Three-dimensional implantable flexible microprobe array substrate with adjustable magnetic field and preparation method of three-dimensional implantable flexible microprobe array substrate

Abstract

The invention discloses a three-dimensional implantable flexible microprobe array substrate with an adjustable and controllable magnetic field and a preparation method of the three-dimensional implantable flexible microprobe array substrate. The preparation method comprises the following steps: sequentially preparing the sacrificial layer and the first flexible material layer on the supporting substrate from bottom to top; growing a magnetic material intermediate layer on the first flexible material layer; preparing a second flexible material layer on the magnetic material intermediate layer; the first flexible material layer and the second flexible material layer are etched through the photoetching technology to achieve hollowing of the microprobe area and thinning of the rotating hinge; and removing the sacrificial layer to release the whole microprobe array substrate, pulling the microprobe array to rotate through a magnetic field to complete the process of converting the microprobe array into the two-dimensional microprobe array into the three-dimensional microprobe array, and curing the hinge through resin to obtain the three-dimensional microprobe array. According to the invention, the performance and reliability of the probe array under the dynamic condition are obviously improved; according to the invention, the microprobe array can capture the change of a three-dimensional signal, provides a high-spatial-resolution monitoring capability, and is suitable for high-precision applications such as real-time neural activity monitoring and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of neural electrical signal detection of flexible devices, and in particular to a three-dimensional implantable flexible microprobe array substrate with controllable magnetic field and a preparation method thereof. Background Art

[0002] Electronic devices and systems that can integrate with the human body and provide diagnostic and therapeutic functions play an important role in basic medical research and clinical medicine. In recent years, the research interest in basic neuroscience and applied neurophysiology has been increasing, especially in revealing the mechanisms of neurological diseases and understanding and regulating the motor cortex, which has led to the development of neural interface devices. Among them, neural probe arrays, as an important bio-integrated device that can be injected into brain tissue, record neural activity and stimulate neurons, have been successfully developed and widely used.

[0003] At present, probes based on silicon materials are widely used due to their superior mechanical and electrical properties and mature manufacturing technology. The common method of manufacturing probe arrays is usually to first determine the electrode path on the silicon wafer, then separate it into individual probes, and finally assemble it into a three-dimensional array with rigid support, mainly represented by the Utah array model. Another method mainly relies on micromachining in the thickness direction of the silicon wafer to form a vertical probe array, such as the Neuropixels probe of IMEC. Both probe arrays have shown good capabilities in neural recording, but these probes are relatively rigid and fixed on a rigid support substrate. However, the mechanical mismatch between rigid probes and soft tissues, poor contact with the curved surface of brain tissue, and lack of adaptability may lead to damage to tissues during movement, especially in chronic implants and active animals or humans.

[0004] In order to solve these problems, some literatures have reported flexible probes based on biocompatible polymer support substrates (such as polyvinylidene fluoride, polyimide, etc.). The main advantages of flexible probes are their plasticity and adaptability, but these probe arrays are usually still rigidly supported and interfaced with external signal extraction and processing units. The design that flexible probe arrays still rely on rigid supports limits the application capabilities of flexible probe arrays in complex environments and cannot flexibly monitor signals in three-dimensional space. This is an important limitation for many applications that require high spatial resolution and stereoscopic imaging. Summary of the invention

[0005] In order to address the mechanical mismatch problem caused by rigid probes, the problem of poor adaptability of rigid array supports to soft curved surfaces, and the need to enrich multi-parameter sensing and stimulation functions through passive electrodes, the present invention proposes a novel thin and flexible, magnetic field-controllable three-dimensional implantable flexible microprobe array substrate and its preparation method. The three-dimensional implantable microprobe array substrate of the present invention can adhere to and adapt to curved surfaces, and can be well adapted to traditional micro-nano preparation processes. These thin implantable microprobes are supported by an ultra-thin polyimide support substrate, which gives them good adaptability to the curved surfaces of brain tissue. The present invention significantly improves the performance and reliability of the microprobe array under dynamic conditions. In addition, the present invention enables the microprobe array to capture changes in three-dimensional signals, providing high spatial resolution monitoring capabilities, and is suitable for high-precision applications such as real-time neural activity monitoring.

[0006] In order to achieve the above-mentioned purpose, the main technical solutions adopted by the present invention are as follows.

[0007] The present invention provides a method for preparing a three-dimensional implantable flexible microprobe array substrate with controllable magnetic field, comprising the following steps: 1) preparing a sacrificial layer and a first flexible material layer in sequence from bottom to top on a supporting substrate; 2) preparing a patterned magnetic material intermediate layer on the first flexible material layer; 3) preparing a second flexible material layer on the magnetic material intermediate layer; 4) etching the first flexible material layer and the second flexible material layer through a photolithography process to hollow out the microprobe area and thin the rotary hinge at the connection between the microprobe and the substrate, so as to facilitate the magnetically controlled rotation of a single microprobe; 5) The sacrificial layer is removed to release the entire flexible microprobe array substrate, and the microprobe array is pulled by a magnetic field to rotate at an angle of 0-180° to complete the process of converting the two-dimensional microprobe array into a three-dimensional one; after adjusting a certain angle, the hinge part is rotated by resin curing to obtain a three-dimensional flexible microprobe array substrate.

[0008] In the present invention, in step 1) and step 3), the supporting substrate is a glass sheet, the sacrificial layer is a polymethyl methacrylate (PMMA) layer, the first flexible material layer and the second flexible material layer are both polyimide layers; the sacrificial layer, the first flexible material layer and the second flexible material layer are all prepared by spin coating.

[0009] In the present invention, in step 1), when preparing the sacrificial layer, a film with a thickness of 1-2 μm is prepared by spin coating a dimethyl sulfoxide (DMSO) solution of polymethyl methacrylate (PMMA), and then heated at a temperature of 170-190° C. for 30-120 s to cure.

[0010] In the present invention, when preparing the first flexible material layer and the second flexible material layer, a polyimide N,N'-dimethylformamide DMF solution is diluted and then spin-coated to prepare a film with a thickness of 1-2 μm, and heated and cured in four stages: heating at a temperature of 100-120° C. for 1-5 min, heating at a temperature of 140-160° C. for 20-40 min, heating at a temperature of 170-190° C. for 40-80 min, and heating at a temperature of 240-260° C. for 100-150 min.

[0011] In the present invention, in step 2), photoresist is evenly applied on the first flexible material layer, and the area where the magnetic film needs to be grown is first defined by photolithography, and then the magnetic film is grown on the first flexible material layer. Finally, the photoresist is removed by a stripping process to retain the magnetic film in the defined area.

[0012] In the present invention, the magnetic material intermediate layer is a metal Fe film layer with a thickness of 300-500nm, and the metal Fe film is grown by magnetron sputtering.

[0013] In the present invention, in step 4), etching and thinning are performed using a reactive ion etching process.

[0014] In the present invention, in step 5), the bottom sacrificial layer PMMA is etched by soaking in acetone to release the entire microprobe array substrate; the rotating hinge is fixed by dripping photoresist on the rotating hinge, and UV curing the photoresist to obtain resin.

[0015] The present invention also provides a three-dimensional implantable flexible microprobe array substrate with controllable magnetic field obtained by the above-mentioned preparation method.

[0016] Furthermore, the present invention provides an application of the above-mentioned three-dimensional implantable flexible microprobe array substrate with controllable magnetic field in the preparation of EEG monitoring electrodes, temperature electrodes and stimulation electrodes.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. The device of the present invention adopts a thin and flexible three-dimensional implantable microprobe array. This design can effectively adapt to the curved surface of biological tissue, improve the contact quality with soft tissue, and reduce the risk of injury caused by mechanical mismatch.

[0018] 2. The three-dimensional implantable microprobe array design of the present invention enriches the multi-parameter sensing and stimulation functions of the device, and can simultaneously monitor multiple physiological signals, providing more comprehensive data support for the application of neural interfaces.

[0019] 3. The present invention overcomes the problem of poor adaptability of rigid array supports to soft curved surfaces, thereby improving the performance and reliability of the equipment under dynamic conditions.

[0020] 4. The present invention improves the structure and layout of the probes. The innovative design allows the flexible probe array to capture changes in three-dimensional signals and provide high spatial resolution monitoring, which is suitable for applications that require precise positioning, such as real-time monitoring of neural activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a schematic diagram of the structure of the magnetically controlled flexible microprobe substrate array provided in an embodiment of the present application.

[0022] Figure 2 It is a top view schematic diagram of the magnetically controlled flexible microprobe substrate array provided in an embodiment of the present application.

[0023] Figure 3 It is a schematic diagram of the structure of a single flexible microprobe provided in an embodiment of the present application.

[0024] Figure 4 It is a side view schematic diagram of a multi-angle fixed flexible microprobe substrate array provided in an embodiment of the present application.

[0025] Figure 5 It is a schematic flow chart of a method for preparing a magnetically controlled flexible microprobe substrate array provided in an embodiment of the present application.

[0026] Figure 6 It is a schematic diagram of the structure after a sacrificial layer is prepared on a supporting substrate provided in an embodiment of the present application.

[0027] Figure 7 It is a schematic diagram of the device structure after preparing the first layer of polyimide flexible film provided in an embodiment of the present application.

[0028] Figure 8 It is a schematic diagram of the device structure after preparing the patterned Fe film provided in the embodiment of the present application.

[0029] Fig. 9 It is a schematic diagram of the device structure after preparing the second layer of polyimide flexible film provided in an embodiment of the present application.

[0030] Fig.10 It is a schematic diagram of the device structure after etching and hollowing out two layers of polyimide flexible film and thinning the second layer of polyimide flexible film provided in an embodiment of the present application.

[0031] Fig.11 It is a schematic diagram of the device structure obtained after removing the sacrificial layer provided in the embodiment of the present application and a schematic diagram of the device structure in which a specified area is deformed by magnetic field control.

[0032] Fig.12 It is an electrode design diagram for realizing EEG monitoring, temperature sensor and electrode stimulation in the embodiment of the present application.

[0033] Fig.13 This is a diagram of the experimental verification results of the temperature sensor implemented in Example 2 of the present application.

[0034] Fig.14 This is a diagram of the experimental verification results when the electrode stimulation application is implemented in Example 3 of the present application.

[0035] Description of reference numerals: 1-flexible microprobe substrate; 11-60° probe array; 12-90° probe array; 13-120° probe array; 101-support substrate; 102-sacrificial layer; 2-magnetically controlled flexible microprobe array; 21-first polyimide flexible film layer; 22-magnetic material intermediate layer; 23-second polyimide flexible film layer, 24-hollow area, 25-thinning area. DETAILED DESCRIPTION

[0036] In order to better explain the present invention, so as to facilitate understanding, the present invention is described in detail through specific embodiments. Although exemplary embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided in order to enable a clearer and more thorough understanding of the present invention, and to be able to fully convey the scope of the present invention to those skilled in the art.

[0037] like Figure 1-Figure 4 As shown, the present invention provides a magnetic field-controlled flexible microprobe array substrate: the flexible microprobe substrate 1 is composed of a three-layer structure, which includes a first polyimide flexible film layer 21 as a supporting material with a thickness of about 1.5 μm, an intermediate layer of a magnetic material intermediate layer 2, the magnetic material intermediate layer 22 adopts a ferromagnetic film with a thickness of about 350 nm, and an encapsulation layer of a second polyimide flexible film layer 23; the planar size of the first polyimide flexible film layer 21 is determined by the size and scale of the magnetically controlled flexible microprobe array 2. In the 4×4 probe array in the embodiment of the present application, the planar size of the first polyimide flexible film layer 21 is 20×20 mm. Figure 3It is a schematic diagram of a single flexible microprobe structure provided in an embodiment of the present application. In the embodiment of the present application, the size of the ferromagnetic film is determined by the size of the probe. The ferromagnetic film is composed of metal Fe. The plane size is divided into two parts, namely, an equilateral triangle tip with a side length of 0.6 mm and a main body of 1.5×0.6 mm. The tip can enhance the ability of electrode implantation, and the top packaging layer is a second polyimide flexible film layer 23 slightly larger than the ferromagnetic film. Each individual electrode will be hollowed out and thinned at the hinge to achieve the optimization of the degree of freedom of the electrode array when it is three-dimensional. Since the ferromagnetic material is encapsulated in the probe, it will be pulled by the magnetic field. After the magnetic field is regulated, the probe is rotated from 0° to 180°. When the probe rotates to the target angle (90° in the embodiment of the present application), the hinge is fixed at the rotating hinge by SU-8 ultraviolet curing material to achieve the preparation of a three-dimensional adjustable probe array substrate.

[0038] A method for preparing a magnetically regulated flexible microprobe array substrate (eg Figure 5 The specific steps are as follows: 1) First polyimide flexible film layer 21: Clean the supporting substrate 101 (glass sheet), spin-coat a PMMA solution (950 PMMA A7 organic reagent) on the glass sheet to prepare a sacrificial layer 102 with a thickness of about 1.2 μm, and heat at 180°C for 90 s to cure; at this time, the structure is as follows Figure 6 As shown. Polyimide was diluted with DMF at a mass ratio of 2.5:1, and a support film with a thickness of about 1.5 μm was prepared by spin coating. The support film was heated and cured in four stages: 110°C for 3 min, 150°C for 30 min, 180°C for 60 min, and 250°C for 120 min. At this time, the structure is as shown Figure 7 shown.

[0039] 2) Magnetic material intermediate layer 22: Photoresist is evenly applied on the first polyimide flexible film layer 21, and the area where the magnetic film needs to be grown is defined by photolithography. Then, the metal Fe film is prepared on the first polyimide flexible film layer 21 using a magnetron sputtering coating device. The power of the magnetron sputtering coating device is set to 150 W for 900 s. At this time, the Fe film on the first polyimide flexible film layer 21 is about 350 nm thick. Finally, the photoresist is removed by a stripping process, and the Fe film in the defined area is retained; at this time, the structure is as follows: Figure 8 shown.

[0040] 3) Second polyimide flexible film layer 23: Diluted polyimide is spin-coated on the magnetic material intermediate layer 22 to prepare a support film with a thickness of about 1.5 μm. The film is heated and cured in four stages: 110°C for 3 min, 150°C for 30 min, 180°C for 60 min, and 250°C for 120 min. At this time, the structure is as follows: Fig. 9 shown.

[0041] 4) Hollowing out the microprobe area: photoresist is evenly applied on the first and second polyimide flexible film layers 21 and 23, and a hollowing area 24 is defined by photolithography. The polyimide in the area to be hollowed out is etched by reactive ion etching (O2 20 sccm, 200 mTorr, 150 W, 600 s) to separate the probe area from the substrate; photoresist is evenly applied on the polyimide encapsulation layer, and a thinning area 25, i.e., the connection between the probe and the substrate, is defined by photolithography. The polyimide in the area to be thinned is etched by reactive ion etching (O2 20 sccm, 200 mTorr, 150 W, 300 s). At this time, the structure is as follows: Fig.10 As shown; 5) Preparation of three-dimensional microprobe array: Soak in acetone to etch the bottom sacrificial layer PMMA to release the entire microprobe array substrate, and use the magnetic field to pull the microprobe array to rotate to complete the process of converting the two-dimensional microprobe array into three-dimensional. After adjusting a certain angle, release the SU-8 droplet at the hinge and cure it by ultraviolet light to achieve the preparation of the adjustable three-dimensional microprobe array. At this time, the structure is as follows Fig.11 shown.

[0042] The following are specific application examples.

[0043] Example 1

[0044] In order to meet different surface morphologies and distribution inside implanted tissues, the three-dimensional microprobe array design of the present invention allows for angle adjustment of different probes in the array. The curing angle of each probe ranges from 0° to 180°, which allows the probe to be flexibly adjusted according to specific implantation requirements and tissue characteristics. Figure 4 When the probe array 11 is 60°, the probe array 12 is 90°, the probe array 13 is 120°, etc., this angle adjustment mechanism not only enhances the adaptability of the probe on various curved surfaces and complex structures, but also optimizes the contact quality between the probe and the biological tissue, thereby improving the monitoring and stimulation effect. By changing the angle of the probe, it can be ensured that it can accurately fit different biological tissue types and morphologies, such as the uneven surface of brain tissue or the complex shape of other soft tissues; Fig.12 The left picture in the figure is a schematic diagram of the electrode design for implementing EEG monitoring in an embodiment of the present application.

[0045] Example 2

[0046] The preparation of temperature electrodes on the three-dimensional implantable microprobe array substrate of the present invention enables real-time monitoring of tissue temperature. This technology not only helps monitor tissue temperature changes during surgery, but also provides important data in long-term monitoring after implantation, which helps to evaluate the physiological state of tissues and postoperative recovery. The electrode design diagram of the temperature sensor is shown in the following figure. Fig.12 As shown in the middle figure, the experimental results are Fig.13 As shown, specifically, the temperature electrode shows a resistance change of 0.27 Ω / °C in the range of 30-50°C. This change rate indicates that the temperature electrode has a high sensitivity to temperature and can promptly reflect subtle changes in tissue temperature.

[0047] Example 3

[0048] On the three-dimensional implantable microprobe array substrate of the present invention, the preparation of stimulation electrodes (such as Fig.12 In order to verify the performance of the system, we mainly tested the sine wave electrical signal in the simulated cerebrospinal fluid. In the experiment, a sine wave voltage signal with a frequency of 0.5kHz and an amplitude of 100 mV was input into the stimulation circuit. Fig.14 As shown in the figure, the output signal monitored by the oscilloscope receiving end is a voltage with a frequency of 0.5 kHz and an amplitude of 50.2 mV, indicating that the signal attenuation during transmission is about 50%. This result shows that the microprobe array has good electrical stimulation capabilities and can effectively transmit stimulation signals to the target tissue. In addition, we also tested square wave and triangle wave signals, and the results showed that their signal attenuation characteristics are similar to those of sine waves, further verifying the stability and reliability of the system under various waveforms.

[0049] As described above, the present invention provides a new type of thin and flexible three-dimensional implantable microprobe array substrate, which aims to solve the problems of mechanical mismatch and insufficient adaptability between traditional rigid probes and soft tissues. The probe array can effectively fit the curved surface of biological tissues, improve the contact quality with soft tissues, and thus reduce the risk of damage to tissues during movement. Compared with existing flexible probe arrays, the present invention overcomes the limitation of poor adaptability of rigid supports to soft surfaces, and significantly improves the performance and reliability under dynamic conditions. In addition, the innovative design enables the array to capture changes in three-dimensional signals and provide high spatial resolution monitoring capabilities, which is suitable for high-precision applications such as real-time neural activity monitoring. The enrichment of this multi-parameter sensing and stimulation function provides more comprehensive data support for the clinical application of neural interfaces and promotes the development of related technologies.

Claims

1. A method for preparing a three-dimensional implantable flexible microprobe array substrate with controllable magnetic field, characterized in that: The following steps are involved: 1) preparing a sacrificial layer and a first flexible material layer in sequence from bottom to top on a supporting substrate; 2) preparing a patterned magnetic material intermediate layer on the first flexible material layer; 3) preparing a second flexible material layer on the magnetic material intermediate layer; 4) Through a photolithography process, the first flexible material layer and the second flexible material layer are etched to hollow out the microprobe area and thin the rotary hinge at the connection between the microprobe and the substrate, so as to facilitate the magnetically controlled rotation of a single microprobe; 5) The sacrificial layer is removed to release the entire flexible microprobe array substrate, and the microprobe array is pulled by a magnetic field to rotate at an angle of 0-180° to complete the process of converting the two-dimensional microprobe array into a three-dimensional one; after adjusting a certain angle, the hinge part is rotated by resin curing to obtain a three-dimensional flexible microprobe array substrate.

2. The preparation method according to claim 1, characterized in that: In step 1) and step 3), the supporting substrate is a glass sheet, the sacrificial layer is a polymethyl methacrylate (PMMA) layer, and the first flexible material layer and the second flexible material layer are both polyimide layers; the sacrificial layer, the first flexible material layer, and the second flexible material layer are all prepared by spin coating.

3. The preparation method according to claim 2, characterized in that In step 1), when preparing the sacrificial layer, a film with a thickness of 1-2 μm is prepared by spin coating a DMSO solution of polymethyl methacrylate (PMMA), and then heated at a temperature of 170-190° C. for 30-120 seconds for curing.

4. The preparation method according to claim 2, characterized in that When preparing the first flexible material layer and the second flexible material layer, a film with a thickness of 1-2 μm is prepared by spin coating a DMF solution of polyimide, and heated and cured in four stages: heating at a temperature of 100-120° C. for 1-5 min, heating at a temperature of 140-160° C. for 20-40 min, heating at a temperature of 170-190° C. for 40-80 min, and heating at a temperature of 240-260° C. for 100-150 min.

5. The preparation method according to claim 1, characterized in that: In step 2), photoresist is evenly applied on the first flexible material layer, and the area where the magnetic film needs to be grown is first defined by photolithography, and then the magnetic film is grown on the first flexible material layer. Finally, the photoresist is removed by a stripping process to retain the magnetic film in the defined area.

6. The preparation method according to claim 5, characterized in that: The magnetic material middle layer is a metal Fe film layer with a thickness of 300-500nm, and the metal Fe film is grown by magnetron sputtering.

7. The preparation method according to claim 1, characterized in that: In step 4), etching and thinning are performed using a reactive ion etching process.

8. The preparation method according to claim 1, characterized in that: In step 5), the entire microprobe array substrate is released by soaking in acetone to etch the bottom sacrificial layer of polymethyl methacrylate (PMMA); the rotating hinge part is fixed by dripping photoresist on the rotating hinge part and further curing the UV resin in the photoresist with ultraviolet light.

9. A three-dimensional implantable flexible microprobe array substrate with controllable magnetic field, prepared according to the preparation method of any one of claims 1 to 8.

10. Use of the magnetic field controllable three-dimensional implantable flexible microprobe array substrate according to claim 9 in preparing EEG monitoring electrodes, temperature electrodes and stimulation electrodes.

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