Flexible optical genetics device and preparation method thereof

Abstract

The invention provides an optogenetics device which sequentially comprises a flexible substrate, a MicroLED layer, a shielding layer, a transparent electrode layer and a top insulating layer from bottom to top, the MicroLED layer comprises a MicroLED chip, the transparent electrode layer comprises a transparent electrode, a modification layer is arranged on the surface of the transparent electrode to reduce electrode impedance, the position of the transparent electrode right faces the MicroLED chip, and the shielding layer is arranged on the top insulating layer. The shielding layer comprises a transparent shielding area between the transparent electrode and the MicroLED chip, and the top insulating layer exposes the transparent electrode.

Description

Technical Field

[0001] The invention relates to an implantable microelectrode in the technical field of biomedical engineering, and in particular to a flexible optogenetic device and a preparation method thereof. Background Art

[0002] In recent decades, electrical stimulation of the brain has greatly advanced our understanding of its function. However, to further advance neuroscience and investigate how large numbers of neurons interact in complex networks, it is necessary to be able to selectively activate and inhibit specific types of individual neurons. Currently, specific activation or inhibition of neurons cannot be effectively achieved through electrical stimulation. However, optogenetics has revolutionized the way neural circuits are analyzed by introducing light-sensitive proteins into specific cell types, which can respond to light stimulation with well-defined action potential patterns. By using appropriate wavelengths to stimulate specific light-sensitive proteins, cell-type specificity can be achieved with good temporal resolution. For example, channelrhodopsin-2 (ChR2) and halogenated rhodopsin can be co-expressed in the same cell, and specific activation or inhibition of neurons can be achieved using blue light (473nm) or yellow light (590nm) to depolarize and hyperpolarize target neurons, respectively.

[0003] Despite the rapid progress of optogenetics in recent years, there is still a lack of reliable means of light stimulation and EEG recording. Early work involving in vivo optogenetics relied on manually assembled commercially available components, such as metal electrodes or optical fibers, which are bulky and have insufficient spatial resolution. In recent years, optogenetic devices integrating microLEDs have become a research hotspot in the field of brain-computer interfaces. MicroLEDs are lossless, small in size, and can be precisely controlled. They can also be integrated with high-density, high-throughput flexible neural electrodes, which is expected to achieve more precise bidirectional manipulation and recording of neurons.

[0004] However, most neural electrodes are currently made of metal materials, which are opaque. Transparent electrode materials such as ITO and GZO have high light transmittance and good conductivity, and can be used to record neural signals. However, the impedance of transparent electrodes is generally too high, which affects the signal acquisition performance. In addition, for optogenetic devices, the main factors affecting signal quality also include electromagnetic interference and photoelectric artifacts. Among them, electromagnetic interference is mainly caused by crosstalk between metal lines and recording electrode lines when microLEDs are working, while photoelectric artifacts mainly occur on metal surfaces.

[0005] In order to overcome the above-mentioned defects in the prior art, the present invention provides an improved flexible optogenetics device. Summary of the invention

[0006] A brief summary of one or more aspects is given below to provide a basic understanding of these aspects. This summary is not an exhaustive overview of all conceived aspects, and is neither intended to identify the key or critical elements of all aspects nor to define the scope of any or all aspects. Its only purpose is to give some concepts of one or more aspects in a simplified form as a prelude to a more detailed description that will be given later.

[0007] According to one aspect of the present invention, an optogenetic device is provided, comprising, from bottom to top, a flexible substrate, a MicroLED layer, a shielding layer, a transparent electrode layer and a top insulating layer, wherein the MicroLED layer comprises a MicroLED chip, the transparent electrode layer comprises a transparent electrode and a surface of the transparent electrode is provided with a modification layer to reduce the electrode impedance, the transparent electrode is positioned opposite to the MicroLED chip, the shielding layer comprises a transparent shielding area between the transparent electrode and the MicroLED chip, and the top insulating layer exposes the transparent electrode.

[0008] In one embodiment, the modification layer on the surface of the transparent electrode includes a Pt nanoparticle layer, a PEDOT:PSS film, or an Ir / IrO x membrane.

[0009] In one example, the MicroLED layer further includes a cathode connection line and an anode connection line of the MicroLED chip, an intermediate insulating layer is provided between the cathode connection line and the anode connection line, and a hole is provided on the intermediate insulating layer for conducting the connection lines of the upper and lower layers.

[0010] In one example, the transparent electrode layer further includes a connection line of the transparent electrode, and the shielding layer further includes a connection line shielding area, and a pattern of the connection line shielding area is consistent with a pattern of the connection line of the transparent electrode.

[0011] In one example, the MicroLED layer, the shielding layer, and the transparent electrode layer are separated by an intermediate insulating layer.

[0012] In one example, the material of the connection line includes one or more combinations of Ti, Cr, Ni, Au, and Cu.

[0013] In one example, the insulating layer is made of a flexible material, and the flexible material is selected from any one or more combinations of polyimide, polydimethylsiloxane, silicone rubber, SU-8 photoresist, or polyparaxylene.

[0014] In one example, the transparent electrode is made of a transparent conductive material, and the transparent conductive material is selected from one or more combinations of graphene, ITO, GZO, and AZO.

[0015] According to another aspect of the present invention, there is provided a method for preparing an optogenetic device, comprising:

[0016] Provide flexible bottom;

[0017] Transferring and manufacturing a MicroLED layer including a MicroLED chip array and cathode and anode circuits thereof on the flexible substrate;

[0018] Fabricating a shielding layer including a transparent shielding region on the MicroLED layer;

[0019] A transparent electrode layer including a transparent electrode is formed on the shielding layer, wherein the transparent electrode is located opposite to the MicroLED chip, and the transparent shielding area is between the MicroLED chip and the transparent electrode;

[0020] Making a modification layer on the surface of the transparent electrode to reduce the electrode impedance; and

[0021] A top insulating layer is formed on the transparent electrode layer to expose the transparent electrode.

[0022] In one embodiment, the modification layer on the surface of the transparent electrode includes: electroplating a Pt nanoparticle layer on the surface of the transparent electrode; or electrochemically depositing a PEDOT:PSS film on the surface of the transparent electrode; or sputtering Ir / IrO on the surface of the transparent electrode. x membrane. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The above features and advantages of the present invention can be better understood after reading the detailed description of the embodiments of the present disclosure in conjunction with the following drawings. In the drawings, the components are not necessarily drawn to scale, and components with similar related properties or features may have the same or similar reference numerals.

[0024] Figure 1 A schematic structural diagram of an optogenetic device according to an embodiment of the present invention is shown;

[0025] Figure 2 A flow chart showing a method for preparing an optogenetic device according to an embodiment of the present invention; and

[0026] Figure 3 A schematic diagram of a strip optogenetic device according to an embodiment of the present invention is shown. DETAILED DESCRIPTION

[0027] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. Note that the aspects described below in conjunction with the accompanying drawings and specific embodiments are only exemplary and should not be construed as limiting the scope of protection of the present invention in any way.

[0028] In addition, the terms "upper", "lower", "left", "right", "top", "bottom", "horizontal" and "vertical" used in the following description should be understood as the directions shown in the paragraph and the related drawings. Such relative terms are only used for the convenience of description and do not mean that the device described therein must be manufactured or operated in a specific direction, and therefore should not be understood as limiting the present invention.

[0029] It is understood that although the terms "first", "second", "third", etc. may be used herein to describe various components, regions, layers and / or parts, these components, regions, layers and / or parts should not be limited by these terms, and these terms are only used to distinguish different components, regions, layers and / or parts. Therefore, the first component, region, layer and / or part discussed below may be referred to as a second component, region, layer and / or part without departing from some embodiments of the present invention.

[0030] According to one aspect of the present invention, an optogenetic device is provided, specifically a light stimulation and signal acquisition device integrating microLED and transparent electrodes. The device uses transparent electrodes to effectively reduce light artifacts and improve signal quality. The device can be in the shape of a probe / strip, which is used for deep brain stimulation. The transparent electrode mainly collects neural pulse (spike) signals. In addition, the transparent electrode is not only used to record signals, but also can be used for electrical stimulation, thereby forming an optoelectronic integrated neural stimulator.

[0031] The optogenetic device of the present invention may include a flexible substrate, a MicroLED layer, a shielding layer, a transparent electrode layer and a top insulating layer from bottom to top, wherein the MicroLED layer may include a MicroLED chip, the transparent electrode layer may include a transparent electrode and the surface of the transparent electrode may be provided with a modified layer to reduce the electrode impedance, and the shielding layer may include a transparent shielding area, the transparent electrode is positioned opposite to the MicroLED chip, and the transparent shielding area is between the transparent electrode and the MicroLED chip. Through the design of the shielding layer, the crosstalk generated by the metal circuit and the recording electrode circuit when the microLED is working is shielded, thereby improving the signal quality. In addition, the use of the transparent electrode reduces photoelectric artifacts, and the modification of the surface of the transparent electrode greatly reduces the originally high impedance of the transparent electrode, thereby improving the conduction efficiency.

[0032] Figure 1 FIG. 2 shows a schematic diagram of the structure of an optogenetic device according to an embodiment of the present invention. Figure 1As shown, the optogenetic device 100 may include a flexible substrate 1, which may be a polymer insulating layer, and a MicroLED layer is located on the flexible substrate 1. The MicroLED layer may include a MicroLED chip 2 and a cathode connection line 4 and an anode connection line 6 connecting the MicroLED chip 2, wherein the cathode connection line 4 and the anode connection line 6 are isolated by an intermediate insulating layer 5. Small holes are provided on the intermediate insulating layer 5 for conducting the upper and lower metal connection lines. The MicroLED layer may also include a bottom insulating layer 3, which is used for the transfer and bonding of the MicroLED chip 2 and exposes the cathode and anode of the MicroLED chip 2.

[0033] The shielding layer is located between the MicroLED layer and the transparent electrode layer, and is used to shield the crosstalk generated by the metal circuit and the recording electrode circuit when the MicroLED is working. Figure 1 As shown, the shielding layer may include a transparent shielding area 9, which is located directly above the MicroLED chip 2 and is made of a transparent conductive material. The shielding layer may also include a circuit shielding area 8, which is composed of a metal circuit, and the pattern of the metal circuit is consistent with the pattern of the metal connection circuit of the transparent electrode. Figure 1 In the example, intermediate insulating layers are provided above and below the shielding layer. Specifically, an intermediate insulating layer 7 is provided between the shielding layer and the MicroLED layer to isolate the MicroLED chip and its metal circuit, and an intermediate insulating layer 10 is provided between the shielding layer and the transparent electrode layer.

[0034] like Figure 1 As shown, the transparent electrode layer may include a transparent electrode 12, and the transparent electrode 12 is located directly above the MicroLED chip 2 and facing the MicroLED chip 2, so as to accurately record the neural activity under the light stimulation. Therefore, the transparent shielding area 9 of the shielding layer is located directly below the transparent electrode 12 and directly above the MicroLED chip 2. The transparent shielding area 9 is located exactly between the transparent electrode 12 and the MicroLED chip 2 to shield the electromagnetic interference of the MicroLED chip 2 to the transparent electrode 12.

[0035] In the present case, a modified layer is provided on the surface of the transparent electrode 12 to reduce the impedance of the transparent electrode. The transparent electrode 12 is made of a transparent conductive material, and the transparent conductive material can be selected from one or more combinations of graphene, indium tin oxide (ITO), gallium-doped zinc oxide (GZO), and aluminum-doped zinc oxide (AZO) to reduce the signal interference caused by the photoelectric effect. However, transparent conductive materials often have high impedance, which affects the conduction performance. Therefore, by providing a modified layer on the surface of the transparent electrode 12, the electrode impedance can be reduced and the conduction efficiency can be improved. In one example, the modified layer on the surface of the transparent electrode may include a Pt nanoparticle layer, a PEDOT:PSS film, or an Ir / IrOx membrane.

[0036] The transparent electrode layer may further include a metal connection line 11 of the transparent electrode 12. As described above, the shielding layer may include a line shielding area 8, which is composed of a metal line, and its metal line pattern is consistent with the pattern of the metal connection line 11 to reduce electromagnetic interference to the metal connection line 11.

[0037] The material of the above-mentioned metal connecting line can be selected from one or a combination of Ti, Cr, Ni, Au, and Cu, and the thickness is 10 to 500 nanometers.

[0038] The transparent electrode layer is covered with an insulating layer to encapsulate the entire optogenetic device, and the transparent electrode 12 is exposed through the insulating layer.

[0039] The above-mentioned insulating layer may be a polymer insulating layer made of a flexible material, and may be specifically selected from any one or more of polyimide, polydimethylsiloxane, silicone rubber, SU-8 photoresist or polyparaxylene.

[0040] Figure 2 A flow chart of a method for preparing an optogenetic device according to an embodiment is shown.

[0041] like Figure 2 As shown, the preparation method 200 may include the following steps.

[0042] Step 210: Providing a flexible bottom.

[0043] A metal sacrificial layer can be deposited on a clean silicon wafer, usually nickel or aluminum is used as the sacrificial material. Then, a layer of polyimide (PI) is covered on the silicon wafer by spin coating as the bottom polymer insulating layer. In one example, the spin coating speed is 3000 rpm, the time is 30 seconds, and the thickness is about 3 microns. After the spin coating is completed, the silicon wafer is placed on a hot plate for semi-curing treatment, the temperature is set to 100°C, and the time is 1 minute.

[0044] Step 220: Fabricate a MicroLED layer including MicroLED chips on a flexible substrate.

[0045] First, the MicroLED chip can be transferred. The MicroLED chip needs to be laser stripped and transferred to the UV tape at one time, with the electrode position of the chip facing downward (in the direction of the UV tape). The prepared MicroLED chip is transferred to the designated position on the flexible substrate through laser transfer technology.

[0046] Then the cathode and anode connection lines of the MicroLED chip can be made. The pattern of the cathode and anode connection lines can be defined around the MicroLED chip by photolithography technology (for example, using photoresist to expose the pattern lines), and then a layer of metal (such as a Ti / Au double-layer structure) is deposited as a connection line by electron beam evaporation. After the metal is deposited, the excess metal can be removed by a photoresist stripping process, leaving only the predetermined line pattern. After this step is completed, the electrical connection line between the MicroLED chip and the outside world is completed. Since microLED has two sets of cathode and anode patterns, and there will be overlapping parts in the middle, it is necessary to make two photolithography lines, which are isolated by a polymer insulating layer in the middle. The thickness of the polymer insulating layer is 2.5 microns.

[0047] A layer of polyimide can be spin-coated again on top of the connection line, with a thickness of about 2 microns. After spin coating, it is cured by high temperature treatment. During the curing process, the temperature is set at 300°C and the time is 1 hour. After curing, tiny holes can be dug in the polymer insulating layer through plasma etching technology to conduct the metal connection lines of the upper and lower layers.

[0048] Step 230: Fabricate a shielding layer including a transparent shielding area on the MicroLED layer.

[0049] The shielding layer may include a transparent shielding area and a connecting wire shielding area, which are respectively a transparent conductive shielding layer and its metal connecting wire.

[0050] The method for making a transparent conductive shielding layer may include depositing, for example, 200 nm of transparent conductive material on the cured intermediate polymer insulating layer by sputtering to form a transparent conductive shielding layer, removing excess parts by a stripping process, and retaining only a predetermined shielding pattern, which is consistent with the transparent electrode pattern below.

[0051] The method for making the metal connection line may include making a metal shielding layer on the cured intermediate polymer insulating layer by photolithography and electron beam evaporation technology. The shielding layer may be made of metal gold, and the thickness is controlled to be, for example, 200 nanometers. After the metal is deposited, the excess part is removed by a photoresist stripping process, and only a predetermined shielding pattern is retained, and the pattern must be consistent with the metal connection line pattern of the transparent electrode below.

[0052] Afterwards, an insulating layer, such as 1.5 micron polyimide, may be deposited on the surface of the shielding layer to isolate the shielding layer.

[0053] Step 240: forming a transparent electrode layer including a transparent electrode on the shielding layer.

[0054] The transparent electrode layer also includes two parts: a transparent electrode and its metal connection line.

[0055] The method for making a metal connection line includes making a metal layer on the solidified intermediate polymer insulating layer by photolithography and electron beam evaporation technology. The metal layer can be made of metal gold, and the thickness is controlled to be, for example, 100 nanometers. After the metal is deposited, the excess part is removed by a photoresist stripping process, leaving only the predetermined circuit pattern.

[0056] The transparent electrode manufacturing method may include defining the pattern of the transparent electrode by photolithography and lift-off technology, the pattern is, for example, a 100 micron diameter circle, located directly above the microLED, depositing, for example, 200 nm of transparent conductive material by sputtering, removing the excess by lift-off process, and retaining only the predetermined circular pattern.

[0057] Step 250: Making a modification layer on the surface of the transparent electrode to reduce the electrode impedance.

[0058] The transparent electrode can be prepared by electroplating a Pt nanoparticle layer, electrochemically depositing a PEDOT:PSS film, or sputtering an Ir / IrO x Taking PEDOT:PSS film as an example, a dedicated PCB board can be used for connection, and the PEDOT:PSS film can be deposited on the surface of the transparent electrode through an electrochemical workstation.

[0059] Step 260: Form a top insulating layer on the transparent electrode layer and expose the transparent electrode.

[0060] A layer of polyimide, for example, can be spin-coated again on top of the transparent electrode layer as a top polymer insulating layer, with a thickness controlled within 1 micron. After spin coating, it is cured by high temperature treatment. During the curing process, the temperature is set at 300°C and the time is 1 hour. After curing, tiny holes are dug in the top polymer insulating layer by plasma etching technology to expose the contact points of the transparent electrode layer.

[0061] In one example, the flexible optogenetic device can be in the form of a probe, such as Figure 3 As shown, Figure 3 A probe-shaped flexible optogenetic device is shown in FIG. For example, the shape of the probe-shaped device can be defined by photolithography and etching techniques, and then the entire device is placed in a dilute acid solution, and the metal sacrificial layer is removed by chemical etching to release the device.

[0062] Finally, a placement machine can be used to weld the interface of the flexible optogenetic device and the corresponding FPC together. For example, the welding pressure can be 10KG, the temperature can be 190 degrees, and the time can be 15 seconds.

[0063] Through the above process steps, a probe-type flexible optogenetic device can be successfully prepared, which has good mechanical flexibility and biocompatibility and is suitable for deep optogenetic research in the cerebral cortex.

[0064] The above examples demonstrate various possible applications and detailed manufacturing processes of the flexible optogenetic devices of the present invention. By rationally selecting materials and optimizing the manufacturing process, high-performance optogenetic devices with different requirements can be realized, providing important tools for brain-computer interface and neuroscience research.

[0065] Although the above methods are illustrated and described as a series of actions for simplicity of explanation, it should be understood and appreciated that these methods are not limited by the order of the actions, because according to one or more embodiments, some actions may occur in a different order and / or concurrently with other actions from those illustrated and described herein or not illustrated and described herein but understandable to those skilled in the art.

[0066] The previous description of the disclosure is provided to enable any person skilled in the art to make or use the disclosure. Various modifications to the disclosure will be apparent to those skilled in the art, and the general principles defined herein may be applied to other variations without departing from the spirit or scope of the disclosure. Thus, the disclosure is not intended to be limited to the examples and designs described herein, but should be granted the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An optogenetic device, characterized in that: From bottom to top, it includes: a flexible substrate, a MicroLED layer, a shielding layer, a transparent electrode layer and a top insulating layer, wherein the MicroLED layer includes a MicroLED chip, the transparent electrode layer includes a transparent electrode and the surface of the transparent electrode is provided with a modification layer to reduce the electrode impedance, the transparent electrode is located opposite to the MicroLED chip, the shielding layer includes a transparent shielding area between the transparent electrode and the MicroLED chip, and the top insulating layer exposes the transparent electrode.

2. The optogenetic device according to claim 1, wherein The surface modification layer of the transparent electrode includes a Pt nanoparticle layer, a PEDOT:PSS film, or an Ir / IrO x membrane.

3. The optogenetic device according to claim 1, wherein The MicroLED layer also includes a cathode connection line and an anode connection line of the MicroLED chip, an intermediate insulating layer is provided between the cathode connection line and the anode connection line, and a hole for conducting the connection lines of the upper and lower layers is provided on the intermediate insulating layer.

4. The optogenetic device according to claim 1, wherein The transparent electrode layer further includes a connection line of the transparent electrode, and the shielding layer further includes a connection line shielding area, and a pattern of the connection line shielding area is consistent with a pattern of the connection line of the transparent electrode.

5. The optogenetic device according to claim 1, wherein: The MicroLED layer, the shielding layer and the transparent electrode layer are separated by an intermediate insulating layer.

6. The optogenetic device according to claim 3 or 4, characterized in that: The material of the connecting line includes one or more combinations of Ti, Cr, Ni, Au, and Cu.

7. The optogenetic device according to claim 1, 3 or 5, characterized in that: The insulating layer is made of a flexible material, and the flexible material is selected from any one or more combinations of polyimide, polydimethylsiloxane, silicone rubber, SU-8 photoresist or polyparaxylene.

8. The optogenetic device according to claim 1, wherein: The transparent electrode is made of a transparent conductive material, and the transparent conductive material is selected from one or more combinations of graphene, ITO, GZO, and AZO.

9. A method for preparing an optogenetic device, characterized in that: include: Provide flexible bottom; Transferring a MicroLED layer including MicroLED chips onto the flexible substrate; Fabricating a shielding layer including a transparent shielding area on the MicroLED layer; A transparent electrode layer including a transparent electrode is formed on the shielding layer, wherein the transparent electrode is located opposite to the MicroLED chip, and the transparent shielding area is between the MicroLED chip and the transparent electrode; Making a modification layer on the surface of the transparent electrode to reduce the electrode impedance; as well as A top insulating layer is formed on the transparent electrode layer to expose the transparent electrode.

10. The method for preparing an optogenetic device according to claim 9, wherein: Producing a modified layer on the surface of the transparent electrode comprises: Electroplating a Pt nanoparticle layer on the surface of the transparent electrode; or Electrochemically depositing a PEDOT:PSS film on the surface of the transparent electrode; or Ir / IrO is sputtered on the surface of the transparent electrode. x membrane.

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