KR101351779B1 - Nano neural sensor having nanomesh structure - Google Patents

Abstract

The present invention relates to a nanosensor for monitoring neurochemical changes in the brain and, more specifically, to a neuro-sensor which is optically implemented to monitor neurochemical changes in the brain in real time based on the surface enhanced Raman scattering theory. According to the present invention, the nanosensor having a nanomesh structure includes: a first optical fiber which is connected to a light source for optical pumping and acts as a path for incident light; a nanomesh structure which is formed at the end tip of the first optical fiber; a porous polymer matrix which fixes the nanomesh structure to the first optical fiber while surrounding the nanomesh structure; a second optical fiber which acts as a path to receive Raman scattered light from the nanomesh structure and delivers the light to a spectroscope; and a thin film mirror which is installed at the end tip of the second optical fiber. The nanoneural sensor given in the present invention has a single molecule-level sensitivity, high selectivity, and long-term reliability and can be implemented at low costs thanks to a simple manufacturing process, thereby significantly advancing medical treatment and improves the quality of life for patients suffering from neurological disorders or diseases.

Description

NANO NEURAL SENSOR HAVING NANOMESH STRUCTURE}

The present invention relates to a nano-sensor for monitoring neurochemical changes in the brain, and more particularly, a neurosensor optically implemented to monitor in real time the neurochemical changes occurring in the brain based on the giant Raman scattering theory.

Electrophysiological and chemical activity and synchronized neurons in the brain control human neuronal behavior. Neurological disorders and diseases are associated with the improper generation and transmission of nerve signals in nerve cells and functional networks of nerve cells.

It is essential to monitor neurochemical and electrophysiological signals in the brain in real time to treat neurological disorders and diseases. Such monitoring also helps to prevent and respond to dangerous medical conditions caused by the onset of unpredictable neurological disorders.

According to the prior art, monitoring the deterioration and abnormal function of neurons in real time is still a very difficult task. For example, there are a number of neural sensing and monitoring methods such as EEG, MEG, PET, MRI, voltage or calcium-sensitive dyes, but each method can be time and spatial resolution, the physical limits of the object within the device, or can be accessed. There are various problems and limitations, such as the area of tissue in which cells are located.

Although electrochemical sensing technology has the ability to record some brain signals, longevity, reliability of sensing, and high susceptibility to environmental noise are present as high barriers, making them difficult to apply to actual brains. It is a difficult state.

The present invention has been made in view of the above, and an object thereof is to provide an optical sensor using an optical fiber having a nanomesh structure having a plurality of nanowires.

Another object of the present invention is to implement a sensor that is surgically implanted in the brain and monitors small changes in neurotransmitter concentrations to essentially record neuronal activity, thereby improving the life of patients suffering from neurological disorders and diseases. It is to improve quality.

Still another object of the present invention is to provide a nano-neural sensor having a single molecule level of sensitivity, high selectivity, long-term reliability, and which can be implemented at low cost by a simple manufacturing process.

Nano-neural sensor having a nano-mesh structure according to the present invention for achieving the above object, the first optical fiber which is connected to the excitation light source and is a path of the incident light; A nanomesh structure formed at an end tip of the first optical fiber; A porous polymer matrix surrounding the nanomesh structure and fixed to the first optical fiber; A second optical fiber serving as a passage for receiving the Raman scattered light formed from the nanomesh structure and transmitting it to the spectroscope; And a thin film mirror provided at an end tip of the second optical fiber.

According to a preferred embodiment of the present invention, each end tip of the first optical fiber and the second optical fiber is inclined at a constant angle, and in particular is produced at an inclination of 45 degrees, so as to form a complete light wave transmission circuit from the excitation light source to the spectroscope. It is characterized by.

In addition, the nano-mesh structure has a plurality of nanowires formed up and down long, a nano-gap is formed in a predetermined portion of the nano-wire, the polymer matrix is wrapped around the nano-wire to maintain the nano-structure and maintain the nano-gap Characterized in that the point, the length of the nanowires can be adjusted according to the wavelength of the excitation light source, the nanogap gap is controlled to 2nm or less, and the material of the nanowires are gold, silver, platinum, copper and It is characterized in that it is used selected from aluminum.

On the other hand, the polymer matrix is that the molecules of the neurotransmitter can be propagated through the porous polymer structure, nafion (poly), poly (vinyl alcohol), polyethylene (Poly (ethylene)), polyethylene It is characterized in that it is selectively used among oxides (Poly (ethyleneoxide)).

In addition, the wavelength of the excitation light source of the present invention is selected in the visible region in order to minimize thermal noise generated from the brain.

In addition, the sensing response time of the nano-neural sensor is characterized in that it is determined by the polymer matrix, nanowire material and structure.

According to the present invention, the optical sensing device has a nanomesh structure on the optical fiber by using the sensing principle of the giant Raman spectrometer, so that it has a single molecule level of sensitivity, a high selectivity, a long-term reliability, and a simple manufacturing process. It can be implemented at low cost.

 The optical sensing device according to the present invention will enable significant advances in medical treatment and also improve the quality of life of patients suffering from neurological disorders and diseases.

1A is a diagram showing the surface charge distribution of adjacent nanowires,
Figure 1b is a plot showing the amplitude of the normalized near field according to the gap size of the nanowire,
2 is a block diagram of a nano-neuron sensor according to an embodiment of the present invention,
3 is a view showing the reaction time of the dopamine diffusion expected in the embodiment of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. While the present invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not limited to the disclosed embodiments. It should be understood, however, that the invention is not intended to be limited to the particular forms disclosed, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

Also, unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning consistent with the meaning of the context in the relevant art and, unless explicitly defined herein, are to be interpreted as ideal or overly formal Do not.

Basic principles for sensing the nano-sensor according to the present invention are as follows.

The present invention seeks to implement an optical sensor, which is surgically implanted in the brain and capable of essentially recording neuronal activity by monitoring small changes in neurotransmitter concentration. The driving of the sensor is based on the sensing principle of the Surface Enhanced Raman Spectroscopy (SERS), and the nanostructure is formed on the optical fiber. Thin optical fibers can be surgically implanted into the brain and connected to an optical sensing module called a micro-spectrometer that sits under the skin through the skull.

Fibers with a diameter of microns provide small compactness and flexibility, making them suitable for use in a variety of implanted and sensing applications. Designs using small narrow fiber optic probes provide access to any area of the brain. Since the introduction of the first single fiber SERS sensing technology in 1991 by Muren et al., Various types of fiber optic sensors have been developed. The fiber optic design was modified and the surface of the fiber was functionalized for the application of sensors in many fields. Because of the advantages of fiber optic sensing technology, many attempts have been made to apply the SERS sensing principle to fiber optic sensing. However, low-intensity SERS signals from thin film-based devices and biocompatibility issues for nanospheres on optical fibers have hampered biomedical applications. In order to solve this problem and increase the functionality, the present invention employs a coupled nanowire mesh structure in a small space at the tip of the optical fiber. This mesh-type nanowire structure is used as a SERS scattering center for sensing SERS neurotransmitters in the brain.

The SERS sensing principle is based on the close-range interaction of sensing molecules with metal nanomaterials such as gold, silver, platinum and copper. Illuminating the surface of the nanomaterial with an excitation wavelength λ ₀ , the nanomaterial of the appropriate size, strongly coupled with the excitation light, forms a strong local field near the material. This field enhancement can be explained by the incoming wave and the plasmonic resonance of the nano-objects. If this resonant frequency band matches the Raman dispersion frequency, then a clear increase in the SERS signal at the level of sensing a single molecule can be obtained. A number of previous studies (J. Aizpurua et al., "Optical properties of coupled metallic nanorods for field enhanced spectroscopy", "Phys. Rev. B, 71, 235420, 2005; A. Pucci," One-Dimensional Nanostructures ", From Lecture Notes in Nanoscale Science and Technology, vol-3. Springer New York, 175-215, 2008, the SERS intensity enhancement factor G, which means an increase in the Raman variance of the intersection, It can be expressed as Equation (1).

In Equation (1), the first term means that the local field is strengthened near the nanostructure by the incident wavelength. The second term refers to the field enhancement formed by the interaction of the particles with the Raman dispersion wavelength and the re-radiation process by the particles. From this relationship, Raman signal strength is enhanced by the fourth power of the local field by the incident wavelength and the resonant nanostructure.

Since intensity enhancement is proportional to the quadratic of near local enhancement, SERS can produce a definite effect, even with field enhancement factors typically around 10-30 produced by a single nanoobject. If two nanowires are placed in close proximity and combined, local field enhancement is further increased. Because of the strong coupling of nanoscale objects placed in close proximity, the opposite charges are strongly concentrated at the ends of the two bars facing each other, as shown in FIG. When two bonded nanowires are considered, the surface charge distribution can be generated in symmetrical or anti-symmetric mode along the nanowires. In antisymmetric mode, very high intensity surface charges accumulate at opposite gaps on the surface of the nanowires in the gap. In the symmetric mode, build-up of surface charges is suppressed by repulsive interactions between charges across the gap.

Mode generation along the nanowire can be computed using the boundary element method through electromagnetic calculation of the Maxwell's equation, including the phenomenon of electromagnetic wave retardation. Assuming that the internal and external materials of the nanosystem are uniform, the eigenvalue Λ _i of the resonance wave function can be obtained by the following equation (2) having a boundary condition.

Where σ _i (s) is the surface charge density, n _s Is a normal vector perpendicular to the surface at point s, and s and s 'are space vectors for the points on surface S of the nanowire, and the integrator is the surface for multiple points s' on surface S. Means integral. As expected, a series of eigenvalues is obtained in relation to the geometry of the bonded nanostructures. The resonance wavelength of each mode can be obtained by the relationship between the eigenvalues and the dielectric function as in Equation (3).

Dielectric functions ε ₁ and ε ₂ depend on the internal and external frequencies of the nanostructures. From the above equations, the size and material of the bonded nanostructures can be determined to produce the selected mode.

The near field response in the gap increases rapidly along the axis of the nanowires when two nanowires are asymmetrically coupled at nanometer-sized distances (A. Pucci, "One- Dimensional Nanostructures, "Lecture Notes in Nanoscale Science and Technology, vol-3. Springer New York, 175-215, 2008). For example, local field enhancement of 200nm nanowires spaced at 2nm intervals results in a factor of about 300 at an excitation wavelength of 650nm. Considering the increase in Raman scattering, which is proportional to the fourth power of the local field enhancement, the SERS enhancement factor can reach 8.1x10 ⁹ .

Based on the basic principle described above, the optical fiber SERS neural sensor device is designed as shown in FIG.

As shown in Figure 2, the nano-neuron sensor having a nano-mesh structure according to an embodiment of the present invention, the first optical fiber 10, the tip of the first optical fiber 10, which is connected to the excitation light source and the passage of the incident light ( tip) is a nano-mesh structure 50 formed on the tip, the porous polymer matrix 80 to wrap the nano-mesh structure 50 to be fixed to the first optical fiber, and a passage for receiving the Raman scattered light formed from the nano-mesh structure and passing it to the spectrometer The second optical fiber 30 and the thin film mirror 90 provided at the end tip of the second optical fiber.

 That is, the neural sensor of the present invention is composed of two optical fibers 10 and 30, and each optical fiber is composed of an optical fiber core 20-1 and an optical fiber cladding 20-2. The first optical fiber 10 provided with the nanomesh structure 50 senses a neurotransmitter using SERS nanomesh, and the second optical fiber 30 reflects the Raman scattering wave using the thin film mirror 90 to spectroscope. To guide and communicate. Both ends of the optical fiber are produced at an angle of 45 degrees to form a complete light wave transmission circuit from the light source to the spectrometer.

In the present invention, one of the main functions is the nanomesh structure 50 arranged vertically on the inclined optical fiber. Because of bio-toxicity, small sized nanoparticles are not included in the design of the present invention. In the present invention, the selection of nanostructures is limited only to mesoscale nanostructures and mixing them in the polymer matrix 80.

The nano mesh structure 50 is composed of a plurality of nanowires 60 formed up and down long, the nanowires 60 are formed in the middle of the nano gap (nano gap) 70, the polymer surrounding the nanowires The matrix 80 serves to maintain the nanostructure, hold the nanogap, and the like. Here, the nano gap 70 is a gap between two nanowires in which opposite charges are concentrated in FIG. 1A, and shows a nano-sized gap denoted by S in FIG. 1B. Detailed design parameters are as follows.

1) Nano mesh structure and nanowire size

A localized field along the nanowire is formed by plasmon charge oscillation. According to the prior art, the half-wave length Γ ₁ of dipolar oscillation requires a slightly longer nanowire compared to the half-wave length L of the light incident into the vacuum. That is, in the L ≒ Γ _1/3 relation is established. Since there is an advantage that the length of the nanowires can be easily controlled, higher order dipole vibrations can be implemented in the present invention. Although field enhancement resulting from the generation of higher order modes is less powerful than field enhancement obtained from primary modes, the field enhancement factor is close to half of the primary dipole resonance.

The nanowire design thus includes a dimension with an odd number for half-wavelength to induce antisymmetric dipolar charge oscillation. In the present invention, it is preferable to use nanowires having a certain length of nanowires having biocompatibility and mechanical stability. For example, tertiary plasmon resonance generally satisfies the relationship of L ≒ Γ ₃ (1 + 1/3). If a 632 nm excitation light source was chosen for SERS sensing, the nanowire length on one side of the coupled optical fiber should be around 500 nm. The other side of the nanowire can be chosen to obtain an asymmetric paired coupling mode. The main field enhancement effect is derived from smaller size nanowires. The length of the nanowires may be adjusted according to the wavelength of the excitation light source.

2) gap spacing of nano mesh structure

In the present invention, the gap spacing of the nanomesh is an important factor for implementing high SERS strength enhancement, and should be kept in nanometer size, and preferably smaller than 2 nm is required. The reinforcement factor decreases drastically as the distance d goes beyond the dimension following the relationship of d ^{- 12} . For example, if two nanowires are placed at 2 nm intervals and tightly bound to each other, the Raman signal from the molecule in the center of the gap can reach 10 ¹⁰ times relative to the molecule in free space, It can be enhanced by 10 ⁵ times relative to measurements from isolated nanowires. In the present invention, the nanogap spacing of the mesh nanostructure on the optical fiber is controlled to 2 nm or less.

3) Material of mesh nanowire

Although various metals such as gold, silver, platinum, copper, and aluminum may be used for strengthening the near field of nanowires combined, the present invention uses biocompatible gold and platinum as main materials.

4) Polarization

The mesh nanowire structure on the optical fiber is placed at an angle of 45 degrees. This angle allows for good resonance and linearly polarized incident wavelengths along the nanowire. Parallel polarization can supply longitudinal vibrations to the nanowires arranged side by side. If the nanostructure is processed perpendicular to the flat end of the fiber, the nanogap spacing is covered by the nanowire itself. Although the lateral oscillation mode can be generated along the radial direction of the nanowire, the interaction and resonance of the nanostructure and the incident wave can be ignored. Local field reinforcement factors resulting from lateral oscillations are largely insignificant due to the large distances between the nanowires, which generally have sub-micron size. Therefore, the design inclined at an angle of 45 degrees with respect to the incoming wave is an important feature of the present invention.

5) Polymer Matrix

The polymeric matrix with the porous structure according to the invention is used for four different functions. The first is primarily a mechanical function that holds the nanomesh structure to prevent mesh nanowires from entering the brain extracellular space. The second is to mechanically maintain the nanogap spacing for SERS sensing. The polymer matrix surrounding the nanowires is responsible for maintaining the nanostructures, keeping them spaced, and maintaining distances within the size of the nanometers. The third function is to isolate nanostructures in biocompatible polymers to prevent direct contact with cells and tissues in the brain that can cause negative effects on cell viability. Fourth, the molecules of neurotransmitter can be propagated through the porous polymer structure. Suitable polymers can be selected from those capable of transporting neurotransmitters such as 8.5 Å in size dopamine. Nafion, poly (vinyl alcohol), polyethylene (Poly (ethylene)), polyethylene oxide (Poly (ethyleneoxide)) may be used as non-degradable and biocompatible polymers.

Sensing effect of the nano-neuron sensor having a nano-mesh structure according to an embodiment of the present invention can be expected as follows.

1) Sensitivity

Assuming that two gold nanowires 50 nm in diameter and 500 nm and 1000 nm in length, respectively, are coupled at a nanogap spacing of 2 nm, they fit within the gap as they are fitted to plasmon resonance near a high frequency band of about 632 nm wavelength. The local field reinforcement of can be close to 100. SERS strength is enhanced by four wins of local field reinforcement, so the Raman intensity reinforcement factor can approach 10 ⁸ levels. If an excitation light source with a wavelength of about 2,400 nm in proximity to infrared light is used in the same structure, local field enhancement can reach up to about 700, and the SERS enhancement factor can increase by 2.4 × ^{10 11} . However, even if a huge increase in SERS enhancement factor is expected by light sources close to the infrared light source, wavelength selection in neural sensing is primarily chosen in the visible region to minimize thermal noise from the brain.

2) reaction time

The sensor response time for the variation of neurotransmitter concentration is mainly determined by the diffusion behavior of neurotransmitter in the polymer. Dopamine diffusion in the Nafion polymer, ie, the normalized neurotransmitter trajectory of dopamine, can be determined by Equation (4) below.

Where C (t) is the dopamine concentration at the nanogap sensing site, C ₀ is the concentration of the bulk solution outside the Nafion thin film, D is the diffusion coefficient of dopamine inside the Nafion film, and l _p is the thickness of the Nafion film T means the time from initial exposure to concentration in the mass. Using the above equations and dopamine diffusion coefficients, the reaction time can be calculated from a given thickness value. According to a conventional study using a Nafion thin film, the reaction time can be controlled within seconds as shown in FIG. The sensing response can be calculated by equation (4). Through the selection of the appropriate polymer and / or the combination of materials, and the manipulation of the material structure, the reaction time can be made faster.

In the foregoing, the invention has been described in an illustrative manner. It is to be understood that the terminology used herein is for the purpose of description and should not be regarded as limiting. Various modifications and variations of the present invention are possible in light of the above teachings. Therefore, unless otherwise indicated, the present invention may be practiced freely within the scope of the claims.

10; First optical fiber 20-1; Fiber optic core
20-2; Optical fiber cladding 30; The second optical fiber
50; Nanomesh structure 60; Nanowire
70; Nano gap 80; Polymer matrix
90; Thin film mirror

Claims (11)

Optical nanosensor for real-time monitoring of neurochemical changes in the brain based on the theory of giant Raman scattering,
A first optical fiber 10 connected to the excitation light source and serving as a passage for the incident light;
A nanomesh structure 50 formed at an end tip of the first optical fiber;
A porous polymer matrix 80 surrounding the nanomesh structure 50 and fixed to the first optical fiber;
A second optical fiber 30 serving as a passage for receiving the Raman scattered light formed from the nano mesh structure and transmitting the scattered light to the spectroscope; And
A thin film mirror 90 provided at an end tip of the second optical fiber;
Nano-neural sensor having a nano-mesh structure, characterized in that configured to include a point. The method of claim 1,
Each end tip of the first optical fiber and the second optical fiber is nano-neuron sensor having a nano-mesh structure, characterized in that configured to be inclined at a predetermined angle. 3. The method of claim 2,
The constant angle is inclined at 45 degrees, the nano-neuron sensor having a nano-mesh structure, characterized in that to form an optical wave transmission circuit from the excitation light source to the spectrometer. The method of claim 1,
The nano-mesh structure 50 has a plurality of nanowires 60 are formed vertically long, the nano-gap 70 is formed in a predetermined portion of the nanowires 60, the nanowires 60 A nano-neuron sensor having a nanomesh structure characterized in that the polymer matrix 80 is wrapped to maintain the nanostructure and hold the nanogap. 5. The method of claim 4,
The nanowire 60 has a nano-mesh structure, characterized in that the length can be adjusted according to the wavelength of the excitation light source. 5. The method of claim 4,
The nano gap 70 is a nano-neuron sensor having a nano-mesh structure, characterized in that the control point of less than 2nm. 5. The method of claim 4,
The nanowires may be made of gold, silver, platinum, copper, and aluminum. The method according to claim 1 or 4,
The polymer matrix (80) is a nano-neural sensor having a nano-mesh structure, characterized in that the molecules of the neurotransmitter can be propagated through a porous polymer structure. The method according to claim 1 or 4,
The polymer matrix 80 is selectively used among nafion, polyvinyl alcohol, poly (ethylene), and polyethylene oxide. Nano nerve sensor with nano mesh structure. The method according to claim 1 or 5,
The wavelength of the excitation light source is a nano-neuron sensor having a nano-mesh structure, characterized in that selected in the visible light region in order to minimize the thermal noise generated from the brain. The method of claim 1,
The nano-neural sensor is a nano-neuron sensor having a nano-mesh structure, characterized in that the sensing response time is determined by the polymer matrix, nanowire material and structure.

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