KR101887282B1 - Bioheater - Google Patents

Abstract

A bio-heater is provided. The bio-heater includes a heater including a bio-metal. The biomass may include Mg or Fe. The heater can be controlled wirelessly by an alternating magnetic field.

Description

BIO HEATER {BIOHEATER}

The present invention relates to a bio heater.

A variety of therapies such as surgical techniques, radiation therapy, and chemotherapy have been developed in relation to brain tumors. However, malignant brain tumor cells may invade normal brain tissue even after brain tumor removal surgery and cause brain tumor recurrence. Therefore, it is necessary to remove the brain tumor cells remaining at the surgical site after brain tumor removal surgery. However, currently available therapies such as radiotherapy and chemotherapy are difficult to inhibit or remove residual brain tumor cells after surgery.

In order to solve the above-mentioned problems, the present invention provides a bio heater that can be used in living bodies such as the human body.

The present invention provides a wirelessly controlled bio heater.

Other objects of the present invention will become apparent from the following detailed description and the accompanying drawings.

The bio-heater according to embodiments of the present invention includes a heater including a bio-metal.

The biomass may include Mg or Fe.

The heater may include a metal pattern formed of the biomaterial. The metal pattern may have a plurality of holes.

The bio heater may further include a first heater protection layer disposed under the heater and a second heater protection layer disposed on the heater.

The heater can be controlled wirelessly by an alternating magnetic field.

The heater may be disposed adjacent to the bio patch to heat the bio patch. The bio patch may include a polymer film including a biopolymer and a drug loaded on the polymer film. The release of the drug can be controlled by the heater.

The bio heater may be inserted into the brain tissue together with the bio patch to be used for treating brain tumors.

The bio-patch according to the embodiments of the present invention can be used in a living body such as a human body. The bio-patch can be decomposed or absorbed naturally after use. The bio patch can strongly bond to the tissue in the body such as brain tissue.

The bio heater according to embodiments of the present invention can be used in a living body such as a human body. The bio heater may be decomposed or absorbed naturally after use. The bio heater can be controlled wirelessly and is easy to use even if it is placed in the human body.

The biosensor according to embodiments of the present invention can be used in a living body such as a human body. The biosensor can be decomposed or absorbed naturally after use. The biosensor can be controlled wirelessly and is easy to use even if it is placed in the human body.

The bioelectronic patch device according to embodiments of the present invention can be used in a living body such as a human body. The bio-patch can be decomposed or absorbed naturally after use. The bio patch can strongly bond to the tissue in the body such as brain tissue. The bio-patch can effectively deliver the drug to the target location. The bio-patch can have an excellent effect on the treatment of brain tumors.

1 shows a bio-patch according to an embodiment of the present invention.
2 illustrates a method of forming a bio-patch according to an embodiment of the present invention.
3 shows a bio heater according to an embodiment of the present invention.
4 shows a method of forming a bio heater according to an embodiment of the present invention.
5 illustrates a biosensor according to an embodiment of the present invention.
6 is a circuit diagram of a biosensor according to an embodiment of the present invention.
7 and 8 show a method of forming a biosensor according to an embodiment of the present invention.
9 is a plan view of a bioelectronic patch device according to an embodiment of the present invention.
10 is an exploded perspective view of the bioelectronic patch device of FIG.
11 to 16 show a method of forming a bioelectronic patch device according to an embodiment of the present invention.
17 shows a bioelectronic patch device according to an embodiment of the present invention applied to a human brain.
Fig. 18 shows an enlarged view of the area A in Fig.
FIG. 19 is a graph showing changes with time after a bioelectronic patch device according to an embodiment of the present invention is attached to the brain of a dog.
FIG. 20 shows drug delivery depths according to heating of a bioelectronic patch device according to an embodiment of the present invention.
FIG. 21 shows a fluorescence microscope image of the bio-electronic patch device and the adhesive interface of the brain according to an embodiment of the present invention.
22 shows the shear adhesive force of the drug patch of the bioelectronic patch device according to an embodiment of the present invention.
FIG. 23 and FIG. 24 show the drug discharge accumulation amount of the bioelectronic patch device according to an embodiment of the present invention.
Figure 25 shows the effect of heating on drug delivery.
26 shows the resonance frequency of the biosensor according to the temperature.
FIGS. 27 to 29 show the comparison of the size change and the survival rate of brain tumors according to the four treatment methods applied to rats having brain tumors.

Hereinafter, the present invention will be described in detail with reference to examples. The objects, features and advantages of the present invention will be easily understood by the following embodiments. The present invention is not limited to the embodiments described herein, but may be embodied in other forms. The embodiments disclosed herein are provided so that the disclosure may be thorough and complete, and that those skilled in the art will be able to convey the spirit of the invention to those skilled in the art. Therefore, the present invention should not be limited by the following examples.

Although the terms first, second, etc. are used herein to describe various elements, the elements should not be limited by such terms. These terms are only used to distinguish the elements from each other. In addition, when an element is referred to as being on another element, it may be directly formed on the other element, or a third element may be interposed therebetween.

The sizes of the elements in the figures, or the relative sizes between the elements, may be exaggerated somewhat for a clearer understanding of the present invention. In addition, the shape of the elements shown in the drawings may be somewhat modified by variations in the manufacturing process or the like. Accordingly, the embodiments disclosed herein should not be construed as limited to the shapes shown in the drawings unless specifically stated, and should be understood to include some modifications.

As used herein, the term "bio" means biodegradable, bioabsorbable, and / or biocompatible and can be applied in living organisms such as the human body. As used herein, the terms "biopolymer", "biomaterial", "biopatch", "bio heater", "biosensor", and "bioelectronic patch device" Means that it can be naturally degraded and / or absorbed in the organism, or remains in the organism and is neither harmful nor minimized.

The term "bio-patch", "bio-heater", "biosensor", and "bioelectronic patch device" are used herein for the treatment of brain tumors and are described as being placed in brain tissue. / RTI > and / or < RTI ID = 0.0 > therapeutic, < / RTI >

[Biopatch]

1 shows a bio-patch according to an embodiment of the present invention.

Referring to FIG. 1, a bio patch 100 may include a polymer film 110 and a drug 120.

The polymer film 110 may include a biopolymer. The biopolymer may include one or more of a bioabsorbable polymer, a biodegradable polymer, and a biocompatible polymer.

The bioabsorbable polymer may be selected from the group consisting of oxidized starch, starch, starch ester, starch ether, alginic acid, carrageenan, chitin, chitosan, chitosan, chondroitin sulfate, dextran, dextran sulfate, dextrose, glycogen, hyaluronic acid, maltose, pectin, pectin, pullulan, avidin, biotin, collagen, elastin, silk, glycerol, phospholipid, triglycerides, TG ), Polylactic acid (PLA), polyglycolic acid (PGA), poly (D, L-lactic-co-glycolic acid) ), Polycaprolactone (PCL), polydioxanone (PDO), poly-beta-hydroxybutyrate yrate, PHB), polytrimethylenecarbonate (PTMC), poly [1,3-bis (p-carboxyphenoxy) propane, poly [ sebacic acid, PCPP: SA), poly (sebacic acid), poly (azelaic anhydride), poly-L-lysine, poly- Poly-L-glutamic acid, poly-L-alanine, poly-gamma -aminobutylic acid (GABA), and polyethylene glycol / polylactic acid polymer glycol / polylactic acid, PELA).

The biodegradable polymer may be selected from the group consisting of agar, cellulose, carboxymethyl cellulose, gum arabic, gum karaya, gum tragacanth, mannan, ), And xanthan gum. ≪ / RTI >

The biocompatible polymer may be selected from the group consisting of polyethylene glycol (PEG), silicones, natural rubbers, synthetic rubbers, polyisobutylene, neoprenes, polybutadiene Polyisoprenes, polysiloxanes, acrylic copolymers, vinyl acetate, polyacrylates, ethylene vinyl acetates, styrene-isoprene copolymers, and the like. isoprene, polyurethanes, polyether amide, and styrene-rubber. The term " polyurethane "

Preferably, the polymeric film 110 may comprise an oxidized starch. The oxidized starch comprises an aldehyde group formed by oxidation of the alcohol group of starch. The oxidation concentration of the oxidized starch, that is, the number of the aldehyde group and the alcohol group contained in the oxidized starch can be controlled by controlling the oxidation reaction of the starch by the oxidizing agent. When the oxidation concentration is increased, the number of aldehyde groups contained in the oxidized starch increases and the alcohol group decreases. The bio patch 100 can covalently bond with brain tissue via the aldehyde group and can hydrogen bond with brain tissue through the alcohol group. That is, the bio patch 100 can strongly bind to the brain tissue through covalent bonding and hydrogen bonding between the oxidized starch on the surface of the polymer film 110 and the brain tissue. In addition, the bio patch 100 may be conformally adhered along the surface of the brain tissue. Thus, the drug 120 in the bio patch 100 can be accurately delivered to a target position around the brain tumor removal site without leaking into normal brain tissue or cerebrospinal fluid.

The drug 120 may include a first drug 121 and a second drug 122. The first drug 121 may be a drug chemically bonded to the polymer film 110 by reacting with an aldehyde group of the polymer film 110 and the second drug 122 may be physically bonded to the polymer film 110, . The number of aldehyde groups in the polymer film 110 can be controlled by adjusting the oxidation concentration of the oxidized starch of the polymer film 110 and the amount of the first drug 121 chemically bound to the polymer film 110 can be controlled . The first drug 121 may be released more slowly than the second drug 122 because the first drug 121 binds strongly to the polymer film 110 as compared to the second drug 122. The bio patch 100 may adjust the amount of the first drug 121 and / or the second drug 122 to extend or control the duration of the drug delivery.

The drug 120 may include various drugs depending on the type of disease and the like. For example, when the bio-patch 100 is used for brain tumor treatment, the drug 120 may include an anti-cancer agent, for example, Doxorubicin, Temozolomide, and the like.

The bio patch 100 may have a diameter of about 18 mm and a thickness of about 200 m.

2 illustrates a method of forming a bio-patch according to an embodiment of the present invention.

Referring to FIG. 2 (a), NaIO ₄ (sodium periodate) can be used as an oxidizing agent for synthesizing oxidized starch. Starch is added to the solution formed by dissolving 2.14 g of NaIO _{4 in} 250 ml of water, and the pH is adjusted to 3 to 5 by adding 35 to 37% hydrochloric acid. The mixed solution is stirred at 40 DEG C for one day to form an oxidized starch having an aldehyde group. The mixed solution is filtered, washed three times with deionized water, and dried at 40 캜 under vacuum for 24 hours to form an oxidized starch powder.

2 (b), 1.5 g of the oxidized starch powder and 50 mg of doxorubicin (DOX) were dissolved in 40 g of water at 80 DEG C to form a mixed solution. The mixed solution was stirred for 24 hours to prepare oxidized starch and doxorubicin (DOX) Thereby forming an imine linkage. 0.45 g of glycerol is added to the mixed solution, and after 1 hour, the mixed solution is placed in a Petri dish and dried at 65 ° C. and 80% humidity for 48 hours to form a biopatch.

By adjusting the amount of the oxidized starch powder and / or the amount of the glycerol, a bio patch with various glycerol concentrations can be formed, and the flexibility of the bio patch can be controlled.

The oxidation concentration (or the number of aldehyde groups) of the oxidized starch can be controlled by adjusting the amount of the oxidized starch powder and / or the amount of the oxidizer.

By adjusting the oxidation concentration, the amount of doxorubicin (DOX) that chemically binds to the oxidized starch can be controlled. The doxorubicin (DOX) loaded on the bio-patch may be divided into a first doxorubicin chemically bound to the oxidized starch and a second doxorubicin physically bound or loaded to the oxidized starch. Since the second doxorubicin has a weak binding force with the oxidized starch as compared to the first doxorubicin, the second doxorubicin can be released more quickly from the biopatch. That is, the amount of the first doxorubicin and the second doxorubicin bound to the oxidized starch can be controlled by controlling the oxidation concentration of the oxidized starch, thereby controlling the amount and the speed of the doxorubicin released from the biopatch. For example, when the amount of the first doxorubicin bound to the oxidized starch is larger than the amount of the second doxorubicin, the amount of doxorubicin initially released from the biopatch is relatively small, When the amount of the first doxorubicin is greater than the amount of the first doxorubicin, the amount of doxorubicin released earlier in the biopatch is relatively large. Thus, the amount and release rate of doxorubicin can be controlled by adjusting the oxidation concentration of the oxidized starch.

[Bio-heater]

3 shows a bio heater according to an embodiment of the present invention.

Referring to FIG. 3, the bio heater 200 may include a heater 210, a first heater protection layer 231, and a second heater protection layer 232.

The heater 210 may comprise a bio-metal. The bio-metal may include magnesium (Mg) or iron (Fe). The heater 210 may include a metal pattern formed of the biomaterial. The heater 210 may include a plurality of holes 210a. The heater 210 can uniformly generate heat by the holes 210a.

The heater 210 can be controlled wirelessly by an alternating magnetic field. When an alternating magnetic field is provided to the heater 210, the heater 210 can generate heat.

The first heater protection layer 231 and the second heater protection layer 232 may be disposed above and below the heater 210 to protect the heater 210, respectively. The first heater protection layer 231 and the second heater protection layer 232 may include a biopolymer, for example, PLA.

Although not shown in the drawings, the bio heater 200 may be disposed in a human body, for example, brain tissue together with a bio patch (100 in FIG. 1) to control drug release of the bio patch. The bio heater 200 can heat the bio patch to accelerate drug release, and the drug release rate can be controlled by controlling the heating temperature.

4 shows a method of forming a bio heater according to an embodiment of the present invention.

Referring to FIG. 4, a heater 210 is formed on the first heater protection layer 231. The first heater protection layer 231 may be formed of a biopolymer, for example, PLA, on a substrate (not shown) by performing a spin coating process.

The heater 210 may be formed as a metal pattern by performing a thermal evaporation process to form a metal layer of a biomaterial on the first heater protection layer 231 and then patterning the metal layer. The metal pattern may have a plurality of holes 210a. The biomass may include Mg or Fe. The metal layer may have a thickness of about 1.5 mu m.

The patterning may be performed by forming a photoresist pattern on the metal layer and etching the exposed metal layer with an etching solution. The etch solution may include nitric acid, deionized water, and ethylene glycol in a ratio of 1: 1: 3.

Although not shown in the drawing, a metal oxide layer such as ZnO may be formed on the first heater protection layer 231 before forming the metal layer. The metal layer can be effectively formed by the metal oxide layer. The heater 210 may be formed directly on the first heater protection layer 231 or may be transferred to the first heater protection layer 231 after being formed elsewhere.

Referring again to FIG. 3, a second heater protection layer 232 covering the heater 210 is formed on the first heater protection layer 231. The second heater protection layer 232 may be formed of a biopolymer, for example, PLA by performing a spin coating process.

[Biosensor]

FIG. 5 shows a biosensor according to an embodiment of the present invention, and FIG. 6 shows a circuit diagram of a biosensor according to an embodiment of the present invention. Fig. 5 (b) shows an enlarged view of the area A in Fig. 5 (a).

5 and 6, the biosensor 300 may include an inductor 310, a capacitor 320, a first sensor protection layer 331, and a second sensor protection layer 332. In addition, the biosensor 300 may include an LC oscillator having an inductor 310 and a capacitor 320.

Inductor 310 may comprise a biomaterial, such as Mg or Fe. The inductor 310 may surround the capacitor 320 in a coil shape. The inductor 310 may be connected in parallel with the capacitor 320.

The capacitor 320 may include a first electrode 321, a second electrode 322, and a dielectric 323. The first electrode 321 and the second electrode 322 may include a biomaterial such as Mg or Fe. The first electrode 321 and the second electrode 321 may have a comb shape to increase an area facing each other. The dielectric 323 may be disposed between the first electrode 321 and the second electrode 322. The dielectric 323 may be filled in the space between the inductor 310 and the capacitor 320 during formation and may cover the inductor 310 and the capacitor 320. The dielectric 323 may comprise a biopolymer having a glass transition temperature in the range of 36 to 42 < 0 > C. The biopolymer may include, for example, PLGA (lactic acid: glycolic acid = 65: 35). The PLGA has a glass transition temperature (Tg) at about 39 DEG C, which is similar to the human body temperature. When the temperature changes at the ambient temperature of the glass transition temperature, the dielectric constant of the dielectric 323 changes, thereby changing the capacitance and changing the resonance frequency. The external device 350 can measure the temperature change by measuring the change of the resonance frequency wirelessly from outside the human body on which the biosensor 300 is disposed. The biosensor 300 can measure the temperature in real time and the measured temperature can be wirelessly read and monitored by the external device 350. [

The first sensor protection layer 331 and the second sensor protection layer 332 may be disposed above and below the heater 210 to protect the inductor 310 and the capacitor 320, respectively. The first sensor protection layer 331 and the second sensor protection layer 332 may comprise a biopolymer, for example, PLA.

Although not shown in the figure, the biosensor 300 is disposed in a human body, for example, brain tissue together with a bio-patch (100 in FIG. 1) and a bio-heater (200 in FIG. 3) to measure the temperature of the bio- The bio heater can be controlled. Thus, the brain tissue can be prevented from being damaged by overheating at a temperature higher than 42 캜 by the bio heater.

7 and 8 show a method of forming a biosensor according to an embodiment of the present invention.

Referring to FIG. 7, an inductor 310, a first electrode 321, and a second electrode 322 are formed on a first sensor protection layer 331. The first sensor protection layer 331 may be formed of a biopolymer, for example, PLA, on a substrate (not shown) by performing a spin coating process.

The inductor 310, the first electrode 321 and the third electrode 322 are thermally evaporated to form a metal layer of a biomaterial on the first sensor protection layer 331 and pattern the metal layer And may be formed of a metal pattern. The biomass may include Mg or Fe. The metal layer may have a thickness of about 1.5 mu m.

The patterning may be performed by forming a photoresist pattern on the metal layer and etching the exposed metal layer with an etching solution. The etch solution may include nitric acid, deionized water, and ethylene glycol in a ratio of 1: 1: 3.

Although not shown in the drawing, a metal oxide layer such as ZnO may be formed on the first sensor protection layer 331 before forming the metal layer. The metal layer can be effectively formed by the metal oxide layer. The inductor 310, the first electrode 321 and the second electrode 322 may be formed directly on the first sensor protection layer 331 and may be formed on the first sensor protection layer 331 after being formed elsewhere. Lt; / RTI >

A dielectric 323 is formed between the first electrode 321 and the second electrode 322. The dielectric 323 may be filled in the space between the inductor 310 and the capacitor 320 during formation and may cover the inductor 310 and the capacitor 320. The dielectric 323 may be formed of a biopolymer having a glass transition temperature in the range of 36 to 42 占 폚. The biopolymer may include, for example, PLGA (lactic acid: glycolic acid = 65: 35).

Referring again to FIG. 5, a second sensor protection layer 332 is formed on the first sensor protection layer 331 to cover the inductor 310 and the capacitor 320. The second sensor protection layer 332 may be formed of a biopolymer, for example, PLA by performing a spin coating process.

[Bio electronic patch device]

FIG. 9 is a plan view of a bioelectronic patch device according to an embodiment of the present invention, and FIG. 10 is an exploded perspective view of the bioelectronic patch device of FIG.

9 and 10, the bioelectronic patch device 10 includes a drug patch 100, a heater 210, a temperature sensor 300, a first passivation layer 410, and a second passivation layer 420, . ≪ / RTI >

The drug patch 100 may include a polymer film 110 and a drug 120.

The polymer film 110 may include a biopolymer. The biopolymer may include one or more of a bioabsorbable polymer, a biodegradable polymer, and a biocompatible polymer.

The bioabsorbable polymer may be selected from the group consisting of oxidized starch, starch, starch ester, starch ether, alginic acid, carrageenan, chitin, chitosan, chitosan, chondroitin sulfate, dextran, dextran sulfate, dextrose, glycogen, hyaluronic acid, maltose, pectin, pectin, pullulan, avidin, biotin, collagen, elastin, silk, glycerol, phospholipid, triglycerides, TG ), Polylactic acid (PLA), polyglycolic acid (PGA), poly (D, L-lactic-co-glycolic acid) ), Polycaprolactone (PCL), polydioxanone (PDO), poly-beta-hydroxybutyrate yrate, PHB), polytrimethylenecarbonate (PTMC), poly [1,3-bis (p-carboxyphenoxy) propane, poly [ sebacic acid, PCPP: SA), poly (sebacic acid), poly (azelaic anhydride), poly-L-lysine, poly- Poly-L-glutamic acid, poly-L-alanine, poly-gamma -aminobutylic acid (GABA), and polyethylene glycol / polylactic acid polymer glycol / polylactic acid, PELA).

The biodegradable polymer may be selected from the group consisting of agar, cellulose, carboxymethyl cellulose, gum arabic, gum karaya, gum tragacanth, mannan, ), And xanthan gum. ≪ / RTI >

The biocompatible polymer may be selected from the group consisting of polyethylene glycol (PEG), silicones, natural rubbers, synthetic rubbers, polyisobutylene, neoprenes, polybutadiene Polyisoprenes, polysiloxanes, acrylic copolymers, vinyl acetate, polyacrylates, ethylene vinyl acetates, styrene-isoprene copolymers, and the like. isoprene, polyurethanes, polyether amide, and styrene-rubber. The term " polyurethane "

Preferably, the polymeric film 110 may comprise an oxidized starch. The oxidized starch comprises an aldehyde group formed by oxidation of the alcohol group of starch. It is possible to control the oxidative concentration of the oxidized starch, that is, the number of aldehyde groups and alcohol groups contained in the oxidized starch by controlling the oxidation reaction of the oxidized starch. When the oxidation concentration is increased, the number of aldehyde groups contained in the oxidized starch increases and the alcohol group decreases. The drug patch 100 can covalently bind to the brain tissue through the aldehyde group and hydrogen bond with the brain tissue through the alcohol group. That is, the drug patch 100 can strongly bind to the brain tissue through covalent bonding and hydrogen bonding between the oxidized starch and the brain tissue on the surface of the polymer film 110. In addition, the drug patch 100 may be conformally adhered along the surface of the brain tissue. Thereby, the drug 120 in the drug patch 100 can be accurately delivered to the target position around the brain tumor removal site without leaking into normal brain tissue or cerebrospinal fluid.

The drug 120 may include a first drug 121 and a second drug 122. The first drug 121 may be a drug chemically bonded to the polymer film 110 by reacting with an aldehyde group of the polymer film 110 and the second drug 122 may be physically bonded to the polymer film 110, . The number of aldehyde groups in the polymer film 110 can be controlled by adjusting the oxidation concentration of the oxidized starch of the polymer film 110 and the amount of the first drug 121 chemically bound to the polymer film 110 can be controlled . The first drug 121 may be released more slowly than the second drug 122 because the first drug 121 binds strongly to the polymer film 110 as compared to the second drug 122. The bio patch 100 may adjust the amount of the first drug 121 and / or the second drug 122 to extend or control the duration of the drug delivery.

The drug 120 may include various drugs depending on the type of disease and the like. For example, if drug patch 100 is used for brain tumor treatment, drug 120 may include anti-cancer agents such as doxorubicin, temozolomide, and the like.

The drug patch 100 may have a diameter of about 18 mm and a thickness of about 200 [mu] m.

The heater 210 may be disposed on the drug patch 100. The heater 210 may comprise a bio-metal. The biomass may include Mg or Fe. The heater 210 may include a plurality of holes 210a. The heater 210 can uniformly generate heat by the holes 210a.

The heater 210 can be controlled wirelessly by an alternating magnetic field. When an alternating magnetic field is provided to the heater 210, the heater 210 can generate heat.

The heater 210 may control the drug release of the drug patch 100. The heater 210 may heat the drug patch 100 to promote drug release and adjust the drug release rate by adjusting the heating temperature.

The temperature sensor 300 may be disposed adjacent to the heater 210 on the drug patch 100. The temperature sensor 300 is capable of measuring the temperature of the heater 210. The temperature sensor 300 may be disposed in the central region of the heater 210 to accurately and effectively measure the temperature of the heater 210. [ The central region of the heater 210 can be removed so that the temperature sensor 300 can be disposed, and the heater 210 can have an annular shape.

The temperature sensor 300 may include an inductor 310 and a capacitor 320. In addition, the temperature sensor 300 may include an LC oscillator having an inductor 310 and a capacitor 320.

Inductor 310 may comprise a biomaterial, such as Mg or Fe. The inductor 310 may surround the capacitor 320 in a coil shape. The inductor 310 may be connected in parallel with the capacitor 320.

The capacitor 320 may include a first electrode 321, a second electrode 322, and a dielectric 323. The first electrode 321 and the second electrode 322 may include a biomaterial such as Mg or Fe. The first electrode 321 and the second electrode 321 may have a comb shape to increase an area facing each other. The dielectric 323 may be disposed between the first electrode 321 and the second electrode 322. The dielectric 323 may be filled in the space between the inductor 310 and the capacitor 320 and in the space between the inductor 310 and the heater 210 during the forming process and the inductor 310, (Not shown). The dielectric 323 may comprise a biopolymer having a glass transition temperature in the range of 36 to 42 < 0 > C. The biopolymer may include, for example, PLGA (lactic acid: glycolic acid = 65: 35). The PLGA has a glass transition temperature (Tg) at about 39 DEG C, which is similar to the human body temperature. When the temperature changes at the ambient temperature of the glass transition temperature, the dielectric constant of the dielectric 323 changes, thereby changing the capacitance and changing the resonance frequency. The external device (350 in FIG. 6) can measure the temperature change by measuring the change of the resonance frequency wirelessly outside the human body in which the temperature sensor 300 is disposed. The temperature sensor 300 can measure the temperature in real time, and the measured temperature can be wirelessly read and monitored by the external device.

The temperature sensor 300 can control the heater 210 by measuring the temperature of the heater 210. Thus, the brain tissue can be prevented from being damaged by overheating at a temperature higher than 42 캜 by the bio heater.

The first passivation layer 410 may be disposed between the heater 210 and the temperature sensor 300 and the drug patch 100 and the second passivation layer 420 may be disposed between the heater 210 and the temperature sensor 300 . The first passivation layer 410 and the second passivation layer 420 may protect the heater 210 and the temperature sensor 300. The first passivation layer 410 and the second passivation layer 420 may include a biopolymer, for example, PLA.

11 to 16 show a method of forming a bioelectronic patch device according to an embodiment of the present invention.

Referring to FIG. 11, a sacrificial layer 22 is formed on the sacrificial substrate 21. The sacrificial substrate 21 may be a silicon substrate. The sacrificial layer 22 may be formed of PMMA (poly (methyl methacrylate)) by performing a spin coating process.

A first polyimide layer (23) is formed on the sacrificial layer (22). The first polyimide layer 23 may be formed of polyimide by performing a spin coating process.

Referring to FIG. 12, a metal pattern including a heater 210, an inductor 310, a first electrode 321, and a second electrode 322 is formed on a first polyimide layer 23. The metal pattern may be formed by performing a thermal evaporation process to form a metal layer of a biomaterial on the first polyimide layer 23 and then patterning the metal layer. The heater 210 may have a plurality of holes 210a. The biomass may include Mg or Fe. The metal layer may have a thickness of about 1.5 mu m.

The patterning may be performed by forming a photoresist pattern on the metal layer and etching the exposed metal layer with an etching solution. The etch solution may include nitric acid, deionized water, and ethylene glycol in a ratio of 1: 1: 3.

Although not shown in the drawing, a metal oxide layer such as ZnO may be formed on the first polyimide layer 23 before forming the metal layer. The metal layer can be effectively formed by the metal oxide layer.

Referring to FIG. 13, a second polyimide layer 24 is formed on the first polyimide layer 23 to cover the metal pattern. The second polyimide layer 24 may be formed by performing a spin coating process to form a polyimide layer and then patterning. At this time, the first polyimide layer 23 may also be patterned in the same shape as the second polyimide layer 24.

14, the sacrificial layer 22 is removed to separate the laminated structure of the first polyimide layer 23, the metal pattern, and the second polyimide layer 24 from the sacrificial substrate 21.

Referring to FIG. 15, the metal pattern is transferred onto the drug patch 100 having the first protective layer 410 formed thereon. After the metal pattern is picked up by the stamp, the first polyimide layer 23 is removed, and the second polyimide layer 24 is removed after the metal pattern is disposed on the first protective layer 410.

The drug patch 100 may be formed using a biopolymer such as oxidized starch and a drug such as doxorubicin. Starch is added to the solution formed by dissolving 2.14 g of NaIO _{4 in} 250 ml of water, and the pH is adjusted to 3 to 5 by adding 35 to 37% hydrochloric acid. The mixed solution is stirred at 40 DEG C for one day to form an oxidized starch having an aldehyde group. The mixed solution is filtered, washed three times with deionized water, and dried at 40 캜 under vacuum for 24 hours to form an oxidized starch powder. 1.5 g of the oxidized starch powder and 50 mg of doxorubicin are dissolved in 40 g of water at 80 DEG C to form a mixed solution, and the mixed solution is stirred for 24 hours to form an immobilized bond between the oxidized starch and doxorubicin. 0.45 g of glycerol is added to the mixed solution, and after 1 hour, the mixed solution is placed in a Petri dish and dried at 65 캜 and 80% humidity for 48 hours to form a drug patch 100.

By adjusting the amount of the oxidized starch powder and / or the amount of the glycerol, the drug patch 100 having various glycerol concentrations can be formed, and the flexibility of the drug patch 100 can be controlled.

The oxidation concentration (or the number of aldehyde groups) of the oxidized starch can be controlled by adjusting the amount of the oxidized starch powder and / or the amount of the oxidizer.

By controlling the oxidation concentration, the amount of doxorubicin that chemically binds to the oxidized starch can be controlled. The doxorubicin loaded on the bio patch may be divided into a first doxorubicin chemically bound to the oxidized starch and a second doxorubicin physically bound to or loaded onto the oxidized starch. Since the second doxorubicin has a weak binding force with the oxidized starch as compared to the first doxorubicin, the second doxorubicin can be released more quickly from the biopatch. That is, the amount of the first doxorubicin and the second doxorubicin bound to the oxidized starch can be controlled by controlling the oxidation concentration of the oxidized starch, thereby controlling the amount and the speed of the doxorubicin released from the biopatch. For example, when the amount of the first doxorubicin bound to the oxidized starch is larger than the amount of the second doxorubicin, the amount of doxorubicin initially released from the biopatch is relatively small, When the amount of the first doxorubicin is greater than the amount of the first doxorubicin, the amount of doxorubicin released earlier in the biopatch is relatively large. Thus, the amount and release rate of doxorubicin can be controlled by adjusting the oxidation concentration of the oxidized starch.

The first passivation layer 410 may be formed of a biopolymer, for example, PLA by performing a spin coating process.

Referring to FIG. 16, a dielectric 323 is formed between the first electrode 321 and the second electrode 322. The dielectric 323 may be filled in the space between the inductor 310 and the capacitor 320 and in the space between the inductor 310 and the heater 210 during the forming process and the inductor 310, (Not shown). The dielectric material 323 may be formed of a biopolymer having a glass transition temperature in the range of 36 to 42 DEG C by performing a spin coating process. The biopolymer may include, for example, PLGA (lactic acid: glycolic acid = 65: 35).

A second passivation layer 420 is formed on the first passivation layer 410 to cover the heater 210 and the temperature sensor 300. The second passivation layer 420 may be formed of a biopolymer, for example, PLA by performing a spin coating process.

FIG. 17 shows a bioelectronic patch device according to an embodiment of the present invention applied to a human brain, and FIG. 18 shows an enlarged view of a region A in FIG.

17 and 18, a bioelectronic patch device (BEP) may be attached to a cavity-shaped surgical site after a resection of a malignant brain tumor. Because of the tackiness and flexibility of the drug patch of the bioelectronic patch device (BEP), the bioelectronic patch device (BEP) can be conforma- tively and strongly attached to the surface of the brain's cavity.

The heater of the bioelectronic patch device (BEP) can be operated wirelessly by an alternating magnetic field to heat the drug patch and increase the drug release rate of the drug patch and the drug penetration depth into the brain tissue.

The temperature sensor of the bio electronic patch device (BEP) can monitor the temperature of the heater and prevent the brain tissue from being overheated.

FIG. 19 is a graph showing changes with time after a bioelectronic patch device according to an embodiment of the present invention is attached to the brain of a dog. Fig. 19 (a) shows an image after one week has elapsed after attaching the bioelectronic patch device, and Fig. 19 (b) shows an image after nine weeks after attaching the bioelectronic patch device. Referring to FIG. 19, as time elapses, the bioelectronic patch device is gradually hydrolyzed and absorbed, and its size gradually decreases.

FIG. 20 shows drug delivery depths according to heating of a bioelectronic patch device according to an embodiment of the present invention. Referring to FIG. 20, the heating of the heater increases the penetration depth of the drug into the brain tissue.

FIG. 21 shows a fluorescence microscope image of the bio-electronic patch device and the adhesive interface of the brain according to an embodiment of the present invention. Referring to FIG. 21, the drug patch of the bioelectronic patch device can be concomitantly adhered to the brain tissue, and the drug can be delivered to the brain tissue without leaking into the cerebrospinal fluid or the like.

22 shows the shear adhesive force of the drug patch of the bioelectronic patch device according to an embodiment of the present invention. Referring to FIG. 22, the oxidized starch exhibits a stronger shear adhesive force than the normal starch. And, as the oxidation concentration of oxidized starch increases, shear adhesion increases. By the shear adhesive force, the drug patch can make a conformational adhesion to brain tissue, which enables more effective drug delivery.

FIG. 23 and FIG. 24 show the drug discharge accumulation amount of the bioelectronic patch device according to an embodiment of the present invention. A solid line graph (A) of FIG. 23 shows a drug patch formed of oxidized starch, and a dotted line graph (B) shows a drug patch formed of normal starch. 23, the drug patch formed of the common starch is physically loaded with the drug, so that a large amount of drug is initially released. However, since the drug is chemically bonded with the oxidized starch, , And the chemically bound drug can be released slowly. Figure 24 shows drug release with temperature. Referring to FIG. 24, the drug patch of the bioelectronic patch device can release more drug at 42 占 폚 than 37 占 폚. That is, the drug release amount increases as the heating temperature for the drug patch increases. Therefore, the drug release amount can be controlled by controlling the heating temperature of the drug patch.

Figure 25 shows the effect of heating on drug delivery. Fig. 25 (a) shows drug delivery when the drug patch is not heated, and Fig. 25 (b) shows drug delivery when the drug patch is heated. Referring to FIG. 25, the amount of diffusion of the drug and the depth of diffusion are both larger in the case of heating the drug patch than in the case of not heating.

26 shows the resonance frequency of the biosensor according to the temperature. The biosensor includes a dielectric formed of PLGA (lactic acid: glycolic acid = 65: 35) having a glass transition temperature of about 39 占 폚. Referring to FIG. 26, when the temperature changes at an ambient temperature of the glass transition temperature (39 DEG C), the dielectric constant of the dielectric changes, thereby changing the capacitance and changing the resonance frequency. The temperature change can be measured by detecting a change in the resonance frequency.

FIGS. 27 to 29 show the comparison of the size change and the survival rate of brain tumors according to the four treatment methods applied to rats having brain tumors. 27 to 29 (a) show changes in brain tumor size and survival rate when the drug is injected by intravenous injection, (b) show a case where the bioelectronic patch device is inserted into the brain tumor region and heated only without drug injection (C) shows a case where a drug is released without heating a drug patch after inserting a bioelectronic patch device into a brain tumor site, (d) shows a case where a bioelectronic patch device is inserted into a brain tumor site, While releasing the drug.

27 and 28, in the case of (a) and (b), the brain tumor rapidly increases with time, whereas in the case of (c), the brain tumor is almost unchanged in the early stage when the size of the brain tumor is small, (D) shows a decrease in brain tumor due to an increase in drug release amount and drug penetration depth.

Referring to FIG. 29, (c) and (d) show higher survival rates than (a) and (b). Especially in (d), the survival rate remains very high even after 50 days have elapsed.

Hereinafter, specific embodiments of the present invention have been described. 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.

10: Bio electronic patch device 100: Bio patch, drug patch
110: polymer film 120: drug
200: Bio heater 210: Heater
300: Biosensor (temperature sensor) 310: Inductor
320: Capacitor

Claims (9)

A heater comprising a bio-metal,
The heater is disposed adjacent to the bio patch to heat the bio patch,
Wherein the bio patch comprises a polymer film including a biopolymer and a drug loaded on the polymer film,
Wherein the biopolymer comprises oxidized starch,
Wherein the bio heater is inserted into brain tissue together with the bio patch to be used for treatment of brain tumor. The method according to claim 1,
Wherein the bio-metal comprises Mg or Fe. The method according to claim 1,
Wherein the heater includes a metal pattern formed of the biomaterial. The method of claim 3,
Wherein the metal pattern has a plurality of holes. The method according to claim 1,
A first heater protection layer disposed below the heater,
And a second heater protection layer disposed on the heater. The method according to claim 1,
Wherein the heater is controlled wirelessly by an alternating magnetic field. delete The method according to claim 1,
And the release of the drug is controlled by the heater. delete

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