Three-dimensional array of integrated biological photoelectrodes

Abstract

The embodiment of the utility model discloses a three-dimensional array of integrated biological photoelectrodes, which comprises a plurality of electrode array layers, and the electrode array layers are laminated and connected along the longitudinal direction; and the electrode array layer is formed by arranging a plurality of integrated biological photoelectrodes in parallel. Integrated biological photoelectrodes with different lengths, LED wavelengths and other characteristics are arranged in multiple dimensions, each integrated biological photoelectrode can be provided with an independent bonding pad set, and during working, the device is inserted into biological brain tissue and immersed in a biological solution, so that the device is formed. And a photodiode is lightened, and a bioelectric signal is collected through a microelectrode array, so that the nerve cells are accurately controlled, and meanwhile, the collection range and the collection density of the nerve signals are effectively improved.

Description

Technical Field

[0001] The utility model relates to the field of photoelectrode array structures, in particular to a three-dimensional array of integrated biological photoelectrodes. Background Art

[0002] Optogenetic tools are a type of technology that uses light-sensitive proteins to control the activities of specific cells or molecules in biological systems. Transgenic tools are used to express light-sensitive proteins on the surface of nerve cell membranes, and then the physiological processes such as signal transduction, cell activity or gene expression in the body are regulated by light activation or inhibition of nerve cells. Optogenetic tools need to have two functions during development: specific targeted light regulation and recording of neural signals. These tools are called photoelectrodes, and their function is to achieve light control and record neural activity.

[0003] At present, photoelectrodes are mainly divided into two types: coupled light source type and integrated type. Coupled light source type photoelectrodes rely on optical fibers, laser sources and external coupling devices. These constraints limit the development of wireless and intelligent photoelectrodes. In order to overcome these limitations, integrated photoelectrodes are considered to be the inevitable development trend of optogenetic tools. Integrated photoelectrodes integrate light-emitting diodes into the top of the probe, making it no longer dependent on external light sources and having greater freedom and flexibility.

[0004] However, the signal collection range of existing integrated photoelectrodes is often limited to a two-dimensional plane, and optical fiber photoelectrodes often have only one light output point. Although an integrated photoelectrode can integrate multiple photodiodes, its signal collection range is often only arranged in one or two dimensions, that is, the microelectrodes that collect signals are concentrated on a line or a surface. This makes it difficult to use in some research that requires large-scale biological signal detection, and it cannot adapt to the needs of large-scale biological signal detection, and its flexibility of use is low. Summary of the invention

[0005] An embodiment of the utility model discloses a three-dimensional array of integrated biological photoelectrodes, which is used to solve the technical problem that the existing integrated photoelectrode structure often has only a one-dimensional or two-dimensional arrangement for signal collection, that is, the microelectrodes collecting signals are concentrated on a line or a surface, which makes it difficult to use in some research requiring large-scale biological signal detection, cannot adapt to the needs of large-scale biological signal detection, and has low flexibility of use.

[0006] The embodiment of the utility model provides a three-dimensional array of integrated biophotoelectrodes, comprising a plurality of electrode array layers, wherein the electrode array layers are stacked and connected in a longitudinal direction;

[0007] The electrode array layer is composed of a plurality of integrated bio-photoelectrodes arranged in parallel, and each of the integrated bio-photoelectrodes is provided with an independent pad group.

[0008] Optionally, the connection mode of the electrode array layer includes pin-and-female connection and resin-filled connection.

[0009] Optionally, each of the integrated bio-photoelectrodes is located on the same wafer;

[0010] The distances between the integrated bio-photoelectrodes are equal.

[0011] Optionally, the electrode array layer further includes a PCB board;

[0012] The integrated bio-photoelectrode is fixedly arranged on the PCB board.

[0013] Optionally, each electrode array layer is provided with an external pad group;

[0014] The independent pad group is connected to the external pad group via a first connection line;

[0015] The external pad groups are connected via a second connecting line;

[0016] The bottommost external pad group is connected to the external PCB board through a third connection line.

[0017] Optionally, the integrated biophotoelectrodes on the same electrode array layer have the same length.

[0018] Optionally, the lengths of the integrated biophotoelectrodes on the same electrode array layer are unequal.

[0019] Optionally, the integrated biophotoelectrode comprises a light emitting diode and / or a microelectrode.

[0020] Optionally, the independent pad groups are arranged on both sides of the integrated bio-photoelectrode, or are arranged at the edge of the electrode array layer and away from the integrated bio-photoelectrode, and are connected via connecting wires or etched circuits.

[0021] Optionally, the integrated biophotoelectrode includes, from bottom to top, a sapphire substrate, n-type gallium nitride, an active layer, p-type gallium nitride, an insulating conductive layer, a first insulating passivation layer, a cathode metal and an anode metal layer, a second insulating passivation layer, a microelectrode layer and a third insulating passivation layer.

[0022] It can be seen from the above technical solutions that the embodiments of the utility model have the following advantages:

[0023] The embodiment of the utility model provides a three-dimensional array of integrated bio-photoelectrodes, which includes a multi-layer electrode array layer, which is stacked and connected in the longitudinal direction; the electrode array layer is composed of a plurality of integrated bio-photoelectrodes arranged in parallel, and each integrated bio-photoelectrode is provided with an independent pad group. The integrated bio-photoelectrodes are arranged in multiple dimensions, and an independent pad group can be provided for each integrated bio-photoelectrode. When working, the device is inserted into biological brain tissue, immersed in a biological solution, and the photodiode is lit and the bioelectric signal is collected through the microelectrode array, thereby effectively improving the collection range and acquisition density of neural signals while achieving precise control of neural cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the utility model or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the utility model. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0025] Figure 1 A schematic structural diagram of a three-dimensional array of integrated biophotoelectrodes provided in an embodiment of the utility model;

[0026] Figure 2 This is a schematic diagram of the structure of a single integrated biophotoelectrode provided in an embodiment of the utility model;

[0027] Figure 3 A three-dimensional diagram of a monolithic integration solution of an electrode array layer provided in an embodiment of the utility model;

[0028] Figure 4 A schematic structural diagram of a three-dimensional array of integrated biophotoelectrodes provided in an embodiment of the utility model;

[0029] Figure 5 A schematic diagram of an electrode array layer provided in an embodiment of the utility model with an external pad group;

[0030] Figure 6 A three-dimensional diagram of a partial light-emitting diode scheme in a three-dimensional array of an integrated biophotoelectrode provided in an embodiment of the utility model;

[0031] Figure 7 A schematic diagram of a three-dimensional array structure composed of integrated bio-photoelectrodes of different lengths provided in an embodiment of the utility model;

[0032] Figure 8 This is a schematic structural diagram of an integrated biophotoelectrode provided in an embodiment of the utility model. DETAILED DESCRIPTION

[0033] An embodiment of the utility model discloses a three-dimensional array of integrated biological photoelectrodes, which is used to solve the technical problem that the existing integrated photoelectrode structure often has only a one-dimensional or two-dimensional arrangement for signal collection, that is, the microelectrodes collecting signals are concentrated on a line or a surface, which makes it difficult to use in some research requiring large-scale biological signal detection, cannot adapt to the needs of large-scale biological signal detection, and has low flexibility of use.

[0034] Optogenetics refers to the use of transgenic technology to express light-sensitive proteins that are sensitive to specific wavelengths on the cell membrane of biological nerve cells. The genetically modified nerve cells can be activated or inhibited by light. By stimulating nerve cells and collecting signals, it can be used for biomedical exploration such as studying signal transmission between nerve cells.

[0035] See also Figure 1 , a schematic structural diagram of a three-dimensional array of integrated biological photoelectrodes provided in an embodiment of the utility model.

[0036] The embodiment of the present application provides a three-dimensional array of integrated biophotoelectrodes, including multiple electrode array layers, wherein the electrode array layers are stacked and connected in a longitudinal direction;

[0037] The electrode array layer is composed of a plurality of integrated bio-photoelectrodes arranged in parallel, and each of the integrated bio-photoelectrodes is provided with an independent pad group.

[0038] Integrated biological photoelectrodes are tools used to study optogenetics. They are in the shape of elongated probes, with integrated light-emitting diodes, microelectrodes, etc. at the top and circuit pads at the end. When the probe is working, the light-emitting diodes emit light under the action of pulse voltage, stimulating biological neurons to generate nerve impulses, and the microelectrodes are used to record the signals generated by biological neuron impulses.

[0039] In the embodiment of the present application, the three-dimensional array is formed by an integrated biological photoelectrode, and multiple integrated biological photoelectrodes are arranged in parallel on the same plane to form a single-layer electrode array layer. Then, the multi-layer electrode array layer is stacked and connected in the longitudinal direction by means of a mother-pin header or a numerical filling method, so as to construct a three-dimensional array.

[0040] Each integrated biophotoelectrode is provided with an independent pad group, through which an external PCB board or an external device is connected, so that the integrated biophotoelectrode can be used.

[0041] In this embodiment, a three-dimensional array of integrated bio-photoelectrodes is provided, and the integrated bio-photoelectrodes are arranged in multiple dimensions, and each integrated bio-photoelectrode can be provided with an independent pad group. When working, the device is inserted into biological brain tissue, and the device is immersed in the biological solution, the photodiode is lit, and the bioelectric signal is collected through the microelectrode array, thereby achieving precise control of nerve cells while effectively improving the collection range and acquisition density of nerve signals.

[0042] See also Figure 2 , Figure 2 Schematic diagram of the structure of a single integrated biophotoelectrode in an embodiment of the present application.

[0043] In this embodiment, in the top view of a single integrated biological photoelectrode, it can be seen that the probe has three or more photodiodes, the microelectrode 11 is located above the photodiode, and an independent pad group is distributed on the rear part of the probe, which includes each microelectrode pad 12, a photodiode cathode pad 13 and a photodiode anode pad 14.

[0044] In one example of the present application, the connection method of the electrode array layer includes pin-and-female connection and resin-filled connection.

[0045] See also Figure 1 , three single integrated bio-photoelectrode probes 15 can be fixed on a PCB board 16 using resin, and the bio-photoelectrode pads 18 can be connected to the pads 19 on the PCB board using welding wires 17, and this can be repeated for three batches to obtain a three-layer electrode array layer. In actual operation, the three PCB boards can be connected to each other using pin and female headers 20, or resin can be filled between the PCB boards to fix the entire three-dimensional array.

[0046] In another example of the present application, each of the integrated bio-photoelectrodes is located on the same wafer;

[0047] The distances between the integrated bio-photoelectrodes are equal.

[0048] In actual operation, it is relatively complicated to solder a single integrated biophotoelectrode to a PCB. In the case of a large-scale three-dimensional array, there are often many integrated biophotoelectrodes that need to be soldered for a single-layer electrode array layer. To further improve the efficiency, standardization and portability of array packaging, the three integrated microelectrodes on the same wafer can be connected at their tails and cut as a whole, such as Figure 3 shown.

[0049] In this embodiment, a single-layer electrode array layer composed of three integrated biological photoelectrodes is taken as an example. They are all on the same wafer and the distance between each other is equal. It can be seen that each probe has 3 or more photodiodes, the microelectrode 11 is located above the photodiode, and the rear part of the probe is distributed with various microelectrode pads 12, photodiode cathode pads 13, and photodiode anode pads 14.

[0050] Furthermore, the electrode array layer also includes a PCB board;

[0051] The integrated bio-photoelectrode is fixedly arranged on the PCB board.

[0052] In this embodiment, since the integrated bio-photoelectrode can be provided in a single electrode or in multiple electrodes on the same wafer, it can be provided as follows: Figure 1 As shown, the electrode array layer may include a PCB board, and the integrated biophotoelectrode may be fixedly disposed on the PCB board, specifically, may be fixed on the PCB board by resin, and the pads may be connected to the pads on the PCB board by welding with welding wires.

[0053] In another example of the present application, Figure 4 As shown, multiple integrated bio-photoelectrodes on the same wafer are fixed on a PCB board, and each pad 18 on the single wafer is connected to a pad 19 on the PCB board through a welding wire 17. The three PCB boards can be interconnected by using a pin header 20, or resin can be filled between the PCB boards to fix the entire microelectrode array.

[0054] Optionally, each electrode array layer is provided with an external pad group;

[0055] The independent pad group is connected to the external pad group via a first connection line;

[0056] The external pad groups are connected via a second connecting line;

[0057] The bottommost external pad group is connected to the external PCB board through a third connection line.

[0058] like Figure 5 As shown, each electrode array layer can be provided with an external pad group, and the independent pad group on each electrode array layer is connected to the external pad group of the next layer via a first connecting line, and then the layer and the next layer of external pad group are connected via a second connecting line. To facilitate the subsequent use and detection of the electrodes, the external pad group of the bottom layer can be connected to an external PCB board via a third connecting line to transmit the data information collected by each electrode array layer.

[0059] Specifically, three biophotoelectrode monoliths 21, 22, and 23 are stacked up and down, wherein the pad 24 on the top monolith 21 is connected to the pad 25 on the middle monolith 22 through a welding wire 27, and then the pad 25 on the middle monolith 22 is connected to the pad 26 on the bottom monolith 23 through a welding wire 28, and finally the pad 24 is connected to the pad 26, and then connected to the external PCB board through the pad 26, thus, through the intermediate pad 26, it can be avoided that the welding wire failure caused by the welding wire being too long and the span being too large when connected to the outside. The pads on the monolith 21 and the monolith 22 are all connected to the pad on the monolith 23 by analogy. Resin is used to fill between each monolith to control and fix the distance between the probes of each layer.

[0060] In one example of the present application, the lengths of the integrated biophotoelectrodes on the same electrode array layer are equal.

[0061] In one example of this application, Figure 6 As shown, the nine biological photoelectrodes are exactly the same, and their light-emitting diodes are all the same color light sources. In scheme four, the tops of the three probes 15 have no light-emitting diodes but only microelectrodes, and the tops of the probes 29 have light-emitting diodes and microelectrodes. This allows the array to detect the activity of nerve cells in the three-dimensional array while having a certain ability to regulate organisms. At the same time, the microelectrodes of the probes without light-emitting diodes have less noise and lower costs, which reduces the cost of the entire array. In addition, biological photoelectrodes of different wavelengths can be assembled into the same array, so that the system has the ability to regulate different activities of nerve cells. In practical applications, the presence or absence of light-emitting diodes on each probe and the spectrum of the light-emitting diodes can be adjusted as needed to meet different experimental requirements.

[0062] In one example of the present application, the lengths of the integrated biophotoelectrodes on the same electrode array layer are unequal.

[0063] In this embodiment, if Figure 7 As shown, the lengths of the integrated bio-photoelectrodes on the same electrode array layer are not equal, and the probes 30, 31, and 32 have different lengths. Bio-photoelectrode probes of different lengths are conducive to detecting biological signals in a wider range of depths. In practical applications, microelectrode probe arrays of different lengths can be designed according to the shape of the experimental animal parts to better detect signals from different animal nerve parts.

[0064] In one example of the present application, the integrated biophotoelectrode includes a light emitting diode and / or a microelectrode.

[0065] In an example of the present application, the independent pad groups are arranged on both sides of the integrated bio-photoelectrode, or are arranged at the edge of the electrode array layer and away from the integrated bio-photoelectrode, and are connected through connecting wires or etched circuits.

[0066] like Figure 3 or Figure 4 As shown in the electrode array layer in the embodiment, the independent pad groups can be directly fixed on both sides of each integrated bio-photoelectrode, such as Figure 3 or Figure 4 Integrated biophotoelectrodes on both sides.

[0067] At the same time, the independent pad group can also be arranged at the edge of the electrode array layer and away from the integrated bio-photoelectrode, and connected through a connecting wire or an etched circuit, such as Figure 3 or Figure 4 The integrated biophotoelectrode in the middle.

[0068] In one example of the present application, the integrated bio-photoelectrode includes, from bottom to top, a sapphire substrate, an n-type gallium nitride, an active layer, a p-type gallium nitride, an insulating conductive layer, a first insulating passivation layer, a cathode metal and an anode metal layer, a second insulating passivation layer, a microelectrode layer and a third insulating passivation layer.

[0069] See also Figure 8 , Figure 8 The schematic diagram of the hierarchical structure of an integrated biophotoelectrode in the embodiment of the present application is shown, which includes, from bottom to top, a sapphire substrate 1, n-type gallium nitride 2, an active layer 3, a p-type gallium nitride 4, an insulating conductive layer 5, a first insulating passivation layer 6, a cathode metal and an anode metal layer 7, a second insulating passivation layer 8, a microelectrode layer 9 and a third insulating passivation layer 10. The microelectrode layer 9 may include microelectrodes, wires and pads.

[0070] In this embodiment, the working principle of the photodiode is that by connecting a forward voltage to the anode pad 14 and grounding the cathode pad 13, the current will flow into the p-type gallium nitride 4 region of the photodiode through the anode contact and the wire, and flow into the n-type gallium nitride 2 through the active layer 3. The current flows out from the cathode pad 13. In this process, the photodiode lights up and activates the biological nerve cells. At the same time, the change in the potential of the biological nerve cells will also generate a signal on the microelectrode 15.

[0071] The working principle of the microelectrode part is that when the probe is inserted into the biological neural tissue, the microelectrode metal directly contacts the tissue fluid, the potential generated by the action of the nerve cells will be transmitted to the microelectrode through the tissue fluid, and finally connected to the external circuit through the microelectrode pad 12, thereby, the biological neural cell signal is collected.

[0072] In a specific implementation, the integrated biophotoelectrode can be prepared by:

[0073] Growing n-type gallium nitride, an active layer and p-type gallium nitride in sequence on a sapphire substrate;

[0074] The transparent conductive layer of indium tin oxide is prepared in a high vacuum argon environment by photolithography and magnetron sputtering process;

[0075] The transparent conductive layer of indium tin oxide is patterned by a lift-off process to prepare a transparent anode and an electromagnetic shielding layer of a light-emitting diode;

[0076] A good ohmic contact is formed between the indium tin oxide transparent conductive layer and the p-type gallium nitride through a rapid thermal annealing process;

[0077] Etching the epitaxial wafer to n-type GaN by photolithography and dry etching in a gas environment of Cl2 and BCl3;

[0078] High temperature activates the active layer;

[0079] A silicon dioxide isolation layer is prepared by photolithography and plasma enhanced chemical vapor deposition process in a gas environment of SiH4 and N2O, a high vacuum and a high temperature environment of 350°C, and the silicon dioxide isolation layer is patterned by a buffered oxide etching solution using a wet etching process to prepare a cathode window and an anode window;

[0080] A metal film is prepared in a high vacuum environment by photolithography and electron beam evaporation processes, and the metal film is patterned by a lift-off process to prepare a light-emitting diode anode electrode, a light-emitting diode anode wire, a light-emitting diode anode pad, a light-emitting diode cathode electrode, a light-emitting diode cathode wire, and a light-emitting diode cathode pad;

[0081] A silicon dioxide passivation layer is prepared by photolithography and plasma enhanced chemical vapor deposition in a gas environment of SiH4 and N2O, a high vacuum and a high temperature environment of 350°C, and the silicon dioxide isolation layer is patterned by a dry etching process to prepare an anode pad window and a cathode pad window;

[0082] A metal film is prepared in a high vacuum environment by photolithography and electron beam evaporation processes, and the metal film is patterned by a lift-off process to prepare microelectrodes, microelectrode wires, and microelectrode pads;

[0083] A silicon dioxide passivation layer was prepared by photolithography and plasma enhanced chemical vapor deposition in a gas environment of SiH4 and N2O, high vacuum and 350°C high temperature environment, and the silicon dioxide isolation layer was patterned by a dry etching process to prepare a microelectrode window, a microelectrode pad window, an anode pad window and a cathode pad window.

[0084] In the embodiment of the present application, the integrated biophotoelectrodes are arranged in an array and a monolithic integration scheme is added, that is, the three probes on the same wafer are cut as a whole and then stacked, so that the assembly of the entire system is more convenient and standardized. At the same time, a variety of optional structures are provided to meet different experimental needs and cost control needs.

[0085] Finally, it should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the presence of other identical elements in the process, method, article or device including the elements.

[0086] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The various embodiments can be combined as needed, and the same or similar parts can refer to each other.

[0087] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A three-dimensional array of integrated biophotoelectrodes, characterized in that: It comprises a plurality of electrode array layers, wherein the electrode array layers are stacked and connected in a longitudinal direction; The electrode array layer is composed of a plurality of integrated bio-photoelectrodes arranged in parallel, and each of the integrated bio-photoelectrodes is provided with an independent pad group.

2. The three-dimensional array of integrated biophotoelectrodes according to claim 1, characterized in that: The connection modes of the electrode array layer include pin-and-female connection and resin-filled connection.

3. The three-dimensional array of integrated biophotoelectrodes according to claim 1, characterized in that: Each of the integrated bio-photoelectrodes is located on the same wafer; The distances between the integrated bio-photoelectrodes are equal.

4. The three-dimensional array of integrated biophotoelectrodes according to claim 1 or 3, characterized in that: The electrode array layer also includes a PCB board; The integrated bio-photoelectrode is fixedly arranged on the PCB board.

5. The three-dimensional array of integrated biophotoelectrodes according to claim 4, characterized in that: Each electrode array layer is provided with an external pad group; The independent pad group is connected to the external pad group via a first connection line; The external pad groups are connected via a second connecting line; The bottommost external pad group is connected to the external PCB board through a third connection line.

6. The three-dimensional array of integrated biophotoelectrodes according to claim 1, characterized in that: The lengths of the integrated biophotoelectrodes on the same electrode array layer are equal.

7. The three-dimensional array of integrated biophotoelectrodes according to claim 1, characterized in that: The lengths of the integrated biophotoelectrodes on the same electrode array layer are not equal.

8. The three-dimensional array of integrated biophotoelectrodes according to claim 1, characterized in that: The integrated biophotoelectrode includes a light emitting diode and / or a microelectrode.

9. The three-dimensional array of integrated biophotoelectrodes according to claim 1, characterized in that: The independent pad groups are arranged on both sides of the integrated bio-photoelectrode, or are arranged at the edge of the electrode array layer and away from the integrated bio-photoelectrode, and are connected via connecting wires or etching circuits.

10. The three-dimensional array of integrated biophotoelectrodes according to claim 1, characterized in that: The integrated biophotoelectrode includes, from bottom to top, a sapphire substrate, n-type gallium nitride, an active layer, p-type gallium nitride, an insulating conductive layer, a first insulating passivation layer, a cathode metal and an anode metal layer, a second insulating passivation layer, a microelectrode layer and a third insulating passivation layer.

Images