CN111938632A - Intracerebral signal acquisition device, preparation method thereof and brain-computer interface - Google Patents
Intracerebral signal acquisition device, preparation method thereof and brain-computer interface Download PDFInfo
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Abstract
The application relates to an intracerebral signal acquisition device, a preparation method thereof and a brain-computer interface, wherein the intracerebral 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 bio-silk protein insulating layer positioned on the brain electrode; an intracranial information acquisition layer located on the first biofilin 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, can acquire electroencephalogram signals and intracranial information, and can monitor the problems of 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 intracerebral signal acquisition device, a preparation method thereof and a brain-computer interface.
Background
In the nervous system, a large number of neurons constantly generate and transmit electrophysiological signals to enable signal communication between the neurons and different areas of the brain. The electroencephalogram signal acquisition and recording is an indispensable research means in basic brain science and brain disease analysis and diagnosis, and the high-performance electroencephalogram signal acquisition technology is not only beneficial to the working principle of decoding the brain, but also promotes a series of high-precision scientific and technological development based on the electroencephalogram signal acquisition and recording, such as brain-computer interface research, nerve regulation and control technology and the like. In the last decade, driven by national and international policy initiatives and the maturation of silicon-based electronics industry manufacturing technologies, several different kinds of neural electrode technologies have emerged that are capable of more accurate, more detailed and longer-term recording of neuronal population activity.
The brain electrodes are generally divided into three types, namely non-invasive type, semi-invasive type and invasive type, according to different implantation positions and information acquisition modes, the non-invasive scalp brain electrodes (acquiring EEG signals) are directly attached to the scalp without operation, but the acquired signals are not accurate due to skull obstruction and attenuation; semi-invasive cortical brain electrodes (collecting ECoG signals) are attached to the cortex, and the brain electrical signals are accurate; the invasive deep electrode (collecting LFP and spike signals) is directly implanted into the deep part of the brain, and the space distance from the invasive deep electrode to the target neuron enables the invasive deep electrode to have higher spatial resolution, detection accuracy and signal-to-noise ratio. Therefore, through minimally invasive implantation, an implanted deep electrode with long-term in-vivo safety and high-flux brain electrical signal acquisition is gradually becoming one of the mainstream technologies of brain science research in the future.
At present, the development history of implantable deep electrodes also undergoes iterative updating of materials and continuous progress 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 metal electrodes, silicon-based microelectrodes represented by michigan electrodes and Utah electrodes have better biocompatibility and good mechanical properties, so that the silicon-based microelectrodes have wider clinical and research applications. 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, and a formed high-density electrode array can record a large number of electroencephalogram signals simultaneously, so that three-dimensional electroencephalogram recording can be realized. The Nitah electrodes are manufactured based on a Micro-Electro-Mechanical System (MEMS) processing technology, a recording point electrode array is arranged at the tip, and the Nitah electrodes have the characteristics of high density, high flux, small volume and the like, can simultaneously collect discharge signals of dozens of or even hundreds of neurons, and can sufficiently meet the requirements of most neuroelectrophysiology experiments. Because of excellent biocompatibility and in vivo safety, utah electrodes are approved by the U.S. Food and Drug Administration (FDA) for use in vivo recording studies for human brain signal recording, with effective chronic in vivo recording times of up to 3 months or more.
On one hand, however, after the two types of electrodes are hard and inflexible electroencephalogram recording and monitoring electrodes and are implanted into brain tissue through an operation, due to the difference between the size and the mechanical property, the electrodes and the brain tissue relatively move slightly and cause inflammatory reaction, and long-term in-vivo stable reading of the neuroelectrophysiological signals is difficult to realize. On the other hand, the surface grooves of the cerebral cortex of the primate are dense, so that the plane electrodes cannot measure signals in a large range generally and can only be used for measuring electroencephalogram and nerve signals in a micro-area.
In addition, for craniotomy use and non-degradable cortical electrodes, it is common to use a very invasive craniotomy procedure, which requires removal of the electrodes and suturing of the wound when the monitoring task is complete. However, for some patients needing long-term cortical electroencephalogram signal monitoring, the brain electrode needs to be kept in the brain and well sutured, meanwhile, long-term electroencephalogram signal observation is carried out, and after recovery, the electrode is cleared by opening the skull for the second time, so that the pain of the patients is increased to a certain extent. The brain electrode is developed to date, and is subjected to a heavily-invasive craniotomized non-degradable brain electrode, a heavily-invasive degradable brain electrode and a minimally-invasive implantable non-degradable brain electrode. The minimally invasive implantable and long-term monitoring non-degradable nerve electrode reported in the existing literature still has the following aspects to be improved urgently: 1) most of the electroencephalogram signal acquisition tools reported at present have single functions or have related functions but poor integration, and can not synchronously measure important biomedical information such as intracranial pressure, intracranial temperature and the like in real time; 2) for some applications, these nerve electrodes implanted into the cranium by a new minimally invasive surgery alleviate the pain of patients during craniotomy, but still need to be removed by a second operation after the electrode monitoring task is completed, and the related electrodes need to be damaged again.
Disclosure of Invention
The embodiment of the application provides an intracerebral signal acquisition device, a preparation method thereof and a brain-computer interface, which have the advantages of being multifunctional, implantable, degradable, capable of recording in-vivo stability for a long time and the like, and the problems that the intracerebral signal acquisition device in the prior art is single in function, incapable of recording in-vivo stability for a long time and the like are solved.
In one aspect, an embodiment of the present application provides an intracerebral 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 bio-silk protein insulating layer positioned on the brain electrode;
an intracranial information acquisition layer located on the first biofilin 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 encapsulation layer is doped with specific sensitive enzyme and is capable of degrading automatically when receiving an external trigger signal.
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 penetrating into 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 degradable metal conductive materials in vivo.
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 encapsulating layer is in vivo degradable silk protein.
On the other hand, the embodiment of the application provides a method for preparing an intracerebral signal acquisition device, which comprises the following steps:
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 the 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;
and releasing the sacrificial layer to obtain the intracerebral 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 biofilin insulating layer, comprising:
growing a thermistor on the first biological silk protein insulating layer by 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 by a photoetching metal process.
Optionally, the biological silk protein substrate is made of silk protein;
after forming a sacrificial layer on a silicon substrate and before forming a biological silk protein substrate on the sacrificial layer, the method comprises the following steps:
obtaining a fibroin substrate;
obtaining a fibroin substrate comprising:
cutting silkworm cocoon, heating in sodium carbonate solution, stirring, and degumming to obtain silk;
placing silk in ultrapure water, stirring, washing, kneading and drying, 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;
putting the mixed solution of the fibroin and the lithium bromide into a dialysis bag, and putting the dialysis bag into ultrapure water for dialysis;
after dialysis, performing centrifugal separation on the solution in the dialysis bag, and collecting supernatant to obtain a fibroin solution;
and (3) solidifying and drying the fibroin solution to obtain the fibroin substrate.
On the other hand, the embodiment of the present application provides a brain-computer interface, which includes the above-mentioned signal acquisition device in the brain, a flat cable, and an external connector; one end of the flat cable is connected with the intracerebral signal acquisition device, and the other end of the flat cable is connected with the external connector; and the external connector is used for connecting the external intracerebral signal output circuit.
The intracerebral signal acquisition device, the preparation method thereof and the brain-computer interface provided by the embodiment of the application have the following beneficial effects:
the intracerebral 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 bio-silk protein insulating layer positioned on the brain electrode; an intracranial information acquisition layer located on the first biofilin 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, can acquire electroencephalogram signals and intracranial information, and can monitor the problems of intracranial hemorrhage, intracranial infection and the like in real time.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
Fig. 1 is a schematic structural diagram of an intracerebral signal acquisition device provided by an embodiment of the present application;
fig. 2 is a schematic structural diagram of an intracerebral signal acquisition device provided by an embodiment of the present application;
fig. 3 is a schematic flow chart of a method for manufacturing an intracerebral signal acquisition device according to an embodiment of the present application;
FIGS. 4a to 4j are schematic diagrams illustrating a manufacturing process of an intracerebral signal acquisition device according to an embodiment of the present disclosure;
fig. 5 is a schematic structural diagram of a brain-computer interface according to an embodiment of the present application;
fig. 6 is a schematic structural diagram of an intracerebral signal acquisition device provided by an embodiment of the present application;
fig. 7 is a schematic structural diagram of an application of a brain-computer interface according to an embodiment of the present application.
Detailed Description
The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It should be noted that the terms "first," "second," and the like in the description and claims of this application and in the drawings described above are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used is interchangeable under appropriate circumstances such that the embodiments of the application described herein are capable of operation in sequences other than those illustrated or 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, 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 intracerebral signal acquisition device, a preparation method thereof and a brain-computer interface, and develops the degradable intracerebral signal acquisition device integrating an electroencephalogram signal acquisition unit, an intracranial temperature sensing unit and an intracranial pressure sensing unit by utilizing the transient electronic related technology, and minimally invasive implantation can be realized by selecting appropriate materials and a substrate structure with reasonable design.
Referring to fig. 1, fig. 1 is a schematic structural diagram of an intracerebral signal acquisition device according to an embodiment of the present application, where the intracerebral signal acquisition device includes:
a biological silk protein substrate 101;
a brain electrode 102 positioned on the biological silk protein substrate 101; the brain electrode 102 is used for collecting brain electrical signals;
a first bio-silk protein insulating layer 103 on the brain electrode 102;
an intracranial information acquisition layer 104 on the first biofilin insulating layer 103; the intracranial information collection layer 104 is used for collecting intracranial temperature and intracranial pressure;
a biofilin encapsulation layer 105 located on the intracranial information acquisition layer 104.
The brain signal acquisition device provided by the embodiment of the application can acquire electroencephalogram signals through the brain electrode 102, 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 that the existing brain signal acquisition device is single in function; secondly, the brain electrode 102 is deeply embedded into the brain through minimally invasive implantation of an intracerebral signal acquisition device, and compared with the traditional brain electrode, the brain electrode has high spatial-temporal resolution, so that the requirement on the quality of the electroencephalogram signal in practical application can be met; in addition, the biological silk protein encapsulation layer 105 prepared by taking the degradable material biological silk protein with good biocompatibility as a base material can protect the brain electrode 102 to work stably for a long time; on the other hand, because the biological silk protein can be degraded in the organism, the patient does not need to undergo secondary operation to eliminate after the acquisition task of the brain signal acquisition device is completed, thereby avoiding secondary injury.
The intracerebral signal acquisition device provided by the embodiment of the application can analyze the acquired intracranial information to diagnose the related brain diseases, and can be used for diagnosing the related brain diseases such as epilepsy in time by carrying the medicine in the biomaterial substrate.
In an alternative embodiment, the biofilin 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 mode, the brain electrode 102 is used to penetrate into the cerebral cortex to collect electroencephalogram signals, and at the time, the brain electrode is an invasive brain electrode and can collect LFP and Spikes signals.
Specifically, the brain electrode 102 can be flexibly implanted into a brain electrode, and the flexibly implanted brain electrode can solve the common-type attachment problem with cerebral cortex tissues, so that high-precision acquisition of brain electrical nerve signals in a three-dimensional large range is realized.
In another alternative, the brain electrode 102 is used to attach to the surface of the cerebral cortex to collect electroencephalogram signals, and at this time, the brain electrode is a semi-invasive brain electrode capable of collecting ECoG signals.
In the embodiment of the application, a micro-nano processing technology, an integrated MEMS technology and a transient soluble processing technology are adopted, and the brain electrode 102 and the intracranial information acquisition layer 104 are integrated on an intracerebral signal acquisition device, so that the integrated monitoring of electroencephalogram signal monitoring, intracranial pressure and intracranial temperature remote sensing can be realized, and the problem of single function of the traditional electroencephalogram signal acquisition device is solved.
In an alternative mode, as shown in fig. 2, the intracranial information acquisition layer 104 includes a thermistor 1041 and a varistor 1042, the thermistor 1041 is used for acquiring intracranial temperature, and the varistor 1042 is used for acquiring intracranial pressure; a second biological silk protein insulating layer 1043 is arranged between the thermistor 1041 and the piezoresistor 1042.
In an alternative mode, the material of the thermistor 1041, the material of the brain electrode 102 and the material of the piezoresistor 1042 are all degradable metal conductive materials in vivo.
Specifically, the degradable metal conductive material in the body can 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 made of in vivo degradable materials, so that the brain signal acquisition device can be degraded in vivo after completing tasks and is taken out without a secondary operation.
Optionally, the biological silk protein encapsulating layer 105 doped with the specific sensitive enzyme is degraded by turning on an external trigger signal (such as light), so that the purpose of self-degradation of the signal acquisition device in the brain is achieved.
In an optional 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 intracerebral signal acquisition device is prepared into an ultrathin flexible micro-nano device which is curled to the minimum volume in vitro so as to realize minimally invasive in-vivo implantation. The curled intracerebral signal acquisition device can be unfolded in vivo as required, and the biological silk protein packaging layer 105 made of biological protein materials can protect the intracerebral signal acquisition device from working stably for a long time.
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 encapsulating layer is in vivo degradable silk protein.
The following describes a specific embodiment of a method for manufacturing an intracerebral signal acquisition device according to the present application, and fig. 3 is a schematic flow chart of a method for manufacturing an intracerebral signal acquisition device according to the embodiment of the present application, and the present specification provides the method operation steps according to the embodiment or the flow chart, but may include more or less operation steps based on conventional or non-inventive labor. The order of steps recited in the embodiments is merely one manner of performing the steps in a multitude of orders and does not represent the only order of execution. Specifically, as shown in fig. 3, the method may include:
s301: and obtaining the silicon substrate.
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 the biological silk protein substrate; the brain electrode is used for collecting brain electrical signals.
S309: and forming a first biological silk protein insulating layer on the brain electrode.
S311: forming an intracranial information acquisition layer on the first biological silk protein insulating layer; the intracranial information collecting layer is used for collecting intracranial temperature and intracranial pressure.
S313: and forming a biological silk protein packaging layer on the intracranial information acquisition layer.
S315: and releasing the sacrificial layer to obtain the intracerebral signal acquisition device.
In an alternative embodiment, a specific sensitive enzyme is incorporated within the encapsulating layer of biological silk proteins.
In an alternative embodiment, the intracranial information acquisition layer comprises a thermistor for acquiring intracranial temperature and a varistor for acquiring intracranial pressure.
An optional embodiment of forming an intracranial information acquisition layer on the first biofilin insulating layer, comprising: growing a thermistor on the first biological silk protein insulating layer by 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 by a photoetching metal process.
The following describes in detail a method for manufacturing an intracerebral signal acquisition device according to the present invention 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 silicon substrate 401 is cleaned by a cleaning solution, and then phosphorosilicate glass is grown on the surface of the silicon substrate 401 to serve as a sacrificial layer 402. In other embodiments, other suitable materials may be selected for the silicon substrate 401 and the sacrificial layer 402, which is not limited herein.
Next, as shown in fig. 4c, a layer of electroencephalogram material is grown on the surface of the sacrificial layer 402 and patterned to form an electroencephalogram 4031.
In an alternative embodiment, the brain electrode 4031 may be made of a material that is degradable in vivo and is a conductive metal material (e.g., iron, magnesium, etc.).
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 during the formation for arranging the lead structure 4032 of the brain electrode 4031.
In this step, the brain electrode 4031 can be used for stimulating to generate an electroencephalogram signal, and can also be used for detecting and collecting the electroencephalogram signal; the brain electrode 4031 can be attached to the cerebral cortex or can be prepared into a structure which can be deep into the cerebral cortex, and the lead structure 4032 is used for connecting the brain electrode 4031 with various external monitoring equipment; the biological silk protein substrate 404 can be prepared from silk protein which is a degradable biological material with good biocompatibility.
In an alternative embodiment, a step of obtaining a fibroin substrate; the method specifically comprises the following steps: cutting silkworm cocoon, heating in sodium carbonate solution, stirring, and degumming to obtain silk; placing silk in ultrapure water, stirring, washing, kneading and drying, 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; putting the mixed solution of the fibroin and the lithium bromide into a dialysis bag, and putting the dialysis bag into ultrapure water for dialysis; after dialysis, performing centrifugal separation on the solution in the dialysis bag, and collecting supernatant to obtain a fibroin solution; and (3) solidifying and drying the fibroin solution to obtain the fibroin substrate.
Next, as shown in fig. 4f, a voltage dependent resistor 4051 is formed on the surface of the biologic silk protein substrate 404 by a photolithography metal process for collecting intracranial pressure information.
In this step, the position of the piezoresistor 4051 is relatively staggered from the positions 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 piezoresistor 4051 and the brain electrode 4031 and the lead structure 4032 thereof to isolate the lead structures of the respective layers.
Next, as shown in fig. 4g, a bio-silk protein insulation layer 406 is formed around the piezo-resistor 4051, and a window of the piezo-resistor 4051 is opened during the formation process for disposing the lead structure 4052 of the piezo-resistor 4051.
Next, as shown in fig. 4h, a thermistor 4071 is grown on the surface of the bio-silk protein insulation 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 structures of the respective layers.
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 encapsulation layer 408 is prepared by using a degradable material biological silk protein with good biocompatibility as a base material, on one hand, the biological silk protein encapsulation layer 408 can protect the brain electrode 4031 from long-term stable work; on the other hand, because the biological silk protein can be degraded in the organism, the patient does not need to undergo secondary operation to eliminate after the acquisition task of the brain signal acquisition device is completed, thereby avoiding secondary injury.
Optionally, the biological silk protein encapsulation layer 408 is doped with a specific sensitive enzyme, and after the acquisition task of the brain signal acquisition device is completed, the brain signal acquisition device can be degraded automatically by turning on an external trigger signal (temperature, pH value and concentration), so that the controllable trigger degradation of the brain signal acquisition device is realized.
Next, as shown in fig. 4j, the sacrificial layer 402 is released, and the signal acquisition device in the brain is obtained.
In the embodiment of the application, the working principle of the signal acquisition in the brain is as follows: the brain electrode 4031 is implanted in the deep part of the cerebral cortex or is contacted with the surface of the cerebral cortex, and electroencephalogram signals are collected in real time; meanwhile, the intracranial pressure and intracranial temperature information is collected in real time through the piezoresistor 4051 and the thermistor 4071; electroencephalogram, intracranial pressure and intracranial temperature information are transmitted to external various monitoring equipment through lead structures 4032, 4052 and 4072, so that long-term electroencephalogram observation can be performed on a patient, and meanwhile, problems of intracranial hemorrhage, intracranial infection and the like can be monitored in real time; after the acquisition task of the intracerebral signal acquisition device is finished, the patient does not need to undergo secondary operation for elimination, and the intracorporeal degradability of the whole material of the intracerebral signal acquisition device can avoid secondary injury.
The signal acquisition device in the Brain of the embodiment of the application can be applied to be made into a Brain-Computer Interface (BCI), and the BCI relates to a core organ of the human Brain. By "brain" in this art, it is meant broadly the brain or nervous system in which a living body is active; "machine" encompasses any external device capable of performing processing activities. In short, the brain-computer interface technology is to establish a direct interactive information channel between the brain of a living body and an external device such as an electronic computer. The brain-computer interface technology has two modes of one-way transmission communication and two-way transmission communication.
As shown in fig. 5, fig. 5 is a schematic structural diagram of a brain-computer interface provided in an embodiment of the present application, including an intracerebral signal acquisition device 501, a flat cable 502, and an external connector 503 in the foregoing embodiment; one end of the flat cable 502 is connected with the signal acquisition device 501 in the brain, and the other end of the flat cable 502 is connected with the external connector 503; and an external connector 503 for connecting an external intracerebral signal output circuit.
In the embodiment of the present application, reference may be made to fig. 6 and the above-described embodiment of the manufacturing method for the structure of the intracerebral signal acquisition device 501 of the brain-computer interface. 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 an 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 a single direction or in two directions; during unidirectional transmission, the brain signal acquisition device 501 transmits the acquired electroencephalogram signal, intracranial pressure information and intracranial temperature information to the external connector 503 through the flat cable 502, and then transmits the information to the external brain signal output circuit through the external connector 503, so as to output a brain signal; in the bidirectional communication, the external connector 503 is connected to other electronic devices, and the brain-computer interface can establish a bidirectional information interaction platform between the brain and the external devices, so as to facilitate the brain and the external devices to perform interactive communication.
The application process of the brain-computer interface obtained in the embodiment of the application is shown in fig. 7, the ultrathin flexible micro-nano intracerebral signal acquisition device 501 is curled to the minimum volume in vitro, the signal acquisition device is implanted into a biological brain through micro-invasion, the curled electroencephalogram chip can be unfolded in vivo as required, and a packaging layer made of a biological protein material is used for protecting the electroencephalogram integration device 501 from long-term stable work; the electroencephalogram integrated device 501 can transmit the acquired electroencephalogram signal, intracranial pressure information and intracranial temperature information to the external connector 503 through the flat cable 502, and output the intracerebral signal through an external intracerebral signal output circuit connected with the external connector 503 positioned outside the brain.
A long-term in vivo recording experiment, which was performed by implanting a brain-computer interface of the present application into the M1 region of the motor cortex of a C57BL/6 strain mouse, is described as an example.
After anesthesia, the mice were shaved of hair, the scalp was cut open and the connective tissue on the skull was removed. A small hole 500 microns in diameter is drilled in the motor cortex M1 and implanted with an intracerebral signal acquisition device 501. Dropping phosphate buffer saline solution along the electrode by using an injector, dissolving the drug-coated biological silk protein substrate wrapping 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-gel was dropped around the implant site and the bare skull surface was sealed with dental cement. The electroencephalogram signals of the mouse can be recorded after 2-3 days, and the intracranial temperature and intracranial pressure information of the mouse can be monitored.
The brain-computer interface in the embodiment of the present application is based on the same application concept as the brain signal acquisition device embodiment.
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 specific embodiments thereof have been described above. Other embodiments are within the scope of the following claims. In some cases, the actions or steps recited in the claims may 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 may also be possible or may be advantageous.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (12)
1. An intracerebral signal acquisition device, comprising:
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 bio-silk protein insulating layer on the brain electrode;
an intracranial information acquisition layer on the first biofilin insulating layer; the intracranial information acquisition layer is used for acquiring intracranial temperature and intracranial pressure;
a biologic silk protein encapsulation layer located on the intracranial information acquisition layer.
2. The device for collecting intracerebral signals according to claim 1, wherein the biological silk protein encapsulating layer is doped with a specific sensitive enzyme and is adapted to be self-degraded upon receiving an external trigger signal.
3. The device for acquiring an electroencephalogram according to claim 1, wherein the brain electrode is used for attaching to a surface of a cerebral cortex to acquire the electroencephalogram signal;
or; the brain electrode is used for penetrating into the cerebral cortex to collect the brain electrical signals.
4. The intracranial signal acquisition device as recited in claim 1, wherein the intracranial information acquisition layer comprises a thermistor for acquiring the intracranial temperature and a varistor for acquiring the intracranial pressure;
and a second biological silk protein insulating layer is arranged between the thermistor and the piezoresistor.
5. The intracerebral signal acquisition device according to claim 4, wherein the material of the thermistor, the brain electrode and the piezoresistor are all metal conductive materials that are degradable in vivo.
6. The intracerebral signal acquisition device according to claim 1, wherein the sum of the thickness of the biologic silk protein substrate, the thickness of the brain electrode, the thickness of the first biologic silk protein insulating layer, the thickness of the intracranial information acquisition layer and the thickness of the biologic silk protein encapsulation layer is less than or equal to 20 microns.
7. The device for collecting brain signals according to claim 1, wherein 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 encapsulating layer is in vivo degradable silk protein.
8. A method for preparing an intracerebral signal acquisition device, which is characterized by comprising the following steps:
obtaining a silicon substrate;
forming a sacrificial layer on the silicon substrate;
forming a biological silk protein substrate on the sacrificial layer;
forming a brain electrode on the 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;
and releasing the sacrificial layer to obtain the intracerebral signal acquisition device.
9. The method of claim 8, further comprising: and (3) incorporating a specific sensitive enzyme into the biological silk protein encapsulating layer.
10. The method of claim 8, wherein the intracranial information acquisition layer comprises a thermistor for acquiring the intracranial temperature and a piezoresistor for acquiring 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 by 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 by a photoetching metal process.
11. The method according to claim 8, wherein the material of the biological silk protein substrate is fibroin;
after the sacrificial layer is formed on the silicon substrate and before the biological silk protein substrate is formed on the sacrificial layer, the method comprises the following steps:
obtaining a fibroin substrate;
the obtaining of the fibroin substrate comprises:
cutting silkworm cocoon, heating in sodium carbonate solution, stirring, and degumming to obtain silk;
placing the silk in ultrapure water, stirring, washing, kneading and drying, repeating for a plurality of 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;
putting the mixed solution of the fibroin and the lithium bromide into a dialysis bag, and putting the dialysis bag into ultrapure water for dialysis;
after dialysis, performing centrifugal separation on the solution in the dialysis bag, and collecting supernatant to obtain a fibroin solution;
and curing and drying the fibroin solution to obtain the fibroin substrate.
12. A brain-computer interface comprising the intracerebral signal acquisition device of any one of claims 1 to 7, a cable, and an external connector; one end of the flat cable is connected with the intracerebral signal acquisition device, and the other end of the flat cable is connected with the external connector;
and the external connector is used for connecting an external intracerebral signal output circuit.
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