradable biological silk protein materials, the material of the thermistor 1041, the material of the brain electrode 102 and the material of the piezoresistor 1042 are made of in-vivo degradable metal conductive materials, and the biological silk protein packaging layer 105 is in-vivo degradable material, so that after the task of the brain signal acquisition device is completed, the brain signal acquisition device can be automatically degraded in vivo without taking out the brain signal acquisition device through secondary operations.
Optionally, the biological silk protein packaging layer 105 doped with the specific sensitive enzyme is degraded by opening an external trigger signal (such as light), so that the aim of self-degradation of the signal acquisition device in the brain is fulfilled.
In an alternative mode, the sum of the thickness of the biological silk protein substrate, the thickness of the brain electrode, the thickness of the first biological silk protein insulating layer, the thickness of the intracranial information acquisition layer and the thickness of the biological silk protein packaging layer is less than or equal to 20 micrometers. Namely, the whole brain signal acquisition device is prepared into an ultrathin flexible micro-nano device, and the ultrathin flexible micro-nano device is curled to the minimum volume in vitro so as to realize minimally invasive in-vivo implantation. The curled brain signal acquisition device can be unfolded in vivo as required, and the biological silk protein packaging layer 105 made of biological protein material can protect the brain signal acquisition device from long-term stable operation.
In an alternative mode, the material of the biological silk protein substrate or the material of the first biological silk protein insulating layer or the material of the biological silk protein packaging layer is in vivo degradable fibroin.
In the following, a specific embodiment of a method for manufacturing an intra-brain signal collecting device according to the present application is described, and fig. 3 is a schematic flow chart of a method for manufacturing an intra-brain signal collecting device according to an embodiment of the present application, where the method according to the embodiment or the flowchart provides the steps of operation, but may include more or less steps based on conventional or non-inventive labor. The order of steps recited in the embodiments is merely one way of performing the order of steps and does not represent a unique order of execution. As shown in fig. 3, the method may include:
s301: a silicon substrate is obtained.
S303: a sacrificial layer is formed on a silicon substrate.
S305: and forming a biological silk protein substrate on the sacrificial layer.
S307: forming a brain electrode on a biological silk protein substrate; the brain electrode is used for collecting brain electrical signals.
S309: a first biological silk protein insulating layer is formed on the brain electrode.
S311: forming an intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure.
S313: and forming a biological silk protein packaging layer on the intracranial information acquisition layer.
S315: releasing the sacrificial layer to obtain the brain signal acquisition device.
In an alternative embodiment, a specific sensitive enzyme is incorporated within the biological silk protein encapsulation layer.
In an alternative embodiment, the intracranial information collection layer comprises a thermistor for collecting intracranial temperature and a piezoresistor for collecting intracranial pressure.
In an alternative embodiment of forming an intracranial information collection layer over a first biological silk protein insulating layer, comprising: growing a thermistor on the first biological silk protein insulating layer through a metal process; forming a second biological silk protein insulating layer on the surface of the thermistor; and forming the piezoresistor on the surface of the second biological silk protein insulating layer through a photoetching metal process.
The preparation method of the brain signal acquisition device of the present application is described in detail below with reference to the accompanying drawings.
First, as shown in fig. 4a and 4b, a silicon substrate 401 is obtained, and a sacrificial layer 402 is grown on the surface of the silicon substrate 401. In the step, a silicon wafer is selected as a substrate material, a cleaning solution is adopted to clean the silicon substrate 401, and then phosphosilicate glass is grown on the surface of the silicon substrate 401 as a sacrificial layer 402. In other embodiments, the silicon substrate 401 and the sacrificial layer 402 may be made of other suitable materials, which is not limited herein.
Next, as shown in fig. 4c, a brain electrode material layer is grown on the surface of the sacrificial layer 402, and the brain electrode material layer is patterned to form a brain electrode 4031.
In an alternative embodiment, brain electrode 4031 may be fabricated using an in vivo degradable metallic conductive material (e.g., iron, magnesium, etc.) as the material.
Next, as shown in fig. 4d to 4e, a bio-silk protein substrate 404 is formed on the surface of the brain electrode 4031, and an electrode window is opened in the forming process for arranging a lead structure 4032 of the brain electrode 4031.
In the step, the brain electrode 4031 can be used for stimulating and generating brain electrical signals, and can also be used for detecting and collecting brain electrical signals; the brain electrode 4031 can be attached to the cerebral cortex, or can be prepared into a structure which can penetrate into the cerebral cortex, and the lead structure 4032 is used for connecting the brain electrode 4031 with various external monitoring devices; the biological silk protein substrate 404 can be prepared from a degradable biological material-fibroin with better biocompatibility.
In an alternative embodiment, the method comprises the step of obtaining a fibroin substrate; the method specifically comprises the following steps:
Cutting silkworm cocoons, placing the cut silkworm cocoons into a sodium carbonate solution, heating and stirring the cut silkworm cocoons, and degumming the cut silkworm cocoons to form silk; placing silk in ultrapure water, stirring, washing, kneading, repeating for several times, and drying; immersing the dried silk in a lithium bromide solution, and preserving heat for a certain time to obtain a mixed solution of fibroin and lithium bromide; filling the mixed solution of fibroin and lithium bromide into a dialysis bag, and placing the dialysis bag into ultrapure water for dialysis; after dialysis, carrying out centrifugal separation on the solution in the dialysis bag, and collecting supernatant to obtain fibroin solution; and (3) solidifying and drying the fibroin solution to obtain the fibroin substrate.
Next, as shown in fig. 4f, a varistor 4051 is formed on the surface of the bio-silk protein substrate 404 by a photolithographic metal process for acquiring intracranial pressure information.
In this step, the position of the piezoresistor 4051 is staggered relative to the position of the brain electrode 4031 and the lead structure 4032 thereof, so that the thickness of the whole device can be reduced; in other embodiments, a bio-silk protein insulating layer may be added between the piezo-resistor 4051 and the brain electrode 4031 and the lead structure 4032 thereof, for isolating the lead structure of each layer.
Next, as shown in fig. 4g, a bio-silk-protein insulating layer 406 is formed around the varistor 4051, and a window is opened in the varistor 4051 during the formation process for disposing the lead structure 4052 of the varistor 4051.
Next, as shown in fig. 4h, a thermistor 4071 is grown on the surface of the bio-silk protein insulating layer 406 by a metal process, and a lead structure 4072 thereof is provided for acquiring intracranial temperature information.
In this step, the thermistor 4071 is offset from the varistor 4051 and its lead structure 4052, so that the thickness of the whole device can be reduced; in other embodiments, a bio-silk protein insulating layer may be added between the thermistor 4071 and the varistor 4051 and the lead structure 4052 thereof, for isolating the lead structure of each layer.
Next, as shown in fig. 4i, a bio-silk protein encapsulation layer 408 is formed on the surface of the thermistor 4071 and the lead structure 4072 thereof.
In the step, the biological silk protein packaging layer 408 is prepared by taking a degradable material biological silk protein with better biocompatibility as a base material, and on one hand, the biological silk protein packaging layer 408 can protect the brain electrode 4031 to perform long-term stable work; on the other hand, because the biological silk protein can be automatically degraded in the organism, the patient does not need to undergo secondary operation to be eliminated after the acquisition task of the signal acquisition device in the brain is completed, thereby avoiding secondary injury.
Optionally, the biological silk protein packaging layer 408 is doped with specific sensitive enzyme, and after the acquisition task of the signal acquisition device in the brain is completed, the signal acquisition device in the brain can be automatically degraded by starting an external trigger signal (temperature, pH value and concentration), so that the controllable trigger degradation of the signal acquisition device in the brain is realized.
Next, as shown in fig. 4j, the sacrificial layer 402 is released, resulting in an intra-brain signal acquisition device.
In the embodiment of the application, the working principle of the signal acquisition signal in the brain is as follows: the brain electrode 4031 is implanted into the deep part of the cerebral cortex or is contacted with the surface of the cerebral cortex, and the brain electrical signals are collected in real time; meanwhile, the intracranial pressure and intracranial temperature information are collected in real time through the piezoresistor 4051 and the thermistor 4071; the electroencephalogram signal, intracranial pressure and intracranial temperature information are transmitted to various external monitoring devices through the lead structures 4032, 4052 and 4072, so that the long-term electroencephalogram signal observation is carried out on a patient, and meanwhile, the problems of intracranial hemorrhage, intracranial infection and the like can be monitored in real time; after the acquisition task of the intra-brain signal acquisition device is completed, the patient does not need to undergo secondary operation to eliminate, and the re-injury can be avoided due to the in-vivo degradability of the whole material of the intra-brain signal acquisition device.
The Brain-computer interface (Brain-computer interface) (Brain-ComputerInterface, BCI) of the Brain-computer signal acquisition device of the embodiment of the application can be applied to a Brain-computer interface, and relates to a core organ of human Brain. In terms of the "brain" in this technology, it generally refers to the brain or nervous system that has vital body activity; "machine" encompasses any external device capable of processing activities. In short, the brain-computer interface technology is to build a direct interactive information path between the brain of a living body and external equipment such as an electronic computer. The brain-computer interface technology is designed to have two modes of unidirectional transmission communication and bidirectional transmission communication.
As shown in fig. 5, fig. 5 is a schematic structural diagram of a brain-computer interface according to an embodiment of the present application, including an intra-brain signal acquisition device 501, a flat cable 502, and an external connector 503 in the above embodiment; one end of a flat cable 502 is connected with an intra-brain signal acquisition device 501, and the other end of the flat cable 502 is connected with an external connector 503; an external connector 503 for connecting an external intra-brain signal output circuit.
In the embodiment of the present application, the structure of the intra-brain signal acquisition device 501 of the brain-computer interface may refer to fig. 6 and the embodiment of the preparation method described above. The size of the brain signal acquisition device 501 can be customized according to actual requirements, and compared with the traditional brain signal acquisition device, the brain signal acquisition device has the advantages of smaller volume, lower impedance, thin implanted part of the electrode, small damage to brain tissues and the like.
In the embodiment of the application, the signal acquisition device 501 in the brain and the external connector 503 can be transmitted in one direction or in two directions; during unidirectional transmission, the brain-in signal acquisition device 501 transmits acquired brain-in signals, intracranial pressure information and intracranial temperature information to the external connector 503 through the flat cable 502, and then the brain-in signals are transmitted to the external brain-in signal output circuit through the external connector 503, so that brain-in signals are output; in the bidirectional transmission communication, other electronic devices are connected through the external connector 503, and the brain-computer interface can build a bidirectional information interaction platform between the brain and the external device, so as to facilitate the brain and the external device to carry out interactive communication.
The application process of the brain-computer interface obtained by the embodiment of the application is shown in fig. 7, an ultrathin flexible micro-nano brain signal acquisition device 501 is curled to the minimum volume in vitro, and the curled brain-computer chip can be unfolded in vivo as required by minimally invasive implantation into the brain of an organism, and a packaging layer made of a biological protein material is used for protecting the brain-computer signal acquisition device 501 to stably work for a long time; the intra-brain signal collection device 501 may transmit the collected brain electrical signal, intracranial pressure information, and intracranial temperature information to the external connector 503 through the flat cable 502, and output the above-mentioned intra-brain signal through an external intra-brain signal output circuit connected to the external connector 503 located outside the brain.
A long-term in-vivo recording experiment performed by implanting the brain-computer interface of the present application into the M1 region of the motor cortex of a C57 BL/6-line mouse is described as an example.
After anesthesia, the mice were shaved with hair, the scalp was cut and the connective tissue on the skull was removed. A small hole of 500 μm diameter is drilled in the motor cortex M1 and an intra-brain signal acquisition device 501 is implanted. And (3) dropwise adding phosphate buffer salt solution along the electrode by using a syringe, dissolving the coated biological silk protein substrate coated on the surface of the brain electrode, and withdrawing the micro tungsten wire for guiding the implantation direction. After about 3 minutes, a small amount of flexible bio-glue was added dropwise around the implantation site and the exposed skull surface was closed with dental cement. After 2-3 days, the brain electrical signals of the mice can be recorded, and meanwhile, the intracranial temperature and intracranial pressure information of the mice can be monitored.
The brain-computer interface and the brain-internal signal acquisition device embodiments in the embodiments of the present application are based on the same application concept.
It should be noted that: the sequence of the embodiments of the present application is only for description, and does not represent the advantages and disadvantages of the embodiments. And the foregoing description has been directed to specific embodiments of this specification. Other embodiments are within the scope of the following claims. In some cases, the actions or steps recited in the claims can be performed in a different order than in the embodiments and still achieve desirable results. In addition, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results. In some embodiments, multitasking and parallel processing are also possible or may be advantageous.
The foregoing description of the preferred embodiments of the application is not intended to limit the application to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the application are intended to be included within the scope of the application.
Claims (9)
1. An intra-brain signal acquisition device, comprising:
a biological silk protein substrate; the biological silk protein substrate is used for carrying medicines;
a brain electrode on the biological silk protein substrate; the brain electrode is used for stimulating to generate brain electrical signals and collecting the brain electrical signals;
a first biological silk protein insulating layer located on the brain electrode;
An intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure;
A biological silk protein packaging layer positioned on the intracranial information acquisition layer; the biological silk protein packaging layer is used for protecting the stable work of the signal acquisition device in the brain;
The biological silk protein packaging layer is doped with specific sensitive enzyme and is used for being automatically degraded when receiving an external trigger signal; the sum of the thickness of the biological silk protein substrate, the thickness of the brain electrode, the thickness of the first biological silk protein insulating layer, the thickness of the intracranial information acquisition layer and the thickness of the biological silk protein packaging layer is less than or equal to 20 micrometers.
2. The brain signal collection device according to claim 1, wherein the brain electrode is configured to collect the brain electrical signal by attaching to a surface of a cortex;
or; the brain electrode is used for penetrating into the cerebral cortex to collect the brain electrical signals.
3. The device of claim 1, wherein the intracranial information acquisition layer comprises a thermistor for acquiring the intracranial temperature and a piezoresistor for acquiring the intracranial pressure;
a second biological silk protein insulating layer is arranged between the thermistor and the piezoresistor.
4. The device of claim 3, wherein the thermistor, brain electrode and piezoresistor are all made of an in vivo degradable metallic conductive material.
5. The device of claim 1, wherein the material of the bio-silk protein substrate or the material of the first bio-silk protein insulating layer or the material of the bio-silk protein encapsulation layer is an in vivo degradable silk protein.
6. A method for preparing an intra-brain signal acquisition device, comprising:
Obtaining a silicon substrate;
Forming a sacrificial layer on the silicon substrate;
Forming a biological silk protein substrate on the sacrificial layer; the biological silk protein substrate is used for carrying medicines;
Forming a brain electrode on the biological silk protein substrate; the brain electrode is used for stimulating to generate brain electrical signals and collecting the brain electrical signals;
forming a first biological silk protein insulating layer on the brain electrode;
forming an intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure;
Forming a biological silk protein packaging layer on the intracranial information acquisition layer, wherein the biological silk protein packaging layer is used for protecting the stable work of the brain signal acquisition device; the biological silk protein packaging layer is doped with specific sensitive enzyme and is used for being automatically degraded when receiving an external trigger signal; the sum of the thickness of the biological silk protein substrate, the thickness of the brain electrode, the thickness of the first biological silk protein insulating layer, the thickness of the intracranial information acquisition layer and the thickness of the biological silk protein packaging layer is less than or equal to 20 micrometers;
and releasing the sacrificial layer to obtain the brain signal acquisition device.
7. The method of claim 6, wherein the intracranial information acquisition layer comprises a thermistor and a pressure sensitive resistor, the thermistor being configured to acquire the intracranial temperature,
The piezoresistor is used for collecting the intracranial pressure;
forming an intracranial information acquisition layer on the first biological silk protein insulating layer, comprising:
Growing the thermistor on the first biological silk protein insulating layer through a metal process;
forming a second biological silk protein insulating layer on the surface of the thermistor;
And forming the piezoresistor on the surface of the second biological silk protein insulating layer through a photoetching metal process.
8. The method of claim 6, wherein the material of the biological silk protein substrate is silk protein;
After the sacrificial layer is formed on the silicon substrate, before the biological silk protein base is formed on the sacrificial layer, the method comprises the following steps:
Obtaining a fibroin substrate;
the obtaining the fibroin substrate comprises the following steps:
Cutting silkworm cocoons, placing the cut silkworm cocoons into a sodium carbonate solution, heating and stirring the cut silkworm cocoons, and degumming the cut silkworm cocoons to form silk;
placing the silk in ultrapure water, stirring, washing, kneading, repeating for several times, and drying;
Immersing the dried silk in a lithium bromide solution, and preserving heat for a certain time to obtain a mixed solution of fibroin and lithium bromide;
Filling the mixed solution of fibroin and lithium bromide into a dialysis bag, and placing the dialysis bag into ultrapure water for dialysis;
After dialysis, carrying out centrifugal separation on the solution in the dialysis bag, and collecting supernatant to obtain fibroin solution;
and solidifying and drying the fibroin solution to obtain the fibroin substrate.
9. A brain-computer interface comprising the brain-in signal acquisition device of any one of claims 1-5, a flat cable, and an external connector; one end of the flat cable is connected with the intra-brain signal acquisition device, and the other end of the flat cable is connected with the external connector;
the external connector is used for being connected with an external brain signal output circuit.
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| CN202010795605.XA CN111938632B (en) | 2020-08-10 | Intra-brain signal acquisition device, preparation method thereof and brain-computer interface |
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| CN202010795605.XA CN111938632B (en) | 2020-08-10 | Intra-brain signal acquisition device, preparation method thereof and brain-computer interface |
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Non-Patent Citations (5)
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| Body-Integrated, Enzyme-Triggered Degradable, Silk-Based Mechanical Sensors for Customized Health/Fitness Monitoring and In Situ Treatment;Zhang, S (Zhang, Shan) [1] , [2] ; Zhou, ZT (Zhou, Zhitao) [1] ; Zhong, JJ (Zhong, Junjie) [3] ; Shi, ZF (Shi, Zhifeng) [3] ; Mao, Y (Mao, Ying) [3] ; Tao, TH (Tao, Tiger H.);《ADVANCED SCIENCE 》;20200708;第7卷(第13期);1-10 * |
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