Flexible Sensors for Deep Brain Detection in Humans and Non-Human Primates and Preparation Methods

Abstract

The present invention provides a flexible sensor for deep brain detection in humans and non-human primates, comprising a flexible electrode and a flexible printed circuit board (flexible PCB); wherein the flexible electrode includes an implantation end and a pad area, the length of the implantation end is 50–70 millimeters, detection sites are distributed thereon, pads are distributed in the pad area, the detection sites are used for detecting nerve signals, the pads are used for welding with the flexible PCB, and the detection sites and the pads are connected by wires; the hierarchical structure of the flexible electrode includes a base layer, a conductive layer and an insulating layer, wherein the base layer and the insulating layer are parylene flexible films, and the conductive layer is composed of a chromium layer and a gold layer. The present invention also discloses a welding method for the flexible sensor, which uses a method of spot hot melting of solder to weld the flexible electrode and the flexible PCB. This welding method can achieve precise alignment and tight connection of the solder joints, the conduction rate of the sensor is good, and it can avoid the rupture and deformation of the flexible sensor. The flexible sensor prepared by the present invention has strong flexibility, high transparency, and small implantation damage, and can detect the brain nerve signals of humans and non-human primates for a long time.

Description

Technical Field

[0001] The present invention relates to the fields of neural sensors and biomedical engineering technologies, and particularly to a flexible sensor for collecting deep brain nerve signals of humans and non-human primates and a preparation method thereof. Background Art

[0002] The neural network system of the brain is precise and complex, having basic functions of regulating the activities of individual organs and perceiving motion, and also having advanced functions of processing emotions, learning and memory, and spatial navigation. High-resolution detection of deep brain nerve signals helps to deeply understand the mechanism of the brain's advanced cognitive functions, and is more helpful for revealing the pathogenesis of major brain diseases and accurately locating the functional lesions thereof. Micro-nano sensors prepared from novel flexible materials can detect nerve signals with high resolution and high sensitivity. Moreover, flexible sensors have excellent biological flexibility, high compatibility, little damage to brain tissue, and are easy to achieve long-term in-vivo detection. Developing long flexible sensors that can detect deep brain nerve signals of humans and non-human primates can provide more scientific basis for the diagnosis and treatment of clinical brain diseases. At present, micro-nano sensor arrays are mostly used for detecting nerve signals in the brains of rodents or the superficial layer of the brains of non-human primates, and it is difficult to collect deep brain nerve signals of humans or non-human primates, which has great limitations. Therefore, there is an urgent need for a flexible micro-nano sensor suitable for detecting deep brain nerve signals of humans and non-human primates. This helps to carry out basic research on the neural mechanism of the brain, deepen the understanding of the brain function and the mechanism of brain diseases, and has important scientific value for the diagnosis and treatment of clinical brain diseases. Summary of the Invention

[0003] (1) Technical Problems to be Solved

[0004] Based on the above problems and requirements, the present invention provides a flexible sensor for deep brain detection of humans and non-human primates and a preparation method thereof to alleviate the problem of the lack of sensors for detecting in-vivo deep brain nerve signals in the current clinical basic research field of the brain.

[0005] (2) Technical Solutions

[0006] To achieve the above object, as one aspect of the present invention, there is provided a flexible sensor for deep brain detection of humans and non-human primates, including a flexible electrode, which is composed of an implantation end and a pad area, wherein the implantation end is used for collecting and detecting deep brain nerve signals; a flexible printed circuit board (flexible PCB) is soldered to the pad area of the flexible electrode to transmit the detected nerve signals to an external recording system; wherein,

[0007] (1) The overall thickness of the flexible electrode is 10 - 15 microns; the length of the implanted end of the flexible electrode is 50 - 70 mm, the width is 400 - 500 microns, the overall pad area is rectangular, the side length is less than or equal to 10 mm, and the middle between the implanted end and the pad area is a trapezoidal transition connection area;

[0008] (2) There are 32 circular detection sites distributed at the tip of the implanted end of the flexible electrode. The detection sites are distributed along the two side edges of the tip, with 16 sites on each side. The diameter of the detection sites is 10 microns, the center distance from the edge is greater than or equal to 20 microns, and the center-to-center spacing between the detection sites is greater than or equal to 50 microns; a reference site is contained at the center position of the tip of the implanted end, which is a 15×1000 - micron rectangle; there is a through - hole at the top of the implanted end, with a diameter less than or equal to 60 microns, for guiding the electrode implantation;

[0009] (3) The pad area of the flexible electrode contains 34 pads. The pads are square with a size of 200×200 microns, and the pads are arranged in a matrix. The center - to - center spacing of the pads is greater than or equal to 400 microns;

[0010] (4) The detection sites and pads of the flexible electrode are connected by wires. The width of the wires is less than or equal to 5 microns, and the wire spacing is less than or equal to 5 microns;

[0011] (5) The flexible PCB material is polyimide, with a thickness of 1 - 2 microns; it has 34 solder joints, and the size and arrangement of the solder joints are the same as those of the pads of the flexible electrode. The flexible PCB and the pads of the flexible electrode are welded by solder - positioning hot - melting method.

[0012] Among them, the hierarchical structure of the flexible electrode includes three - layer structures: a base layer, a conductive layer, and an insulating layer; the base layer is located at the bottom, serving as the back side of the flexible electrode, with a thickness of 7 - 10 microns; the conductive layer is located on the base layer, with a thickness less than or equal to 1 micron, and the detection sites, wires, and pads are located within the conductive layer; the insulating layer is located on the conductive layer, with a thickness of 3 - 5 microns.

[0013] Among them, the base layer and the insulating layer are parylene films; the conductive layer includes a chromium bottom layer and a gold layer.

[0014] Among them, the solder - positioning hot - melting method includes the following steps:

[0015] (1) Fix the flexible PCB, apply solder paste on the surface of the solder joints, and place the solder on the solder joints in batches through a positioning stencil;

[0016] (2) Use a constant - temperature heating table to heat the back of the flexible PCB to melt the solder and make the solder weld on the surface of the solder joints;

[0017] (3) Apply solder paste on the surface of the pads of the flexible electrode, then place it against the front of the solder joints (already welded with solder) of the flexible PCB and align them one by one;

[0018] (4) Heat the back of the flexible PCB using a constant-temperature heating stage to remelt the solder and complete the soldering.

[0019] Among them, the solder is characterized in that it is solid micro solder balls or semi-solid solder paste, and the melting point is less than 150 °C.

[0020] Among them, the aperture size and arrangement pattern of the positioning holes of the positioning steel mesh need to be exactly the same as those of the flexible electrode pads.

[0021] Among them, the temperature of the constant-temperature heating stage is 130 - 250 °C.

[0022] As another aspect of the present invention, a method for preparing the flexible sensor as described above is provided, including the following steps:

[0023] (1) In a vacuum chamber, pyrolyze poly-p-xylene powder, and then deposit it as a transparent film on a silicon wafer carrier as a flexible electrode substrate;

[0024] (2) Use photolithography, evaporation, and stripping processes to prepare a chromium layer and a gold layer as conductive layers on the base layer;

[0025] (3) In a vacuum chamber, pyrolyze poly-p-xylene powder, and then deposit it as a transparent film on the base layer and the conductive layer as a flexible electrode insulating layer;

[0026] (4) Use photoresist as a mask protection, and use an oxygen plasma etching process to etch the insulating layer to expose the flexible electrode detection sites and pads;

[0027] (5) Use photoresist as a mask protection, and use an oxygen plasma etching process to etch the insulating layer and the base layer to determine the shape of the flexible electrode and release the flexible electrode;

[0028] (6) Weld the flexible electrode and the flexible PCB, and complete the encapsulation to make a flexible sensor.

[0029] Among them, in the preparation method, the air pressure in the vacuum chamber is less than 3 Pa; the poly-p-xylene powder is Parylene C type powder; the pyrolysis temperature is 650 - 750 °C; the deposition temperature is 25 °C; the viscosity of the photoresist is greater than 400 mPa·s; the power of the oxygen plasma etching is 50 - 100 W.

[0030] (III) Beneficial effects

[0031] It can be seen from the above technical solutions that the flexible neural sensor and the preparation method thereof for deep brain detection of humans and non-human primates have at least one or some of the following beneficial effects:

[0032] (1) The flexible sensor provided by this technical solution has an implantation end length of up to 70 mm, which can detect neural signals at all levels of the brains of humans and non-human primates; its detection site is only 10 microns, and the size of mature nerve cells in humans and non-human primates is dozens of microns. Therefore, this sensor can detect the signals of single nerve cells and has a very high spatial resolution; the maximum thickness of the implantation end of the sensor is 15 microns, which can greatly reduce the implantation damage and is beneficial to protecting the normal physiological functions of the brain.

[0033] (2) The material used for the flexible sensor is parylene film, which has very stable chemical properties, is resistant to acid and alkali corrosion, high temperature, and has high light transmittance. This flexible sensor can well adapt to the thermal environment of the brains of humans or non-human primates, and has low toxicity to nerve cells, greatly reducing the physiological reactions of acute inflammatory response and glial cell hyperplasia. This is beneficial to the stability of long-term implantation and ensures the detection quality of neural signals.

[0034] (3) The welding method provided by this technical solution has reliable welding and excellent conduction rate. The temperature used for this welding is much lower than the melting temperature of the Parylene C film, which can prevent damage to the sensor substrate and the insulating layer. Moreover, it avoids squeezing and pulling on the flexible sensor, can better ensure the integrity of the sensor, and ensure the performance of signal detection. At the same time, it can perform batch welding on the solder joints, greatly improving the welding efficiency. Brief Description of the Drawings

[0035] Figure 1 It is a schematic diagram of the morphological structure of the flexible neural sensor for deep brain detection of humans and non-human primates described in the embodiments of the present invention.

[0036] Figure 2 It is a schematic diagram of the solder positioning hot melting method described in the embodiments of the present invention.

[0037] Figure 3 It is a process flow chart of the preparation of the flexible neural sensor described in the embodiments of the present invention.

[0038] In the above drawings, the meanings of the reference numerals are as follows:

[0039] 1 - Implantation end of the flexible electrode; 2 - Pad area; 3 - Pad; 4 - Detection site; 5 - Lead wire; 6 - Guide hole; 7 - Positioning steel mesh; 8 - Polyimide flexible PCB; 9 - Solder; 10 - Constant temperature heating table; 11 - Arrangement of flexible electrode pads; 12 - Parylene bottom layer; 13 - Silicon wafer carrier; 14 - Conductive layer; 15 - Parylene insulating layer; 16 - Photoresist ①; 17 - Oxygen plasma etching; 18 - Photoresist ②; 19 - Flexible electrode. Detailed Embodiments

[0040] The present invention discloses a flexible sensor for deep brain detection in humans and non-human primates, which can achieve high-resolution acquisition of deep brain nerve signals in humans and non-human primates; on the other hand, it also discloses a new method for welding flexible sensors and flexible PCBs. The technical solution of the present invention helps to deepen the understanding of brain functions and the mechanisms of brain diseases, and has important scientific significance for the diagnosis and treatment of clinical brain diseases.

[0041] To make the objectives, technical solutions, and advantages of the present invention clearer and more understandable, the following further elaborates on the present invention in detail with reference to specific embodiments and the accompanying drawings.

[0042] It should be noted that in the description of the drawings or the specification, similar or identical parts are denoted by the same reference numerals. Moreover, in the drawings, the embodiments are presented in a simplified or convenient manner for marking. Furthermore, elements or implementation manners not depicted or described in the drawings are in forms known to those of ordinary skill in the art. Additionally, although this document may provide examples containing parameters with specific values, the parameters do not necessarily exactly equal the corresponding values, but may approximate the corresponding values within an acceptable error tolerance or design constraints.

[0043] In this embodiment, the flexible electrode part of the flexible sensor is as shown in Figure 1 (a), and includes: a flexible electrode implantation end 1 and a flexible electrode pad area 2. One end of the flexible electrode implantation end 1 is connected to the flexible electrode pad area 2, and the other end of the flexible electrode implantation end 1 is the implantation end tip. Among them, the flexible electrode implantation end 1 is used for deep brain nerve signal acquisition and detection; a flexible printed circuit board (flexible PCB) is welded to the pad area 2 of the flexible electrode to transmit the detected nerve signals to an external recording system. The overall thickness of the flexible electrode is 15 micrometers, the length of the implantation end is 60 millimeters, and the width is 500 micrometers; the length of the pad area is 6.5 millimeters, and the width is 3 millimeters; the implantation end and the pad area are connected by a trapezoidal transition area; an enlarged view of the pad area is as shown in Figure 1 (b), and 34 pads 3 are arranged on the pad area. The shape of the pad 3 is a square with a size of 200×200 micrometers, arranged in a matrix. The center-to-center distance between adjacent pads on the long side of the pad array is 850 micrometers, and the center-to-center distance between adjacent pads on the wide side is 425 micrometers; an enlarged view of the implantation end tip is as shown in Figure 1 (c), and 32 circular detection sites 4 are distributed along both sides of the implantation end tip. There are 16 sites on each side. The center of the site is 100 micrometers away from the edge, the diameter of the site is 10 micrometers, and the distance between adjacent detection sites 4 is 70 micrometers; the detection sites 4 and the pads 3 are connected one by one by wires 5. The width of the wire is less than or equal to 5 micrometers, and the wire spacing is less than or equal to 5 micrometers. A reference site is included at the center position of the implantation end tip, which is a rectangle with a size of 15×1000 micrometers. The specific shape and size of the detection sites 4 are as shown in Figure 1 (d); as shown in Figure 1As shown in (e), the tip of the implantation end has a guiding hole 6, which is a through hole with a diameter of 60 microns for guiding the implantation of the electrode, and thus can guide the implantation of the sensor.

[0044] In this embodiment, the hierarchical structure of the flexible electrode of the flexible sensor is composed of a base layer, a conductive layer, and an insulating layer; the base layer and the insulating layer are parylene films; the base layer is located at the bottom and serves as the back side of the flexible electrode with a thickness of 10 microns; the conductive layer is located on the upper surface of the base layer and is composed of a 30-nanometer chromium bottom layer and a 200-nanometer gold layer; the insulating layer is located above the conductive layer with a thickness of 5 microns. The detection site 4, the wire 5, and the pad 3 are located within the conductive layer.

[0045] In this embodiment, the parylene flexible electrode and the polyimide flexible PCB are welded by solder positioning and hot melting method, and a complete flexible sensor is obtained after encapsulation. The flexible PCB material is polyimide with a thickness of 1 - 2 microns; it has 34 solder joints, and the size and arrangement of the solder joints are the same as those of the flexible electrode pad 3. The flexible PCB and the flexible electrode pad are welded by solder positioning and hot melting method.

[0046] As Figure 2 shown, the welding steps include:

[0047] (a) Apply flux on the surface of the polyimide flexible PCB 8, place the positioning stencil 7 on the upper surface of the polyimide flexible PCB 8, and align the positioning holes of the stencil with the PCB solder joints one by one;

[0048] (b) Evenly spread the solder 9 on the positioning stencil, and the solder adheres to the PCB solder joints through the positioning holes; in this embodiment, the solder used is a micro low-temperature solder ball with a melting point of 138 °C;

[0049] (c) Place the polyimide flexible PCB with the adhered solder on the constant temperature heating table 10 at a temperature of 200 °C. When the solder melts, remove the PCB and let it cool down statically;

[0050] (d) Apply flux on the front surface of the flexible electrode pad 3, then attach it to the solder joints of the polyimide flexible PCB with the adhered solder obtained in the previous step, and align the flexible electrode pad 3 with the polyimide flexible PCB solder joints one by one. At this time, the solder should be located between the flexible electrode pad and the flexible PCB solder joints; among them, the arrangement 11 of the flexible electrode pads is as Figure 2 (d) shown.

[0051] (e) Place the whole of the flexible electrode and the flexible PCB on the constant temperature heating table 10 at a temperature of 200 °C. When the solder on the flexible PCB solder joints melts, gently press the flexible electrode pad with a micro tweezer to make the pad and the solder fully contact. Then turn off the heating table and let the solder cool and solidify to complete the welding.

[0052] In this embodiment, the preparation method of the deep brain flexible neural sensor is as follows: Figure 3 as shown:

[0053] (a) In a vacuum chamber, pyrolyze parylene powder at high temperature, and then deposit a low-temperature parylene bottom layer 12 with a thickness of 10 μm on the upper surface of the silicon wafer carrier 13 as the flexible electrode substrate; the silicon wafer carrier 13 only serves as the carrier of the thin film substrate and plays a supporting role, and does not belong to any part of the flexible sensor; in this embodiment, the parylene powder used is Parylene C type powder; the air pressure in the vacuum chamber is 0.09 Pa; the pyrolysis temperature is 650 °C; the deposition temperature is 25 °C;

[0054] (b) Prepare by using photolithography, evaporation and stripping processes. Deposit a 30-nm chromium bottom layer and a 200-nm gold layer on the upper surface of the base layer in sequence to complete the preparation of the conductive layer 14, and form the detection site 4, the wire 5 and the pad 3;

[0055] (c) In a vacuum chamber, pyrolyze parylene Parylene C powder at high temperature, and deposit a parylene insulating layer 15 with a thickness of 3 μm on the conductive layer at low temperature as the flexible electrode insulating layer; the air pressure in the vacuum chamber is 0.09 Pa; the pyrolysis temperature is 650 °C; the deposition temperature is 25 °C;

[0056] (d) Spin-coat photoresist ① 16 on the upper surface of the parylene insulating layer 15 for mask protection. In this embodiment, the photoresist ① 16 used is AZ4620 positive photoresist; then complete photolithography to preliminarily determine the relative positions of the detection site 4 and the pad 3;

[0057] (e) Etch the parylene insulating layer 15 by oxygen plasma etching 17 with a power of 50 W; due to the protection of the photoresist ① 16, only part of the insulating layer is etched through, exposing the detection site 4 and the pad 3 of the conductive layer 14;

[0058] (f) Use acetone to wash off the photoresist ① 16, and then spin-coat photoresist ② 18 on the surface of the insulating layer 15 for mask protection. In this embodiment, the photoresist ② 18 used is AZ4903 positive photoresist; then complete photolithography to determine the shape of the flexible electrode;

[0059] (g) Use oxygen plasma etching 17 to etch the insulating layer 15 and the parylene bottom layer 12 with a power of 50 W or 100 W to etch out the shape of the flexible electrode and complete the preparation of the flexible electrode; after the etching is completed, soak it in deionized water to release the prepared flexible electrode 19 from the silicon wafer carrier 13;

[0060] Finally, use the solder positioning hot melting method to weld and package the flexible electrode 19 with the polyimide flexible PCB to complete the preparation of the flexible sensor.

[0061] The specific embodiments described above have further elaborated in detail the purpose, technical solutions and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A flexible sensor for deep brain detection in humans and non-human primates, characterized in that, It includes a flexible electrode, which is composed of a flexible electrode implantation end and a pad area. One end of the flexible electrode implantation end is connected to the pad area, and the other end of the flexible electrode implantation end is the implantation end tip; wherein the flexible electrode implantation end is used for deep brain nerve signal acquisition and detection; a flexible printed circuit board, which is soldered to the pad area of the flexible electrode to transmit the detected nerve signals to an external recording system; wherein, the overall thickness of the flexible electrode is 10–15 microns; the length of the flexible electrode implantation end is 60-70 mm, the width is 400–500 microns, the overall pad area is rectangular, the side length is less than or equal to 10 mm, and the middle between the flexible electrode implantation end and the pad area is a trapezoidal transition connection area; 32 circular detection sites are distributed at the tip of the flexible electrode implantation end. The detection sites are distributed along the two side edges of the tip, with 16 sites on each side. The diameter of the detection sites is 10 microns, the center of the sites is more than or equal to 20 microns away from the edge, and the center-to-center spacing between adjacent detection sites is more than or equal to 50 microns; a reference site is contained at the center position of the tip of the implantation end. The reference site is a 15×1000 micron rectangle; there is a through hole at the top of the implantation end, with a diameter less than or equal to 60 microns, which is used to guide the implantation of the electrode; the pad area of the flexible electrode contains 34 pads. The pads are square with a size of 200×200 microns, and the pads are arranged in a matrix. The center-to-center spacing between adjacent pads is more than or equal to 400 microns; the detection sites and pads of the flexible electrode are connected by wires; the width of the wires is less than or equal to 5 microns, and the spacing between adjacent wires is less than or equal to 5 microns; the material of the flexible printed circuit board is polyimide, and the thickness of the flexible printed circuit board is 1–2 microns; the flexible printed circuit board has 34 solder joints, and the size and arrangement of the solder joints are the same as those of the pads of the flexible electrode. The flexible printed circuit board and the pads of the flexible electrode are welded by solder positioning hot melting method; the solder positioning hot melting method includes the following steps: (a)Fix the flexible printed circuit board, apply soldering flux on the surface of the solder joints, and place the solder on the solder joints in batches through a positioning stencil; (b)Use a constant temperature heating table to heat the back of the flexible printed circuit board to melt the solder and make the solder weld on the surface of the solder joints; (c)Apply soldering flux on the surface of the pads of the flexible electrode, and then lean against the front of the solder joints of the flexible printed circuit board with the solder already welded, and align them one by one; (d)Use a constant temperature heating table to heat the back of the flexible printed circuit board to melt the solder again and complete the welding.

2. The flexible sensor according to claim 1, wherein The hierarchical structure of the flexible electrode includes three layers: a base layer, a conductive layer, and an insulating layer; the base layer is located at the bottom and serves as the back side of the flexible electrode, with a thickness of 7-10 microns; the conductive layer is located on the base layer, with a thickness less than or equal to 1 micron, and the detection sites, wires, and pads are located in the conductive layer; the insulating layer is located on the conductive layer, with a thickness of 3-5 microns.

3. The flexible sensor according to claim 2, wherein, the base layer and the insulating layer are parylene films; the conductive layer includes a chromium bottom layer and a gold layer.

4. The flexible sensor according to claim 1, wherein, the solder is a solid micro solder ball or a semi-solid solder paste, and the melting point is less than 150°C; The aperture size and arrangement pattern of the positioning holes of the positioning stencil need to be exactly the same as those of the flexible electrode pads; The heating temperature of the constant temperature heating table is 130–250 °C.

5. A method for preparing the flexible sensor according to any one of claims 1–4, characterized in that, Prepare the flexible electrode base layer, conductive layer and insulating layer in sequence, etch out the electrode shape, and finally release the electrode, and weld the flexible electrode and the flexible printed circuit board; Specifically, it includes the following steps: (1) In a vacuum chamber, pyrolyze parylene powder, and then deposit a transparent film on the silicon wafer carrier as the flexible electrode substrate; (2) Use photolithography, evaporation and stripping processes to prepare a chromium layer and a gold layer on the base layer as the conductive layer; (3) In a vacuum chamber, pyrolyze parylene powder, and then deposit a transparent film on the base layer and the conductive layer as the flexible electrode insulating layer; (4) Use photoresist as a mask protection, and use oxygen plasma etching process to etch the insulating layer to expose the flexible electrode detection sites and pads; (5) Use photoresist as a mask protection, and use oxygen plasma etching process to etch the insulating layer and the base layer to determine the shape of the flexible electrode, and release the flexible electrode; (6) Weld the flexible electrode and the flexible printed circuit board, and complete the encapsulation to make a flexible sensor.

6. The method according to claim 5, wherein, The air pressure in the vacuum chamber is less than 3 Pa; The parylene powder is Parylene C type powder; The pyrolysis temperature is 650–750 °C; The deposition temperature is 25 °C; The viscosity of the photoresist is greater than 400 mPa·s; The power of the oxygen plasma etching is 50–100 W.

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