KR20200016102A - Deep brain stimulation transparent electrodes array and neural signal detection method using the same - Google Patents

Abstract

The present invention relates to a deep brain stimulating transparent electrode array and a method of detecting neural signals by using the same. The deep brain stimulating transparent electrode array includes a transparent graphene neutral electrode; and an optical fiber. The transparent graphene neutral electrode includes: a biocompatible dielectric substrate; a plurality of electrode sites which are disposed in one side on the substrate and include a graphene sheet; a plurality of electroconductive contacts which are disposed in the other side on the substrate; and an electroconductive interconnector which connects the electrode sites and the contacts. The deep brain stimulating transparent electrode array according to the present invention enables electrical stimulation of deep brain and detection of brain waves while minimizing image distortion in magnetic resonance images, and can perform a convergence research on nerve cell stimulation through light stimulation and optical imaging of nerve cells.

Description

Deep brain stimulation transparent electrode array and method for detecting neural signal using same {DEEP BRAIN STIMULATION TRANSPARENT ELECTRODES ARRAY AND NEURAL SIGNAL DETECTION METHOD USING THE SAME}

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

Treatment of neurological diseases such as Parkinson's disease, Epilepsy and Tourette syndrome has been widely applied. In particular, deep brain stimulation (DBS), which stimulates the brain's core to alleviate the symptoms of neurological diseases, has become an effective surgical treatment for patients who have difficulty relieving symptoms with drug therapy. In Korea, hundreds of brain deep stimulations are performed annually in about 20 medical centers, and their utilization is increasing worldwide.

Brain deep stimulation electrodes (hereinafter referred to as DBS electrodes) are 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. Such electrical stimulation has been widely applied to the treatment of Alzheimer's disease, obesity, and addiction as well as Parkinson's disease, Essential tremor, depression, and epilepsy.

However, the existing DBS electrode is made of opaque metals such as tungsten and platinum to bring image artifacts in medical images such as magnetic resonance imaging (MRI). The distorted image information may interfere with accurate positioning of the DBS electrode during surgery, or accurate diagnosis of other neurological diseases after electrode implantation.

The image distortion phenomenon in MRI is because the magnetic susceptibility of the metal material is significantly larger than the tissue and in vivo moisture (H ₂ O). Therefore, an electrode using carbon fiber having a relatively small susceptibility has been proposed. However, the large amount of carbon atoms in the carbon fiber was limited in reducing MRI image distortion. In addition, carbon fiber has a weak mechanical strength, and there is a potential risk of electrical disconnection when implanted in vivo for a long time.

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

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

The present invention is a transparent graphene nerve electrode; And an optical fiber, wherein the transparent graphene neural electrode is a biocompatible dielectric substrate, a plurality of electrode sites disposed on one side of the substrate and including graphene sheets, and a plurality of electrically conductive layers disposed on the other side of the substrate. A deep brain stimulation transparent electrode array comprising a contact and an electrically conductive interconnect connecting the electrode site and the contact.

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

The transparent graphene nerve 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.

One end length of the transparent graphene neural electrode is longer than one end length of the optical fiber, and 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 sites May cover one end of the optical fiber.

The present invention also provides a neural signal detection method using the deep brain stimulation transparent electrode array.

The neural signal detection method using the deep brain stimulation transparent electrode array includes inserting the deep brain stimulation transparent electrode array on electrically active biological tissue; And recording the neural response generated by the neuron in the neural tissue of the electrode site.

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

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

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

Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art may easily implement the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. Like parts are designated by like reference numerals throughout the specification.

1 is an exploded perspective view showing a deep brain 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 illustrates the transparent graphene neural electrode 100. The transparent graphene neural electrode 100 is 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 interconnect 140 connecting the electrode site 120 and the contact 130.

The interconnector 140 refers to a circuit 141 that transmits an electrical signal of the electrode site 120, a circuit 142 that transmits an electrical signal of the contact 130, and a portion of the interconnector 140.

An overlayer 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 may be exposed and connected to an external device.

Each electrode site 120 includes a single or two or more layers of graphene sheets 121. The graphene sheet 121 may be transparent at a wide range of wavelengths, including wavelengths in the ultraviolet (UV), visible 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 high electrical conductivity as the number of sheets increases, but since transparency may be reduced, the number of layers of the graphene sheet 121 present in the electrode portion may be 1 to 10. 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. Biocompatible in the present invention means that the material does not harm or irritate the scars of nearby tissues or degrade the intended function in the characteristics of the biological tissue to be implanted. The substrate 110 may be a transparent and biocompatible material as a whole, but may include a partially opaque or non-biocompatible material as necessary.

In addition, the substrate 110 may be mechanically flexible to conform to tissue such as the surface of the cerebral cortex without causing cracks, cleavage or other damage to the device.

Like the substrate 110, the overlayer 150 may 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 overlayer 150 materials include parylene C, polyethylene, polydimethylsiloxane (PDMS), polyester (PET), polyimide (PI), polyethylene naphthalate ( PEN), polyetherimide (PEI) and copolymers thereof may be any one selected from the group consisting of.

The polymer may also be a shape memory polymer, ie a polymer that undergoes a deformation from planar to nonplanar 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 may adopt a non-planar shape at a body temperature of a subject to which the transparent graphene neural electrode 100 is implanted.

Examples of such transparent, biocompatible, 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 contents of which are incorporated herein by reference as they relate to shape memory polymers.

The substrate 110 and overlayer 150 preferably have a sufficiently thin thickness to provide sufficient transparency and a mechanically flexible device. Specifically, the substrate 110 and the overlayer 150 may have a thickness of 100 μm or less, preferably 50 μm or less, and most preferably 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 and infrared (IR) regions of the electromagnetic spectrum, specifically 300 It may be transparent in the wavelength range of from 2000 nm, preferably 400 to 1800 nm.

The deep brain stimulation transparent electrode array 1000 may further include an optical fiber 200. The deep brain stimulation transparent electrode array 1000 may further include the optical fiber 200 to detect an electrical signal generated in response to an optical stimulus. Optogenetics, the latest genetic technology, allows neurons to respond to optical stimuli and can be used for neurological and neurosurgery research. In particular, transparent electrode arrays can pass optical stimuli from adjacent optical fibers with high efficiency (about 90% transparency), which has advantages in integrating photoelectricity over metal based electrodes. The combination of the transparent electrode array and the optical fiber is also advantageous for calcium imaging, which reads the electrical signals of nerve cells as optical signals. That is, bi-directional signal transmission is possible through the optical fiber, and the transparent neural electrode array may increase the optical signal transmission efficiency and additionally detect electrical signals.

Specifically, optogenetics is an example of a technique that uses optical stimulation to induce nerve stimulation. Photogenetics uses modified biological cells to introduce light-sensitive proteins into the cell membrane, such as channelrhodopsin (ChR) and halohodopsin (NpHR). These proteins act as ion channels activated by light, allowing the flow of certain ions into and out of cells when exposed to light with a particular wavelength. Depending on the type of ion channel, ion diffusion leads to cell depolarization or hyperpolarization and, in the case of neurons, to excitement or inhibition of nerve activity. When the photosensitized cells are exposed to incident light of the appropriate wavelength, optically induced neural signals are generated. The appropriate wavelength range depends on the specific photosensitive protein used. Typically, however, 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 cladding serves to form a wave guide that traps light in the core by surrounding the core. It may be made of 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 serve as a coating to protect the core 201 from physical or environmental damage and to improve 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 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 transmitting an input optical signal to the optical fiber and a light receiving unit (not shown) for measuring the light amount of the output optical signal 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 an optical signal can be reflected to the light emitting unit and the light receiving unit by optical fiber ( It may be formed together at one end of the 200).

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 a brain insertion problem due to a thin thickness, or disconnection. If the thickness is larger than 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 may be used.

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

4 and 5 illustrate the deep brain stimulation transparent electrode array 1000 when the transparent graphene neural electrode 100 is disposed in a form surrounding the optical fiber 200. In this case, as shown in FIG. 4, the electrode site 120 of the transparent graphene neural electrode 100 may be positioned on a circumference of the optical fiber 200. 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, one end length of the transparent graphene neural electrode 100 is greater than one end length of the optical fiber 200. Long, one end of the transparent graphene nerve electrode 100 is folded toward one end of the optical fiber 200 so that some or all of the electrode sites 120 of the transparent graphene nerve electrode 100 is the optical fiber 200 It may cover one end of the). In this case, the optical stimulation through the optical fiber or the electrical signal through the optical signal extraction site and the transparent electrode can be obtained in the same nerve cell. That is, by directly detecting a signal in the nerve cells located at the transparent electrode and the optical fiber terminal can maximize the use of the transparent electrode. This effect can be clearly seen as compared with the case of using an opaque metal electrode instead of a transparent electrode.

Hereinafter, a neural signal detection method using the deep brain stimulation transparent electrode array will be described in detail.

Specifically, the neural signal detection method comprises inserting the deep brain stimulation transparent electrode array on electrically active biological tissue; And recording the neural response produced by the nerve cell in the neural tissue of the electrode site.

In the method for detecting nerve signals using the deep brain stimulation transparent electrode array 1000, since the deep brain stimulation transparent electrode array 1000 exhibits transparent characteristics, the deep brain stimulation transparent electrode array 1000 is inserted into the deep brain region. In addition, there is an advantage that the tissue under the electrode site 120 can be imaged while taking an electrophysiological record. Specifically, the image of the tissue is obtained by directing incident light onto the tissue and recording the light reflected from the tissue through the transparent electrode site 120 and transmitted through the transparent electrode site 120, the returned light being caused by the tissue. It may be light reflected or emitted by tissue in response to incident light. Imaging technologies that can be used with the electrophysiology include fluorescence microscopy, optical coherence tomography (OCT) technology, magnetic resonance imaging (MRI), and computed tomography (CT). have. In this case, since the deep brain 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, the tissue is labeled with a fluorescent biomarker. This can be accomplished, for example, by injecting a fluorescently labeled probe into a blood vessel that penetrates the tissue. Incident light having a wavelength suitable to induce the fluorescent material is directed onto the tissue and the resulting fluorescence is recorded by a light detector such as a fluorescence microscope. The optimal wavelength for incident light depends on the particular fluorophore and the excitation process. Typically the incident wavelength comprises a wavelength 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 exhibit differences in optical backscattering in the cross-sectional plane or tissue volume. Optical coherence tomography imaging is performed by directing a beam of incident light onto a structure where some of the light has back optical reflections from a structure having different optical properties and a boundary between the different structures.

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

The magnetic resonance image generates an organ image of the body using a magnetic field and an electric field. The difference in the degree of susceptibility (magnetic susceptibility) of each substance to the body to the magnetic field is divided into images, and the carbon of graphene is large in the moisture (H ₂ O), hydrogen (H), etc. There is no difference and it appears transparent in MRI image. On the other hand, most metals have a large susceptibility, resulting in large image distortion in MRI images.

The computed tomography technique uses a computer-processed combination of X-ray measurements to generate a tomographic image in a specific area so that the inside of the living body can be viewed. MRI Imaging Similarly, the carbon component of graphene has a similar response to X-rays, so it can minimize image distortion unlike metals.

Using the transparent and low-interference deep brain stimulation transparent electrode array and neural signal detection method using the same according to the present invention, the present invention will provide new research tools to brain and neuroscience researchers as well as patients and hospitals associated with neurological diseases. In addition, it can be applied to various body parts such as spine, joint, muscle, etc., so that it can be applied to optic nerve examination 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 can easily implement the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.

Preparation Example 1: Manufacture of Deep Brain Stimulation Transparent Electrode Array

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

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Electrode site materials
(thickness) Graphene tungsten
(100 μm) tungsten
(50 μm) platinum
(100 μm) Platinum-Iridium
(127 μm) Fiber optic ○ X X X X

Experimental Example 1: Virtual Brain and Animal Experiment

In order to evaluate the MRI image distortion caused by the injected neural electrode, a Phantom brain using agarose gel was made and an MRI study was performed. 6 and 7 compare the difference in the degree of distortion of the MRI image according to the susceptibility by injecting the electrode array prepared in Preparation Example 1 into the virtual brain.

Looking at the drawings, a combination of graphene and optical fiber (Example 1) when compared to tungsten (Comparative Examples 1, 2), platinum (Comparative Example 3), platinum-irinium (Comparative Example 4) and the like that are commonly used as a conventional nerve electrode ) Showed no image distortion so that it was hardly visible in 1.5T MRI images. In addition to the optical and electrical signal detection capability of the graphene transparent electrode-optic fiber combination, it is expected to assist in accurate medical diagnosis by providing low distortion medical images.

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 right.

1000: deep brain stimulation transparent electrode array
100: transparent graphene nerve 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: overlayer
200: optical fiber
201: core 202: adhesive layer
203: cladding

Claims (7)

Transparent graphene neurons; And include 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 electrically conductive contacts disposed on the other side of the substrate, and the electrode sites. Including an electrically conductive interconnect connecting the contact with the
Deep brain stimulation transparent electrode array. The method of claim 1,
The optical fiber is deep brain stimulation transparent electrode array is bonded below the substrate of the transparent graphene nerve electrode. The method of claim 1,
The transparent graphene nerve electrode is deep brain stimulation transparent electrode array that is disposed in the form surrounding the optical fiber. The method of claim 1,
The deep graphene nerve electrode and the optical fiber are adhered by any one adhesive selected from the group consisting of polydimethylsiloxane, polyimide, and silylated polyurethanes Transparent electrode array. The method of claim 1,
One end length of the transparent graphene neural electrode is longer than one end length 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 electrode site covers one end of the optical fiber deep brain stimulation transparent electrode array. Neural signal detection method using a deep brain stimulation transparent electrode array according to any one of claims 1 to 5. The method of claim 6,
Inserting the brain deep stimulation transparent electrode array on electrically active biological tissue; And
Recording neural responses produced by nerve cells in neural tissue at the electrode site;
Neural signal detection method using deep brain stimulation transparent electrode array.

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