JP5265206B2 - Vasodilator - Google Patents

Abstract

It is intended to provide an apparatus for dilating the vascular wall with the use of a high-intensity pulsed light. A vasodilator with the use of high-intensity pulsed light irradiation comprising a high-intensity pulsed light irradiation system, which is a high-intensity pulsed light irradiation system capable of generating steam bubbles in a vessel and having a high-intensity pulsed light generation unit, a high-intensity pulsed light transfer unit and a unit of irradiating the high-intensity pulsed light in a vessel, whereby steam bubbles are generated in the vessel by the irradiation with the high-intensity pulsed light and thus the vascular wall is spread and the vessel is dilated due to the function of the vapor bubbles.

Description

  The present invention relates to an apparatus for generating a water vapor bubble in a blood vessel by irradiation with high-intensity pulsed light, expanding a blood vessel wall by the action of the water vapor bubble, and expanding the blood vessel.

  Angioplasty that inserts an expansion balloon catheter, which is a catheter with a balloon, into a lesion such as a stenosis of a blood vessel to expand and expand the lesion of a blood vessel for the treatment of myocardial infarction and angina is widely used. (See Non-Patent Document 1).

  A photothermodynamic balloon has also been reported in which an angioplasty is performed by applying heat to a lesioned part of a blood vessel by heating the balloon (see Patent Document 1).

  The balloon catheter can only expand the blood vessel while the vessel wall is being expanded by the balloon. In order to expand the lesion over a long period of time, the stent can be used to expand the lesion expanded using the balloon. It was necessary to use and spread out.

  In addition, the balloon catheter has a large outer diameter and can be applied to blood vessels with a certain thickness such as coronary arteries. Further, when the balloon is expanded, there are cases where smooth treatment is difficult, for example, pressure is received from the stenosis of the blood vessel and the position of the balloon is displaced from the lesion.

  On the other hand, a method using high-intensity pulsed light such as laser light has been developed as a method of angioplasty. For example, there has been a method of irradiating a laser beam in a blood vessel to induce a sound pressure wave and forming a blood vessel by the energy of the sound pressure wave (see Patent Document 2). On the other hand, there was a report that the blood vessel is damaged by the bubble formation by laser light irradiation in the blood vessel (see Non-Patent Document 2).

JP 09-084879 A JP 2004-357792 A Edited by Morton J. Kahn, “Cardiac Catheter Handbook”, 2nd edition, Medical Science International, Inc., April 21, 2004, p.407-451 ASHLEY J. WELCH et al., “OPTICAL-THERMAL RESPONSE OF LASER IRRADIATED TISSUE”, (US), Plenum Press, 1995 Year, p.732-740

  An object of the present invention is to provide an apparatus for expanding a blood vessel wall using high-intensity pulsed light.

  The present inventors paid attention to a phenomenon in which water vapor bubbles are generated when laser is irradiated in a liquid, and found that the blood vessels can be expanded by the water vapor bubbles by generating the water vapor bubbles in the blood vessel. The inventors of the present invention have made further studies on a method of expanding a blood vessel by generating water vapor bubbles with a laser, and the pressure applied to the blood vessel wall by the water vapor bubbles varies depending on the irradiation condition of the laser, and the blood vessel wall is heated by the laser. The inventors have found that the expanded state of the blood vessel wall can be maintained by changing the orientation of the collagen contained in the blood vessel wall, and have completed the present invention.

That is, the present invention is as follows.
[1] High-intensity pulsed light irradiation means capable of generating water vapor bubbles in a blood vessel, comprising high-intensity pulsed light generation means, high-intensity pulsed light transmission means, and means for irradiating high-intensity pulsed light into the blood vessel A blood vessel dilation device using high-intensity pulsed light irradiation that includes an intensity pulsed light irradiation unit, generates water vapor bubbles in a blood vessel by high-intensity pulsed light irradiation, and expands the blood vessel wall by the action of the water vapor bubbles.
[2] The vasodilator using high-intensity pulsed light irradiation according to [1], wherein pressure and heat are applied to the blood vessel wall by the action of water vapor bubbles, and the orientation of collagen fibers in the blood vessel wall is aligned.
[3] The vasodilator by high-intensity pulsed light irradiation according to [1] or [2], wherein the pressure applied to the blood vessel wall is 0.1 to 5.0 atm and the temperature is 60 ° C. or higher.
[4] The vasodilator by high-intensity pulsed light irradiation according to [1] or [2], wherein the high-intensity pulsed light transmission means is an optical transmission fiber.
[5] A device including a catheter having no balloon, and is provided with an optical transmission fiber for transmitting high-intensity pulsed light in the catheter, thereby expanding blood vessels by irradiation with high-intensity pulsed light according to any one of [1] to [4] apparatus.
[6] The vasodilator by high-intensity pulsed light irradiation according to [5], wherein the position of the irradiation part of the high-intensity pulsed light irradiation means is located inside the distal end of the catheter.
[7] The vasodilator by high-intensity pulsed light irradiation according to [6], wherein the position of the irradiation part of the high-intensity pulsed light irradiation means is located within 0.5 to 5 mm from the distal end of the catheter.
[8] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [7], which has a radiopaque marker near the distal end of the optical transmission fiber.
[9] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [8], which has an X-ray opaque marker near the distal end of the catheter.
[10] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [9], which is applied to a stenosis site of a blood vessel to expand the stenosis site of the blood vessel.
[11] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [10], which can maintain vasodilation for at least 10 minutes.
[12] The vasodilator using high-intensity pulsed light irradiation according to [11], which can permanently maintain vasodilation.
[13] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [12], wherein the wavelength of the high-intensity pulsed light is in the range of 1 to 3 μm.
[14] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [13], wherein the high-intensity pulsed light is a pulsed laser.
[15] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [14], wherein the pulse width of high-intensity pulsed light irradiation is 50 μs to 1 ms.
[16] The vasodilator using high-intensity pulsed light irradiation according to any one of [1] to [15], wherein the blood vessel is expanded by repeating irradiation with high-intensity pulsed light at least 25 times and 100 times or less.
[17] The vasodilator using high-intensity pulsed light irradiation according to [16], wherein the blood vessel is expanded by repeating irradiation with high-intensity pulsed light at least 50 times and not more than 100 times.
[18] Including high-intensity pulsed light irradiation means capable of generating water vapor bubbles in the blood vessel, high-intensity pulsed light generation means, and high-intensity pulsed light transmission means, A method of controlling a vasodilator by irradiation with high-intensity pulsed light that expands a blood vessel by expanding the blood vessel wall by the action of the water vapor bubble, the size and shape of the water vapor bubble generated in the blood vessel and the heat applied to the blood vessel wall A control method in which the control means of the vasodilator controls the high-intensity pulsed light irradiation means to change the intensity of the high-intensity pulsed light and the number of times of irradiation.
[19] A high-intensity pulsed light irradiation unit capable of generating water vapor bubbles in a blood vessel, a high-intensity pulsed light generation unit, and a high-intensity pulsed light transmission unit. A method for controlling a vasodilator by high-intensity pulsed light irradiation that expands a blood vessel wall and expands a blood vessel by the action of the water vapor bubbles, wherein the distance between the irradiation part position of the high-intensity pulsed light irradiation means and the distal end of the catheter is determined. A control method for adjusting and controlling the shape and pressure of the generated water vapor bubbles.

  If the apparatus of this invention is used, the lesioned part of the blood vessel can be expanded accurately and safely by the pressure of water vapor bubbles generated in the blood vessel, and angioplasty can be performed. When the apparatus of the present invention is used, the degree of collagen degeneration on the blood vessel wall can be controlled by controlling the intensity of the high-intensity pulsed light and the number of times of irradiation, and the blood vessel maintains an expanded state depending on the degree of degeneration. You can control the time to do. Furthermore, since only a thin optical transmission fiber is required to be inserted into the blood vessel in the apparatus of the present invention, an angioplasty is performed even on a thin blood vessel, which was impossible with a conventional method using a balloon catheter. It is possible.

  Hereinafter, the present invention will be described in detail.

  The present invention is a vasodilator for angioplasty using high-intensity pulsed light. Angioplasty is performed, for example, at a vascular stenosis site in an angina patient or a myocardial infarction patient.

  The apparatus of the present invention includes at least high-intensity pulsed light irradiation means for irradiating a high-intensity pulsed light into a blood vessel, and further guides the high-intensity pulsed light irradiation unit to an angioplasty site to be expanded in the blood vessel. Other catheters may be included. FIG. 1 shows a schematic diagram of the apparatus of the present invention.

  The high-intensity pulsed light irradiation means includes high-intensity pulsed light generation means (high-intensity pulsed light source), means for transmitting high-intensity pulsed light into the blood vessel, means for irradiating high-intensity pulsed light into the blood vessel (irradiation site), etc. A portion for transmitting high-intensity pulsed light is an optical transmission fiber.

  The means for irradiating the high-intensity pulsed light into the blood vessel is provided as a high-intensity pulsed light irradiation unit at the distal end of the optical transmission fiber. The high-intensity pulsed light irradiation unit may be provided with a member such as a prism for changing the pulsed light irradiation angle, but usually no special member is required, and the distal end of the optical fiber is irradiated with high-intensity pulsed light. Can act as a part.

  The vascular catheter optionally included in the apparatus of the present invention is a tube for inserting a part of the apparatus of the present invention into a blood vessel, and is used as a guide when moving a part of the apparatus to a target site. As the catheter, a commonly used catheter can be used, and its diameter and the like are not limited, and can be appropriately designed according to the thickness of the blood vessel to be treated. Since the apparatus of the present invention only requires one optical fiber for transmitting high-intensity pulse light in the catheter, the diameter of the catheter can be reduced. For example, the diameter of the catheter sheath portion is 2 mm or less.

  In the device of the present invention, the presence of the catheter is optional, and only the optical transmission fiber may be inserted into the blood vessel. The fiber in this case is called bare fiber.

  Therefore, it can be inserted into a thin blood vessel that could not be inserted with a conventional balloon catheter, and an angioplasty can be performed in the thin blood vessel. The target of angioplasty in the conventional method is a thick artery such as the external carotid artery, coronary artery, renal artery, sternum artery, superficial femoral artery, and knee joint artery. It is possible to treat not only arteries but also thinner blood vessels with an inner diameter of about 2.5 mm or less.

  Furthermore, the apparatus of this invention may be equipped with the marker for monitoring the position of a high intensity | strength pulsed light irradiation part. As the marker, an X-ray opaque marker may be used. By observing with X-ray fluoroscopy from the outside, the existence position of the high-intensity pulsed light irradiation unit can be known, and the irradiation unit can be positioned at the treatment site. As a radiopaque marker, a metal that is opaque to X-rays can be used, and platinum, gold, iridium, and the like, and alloys thereof are preferable from the viewpoint of affinity for a living body. When the device of the present invention includes a catheter, one or more radiopaque markers may be provided at the distal end of the catheter, for example. When the device of the present invention does not include a catheter, for example, one or more may be provided at the distal end of the optical transmission fiber.

  The high-intensity pulsed light includes pulsed light generated by a laser and an optical parametric oscillator (OPO).

As the laser generating means, a normal laser generating device can be used, and the laser species is not limited as long as it is a laser having a wavelength band in which the water absorption coefficient is 10 to 1000 cm ⁻¹ , preferably 10 to 100 cm ⁻¹ , and rare earth A solid-state laser using ions, a XeCl excimer laser, or the like can be used. The oscillation wavelength of the laser is 0.3 to 3 μm, preferably 1.5 to 3 μm, more preferably 1.5 to 2.5 μm, and more preferably a wavelength in the vicinity of the maximum absorption wavelength of water (1.9 μm). The laser is represented by the element ions that generate the laser and the type of the base material that holds the ions. Ho (holonium), Tm (thulium), Er (erbium), Nd (neodymium) belonging to rare earths as elements. Of these, Ho and Tm are preferred. Examples of the base material include YAG, YSGG, and YVO. For example, Ho: YAG laser, Tm: YAG laser, Ho: YSGG laser, Tm: YSGG laser, Ho: YVO laser, Tm: YVO laser, and XeCl excimer laser (oscillation wavelength 308 nm) can be used. Among these, Ho: YAG laser (oscillation wavelength 2.1 μm), Tm: YAG laser (oscillation wavelength 2.01 μm), etc., in which the oscillation wavelength of the laser exists in the vicinity of the maximum absorption wavelength of water (1.9 μm) are preferable.

  Examples of the laser generator include LASER1-2-3 SCHWARTZ (manufactured by ELECTRO-OPTICS).

An optical parametric oscillator (OPO) can continuously change the wavelength of pulsed light, and may select pulsed light having a wavelength band in which the water absorption coefficient is 10 to 1000 cm ⁻¹ . For example, the wavelength may be selected in the vicinity of 0.3 to 3 μm, preferably 1.5 to 3 μm, more preferably 1.5 to 2.5 μm, and more preferably water absorption wavelength maximum (1.9 μm).

  The irradiation intensity of the high-intensity pulsed light is not limited and may be appropriately determined according to the thickness of the target blood vessel and the severity of the lesion, but is preferably 1 to 2 J / pulse, more preferably 1.2 to 1.6 J. / pulse. The pulse width of the high-intensity pulsed light is not limited, but is 10 ns to 1 ms, preferably 300 μs to 400 μs. The pulse width is indicated by the full width at half maximum.

  The greater the number of repeated irradiations of high-intensity pulsed light, the greater the degree of collagen denaturation and the longer the time during which the blood vessel wall remains in an expanded state. The number of repeated irradiations is 10 to 1000 times, preferably 25 to 100 times, more preferably 50 to 100 times. The time that the vessel wall remains dilated is at least 10 minutes, preferably at least 1 hour, more preferably permanent. For example, if irradiated at high intensity 10 times or more, the expanded state can be maintained for at least about 10 minutes.

  The means for transmitting high-intensity pulsed light into the blood vessel includes means for irradiating high-intensity pulsed light (high-intensity pulsed light irradiation part) located near the distal end of the catheter and high-intensity pulsed light as high-intensity pulsed light. A high-intensity pulsed light transmission fiber that is transmitted from the light generator to the high-intensity pulsed light irradiation means is included. As used herein, “near the distal end” means a portion near the end opposite to the end (proximal end) connected to the high-intensity pulsed light generator, It refers to a portion of about several tens of centimeters from the distal end.

  One end of the quartz fiber is connected to a high-intensity pulsed light generator, and the other end is connected to high-intensity pulsed light irradiation means (high-intensity pulsed light irradiation unit). The quartz fiber used in the present invention is inserted into a blood vessel as it is, from a very thin fiber having a diameter of about 0.05 to 0.3 mm to a visible thickness, or placed in a catheter and placed in a blood vessel. A wide variety of diameters can be used as long as they are inserted and can transmit high-intensity pulsed light energy.

  The high-intensity pulsed light irradiation means is a means for irradiating the blood vessel with high-intensity pulsed light, and is generated by a high-intensity pulsed light generator (high-intensity pulsed light source) outside the body. The high-intensity pulsed light transmitted along the blood vessel is irradiated into the blood vessel so that water vapor bubbles are formed in the blood. At this time, the direction of irradiation with high-intensity pulsed light is not limited. Further, as described above, a plurality of high-intensity pulsed light transmission fibers may be dispersed. The diameter of the fiber is preferably between 100 μm and 1000 μm.

  The range (length) of the blood vessel wall to be expanded can be varied by controlling the shape of water vapor bubbles generated by irradiating high-intensity pulsed light. The shape of the water vapor bubbles is such that when the size of the blood vessel is in the vertical direction and the direction perpendicular to the blood vessel is in the horizontal direction, the shape of the water vapor bubbles spreading in the horizontal direction is greater than the pressure in the horizontal direction. And the blood vessel wall can be reliably expanded. Therefore, the steam bubbles generated by the apparatus of the present invention preferably have a mushroom shape or a western shape that spreads in the lateral direction. The generated steam bubbles are preferably steam bubbles having a length in the transverse direction with respect to the direction of irradiation with high-intensity pulsed light that is 1/2 or more of the length in the longitudinal direction, and are the same as the length in the longitudinal direction or Large steam bubbles are preferred. Further, a water vapor bubble having a size that does not cause excessive damage to the blood vessel wall by over-expanding the blood vessel wall is preferable. Water vapor bubbles having a size of 2 times or less of these are preferable, and water vapor bubbles smaller than the inner diameter of the blood vessel are more preferable.

  Specifically, the generated water vapor bubbles have a length in the horizontal direction as defined above of 50% to 500%, preferably 75% to 500%, more preferably 100% to 500% of the length in the vertical direction. It is desirable. Further, the lateral length varies depending on the thickness of the blood vessel to be treated, but is preferably 10% to 200%, preferably 10% to 150%, more preferably 10% to 100% of the inner diameter of the blood vessel. . For example, in the case of the coronary aorta, since the inner diameter of the blood vessel is about 3 mm, the lateral length of the water vapor bubbles is about 0.3 to 6 mm, preferably 0.3 to 4.5 mm, more preferably 0.1 to 3 mm. .

  In order to generate water vapor bubbles that can generate an appropriate expansion pressure as described above, the positional relationship between the position of the high-intensity pulsed light irradiation means at the distal end of the high-intensity pulsed light transmission means and the distal end of the catheter is adjusted. do it. When the position of the irradiation part of the high-intensity pulsed light irradiation means is outside the distal end of the catheter, the size, shape, etc. of the water vapor bubbles are the same as when using bare fibers. Irradiation with high-intensity pulsed light in a state where the position of the high-intensity pulsed light irradiation means is located within a few mm from the distal end of the catheter is called intra-catheter irradiation. On the other hand, irradiation in a bare fiber state is called a bare irradiation method. When the high-intensity pulsed light irradiation means is retracted into the catheter, water vapor bubbles are generated inside the catheter immediately in front of the high-intensity pulsed light irradiation means, and the inside of the catheter proceeds outward while expanding and out of the catheter. Get out. At this time, the shape of water vapor bubbles generated outside the catheter and in the blood vessel can also be adjusted by changing the shape or the like inside the distal end of the catheter. The pressure generated in the lateral direction can be adjusted by adjusting the shape of the water vapor bubbles.

  For example, by placing the high-intensity pulsed light irradiation part at the tip of the optical fiber within a few millimeters from the distal end of the catheter, it is possible to generate a more appropriately shaped water vapor bubble, and as a result, a higher expansion pressure can be applied to the blood vessel. Can act on the wall. It is desirable that the high-intensity pulsed light irradiation part at the tip of the optical fiber is located within the catheter 0.5 to 5 mm, preferably 1 to 3 mm, more preferably 1 to 2 mm with respect to the catheter tip. Also, the shape of the water vapor bubble can be adjusted by the shape inside the distal end of the catheter, and as a result, the expansion pressure acting on the blood vessel wall can be adjusted. When the high-intensity pulsed light irradiation part exists inside the catheter, water vapor bubbles are generated inside the catheter and go out from the inside of the catheter while expanding. At this time, when the water vapor bubbles go outside in the catheter, Suppressing the speed at which the water vapor bubble expands in the catheter travel direction prevents the water vapor bubble from expanding in the catheter travel direction, and the front edge of the air bubble wraps around the rear, resulting in a more umbrella-shaped lateral expansion. Water vapor bubbles can be generated. For this purpose, for example, a convex portion that can suppress the expansion of water vapor bubbles in the vertical direction, a groove, or a continuous uneven portion may be provided inside the distal end of the catheter. Further, the structure may be changed at the distal end portion of the catheter so that the inner diameter of the distal end portion increases.

  In the case of the catheter irradiation method, irradiation with the high-intensity pulsed light irradiation unit in contact with the blood vessel wall can be prevented, so that blood vessel dilation can be performed more safely.

  Further, even when high-intensity pulsed light having the same intensity is irradiated, the magnitude of the expansion pressure generated varies depending on the positions of the high-intensity pulsed light irradiation part of the optical transmission fiber and the catheter tip part. For example, as the position of the high-intensity pulsed light irradiation part of the fiber for optical transmission and the tip of the catheter are separated, that is, as the high-intensity pulsed light irradiation part is retracted inside the catheter, the high-intensity pulsed light of the same energy is irradiated. However, the generated expansion pressure becomes high. An appropriate expansion pressure can be generated by appropriately adjusting the position of the light irradiation unit according to the thickness of the catheter or the optical transmission fiber.

  Further, the expansion pressure changes not only by the positional relationship between the catheter tip and the high-intensity pulsed light irradiation unit but also by the combination of the positional relationship and the intensity of the high-intensity pulsed light to be irradiated.

  Therefore, the present invention is generated by changing the intensity of the high-intensity pulsed light to be irradiated, changing the position of the irradiation part of the high-intensity pulsed light and the catheter tip, or changing the structure inside the catheter distal end. It is a device capable of adjusting the size and / or shape of water vapor bubbles to adjust the generation of expansion pressure that dilates the blood vessel wall.

  When high-intensity pulsed light is directly applied to blood, the portion of red blood cells is destroyed, and therefore it is desirable to replace that portion of blood with physiological saline or the like. As such a liquid, an infusion solution such as a dialysis solution is used in addition to physiological saline. In this case, a liquid feeding means is incorporated in the catheter of the treatment apparatus of the present invention, and a physiological saline or the like is irradiated with high intensity pulsed light in the blood vessel using the liquid feeding means, that is, high intensity pulsed light irradiation. What is necessary is just to inject | pour into the irradiation part vicinity of a part. The liquid feeding means includes a liquid feeding channel provided in the catheter, an injection port provided at a distal end of the liquid feeding channel, a liquid reservoir connected to the channel, a pump for feeding, and the like. For example, a lumen may be provided in the catheter and the lumen may be used as the liquid supply channel, or a separate channel tube may be provided in the catheter. In this case, the high-intensity pulsed light from the high-intensity pulsed light irradiating means is irradiated into the blood vessel in order to replace the local blood part where the high-intensity pulsed light is radiated into the blood vessel and water vapor bubbles start to be generated. And the inlet of the liquid feeding means need to be located at positions close to each other. For example, a lumen may be provided in the catheter, and a high-intensity pulse light transmission fiber may be passed through the lumen, and physiological saline or the like may be sent through the lumen. The amount of physiological saline to be delivered is not limited, but about 1/10 to 1/1000 of the amount delivered when using an endoscope that injects flush solution and observes the lumen of the blood vessel is sufficient. . For example, in the method of injecting the flash solution when observing the lumen of the blood vessel with an endoscope, it is necessary to inject the flash solution of 1 to 2 mL / second, but the injection amount in the present invention is about 1 mL / min. It ’s enough. With this level of liquid delivery, oxygen supply to the periphery can be secured without hindering blood flow.

  By irradiating the high-intensity pulsed light into the blood vessel, the energy density is increased in front of the irradiation part of the high-intensity pulsed light, and water vapor bubbles are generated in the region, the bubbles expand in the blood vessel, and the surroundings of the water vapor bubbles Push away blood or saline that is present in the body. The blood vessel wall is expanded by the pressure of water vapor bubbles and the pressure of blood or physiological saline. The pressure (expansion pressure) applied to the blood vessel wall by the device of the present invention is 0.1 to 5.0 atm. At the same time, heat is generated by the high-intensity pulsed light, and the blood vessel wall is expanded and heated at the same time. As a result, the collagen fibers in the blood vessel wall are denatured by heat, the orientation of the collagen fibers changes, and the blood vessel wall continues to expand for a long time. In addition, when the degree of collagen denaturation is strong, the expansion of the blood vessel wall continues permanently. However, if the denaturation of the collagen is strong, the collagen is easily broken and the strength of the blood vessel wall may be lowered. Therefore, it is desirable to avoid excessive heat denaturation. In addition, elastin is also involved in vasodilation, and the elastin fiber stretches with the collagen fibers softened due to heat generated by the generation of bubbles and the pressure of bubble growth, and then the elastin fibers remain stretched due to further heat denaturation of the collagen fibers. Fixed. The denaturation of collagen and elastin can measure Young's modulus. Accordingly, laser irradiation can be performed in a model experimental system to measure the Young's modulus of collagen and elastin, and appropriate irradiation conditions can be determined. The heating temperature of the blood vessel wall with the high-intensity pulsed light is 60 ° C. or higher, preferably 80 ° C. or higher. The degree of collagen denaturation can be adjusted by the intensity of the high-intensity pulse light to be irradiated, the number of times of irradiation, and the like. When the degree of collagen denaturation is low, the dilated vessel wall is restored over time. In this case, while the blood vessel wall is expanded and the blood vessel wall is maintained in the expanded state, a stent may be inserted and placed in the expanded portion to maintain the expanded state. In the case where the device of the present invention includes a catheter, the stent may be placed in advance on the catheter, irradiated with high-intensity pulsed light to expand the blood vessel wall, and then placed in the blood vessel. In addition, when the device of the present invention is made of an optical transmission fiber without including a catheter, it may be placed in a blood vessel using another catheter. In addition, it is preferable to use a self-expandable type (self-expanding type) as the stent.

  FIG. 2 is a diagram showing a process from generation to disappearance of water vapor generated by laser light irradiation.

  The vasodilator of the present invention may be applied to, for example, a stenosis portion of a blood vessel of an angina or myocardial infarction patient, and may be applied to a patient having a stenosis rate of 50% or more, preferably 90% or more.

  The degree of expansion of the blood vessel expanded by the apparatus of the present invention varies depending on the type of target blood vessel, the intensity of the high-intensity pulsed light to be irradiated, and the number of times of irradiation, but preferably the inner diameter of the blood vessel wall is 1.1 times or more, More preferably, it can be expanded 1.3 times or more, particularly preferably 1.5 times or more.

  Note that it is desirable that the high-intensity pulsed light irradiation is delayed and synchronized with the pulsation of the blood flow, that is, the pulsating blood flow. Blood flow is a pulsatile flow. When blood flow is flowing, that is, when the kinetic energy (dynamic pressure) of the blood flow is large, the generation of water vapor bubbles affects not only blood pressure (static pressure) but also dynamic pressure. box office. On the other hand, if the blood flow is completely stopped, the blood is a non-Newtonian fluid, so that the viscosity becomes large and water vapor bubbles are hardly generated. Therefore, there is an optimal timing when the pulsatile blood flow rate has decreased (before the blood flow stops). The timing can be detected by setting a delay time specific to the observation blood vessel in the heartbeat information from the electrocardiogram. In this case, the electrocardiogram and the laser generator are electronically connected, and the electrocardiogram signal is passed through the delay generator to the high-intensity pulsed light generator so that the high-intensity pulsed light is emitted when the pulsatile blood flow decreases. Just communicate. How much time delay is applied can be appropriately determined by a combination of an electrocardiograph, a delay generator, and a high-intensity pulsed light generator. A person skilled in the art can easily determine the timing for transmitting a signal such that a high-intensity pulsed light is emitted when the pulsatile blood flow is reduced from the electrocardiograph based on the known relationship between the cardiac cycle, the aortic blood flow velocity, and the electrocardiogram.

  For example, in the case of coronary arteries, blood hardly flows during the systole when the aortic blood flow rate is large, and blood flows during the diastole when the aortic blood flow rate is small. Therefore, the blood flow velocity in the coronary artery is maximized during the appearance of the P wave after the appearance of the T wave in the electrocardiogram, and the irradiation timing of the high-intensity pulsed light is preferably from the appearance of the P wave to the disappearance of the QRS wave. Furthermore, a pressure sensor or the like is disposed on the catheter of the treatment apparatus of the present invention, and the pulsation of the blood flow is monitored by the sensor so that the high-intensity pulsed light is emitted when the pulsating blood flow is reduced. May be. Also in this case, the pressure sensor and the high intensity pulsed light generator are electronically connected, and a signal from the pressure sensor is transmitted to the high intensity pulsed light generator with a delay.

Method of using the device of the present invention When using the device of the present invention, the high-intensity pulsed light irradiation section is guided to a blood vessel site to be expanded. The blood vessels targeted by the apparatus of the present invention are not limited, and the present invention can be applied to any coronary artery or other blood vessels thinner than this. In the device of the present invention, the portion to be inserted into the blood vessel may be a small diameter catheter including one optical fiber for transmitting high-intensity pulsed light, so that it is not from a large blood vessel such as a femoral artery blood vessel but a thin artery such as a radial artery. It can also be inserted from a blood vessel.

  What is necessary is just to irradiate the high intensity | strength pulse light to the blood vessel site | part which expands the high intensity | strength pulse light irradiation part of the apparatus of this invention, and not to close a blood flow in whole blood. By high-intensity pulsed light irradiation, water vapor bubbles are generated at the end of the irradiated portion in whole blood, the bubbles expand, and the blood vessel wall is expanded and expanded. At this time, as described above, a small amount of physiological saline or the like may be injected into the portion of the blood vessel irradiated with the high-intensity pulsed light as described above.

  Further, the present invention includes high intensity pulsed light irradiation means, high intensity pulsed light generation means and high intensity pulsed light transmission means capable of generating water vapor bubbles in the blood vessel, and generates water vapor bubbles in the blood vessel by high intensity pulsed light irradiation. And a method of controlling a vasodilator by high-intensity pulsed light irradiation that expands a blood vessel wall and expands a blood vessel by the action of the water vapor bubbles. In this method, in order to change the size and shape of water vapor bubbles generated in the blood vessel and the heat applied to the blood vessel wall, the control means of the vasodilator controls the high-intensity pulsed light irradiating means to control the high-intensity pulsed light. Performing a step of changing the intensity and the number of times of irradiation. At this time, the diameter (inner diameter or outer diameter) of the blood vessel to be expanded or the stenosis rate when stenosis is observed are measured in advance, and the high-intensity pulsed light can be appropriately expanded based on the measured value. What is necessary is just to control intensity | strength and the frequency | count of irradiation. In addition, once irradiated with high-intensity pulsed light in the blood vessel, the blood vessel wall is dilated, the degree of dilation is monitored, and if the degree of dilation is insufficient, high intensity can be achieved to achieve further dilation The intensity of the pulsed light and the number of irradiations may be controlled.

  The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.

Example 1 Vasodilation by laser irradiation using porcine carotid artery
A system that allows physiological saline or blood to flow into blood vessels ex vivo was prepared and used. As the blood vessel, an isolated porcine carotid artery was used. The size of the isolated porcine carotid artery used was 3.5 cm in length and 4.7 mm in outer diameter.

  An optical fiber with a core diameter of 600μm is inserted into the isolated porcine carotid artery, and a Ho: YAG laser generator (IH102 (Neek)) is used to pass a Ho: YAG laser (wavelength: 2.1 Oμm) into a blood vessel with physiological saline or blood Irradiated with. The irradiation intensity was 170-1300 J / pulse (1.7-13 W), the number of irradiations was 20-100 times, and the frequency was 2.5 Hz.

  FIG. 3 shows the configuration of the apparatus used.

  Changes in blood vessel outer diameter were photographed with a flash lamp (Nisshin Denshi Kogyo) photography.

  Changes in blood vessel outer diameter before and after laser light irradiation were measured. Further, after irradiation, HE-stained specimens of blood vessels were prepared and prepared by a conventional method, observed with a microscope, and observed with a polarizing microscope.

  When irradiated 20 times at a light intensity of 1.3 J / pulse, it was observed that the blood vessels were dilated. In addition, the dilated blood vessels did not return to the original state even after the end of irradiation, and maintained the dilated state for at least 10 minutes.

  A blood vessel with an outer diameter of 4.7mm was expanded to 1.3mm by irradiation 20 times (1.3 times). The expanded area (length) was about 13 mm with respect to the direction of blood flow. FIG. 4 shows photographs of blood vessels before laser irradiation, during 20th irradiation, and after 20th irradiation. 4A shows a state before irradiation, FIG. 4B shows a state during the 20th irradiation, and FIG. 4C shows a state after irradiation.

  FIG. 5 shows an HE-stained blood vessel image. FIG. 5A shows a stained image of a blood vessel cross section that was not irradiated with laser light, and FIG. 5B shows an HE stained image of a blood vessel cross section irradiated 20 times with a light intensity of 400 mJ / pulse. As shown in the figure, extension and expansion of the blood vessel wall was observed in the blood vessel irradiated with laser.

  FIG. 6 shows an observation image with a polarizing microscope. FIG. 6A is an observation image of a blood vessel cross section that was not irradiated with laser light. FIG. 6B, FIG. 6C, and FIG. 6D show observation images of a cross section of a blood vessel irradiated 20 times with an intensity of 0.17 J / pulse, 20 times with an intensity of 0.41 J / pulse, and 20 times with an intensity of 0.81 J / pulse, respectively. .

  As shown in the figure, when irradiated with light having an intensity of 0.41 J / pulse or more, collagen fibers were stretched and aligned by the influence of heat and pressure on the inner membrane side of the blood vessel wall.

  Furthermore, with respect to blood vessels irradiated with laser light and blood vessels not irradiated, mechanical property values of the blood vessels were measured by a tensile test. In the tensile test, a blood vessel was pulled with an automatic stage (Sigma Kogyo Co., Ltd.), and the stress was measured using a load cell (A & D Co.). FIG. 7 shows an outline of the tensile test method. FIG. 8 shows a stress-strain diagram of a blood vessel by a tensile test.

  After 100 irradiations with an intensity of 0.8 J / pulse, there was no difference from the unirradiated blood vessels in the elastin region. On the other hand, the characteristics changed in the collagen region. This result shows that the characteristics of collagen are changed by laser irradiation and the blood vessel wall tends to become hard. In the figure, the region where the strain is less than 1 is the elastin region where the contribution of elastin is large, and the region where the strain is larger and the inclination of the stress strain line is large is the collagen region where the contribution of collagen is large.

  Further, irradiation was performed 100 times at an intensity of 1300 J / pulse, and the fluctuations in the expansion of the vascular wall were measured before irradiation, immediately after irradiation, 1 minute, 3 minutes and 10 minutes after irradiation. The expansion of the blood vessel wall was calculated from the captured image.

  FIG. 9 shows the result. In FIG. 9, the vertical axis represents the blood vessel outer diameter, and the horizontal axis represents the position in the blood flow direction. 0 on the horizontal axis is the tip position of the optical transmission fiber. As shown in FIG. 9, when the irradiation was performed 100 times with an intensity of 1300 J / pulse, the dilated state of the blood vessel was maintained even after 10 minutes.

Example 2 Examination of laser-induced water vapor bubbles in intra-catheter irradiation
We investigated the dynamics of Ho: YAG laser-induced water vapor bubbles generated in water when the laser was irradiated by the Ho: YAG laser device using the bare irradiation method and the intra-catheter irradiation method, and the influence on the blood vessel wall was investigated.

  As a Ho: YAG laser device, a Ho: YAG laser treatment device (wavelength 2.1 μm) approved for medical use (IH102, Nikke, Tokyo) was prepared. A closed cycle cooling system of primary cooling water cooling and secondary cooling air cooling is integrated. The laser beam was transmitted by a dedicated quartz optical fiber (fiber guide 600, Nikke, Tokyo) with a core diameter of 600 μm and an outer diameter of 1000 μm. The maximum energy at the output end of the optical fiber was 1300 mJ / pulse, which was a higher output than the Ho: YAG laser devices # 1 and # 2. The repetition frequency was set to 2.5 Hz, which is the lowest frequency of this laser device, in order to reduce the influence of heat on the irradiation target. The full width at half maximum of the laser pulse waveform was 170 μs when the pulse energy at the emission end was 400 mJ / pulse. In order to enable timing control of the external device, the laser excitation flash lamp light was measured with a silicon photodiode (S2281, Hamamatsu Photonics, Shizuoka), and the voltage was output to the outside.

  The generated bubbles were photographed by time-resolved flash photography. Time-resolved flash photography is a time-resolved imaging method that can capture repetitive high-speed phenomena [T. G. van Leeuwen et al., Lasers Surg Med, vol. 11, pp. 26-34, 1991]. The bubble size was calculated from the photographed bubble. The bubble was assumed to be symmetric about the optical fiber, and the bubble was divided pixel by pixel in the vertical direction of the optical fiber, and the cylinder was integrated into the volume.

  Bubbles were taken with a high-speed camera. A high-speed camera is a device that performs high-speed shooting of several hundred to several tens of thousands of images per second and visualizes one phenomenon by high-speed time resolution. Images were taken using a high-speed camera (FASTCAM APX RS, Photoron, Tokyo) that can capture 10,000 frames / s with a resolution of 512 x 512 pixels. A high-speed camera was installed on a stereo microscope (SZX7, Olympus, Tokyo) equipped with a 0.75x objective lens. A thermostatic bath (260 mm long, 380 mm wide, 160 mm deep) was filled with pure water at 37 ° C., and an optical fiber was installed approximately 10 mm below the water surface in parallel with the water surface. An objective lens was installed approximately 15 mm above the water surface of the thermostatic bath to photograph the bubbles. Using a metal halide lamp (LS-M350, Sumita Optical Glass, Saitama), continuous illumination was performed from approximately 20 mm above the water surface. The angle between the objective lens and the metal halide lamp was about 60 °. The frame rate of the high-speed camera was set to 10,000 frames / s, and the shutter speed was set to 1 / 30000s. The high-speed camera started shooting using a TTL signal from a delay generator (WF1944A, NF circuit block, Yokohama). The bubble size was determined from the photograph taken.

  An optical fiber having a thickness of 600 μm was used. The repetition frequency was 2.5 Hz. The laser energy at the output end of the optical fiber was 100-1000 mJ / pulse.

As shown in FIG. 10, the present inventors have reported a method of irradiating an optical fiber tip positioned inside the catheter tip [E. Nakatani et al., Proc. Of SPIE, vol. 6084, pp. 60840W-6, 2006]. If this method is used, it is possible to change the bubble shape with the same laser energy. In the experiment of this irradiation method, the above-mentioned Ho: YAG laser device, an optical fiber having a core diameter of 600 μm and an outer diameter of 1000 μm was used. The tip of the optical fiber is positioned 1-5mm from the tip of the catheter (outer diameter: 1.7mm, inner diameter: 1.3mm) of the indwelling needle (Surflow F & F 16G x 2 _1/2 ", Terumo, Tokyo). The repetition frequency was 2.5 Hz, the laser energy at the optical fiber exit end was 200-800 mJ / pulse, and the irradiation method for the single optical fiber was the bare irradiation method, and the optical fiber tip was positioned inside xmm from the catheter tip. The method will be described as intracatheter irradiation (xmm).

  FIGS. 11 to 15 are photographs of the shape of bubbles taken with a high-speed camera when the Ho: YAG laser device and the optical fiber having a core diameter of 600 μm are used and the irradiation method is the bare irradiation method and the intra-catheter irradiation method. Results are shown. FIG. 11 shows a photograph of the shape of the bubble at each time taken with a high-speed camera when the laser energy is 400 mJ / pulse and the bare irradiation method is used. FIG. 12 shows a photograph of the shape of bubbles when the volume is maximum when the laser energy is changed by the bare irradiation method. FIG. 13 shows photographs of the shape of bubbles at each time when the laser energy is 400 mJ / pulse and the intra-catheter irradiation method (3 mm). FIG. 14 shows a photograph of the bubble shape at the time of maximum volume when the laser energy is constant at 400 mJ / pulse, the intra-catheter irradiation method (1, 3, 5 mm), and the distance between the catheter tip and the optical fiber tip is changed. For comparison, FIG. 14 also shows a photograph of the shape of bubbles in the bare irradiation method. FIG. 15 shows a photograph of the shape of bubbles when the volume is maximum when the laser energy is changed by the intra-catheter irradiation method (3 mm). From FIG. 13 and FIG. 14, in the case of the intra-catheter irradiation method, it can be seen that the front edge of the bubble has an umbrella shape around the rear. In the case of such bubbles, the volume of the bubbles cannot be obtained from the outer shape. The maximum bubble diameter in the direction perpendicular to the optical fiber central axis is used as the bubble size. The maximum diameter in the direction perpendicular to the central axis of the optical fiber measured from FIG. 14 is 3.7 mm for the intra-catheter irradiation method (3 mm) and 3.4 mm for the bare irradiation method, and the maximum length in the direction parallel to the optical fiber is They are 2.7mm and 3.7mm respectively. Therefore, the ratio between the optical fiber direction and the length in the vertical direction is 0.7 and 1.1, and the shape of bubbles generated by the intra-catheter irradiation method (3 mm) is a shape spreading in the vertical direction of the optical fiber. When three types of intra-catheter irradiation methods with different optical fiber tip positions were compared, the intra-catheter irradiation method (3 mm) was the most widened in the vertical direction of the optical fiber. When the bubble size is measured from Fig. 15, when the laser energy is changed to 200, 400, and 800 mJ / pulse, the maximum diameter in the direction perpendicular to the optical fiber central axis is 2.9, 3.7, and 4.5 mm, respectively. It became larger with the increase of. In order to compare the dynamics of bubbles due to the difference in the distance between the tip of the catheter and the tip of the optical fiber, it is perpendicular to the central axis of the optical fiber in the case of various irradiation methods, as measured in FIG. The time change from the start of laser oscillation of the maximum bubble diameter in the direction is shown. The pulse waveform of Ho: YAG laser is also shown. From FIG. 16, for example, in the intra-catheter irradiation method (5 mm), the time when bubbles are generated is 100 μs later than the bare irradiation method. Increasing the distance between the tip of the catheter and the tip of the optical fiber delayed the time at which the bubbles reached the outside of the catheter. As shown in FIG. 16, in the bare irradiation method, bubbles start to be generated with laser oscillation, but in the intra-catheter irradiation method (5 mm), bubbles appear outside the catheter when the laser pulse intensity attenuates to 60% of the peak intensity. From FIG. 16, the bubble diameter in the direction perpendicular to the central axis of the optical fiber due to the difference in the irradiation method is the largest in the case of the intra-catheter irradiation method (5 mm). FIG. 17 shows the maximum bubble diameter in the direction perpendicular to the optical fiber central axis with respect to the laser energy in the bare irradiation method and the intra-catheter irradiation method (3 mm) measured from FIGS. When the laser energy is the same, the maximum bubble diameter in the direction perpendicular to the central axis of the optical fiber is 1.1 to 1.2 times greater in the intra-catheter irradiation method (3 mm) than in the bare irradiation method. In both irradiation methods, the maximum bubble diameter increases with increasing irradiation energy.

In the intra-catheter irradiation method, bubbles that are spread in the vertical direction of the optical fiber are generated as compared with the bare irradiation method. It seems that the bubble shape changes as the tip of the optical fiber is retracted into the catheter as compared with the bare irradiation method because of fluid resistance in the catheter. The bubble diameter in the direction perpendicular to the central axis of the optical fiber was the largest when the intra-catheter irradiation method (5 mm) was used. Increasing the distance between the distal end of the catheter and the distal end of the optical fiber delayed the time at which bubbles reached the outside of the catheter. For example, in the intra-catheter irradiation method (5 mm), it was 100 μs later than the bare irradiation method (FIG. 16). The bubble growth rate is 8.2 × 10 ⁻⁵ m ³ / s from the inclination of FIG. 16 in the case of 400 mJ / pulse irradiation by the bare irradiation method. Assuming that the bubble travels forward in the catheter having an inner diameter of 1.3 × 10 ⁻³ m at this growth rate, the speed at which the bubble interface travels in the catheter can be calculated as 62 m / s. Therefore, in the case of the intra-catheter irradiation method (5 mm), the time required for the bubbles to reach the outside of the catheter is determined to be about 80 μs, which almost coincides with the above-mentioned delay of 100 μs. It is considered that the shape of the bubble can be controlled by changing not only the positional relationship between the optical fiber and the catheter tip but also the outer diameter of the optical fiber and the inner diameter of the catheter.

From FIG. 16, the bubble diameter in the direction perpendicular to the central axis of the optical fiber was 1.1 to 1.2 times larger in the intra-catheter irradiation method (3 mm) at the same laser energy than in the bare irradiation method. The average acceleration of bubble growth in the direction perpendicular to the central axis of the optical fiber was calculated from the slope of the bubble growth rate curve obtained from FIG. 16 and found to be 400 mJ / pulse and 9.1 × 10 ⁴ m / s ² for the bare irradiation method. , 400 mJ / pulse, and 1.7 × 10 ⁵ m / s ² in the case of intracatheter irradiation (3 mm). Compared to the intra-catheter irradiation method (3 mm), the bare irradiation method has a larger average acceleration and is considered to have a larger force on the blood vessels.

Direct heating of blood vessel wall by laser light As a report on the effects of direct irradiation of the blood vessel wall with infrared light, when a rat-extracted aortic ring was irradiated with a 800 nm wavelength titanium sapphire laser, heat of 2.5 ° C or higher was generated. And 11% increase in tension due to vasoconstriction [H. Matsuo et al., Lasers in Medical Science, vol. 15, pp. 181-187, 2000]. Therefore, when Ho: YAG laser light is directly applied to the blood vessel wall, it is considered that heat is generated and blood vessel contraction occurs. Since the density of water in the bubbles is 1/1000 or less of that of the liquid, the absorption coefficient is about the same. Compared to the condition where blood vessels are filled with blood or saline, 2.1μm light propagates in the bubbles when bubbles are generated [TG van Leeuwen et al., Lasers Surg Med, vol. 11, pp. 26- 34, 1991] and reaches the blood vessel wall. FIG. 18 shows a schematic diagram of estimation of direct heating of the blood vessel wall by laser light. For example, the estimation is performed using a blood vessel having an inner diameter of 2 mm (FIG. 18 (i)). When the numerical aperture of the optical fiber is 0.2, all the laser light is absorbed by blood when the blood vessel is filled with blood. From the volume of bubbles in water measured in 4.3, assuming that the vessel wall does not expand and estimating the bubbles in the vessel, bubbles are generated from the tip of the optical fiber to 8.0 mm when the laser energy is 800 mJ / pulse (Fig. 18C (ii), (iii)). When the bubble absorption coefficient is 0, the laser light directly reaches the blood vessel wall ahead of 3.5 mm from the tip of the optical fiber (FIG. 18 (iii)). The energy irradiated from 3.5 to 8.0 mm from the tip of the optical fiber can be estimated to be about 260 mJ (FIG. 18 (iv)). Assuming that all of this energy is absorbed by the blood vessel wall up to 0.3 mm, which is the light penetration length of Ho: YAG laser light into water, heat generation can be calculated as 6.4 ° C. (FIG. 18 (v)). This heat generation may cause shrinkage.

  In the intra-catheter irradiation method, it takes time until the bubbles reach the outside of the catheter. For example, in the intra-catheter irradiation method (5 mm), the time when the bubbles are generated is delayed by 100 μs as compared with the bare irradiation method, as shown in FIG. In the bare irradiation method, bubbles start to be generated with laser oscillation, but in the intra-catheter irradiation method (5 mm), bubbles start to be generated outside the catheter after the laser pulse waveform reaches 60% of the peak. Therefore, it is considered that the laser energy that reaches the blood vessel wall directly from the inside of the bubble is smaller in the intra-catheter irradiation method. Estimate heat generation as described above. In the case of the intra-catheter irradiation method (5 mm) and the laser energy of 400 mJ / pulse, the laser energy after bubbles are generated outside the catheter is 213 mJ. Of this energy, the energy that reaches the outside of the catheter is 120 mJ. If the bubble in the blood vessel is estimated from the volume of the bubble in water assuming that the vessel wall does not expand, the bubble is generated up to 4.4 mm from the catheter tip. If the bubble absorption coefficient is 0, the laser beam directly reaches the tip of the catheter or the blood vessel wall in front of 1.75 mm. The energy irradiated from the catheter tip to 1.75-4.4 mm can be estimated to be about 14 mJ. Assuming that all of this energy is absorbed by the blood vessel wall up to 0.3 mm, the length of penetration of the Ho: YAG laser light into water, heat generation can be calculated as 0.67 ° C. Therefore, in the bubbles generated by the intra-catheter irradiation method, the Ho: YAG laser light that reaches the blood vessel wall is about an order of magnitude smaller than the bare irradiation method, and it is considered that the blood vessel heat generation and the accompanying blood vessel contraction are small.

Example 3 Vasodilation effect by Ho: YAG laser-induced water vapor bubbles Dilation of the isolated porcine carotid artery when Ho: YAG laser induced water vapor bubbles are generated (1) Measuring method of blood vessel outer diameter In this example, physiological saline was used as a perfusate.
Twenty-four freshly isolated porcine carotid arteries (Tokyo Shibaura Organ, Tokyo) were used. FIG. 19 shows dimensions of a blood vessel cross section measured by cutting out a part of all blood vessels. The dimensions of the blood vessel cross section were an inner diameter of 0.8-2.5 mm and a wall thickness of 0.6-0.9 mm. The relationship between the inner diameter and outer diameter of the blood vessel used this time was obtained by the method of least squares.
(Inner diameter) = 1.1 × (Outer diameter) −1.9
The unit is mm. Hereinafter, the inner diameter was estimated from the measured blood vessel outer diameter using the above formula. A schematic diagram of the experimental system is shown in FIG. Since blood vessels are released from tension in the blood flow direction and their dimensions change at the time of excision, similar to the experimental method of J. Perree et al. [J. Perree et al., Am J Pathol, vol. 163, pp. 1743-1750, 2003] The blood vessels were fixed in a state where they were extended 150% in the long axis direction. The blood vessel was heated and pressurized perfused with physiological saline so that the blood vessel temperature was 37 ° C., the blood pressure was 45-90 mmHg, and the flow rate was 75-100 ml / min. In this state, the blood vessel outer diameter was 2.6-4.8 mm, and the estimated inner diameter was 0.9-3.7 mm. In the experiment, the Ho: YAG laser device approved for medical use used in Example 2 was used. Laser light was transmitted through an optical fiber having a core diameter of 600 μm and an outer diameter of 1000 μm. The thermostatic bath was filled with pure water at 37 ° C., and a blood vessel was placed approximately 10 mm below the water surface in parallel with the water surface. While sealing with a Y connector, an optical fiber was inserted into the blood vessel and irradiated with Ho: YAG laser light. The irradiation method was the bare irradiation method and intra-catheter irradiation method (1, 3, 5 mm) described in Example 2. The laser energy at the output end of the optical fiber was 200, 400, and 800 mJ / pulse, and irradiation was performed up to 200 times while observing with time. The blood vessel outline was imaged from above the blood vessel using a high-speed camera in the same manner as the bubble imaging in Example 2. The distance between the water surface and the microscope lens was about 15 mm. The distance between the illumination light and the water surface was about 20 mm, and the angle between the illumination light and the microscope lens was about 60 °. The outer diameter of the blood vessel was determined from the obtained photograph of the outer shape of the blood vessel, and the inner diameter was calculated from the above formula.

Results FIGS. 21A and 21B, and FIGS. 22A and 22B show photographs of the blood vessel outline at each time starting from the start of laser oscillation at the time of the first laser irradiation taken by the high-speed camera. FIGS. 21A and B, and FIGS. 22A and B show cases where the bare irradiation method and the intra-catheter irradiation method (3 mm) were used, respectively, and the laser energy was 400 mJ / pulse. FIGS. 23A and 23B and FIGS. 24A and 24B show photographs of blood vessel outlines before, during, and after laser irradiation for each number of times of laser irradiation taken with a high-speed camera. FIGS. 23A and B and FIGS. 24A and B show the cases where the bare irradiation method and the intra-catheter irradiation method (3 mm) were used, respectively, and the laser energy was 400 mJ / pulse. FIG. 25 and FIG. 26 show the blood vessel outer diameter with respect to the distance from the optical fiber or catheter tip of the blood vessel measured from the photographs of FIG. 23 and FIG. 25 and 26, the blood vessel repeats expansion and contraction for each laser irradiation, but the blood vessel outer diameter after a series of laser irradiations is larger than that before irradiation. From Fig. 25, the outer diameter of the blood vessel after irradiation with laser energy of 400mJ / pulse and 200 times with the bare irradiation method increased by 1.5-2.1mm from the initial outer diameter in the range of 3.0mm behind the optical fiber tip to 5.0mm ahead of the optical fiber tip. ing. The position where the outer diameter increased the most was 0.4 mm in front of the tip of the optical fiber. From FIG. 26, the blood vessel outer diameter after irradiation 200 times with laser energy of 400 mJ / pulse by intra-catheter irradiation method (3 mm) is 0.4-0.8 from the initial outer diameter in the range of 1.5 mm behind the catheter tip to 6.0 mm forward of the catheter tip. mm has increased. The position where the outer diameter increased the most was 4.3 mm in front of the catheter tip. FIG. 27 shows the first laser at a position where the outer diameter of the blood vessel increased most compared to the initial outer diameter after 200 times of irradiation with laser energy of 400 mJ / pulse in the case of bare irradiation method and intra-catheter irradiation method (3 mm). The time change of the blood vessel outer diameter during irradiation is shown. In the case of intra-catheter irradiation (3 mm), it is considered that it takes about 50 μs for the bubble to reach the outside of the catheter, so it is assumed that the bubble grows from 50 μs after laser oscillation. Calculate the average speed. The average rate of displacement (expansion) to the outside of the blood vessel wall for the first time of laser irradiation is 3.7 m / s with bare irradiation method, laser energy 400 mJ / pulse, irradiation method with catheter (3 mm), and laser energy 400 mJ / pulse. It was 3.6 m / s, which was similar. Acceleration is obtained from the gradient of the velocity of displacement (dilation) to the outside of the blood vessel wall, the bear irradiation method, 6.0 × 10 ⁴ m / s ² when the laser energy is 400 mJ / pulse, intracatheter irradiation method (3 mm), laser energy At 400 mJ / pulse, it was 3.1 × 10 ⁴ m / s ² , and the bare irradiation method was about twice as large. FIG. 28 to FIG. 30 show the blood vessel outer diameter at each number of times of laser irradiation at the position where the blood vessel outer diameter increased most after the laser irradiation 200 times compared with the initial outer diameter. The blood vessel outer diameter was normalized by the outer diameter before the first laser irradiation (initial outer diameter), and the average value (n = 3) was displayed. This value is called the blood vessel outer diameter expansion rate. FIG. 28 shows the blood vessel outer diameter expansion rate (bear irradiation method, laser energy change) with respect to the number of times of laser irradiation. In the case of 200 mJ / pulse, the blood vessel outer diameter expansion rate after 200 irradiations was 1.1. The estimated vessel inner diameter after 200 irradiations was 1.3 times larger than the initial estimated vessel inner diameter. The blood vessel outer diameter expansion rate is 1.4 in the case of 400 mJ / pulse, 1.2 in the case of 800 mJ / pulse, and 400 mJ / pulse is larger. The blood vessel outer diameter finally reached was about 4.9 mm and 5.0 mm, respectively. FIG. 29 shows the blood vessel outer diameter expansion rate (irradiation method change, laser energy 400 mJ / pulse constant) with respect to the number of times of laser irradiation. In the case of the bare irradiation method, the blood vessel outer diameter expansion rate during the 200th pulse was 1.6, and the blood vessel outer diameter expansion rate was maintained at 1.5 after irradiation. At this time, the estimated blood vessel inner diameter after 200 irradiations was an expansion of 2.2 times the initial estimated blood vessel inner diameter. On the other hand, the intra-catheter irradiation method (5 mm) expanded to 1.6 times the initial outer diameter during the 200th irradiation, but 1.2 times after the irradiation. At this time, the estimated blood vessel inner diameter after 200 irradiations was 1.4 times the initial estimated blood vessel inner diameter. Compared with the intra-catheter irradiation method, the bare irradiation method had a smaller difference between the maximum blood vessel outer diameter during laser irradiation and the blood vessel outer diameter after laser irradiation, and the expansion was maintained. FIG. 30 shows the blood vessel outer diameter expansion rate (intracatheter irradiation method (3 mm), laser energy change) with respect to the number of times of laser beam irradiation. The blood vessel outer diameter expansion rate after 200 laser irradiations was about 1.2-1.3 in all conditions. The estimated blood vessel inner diameter at this time was 1.6 to 1.9 times the initial estimated blood vessel inner diameter. In FIG. 28 to FIG. 30, the blood vessel outer diameter expansion rate increases with the number of irradiations, but is saturated at about 100 irradiations.

(2) Mechanical property change method of blood vessel Young's modulus of a blood vessel irradiation site and a non-irradiation site of the blood vessel was measured. As described above, the blood vessel was placed in the perfusion apparatus, and intravascular laser irradiation was performed. The irradiation method was a bare irradiation method and an intra-catheter irradiation method (3 mm). The laser energy was 800 mJ / pulse, and the number of irradiations was 20 or 100 times. Cut the laser irradiated part and non-irradiated part into a ring of about 3 mm in length, and use an automatic stage (SGSP33-100 (x), Sigma Kogyo, Tokyo) and a controller (SHOT-202, Sigma Kogyo, Tokyo) The sample was pulled at a constant speed of 0.5 mm / s and the load was measured with a load cell (LC-4101, A & D, Tokyo) to obtain a stress strain diagram. In the low-strain region, elastin fibers are shared in the blood vessel wall, and in the high-strain region, collagen fibers are said to share the weight [RL Armentano et al., American Journal of Physiology, vol. 260, pp. H1870-H1877, 1991 RE Shadwick et al., Journal of Experimental Biology, vol. 202, pp. 3305-3313, 1999], the Young's modulus of the low strain region is the Young's modulus of the elastin fiber and the Young's modulus of the high strain region is the Young of the collagen fiber. Think of it as a rate.

Results FIG. 31 shows stress-strain diagrams of the laser irradiation site and the non-irradiation site when the laser energy is 800 mJ / pulse and the laser pulse is irradiated 100 times by the intra-catheter irradiation method (3 mm). From the slope of this stress strain diagram, the Young's modulus (E _e ) of the elastin fiber and the Young's modulus (E _c ) of the collagen fiber were determined. FIG. 32 shows the Young's modulus (E _e ) of the elastin fiber at the laser irradiation site and the non-irradiation site, and FIG. 33 shows the Young's modulus (E _c ) of the collagen fiber at the laser irradiation site and the non-irradiation site. The laser irradiation conditions were as follows: irradiation method: bare irradiation method and intra-catheter irradiation method (3 mm), laser energy: constant 800 mJ / pulse, laser pulse irradiation frequency: 20 times and 100 times. Both E _e and E _c were larger in the laser irradiated part than in the non-irradiated part. For example, in the intra-catheter irradiation method (3 mm), when the laser energy is irradiated 100 times with a laser energy of 800 mJ / pulse, E _e of the laser non-irradiated part is 0.11 MPa, whereas E _{e of the} laser irradiated part is 0.59 MPa. Under the same irradiation conditions, the E _c of the laser non-irradiated site was 0.86 MPa, whereas the E _{c of the} laser irradiated site was 1.82 MPa. Among the laser irradiation conditions in this experiment, the maximum E _e at the laser irradiation site was obtained when the laser energy was irradiated at a laser energy of 800 mJ / pulse and 100 times of laser pulses by the intra-catheter irradiation method (3 mm). In the laser irradiation conditions of this experiment, the E _c of the laser irradiated portion becomes maximum, was when the laser energy 800 mJ / pulse, 100 times the laser pulses at bare irradiation method.

2. Expansion effect of Ho: YAG laser-induced water vapor bubbles in the rabbit aorta: in vivo animal experiments
Since various factors are thought to contribute to the reaction of the blood vessel wall when the Ho: YAG laser is irradiated in the blood vessel, it is necessary to conduct experiments in vivo. In order to investigate the vasodilation effect of Ho: YAG laser irradiation in vivo, we conducted experiments using rabbits.

Method
The experiment was conducted using two Japanese white varieties (male, 2.4 kg). Pentobarbital sodium was administered at 30 mg / kg from the auricular marginal vein of the rabbit, and general anesthesia was applied. Cut down the surgically exposed femoral artery and insert a 4 Fr. sheath (outer diameter: 1.88 mm, inner diameter: 1.58 mm, length: 250 mm) (CS 40P25 TS, Medikit) retrogradely into the aorta did. This sheath was selected so that bubbles having the same size as bubbles generated in the catheter of the indwelling needle in the intra-catheter irradiation method were generated. Here, the inner diameter of the rabbit aorta was measured using an intravascular ultrasound (IVUS) and found to be 2.0-3.5 mm. An optical fiber (core diameter: 600 μm, outer diameter: 1000 μm) was inserted from the check valve port of the sheath. Irradiation was performed with the optical fiber tip positioned 3 mm inside the sheath tip. Hereinafter, this irradiation method is referred to as an intra-sheath irradiation method (3 mm). The laser energy was 100 mJ / pulse or 200 mJ / pulse, and 20 irradiations were performed in the descending aorta. Rabbits were sacrificed immediately after laser irradiation or one week later, and immediately after the aorta was fixed with 10% formalin perfusion and removed. A blood vessel HE-stained specimen was prepared.

Results FIGS. 34A and 34B show rabbit aorta HE-stained specimen images after in vivo laser light irradiation. (A) In-sheath irradiation method (3 mm), laser energy 100 mJ / pulse, immediately after 20 irradiations, (b) (a) control part, (c) In-sheath irradiation method (3 mm), laser energy 100 mJ / pulse 1 week after 20 irradiations, (d) (c) is the control site. In (a), as compared with (b), extension of the elastic plate of the media is seen. In (c) after one week, the elastic membrane of the media is stretched compared to (d), and the stretched state in (a) is maintained. In both (a) and (c), the inner elastic plate is not extended. In both (a) and (c), no vascular dissociation is observed.

3. Discussion (1) Principle of vasodilation by Ho: YAG laser-induced water vapor bubbles
Ho: YAG laser-induced water vapor bubbles expanded the isolated porcine carotid artery with an outer diameter of 1.1-1.5 times the initial outer diameter. The estimated blood vessel inner diameter at this time was 1.3-2.2 times the initial estimated blood vessel inner diameter. In this chapter, we performed healthy blood vessels. However, angioplasty is intended for blood vessels that have become stenotic, and this result cannot be applied directly to pathological blood vessels. A short-time warming angioplasty, Photo-thermo dynamic balloon angioplasty: PTDBA has been reported to have a good dilation effect at a low pressure of about 2 atm while heating at about 70 ° C for 15s [T. Arai et al. al., Proc. of SPIE, vol. 2671, pp. 36-39, 1996; N. Shimazaki et al., Proc. of SPIE, vol. 6424, pp. 642424, 2007, etc.]. With reference to this vasodilation by PTDBA, we discuss vasodilation by Ho: YAG laser-induced water vapor bubbles.

The HE-stained specimen image after Ho: YAG laser irradiation in the rabbit aorta in FIG. 34 shows the extension of the elastic plate of the media. Therefore, the increase in E _e after laser irradiation is thought to be due to the elastin fiber stretching, although there are differences in vivo and ex vivo. That is, the elastin fibers on the blood vessel wall can be stretched and fixed by Ho: YAG laser-induced water vapor bubbles. In FIG. 32, when the bare irradiation method and the intra-catheter irradiation method are compared, the E _e of the blood vessel irradiated 100 times by the bare irradiation method is 3.8 times the E _e of the non-laser irradiated region, whereas the intra-catheter irradiation is performed. The law has changed greatly by 5.4 times. This suggests that the extension of elastin fibers is comparable in intracatheter irradiation. As shown in Example 2, it is considered that the intra-catheter irradiation method has a larger bubble diameter and growth acceleration in the direction perpendicular to the central axis of the optical fiber than the bare irradiation method, and bubbles with large expansion pressure are generated. About 70 ° C. The excised porcine carotid artery in PTDBA, while performing the heating of the 15s, E _e of the vessel subjected to extension of 2atm is reported to 0.16MPa [N. Shimazaki et al., Proc. Of SPIE, vol.6424, pp. 642424, 2007]. The control site E _e is reported to be 0.11 MPa. On the other hand, catheter irradiation at (3 mm), E _e of the laser energy 800 mJ / pulse, 100 irradiations were vessel was 0.59 MPa. At this time, E _{e of the} non-laser irradiated portion was 0.11 MPa. Comparing these results with the report of PTDBA, it is shown that the expansion of elastin fibers is larger in the expansion by Ho: YAG laser-induced water vapor bubbles than in the expansion of PTDBA. On the other hand, in FIG. 33, it is considered that the reason why E _c increases after laser irradiation is due to thermal denaturation of collagen fibers. Laser energy 800 mJ at Bear irradiation / pulse, 100 times E _c of the vessel was irradiated is 2.8 MPa, catheter irradiation method (3 mm) in the laser energy 800 mJ / pulse, 100 irradiations were vessels E _c Was 1.8 MPa. The E _{c of the} non-laser irradiated part was 1.0 MPa and 0.86 MPa, respectively. The higher E _c in blood vessels irradiated with laser light by the bare irradiation method than in the intra-catheter irradiation method seems to indicate that the proportion of heat-denatured collagen fibers is higher. It has been reported that the E _c of the blood vessel expanded by 2 atm while heating the isolated porcine carotid artery with PTDBA at about 70 ° C for 15 s [N. Shimazaki et al., Proc. Of SPIE, vol.6424, pp. 642424, 2007]. At this time, E _c of the control site is reported to be 1.6 MPa. E _c of the vessel in the vessel and PTDBA subjected to laser irradiation were heated with extension catheter irradiation method (3 mm) is comparable, Ho: The extended by YAG laser-induced vapor bubbles, extended elastin fibers It is considered that sufficient heat denaturation of the collagen fibers has occurred to be fixed as it is. As shown in Example 2, the temperature rise due to direct irradiation of the laser beam by the Ho: YAG laser-induced water vapor bubble and the heat transfer from the bubble was 6.4 ° C. and 0.66 ° C., respectively, and about 70 ° C. by PTDBA. Small compared to the warming. Nevertheless, it is considered that the same degree of heat denaturation is applied. The expansion by Ho: YAG laser-induced water vapor bubbles may involve the heat generated by the deformation of the blood vessel wall.

  In summary, the principle of obtaining a vasodilator effect by Ho: YAG laser-induced water vapor bubbles is that the elastin fibers are stretched while the collagen fibers are softened by the heat generated by the generation of bubbles and the pressure of bubble growth, and then further collagen fibers. It was presumed that the elastin fibers were fixed while stretched by heat denaturation of.

(2) Bubbles suitable for vasodilation
In the Ho: YAG laser-induced water vapor bubbles, the diameter in the direction perpendicular to the central axis of the optical fiber is about 4.5 mm at the maximum, and this defines the upper limit of the expandable blood vessel diameter. It is considered that the site where vasodilation by this Ho: YAG laser-induced water vapor bubbles can be applied is the coronary artery or the sub-knee artery. Based on the estimated expansion principle, it is considered that the bubble generation method and laser irradiation conditions suitable for expansion vary depending on the inner diameter of the blood vessel, the wall thickness, and the ratio of elastin fibers / collagen fibers in the media. Specifically, the bubble diameter, growth acceleration, and heat generated by the bubble generation can be controlled by changing the laser energy and the irradiation method (bear irradiation method and intra-catheter irradiation method).

  Intracatheter irradiation can reduce risks such as optical fiber tip contact to the blood vessel wall and direct irradiation of Ho: YAG laser light, which can cause blood vessel perforation in the case of bare irradiation. Regarding the number of times of irradiation, both the bare irradiation method and the intra-catheter irradiation method saturated the blood vessel dilatation rate after about 100 irradiations (see FIGS. 28 to 30). For example, with a bare irradiation method, a laser energy of 400 mJ / pulse, 1.5 for 100 irradiations, and with an intracatheter irradiation method (3 mm), a laser energy of 400 mJ / pulse, with a 100 irradiations, a blood vessel outer diameter expansion rate of 1.3 is obtained. It has been. Therefore, in order to reduce side effects due to excessive heat input, the number of irradiations is expected to be 100 times or less.

(3) In vivo vasodilator effect
In vivo rabbit aorta was irradiated with laser energy 100mJ / pulse or 200mJ / pulse 20 times by intra-sheath irradiation method (3mm), and vascular wall stretched findings were observed. As shown in FIG. 34B, this extension effect was maintained even after one week, so that a longer-term expansion effect would be expected.

  The bubbles generated in the blood vessel will be discussed based on the results obtained in Example 2.

  In the case of a laser energy of 200 mJ / pulse, the diameter in the vertical direction of the optical fiber of bubbles generated in water by the intra-catheter irradiation method (3 mm) was 2.86 mm. Since the volume of bubbles in blood is 1.03-1.25 times that in water, the length is 1.01-1.08 times. From the above, when the laser energy is 200 mJ / pulse, it is estimated that the diameter of bubbles generated in the blood in the vertical direction of the optical fiber was 2.9-3.1 mm. Similarly, when the laser energy is 100 mJ / pulse, the diameter of bubbles generated in the blood in the vertical direction of the optical fiber is estimated to be 1.5 to 1.6 mm. Since the inner diameter of the rabbit aorta was 2.0-3.5 mm, the diameter of the bubble in the vertical direction of the optical fiber is considered to be less than or equal to the inner diameter of the blood vessel. With the Ho: YAG laser-induced water vapor bubble method of the present invention, the structure can be expanded without closing the blood flow without using a complicated and expensive balloon catheter, and treatment can be performed using only a thin optical fiber and a sheath. There is a possibility of developing a simple and inexpensive treatment device that can be used.

  When 200: 800 mJ / pulse Ho: YAG laser light was irradiated inside the blood vessel 200 times using the bare irradiation method and the intra-catheter irradiation method, the ex vivo porcine carotid artery was exposed by the effect of Ho: YAG laser-induced water vapor bubbles. A vasodilatory effect 1.1 to 1.5 times in diameter was obtained. The inner diameter estimated from the relationship between outer diameter and inner diameter was 1.3-2.2 times. Intrasheath irradiation (3 mm) was performed with 100 mJ / pulse and 20 irradiations, and in vivo rabbit aorta showed that the elastic membrane of the media was extended even after 1 week. The principle that the vasodilation effect is obtained by the Ho: YAG laser-induced water vapor bubbles is that the elastin fibers are stretched while the collagen fibers are softened due to the heat generated by the bubbles and the pressure of the bubble growth, and then further heat denaturation of the collagen fibers. It was estimated that the elastin fiber was fixed while stretched. The intra-catheter irradiation method can achieve the same expansion rate as the bare irradiation method, and can be used safely with less influence of light and heat. Expansion by Ho: YAG laser-induced water vapor bubbles can be performed without closing the blood flow without using a complicated and expensive balloon catheter, and can be treated with only a small diameter optical fiber and sheath. There is potential for development of therapeutic devices.

  The present invention can be used safely and reliably for angioplasty.

1 is a schematic view of an apparatus of the present invention. It is a photograph showing the process from generation | occurrence | production to extinction of the water vapor | steam generate | occur | produced by laser beam irradiation. It is a figure which shows the structure of the apparatus used in the Example. It is a photograph which shows the state of the blood vessel before and behind laser beam irradiation. A is a photograph before irradiation with Ho: YAG laser, B is irradiation with Ho: YAG laser at 1.3 J / pulse 20 times, and C is a photograph after irradiation with Ho: YAG laser at 1.3 J / pulse 20 times. 2 is a photograph showing HE-stained blood vessel images before and after laser light irradiation. A shows a HE-stained control blood vessel cross-section, and B shows a HE-stained blood vessel cross-section after chronic irradiation with Ho: YAG laser at 400 mJ / pulse 20 times. It is a photograph which shows the observation image by the polarization microscope before and behind laser beam irradiation. In the photographs A to D, the right side is the vascular intima side, and the left side is the adventitia side. A is a healthy blood vessel, B is a blood vessel irradiated 20 times at 0.17 J / pulse, C is a blood vessel irradiated 20 times at 0.41 J / pulse, and D is a blood vessel irradiated 20 times at 0.81 J / pulse. It is a figure which shows the outline | summary of the method of the tensile test of the blood vessel wall. The stress-strain diagram of the blood vessel by the tension test before and behind laser beam irradiation is shown. It is a figure which shows the fluctuation | variation of the vascular wall expansion before and behind laser beam irradiation. It is a figure which shows the outline | summary of the method of irradiating with the optical fiber front-end | tip located inside a catheter front-end | tip. It is a photograph of the shape of a bubble when irradiated by the bear irradiation method. It is a photograph of the shape of a bubble when laser energy is changed and irradiated by the bare irradiation method. It is a photograph of the shape of a bubble when it irradiates by the catheter injection method. It is the photograph of the shape of a bubble when changing the distance of an optical fiber front-end | tip and a catheter front-end | tip, and irradiating by the catheter injection method. It is a photograph of the shape of bubbles when laser energy is changed and irradiation is performed by an intra-catheter irradiation method. The time variation of the maximum diameter in the direction perpendicular to the optical fiber central axis of bubbles generated when the irradiation method was changed with a laser energy of 400 mJ / pulse using a Ho: YAG laser device and the Ho: YAG laser It is a figure which shows a pulse waveform (a continuous line, a right axis). It is a figure which shows the largest bubble diameter of the direction perpendicular | vertical to the optical fiber central axis with respect to laser energy. It is an estimate schematic diagram of direct heating of a blood vessel wall by laser light. It is a figure which shows the relationship between the outer diameter of a blood vessel, and an internal diameter. It is a schematic diagram of an ex vivo blood vessel outer diameter change observation experiment. It is the photograph which shows the blood vessel external shape in each time during the laser irradiation of the 1st time image | photographed with the high-speed camera in the case of the laser energy of 400 mJ / pulse by the bare irradiation method. An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. FIG. 22B is a photograph showing the outer shape of the blood vessel at each time during the first laser irradiation imaged by a high-speed camera when the laser energy is 400 mJ / pulse in the bare irradiation method (continuation of FIG. 21A). An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. 3 is a photograph showing the blood vessel outline at each time during the first laser irradiation, which was taken with a high-speed camera, in the case of laser energy of 400 mJ / pulse in the intra-catheter irradiation method (3 mm). An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. It is the photograph which shows the blood vessel external shape in each time during the laser irradiation of the 1st time image | photographed with the high-speed camera in the case of the laser energy of 400 mJ / pulse in the intra-catheter irradiation method (3 mm) (continuation of FIG. 22A). An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. It is the photograph which shows the blood vessel external shape before, during and after the laser irradiation image | photographed with the high-speed camera in the case of the laser energy of 400 mJ / pulse by the bare irradiation method. An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. FIG. 23B is a photograph showing the blood vessel outline before, during and after laser irradiation taken with a high-speed camera in the case of laser energy of 400 mJ / pulse in the bare irradiation method (continuation of FIG. 23A). An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. It is the photograph which shows the blood vessel external shape before, during and after the laser irradiation image | photographed with the high-speed camera in the case of the laser energy of 400 mJ / pulse in the intra-catheter irradiation method (3 mm). An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. FIG. 24B is a photograph showing the external shape of a blood vessel before, during and after laser irradiation taken with a high-speed camera when the laser energy is 400 mJ / pulse in the intra-catheter irradiation method (3 mm) (continuation of FIG. 24A). An arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber. It is a figure which shows the blood vessel outer diameter with respect to the position of the flow direction of the blood vessel in the case of the laser energy of 400 mJ / pulse by the bare irradiation method. The position starts from the tip of the optical fiber. It is a figure which shows the blood vessel outer diameter with respect to the position of the flow direction of the blood vessel in the case of the laser energy of 400 mJ / pulse in the intra-catheter irradiation method (3 mm). The position starts from the tip of the optical fiber. It is a figure which shows the time change of the blood vessel outer diameter in the time of the 1st laser irradiation in the position where the blood vessel outer diameter increased most compared with the initial outer diameter after 200 times of laser energy 400mJ / pulse irradiation. It is a figure which shows the blood vessel outer diameter expansion rate (bear irradiation method, laser energy change) with respect to the number of times of laser irradiation. It is a figure which shows the blood vessel outer diameter expansion rate (laser energy constant, irradiation method change) with respect to the frequency | count of laser irradiation. It is a figure which shows the blood vessel outer diameter expansion rate (intracatheter irradiation method (3 mm), laser energy change) with respect to the number of times of laser irradiation. A stress strain diagram of a blood vessel when the laser energy is 800 mJ / pulse and the number of irradiations is 100 times in the intra-catheter irradiation method (3 mm) is shown. It illustrates the laser beam irradiation site and the Young's modulus of elastin fibers in the non-irradiated sites (E _e) (laser energy 800 mJ / pulse constant). It illustrates the laser beam irradiation site and the Young's modulus of the collagen fibers of the non-irradiated sites (E _c) (laser energy 800 mJ / pulse constant). It is a photograph which shows the rabbit aorta HE dyeing | staining sample image after in vivo laser beam irradiation. The upper side of the photograph represents the lumen of the blood vessel, and the lower side represents the outer membrane. It is a photograph which shows the rabbit aorta HE dyeing | staining sample image after in vivo laser beam irradiation. The upper side of the photograph represents the lumen of the blood vessel, and the lower side represents the outer membrane. DESCRIPTION OF SYMBOLS 1 Catheter 2 High-intensity pulsed light irradiation unit 3 X-ray opaque marker 4 High-intensity pulsed light transmission fiber 5 High-intensity pulsed light source

Claims (19)

High-intensity pulsed light irradiation means capable of generating water vapor bubbles in a blood vessel, comprising high-intensity pulsed light generation means, high-intensity pulsed light transmission means, and means for irradiating high-intensity pulsed light into the blood vessel Vascular dilation apparatus using high-intensity pulsed light irradiation that includes irradiation means, forms water vapor bubbles in the blood in the blood vessel by irradiation with high-intensity pulsed light, and expands the blood vessel wall by expanding the blood vessel wall by the pressure during expansion of the water-vapor bubble . Heat is applied by the high-intensity pulsed light reaching directly to the vessel wall through the water vapor in the bubbles as the pressure at the time of expansion of the vapor bubbles in the blood vessel wall is added, expanded soften denatured collagen fibers of the vessel wall, the vessel wall The vasodilator by irradiation with high-intensity pulsed light according to claim 1 , wherein the orientation of the collagen fibers is aligned and the dilated state of the blood vessel is maintained .   The vasodilator by high-intensity pulsed light irradiation according to claim 1 or 2, wherein the pressure applied to the blood vessel wall is 0.1 to 5.0 atm and the temperature is 60 ° C or higher.   The blood vessel dilator according to claim 1 or 2, wherein the high-intensity pulsed light transmission means is an optical transmission fiber.   The device including a catheter having no balloon, the device for vascular dilation by irradiation with high-intensity pulsed light according to any one of claims 1 to 4, further comprising an optical transmission fiber for transmitting high-intensity pulsed light in the catheter. .   The vasodilator by high-intensity pulsed light irradiation according to claim 5, wherein the position of the irradiation part of the high-intensity pulsed light irradiation means is located inside the distal end of the catheter.   The vasodilator by high intensity pulsed light irradiation according to claim 6, wherein the position of the irradiation part of the high intensity pulsed light irradiation means is located within 0.5 to 5 mm from the distal end of the catheter.   The vasodilator by high-intensity pulsed light irradiation according to any one of claims 1 to 7, wherein an X-ray opaque marker is provided in the vicinity of a distal end portion of the optical transmission fiber.   The vasodilator by high-intensity pulsed light irradiation according to any one of claims 1 to 8, which has an X-ray opaque marker near the distal end of the catheter.   The vasodilator device by high-intensity pulsed light irradiation according to any one of claims 1 to 9, which is applied to a stenosis region of a blood vessel to expand the stenosis region of the blood vessel.   The blood vessel dilation device by high-intensity pulsed light irradiation according to any one of claims 1 to 10, wherein the blood vessel dilation can be maintained for at least 10 minutes.   The vasodilator by high-intensity pulsed light irradiation according to claim 11, wherein the vasodilation can be permanently maintained.   The vasodilator by high-intensity pulsed light irradiation according to any one of claims 1 to 12, wherein the wavelength of the high-intensity pulsed light is in the range of 1 to 3 µm.   The vasodilator by high intensity pulsed light irradiation according to any one of claims 1 to 13, wherein the high intensity pulsed light is a pulse laser.   The vasodilator by high intensity pulsed light irradiation according to any one of claims 1 to 14, wherein the pulse width of the high intensity pulsed light irradiation is 50 µs to 1 ms.   The vasodilator by high-intensity pulsed light irradiation according to any one of claims 1 to 15, wherein the blood vessel is expanded by repeating irradiation with high-intensity pulsed light at least 25 times and not more than 100 times.   The vasodilator by high-intensity pulsed light irradiation according to claim 16, wherein the blood vessel is expanded by repeating irradiation with high-intensity pulsed light at least 50 times and not more than 100 times. Including high intensity pulsed light irradiation means capable of generating water vapor bubbles in the blood vessel, high intensity pulsed light generation means and high intensity pulsed light transmission means, forming water vapor bubbles in the blood in the blood vessel by high intensity pulsed light irradiation, A method for controlling a vascular dilation device by high-intensity pulsed light irradiation that expands a blood vessel wall and expands a blood vessel by the pressure at the time of expansion of the water vapor bubble, and the size and shape of the water vapor bubble formed in the blood in the blood vessel In addition, in order to change the heat applied to the blood vessel wall by the high-intensity pulsed light that has directly passed through the water vapor bubble and reached the blood vessel wall, the control means of the vasodilator controls the high-intensity pulsed light irradiation means to control the high-intensity pulsed light. The control method which performs the process of changing the intensity | strength and the frequency | count of irradiation. Including high intensity pulsed light irradiation means capable of generating water vapor bubbles in the blood vessel, high intensity pulsed light generation means and high intensity pulsed light transmission means, forming water vapor bubbles in the blood in the blood vessel by high intensity pulsed light irradiation, A method of controlling a vasodilator by high-intensity pulsed light irradiation that expands a blood vessel wall and expands a blood vessel by the pressure at the time of expansion of the water vapor bubbles, the position of the irradiation part of the high-intensity pulsed light irradiation means and the distal end of the catheter A control method for controlling the shape and pressure of the water vapor bubbles formed by adjusting the distance of the water vapor.

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