KR102128092B1 - Deep brain stimulation transparent electrodes array and neural signal detection method using the same - Google Patents

Abstract

The present invention relates to a brain deep stimulation transparent electrode array and a method for detecting neural signals using the same, wherein the brain deep stimulation transparent electrode array comprises: a transparent graphene neural electrode; And comprising a fiber, the transparent graphene neural electrode is a biocompatible dielectric substrate, a plurality of electrode sites disposed on one side of the substrate and including a graphene sheet, a plurality of electrical conductivity disposed on the other side of the substrate And an electrically conductive interconnect that connects the contact with the electrode site.
The brain deep stimulation transparent electrode array of the present invention is capable of detecting deep brain electrical stimulation and brain waves while minimizing image distortion in magnetic resonance imaging, and conducts fusion studies on nerve cell stimulation through light stimulation and optical imaging of nerve cells. can do.

Description

DEEP BRAIN STIMULATION TRANSPARENT ELECTRODES ARRAY AND NEURAL SIGNAL DETECTION METHOD USING THE SAME

The present invention relates to a brain deep stimulation transparent electrode array capable of detecting brain deep electrical stimulation and brain waves while minimizing image distortion in a magnetic resonance image and a method for detecting neural signals using the same.

Treatment using brain electrical stimulation has been extensively applied to the treatment of neurological disorders such as Parkinson's disease, Epilepsy, Tourette syndrome, and the like. In particular, deep brain stimulation (DBS), which stimulates the deep brain to alleviate the symptoms of a neurological disease, has become an effective surgical therapy for patients with difficult symptoms with drug therapy. In Korea, about 20 medical centers are performing hundreds of deep brain stimulations annually, and their utilization is increasing worldwide.

The deep brain stimulation electrode (hereinafter referred to as DBS electrode) is one of various types of neural electrodes. Deep brain stimulation assists the activation of dopamine neurons by injecting DBS electrodes into the deep brain to provide periodic electrical stimulation. The electrical stimulation is Parkinson's disease, essential tremor (Essential tremor), depression, epilepsy, as well as Alzheimer's, obesity, addiction to the treatment of the field of application has been widened and more active research has been made in recent years.

However, existing DBS electrodes are made of opaque metals such as tungsten and platinum, which brings image artifacts from medical images such as magnetic resonance imaging (MRI). Distorted image information can interfere with the correct positioning of the DBS electrode during surgery, or the correct diagnosis of other neurological diseases after electrode implantation.

The image distortion phenomenon in MRI is because the magnetic susceptibility of metallic materials is significantly larger than that of living tissue (tissue) and water in vivo (H ₂ O). Therefore, an electrode using carbon fiber having a relatively small magnetization rate has been proposed. However, due to the large amount of carbon atoms in the carbon fiber, there was a limit in reducing the distortion of the MRI image. In addition, carbon fiber has a weak mechanical strength, and thus there is a potential danger that electrical connection may be lost when transplanted in vivo for a long time.

An object of the present invention is to provide a brain deep stimulation transparent electrode array capable of detecting brain deep electrical stimulation and brain waves while minimizing image distortion in magnetic resonance imaging.

Another object of the present invention is to provide a method for detecting neural signals using the transparent electrode array for deep brain stimulation.

The present invention is a transparent graphene neural electrode; And comprising an optical fiber, the transparent graphene neural electrode is a biocompatible dielectric substrate, a plurality of electrode sites disposed on one side of the substrate and including a graphene sheet, a plurality of electrical conductivity disposed on the other side of the substrate It provides a brain deep stimulation transparent electrode array comprising a contact, and an electrically conductive interconnector connecting the electrode site and the contact.

The optical fiber may be bonded under the substrate of the transparent graphene neural electrode.

The transparent graphene neural electrode may be disposed in a form surrounding the optical fiber.

The transparent graphene neural electrode and the optical fiber may be adhered by any one adhesive selected from the group consisting of polydimethylsiloxane, polyimide and silylated polyurethanes.

The length of one end of the transparent graphene neural electrode is longer than the length of one end of the optical fiber, and one end of the transparent graphene neural electrode is folded toward one end of the optical fiber, so that part or all of the transparent graphene neural electrode site is folded. It may be to cover one end of the optical fiber.

The present invention also provides a method for detecting neural signals using the transparent electrode array for deep brain stimulation.

The method of detecting a nerve signal using the brain deep stimulation transparent electrode array includes inserting the brain deep stimulation transparent electrode array on an electrically active biological tissue; And recording a neural response generated by a nerve cell in the nerve tissue at the electrode site.

The brain deep stimulation transparent electrode array of the present invention can detect deep brain electrical stimulation and brain waves while minimizing image distortion in magnetic resonance imaging.

In addition, the brain deep stimulation transparent electrode array of the present invention can perform a fusion study on nerve cell stimulation through light stimulation.

In addition, the brain deep stimulation transparent electrode array of the present invention can observe the optical signal generated inside the living body from outside the living body.

1 is an exploded perspective view showing a deep electrode stimulation transparent electrode array according to an embodiment of the present invention.
2 is a view showing a transparent graphene neural electrode.
3 is a view showing an optical fiber.
4 is a view showing a deep electrode stimulation transparent electrode array according to an embodiment of the present invention.
5 is a view showing a brain deep stimulation transparent electrode array according to another embodiment of the present invention.
6 and 7 are views showing MRI images of the injected neural electrodes according to Experimental Example 1 of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art to which the present invention pertains may easily practice. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. The same reference numerals are used for similar parts throughout the specification.

1 is an exploded perspective view showing a deep electrode stimulation transparent electrode array according to an embodiment of the present invention. The deep brain stimulation transparent electrode array 1000 includes a transparent graphene neural electrode 100 and an optical fiber 200.

2 is a view showing the transparent graphene neural electrode 100. The transparent graphene neural electrode 100 includes a biocompatible dielectric substrate 110; A plurality of electrode sites 120 disposed on one side of the substrate and including a graphene sheet 121; A plurality of electrically conductive contacts 130 disposed on the other side of the substrate; And an electrically conductive interconnector 140 connecting the electrode site 120 and the contact 130.

The interconnect 140 refers to a circuit 141 that transmits the electrical signal of the electrode site 120, a circuit 142 that transmits the electrical signal of the contact 130, and a portion in contact with them.

An overlay layer 150 may be further included on the electrode site 120 and the contact 130. The overlayer 150 protects and isolates the interconnector 140. The overlayer 150 may be provided with an opening 151 so that the electrode site 120 and the contact 130 are exposed and connected to an external device.

Each electrode site 120 includes a single or two or more graphene sheet 121 layers. The graphene sheet 121 is transparent in a wide range of wavelengths, including wavelengths in the ultraviolet (UV), visible (vis) and infrared (IR) regions of the electromagnetic spectrum, and specifically, may be transparent at 300 nm to 2000 nm. have.

The graphene sheet 121 may provide higher electrical conductivity as the number of sheets increases, but since transparency can be reduced, the number of layers of the graphene sheet 121 present in the electrode region is 1 to 10 individuals. desirable.

The contact 130 receives a signal recorded at the electrode site 120, amplifies, displays, stores, analyzes, and is electrically connected to an external device.

The substrate 110 may be formed of a transparent biocompatible dielectric material. All. In the present invention, biocompatible means that the material is not harmful to the scars of nearby tissues, does not cause irritation, or does not degrade the intended function in the characteristics of the tissues to be transplanted. The substrate 110 may be entirely transparent and a biocompatible material, but may include a partially opaque or non-biocompatible material, if necessary.

In addition, the substrate 110 mechanically exhibits flexibility, so that it can conform to tissue such as the surface of the cerebral cortex without causing cracks, divisions, or other damage to the device.

Like the substrate 110, the overlayer 150 may also include a transparent and biocompatible dielectric material, and may be mechanically flexible. The overlayer 150 may be made of the same material as the substrate 110, but is not limited thereto.

Polymers that can be used as the substrate 110 and the overlayer 150 are parylene C, polyethylene, polydimethylsiloxane (PDMS), polyester (PET), polyimide (PI), polyethylene naphthalate ( PEN), polyetherimide (PEI) and copolymers thereof.

Further, the polymer may be a shape memory polymer, that is, a polymer that undergoes a planar to non-planar deformation in response to a change in temperature. For example, the shape memory polymer may have a planar structure at room temperature (about 23° C.), but a non-planar shape may be adopted at the body temperature of the subject to which the transparent graphene neural electrode 100 is implanted.

Examples of such transparent, biocompatible and dielectric shape memory polymers include T. Ware, D. Simon, RL Rennaker, W. Voit, Smart Polymers for Neural Interfaces, Polymer Reviews 53 (1), 108-129 and Xie T. Recent advances in polymer shape memory. Polym. 2011; 52:4985-5000, the content of which is related to the shape memory polymer and is incorporated herein by reference.

It is preferable that the substrate 110 and the overlayer 150 have a sufficiently thin thickness to provide sufficient transparency and a mechanically flexible device. Specifically, the thickness of the substrate 110 and the overlayer 150 may be 100 μm or less, preferably 50 μm or less, and most preferably have a thickness of 20 μm or less.

The transparency of the transparent graphene neural electrode 100 reflects the combined transparency of the graphene sheet 121, the substrate 110 material, and the overlayer 150 material. In one embodiment, the transparency of the transparent graphene neural electrode 100 is transparent in a wide range of wavelengths, including wavelengths in the ultraviolet (UV), visible (vis) and infrared (IR) regions of the electromagnetic spectrum, specifically 300 It may be transparent in the wavelength range of 2000 nm to 400 nm, preferably 400 to 1800 nm.

Meanwhile, the brain deep stimulation transparent electrode array 1000 further comprises an optical fiber 200. The brain deep stimulation transparent electrode array 1000 may further include the optical fiber 200 to sense electrical signals generated in response to optical stimuli. The latest genetic technology, optogenetics, allows neurons to respond to optical stimuli and can be used in neurological and neurosurgical studies using them. In particular, the transparent electrode array can pass optical stimuli from adjacent optical fibers with high efficiency (transparency of about 90% or more), and thus has advantages in grafting with optogenetics compared to metal-based electrodes. The grafting of the transparent electrode array and the optical fiber is advantageous for calcium imaging, which reads electrical signals from nerve cells as optical signals. That is, bidirectional signal transmission is possible through an optical fiber, and the transparent neural electrode array can additionally detect an electrical signal while increasing the efficiency of optical signal transmission.

Specifically, optogenetics is an example of a technique that uses light stimulation to induce nerve stimulation. Optogenetics uses modified biological cells to introduce light-sensitive proteins into the cell membrane, such as channellodopsin (Channelrhodopsin, ChR) and halodopsin (NpHR). These proteins act as ion channels activated by light, allowing the flow of specific ions into and out of cells when exposed to light with a specific wavelength. Depending on the type of ion channel, ion diffusion causes depolarization or hyperpolarization of cells, and in the case of nerve cells, excitation or suppression of nerve activity. When the photosensitized cells are exposed to incident light of an appropriate wavelength, an optically induced nerve signal is generated. The appropriate wavelength range depends on the specific photosensitive protein used. However, typically, incident light having a wavelength in the UV or visible range is used. In the present invention, the optical fiber 200 is included to inject the incident light.

An example of the optical fiber 200 is shown in FIG. 3. The optical fiber is made of glass or plastic, and a core (201), which is an area where actual light is propagated, and a cladding (Cladding) that surrounds the core and serves to form a waveguide that traps light in the core. ) 203. However, the present invention is not limited thereto, and the optical fiber 200 may be formed of only the core 201 without the cladding 203.

The optical fiber 200 may further include an adhesive layer 202 for adhesion to the transparent graphene neural electrode 100. In addition, the adhesive layer 202 may also serve as a coating for protecting the core 201 from physical or environmental damage and improving strength.

The adhesive layer 202 may include any one silicone-based polymer selected from the group consisting of polydimethylsiloxane, polyimide, and silylated polyurethanes. The silicone-based polymer is most preferably polydimethylsiloxane for reasons of high transparency and biocompatibility.

In addition, the optical fiber 200 may further include a light emitting unit (not shown) for sending an input optical signal to the optical fiber, and a light receiving unit (not shown) for measuring the amount of light output through the optical fiber. The light-emitting unit and the light-receiving unit may be formed at one end and the other end of the optical fiber 200, or by forming a reflective layer at the other end of the optical fiber 200 so that the optical signal can be reflected, so that the light-emitting unit and the light-receiving unit are optical fibers ( 200) may be formed together.

The optical fiber 200 may have a diameter of 50 micrometers (µm) to 1 millimeter (mm). If the thickness is less than 50 μm, there may be a reliability problem such as an internal brain insertion problem or a disconnection due to a thin thickness, and if it exceeds 1 mm, there may be a problem such as excessive damage of nerve cells.

The optical fiber 200 may be used as a single fiber or a series of optical fiber bundles.

Meanwhile, in the brain deep stimulation transparent electrode array 1000, the transparent graphene neural electrode 100 may be disposed in a form surrounding the optical fiber 200. In this case, since the transparent graphene neural electrode 100 can also serve as the cladding 203 of the optical fiber 200, as described above, the optical fiber 200 may consist of the core 201 only. .

4 and 5 are diagrams illustrating the deep electrode stimulation transparent electrode array 1000 when the transparent graphene neural electrode 100 is disposed in a form surrounding the optical fiber 200. At this time, as shown in FIG. 4, the electrode site 120 of the transparent graphene neural electrode 100 may be located on the periphery of the optical fiber 200, and as shown in FIG. 5, the transparent graphene nerve The electrode site 120 of the electrode 100 may be located at the end of the optical fiber 200.

When the electrode site 120 is positioned at the end of the optical fiber 200 in more detail, the length of one end of the transparent graphene neural electrode 100 is greater than the length of one end of the optical fiber 200. Long, one end of the transparent graphene neural electrode 100 is folded toward one end of the optical fiber 200 so that all or part of the electrode site 120 of the transparent graphene neural electrode 100 is the optical fiber 200 ) May be covering one end. In this case, it is possible to obtain an effect capable of performing optical stimulation through an optical fiber or detecting an electrical signal through an optical signal extraction site and a transparent electrode in the same neuron. That is, it is possible to maximize the effect of using the transparent electrode by detecting the signal directly from the transparent electrode and the nerve cell located at the end of the optical fiber. This effect can be clearly seen in contrast to the case of using an opaque metal electrode instead of a transparent electrode.

Hereinafter, a method of detecting a nerve signal using the transparent electrode array for deep brain stimulation will be described in detail.

Specifically, the method for detecting a nerve signal includes inserting the deep electrode stimulation transparent electrode array on an electrically active biological tissue; And recording the neural response produced by the nerve cells in the neural tissue at the electrode site.

In the method for detecting a nerve signal using the brain deep stimulation transparent electrode array 1000, since the brain deep stimulation transparent electrode array 1000 exhibits transparent characteristics, the brain deep stimulation transparent electrode array 1000 is inserted into the brain deep. , The advantage of being able to image the tissue under the electrode site 120 even while taking an electrophysiological record. Specifically, the image of the tissue is obtained by directing incident light to the tissue, and recording light transmitted through the transparent electrode site 120 reflected from the tissue through the transparent electrode site 120, and the returned light is generated by the tissue. It may be reflected or light emitted by the tissue in response to incident light. Imaging techniques that can be used with the electrophysiology include fluorescence microscopy and optical coherence tomography (OCT) technology, magnetic resonance imaging (MRI), and computed tomography (CT). have. At this time, since the brain deep stimulation transparent electrode array 1000 is transparent and does not reflect or distort the light, it may not interfere with the imaging.

In the fluorescence microscopy, tissue is labeled with a fluorescent biomarker. This can be achieved, for example, by injecting a fluorescent labeled probe into the blood vessel penetrating the tissue. Incident light having a wavelength suitable for inducing a fluorescent substance is directed onto the tissue, and as a result, fluorescence is recorded by a photo detector such as a fluorescence microscope. The optimal wavelength for incident light depends on the specific fluorophore and excitation process. Typically incident wavelengths include wavelengths in the range of about 400 nm to about 1800 nm.

In the optical coherence tomography technique, imaging is performed by measuring echo time delay and intensity backscattered from tissue. As such, optical coherence tomography images show differences in optical backscattering in the cross-section plane or tissue volume. Optical coherence tomography imaging is performed by directing a beam of incident light onto a structure where a portion of the light has different optical properties and a structure that is reflected back from the boundary between the different structures.

Typically, the incident light is short-wave light having a wavelength in the infrared region of the electromagnetic spectrum having a wavelength in the range of about 700 nm to about 1 mm, or continuous wave light having a short interference length. The shape and dimensions of the various structures in the tissue are determined by echo measurements.

The magnetic resonance image generates a long-term image of the body using a magnetic field and an electric field. Degree to which the respective material of the body in response to a magnetic field (magnetic susceptibility) is naeneunde distinguish the image using the difference, So carbon forming the pin constituting the body water (H ₂ O), hydrogen (H) as large in magnetic susceptibility There is no difference, so it appears transparently on MRI images. On the other hand, most metals have large susceptibility, resulting in large image distortion in MRI images.

The computed tomography technology allows to view the inside of a living body by generating a tomography image in a specific area using a combination of computerized X-ray measurement values. Similar to MRI imaging, the carbon component constituting graphene has a response to X-rays similar to a biological component, and thus, unlike metals, image distortion can be minimized.

The present invention provides a new research tool for brain and neuroscience researchers as well as patients and hospitals associated with neurological diseases by using a transparent and low-interference brain deep stimulation transparent electrode array and a method for detecting neural signals using the same according to the present invention It can be applied to various parts of the body, such as the spine, joints, and muscles, so it can be applied to future optic nerve sensor, diabetes measurement sensor, and neurotransmitter sensor research.

Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art to which the present invention pertains can easily practice. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein.

[Production Example 1: Preparation of deep electrode stimulation transparent electrode array]

Electrode sites according to the following examples and comparative examples were prepared using the materials shown in Table 1 below. The brain deep stimulation electrode array of FIG. 2 was manufactured using the prepared electrode site. Example 1 including the optical fiber is as shown in FIG. 4.

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Electrode site material
(thickness) Graphene tungsten
(100㎛) tungsten
(50㎛) platinum
(100㎛) Platinum-iridium
(127㎛) Optical fiber ○ X X X X

[Experimental Example 1: Virtual brain and animal experiment]

In order to evaluate the distortion of the MRI image by the injected neural electrode, a virtual brain using an agarose gel was created and an MRI study was performed. Injecting the electrode array prepared in Preparation Example 1 into the virtual brain, and comparing the difference in the degree of distortion of the MRI image according to the susceptibility are shown in FIGS. 6 and 7.

Looking at the drawing, the combination of graphene and optical fiber compared to tungsten (Comparative Example 1, 2), platinum (Comparative Example 3), and platinum-irinium (Comparative Example 4), which are frequently used as existing neural electrodes (Example 1) ) Was found to be almost invisible in the 1.5T MRI image and there was no image distortion. This is expected to assist in precise medical diagnosis by providing low distortion medical images in addition to the optical and electrical signal detection capabilities of the graphene transparent electrode-optical fiber combination.

Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements of those skilled in the art using the basic concepts of the present invention defined in the following claims are also provided. It belongs to the scope of rights.

1000: brain deep stimulation transparent electrode array
100: transparent graphene neural electrode
110: substrate 120: electrode site
121: graphene sheet 130: electrically conductive contact
140: interconnector 141: electrode site electrical signal transmission circuit
142: contact electrical signal transmission circuit 150: overlay
200: optical fiber
201: core 202: adhesive layer
203: cladding

Claims (7)

Transparent graphene nerve electrode; And includes fiber optics,
The transparent graphene neural electrode is a biocompatible dielectric substrate, a plurality of electrode sites disposed on one side of the substrate and including a graphene sheet, a plurality of electrically conductive contacts disposed on the other side of the substrate, and the electrode site And an electrically conductive interconnector connecting the contact with the
The length of one end of the transparent graphene neural electrode is longer than the length of one end of the optical fiber,
One end of the transparent graphene neural electrode is folded toward one end of the optical fiber so that some or all of the transparent graphene neural electrode site covers one end of the optical fiber.
Deep electrode stimulation transparent electrode array. According to claim 1,
The optical fiber is a transparent electrode array for deep brain stimulation that is bonded under the substrate of the transparent graphene neural electrode. According to claim 1,
The transparent graphene neural electrode is a deep electrode stimulation transparent electrode array arranged in a form surrounding the optical fiber. According to claim 1,
The transparent graphene neural electrode and the optical fiber are brain stimuli that are adhered by any one adhesive selected from the group consisting of polydimethylsiloxane, polyimide, and silylated polyurethanes. Transparent electrode array. delete A method for detecting a nerve signal using a deep electrode stimulation transparent electrode array according to any one of claims 1 to 4. The method of claim 6,
Inserting the brain deep stimulation transparent electrode array on an electrically active biological tissue; And
Recording a nerve response produced by a nerve cell in a nerve tissue at the electrode site
Neural signal detection method using transparent electrode array for deep brain stimulation.

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