KR20180129468A - Biomaterial for Sencing and Control of Pain in Realtime - Google Patents

Abstract

The present invention relates to a biomaterial for real-time pain sensing and control. The biomaterial can objectively determine the pain by sensing pain-associated bio-factors, and can be useful as a tool for integrated pain treatment since a standard and fixed amount of pain killers can be used based on a judgment index. To this end, the biomaterial contains a magnetic material, a paramagnetic material, and the pain killers.

Description

[0002] Biomaterials for Sense and Control of Pain in Real Time [

The present invention relates to a biomaterial for real-time pain sensing and control.

Because of the increase in the average life span due to the development of medical technology, the proportion of geriatric diseases frequently accompanied by pain is increasing. Patients with intractable chronic pain are increasing. Furthermore, due to the increase in industrial accidents and traffic accidents due to the rapid development of society, The incidence of chronic pain is steadily increasing.

In the case of pain diagnosis, there is no definite criteria for pain due to the use of VAS or VDS, which relies on subjective description of the patient. There is no definite criterion for pain. In the case of pain treatment, WHO analgesic ladder judges the dose and type of medication, There is concern about abuse and abuse of drugs or side effects because they are not based on the degree of pain.

Compared to the past material development process, which has been based on trial and error, the development of efficient materials through computational science based design, which is possible due to the rapid development of computers and the development of various simulation techniques, has recently been studied mainly in major industrialized countries. In order to develop intelligent smart biomaterials, biocompatibility such as non-toxicity and biodegradability must be satisfied as well as functionality of materials required for pain sensing and control. In order to meet these various requirements, advanced calculation based on multi- Science-based material development is needed.

Accordingly, the present inventors have made efforts to overcome the limitations of the more efficient and safe pain treatment and the existing treatment method, and as a result, based on the bio-signals, the pain is more accurately quantified and visualized, and the existing developed drugs are used, The present inventors have completed the present invention by developing a biomaterial for pain sensing and control capable of releasing an accurate amount of drug to a local site.

Korean Patent No. 10-1446514

It is an object of the present invention to provide a biomaterial for real-time pain sensing and control.

It is another object of the present invention to provide a real-time pain sensing and control method for imaging a pain signal at a pain site.

It is another object of the present invention to provide a real-time pain sensing and control method for imaging a pain signal of the brain.

In one aspect of the present invention, there is provided a biological material for real-time pain sensing and control comprising a magnetic substance, a paramagnetic substance and a drug for treating pain, wherein the magnetic substance, the paramagnetic substance and the drug for treating pain are combined by two or more linker peptides And provides a biomaterial for real-time pain sensing and control.

A biological material is a general term of a material used in contact with a living tissue of a human body among materials used for a medical device and an artificial organ, and includes a diagnostic device using a material and a living tissue in contact with blood as a specimen. Polymers, ceramics, metals, bio-organic materials, composites thereof, and the like.

As used herein, the term " drug for treating pain " refers to a drug used for the purpose of eliminating or alleviating pain, and includes narcotic analgesics, non-narcotic analgesics, antidepressants, anticonvulsants, Muscle relaxants, local anesthetics, nerve stabilizers, and sympathomimetics.

According to one embodiment of the present invention, the magnetic material may be magnetic nanoparticles. Preferably, the magnetic nanoparticles are Zn _{0 . 4} Fe _{2 . 6} O _{4 ,} Fe ₃ O ₄ , CoFe ₂ O ₄ And MnFe ₂ O ₄ .

The term " magnetic nanoparticles " used in the present invention means nano-sized particles acting as a superparamagnetic quencher, and includes magnetite (Fe ₃ O ₄ ), maghemite (Fe ₂ O ₃ ), ferrite such as cobalt (CoFe ₂ O ₄ ) and yaffosite (MnFe ₂ O ₄ ) in which one Fe element is replaced with another magnetic element in iron oxide Ferrite) and alloys such as iron-platinum (FePt) alloys and cobalt-platinum (CoPt) alloys for improving conductivity and stability.

Superparamagnetic is a form of magnetism that appears in small ferromagnetic or ferrimagnetic nanoparticles. When a sufficiently small nanoparticle (100 Å in diameter) has all the electrons' spin aligned in the same direction, Refers to a property that the spin is not organized as a whole, and the dimmer means a molecule that acts on a luminescent excited molecule to remove excitation energy and inhibit luminescence.

According to one embodiment of the present invention, the paramagnetic material may be Gd-chelate or Manganese oxide.

According to one embodiment of the present invention, the linker peptide can be degraded by a protein hydrolase that is overexpressed in pain. Preferably, the protein hydrolase is selected from the group consisting of MMP-9, SerpinA3N, and Cathepsin.

As used herein, the term " linker protein " refers to a protein used to bind the magnetic substance, the paramagnetic substance and / or the drug for treating pain, Quot; means a polypeptide having a sequence to be cleaved.

Cathepsin is a generic term for many proteases present in lysosomes in animal cells. Depending on the reactivity to the optimal pH inhibitor, substrate specificity, molecular weight, etc., Cathepsin A, B, C, D, H, L, and so on. Cathepsin A acts to liberate amino acids sequentially at the C-terminus of the peptide chain, Cathepsin B acts as an endopeptidase that fuses peptide bonds within the peptide chain, and a sequestered dipeptide at the C-terminus of the peptide chain Cathepsin C hydrolyzes denatured hemoglobin at an optimum pH of 3 to 4. Cathepsin H acts as an endopeptidase and acts as a sequential amino acid at the N-terminus of the peptide chain, while Cathepsin C liberates dipeptides sequentially at the N-terminus of the peptide chain. And Cathepsin L acts as a strong endopeptidase with cysteine protease. As the cathepsins used in the present invention, one or more of the cathepsins classified as above can be used.

Another aspect of the present invention is a method for preparing a biomaterial comprising: (a) administering the biomaterial of claim 1 to a subject; (b) imaging the paramagnetic material separated from the biomaterial by magnetic resonance imaging (MRI), wherein the linker peptide of the biomaterial is degraded by a hydrolase that is overexpressed in the pain site; (c) when the linker peptide is degraded, the pain is controlled by a drug for treating pain separated from the biomaterial; And (d) imaging a pain signal of the pain site on the photographed magnetic resonance image.

Magnetic Resonance Imaging (MRI) is a technique for imaging a difference in signal from each tissue by resonating a hydrogen nucleus in a body part by generating a high frequency after allowing the human body to enter a large magnetic barrel generating a magnetic field. It is necessary to reconstruct a difference between signals using an image diagnostic technique such as an image (MRI) or a functional magnetic resonance imaging (fMRI) through an analysis device such as a computer, thereby converting the image into digital information and imaging the image. This includes imaging the change in signal difference over time by comparing the measurement of the difference in signal at a plurality of points in time through the analyzer.

According to an embodiment of the present invention, there is provided a method of detecting a pain, comprising the steps of: (a) repeating the steps (a) to (d) And (f) comparing the photographed image of the step (d) with the photographed image of the step (e), and imaging the change of the pain signal of the pain site.

According to still another aspect of the present invention, there is provided a method for detecting a brain of a subject, comprising the steps of: (a) photographing a functional magnetic resonance imaging (fMRI) (b) administering the biomaterial of claim 1 to a subject; (c) photographing the paramagnetic material separated from the biomaterial by the functional magnetic resonance imaging (fMRI) by decomposing the linker peptide of the biomaterial by the hydrolytic enzyme over-expressed in the pain site; (d) controlling pain by a pain treatment drug separated from the biomaterial when the linker peptide is degraded; And (e) comparing the photographed image of step (a) with the photographed image of step (c) to image the pain signal of the brain.

In the above process, functional magnetic resonance imaging (fMRI) refers specifically to functional brain imaging, which indicates local metabolic and hemodynamic changes due to nerve cell activation by sensory, motion, or cognitive performance as a difference in signal intensity on brain magnetic resonance imaging .

According to the real-time pain sensing and control biomaterial of the present invention, the pain can be objectively determined through the bio-physical sensing of the pain, and since the standardized amount of the pain treatment drug can be used according to the judgment index, Can be used as a tool of the present invention.

1 is a view showing the concept of a biological material for pain sensing and control.
FIG. 2 is a view showing a biomaterial for pain sensing and control acting in real time at a pain site.

Hereinafter, one or more embodiments will be described in more detail by way of examples. However, these embodiments are intended to illustrate one or more embodiments, and the scope of the present invention is not limited to these embodiments.

Example  One: To the pain target factor  Construction of a specifically cleaved protease library

A library of hydrolytic enzymes for proteins was constructed to specifically link pain medicinal drugs and magnetic / paramagnetic materials by specifically cleavage to pain target factors.

Specific hydrolytic enzymes were screened for protein hydrolysates that were overexpressed during pain and MMP-9, SerpinA3N and Cathepsin hydrolytic enzymes were screened for proteins that could bind pain medicines and magnetic / Were selected as final candidates.

Example  2: Pain To sense  Selectable MRI Signal Factor

Magnetic resonance imaging (MRI) signaling was selected for imaging and sensing when pain occurred.

Specifically, as a result of searching for magnetic and paramagnetic materials showing that the MRI signal becomes stronger when they are separated from each other and the MRI signal weakens when they are close to each other, Zn _{0 . 4} Fe _{2 . 6 O 4, Fe 3 O 4} , CoFe 2 O 4 , and MnFe ₂ O in a _4, a paramagnetic material is gadolinium-chelate of Gd-DOTA (Gd (III) 1,4,7,10-tetraazacyclododecane-1,4, 7,10-tetraacetic acid) and manganese oxide (Mn ₃ O ₄ ) were selected.

Example  3: Fabrication of biomaterials using library-based proteins

Biomaterials were prepared by using library - based proteins to produce biomaterials by combining drugs for pain therapy and magnetic / paramagnetic materials.

Specifically, a drug, a magnetic substance and a paramagnetic substance for treating pain were cross-linked using a linker peptide degraded by a hydrolytic enzyme selected as a candidate group.

As a result, when a linker peptide was degraded in the presence of an overexpressed protease in the case of pain, a bioactive material capable of separating the medicament for treating pain, the magnetic substance and the paramagnetic substance was prepared.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (9)

A biological material for real-time pain sensing and control, comprising a magnetic substance, a paramagnetic substance and a drug for treating pain,
Wherein the magnetic material, the paramagnetic material and the pain treatment drug are bound by at least two linker peptides. The method according to claim 1,
Wherein the magnetic material is magnetic nanoparticles. 3. The method of claim 2,
The magnetic nanoparticles are Zn _{0 . 4} Fe _{2 . 6} O _{4 ,} Fe ₃ O ₄ , CoFe ₂ O ₄ And MnFe < ₂ > O < ₄ >. The method according to claim 1,
Wherein the paramagnetic material is a gadolinium chelate or a manganese oxide. The method according to claim 1,
Wherein the linker peptide is degraded by proteolytic enzymes that are overexpressed during pain. 6. The method of claim 5,
Wherein the protein hydrolyzing enzyme is an enzyme selected from the group consisting of MMP-9, SerpinA3N, and Cathepsin. (a) administering the biomaterial of claim 1 to a subject;
(b) imaging the paramagnetic material separated from the biomaterial by magnetic resonance imaging (MRI), wherein the linker peptide of the biomaterial is degraded by a hydrolase that is overexpressed in the pain site;
(c) when the linker peptide is degraded, the pain is controlled by a drug for treating pain separated from the biomaterial; And
(d) imaging the pain signal of the pain site in the photographed magnetic resonance image
Time pain sensing and control method. 8. The method of claim 7,
After step (d)
(e) re-imaging a magnetic resonance image (MRI) of the pain site; And
(f) comparing the photographed image of step (d) with the photographed image of step (e), and imaging the change of the pain signal of the pain part
Further comprising the steps of: (a) photographing a functional magnetic resonance image (fMRI) of a subject's brain;
(b) administering the biomaterial of claim 1 to a subject;
(c) photographing the paramagnetic material separated from the biomaterial by the functional magnetic resonance imaging (fMRI) by decomposing the linker peptide of the biomaterial by the hydrolytic enzyme over-expressed in the pain site;
(d) controlling pain by a pain treatment drug separated from the biomaterial when the linker peptide is degraded; And
(e) comparing the photographed image of step (a) with the photographed image of step (c), and imaging the pain signal of the brain
Time pain sensing and control method.

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