WO2022270494A1

WO2022270494A1 - Collagen decomposition device and method for operating collagen decomposition device

Info

Publication number: WO2022270494A1
Application number: PCT/JP2022/024660
Authority: WO
Inventors: 一平八木
Original assignee: 東京都公立大学法人
Priority date: 2021-06-21
Filing date: 2022-06-21
Publication date: 2022-12-29
Also published as: JPWO2022270494A1

Abstract

This collagen decomposition device comprises: a stress application device for applying stress to a first range of a subject tissue; and a heat source device for imparting thermal energy to a second range, at least a portion of which overlaps the first range.

Description

Collagen degrading device and method of operating the collagen degrading device

The present invention relates to a collagen decomposing device and a method of operating the collagen decomposing device. This application claims priority to Japanese Patent Application No. 2021-102278 filed in Japan on June 21, 2021, the contents of which are incorporated herein.

　Fibrous stenosis, in which stenosis occurs due to the progress of fibrosis in the treated area after treatment of the gastrointestinal tract, is known. Fibrous strictures can be surgically resected. As a non-invasive treatment method for fibrous stenosis, balloon dilatation is known, in which a balloon catheter is placed at a site of stenosis in the gastrointestinal tract and the balloon is inflated to dilate the site of stenosis.

Also known as a treatment method using a balloon catheter is balloon ablation, in which a balloon is guided to a lesion area and the balloon is heated to cauterize the lesion area (see, for example, Patent Document 1).

JP 2007-229095 A

It is known that even if the site of stenosis is surgically resected, inflammation often occurs at the same site after surgery, and fibrosis progresses again, resulting in restenosis at the same site in many cases. In addition, even in non-invasive balloon dilatation, collagen fibers are hard, and dilation of the balloon may crack the gastrointestinal tract wall at the dilated site, often resulting in restenosis as in surgical procedures. In other words, it is thought that restenosis occurs due to inflammation caused by cell damage due to dilatation, and collagen fibers being produced.
SUMMARY OF THE INVENTION An object of the present invention is to provide a collagen degradation device and a method of operating the collagen degradation device that can selectively destroy collagen fibers while suppressing damage to cells.

According to a first aspect of the present invention, a collagen degradation device includes a stress applying device that applies stress to a first area of a target tissue, and a second area that has at least a portion that overlaps with the first area and applies thermal energy to the second area. and a heat source device that supplies heat.

According to a second aspect of the present invention, a method for operating a collagen decomposing device is the method for operating a collagen decomposing device according to the first aspect, wherein the control device causes the heat source device to heat in the second range. the step of outputting a heating start instruction to start, the step of the control device outputting an addition start instruction to cause the stress applying device to start applying stress to the first range after the heating start instruction, the step of controlling a step of the device outputting a heating stop instruction to the heat source device to stop heating; and a step of the control device outputting an addition stop instruction to the stress applying device to stop applying the stress after the heating stop instruction. and including.

According to at least one aspect described above, the collagen degrading device can selectively destroy collagen fibers while suppressing damage to cells.

It is a figure which shows the structure of the gastrointestinal tract expansion apparatus 2 which concerns on 1st Embodiment. 4 is a flow chart showing a control method of the gastrointestinal tract expansion device 2 according to the first embodiment. FIG. 10 is a diagram showing Young's modulus-stress characteristics for different temperatures obtained from the results of the first experiment; FIG. 4 is a diagram showing the relationship between temperature and Young's modulus obtained as a result of a first experiment; It is a figure which shows the procedure of a 2nd experiment. FIG. 10 is a diagram showing the relationship between the traction force and the elongation rate of the test piece I according to the second experiment; FIG. 10 is a diagram showing the relationship between the traction force and the elongation rate of the test piece II according to the second experiment; It is a figure which shows the relationship between the traction force of the test piece and elongation rate which concern on a 3rd experiment. FIG. 10 is a diagram showing the relationship between the internal pressure of the balloon and the diameter of the stenosis model according to the fourth experiment; FIG. 11 shows the results of a fifth experiment; FIG. 12 is a diagram showing the relationship between the diameter of the balloon and the diameter of the stenosis model without heating according to the sixth experiment. FIG. 10 is a diagram showing the relationship between the diameter of a balloon and the diameter of a heated stenosis model according to the sixth experiment. FIG. 11 is a diagram showing changes in the state of tissue according to the seventh experiment; Fig. 3 is a perspective view showing the configuration of a collagen decomposing device 1 according to a second embodiment; Fig. 2 is a cross-sectional view of a collagen decomposing device 1 according to a second embodiment;

<First embodiment>
FIG. 1 is a diagram showing the configuration of a gastrointestinal tract expansion device 2 according to the first embodiment. The gastrointestinal tract expansion device 2 according to the first embodiment is a device for dilating a constricted portion of the gastrointestinal tract while suppressing the possibility of restenosis.

<<Structure of gastrointestinal tract expansion device 2>>
The digestive tract expansion device 2 includes a tank 21 , a pump 22 , a balloon catheter 23 and a control device 24 . The tank 21 is filled with a heat medium (for example, diluted contrast medium, distilled water, etc.) for supplying the balloon catheter 23 . A temperature controller 211 for heating the heat medium is provided inside the tank 21 . The temperature controller 211 may be a heater or a heat exchanger. The pump 22 pressure-feeds the heat medium filled in the tank 21 to the balloon catheter 23 .

The balloon catheter 23 has an inner shaft 231 , a balloon 232 and an outer shaft 233 .
The inner shaft 231 is provided from the proximal end to the distal end of the balloon catheter 23 . The inner shaft 231 has a hollow structure for passing a guide wire for guiding the balloon 232 to a desired position.
The balloon 232 is provided near the distal end of the balloon catheter 23 so as to cover the inner shaft 231 . The tip of the inner shaft 231 may protrude outside the balloon 232 or may be covered with the balloon 232 .
The outer shaft 233 is provided so as to cover the inner shaft 231 from the proximal end of the balloon catheter 23 to the proximal end of the balloon 232 . The outer shaft 233 has a hollow structure. A first lumen L1 for supplying the heat medium to the balloon 232 and a second lumen L2 for recovering the heat medium from the balloon 232 are provided between the outer shaft 233 and the inner shaft 231 . A first lumen L1 connects the pump 22 and the balloon 232 . A second lumen L2 connects the balloon 232 and the tank 21 .

The maximum diameter of the balloon catheter 23 when stored is narrower than the inner diameter of the forceps channel of the endoscope. For example, the maximum diameter of the balloon catheter 23 when stored is 3.2 mm or less.

After positioning the balloon 232 at the constricted part of the gastrointestinal tract, the gastrointestinal tract expansion device 2 supplies a heated heat medium to heat the constricted part and pressurize the constricted part from the inside to the outside. . When the temperature of the narrowed portion rises to near the denaturation temperature of the collagen fibers due to heat exchange between the narrowed portion and the heat medium, part of the collagen fibers is denatured into gelatin. Gelatin has a random coil structure, whereas collagen fibers have a triple-stranded helix structure. Therefore, gelatin has low strength compared to collagen fibers. Specifically, the material strength of collagen is about 1.3N, while the material strength of gelatin is about 0.6N. The balloon 232 pressurizes the stenotic site to expand it, but the stenotic site is softened due to the denaturation of part of the collagen fibers into gelatin, which causes destruction of the cell tissue of the gastrointestinal tract wall. can be suppressed. The gastrointestinal tract expansion device 2 is an example of a collagen degradation device.

<<Method for controlling gastrointestinal tract expansion device 2>>
FIG. 2 is a flow chart showing a control method for the gastrointestinal tract expansion device 2 according to the first embodiment.
A user (for example, a doctor) of the gastrointestinal tract expansion device 2 first inserts the endoscope into the patient's body and positions the distal end of the endoscope near the stenotic site. The user injects a contrast agent into the stenotic site through the forceps channel of the endoscope, and obtains information such as the length and diameter of the stenotic site by imaging with X-rays. The user then passes the balloon catheter 23 through the forceps channel of the endoscope and advances the balloon catheter 23 so that the balloon 232 resides across the stenosis.

The user operates the control device 24 to start extended control by the control device 24. The controller 24 supplies power to the temperature controller 211 to heat the heat medium (step S1). The temperature of the heat medium required to apply the desired heat to the constricted portion can be obtained in advance using the specifications (thermal conductivity, thickness, surface area, etc.) of the balloon 232 and the outer shaft 233 . For example, since the heat transfer between the balloon 232 and the narrowed portion is expressed by the following equation (1), the required temperature of the heat medium in the balloon 232 can be obtained by solving the equation (1).

In equation ( ₁ ), Q is the amount of heat that passes through, T _h is the temperature of the heat medium in the balloon 232, T _c is the temperature of the constriction (body temperature), h1 is the heat transfer coefficient between the heat medium and the balloon ₂₃₂ , and h2 is the heat transfer coefficient between the constricted portion and the balloon 232, λ is the heat conductivity of the balloon 232, L is the thickness of the balloon 232, and A is the surface area of the balloon 232. For example, when a balloon with a thermal conductivity λ of 0.27 W/mK, a thickness L of 0.03 mm, and a surface area A of 0.2 mm ² is used to apply heat of 36 W to the constriction site, the temperature of the heat medium in the balloon 232 is T _h should be about 90°C.

Next, the control device 24 drives the pump 22 so as to discharge the heat medium at the first flow rate, and supplies the heat medium to the balloon 232 (step S2). Heat transfer medium is supplied to the balloon 232 through the first lumen L1 and returns to the tank 21 through the second lumen L2. The internal pressure of balloon 232 is determined by the first flow rate. The first flow rate is such that the balloon 232 is in contact with the stenotic site, and the flow rate is such that the stress (for example, less than 100 kPa) is applied to the extent that the stenotic site does not expand (crack does not occur). The controller 24 continues supplying the heat medium at the first flow rate for a certain period of time (for example, 60 seconds) (step S3). During this time, it can be expected that the constricted site is heated by heat exchange between the heat medium and the constricted site, and the collagen fibers are denatured into gelatin.

Next, the control device 24 drives the pump 22 so as to discharge the heat medium at the second flow rate (step S4). The second flow rate is larger than the first flow rate, and is a flow rate that gives a predetermined stress (for example, a stress of 40 kPa or more and 500 kPa or less) to the constricted portion. As a result, the narrowed portion is pressed from the inside to the outside, and the narrowed portion can be expanded. In the conventional balloon dilatation, a stress of 100 kPa or more and 500 kPa or less is applied, but according to the gastrointestinal dilation device according to the first embodiment, the stricture can be expanded even in a range of 40 kPa or more and less than 100 kPa. be able to. Since the collagen fibers are denatured into gelatin, the Young's modulus at the stenosis site is reduced, and the possibility of cracking at the stenosis site is low.

Next, the control device 24 cools the heat medium (step S5). When the temperature controller 211 is a heater, the control device 24 stops the heating of the heat medium by stopping the heater. When the temperature controller 211 is a heat exchanger, the control device 24 cools the heat medium by supplying the heat exchanger with a low-temperature refrigerant (for example, below the gelling temperature of gelatin). The controller 24 continues supplying the heat medium at the second flow rate for a certain period of time (for example, 60 seconds) (step S6). In other words, the gastrointestinal tract expansion device 2 cools the constricted site while dilating the constricted site. As a result, a phase change of gelatin from a sol state to a gel state and redenaturation of gelatin to collagen fibers can be expected in a state in which the constriction site is dilated. By degenerating into collagen fibers in an expanded state, it can be expected that the expanded diameter will be maintained even after the end of the pressing by the balloon 232 .

The control device 24 stops the pump 22 and stops the supply of the heat medium (step S7). After the heat medium is recovered from the balloon catheter 23, the user pulls out the balloon catheter 23 from the forceps channel of the endoscope.

In this way, the gastrointestinal tract expansion device 2 according to the first embodiment applies thermal energy to the constricted portion of the gastrointestinal tract and further applies stress. As a result, the gastrointestinal tract expansion device 2 can dilate the constricted site while reducing the Young's modulus by denaturing the collagen fibers at the constricted site to gelatin. As a result, collagen fibers can be prevented from being ruptured, so that collagen fibers can be selectively destroyed while suppressing damage to the cell tissue of the gastrointestinal tract wall. As a result, the gastrointestinal tract expansion device 2 can expand the constricted site without causing cracks in the constricted site.

Further, the gastrointestinal tract expansion device 2 according to the first embodiment heats the fluid for expanding the balloon 232 to supply thermal energy to the constricted portion. Accordingly, the temperature controller 211 is provided outside the balloon catheter 23, and the size of the balloon catheter 23 can be reduced. This allows the balloon catheter 23 to pass through the forceps channel of the endoscope. Note that in other embodiments, a heater or the like may be provided inside the balloon.

The gastrointestinal tract expansion device 2 according to the first embodiment supplies thermal energy to the constricted portion by supplying a heated heat medium to the balloon 232, but the present invention is not limited to this. For example, in another embodiment, heat energy may be supplied to the stenotic portion from the outside of the balloon catheter 23 by means of waves (for example, electromagnetic waves such as near-infrared light).
In addition, the gastrointestinal tract expansion device 2 according to the first embodiment presses the constricted portion with the balloon 232, but the present invention is not limited to this. For example, in other embodiments, pressing may be performed using other devices such as bougies.

Experimental results that support the effects of the gastrointestinal tract expansion device 2 according to the first embodiment will be described below.

《First experiment》
The inventor conducted a first experiment to verify changes in Young's modulus of collagen fibers with temperature. In the first experiment, a test piece of collagen fiber was immersed in water at different temperatures for 5 minutes and pulled until it broke, and the relationship between load and displacement was measured. In the first experiment, bovine Achilles tendons embedded in silicone resin and sliced to a thickness of 1.0±0.1 mm were used as collagen fiber test pieces. In the following experiments, similar specimens were used for tensile tests.

FIG. 3 is a diagram showing Young's modulus-stress characteristics by temperature obtained from the results of the first experiment. As a result of the first experiment, it was found that there is no large difference in Young's modulus up to 4 MPa at 25°C and 60°C, but the Young's modulus drops significantly at 70°C.

FIG. 4 is a diagram showing the relationship between temperature and Young's modulus obtained as a result of the first experiment. As a result of the first experiment, it was found that the Young's modulus exceeds 30 kPa when the temperature of the water is 60°C or lower, while the Young's modulus becomes 10 kPa or lower when the temperature exceeds 65°C. The Young's modulus at 65°C was 1/5 of the Young's modulus at 60°C.
From these results, it can be read that denaturation of collagen fibers occurs at around 65°C.

《Second experiment》
The inventor hypothesized that the collagen fibers would harden by applying a pulling force to the heated collagen fibers and then cooling them, and conducted a second experiment to verify this hypothesis. FIG. 5 is a diagram showing the procedure of the second experiment. In the second experiment, after immersing the collagen fiber test piece I in water at 35° C. for 5 minutes, a tensile test was performed on the test piece I with a pulling force of 4 N (0.8 MPa) (T1). After that, the test piece I was immersed in water at 65° C. for 10 minutes, and then subjected to a tensile test with a traction force of 4N (T2). After that, the test piece I was immersed in water at 35° C. for 5 minutes, and then subjected to a tensile test with a traction force of 4N (T3). Also, after immersing the collagen fiber test piece II in water at 35° C. for 5 minutes, a tensile test was performed on the test piece II with a pulling force of 4 N (T1). After that, the test piece II was immersed in water at 65° C. for 10 minutes, and then subjected to a tensile test with a traction force of 4N (T2). After that, the test piece II was immersed in water at 35° C. for 5 minutes while manually applying a pulling force of 30 N, and then a tensile test was performed on the test piece II with a pulling force of 4 N (T3).

FIG. 6 is a diagram showing the relationship between the traction force and the elongation rate of the test piece I according to the second experiment. As shown in FIG. 6, the test piece elongates during traction regardless of the temperature, but returns to its original length when the traction is stopped. For this reason, conventionally, it was necessary to expand until collagen fibers were broken, and it can be said that there was no choice but to give damage to cell tissues. Moreover, according to FIG. 6, it can be seen that the length of the test piece is shortened by about 20% by heating. This is considered to be due to shrinkage due to thermal denaturation of the collagen tissue. In other words, it can be seen from the second experiment that the stricture cannot be dilated simply by applying heat.

FIG. 7 is a diagram showing the relationship between the traction force and the elongation rate of the test piece II according to the second experiment. As shown in FIG. 7, it can be seen that the length of the specimen was shortened by heating, but the length of the specimen was elongated by continuing to apply a traction force during cooling. When the traction was stopped after cooling, the length was shortened, but it was elongated by about 80% compared to when the test was started. From this, it can be seen that the collagen fibers are fixed while maintaining the state at the time of being pulled by cooling while applying a pulling force.

《Third experiment》
The inventors conducted a third experiment to examine the traction force required for elongation of collagen fibers. In a third experiment, a specimen of collagen fibers was immersed in water at 65°C for 10 minutes, then the specimen was immersed in water at 35°C for 5 minutes while applying a traction force, and the specimen was subjected to a tensile test with the same traction force. . In a third experiment, the traction force during cooling was varied from 0.8 MPa, 2 MPa, 4 MPa, 5 MPa, 6 MPa and 7 MPa. Note that the traction force was set to 4 N (0.8 MPa) during the tensile test.

FIG. 8 is a diagram showing the relationship between the traction force and elongation rate of the test piece according to the third experiment. As shown in FIG. 8, when the tensile force is less than 4 MPa, the elongation rate of the test piece after cooling is less than the elongation rate before heating. It can be seen that when the tensile force is 4 MPa, the elongation rate of the test piece after cooling is approximately the same as the elongation rate before heating. It can be seen that when the tensile force exceeds 4 MPa, the elongation of the specimen after cooling is greater than that before heating. Thus, from the third experiment, it can be seen that a pressure greater than 4 MPa should be applied when dilating the stricture.

《Fourth Experiment》
The inventor conducted a fourth experiment in order to confirm the expansion effect of the balloon catheter. In the fourth experiment, a test piece of collagen fibers was rolled into a cylindrical shape and fixed to a diameter of 4 mm with a cyanoacrylate adhesive to create a stricture model simulating an esophageal stricture. Then, a balloon catheter was passed through the stenosis model, and the internal pressure of the balloon was gradually increased. When the internal pressure of the balloon reached 30 kPa, the balloon was put into hot water, and then the internal pressure of the balloon was further increased.

FIG. 9 is a diagram showing the relationship between the internal pressure of the balloon and the diameter of the stenosis model according to the fourth experiment. As shown in FIG. 9, it can be seen that the diameter of the constricted model changes significantly before and after hot water injection. On the other hand, when the stenosis model was observed after the fourth experiment, it was confirmed that fibrous structures remained in the stenosis model. Then, when the sample removed from the balloon catheter was put into hot water again, contraction of the stenosis model was confirmed. It is presumed that this is because many collagen fibers that were not denatured into gelatin remained during the experiment. In other words, it is presumed that even if heating is performed while a traction force is being applied, denaturation of the collagen fibers does not progress easily.

《Fifth Experiment》
Based on the knowledge obtained in the fourth experiment, the inventor hypothesized that it is preferable to heat the collagen fibers and then apply a traction force in order to effectively denature the collagen fibers. To prove this hypothesis, the inventor conducted a fifth experiment.
In the fifth experiment, test piece A that is not pulled and heated, test piece B that is pulled and not heated, test piece C that is pulled and heated in the middle, and test piece D that is heated and pulled in the middle , the degree of collagen fiber denaturation was confirmed. The degree of collagen fiber denaturation was determined by fluorescence detection of CHP (Collagen Hybridizing Peptide) added to the test piece. CHP is a probe that specifically binds to damaged collagen chains.

FIG. 10 is a diagram showing the results of the fifth experiment. As shown in FIG. 10, it can be seen that the denaturation of collagen fibers progresses by heating, and that the denaturation progresses greatly by applying a traction force after heating. In addition, as hypothesized above, there was no significant difference when heating was performed halfway through traction compared to heating only. From the results of the fifth experiment, it can be seen that in order to effectively denature the collagen fibers, it is preferable to apply traction force after heating the collagen fibers.

《Sixth experiment》
The inventor conducted a sixth experiment in order to confirm the expansion effect of the balloon catheter when heating was performed. In the sixth experiment, a balloon catheter was passed through a stenosis model at 37° C. (equivalent to body temperature) and a stenosis model heated to 70° C., the internal pressure of the balloon was gradually increased, and the diameter of the balloon and the diameter of each stenosis model were adjusted. compared.

FIG. 11 is a diagram showing the relationship between the diameter of the balloon and the diameter of the stenosis model without heating according to the sixth experiment. The diameter of all stenosis models without heating was well below the diameter of the balloon until the internal pressure of the balloon was 100 kPa. In addition, all stenosis models ruptured when the internal pressure of the balloon reached 160 kPa. Plots that greatly exceed the balloon diameter in FIG. 11 indicate rupture.

FIG. 12 is a diagram showing the relationship between the diameter of the balloon and the diameter of the heated stenosis model according to the sixth experiment. When the internal pressure of the balloon exceeded 40 kPa, the diameters of all of the heated stenosis models became almost equal to the diameter of the balloon. This indicates that the stenosis model has expanded sufficiently to follow the diameter of the balloon. Also, all constriction models with heating were expanded to 160 kPa without breaking.
A sixth experiment confirmed that application of traction followed by heating can expand the diameter of the stenosis to the balloon diameter without causing rupture of the stenosis.

《Seventh Experiment》
The inventor conducted a seventh experiment to confirm changes in the state of tissue due to heating and traction. In the seventh experiment, a bovine Achilles tendon was HE-stained, heated at 70° C. for 15 minutes, then pulled so that a stress of 6 MPa was applied, and observed before heating, after heating, and after pulling.

FIG. 13 is a diagram showing changes in tissue state according to the seventh experiment. In FIG. 13, by HE staining, cell nuclei were stained bluish purple (dark gray in FIG. 13), and collagen fibers were stained red (light gray in FIG. 13). Heating turned the unstained area (white in FIG. 13) red. This is because the fibrous structure was destroyed by the denaturation of collagen fibers into gelatin. On the other hand, focusing on the cell nucleus, it can be seen that the cell nucleus remains both after heating and after pulling. In other words, no morphological change in cells was observed within the range of heat load/stress load of the method according to the first embodiment. From this, it can be seen that according to the first embodiment, it is possible to selectively destroy collagen fibers while suppressing damage to cells.

<Second embodiment>
A technique called HIFU (High Intensity Focused Ultrasound) that obtains a therapeutic effect by selectively destroying living tissue noninvasively with ultrasound is known. Also, in order to soften a tissue containing collagen fibers, there is known a technique of cutting a part of collagen fibers with high strength, but a technique for non-invasively softening a tissue containing collagen fibers is desired. .

The range of destruction by HIFU is determined by the aperture area of the ultrasonic transmitter and the wavelength of the ultrasonic waves. Therefore, the destruction range by HIFU is about 5 mm ³ at the smallest. Collagen fibers are randomly distributed on a micrometer scale, and nerves and blood vessels run near the collagen fibers. Therefore, it has been difficult to selectively destroy collagen fibers using ultrasonic waves without destroying unintended biological tissues.
An object of the second embodiment is to provide a collagen decomposition device and a method of operating the collagen decomposition device that can selectively destroy collagen fibers in a range narrower than the irradiation range of ultrasonic waves.

<<Configuration of Collagen Decomposition Device 1>>
Hereinafter, embodiments will be described in detail with reference to the drawings.
FIG. 14 is a perspective view showing the configuration of the collagen decomposing device 1 according to the second embodiment. FIG. 15 is a cross-sectional view of the collagen decomposing device 1 according to the second embodiment.
Collagen degradation device 1 includes housing 11 , gel pad 12 , ultrasonic irradiation device 13 , laser device 14 and control device 15 . The housing 11 is configured in a substantially cylindrical shape having a through hole 111 . That is, the housing 11 has a disk-shaped bottom surface with a hole in the center. Gel pad 12 is provided to cover the bottom surface of housing 11 . The gel pad 12 is made of polyurethane gel, for example. The gel pad 12 does not have to have through-holes at locations corresponding to the through-holes 111 of the housing 11 . The ultrasonic irradiation device 13 is provided inside the housing 11 . The ultrasonic irradiation device 13 irradiates ultrasonic waves from the bottom surface of the housing 11 . The laser device 14 is provided inside the through hole 111 of the housing 11 . Laser device 14 irradiates laser light through through hole 111 and gel pad 12 . The control device 15 controls outputs of the ultrasonic irradiation device 13 and the laser device 14 .

The collagen decomposition apparatus 1 according to the second embodiment brings the bottom surface of the housing 11 and an object T (for example, a living body) into close contact with each other via the gel pad 12, and irradiates the object T with laser light and ultrasonic waves. , selectively destroys collagen fibers at target locations of the object T, resulting in tissue softening. Note that in other embodiments, water or jelly may be used instead of the gel pad 12 .

The ultrasonic irradiation device 13 uses the bottom surface of the housing 11 as an opening surface. Therefore, the irradiation range R1 of the ultrasonic waves covers at least the range obtained by extending the bottom surface of the housing 11 in the direction of irradiation of the ultrasonic waves. The ultrasonic irradiation device 13 irradiates ultrasonic waves having a frequency of 200 kHz or more and 10 MHz or less, a power of 0.4 kW/cm ² or more and 10 kW/cm ² or less, and a sound pressure of 1 MPa or more and 150 MPa or less. The sound pressure of the ultrasonic waves is preferably 1 MPa or more and 25 MPa or less. More preferably, the ultrasonic irradiation device 13 applies ultrasonic waves under the conditions of 250 kHz, 0.4 kW/cm ² and 3.5 MPa. Under these conditions, the ultrasonic waves emitted by the ultrasonic irradiation device 13 do not damage non-target tissues such as skin, muscles, blood vessels, and nerves among living tissues, and collagen fibers are thermally denatured. gelatin can be selectively destroyed. If the frequency of the ultrasonic wave is less than 200 kHz, the focal area becomes large with respect to the living tissue, so the damage to the non-target tissue becomes large. When the power exceeds 10 kW/cm ² or when the sound pressure of the ultrasonic waves exceeds 150 MPa, the number of cavitation occurrences becomes excessive, resulting in greater damage to non-target tissues. When the frequency of ultrasonic waves exceeds 10 MHz or the power is less than 0.4 kW/cm ² , the ultrasonic waves irradiated from the outside of the body are attenuated inside the body, so the cavitation generation threshold is exceeded and the destructive force against gelatin is small. turn into. In addition, when the sound pressure of the ultrasonic waves is less than 1 MPa, the number of cavitation occurrences becomes too small, and the destructive force against gelatin becomes small. In other words, the ultrasonic irradiation device 13 irradiates ultrasonic waves having a frequency that generates cavitation having an intensity capable of destroying gelatin without destroying living tissue.

The laser device 14 emits laser light having an absorption wavelength of collagen fibers. Specifically, the laser device 14 emits laser light with a wavelength of 400 nm or more and 900 nm or less. Laser light is an example of thermal energy. The irradiation range R2 of the laser light output by the laser device 14 is narrower than the irradiation range R1 of the ultrasonic irradiation device 13 . A wavelength of 400 nm or more and 900 nm or less is a wavelength at which the absorption coefficient of collagen is higher than that of hemoglobin, lipid, and water, which are components of biological tissue having relatively high absorption coefficients.

The control device 15 is connected to the ultrasonic irradiation device 13 and the laser device 14 via cables, and outputs control signals to the ultrasonic irradiation device 13 and the laser device 14 . Further, the control device 15 may supply power for driving the ultrasonic irradiation device 13 and the laser device 14 through cables.
When the collagen decomposition device 1 is operated, the control device 15 starts irradiation of ultrasonic waves by the ultrasonic irradiation device 13 and irradiation of laser light by the laser device 14 . The control device 15 controls the laser device 14 so as to repeat irradiation of pulsed light with a pulse time width of 1 ns or more and 20 ms or less at a frequency of 0.1 Hz or more and 100 kHz or less. Irradiation of pulsed light is preferably performed at a frequency of 0.1 Hz or more and 1 kHz or less and a pulse time width of 1 ns or more and 1 ms or less. As a result, the controller 15 can raise the temperature of the collagen fibers irradiated with the laser beam to near the denaturation temperature (45° C.), thereby partially denaturing the collagen fibers into gelatin. That is, the laser device 14 irradiates thermal energy with a power that raises the temperature of the collagen fibers present within the irradiation range R2 of the laser light to a temperature near the denaturation temperature of collagen.

Since the denaturation to gelatin is limited to the irradiation range R2 of the laser beam, the temperature drops while the laser beam is not irradiated, and the collagen fibers return to collagen fibers. In the object T, thermal diffusion outside the irradiation range R2 of the laser light occurs in about 20 ms. Therefore, by setting the pulse time width of the laser light to 20 ms or less, the controller 15 can suppress the occurrence of thermal diffusion of the laser light. That is, the laser device 14 irradiates heat energy for a period of time shorter than the period of time required for the temperature of collagen fibers existing outside the irradiation range R2 of the laser light to rise to the denaturation temperature due to thermal diffusion.
Preferably, the laser device 14 irradiates laser light under the conditions of 532 nm and 1 mJ/mm ² .

<<Action and effect of collagen decomposition device 1>>
When the user inputs an irradiation instruction to the control device 15 while the bottom surface of the housing 11 is in close contact with the object T, the control device 15 outputs a laser light irradiation instruction to the laser device 14, and simultaneously emits ultrasonic waves. An ultrasonic wave irradiation instruction is output to the irradiation device 13 . That is, the control device 15 outputs an irradiation instruction to the ultrasonic irradiation device 13 at least while the laser device 14 is operating. When the object T is irradiated with the laser light from the laser device 14, the temperature of the collagen fibers present in the irradiation range R2 rises. When the temperature of the collagen fibers reaches the denaturation temperature, some of the collagen fibers are denatured into gelatin. Gelatin has a random coil structure, whereas collagen fibers have a triple-stranded helix structure. Therefore, gelatin has low strength compared to collagen fibers. Specifically, the material strength of collagen is about 1.3N, while the material strength of gelatin is about 0.6N. Therefore, cavitation caused by ultrasonic waves emitted from the ultrasonic irradiation device 13 is often generated in locations where gelatin in which collagen fibers are denatured exists. When cavitation caused by ultrasound expands and ruptures, weak gelatin is destroyed, while collagen fibers and other living tissues, which are stronger than gelatin, are not damaged. Also, the acoustic energy of ultrasonic waves damages gelatin, which is weak in intensity, but does not damage collagen fibers and other living tissues. By selectively destroying gelatin by cavitation bursting or acoustic energy, portions of collagen fibers irradiated with laser light are selectively destroyed. In addition, cavitation expands and ruptures between the tangled collagen fibers, so that a force can be generated in the direction of separating the collagen fibers from each other. As a result, even if the irradiation of the laser light is stopped and the heating of the collagen fibers is stopped, the flexibility of the fibers as a whole can be maintained.

As described above, according to the collagen degradation apparatus 1 according to the second embodiment, the laser beam partially denatures collagen existing in a portion narrower than the irradiation range R1 of the ultrasonic wave to gelatin, and then irradiates the collagen with the ultrasonic wave. . As a result, the collagen degradation device 1 can selectively destroy collagen fibers in a range narrower than the ultrasonic wave irradiation range.

<Other embodiments>
Although one embodiment has been described in detail above with reference to the drawings, the specific configuration is not limited to the one described above, and various design changes and the like can be made.

The collagen decomposition device 1 according to the second embodiment is provided with a laser device 14 in the through hole 111 of the housing 11, and the ultrasonic irradiation device 13 irradiates laser light to the center of the ultrasonic irradiation range. On the other hand, other embodiments are not limited to this configuration. For example, in the collagen degradation device 1 according to another embodiment, the irradiation direction of ultrasonic waves and the irradiation direction of laser light may not match. In this case, for example, the collagen decomposition device 1 may be provided with the ultrasonic irradiation device 13 and the laser device 14 so that the irradiation range of ultrasonic waves and the irradiation range of laser light intersect.

In addition, although the collagen decomposition device 1 according to the second embodiment includes one laser device 14 and one ultrasonic irradiation device 13, the present invention is not limited to this. For example, the collagen degradation device 1 according to another embodiment may include multiple laser devices 14 and ultrasonic irradiation devices 13 . For example, the collagen decomposition device 1 according to another embodiment is provided with a plurality of laser devices 14 so that the laser beams intersect at one point, so that the collagen fibers at the points where the laser beams intersect can be denatured into gelatin. may be configured. In this case, the control device 15 may adjust the angle of the laser device 14 to change the depth to the epidermis of the point where the laser beams intersect.

Also, in the collagen decomposition device 1 according to another embodiment, instead of the laser device 14, another heat source device capable of irradiating thermal energy to a range narrower than the range of ultrasonic wave irradiation may be used. For example, the collagen decomposing device 1 according to another embodiment may be equipped with a heater by thermal radiation.

<Computer configuration>
The control device 15 includes a processor, a memory, an auxiliary storage device, etc. connected via a bus, and functions as the control device 15 that controls the ultrasonic irradiation device 13 and the laser device 14 by executing a program. Examples of processors include CPUs (Central Processing Units), GPUs (Graphic Processing Units), microprocessors, and the like.
The program may be recorded on a computer-readable recording medium. A computer-readable recording medium is, for example, a storage device such as a magnetic disk, a magneto-optical disk, an optical disk, or a semiconductor memory. The program may be transmitted over telecommunications lines.

All or part of each function of the control device 15 may be realized using a custom LSI (Large Scale Integrated Circuit) such as an ASIC (Application Specific Integrated Circuit) or a PLD (Programmable Logic Device). Examples of PLDs include PAL (Programmable Array Logic), GAL (Generic Array Logic), CPLD (Complex Programmable Logic Device), and FPGA (Field Programmable Gate Array). Such an integrated circuit is also included as an example of a processor.

1... Collagen decomposition device 11... Housing 12... Gel pad 13... Ultrasonic irradiation device 14... Laser device 15... Control device

Claims

a stress applying device for applying stress to a first area of target tissue;
and a heat source device that applies thermal energy to a second area that has at least a portion that overlaps with the first area.
The stress applying device applies a stress to the first area that selectively destroys sites where collagen fibers are thermally denatured without damaging non-target tissues within the target tissue.
Collagen degradation device according to claim 1.
The collagen degradation device according to claim 2, wherein the stress application device applies a stress of 40 kPa or more and 500 kPa or less to the first area.
4. The collagen decomposition apparatus according to any one of claims 1 to 3, wherein the heat source device provides thermal energy with a power that raises the temperature of collagen fibers existing within the second range to a collagen denaturation temperature or higher. .
The stress applying device presses the tubular organ, which is the target tissue, radially outward from the inside.
The device for decomposing collagen according to any one of claims 1 to 3.
comprising a balloon that is inflated by a supply of fluid;
The first range and the second range are ranges of the tubular organ with which the balloon contacts,
the stress applying device presses the tubular organ radially outward from the inside by supplying the fluid to the balloon;
The collagen decomposition device according to claim 5, wherein the heat source device heats the fluid to apply thermal energy to the tubular organ.
A control device that controls the stress applying device and the heat source device,
The control device is
outputting a heating start instruction to the heat source device;
After starting heating by the heat source device, outputting a first addition start instruction for causing the stress applying device to apply a first stress capable of selectively destroying the site where the collagen fibers are thermally denatured,
outputting a heating stop instruction to the heat source device;
7. The collagen decomposition apparatus according to claim 6, wherein after stopping the heating by the heat source device, an addition stop instruction for stopping the stress application by the stress application device is output.
A control device that controls the stress applying device and the heat source device,
The control device is
8. Collagen decomposition according to claim 7, wherein before outputting the heating start instruction, a second addition start instruction is output to cause the stress applying device to apply a second stress that does not damage non-target tissues within the target tissue. Device.
The heat source device outputs the thermal energy using waves as a medium,
The collagen degradation device according to any one of claims 1 to 3, wherein the waves are irradiated so as to converge at a portion of the target tissue where collagen fibers are present.
The collagen degradation device according to any one of claims 1 to 3, wherein the second range is narrower than the first range.
an ultrasonic irradiation device for applying ultrasonic waves to a first irradiation range;
and a heat source device that irradiates thermal energy to a second irradiation range that is inside the first irradiation range and narrower than the first irradiation range.
The collagen decomposition apparatus according to claim 11, wherein the heat source device irradiates the second irradiation range with laser light having a wavelength of 400 nm or more and 900 nm or less.
The collagen decomposition apparatus according to claim 12, wherein the heat source device irradiates the second irradiation range with a laser beam having a wavelength of 400 nm or more and 900 nm or less with a pulse time width of 1 ns or more and 20 ms or less.
14. The heat source device according to any one of claims 11 to 13, wherein the heat source device irradiates thermal energy with a power that raises the temperature of collagen fibers existing within the second irradiation range to a temperature near the denaturation temperature of collagen. Collagen degradation device as described.
15. The collagen decomposition apparatus according to claim 14, wherein the heat source device irradiates heat energy for a period of time shorter than a period of time for temperature of collagen fibers existing outside the second irradiation range to rise to the denaturation temperature due to thermal diffusion.
14. The collagen decomposition apparatus according to any one of claims 11 to 13, wherein the ultrasonic irradiation device emits ultrasonic waves having a frequency that generates cavitation having an intensity capable of destroying gelatin without destroying biological tissue. .
14. The ultrasonic irradiation device according to any one of claims 11 to 13, wherein the ultrasonic irradiation device irradiates ultrasonic waves having a frequency of 200 kHz or more and 10 MHz or less with a power of 0.4 kW/cm 2 or more and 10 kW/cm 2 or less. Collagen degradation device.
A housing having a disk-shaped bottom surface with a hole in the center,
The ultrasonic irradiation device irradiates the ultrasonic waves from the bottom surface of the housing,
The collagen decomposition device according to any one of claims 11 to 13, wherein the heat source device irradiates the thermal energy through the hole.
A method for operating a collagen decomposition device comprising an ultrasonic irradiation device, a heat source device, and a control device,
a step in which the control device outputs an irradiation instruction to a heat source device to irradiate a second irradiation range with thermal energy; and a range including the second irradiation range during operation of the heat source device, A step of outputting an irradiation instruction to the ultrasonic irradiation device to irradiate ultrasonic waves in a first irradiation range wider than the second irradiation range;
A method of operating a collagen degrading device comprising:
A method for operating the collagen degradation device according to any one of claims 1 to 3,
a control device outputting a heating start instruction for causing the heat source device to start heating the second range;
a step in which the control device outputs an addition start instruction for causing the stress applying device to start applying stress to the first area after the heating start instruction;
a step in which the control device outputs a heating stop instruction to the heat source device to stop heating;
a step in which the control device outputs an application stop instruction for causing the stress application device to stop applying the stress after the heating stop instruction;
A method of operating a collagen degrading device comprising: