JP2011251042A - Implant for hyperthermia and its manufacturing method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an implant for hyperthermia which excels in exothermic efficiency and in biocompatibility, meters temperature in a metered section with sufficient accuracy, and can function appropriately also as a heating element which warms a metered section, and its manufacturing method.SOLUTION: The implant for hyperthermia has a coating layer containing gold on a surface of a temperature sensitive ferrite. The method for manufacturing the implant for hyperthermia includes: a process which covers a material containing gold on a surface of the temperature sensitive ferrite to be a first covering layer; and a process which covers a material containing gold on the surface of the first covering layer to be a second coating layer.

Description

  The present invention relates to an implant that can be suitably used in hyperthermia (hyperthermia) and a method for producing the implant.

  One therapy for malignant tumors is hyperthermia using microwaves or high-frequency currents as energy sources. When performing thermotherapy, it is necessary to accurately measure the temperature using a method suitable for measuring the temperature of the affected area, and to confirm that the temperature of the affected area has reached the target temperature.

  As a temperature measurement technique, for example, there is a technique using a thermal camera using infrared rays, but this is mainly limited to the surface temperature measurement application, and it is difficult to measure the internal temperature of a living body or the like that cannot transmit infrared rays. is there. It is also possible to measure the temperature of the affected area by inserting a temperature probe such as a thermistor or thermocouple into the body invasively. However, this method causes a lot of pain and burden on the patient, and causes infectious diseases. It is not preferable from the viewpoint of hygiene.

  As a temperature measurement technique that can solve the above problem, for example, Patent Document 1 includes a temperature measurement element that includes a permanent magnet and a plurality of temperature-sensitive magnetic bodies having different Curie points covering the periphery of the permanent magnet. The temperature at which the magnetic flux that leaks depending on the temperature from the temperature measurement element is detected by a magnetic sensor placed at a position away from the temperature measurement element, and the temperature of the measured part is measured based on the output. A measurement method is disclosed.

JP 2001-33317 A

  According to the technique according to Patent Literature 1, it is possible to measure the temperature of the measurement target portion from a position distant from the wireless, and it is possible to reduce pain to the patient and to solve some problems in hygiene. However, in Patent Document 1, since the temperature measuring element is composed of a permanent magnet and a plurality of temperature-sensitive magnetic bodies, it is difficult to downsize the temperature measuring element itself. Therefore, in view of the arrangement in the patient's body, it has been desired to further reduce the temperature measurement element itself and further reduce the burden on the patient.

  In view of this, the present inventors have invented a completely new temperature measurement method and temperature measurement system in which a temperature measurement probe to be placed in a living body is made smaller than before (Japanese Patent Application No. 2008-163226, Patent Application). 2009-173062, and International Publication No. 2009/088062 pamphlet). This technology uses only a temperature-sensitive magnetic body as a temperature measurement probe to be placed in the living body. By making the temperature-sensitive magnetic body into fine particles, the temperature measuring probe can be miniaturized and easily moved into the living body. Injection and placement are possible. That is, it can be said that it is an excellent technique in which the burden on the patient is further reduced.

  On the other hand, as a result of further research on temperature measurement in the living body, the present inventors have placed only the above-mentioned temperature-sensitive magnetic body, and when performing temperature measurement, due to the poor heat generation efficiency of the temperature-sensitive magnetic body, It has been found that it is not suitable to use the thermosensitive magnetic material itself as a heating element for hyperthermia. For example, it was considered that if the implant can function not only as a temperature measurement probe but also as a heating element, the volume of the implant placed in the affected area can be further reduced. Furthermore, in view of the arrangement in the body, there is room for studying biocompatibility.

  The present invention has been made in view of the above problems, and has excellent heat generation efficiency and biocompatibility, and functions appropriately as a heating element that warms the measurement target portion while accurately measuring the temperature in the measurement target portion. It is an object of the present invention to provide a hyperthermia implant to be obtained.

In order to solve the above problems, the present invention adopts the following configuration. That is,
A first aspect of the present invention is a hyperthermia implant having a coating layer containing gold on the surface of a temperature-sensitive magnetic body.

  In the present invention, the “temperature-sensitive magnetic body” means a magnetic body made of a magnetic material in which the Curie point can be arbitrarily set by changing the composition ratio, adding an additive, heat treatment, or the like. Specific examples of the magnetic material that can be used in the present invention include Ni—Zn ferrite and Mn—Cu—Zn ferrite. The “coating layer containing gold” is a concept including a coating layer made only of gold in addition to a coating layer made of gold and other substances.

  In the first aspect of the present invention, it is preferable that the temperature-sensitive magnetic substance has a particle size of 50 μm or more and 2000 μm or less. This is because in the case of measuring the temperature in the living body, the implant can be easily injected and placed in the living body, and further, it can sufficiently function as a temperature probe.

  1st aspect of this invention WHEREIN: It is preferable that the thickness of a coating layer is 0.005 micrometer or more and 1 micrometer or less. This is because the implant can be easily manufactured and has excellent heat generation efficiency. In particular, if the thickness is greater than this, the magnetic flux is shielded and attenuated by the coating layer, so that the change in the magnetic flux vector around the temperature-sensitive magnetic body around the Curie point becomes relatively small, and it may be difficult to detect the ultimate temperature. .

  According to a second aspect of the present invention, the surface of the temperature-sensitive magnetic material is coated with a material containing gold to form a first coating layer, and the surface of the first coating layer is coated with a material containing gold, It is a manufacturing method of the implant for hyperthermia provided with the process used as a coating layer.

  In the second aspect of the present invention, it is preferable to use a thermosensitive magnetic material having a particle size of 50 μm or more and 2000 μm or less. This is because the implant can be easily injected and placed in the living body when measuring the temperature in the living body.

  In the second aspect of the present invention, it is preferable that the first coating layer is formed by sputtering and the second coating layer is formed by electroless plating. This is because a coating layer can be appropriately formed on the surface of the temperature-sensitive magnetic body.

  In the second aspect of the present invention, the total thickness of the first coating layer and the second coating layer is preferably 0.005 μm or more and 1 μm or less. This is because the implant can be easily manufactured and has excellent heat generation efficiency.

  According to the hyperthermia implant of the present invention, since the surface of the temperature-sensitive magnetic body is coated with the material containing gold, the heat generation efficiency of the implant itself can be improved. That is, in addition to the function as a temperature measurement probe possessed by the temperature-sensitive magnetic body itself, it can also function as a heating element by induction heating. Specifically, in hyperthermia, it can function as a heating element that heats the affected area to a predetermined temperature, and can also function as a measurement probe that accurately measures whether or not the temperature of the affected area is a predetermined temperature. It is also possible to reduce the volume of the implant to be placed in the affected area by balancing the functions. Further, since the surface exposure amount of the temperature-sensitive magnetic material is reduced and gold is exposed on the surface, it is excellent in biocompatibility and can be used in vivo without problems.

It is the schematic for demonstrating the temperature measurement principle using a temperature-sensitive magnetic body. It is the schematic which shows an example of the implant for hyperthermia. It is a figure for demonstrating the manufacture example of the implant for hyperthermia. It is the schematic for demonstrating the manufacture example of the implant for hyperthermia. It is the schematic for demonstrating the evaluation apparatus which concerns on an Example. It is a figure which shows the heat_generation | fever characteristic of various materials. It is a figure which shows the heat_generation | fever characteristic of the implant for hyperthermia at the time of changing plating time. It is a figure which shows the heat_generation | fever characteristic of the implant for hyperthermia when a plating area is changed. It is a figure for comparing each heat-generating characteristic of a thermosensitive magnetic body, a sputtering thermosensitive magnetic body, and a hyperthermia implant. It is a figure which shows the heat_generation | fever characteristic of the implant for hyperthermia when an installation location is changed. It is a figure which shows the heat_generation | fever characteristic of the implant for hyperthermia at the time of an endurance test. It is a figure which shows the average value of the temperature increase rate of the implant for hyperthermia at the time of an endurance test. It is the schematic for demonstrating the evaluation apparatus which concerns on an Example. It is a figure which shows the time-dependent change of the temperature and pick-up voltage of the implant for hyperthermia. It is a figure which shows the relationship between the temperature of the implant for hyperthermia, and a pick-up voltage. It is a figure which shows the time-dependent change of the temperature of the implant for hyperthermia at the time of reproducibility evaluation, and a pick-up voltage. It is a figure which shows the relationship between the temperature of the implant for hyperthermia at the time of reproducibility evaluation, and a pick-up voltage.

1. Principle of temperature measurement using temperature-sensitive magnetic material In temperature measurement using temperature-sensitive magnetic material, the magnetic flux vector of the magnetic field generated from the magnetic field source depends on the temperature of the temperature-sensitive magnetic material placed in the measurement target part. And take advantage of changing. Hereinafter, the temperature measurement principle using the temperature-sensitive magnetic material, which is a premise of the present invention, will be described with reference to FIG.

  As shown in FIG. 1, in temperature measurement using a temperature-sensitive magnetic body, a temperature-sensitive magnetic body 1, a drive coil 2, and a pickup coil 3 are used, and the drive coil 2 flows an alternating current from a power source 4. An alternating magnetic field is generated, and the pickup coil 3 detects a change in the magnetic flux vector of the alternating magnetic field generated from the drive coil 2. Here, as shown in FIG. 1, the pickup coil 3 is preferably disposed between the temperature-sensitive magnetic body 1 and the drive coil 2, and the axial directions of the drive coil 2 and the pickup coil 3 are orthogonal to each other. It is preferable to arrange so as to. By adopting such a configuration, it becomes easy for the pickup coil 3 to detect a change in the magnetic flux vector generated from the drive coil 2 and changing depending on the temperature of the temperature-sensitive magnetic body 1.

  Depending on the temperature of the temperature-sensitive magnetic body 1, the magnetic flux vector changes as follows. 1A shows the state of the magnetic flux vector when the temperature of the temperature-sensitive magnetic body 1 is lower than the Curie point, and FIG. 1B shows the magnetic flux vector when the temperature of the temperature-sensitive magnetic body 1 is higher than the Curie point. The state of is shown.

  When the temperature of the temperature-sensitive magnetic body 1 is lower than the Curie point, the temperature-sensitive magnetic body 1 has a high magnetic permeability. Therefore, as shown in FIG. 1A, the magnetic flux of the alternating magnetic field generated from the drive coil 2 is attracted to the temperature-sensitive magnetic body 1, and the magnetic flux vector is bent. At this time, if the drive coil 2 and the pickup coil 3 are arranged so that their axial directions are orthogonal to each other, the induced electromotive force generated in the pickup coil 3 increases in proportion to the displacement of the orthogonal component of the magnetic flux vector. The potential detected by the voltmeter 5 increases.

  On the other hand, when the temperature of the temperature-sensitive magnetic body 1 is equal to or higher than the Curie point, the magnetism of the temperature-sensitive magnetic body 1 is approximately the same as that of air. Therefore, as shown in FIG. 1B, the magnetic flux of the alternating magnetic field generated from the drive coil 2 travels substantially straight without being attracted to the temperature-sensitive magnetic body 1. At this time, if the drive coil 2 and the pickup coil 3 are arranged so that their axial directions are orthogonal to each other, the magnetic flux vector and the axial direction of the pickup coil 3 are substantially orthogonal. Therefore, the induced electromotive force generated in the pickup coil 3 is reduced as compared with the case where the temperature of the temperature-sensitive magnetic body 1 is less than the Curie point.

  As described above, when the temperature of the temperature-sensitive magnetic body 1 is increased, the induced electromotive force generated in the pickup coil 3 near the Curie point changes abruptly, and this change is caused by the voltmeter 5 connected to the pickup coil 3. Can be confirmed. That is, the temperature-sensitive magnetic body 1 is arranged in a measurement target part (for example, an affected part in a living body), an alternating magnetic field is generated at a location away from the temperature-sensitive magnetic body 1, and the temperature-sensitive magnetic body 1 is at or above the Curie point. It is possible to confirm whether or not the temperature around the temperature-sensitive magnetic body 1 (for example, the affected part temperature) is equal to or higher than a predetermined temperature. For example, by using the temperature-sensitive magnetic body 1 having a Curie point of about 43 ° C., it is possible to accurately detect whether or not the affected part has reached a temperature suitable for hyperthermia.

  In such a temperature measurement method, since the heat generation efficiency of the temperature-sensitive magnetic body 1 is poor, it is not preferable to use the temperature-sensitive magnetic body 1 itself as a heat generation body by induction heating. That is, when applied to hyperthermia, it is necessary to use another means as a heating element in addition to the temperature-sensitive magnetic body 1. For example, a method of heating using an external heating means, a method of injecting and arranging a heat generating material separately in the living body, and generating heat by induction heating, etc. can be considered. As an external heating means, for example, a thermotron or the like can be considered, but there is a problem that not only the apparatus becomes large, but appropriate heating cannot be performed by subcutaneous fat or the like. On the other hand, in the case where the heat generating means is separately arranged in the living body, in addition to the trouble of separately preparing the necessary amount of heat generating means and materials together with the temperature-sensitive magnetic material, the problem of uneven heat generation, the heat generating means and the temperature sensitive There are also problems such as temperature measurement errors due to separation from the magnetic material. In view of such problems, the present inventors have developed a completely new hyperthermia that has both a function as a heating element and a function as a temperature measurement probe, and also improved biocompatibility by assuming injection into the living body. The implant was completed. Hereinafter, the hyperthermia implant of the present invention will be described.

2. Hyperthermia Implant FIG. 2 is a schematic view of a hyperthermia implant 10 of the present invention according to an embodiment (hereinafter, simply referred to as “implant 10”). As shown in FIG. 2, the implant 10 has a core-shell structure including a core 11 made of a temperature-sensitive magnetic material and a coating layer (shell) 12 made of a material containing gold.

  The core 11 is made of particles of a temperature-sensitive magnetic material. The temperature-sensitive magnetic material is not particularly limited as long as it is a magnetic material made of a magnetic material in which the Curie point can be arbitrarily set by changing the composition ratio, adding an additive, heat treatment, or the like. For example, Ni-Zn ferrite, Mn-Cu-Zn based ferrite and the like can be mentioned. Since these can set the Curie point to about 43 ° C., they can be more suitably used for hyperthermia.

  The diameter of the core 11 (particle diameter of the thermosensitive magnetic material) is preferably 50 μm or more and 2000 μm or less, more preferably 50 μm or more and 800 μm or less, and particularly preferably 50 μm or more and 300 μm or less. The “diameter of the core 11 (particle diameter of the temperature-sensitive magnetic material)” refers to the maximum diameter of the temperature-sensitive magnetic material particles. By setting the diameter of the core 11 within the range, for example, injection / arrangement into a living body becomes easy, and the core 11 can function appropriately as a temperature measuring element. Furthermore, it is possible to prevent movement of the thermosensitive magnetic fine particles due to flowing into capillaries or new blood vessels in the living body.

  The shell 12 is made of a material containing gold. The shell 12 may contain a noble metal other than gold or a transition metal (for example, titanium or stainless steel), but it is preferably made of only gold from the viewpoint of further improving the heat generation efficiency. The thickness of the shell 12 is preferably 0.005 μm or more and 2 μm or less, more preferably 0.01 μm or more and 1.5 μm or less, and particularly preferably 0.1 μm or more and 1 μm or less. If the shell 12 is too thin, the heat generation efficiency of the implant 10 will not increase sufficiently. On the other hand, if the shell 12 is too thick, the influence of the magnetic inductivity of the core 11 is reduced, and there is a possibility that it does not function properly as a temperature measuring element. As will be described later, when the core 11 is coated with gold using sputtering and electroless plating, the shell 12 having a thickness of 1 μm or less can be easily formed.

  As described above, in the temperature measurement according to the present invention, the temperature measuring element is injected and arranged in the living body. Therefore, it is preferable that the temperature measuring element is made of a material excellent in biocompatibility. In this regard, the surface of the implant 10 is coated with gold having excellent biocompatibility, and contact between the living body and a substance that may cause harm to the living body can be reduced. For example, even when Ni-based ferrite is used as the temperature-sensitive magnetic body constituting the core 11, contact between Ni and the living body can be suppressed. In addition, the implant 10 is provided with a shell 12 containing gold on the surface of a core 11 made of a temperature-sensitive magnetic material, thereby increasing the heat generation efficiency when the implant 10 is induction-heated. That is, the implant 10 can be used as a heating element for hyperthermia. On the other hand, since a temperature-sensitive magnetic body is used for the core 11, the core 11 also functions properly as a temperature measurement probe using the above-described Curie point. That is, the implant 10 according to the present invention is excellent in heat generation efficiency and biocompatibility, and is capable of appropriately functioning as a heating element that warms the affected part while accurately measuring the temperature in the measured part (affected part). It can be suitably used as an implant.

3. Method for Manufacturing Hyperthermia Implant An example of a method for manufacturing a hyperthermia implant according to the present invention (manufacturing method S10) will be described with reference to FIGS. As shown in FIG. 3, in the manufacturing method S10, the coating layer containing gold is formed on the surface of the temperature-sensitive magnetic body by the step S1 for forming the first coating layer and the step S2 for forming the second coating layer. To do. FIG. 4 schematically shows the form of the implant in each step of FIG.

  In step S1, the surface of the temperature-sensitive magnetic material is coated with a material containing gold (for example, a material containing gold, other noble metals, transition metals such as titanium, stainless steel, etc.), preferably a material made only of gold. , A step of forming a first coating layer. For example, a temperature-sensitive magnetic body 11 having a predetermined particle diameter as shown in FIG. 4 (A) is prepared, and the surface of the temperature-sensitive magnetic body 11 is coated with a first coating layer 12a as shown in FIG. 4 (B). And a process of performing. The form of the temperature-sensitive magnetic body 11 is as described above. In particular, the step S1 is preferably a step of coating the surface of the temperature-sensitive magnetic body 11 with a material containing gold, preferably a material made only of gold, by sputtering. This is because the first coating layer 12a can be formed by a simple method and the second coating layer 12b can be easily formed. As the sputtering, any known method such as DC sputtering, RF sputtering, magnetron sputtering, or ion beam sputtering can be used. The thickness of the 1st coating layer 12a should just be about 5-20 nm. Further, if the sputtering is performed on at least a part of the surface of the temperature-sensitive magnetic substance particle, a coating layer can be formed on at least a part of the surface of the temperature-sensitive magnetic substance particle in step S2 to be described later, thereby improving the heat generation efficiency. However, from the viewpoint of further improving the heat generation efficiency and biocompatibility, it is preferably performed on the entire surface.

  Step S2 is a material containing gold on the surface of the first coating layer formed in step S1 (for example, other than gold, other precious metals, materials containing transition metals such as titanium, stainless steel, etc.), preferably gold. This is a step of coating a material consisting of only to form a second coating layer. For example, as shown in FIG. 4C, a step of coating the surface of the first coating layer 12a with the second coating layer 12b can be performed. In step S2, it is particularly preferable to form the second coating layer 12b by electroless plating. For example, the second coating layer 12b made of gold can be formed by electroless gold plating using sulfite-type reduced gold plating. In step S2, the total thickness of the first coating layer 12a and the second coating layer 12b is preferably 0.005 μm or more and 2 μm or less, more preferably 0.01 μm or more and 1.5 μm or less. It is particularly preferable that the thickness be 1 μm or more and 1 μm or less. In addition, when the 2nd coating layer 12b is formed by electroless plating at process S2, the total thickness of the 1st coating layer 12a and the 2nd coating layer 12b can be 1 micrometer or less. With such a thickness, the manufactured implant can be suitably used as a temperature measurement probe in a living body or as a heating element that heats a measurement target in the living body by induction heating.

  Through steps S1 and S2, an implant 10 including a core made of a temperature-sensitive magnetic body 11 and a shell made of a coating layer 12 (12a, 12b) containing gold can be manufactured. As described above, the implant 10 has excellent heat generation efficiency and biocompatibility, and can be used as a hyperthermia implant that can appropriately function as a heating element that warms the affected area while accurately measuring the temperature in the measured area (affected area). It can be used suitably.

  Hereinafter, based on an Example, the implant for hyperthermia which concerns on this invention is further explained in full detail.

<Experiment 1: Selection of exothermic material and evaluation of exothermic efficiency>
First, an optimal heat generating material was selected to improve the heat generation efficiency of the implant. The metal having high heat generation efficiency required in the present invention can be selected according to the following criteria.
(1) High heat generation efficiency due to a high-frequency magnetic field.
(2) Chemical properties are stable and biocompatibility is excellent.

  In order to satisfy the condition (1), a material having a large iron loss (eddy current loss, hysteresis loss) is desirable. Particularly in the case of eddy current loss, the greater the electrical conductivity, the greater the amount of heat generated. Furthermore, in order to satisfy the condition (2), materials were selected in consideration of metal allergy, toxicity, carcinogenicity, etc. given to the living body. Details of the selected heat generating materials are shown in Table 1 below.

Using the system 20 as shown in FIG. 5, the heat generation efficiency of the selected heat generating material was actually examined. The experimental procedure is as follows.
(1) Put the evaluation object 21 (heat generating material) in the test tube 22 and mix with pure water.
(2) The optical fiber thermometer 24 is installed at the center of the evaluation target 21.
(3) The evaluation target 21 is installed at a position 5 cm above the central axis of the output coil 23.
(4) A current is supplied from the induction power supply 25 to the output coil 23, a magnetic field is applied to the evaluation target 21, and induction heating is performed.
(5) The temperature value measured by the optical fiber thermometer 24 is recorded in the computer 26.
(6) After 600 seconds from the start of measurement, induction heating is stopped.

The experimental conditions were as follows.
Induction current: 501A
Frequency: 190kHz
Measurement position and distance: 5 cm (3.87 mT) from the top surface of the coil at the center axis of the output coil
Pure water: 50 μL
Measurement time: 600s

  The results are shown in FIG. From FIG. 6, when only the temperature-sensitive magnetic material was induction-heated by the above procedure, the temperature increased only from 25 ° C. to 30 ° C. even after 600 seconds had passed (temperature increase rate: 0. 0). 017 ° C./s). On the other hand, the heat generation materials related to gold, titanium, and stainless steel each had the highest heat generation efficiency than the temperature-sensitive magnetic material. In particular, the heat generating material made of gold has the highest heat generation efficiency, and when the induction heating was performed for 100 seconds, the temperature rose from 25 ° C. to 50 ° C. (temperature increase rate: 0.250 ° C./s). The heating rate for both the heating material made of titanium and the heating material made of stainless steel was about 0.1 ° C./s. From the above, from the viewpoint of performing induction heating and functioning as a heating element, it is not suitable to use only the temperature-sensitive magnetic body, and in order to improve the heat generation efficiency of the temperature-sensitive magnetic body, a material containing gold, preferably only gold. It has been found preferable to use a material comprising

  From the above experiment, it was found that the material having excellent heat generation efficiency is gold. Therefore, various experiments were conducted on the assumption that gold is used in combination with a temperature-sensitive magnetic material.

<Experiment 2: Preliminary experiment>
First, as a preliminary experiment, 1.0 g each of gold and a temperature-sensitive magnetic material was prepared, and the heat generation characteristics of the mixed powder were examined. As a result, it was found that uneven heat generation occurs in the mixed powder of gold and the temperature-sensitive magnetic material. In addition, when the powder mixture was used, the volume increased compared to the temperature-sensitive magnetic substance alone, and there was a concern about the burden on patients during clinical application. Accordingly, the surface of the temperature-sensitive magnetic body was covered with gold to solve the problem of uneven heat generation and to reduce the volume.

<Experiment 3: Gold coating on temperature-sensitive magnetic material>
In order to coat the surface of the temperature-sensitive magnetic body with gold, gold plating is preferable. However, since the temperature-sensitive magnetic material is an insulator, electroless gold plating generally used as a gold plating method cannot be performed as it is. Here, in order to perform electroless gold plating on the surface of the insulator, it is necessary to perform coating with Ni as a base treatment, but Ni is inferior in biocompatibility and may be carcinogenic. Therefore, it is not preferable to perform the base treatment with Ni as a hyperthermia implant. As a result of intensive studies, the inventors have invented a new base treatment that does not use Ni as the base. In this method, the surface of the temperature-sensitive magnetic material is coated with gold as a first layer by sputtering, and the second layer is formed on the surface by electroless gold plating. Thus, the following effect is show | played by setting it as the implant by which the surface of the thermosensitive magnetic body was coat | covered with gold | metal | money.
(1) Gold can be more uniformly bonded to the temperature-sensitive magnetic material, and uneven heat generation can be suppressed.
(2) Compared with the case where the heat generating material and the temperature-sensitive magnetic material are individually mixed, the total volume can be suppressed to about ½, and the burden on the patient can be reduced.
(3) Since Ni which is inferior in biocompatibility is not used for the base treatment, an implant excellent in biocompatibility can be obtained. Furthermore, since the contact between the temperature-sensitive magnetic body itself and the living body is reduced, for example, when Ni-based ferrite is used as the temperature-sensitive magnetic body, the contact between Ni and the living body can be suppressed.
(4) By covering the gold thin film formed by sputtering with a thick layer by electroless gold plating, the durability of the gold coating layer can be improved.

(Pretreatment by sputtering, formation of the first layer)
The sputtering apparatus for forming the first layer was specified as follows.
Equipment: Ion Sputter (Hitachi Naka Seiki Co., Ltd.)
Specifications: Target ... Gold ring discharge voltage ... DC500V, 2400V two-stage switching mode ... Coating, ion bombardment hydrophilic treatment exhaust pump ... 50 l / min oil rotary vacuum pump discharge voltage application method ... Automatic slow-up type sample stage ... Diameter 80mm
Vacuum degree adjustment ... Needle valve type (with atmospheric gas inlet)
Timer ... Electronic timer (0 to 10 minutes)
Indicator instrument… Pirani vacuum gauge, ion ammeter power supply… AC100V 50 / 60Hz 1kVA

Sputtering was performed according to the following flow.
(1) Take 0.5 g of the temperature-sensitive magnetic material on the sample plate and place it on the sample table.
(2) The degree of vacuum in the sample atmosphere is stabilized at about 0.05 Torr.
(3) Sputter for 10 minutes.
(4) Repeat (3) three times.
(5) Take out the sample, shake the sample dish lightly, and direct the unsputtered part to the surface.
(6) Repeat (2) to (5) until gold adheres to the entire surface of the temperature-sensitive magnetic material.

(Electroless gold plating, formation of second layer)
After forming a first gold layer on the temperature-sensitive magnetic material by sputtering, electroless gold plating was performed to form a second layer, thereby producing a hyperthermia implant. As a solution for electroless gold plating, sulfite type reduced gold plating was used. Here, the gold plating implementation time was changed, and three types of hyperthermia implants with different plating thicknesses were prepared (Examples 1 to 3). Moreover, one type of hyperthermia implant in which the sputtering process conditions were changed was also prepared (Example 4). Here, in the sputtering process, “full gold plating” is obtained by sputtering the entire surface of the temperature-sensitive magnetic fine particles (Examples 1 to 3), and only one half of the temperature-sensitive magnetic fine particles is sputtered (Example 4). It is called "partial gold plating". About the four types of prepared hyperthermia implants, the thickness of the coating layer (total average thickness of the first layer and the second layer) was measured using a fluorescent X-ray film thickness meter, and the results were as follows.
(Example 1) Full gold plating, electroless gold plating 30 minutes ... Average thickness: 0.364 μm
(Example 2) Full gold plating, electroless gold plating 60 minutes ... Average thickness: 0.778 μm
(Example 3) Full gold plating, electroless gold plating 120 minutes ... Average thickness: 0.754 μm
(Example 4) Partial gold plating, electroless gold plating 120 minutes ... Average thickness: 0.823 μm

  As can be seen from the results, when the coating layer is formed by sputtering and electroless gold plating, the thickness of the coating layer is 1 μm or less regardless of the electroless gold plating time. That is, when electroless gold plating is performed on a temperature-sensitive magnetic material that has been ground-treated by sputtering, the thickness of the coating layer does not continue to increase in proportion to the electroless gold plating time, but is maintained at that thickness when the thickness is constant. I found out that

<Experiment 4: Heat generation characteristics of hyperthermia implant>
Using the system 20 as shown in FIG. 5, the heat generation characteristics of the hyperthermia implants according to Examples 1 to 4 were evaluated. Specifically, an evaluation experiment was performed according to the following procedure.
(1) Put the evaluation target 21 (hyperthermia implant) in the test tube 22 and mix it with pure water.
(2) The temperature sensor 24 is installed at the center of the evaluation target 21.
(3) The evaluation target 21 is installed at a predetermined position on the upper surface of the center axis of the output coil 23.
(4) A current is supplied from the induction power supply 25 to the output coil 23, a magnetic field is applied to the evaluation target 21, and induction heating is performed.
(5) The temperature value measured by the temperature sensor 24 is recorded in the computer 26.
(6) After reaching a predetermined measurement time, induction heating is stopped. However, if the temperature exceeds 65 ° C, the experiment is immediately stopped.

The experimental conditions were as follows.
Evaluation target mass: 1.0 g
Induction current: 500A
Frequency: 190Hz
Measurement position and distance: For Example 3, the upper surface of the output coil is 1 cm, 3 cm, and 5 cm. For Examples 1, 2, and 4, the upper surface of the output coil is 5 cm.
Pure water: 50 μL
Measurement time: 500 seconds

(Relationship between electroless gold plating time and heat generation efficiency)
The results are shown in FIG. From FIG. 7, the hyperthermia implant according to Example 1 is from 25.0 ° C. to 43.8 ° C., and the hyperthermia implant according to Example 2 is from 27.2 ° C. to 44.9 ° C. As for the hyperthermia implant according to No. 3, an increase in temperature was confirmed from 25.0 ° C. to 45.3 ° C., respectively. That is, in any case, the heat generation efficiency was superior to the case of the temperature-sensitive magnetic substance alone.

  For each of the hyperthermia implants according to Examples 1 to 3, the temperature increase rate for 200 seconds from the start of the experiment was determined. As a result, the average for Example 1 was 0.078 ° C./s, and the example 2 was 0.081 ° C./s. In Example 3, it was found that the temperature increased at an average rate of 0.092 ° C./s. From this, it was found that the longer the electroless gold plating time, the better the heat generation efficiency.

(Relationship between electroless gold plating area (sputter area) and heat generation efficiency)
The heat generation efficiency was compared between the hyperthermia implant according to Example 3 and the hyperthermia implant according to Example 4. The results are shown in FIG. As described above, when a high frequency magnetic field of 190 Hz and 7.82 mT was applied for 500 seconds, it was confirmed that the temperature of the hyperthermia implant according to Example 3 increased from 25.0 ° C. to 45.3 ° C. . On the other hand, about the hyperthermia implant which concerns on Example 4, it has confirmed that temperature rose from 25.0 degreeC to 45.2 degreeC. That is, it was confirmed that both were superior in heat generation efficiency than the case of the temperature-sensitive magnetic material alone, and both rose to the same temperature.

  For each of the hyperthermia implants according to Examples 3 and 4, when the temperature increase rate for 200 seconds from the start of the experiment was determined, as described above, the temperature increased for Example 3 at an average rate of 0.092 ° C./s. On the other hand, in Example 4, it was found that the temperature increased at an average rate of 0.084 ° C./s. Thus, it was found that the larger the electroless gold plating area (sputter area), the better the heat generation efficiency.

<Experiment 5: Comparison of heat generation efficiency between thermosensitive magnetic body, thermosensitive magnetic body in case of sputtering, and hyperthermia implant (Example 3)>
A new thermosensitive magnetic body, a thermosensitive magnetic body that was only sputtered, and a hyperthermia implant prepared in the same manner as in Example 3 were prepared, and the heat generation efficiency was compared. The results are shown in FIG. When a high frequency magnetic field of 190 Hz and 7.82 mT is applied for 500 seconds, the temperature-sensitive magnetic material is from 25.5 ° C. to 30.7 ° C., the sputtering temperature-sensitive magnetic material is from 24.9 ° C. to 43.6 ° C., for hyperthermia It was confirmed that the temperature of the implant rose from 25.0 ° C. to 48.6 ° C. As a result, although it was expected that the heat generation efficiency could be improved to some extent only by sputtering, it was found that the heat generation efficiency was further improved by performing electroless gold plating.

  For each of the temperature-sensitive magnetic material, the temperature-sensitive magnetic material subjected only to sputtering, and the hyperthermia implant, the temperature increase rate for 200 seconds from the start of the experiment was determined. The temperature-sensitive magnetic material was 0.010 ° C./s, sputtering. It was found that the temperature was increased at a rate of 0.085 ° C./s for the thermosensitive magnetic material and 0.107 ° C./s for the hyperthermia implant. From these results, it was found that although the heat generation efficiency can be improved to some extent by sputtering alone, the heat generation efficiency is further improved by electroless gold plating.

<Experiment 6: Relationship between measurement distance and heat generation characteristics>
About the installation position of the implant for hyperthermia which concerns on Example 3, each heat_generation | fever characteristic at the time of changing the distance from the upper surface of the output coil 23 to 1 cm, 3 cm, and 5 cm was evaluated. The results are shown in FIG. From FIG. 10, it was found that the temperature rises to 65 ° C. in 75 seconds when the distance is 1 cm, increases to 60 ° C. in 250 seconds in the case of 3 cm, and increases to 47 ° C. in 250 seconds in the case of 5 cm. The magnetic flux density generated from the high frequency current of 190 kHz and 500 A was 31.6 mT in the case of 1 cm, 24.33 mT in the case of 3 cm, and 7.82 mT in the case of 5 cm. From this result, the shorter the distance to the output coil 23 is, the larger the magnetic flux density becomes. As the magnetic flux density increases, the eddy current loss and hysteresis loss of the hyperthermia implant increase, and the loss increases, thereby increasing the heat generation efficiency. I found it to be higher.

  Here, it can be confirmed that the temperature continues to rise after reaching the Curie point of the temperature-sensitive magnetic material under the conditions of distances of 1 cm and 3 cm, whereas after reaching the Curie point under the condition of distance of 5 cm. It was confirmed that the temperature was almost constant. That is, it is considered that the hyperthermia implant can be controlled and maintained at a predetermined temperature or higher, and it has been found that the hyperthermia implant according to the present invention is suitably used for maintaining warming in a living body.

<Experiment 7: Durability test>
In hyperthermia, it is assumed that the induction heating of the implant is repeated in vivo, and the durability of the implant is required. If the gold coating layer of the implant is cracked or peeled off due to repeated induction heating, it becomes difficult to use for hyperthermia. Therefore, the durability of the hyperthermia implant according to the present invention was evaluated by the following test. The durability test was performed by repeating induction heating under the same conditions as in Experiment 4 50 times. The results are shown in FIG. As shown in FIG. 11, it was found that the implant rose to almost the same temperature in the measurement time of 600 seconds and 50 times in the repeated test. However, it was also found that the standard deviation was large in the temperature rising process. FIG. 12 shows the average temperature increase rate for 200 seconds from the start of the experiment. From FIG. 12, it can be seen that the rate of temperature increase varies from trial to trial, but the standard deviation is 1.03 ° C./s, indicating that the variation is small. Further, when the surface was observed before and after the durability test with an electron microscope, no peeling of the gold film was observed before and after the durability test. That is, it was suggested that the hyperthermia implant according to the present invention has no problem in durability when used in vivo.

  From the above, it was found that the hyperthermia implant according to the present invention can function appropriately as a heating element by induction heating. Subsequently, the hyperthermia implant according to the present invention was evaluated as a temperature measurement probe. That is, it was confirmed that the hyperthermia implant according to the present invention has the functions of both a heating element for heating an affected part and a temperature measuring probe for measuring the temperature of the affected part as follows.

<Experiment 8: Evaluation of validity of induction heating and wireless temperature measurement system>
A high frequency magnetic field was applied to the hyperthermia implant according to the present invention, and whether or not the implant reached the Curie point was verified as a non-contact measurement as an induction voltage of the pickup coil accompanying a change in the magnetic flux vector.

Experiments were performed using a system 30 as shown in FIG. The experimental procedure is as follows.
(1) The hyperthermia implant 21 is placed in a resinous test tube 22 (Eiken Equipment Co., Ltd.) and mixed with pure water.
(2) The search coil 28 (30 enamel wires having an outer diameter of 11.5 mm, an inner diameter of 10.0 mm, a number of turns of 1, a DC resistance value of 0.8Ω, and a wire diameter of 0.08 cm) against the magnetic flux generated in the output coil 23 Installed so that the central axis of the twisted litz wire is parallel, the pickup coil 27 (outer diameter 16.50 mm, inner diameter 10.00 mm, number of turns 10 turns, DC resistance value 1.0Ω, similar to the search coil 28 The surroundings of the material and the coil are installed so that acrylic resin (GM9002, not shown) is orthogonal to the magnetic flux. A signal detected by the search coil 28 is used as a reference signal, and a signal detected by the pickup coil 27 is used as a measurement signal so that the signal is connected to a digital lock-in amplifier 29 (Toyo Technica Corp., 7265). The induced electromotive force of the coil 27 is synchronously detected.
(3) The test tube 22 is installed so that the hyperthermia implant 21 is located 3 cm away from the upper surface of the output coil 23 along the central axis.
(4) The sensor of the optical fiber thermometer 24 is installed in the central part of the hyperthermia implant 21 and the temperature change is automatically measured by the PC 16.
(5) The induction power supply 25 is turned on, and a high frequency current of 190 kHz and 500 A is passed through the output coil 23 to generate a high frequency magnetic field.
(6) The voltage value displayed on the digital lock-in amplifier 29 is recorded with the temperature displayed on the optical fiber thermometer 24 as a reference.

The experimental conditions were as follows.
Mass of hyperthermia implant: 1.0 g
Induction current: 500A
Frequency: 190Hz
Measurement position and distance: 3 cm from the top of the output coil
Pure water: 50 μL
Measurement time: 250 seconds

  FIG. 14 shows changes with time in the temperature of the hyperthermia implant and the pickup voltage. FIG. 14 shows that the hyperthermia implant rises from 29.0 ° C. to 49.4 ° C. under the above conditions, and can be raised to 43 ° C. or higher required for hyperthermia. In addition, at 43 ° C. or higher, the induction voltage detected by the pickup coil 27 dropped rapidly from 119 mV to 114 mV, and a change value of 5 mV was confirmed.

  FIG. 15 shows the relationship between the temperature of the hyperthermia implant and the pickup voltage. FIG. 15 shows that when the temperature of the hyperthermia implant reaches the Curie point (43 ° C.), the induced voltage detected by the pickup coil 27 decreases rapidly. From this, it was found that it was possible to detect noninvasively that the hyperthermia implant reached the Curie point using the change in the pickup voltage as a clue.

<Experiment 9: Reproducibility evaluation experiment>
Experiments were performed using a system 30 as shown in FIG. The experimental procedure is as follows.
(1) The hyperthermia implant 21 is placed in a resinous test tube 12 (Eiken Equipment Co., Ltd.) and mixed with pure water.
(2) The search coil 28 is installed so that the central axis of the search coil 28 is parallel to the magnetic flux generated by the output coil 23, and the pickup coil 27 is installed so as to be orthogonal to the magnetic flux. The signal detected by the search coil 28 is used as a reference signal, and the signal detected by the pickup coil 27 is connected to the digital lock-in amplifier 29 so as to be a measurement signal, and the induced electromotive force of the pickup coil 27 accompanying the change in the magnetic flux vector is synchronized. Detect.
(3) The test tube 22 is installed so that the hyperthermia implant 21 is located 3 cm away from the upper surface of the output coil 23 along the central axis.
(4) The sensor of the optical fiber thermometer 24 is installed in the central part of the hyperthermia implant 21 and the temperature change is automatically measured by the PC 26.
(5) The induction power supply 25 is turned on, and a high frequency current of 190 kHz and 500 A is passed through the output coil 23 to generate a high frequency magnetic field.
(6) The voltage value displayed on the digital lock-in amplifier 29 is recorded with the temperature displayed on the optical fiber thermometer 24 as a reference.
(7) After the measured temperature exceeds the Curie point and a sufficient time has elapsed, induction heating is stopped, and the hyperthermia implant 21 is placed in cold water and cooled to room temperature.
(8) Repeat operations (3) to (7) three times.

The experimental conditions were as follows.
Mass of hyperthermia implant: 1.0 g
Induction current: 500A
Frequency: 190Hz
Measurement position and distance: 3 cm from the top of the output coil
Pure water: 50 μL
Number of measurements: 3 times

  FIG. 16 shows changes with time in the temperature and pick-up voltage of the hyperthermia implant during reproducibility evaluation. FIG. 16 shows that the temperature of the hyperthermia implant rose from 30.0 ° C. to 49.0 ° C. in any of the three repetitions under the above conditions. Furthermore, it was confirmed that the pickup voltage with respect to the temperature change of the hyperthermia implant decreased from 120 mV to 112 mV in the first time, from 120 mV to 110 mV in the second time, and from 117 mV to 109 mV in the third time.

  FIG. 17 shows the relationship between the temperature of the hyperthermia implant and the pickup voltage at the time of reproducibility evaluation. From FIG. 17, it can be seen that when the temperature of the hyperthermia implant reaches the Curie point of around 43 ° C. in all trials, the pickup voltage changes abruptly. That is, it was found that the hyperthermia implant can be applied as a heating element that heats the affected area by induction heating and as a temperature measurement probe that measures the temperature of the affected area by changing the magnetic flux vector.

  Although the present invention has been described with reference to the most practical and preferred embodiments at the present time, the invention is not limited to the embodiments disclosed herein. The hyperthermia implant and the method for manufacturing the same are also included in the technical scope of the present invention, as long as they do not contradict the gist or concept of the invention that can be read from the claims and the entire specification. Must be understood.

  For example, in the above description, the hyperthermia implant 10 according to the present invention has been described as having a core-shell structure, but the present invention is not limited to this form. If a coating layer made of a material containing gold is formed on at least a part of the surface of the temperature-sensitive magnetic body, the heat generation efficiency of the implant can be improved. However, from the standpoint of achieving both a further improvement in heat generation efficiency and a further improvement in biocompatibility, and a more appropriate function as a heating element and a temperature measurement probe, the entire surface of the thermosensitive magnetic body It is preferable to cover with a coating layer made of a material containing gold to form a core / shell structure.

  In the above description, the hyperthermia implant 10 according to the present invention has been described as being manufactured by forming the first coating layer by sputtering and then forming the second coating layer by electroless plating. The present invention is not limited to the embodiment. For example, the coating layer containing gold may be formed on the surface of the temperature-sensitive magnetic body only by sputtering. That is, even if the coating layer containing gold having a thickness of 5 nm or more is only formed on the surface of the temperature-sensitive magnetic body by sputtering, the heat generation efficiency of the hyperthermia implant can be improved. Alternatively, the coating layer may be formed by a coating method other than sputtering or electroless plating. For example, spray coating, vacuum deposition, or the like can be applied.

  The present invention can function as a heating element that heats the affected area to a predetermined temperature by induction heating, and also functions as a measurement probe that accurately and non-invasively measures whether or not the temperature of the affected area is a predetermined temperature. It can be suitably used as an obtained hyperthermia implant.

DESCRIPTION OF SYMBOLS 1 Temperature-sensitive magnetic body 2 Drive coil 3 Pickup coil 4 Power supply 5 Voltmeter 10 Hyperthermia implant 11 Core (temperature-sensitive magnetic body)
12 Shell (coating layer containing gold)
12a 1st coating layer 12b 2nd coating layer 21 Evaluation object (Heat generating material or hyperthermia implant)
22 Test tube 23 Output coil (drive coil)
24 Optical fiber thermometer 25 Inductive power supply 26 PC
27 Pickup coil 28 Search coil 29 Digital lock-in amplifier

Claims (7)

  An implant for hyperthermia having a coating layer containing gold on the surface of a temperature-sensitive magnetic body.   The hyperthermia implant according to claim 1, wherein the temperature-sensitive magnetic substance has a particle size of 50 µm or more and 2000 µm or less.   The hyperthermia implant according to claim 1 or 2, wherein the coating layer has a thickness of 0.005 µm to 1 µm. Coating the surface of the temperature-sensitive magnetic body with a material containing gold to form a first coating layer;
Coating the surface of the first coating layer with a material containing gold to form a second coating layer;
A method for producing an implant for hyperthermia.   The method for producing an implant for hyperthermia according to claim 4, wherein the thermosensitive magnetic material has a particle diameter of 50 µm or more and 2000 µm or less.   The method for manufacturing an implant for hyperthermia according to claim 4 or 5, wherein the first coating layer is formed by sputtering and the second coating layer is formed by electroless plating.   The hyperthermia implant manufacturing method according to claim 6, wherein a total thickness of the first coating layer and the second coating layer is set to 0.005 µm to 1 µm.

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