CN112120695A - Deep flexible brain electrode combined with drug delivery channel and preparation method thereof - Google Patents
Deep flexible brain electrode combined with drug delivery channel and preparation method thereof Download PDFInfo
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- A61B2562/164—Details of sensor housings or probes; Details of structural supports for sensors the sensor is mounted in or on a conformable substrate or carrier
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
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Abstract
The invention discloses a deep flexible brain electrode combined with a drug delivery channel and a preparation method thereof, wherein the deep flexible brain electrode comprises a flexible electrode and a flexible drug delivery channel arranged in parallel with the surface of the flexible electrode, the rear end of the flexible electrode is provided with a silicon substrate, one end of the flexible drug delivery channel is fixed on the silicon substrate, and a flexible implanted part of the flexible electrode is attached to the flexible drug delivery channel in parallel. The flexible drug delivery channel is arranged on the flexible electrode, and the combined deep flexible brain electrode is flexible as a whole, so that the flexible drug delivery channel has good biocompatibility and longer service life; the flexible drug delivery channel and the flexible electrode are convenient and simple to combine, and the assembly power is high; the deep flexible brain electrode can realize simultaneous drug stimulation and electrophysiological recording.
Description
Technical Field
The invention relates to the technical field of brain function detection, in particular to a deep flexible brain electrode combined with a drug delivery channel and a preparation method thereof.
Background
Implantable nerve probes are the most widespread tool for recording single-cell, sub-millisecond resolution neural activity, but their signals tend to degrade over time due to chronic inflammatory reactions and neuronal cell inactivation around the implantation site. The failure of implanted nerve probes for long-term recording is one of the most critical challenges in longitudinal studies of cognitive function (e.g., learning and memory) and high fidelity nerve repair techniques. Experimental evidence indicates that the flexible nerve probe with mechanical strength close to that of brain tissue can reduce relative shearing movement, thereby improving the stability of electrode recording and the service life of the electrode recording.
The micro-fluidic administration channel is a common way for regulating the activity of intracranial neurons and injecting virus expression. The traditional intracranial administration channel is often single in function and does not have the function of recording the neural activity. A part of the deep electrode probe is combined with the administration channel, so that the change of the neural activity can be rapidly obtained while the medicine is delivered to the cranium. However, most of the electrodes are hard silicon-based electrodes, and have the defects of large implantation trace and easy causing rejection reaction and intracranial tissue damage. These disadvantages severely affect the working life of this class of drug delivery electrodes, making it difficult to apply them to behavioral and intracranial viral expression experiments with long experimental periods. Therefore, how to provide a stimulation/recording system which combines a flexible electrode with a flexible drug delivery channel, has good biocompatibility and recording stability, and can work in vivo for a long time becomes a technical problem to be solved in the field urgently.
Disclosure of Invention
The invention aims to provide a deep flexible brain electrode combined with a drug delivery channel and a preparation method thereof, which are used for overcoming the technical problems in the background art.
The invention is realized by the following technical scheme:
the invention provides a deep flexible brain electrode combined with a drug delivery channel, which comprises a flexible electrode and a flexible drug delivery channel arranged in parallel with the surface of the flexible electrode, wherein a silicon substrate is arranged at the rear end of the flexible electrode, one end of the flexible drug delivery channel is fixed on the silicon substrate, and a flexible implantation part of the flexible electrode is attached to the flexible drug delivery channel in parallel.
Further, the surfaces of the flexible implantation part and the flexible drug delivery channel are coated with biocompatible biological glue which is used for bonding and reinforcing the flexible implantation part and the flexible drug delivery channel.
Furthermore, the flexible electrode sequentially comprises an electrode supporting layer, a lead structure, an electrode isolation layer and an exposed electrode from bottom to top, a welding spot is arranged on the silicon substrate, and the lead structure is electrically connected with the welding spot and the exposed electrode.
Further, the lead structure and the exposed electrode are both formed of a metal having a predetermined ductility and being harmless to a human body.
Further, SU8 photoresist or polyimide is adopted as the material of the electrode supporting layer and the electrode isolation layer.
Further, the flexible drug delivery channel is a flexible pipeline formed by polymer materials, the flexible drug delivery channel is provided with an implanting end and an input end used for inputting drugs, the input end is fixed on the silicon substrate, and the implanting end is used for implanting into the brain for drug delivery.
Further, in the using process of the flexible brain electrode, the medicine injection of the flexible medicine feeding channel and the brain electrical signal recording of the flexible electrode are alternately and repeatedly carried out.
The invention also provides a preparation method of the deep flexible brain electrode combined with the drug delivery channel, which comprises the following steps:
fixing one end of a flexible drug delivery channel on a silicon substrate at the rear end of a flexible electrode, and fixing the rear end of the flexible electrode on a mechanical arm capable of moving vertically;
immersing the flexible electrode and the extended part of the flexible administration channel into water, wherein the flexible implanted part at the front end of the flexible electrode floats on the water surface;
and controlling the mechanical arm to slowly draw out the flexible electrode and the flexible drug delivery channel, and controlling the flexible implantation part by using a fine tungsten wire under a microscope to enable the flexible implantation part to be parallelly attached to the flexible drug delivery channel through capillary tension.
Further, after the step of controlling the mechanical arm to slowly draw out the flexible electrode and the flexible drug delivery channel and controlling the flexible implantation part with a fine tungsten wire under a microscope to attach the flexible implantation part to the flexible drug delivery channel in parallel by capillary tension, the method further comprises the following steps:
and polyethylene glycol or high-concentration protein or chitosan is coated on the surfaces of the flexible implantation part and the flexible administration channel, so that the flexible implantation part is firmly attached to the surface of the flexible administration channel.
Further, before the steps of fixing one end of the flexible drug delivery channel on the silicon substrate at the rear end of the flexible electrode and fixing the rear end of the flexible electrode on a mechanical arm capable of moving vertically, the method further comprises the preparation of the flexible electrode, wherein the preparation of the flexible electrode specifically comprises the following steps:
providing a silicon substrate;
growing a sacrificial layer on the surface of the silicon substrate;
forming a patterned electrode supporting layer on the surface of the sacrificial layer;
growing an electrode material layer on the patterned electrode supporting layer to form a lead structure;
forming an electrode isolation layer on the electrode supporting layer and the lead structure, and patterning the electrode isolation layer to expose the connection part of the lead structure and the exposed electrode;
growing an electrode material layer on the surface of the connecting part of the exposed electrode;
patterning the electrode material layer to form an exposed electrode;
and releasing the sacrificial layer to obtain the flexible electrode.
The implementation of the invention has the following beneficial effects:
according to the invention, the flexible drug delivery channel is arranged on the flexible electrode, and the combined deep flexible brain electrode is flexible as a whole, so that the deep flexible brain electrode has good biocompatibility and longer service life; the flexible drug delivery channel and the flexible electrode are convenient and simple to combine, and the assembly power is high; the deep flexible brain electrode can realize simultaneous drug stimulation and electrophysiological recording.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions and advantages of the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a schematic diagram of the structure of a deep, flexible electroencephalogram electrode provided by an embodiment of the present invention;
FIG. 2 is a schematic diagram of the structure of a flexible brain electrode in combination with a flexible administration channel according to an embodiment of the present invention;
FIG. 3 is a schematic structural diagram corresponding to the method for preparing a flexible electroencephalogram according to an embodiment of the present invention;
wherein the reference numerals in the figures correspond to: 1-flexible electrode, 2-flexible drug delivery channel, 11-silicon substrate, 12-sacrificial layer, 13-electrode supporting layer, 14-lead structure, 15-electrode isolating layer and 16-exposed electrode.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following examples. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic may be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
In the description of the present invention, it is to be understood that the terms "comprises" and "comprising," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or server that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
In the description of the present invention, it will be understood that when an element is referred to as being "on …", "above …", "below …" or "below …" with respect to another element, it can be directly "on …", "above …", "below …" or "below …" with respect to the other element, respectively, or intervening elements may also be present. Thus, terms such as "on …", "above …", "below …", or "below …" as used herein are for illustrative purposes only and are not intended to limit embodiments.
Examples
The existing intracranial drug delivery system is often single in function and does not have an electrode recording function. Part of silicon-based hard probes are combined with a drug delivery channel, but because the mechanical properties of the electrodes are not matched with soft brain tissues, intracranial rejection reaction and inflammation are often caused, and long-term recording cannot be realized. Referring to fig. 1, the deep flexible brain electrode combined with a drug administration channel in the present embodiment includes a flexible electrode 1 and a flexible drug administration channel 2 disposed in parallel with a surface of the flexible electrode 1, a silicon substrate is disposed at a rear end of the flexible electrode 1, one end of the flexible drug administration channel 2 is fixed on the silicon substrate, and a flexible implanted portion of the flexible electrode 1 is attached to the flexible drug administration channel 2 in parallel. In the embodiment, the flexible drug delivery channel is arranged on the flexible electrode, so that a regulation/recording system for simultaneously carrying out drug stimulation and electrophysiological recording can be realized, and the combined deep flexible brain electrode probe is flexible as a whole, and has good biocompatibility and longer service life; the flexible drug delivery channel and the flexible electrode are convenient and simple to combine, and the assembly power is high; the deep flexible brain electrode can realize a stimulation/recording system integrating long-term stable recording and drug administration channel intracranial regulation and control functions, and has important significance for neuroscience and animal behavior research.
As a specific implementation mode, the surfaces of the flexible implantation part and the flexible drug delivery channel 2 are coated with biocompatible biological glue, and the biological glue is used for bonding and reinforcing the flexible implantation part and the flexible drug delivery channel so as to enable the flexible electrode to be attached to the surface of the flexible drug delivery channel more firmly.
As a specific implementation mode, the flexible electrode sequentially comprises an electrode supporting layer, a lead structure, an electrode isolation layer and an exposed electrode from bottom to top, a welding spot for electric connection is arranged on the silicon substrate, the exposed electrode is directly contacted with brain tissue and used for recording nerve activity signals, and the lead structure is electrically connected with the welding spot and the exposed electrode.
As a specific embodiment, the silicon substrate is a silicon wafer for growing 2 μm silicon dioxide, and the solder joint on the silicon substrate is formed by depositing nickel and gold on the chromium layer in this order, and specifically, for example, the solder joint may be formed by depositing 100nm nickel and 10nm gold on 5-10nm chromium.
As a specific embodiment, the lead structure is formed by using a metal having a predetermined ductility and being harmless to the human body, wherein the predetermined ductility can be set according to a ductility requirement of the lead structure in practical applications. Specifically, the lead structure is formed by using chromium with a thickness of 5-10nm and gold/platinum with a thickness of 100nm, in some other embodiments, the lead structure may also use other metals with good biocompatibility, such as one or more of gold, platinum, black gold, platinum black, iridium-platinum alloy, and conductive carbon nanotubes, and those skilled in the art may make any suitable adjustment.
As a specific embodiment, the exposed electrode directly contacts with the cerebral cortex, and is formed by metal with preset ductility and harmless to human body, wherein the preset ductility can be set according to the ductility requirement of the exposed electrode in practical application. Specifically, the exposed electrode is formed by using chromium with a thickness of 5-10nm and gold/platinum with a thickness of 100nm, in other embodiments, the exposed electrode may also be formed by using other metals with good biocompatibility, such as one or more of gold, platinum, black gold, platinum black, iridium-platinum alloy and conductive carbon nanotubes, and any suitable adjustment may be performed by those skilled in the art.
As a specific implementation mode, SU8 photoresist or polyimide is adopted as the material of the electrode supporting layer and the electrode isolating layer, and SU8 photoresist or polyimide has good biocompatibility.
In one embodiment, the flexible drug delivery channel is a flexible tube formed of a polymer material, and the flexible drug delivery channel has an implantation end and an input end for inputting drugs, the input end is fixed on the silicon substrate and can be connected with a port of a capsule or a drug delivery pump, and the implantation end is used for implantation in the brain for drug delivery. The flexible administration channel may be any commercially available flexible administration channel, and the embodiment of the present invention is not limited thereto.
In this embodiment, before the flexible brain electrode is implanted, the injection rate of the flexible brain electrode with drug delivery function needs to be calibrated. Specifically, the infusion rate can be calibrated by measuring the time and output weight at target rates of 1nl/s, 10nl/s, 20nl/s, and 50nl/s, respectively, by means of water injection to facilitate post-implantation drug delivery control.
As a specific embodiment, during the use process of the flexible brain electrode, the drug injection of the flexible drug delivery channel and the brain electrical signal recording of the flexible electrode are performed alternately and repeatedly. Specifically, the drug injection of the flexible drug delivery channel and the electroencephalogram signal recording of the flexible electrode can be alternately carried out for 3 minutes and repeatedly carried out.
Another embodiment of the present invention provides a method for manufacturing a deep flexible brain electrode in combination with an administration channel in the above embodiments, the method for manufacturing a deep flexible brain electrode in this embodiment, including the steps of:
s1, fixing one end of the flexible drug delivery channel on a silicon substrate at the rear end of the flexible electrode, and fixing the rear end of the flexible electrode on a mechanical arm capable of moving vertically, so that the flexible electrode can be conveniently pulled out of water in the subsequent steps;
s2, immersing the flexible electrode and the extended part of the flexible administration channel into water, wherein the flexible implanted part at the front end of the flexible electrode floats on the water surface;
s3, controlling the mechanical arm to slowly draw out the flexible electrode and the flexible drug delivery channel, as shown in figure 2, wherein the arrow direction in the figure indicates the drawing-out direction, and controlling the flexible implantation part by using a thin tungsten wire under a microscope to enable the flexible implantation part to be attached to the flexible drug delivery channel in parallel through capillary tension.
As a specific embodiment, after the step of controlling the mechanical arm to slowly draw out the flexible electrode and the flexible drug delivery channel and controlling the flexible implantation part by using a fine tungsten wire under a microscope to enable the flexible implantation part to be attached to the flexible drug delivery channel in parallel through capillary tension, the method further comprises the following steps:
polyethylene glycol or high-concentration fibroin solution or chitosan is coated on the surfaces of the flexible implantation part and the flexible drug delivery channel, so that the flexible implantation part is firmly attached to the surface of the flexible drug delivery channel, and in other embodiments, other materials with good biocompatibility can be adopted to realize the firm attachment between the flexible implantation part and the flexible drug delivery channel.
As a specific embodiment, before the steps of fixing one end of the flexible drug delivery channel on a silicon substrate at the rear end of the flexible electrode and fixing the rear end of the flexible electrode on a vertically movable mechanical arm, the method further includes the preparation of the flexible electrode, as shown in fig. 3, the preparation of the flexible electrode specifically includes:
s01, providing a silicon substrate 11; specifically, a silicon wafer on which 2 μm silicon dioxide is grown may be selected as the silicon substrate 11.
S02, growing a sacrificial layer 12 on the surface of the silicon substrate 11; specifically, the silicon substrate 11 is cleaned by a cleaning solution, such as concentrated sulfuric acid, and then 5-10nm of chromium plus 100nm of nickel or aluminum is grown on the surface of the silicon substrate 11 as the sacrificial layer 12 by a chemical vapor deposition method. In other embodiments, the silicon substrate 11 and the sacrificial layer 12 may also be selected from other suitable materials, which are not limited herein.
S03, forming a patterned electrode supporting layer 13 on the surface of the sacrificial layer 12; in this step, the electrode support layer 13 is made of a non-degradable flexible thin film material, and specifically, SU8 photoresist or polyimide may be spin-coated on the surface of the sacrificial layer 12 to serve as the electrode support layer 13. Of course, in other embodiments, the electrode support layer 13 may be made of other suitable non-degradable flexible film materials, and is not limited herein.
S04, growing an electrode material layer on the patterned electrode supporting layer 13 to form a lead structure 14; the lead structure 14 is used for electrically connecting the welding points on the silicon substrate 11 and for directly contacting the exposed electrodes with cerebral cortex, and the electrode material layer is made of metal which has good ductility and is harmless to human bodies. Specifically, chromium of 5-10nm thickness plus gold/platinum of 100nm thickness can be sputtered as the electrode material layer. In other embodiments, other suitable metal conductive materials may also be used as the electrode material, such as one or more of gold, platinum, black gold, platinum black, iridium-platinum alloy, and conductive carbon nanotubes, which may be adjusted by those skilled in the art at will, and in addition, the thickness of the electrode material layer may also be adjusted by those skilled in the art as appropriate, which is not limited in the embodiments of the present invention.
S05, forming an electrode isolation layer 15 on the electrode support layer 13 and the lead structure 14, and patterning the electrode isolation layer 15 to expose the connection portion of the lead structure 14 and the exposed electrode; the electrode isolation layer 15 is a non-conductive flexible film material. Specifically, SU8 photoresist or polyimide may be spin-coated as the electrode isolation layer 15. Of course, in other embodiments, the electrode isolation layer 15 may be other suitable non-conductive flexible film materials, and is not limited herein.
S06, growing an electrode material layer on the surface of the connecting part of the exposed electrode; specifically, the electrode material layer is made of a metal having good ductility and harmless to the human body. Specifically, chromium of 5-10nm thickness plus gold/platinum of 100nm thickness can be sputtered as the electrode material layer. In other embodiments, other suitable metal conductive materials may also be used as the electrode material, such as one or more of gold, platinum, black gold, platinum black, iridium-platinum alloy, and conductive carbon nanotubes, which may be adjusted by those skilled in the art at will, and in addition, the thickness of the electrode material layer may also be adjusted by those skilled in the art as appropriate, which is not limited in the embodiments of the present invention.
S07, patterning the electrode material layer to form an exposed electrode 16; in this step, the exposed electrode 16 may be in direct contact with the cerebral cortex, and the electrode material layer is made of a metal having good ductility and harmless to the human body. Specifically, chromium of 5-10nm thickness plus gold/platinum of 100nm thickness can be sputtered as the electrode material layer. In other embodiments, other suitable metal conductive materials may also be used as the electrode material, such as one or more of gold, platinum, black gold, platinum black, iridium-platinum alloy, and conductive carbon nanotubes, which may be adjusted by those skilled in the art at will, and in addition, the thickness of the electrode material layer may also be adjusted by those skilled in the art as appropriate, which is not limited in the embodiments of the present invention.
S08, releasing the sacrificial layer 12 to obtain the flexible electrode, specifically, because the sacrificial layer 12 is formed by depositing nickel or aluminum on the chromium layer, a method of corroding by using a metal corrosive liquid can be adopted to corrode the sacrificial layer 12 in the metal corrosive liquid, thereby releasing to obtain the flexible electrode.
The above embodiment of the invention has the following beneficial effects:
according to the embodiment of the invention, the flexible drug delivery channel is arranged on the flexible electrode, and the combined deep flexible brain electrode is flexible as a whole, so that the deep flexible brain electrode has good biocompatibility and longer service life; the flexible drug delivery channel and the flexible electrode are convenient and simple to combine, and the assembly power is high; the deep flexible brain electrode provided by the embodiment of the invention can realize simultaneous drug stimulation and electrophysiological recording.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (10)
1. The deep flexible brain electrode combined with the drug administration channel is characterized by comprising a flexible electrode and a flexible drug administration channel arranged in parallel with the surface of the flexible electrode, wherein a silicon substrate is arranged at the rear end of the flexible electrode, one end of the flexible drug administration channel is fixed on the silicon substrate, and a flexible implantation part of the flexible electrode is attached to the flexible drug administration channel in parallel.
2. The deep flexible brain electrode according to claim 1, wherein the flexible implanted portion and the flexible drug delivery channel are coated with bio-compatible bio-glue for adhesion reinforcement of the flexible implanted portion and the flexible drug delivery channel.
3. The deep, flexible brain electrode in combination with an administration channel of claim 1, wherein the flexible electrode comprises, in order from bottom to top, an electrode support layer, a lead structure, an electrode isolation layer and an exposed electrode, the silicon substrate having a solder joint thereon, the lead structure electrically connecting the solder joint and the exposed electrode.
4. The deep, flexible brain electrode in combination with an administration channel of claim 3, wherein the lead structure and the exposed electrode are each formed of a metal having a predetermined ductility and being harmless to the human body.
5. The deep, flexible brain electrode in combination with a drug delivery channel of claim 3, wherein the material of the electrode supporting layer and the electrode isolation layer is SU8 photoresist or polyimide.
6. The deep flexible brain electrode in combination with a drug delivery channel of claim 1, wherein the flexible drug delivery channel is a flexible tube formed of a polymer material, the flexible drug delivery channel having an implanted end and an input end for drug delivery, the input end being affixed to a silicon substrate, the implanted end being configured to be implanted in the brain for drug delivery.
7. The deep flexible brain electrode in combination with a drug delivery channel according to claim 1, wherein the drug infusion of the flexible drug delivery channel is alternated and repeated with the recording of brain electrical signals of the flexible electrodes during the use of the flexible brain electrode.
8. A method of making a deep flexible brain electrode incorporating a drug delivery channel according to any one of claims 1 to 7, comprising the steps of:
fixing one end of a flexible drug delivery channel on a silicon substrate at the rear end of a flexible electrode, and fixing the rear end of the flexible electrode on a mechanical arm capable of moving vertically;
immersing the flexible electrode and the extended part of the flexible administration channel into water, wherein the flexible implanted part at the front end of the flexible electrode floats on the water surface;
and controlling the mechanical arm to slowly draw out the flexible electrode and the flexible drug delivery channel, and controlling the flexible implantation part by using a fine tungsten wire under a microscope to enable the flexible implantation part to be parallelly attached to the flexible drug delivery channel through capillary tension.
9. The method for preparing a deep flexible brain electrode combined with a drug delivery channel according to claim 8, further comprising the step of controlling the flexible implant part with a fine tungsten wire under a microscope while controlling the mechanical arm to slowly draw out the flexible electrode and the flexible drug delivery channel so that the flexible implant part is attached to the flexible drug delivery channel in parallel by capillary tension, and the step of:
and polyethylene glycol or high-concentration protein or chitosan is coated on the surfaces of the flexible implantation part and the flexible administration channel, so that the flexible implantation part is firmly attached to the surface of the flexible administration channel.
10. The method for preparing a deep flexible brain electrode combined with a drug delivery channel according to claim 8, wherein the method further comprises the step of preparing the flexible electrode before the steps of fixing one end of the flexible drug delivery channel on the silicon substrate at the rear end of the flexible electrode and fixing the rear end of the flexible electrode on a vertically movable mechanical arm, and the step of preparing the flexible electrode specifically comprises the following steps:
providing a silicon substrate;
growing a sacrificial layer on the surface of the silicon substrate;
forming a patterned electrode supporting layer on the surface of the sacrificial layer;
growing an electrode material layer on the patterned electrode supporting layer to form a lead structure;
forming an electrode isolation layer on the electrode supporting layer and the lead structure, and patterning the electrode isolation layer to expose the connection part of the lead structure and the exposed electrode;
growing an electrode material layer on the surface of the connecting part of the exposed electrode;
patterning the electrode material layer to form an exposed electrode;
and releasing the sacrificial layer to obtain the flexible electrode.
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| CN113786198A (en) * | 2021-09-10 | 2021-12-14 | 中国科学院空天信息创新研究院 | Dormancy detection, regulation and control integrated implanted flexible neural electrode and test system |
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