METHOD OF MANUFACTURING A NERVE ELECTRODE PROVIDED WITH ANTI-INFLAMMATORY DRUG
A method for manufacturing a nerve electrode that is inserted into a living body and that is configured to attach to nerves is provided. The nerve electrode includes: i) a flexible substrate; ii) a plurality of electrodes that are separately positioned on the flexible substrate; and iii) an insulating layer that is positioned at a separation space of the plurality of electrodes and that insulates the plurality of electrodes. The plurality of electrodes include i) at least one linear electrode, and ii) a planar electrode that is separated from the linear electrode. An anti-inflammatory drug transfer layer is positioned on the planar electrode.
This application is a divisional of U.S. application Ser. No. 13/688,729, filed Nov. 29, 2012, which claims the benefit of Korean Patent Application No. 10-2012-0112557 filed in the Korean Intellectual Property Office on Oct. 10, 2012, the entire contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION(a) Field of the Invention
The present invention relates to a method of manufacturing a nerve electrode. More particularly, the present invention relates to a method of manufacturing a nerve electrode that suppress inflammation when inserting anti-inflammatory drugs into a living body while having the anti-inflammatory drugs.
(b) Description of the Related Art
For development of original technology for rehabilitation and welfare and practical use of the technology, a nerve stimulus apparatus using a nerve element facilitates improvement of quality of life of the soaring number of senior citizens as well as disabled people, and localizes rehabilitation and welfare related original devices through industrialization of related technology, and thus secures technical superiority in the world medical device market, and much research has thus been performed.
Implant type nerve electrode technology and medical treatment technology using the same is technology corresponding to an introduction time, and is expected to bring an economic/social/technical ripple effect through prior occupation of higher value-added original technology, as it contributes to improvement in quality of life of the socially disadvantaged such as senior citizens and disabled people. Presently used nerve devices include a heart pulsation stimulus device, a cerebral nerve stimulus device for Parkinson's disease, epilepsy, or chronic pain treatment, a central nerve stimulus device, and a pneumogastric nerve stimulus device, and various products have been launched and much research is being performed by medical equipment companies from various countries such as the U.S., Japan, and Europe.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the invention and therefore it may contain information that does not form the prior art that is already known in this country to a person of ordinary skill in the art.
SUMMARY OF THE INVENTIONThe present invention has been made in an effort to provide a method of manufacturing a nerve electrode that is inserted into a living body and that is configured to attach to nerves, the method including: i) providing a substrate; ii) providing a first polyimide layer on the substrate; iii) providing a first photoresist layer on the first polyimide layer; iv) partially exposing the first polyimide layer to the outside by partially removing the first photoresist layer; v) providing a plurality of electrodes that are separated by coating a conductive material on the partially exposed first polyimide layer; vi) exposing a first polyimide layer corresponding to a separation space between the plurality of electrodes to the outside by removing the first photoresist layer; vii) covering the plurality of electrodes by providing a second polyimide layer and covering the first polyimide layer corresponding to the separation space between the plurality of electrodes with the second polyimide layer; viii) providing a second photoresist layer on the second polyimide layer; ix) maintaining the second photoresist layer at a position corresponding to the separation space between the plurality of electrodes by partially removing the second photoresist layer; x) exposing the plurality of electrodes to the outside by etching the second polyimide layer and the second photoresist layer; and xi) providing a drug transfer layer on the exposed plurality of electrodes by electrospinning a solution in which anti-inflammatory drugs are contained. In the providing of a plurality of electrodes, the plurality of electrodes include i) a plurality of linear electrodes, and ii) a planar electrode enclosing the plurality of linear electrodes. In the providing of a drug transfer layer, the drug transfer layer is provided on the planar electrode.
The method may further include providing a hydrogel layer on the drug transfer layer, wherein the hydrogel layer may include at least one material that is selected from a group consisting of PEG, HAAEMA, and GelatinHA. The method may further include enabling the linear electrode and the PEDOT layer to directly contact by providing the PEDOT layer on the linear electrode. In the providing of a plurality of electrodes, the conductive material may include at least one metal that is selected from a group consisting of platinum and titanium.
In the maintaining of the second photoresist layer, the second photoresist layer may additionally remain at a position corresponding to an edge of the plurality of electrodes. In the providing of a drug transfer layer, the anti-inflammatory drugs may include at least one drug that is selected from a group consisting of dexamethasone, sulindac, and tolmetin. The method may further include removing the substrate.
Inflammation occurring due to insertion of a nerve electrode can be suppressed through a drug transfer layer. Further, because the drug transfer layer includes nanofibers that are made of a material having excellent biodegradability, the drug transfer layer does not harm a human body. Nanofibers are covered by a hydrogel layer, and by adjusting a thickness of the hydrogel layer, a quantity of drugs that are transferred to nerves can be easily adjusted.
When it is said that any part is positioned “on” another part, it means the part is directly on the other part or above the other part with at least one intermediate part. In contrast, if any part is said to be positioned “directly on” another part, it means that there is no intermediate part between the two parts.
Terms such as first, second, and third are used for describing various portions, components, areas, layers, and/or sections, but the terms are not limited thereto. The terms are used only for distinguishing any portion, component, area, layer, or section from other portions, components, areas, layers, or sections. Therefore, a first portion, component, area, layer, or section described hereinafter may be described as a second portion, component, area, layer, or section within the scope without deviating from the scope of the present invention.
Technical terms used here are to only describe a specific exemplary embodiment and are not intended to limit the present invention. Singular forms used here include plural forms unless explicitly described to the contrary. A meaning of “comprising” used in a specification embodies a specific characteristic, area, integer, step, operation, element, and/or component, and does not exclude presence or addition of another characteristic, area, integer, step, operation, element, and/or component.
Terms representing relative space of “lower” and “upper” may be used for more easily describing a relationship with another portion of a portion shown in the drawings. Such terms are intended to include other meanings or operations of an apparatus used together with a meaning that is intended in the drawings. For example, when an apparatus is inverted in the drawings, any portion described as disposed at a “lower” portion of other portions is described as being disposed at an “upper” portion of other portions. Therefore, the illustrative term “lower” includes both upper and lower directions. An apparatus may be rotated by 90° or another angle, and terms representing relative space are accordingly analyzed.
If not differently defined, all terms including technical terms and scientific terms used herein have the same meanings as those that may be generally understood by a person of common skill in the art. Terms defined in a generally used dictionary have meanings corresponding to a related technology document and presently disclosed contents, and are not to be construed as an idealized or very formal meaning unless stated otherwise.
An exemplary embodiment of the present invention described with reference to a cross-sectional view specifically illustrates an ideal exemplary embodiment of the present invention. As a result, various changes of explanatory diagrams, for example, changes of a manufacturing method and/or a specification, are expected. Therefore, an exemplary embodiment is not limited to a specific form of a shown area and may include, for example, form deformation by production. For example, an area shown or described as a flat area may have generally characteristics of rough or rough and nonlinear. Further, a portion shown as having a sharp angle may be round. Therefore, an area shown in the drawings is generally an approximate area, and a form thereof is not intended to illustrate an accurate form of an area and is not intended to narrow the scope of the present invention.
The present invention will be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. 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.
The nerve electrode 100 that is shown in
In addition, the nerve electrode 100 may further include other elements. For example, a nerve stimulus apparatus further includes a drawn-out line 70 and a drawn-out terminal 75. The nerve electrode 100 is inserted into a living body and is attached to nerves. The nerve electrode 100 includes the flexible substrate 10 that is applied to well attach it to nerves, and is formed using polyimide (PI).
As shown in
As shown in
At step S30 of
Next, at step S40 of
At step S50 of
Next, at step S60 of
At step S70 of
Next, at step S80 of
At step S90 of
Next, at step S100 of
At step 110 of
Because the drug transfer layer 50 is stacked and formed using electrospinning, the thickness of the drug transfer layer 50 can be adjusted. When electrospinning, a suspension containing anti-inflammatory drugs is filled into a syringe pump and is slowly ejected in a constant speed. In this way, an ejected suspension is electrospun.
In an electrospinning processing process, a sol-gel reaction is performed due to solvent evaporation at the inside of the suspension. As a result, the drug transfer layer 50 is formed with nanofibers in which drugs are evenly distributed. Because nanofibers are slowly dissolved within a living body for 6 months to 1 year, drugs can be slowly and efficiency transferred.
The drug transfer layer 50 includes a plurality of nanofibers. Because nanofibers are formed for discharging drugs containing antibiotics, a phenomenon that inflammation occurs in nerves can be prevented. As antibiotics, dexamethasone, sulindac, or tolmetin may be used. By removing the used mask layer, the nerve electrode 100 (shown in
Here, an average thickness t60 of the hydrogel layer 60 may be 200 μm to 500 μm. If an average thickness of the hydrogel layer 60 is excessively small, all electrospun nanofibers cannot be coated. Further, if an average thickness of the hydrogel layer 60 is excessively large, an initial discharging amount of drugs that are loaded in nanofibers is very small and thus inflammation may occur. Therefore, an average thickness of the hydrogel layer 60 is adjusted to the above-described range.
The hydrogel layer 60 is coated on the drug transfer layer 50, and a release speed of drugs is adjusted according to a thickness thereof. Therefore, when the hydrogel layer 60 has a small thickness, drugs are quickly emitted. In contrast, when the hydrogel layer 60 has a large thickness, drugs are slowly discharged. The hydrogel layer 60 is made of a material such as polyethylene glycol (PEG), aminoethyl methacrylated hyaluronic acid (HAAEMA), or gelatin hyaluronic acid (GelatinHA).
Hereinafter, the present invention will be described in detail through Experimental Examples. Such Experimental Examples only illustrates the present invention, and the present invention is not limited thereto.
A nerve electrode was produced with the same method as that shown in
A drug release profile using nerve electrodes that are produced according to Experimental Examples 1 to 3 of the present invention was sequentially analyzed and an effect thereof was determined.
Drug Release Experiment and Result
The nerve electrode of Experimental Example 2 was produced by changing the thickness of PEG, and a drug release difference according to PEG thickness was also analyzed. The thickness of PEG was formed so that thin PEG is 200 nm and thick PEG is 450 nm to 500 nm. As an analysis result, it was observed that a nerve electrode according to an exemplary variation of Experimental Example 2 is slower and more constant in drug release speed than the nerve electrode of Experimental Example 2.
Electrochemical Impedance Experiment and Result
Electrochemical impedance was analyzed using nerve electrodes that were produced according to Experimental Examples 2 and 3 of the present invention, and an effect thereof was determined.
As an impedance analysis result, in a nerve electrode of a control group, when a frequency thereof rises, impedance drops, but it was observed that nerve electrodes that are produced according to Experimental Examples 2 and 3 of the present invention maintain a relatively constant value. Further, it was observed that the nerve electrode has a lower resistance value.
Cyclic Voltammetry Experiment and Result
Cyclic voltammetry was analyzed using the nerve electrodes that are produced according to Experimental Examples 2 and 3 of the present invention, and an effect thereof was determined.
As a CV analysis result, it was observed that the nerve electrodes that are produced according to Experimental Examples 2 and 3 of the present invention represent a constant current density and there is no difference in an active area of a CV result. However, it was observed that a control group represents a larger active area than the nerve electrodes that are produced according to Experimental Examples 2 and 3 of the present invention according to a change of a potential value.
Anti-Inflammation and Biocompatibility Experiment and Result
Improvement of anti-inflammation and biocompatibility through surface coating of a nerve electrode was determined.
As shown in
Next, as shown in
As shown in
A nerve cuff electrode was prepared. In order to determine an effect of the nerve electrode, a beagle was selected as an animal model, and the nerve electrode was implanted to sciatic nerves and an effect thereof was determined.
The nerve cuff electrode was implanted to the sciatic nerves of a leg portion under a pelvis of the beagle, a current stimulus was applied to the sciatic nerves and the peroneal nerves in an anesthetized state, and an output signal was determined.
Experiment Result of Comparative Example 1As shown in
By observing sciatic nerve and tibial nerve section tissues of the beagle, an influence of a current stimulus was determined.
Experiment Result of Comparative Example 2
-
- 10. flexible substrate
- 20, 201, 203. electrode
- 30. insulating layer
- 40. electrode fixing layer
- 50. drug transfer layer
- 60. hydrogel layer
- 65. poly(3,4-ethylenedioxythiophene) layer
- 70. drawn-out line
- 75. drawn-out terminal
- 80. substrate
- 82, 86, 821, 861. polyimide layer
- 84, 841, 88, 89, 881. photoresist layer
- 100, 200, 300. nerve electrode
While this invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
Claims
1. A method of manufacturing a nerve electrode that is inserted into a living body and that is configured to attach to nerves, the method comprising:
- providing a substrate;
- providing a first polyimide layer on the substrate;
- providing a first photoresist layer on the first polyimide layer;
- partially exposing the first polyimide layer to the outside by partially removing the first photoresist layer;
- providing a plurality of electrodes that are separated by coating a conductive material on the partially exposed first polyimide layer;
- exposing a first polyimide layer corresponding to a separation space between the plurality of electrodes to the outside by removing the first photoresist layer;
- covering the plurality of electrodes by providing a second polyimide layer and covering the first polyimide layer corresponding to the separation space between the plurality of electrodes with the second polyimide layer;
- providing a second photoresist layer on the second polyimide layer;
- maintaining the second photoresist layer at a position corresponding to the separation space between the plurality of electrodes by partially removing the second photoresist layer;
- exposing the plurality of electrodes to the outside by etching the second polyimide layer and the second photoresist layer; and
- providing a drug transfer layer on the exposed plurality of electrodes by electrospinning a solution in which anti-inflammatory drugs are contained,
- wherein in the providing of a plurality of electrodes, the plurality of electrodes comprise:
- a plurality of linear electrodes, and
- a planar electrode enclosing the plurality of linear electrodes,
- wherein in the providing of a drug transfer layer, the drug transfer layer is provided on the planar electrode.
2. The method of claim 1 further comprising providing a hydrogel layer on the drug transfer layer,
- wherein the hydrogel layer comprises at least one material that is selected from a group consisting of PEG, HAAEMA, and GelatinHA.
3. The method of claim 1 further comprising enabling the linear electrode and the PEDOT layer to directly contact by providing the PEDOT layer on the linear electrode.
4. The method of claim 1, wherein in the providing of a plurality of electrodes, the conductive material comprises at least one metal that is selected from a group consisting of platinum and titanium.
5. The method of claim 1, wherein in the maintaining of the second photoresist layer, the second photoresist layer additionally remains at a position corresponding to an edge of the plurality of electrodes.
6. The method of claim 1, wherein in the providing of a drug transfer layer, the anti-inflammatory drugs comprise at least one drug that is selected from a group consisting of dexamethasone, sulindac, and tolmetin.
7. The method of claim 1 further comprising removing the substrate.
Type: Application
Filed: Jun 8, 2015
Publication Date: Sep 24, 2015
Inventors: Soo Hyun LEE (Seoul), Ji Yoon KANG (Seoul), Nakwon CHOI (Seoul)
Application Number: 14/733,467