WO2008088062A1 - 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

 Description Vasodilator Technical Field

 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 and expanding the blood vessel by using the water vapor bubble. Background art

 For the treatment of myocardial infarction and angina pectoris, an angioplasty is performed by inserting an expanded balloon catheter, which is a catheter with a balloon, into a lesion such as a stenosis of a blood vessel, and expanding and expanding the lesion of the blood vessel. Widely used (see Non-Patent Document 1).

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

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

 In addition, balloon catheters that can be used with large outer diameters are limited to vessels with a certain thickness such as coronary arteries. In addition, when the balloon was expanded, pressure was received from the stenosis part of the blood vessel, and the balloon position was displaced from the lesion part.

 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 using the energy of the sound pressure wave (see Patent Document 2). On the other hand, there was a report that the blood vessel was damaged by the bubble formation by laser light irradiation in the blood vessel (see Non-Patent Document 2). Patent Document 1 Japanese Patent Application Laid-Open No. 09-084879

Patent Document 2 JP 2004-357792 A Non-Patent Document 1 edited by Morton J. Kahn, “Cardiac Catheter Handbook”, 2nd edition, Medical Company 'Science International, April 21, 2004 ρ · 407-451 Non-patent Document 2 Ashley J. WELCH) et al., "OPTICAL-THERMAL RESPONSE OF LASER IRRADIATED TISSUE", (USA), Plenum Press, 1995, p. 732-740 Disclosure of the Invention

 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 further studied diligently 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 formed by the laser. The inventors discovered that the expanded state of the blood vessel wall can be maintained by heating and changing the orientation of the collagen contained in the blood vessel wall, thereby completing 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 dilating device using high-intensity pulsed light irradiation that includes high-intensity pulsed light irradiation means, generates water vapor bubbles in the 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 without a balloon, and a high intensity pulse in the catheter A vasodilator using high-intensity pulsed light irradiation according to any one of [1] to [4], equipped with an optical transmission fiber that transmits light.

 [6] The vasodilator using 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] A vasodilator by irradiation with high-intensity pulsed light according to any one of [1:] to [7], having an X-ray opaque marker near the distal end of the optical transmission fiber.

 [9] The vasodilator with high-intensity pulsed light irradiation according to any one of [1 :! to [8], having an X-ray opaque marker near the distal end of the catheter.

 [10] A vasodilator using high-intensity pulsed light irradiation according to any one of [1] to [9] for applying to a stenotic site of a blood vessel and expanding the stenotic site of a blood vessel.

 [1 1] A vasodilator using high-intensity pulsed light irradiation according to any one of [1] to [1 0] capable of maintaining vasodilation for at least 10 minutes.

 [1 2] The vasodilator with high-intensity pulsed light irradiation according to [1 1], which can maintain vascular dilation permanently.

 [1 3] The vasodilator by high-intensity pulsed light irradiation according to any one of [1] to [1 2], wherein the wavelength of the high-intensity pulsed light is in the range of 1 to 3 μπι.

 [14] The vasodilator according to any one of [1] to [13], wherein the high-intensity pulsed light is a pulsed laser.

 [15] The vasodilator according to any one of [1] to [14], wherein the pulse width of irradiation with high-intensity pulsed light is 50; us to lms.

 [16] The blood vessel dilator using the high-intensity pulsed light irradiation according to any one of [1] to [15], wherein the blood vessel is expanded by repeating high-intensity pulsed light irradiation at least 25 times and 100 times or less.

[17] The vasodilator using high-intensity pulsed light irradiation according to [16], which expands the blood vessel by repeating irradiation with the high-intensity pulsed light at least 50 times and 100 times or less.

[18] A high-intensity pulsed light irradiation means capable of generating water vapor bubbles in a blood vessel, a high-intensity pulsed light generation means and a high-intensity pulsed light transmission means. High-intensity pulse that expands blood vessels by expanding the blood vessel wall by the action of the water vapor bubbles A method of controlling a vasodilator by light irradiation, wherein the control means of the vasodilator is used to change the size and shape of water vapor bubbles generated in the blood vessel and the heat applied to the blood vessel wall. A control method of performing a step of changing the intensity and the number of times of irradiation of high-intensity pulsed light by controlling the irradiation means.

 [19] 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 blood vessels, and generates water vapor bubbles in blood vessels by high intensity pulsed light irradiation. A method of controlling a vasodilator by high-intensity pulsed light irradiation, which expands a blood vessel by expanding the blood vessel wall by the action of the water vapor bubbles, comprising the position of the irradiation part of the high-intensity pulsed light irradiation means and the distal end of the catheter A control method that controls the shape and pressure of the generated water vapor bubbles by adjusting the distance.

 This specification includes the contents described in the specification or drawings of Japanese Patent Application No. 2007-008503, which is the basis of the priority of the present application. Brief Description of Drawings

 FIG. 1 is a schematic diagram of the apparatus of the present invention.

 Figure 2 is a photograph showing the process from the generation to the disappearance of water vapor generated by laser light irradiation.

 FIG. 3 is a diagram showing the configuration of the apparatus used in the example.

 FIG. 4 is a photograph showing the state of blood vessels before and after laser beam irradiation. A is a photo after Ho: YAG laser irradiation, B is Ho: YAG laser irradiation 20 times at 1.3 J / pulse, and C is a photo after 20 times irradiation with Ho: YAG laser at 1.3 J / pulse.

 Figure 5 is a photograph showing HE-stained blood vessel images before and after laser light irradiation. A shows a HE-stained cross-section of a control blood vessel, and B shows a HE-stained blood vessel cross-section after 20 irradiations with a Ho: YAG laser at 400 mJ / pulse.

 Figure 6 is a photograph showing images observed with a polarizing microscope before and after laser light irradiation. A ~! ), 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.

FIG. 7 is a diagram showing an outline of a method for a tensile test of a blood vessel wall. Figure 8 shows the stress-strain diagram of the blood vessel in the tensile test before and after laser light irradiation. FIG. 9 is a diagram showing fluctuations in vascular wall dilation before and after laser beam irradiation.

 FIG. 10 is a diagram showing an outline of a method of irradiating with one optical fiber tip positioned inside the catheter tip.

 Fig. 11 is a photograph of the shape of bubbles when irradiated by the bare irradiation method.

 Figure 12 shows a photograph of the bubble shape when the laser energy is changed and irradiated by the bare irradiation method.

 Fig. 13 is a photograph of the shape of bubbles when irradiated by catheter injection.

 Fig. 14 is a photograph of the shape of the bubble when the distance between the tip of the optical fiber and the tip of the catheter is changed and irradiation is performed by the catheter injection method.

 Fig. 15 is a photograph of the shape of bubbles when the laser energy is changed and irradiated by the intra-catheter irradiation method.

 Figure 16 shows the time variation of the maximum diameter in the direction perpendicular to the central axis of the optical fiber of the bubble generated when the irradiation method was changed at a laser energy of 400 mJ / pulse using a Ho: YAG laser (plot left) (Axis) and Ho: YAG laser pulse waveform (solid line, right axis).

 Figure 17 shows the maximum bubble diameter in the direction perpendicular to the central axis of the optical fiber with respect to the laser energy.

 Figure 18 is an estimated schematic diagram of direct heating of the blood vessel wall by laser light.

 FIG. 19 is a diagram showing the relationship between the outer diameter and inner diameter of a blood vessel.

 FIG. 20 is a schematic diagram of an ex vivo blood vessel outer diameter change observation experiment.

 Fig. 21A is a photograph showing the blood vessel outline at each time during the first laser irradiation, which was taken with a high-speed camera, when the laser energy in the bare irradiation method was 400 mJ / pulse. The arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber.

 Fig. 21B is a photograph showing the blood vessel outline at each time during the first laser irradiation, which was taken with a high-speed camera when the laser energy was 400 mJ / pulse in the bare irradiation method (continuation of Fig. 21 A). ). An arrow starting from the start of laser oscillation indicates the position of one end of the optical fiber.

Figure 22A is a photograph showing the blood vessel outline at each time during the first laser irradiation, which was taken with a high-speed camera when the laser energy was 400 mJ / pulse in the intra-catheter irradiation method (3 mm). An arrow starting from the start of laser oscillation indicates the position of one end of the optical fiber. Fig. 2 2 B is a photograph showing the blood vessel outline at each time during the first laser irradiation taken with a high-speed camera when the laser energy is 400 mJ / pulse in the intra-catheter irradiation method (3 mm) (Fig. 2). Continuation of 2 A). The arrow starting from the start of laser oscillation indicates the position of the tip of the optical fiber.

 Fig. 23 A is a photograph showing the blood vessel outline before, during and after laser irradiation taken with a high-speed camera when the laser energy in the bare irradiation method is 400 mJ / pulse. The 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 when the laser energy in the bare irradiation method is 400 mJ / pulse (continuation of Fig. 23 A). ). An arrow starting from the start of laser oscillation indicates the position of one end of the optical fiber.

 Fig. 24 A is a photograph showing the blood vessel outline 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). An arrow starting from the start of laser oscillation indicates the position of one end of the optical fiber.

 Fig. 24B is a photograph showing the blood vessel outline 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) (Fig. Continuation of 2 4 A). An arrow starting from the start of laser oscillation indicates the position of one end of the optical fiber. FIG. 25 is a diagram showing the blood vessel outer diameter with respect to the position in the blood vessel flow direction when the laser energy is 400 mJ / pulse in the bare irradiation method. The position starts from the tip of the optical fiber.

 FIG. 26 is a diagram showing the blood vessel outer diameter with respect to the position in the blood vessel flow direction when the laser energy is 400 mJ / pulse in the intra-catheter irradiation method (3 nmi). The position starts from one end of the optical fiber.

 Figure 27 shows the time variation of the blood vessel outer diameter during the first laser irradiation at the position where the blood vessel outer diameter increased most compared to the initial outer diameter after 200 times of laser energy 400 mJ / pulse. FIG.

 Fig. 28 is a diagram showing the blood vessel outer diameter expansion rate (bear irradiation method, laser energy change) versus the number of laser irradiations.

 Fig. 29 is a graph showing the blood vessel outer diameter expansion rate (laser energy constant, irradiation method change) with respect to the number of laser irradiations.

Figure 30 shows the rate of blood vessel outer diameter expansion with respect to the number of laser irradiations (intracatheter irradiation method (3 thighs), It is a figure which shows the 1 energy change.

 Figure 31 shows the stress-strain diagram of the blood vessel when the laser energy is 800 mJ / pulse and the number of irradiations is 100 in the intra-catheter irradiation method (3 stomachs 1).

Fig. 32 shows the Young's modulus (E _e ) (laser energy 800 mJ / pulse-constant) of the elastin fibers at the laser beam irradiated and non-irradiated sites.

 Fig. 33 shows the Young's modulus (E.) (laser energy 800 mJ / pulse-constant) of the collagen fibers at the laser beam irradiation site and non-irradiation site.

 Fig. 34 A is a photograph showing a rabbit aorta HE-stained specimen image after in vivo laser light irradiation. The upper part of the photograph represents the lumen of the blood vessel, and the lower part represents the adventitia.

 Fig. 34B is a photograph showing a rabbit aorta HE-stained specimen image after in vivo laser light irradiation. The upper part of the photograph represents the lumen of the blood vessel, and the lower part represents the adventitia.

Explanation of symbols

1 catheter

2 High-intensity pulsed light irradiation unit

3 X-ray opaque marker

4 High intensity pulsed optical fiber

5 High-intensity pulsed light source BEST MODE FOR CARRYING OUT THE INVENTION

 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 in the blood vessel, and further guides the high-intensity pulsed light irradiation unit to the angioplasty site to be expanded in the blood vessel. Other catheters may be included. Figure 1 shows a schematic diagram of the device 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 unit) The portion that transmits high intensity pulse 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. A member for changing the pulsed light irradiation angle such as a prism may be arranged in the high-intensity pulsed light irradiating unit, but usually no special member is required and the distal end of the optical fiber is at the high-intensity pulsed light. It can act as a light irradiation 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. The device of the present invention requires only one optical fiber for transmitting high-intensity pulsed light in the force taper, so that the diameter of the catheter can be reduced. For example, the diameter of the catheter sheath portion is 2 ram or less.

 In the apparatus 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 is possible to insert into a thin blood vessel that cannot be inserted with a conventional balloon catheter, and angioplasty can be performed on the thin blood vessel. In the conventional method, the target of angioplasty was a thick artery such as the external carotid artery, coronary artery, renal artery, sternum artery, superficial femoral artery, and knee joint artery. Not only these arteries but also thinner blood vessels with an inner diameter of about 2.5 mm or less can be treated.

 Furthermore, the apparatus of the present invention may include a marker for monitoring the position of the high-intensity pulsed light irradiation unit. As the marker, an X-ray opaque marker may be used. By observing from the outside under X-ray fluoroscopy, the location of the high-intensity pulsed light irradiation unit can be known, and the irradiation unit can be positioned at the treatment site. As the X-ray opaque marker, a metal that is impermeable 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 force tail, one or more radiopaque markers may be provided at the distal end of the catheter, for example. When the apparatus 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.

 For high-intensity pulsed light, laser and optical parametric oscillators (0P0;

This includes pulsed light generated by an optical parametric oscillator.

As the laser generating means, a normal laser generating device can be used, and the laser type is water absorption. The laser is not limited as long as the coefficient is lO lOOOcnf ^, preferably 10 to 100 cm- ¹ , and a solid-state laser using rare earth ions or a XeCl excimer laser can be used. The oscillation wavelength of the laser is 0.3 to 3 μηι, preferably 1 · 5 to 3 μπι, more preferably 1.5 to 2.5 μπι, and still more preferably a wavelength near the absorption maximum of water (1.9 μιη). The laser is expressed by the element ions that generate the laser and the type of the base material that holds the ions. Ho (holum), Tin (thulium), Er (erbium), Nd belonging to rare earths as elements (Neodymium) and the like, and Ho and Tm are preferable. Examples of base materials include YAG, YSGG, and YV0. For example, Ho: YAG laser, Tm: YAG laser, Ho: YSGG laser, Tra: YSGG laser, Ho: YV0 laser, Tm: YV0 laser and XeCl excimer laser (oscillation wavelength 308 nm) can be used. . Among these, Ho: YAG laser (oscillation wavelength 2.1 μπι), Tm: YAG laser (oscillation wavelength 2.01 m), etc., in which the oscillation wavelength of the laser exists in the vicinity of the maximum absorption wavelength of water (19 · 9μιη) are preferable.

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

An optical parametric oscillator (0P0; Optical Parametric Oscillator) can continuously change the wavelength of the pulsed light, and it is only necessary to select the pulsed light in the wavelength band where the water absorption coefficient is lO lOOOcnT ¹ . For example, a wavelength in the vicinity of 0.3 to 3 ^ ιη, preferably 1.5 to 3 μηι, more preferably 1.5 to 2.5 μπι, more preferably water absorption wavelength maximum (1.9 Aim) may be selected.

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 preferably 1 to 2 J / pulse, more preferably 1.2 to 1.6 J / _P ulse. The pulse width of the high-intensity pulsed light is not limited, but is 10 ns to lras, preferably 300 μS to 400 s. The pulse width is shown in 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 it takes for the vessel wall to remain 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 is the means for irradiating high-intensity pulsed light (high-intensity pulsed light irradiation part) located near the distal end of the force taper. A fiber for transmitting high-intensity pulsed light that is transmitted from the intensity pulsed 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, This refers to a part of 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 a 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 one having a diameter of about 0.05 to 0.3 mm to a visible thickness, or into a catheter. A wide variety of diameters can be used as long as they can be inserted into blood vessels and transmit high-intensity pulsed light energy.

 High-intensity pulsed light irradiation means is used to irradiate blood vessels with high-intensity pulsed light, and is generated by an external high-intensity pulsed light generator (high-intensity pulsed light source). 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. In addition, as described above, a plurality of high-intensity pulsed light transmission fibers may be dispersed. The fiber diameter is preferably 100 μπ! ~ 1000 / z m.

The range (length) of the vascular wall to be expanded can be varied by controlling the shape of the water vapor bubbles generated by irradiating high-intensity pulsed light. The shape of the water vapor bubbles is larger in the horizontal direction than in the case where the size of the direction in which the blood vessel advances is vertical and the direction perpendicular to the direction in which the blood vessel advances is horizontal. Pressure can be generated, and the blood vessel wall can be expanded reliably. 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 whose length in the transverse direction with respect to the direction of irradiation with high-intensity pulsed light is more than 1/2 of the length in the longitudinal direction, and is the same as the length in the longitudinal direction? Or large water vapor bubbles are preferred. Furthermore, 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 that are twice the size of Smaller steam bubbles are preferred.

 Specifically, the generated steam 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. I hope that. Further, the lateral length varies depending on the thickness of the blood vessel to be treated, but preferably 10% to 200%, preferably 10% to 150%, more preferably 10% to 100% of the inner diameter of the blood vessel. It is. For example, in the case of the coronary aorta, the inner diameter of the blood vessel is about 3 mm, so 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. 1-3 wake up.

 As described above, in order to generate a water vapor bubble that can generate an appropriate expansion pressure, 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 position of the distal end of the catheter is determined. Adjust it. When the position of the irradiation part of the high-intensity pulsed light irradiation means is out of the distal end of the catheter, the size and shape of the water vapor bubbles are the same as when using bare fibers. Irradiation with high-intensity pulsed light when the high-intensity pulsed light irradiation means is located within several thighs from the distal end of the catheter is called intra-catheter irradiation. On the other hand, irradiation in the state of bare fiber 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 advances toward the outside while being escaped. 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 inside the distal end of the catheter. By adjusting the shape of the water vapor bubbles, the pressure generated in the lateral direction can be adjusted.

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, resulting in higher expansion. Pressure can be applied to the vessel wall. The high-intensity pulsed light irradiating part at the tip of the optical fiber is located within 0.5 to 5 mra, preferably 1 to 3 mm, more preferably l to 2 mm inside the catheter with respect to the catheter tip. It is desirable. 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 a high-intensity pulsed light irradiation part is present inside the catheter, water vapor bubbles are generated inside the catheter and are expanded while being categorized. At this time, the water vapor bubbles are expanded in the catheter advancing direction by suppressing the speed at which the water vapor bubbles etaspan in the catheter traveling direction. The front edge of the bubble wraps around backwards, and as a result, it is possible to generate steam bubbles that are expanded more in the umbrella-like lateral direction. For this purpose, for example, a convex portion that can suppress the expansion of water vapor bubbles in the longitudinal direction, a groove, or a continuous irregular portion may be provided inside the distal end of the catheter. Further, the structure may be changed so that the inner diameter of the distal end portion of the catheter becomes wider at the distal end portion.

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

 Also, even when high-intensity pulsed light of the same intensity is irradiated, the magnitude of the expansion pressure generated varies depending on the position of the high-intensity pulsed light irradiation part of the optical transmission fiber and the catheter tip. For example, as the position of the high-intensity pulsed light irradiation part of the fiber for optical transmission and the distal end of the catheter are separated, that is, as the high-intensity pulsed light irradiation part is retracted into the catheter, the high-intensity pulsed light of the same energy is irradiated. However, the expansion pressure generated is high. Force The position of the light irradiation part can be adjusted as appropriate depending on the thickness of the tape or optical transmission fiber, and an appropriate expansion pressure can be generated.

 Moreover, 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, in the present invention, the intensity of the high-intensity pulsed light to be irradiated is changed, the positions of the irradiation part of the high-intensity pulsed light and the catheter tip are changed, or the internal structure of the catheter distal end is changed. It is a device that can adjust the size and / or shape of the water vapor bubble to adjust the generation of expansion pressure to expand the blood vessel wall.

When high-intensity pulsed light is directly applied to blood, the erythrocyte destruction of that part occurs, so it is desirable to replace that part of blood with physiological saline or the like. As such liquid, in addition to physiological saline, infusion solutions such as dialysate are used. In this case, a liquid feeding means is incorporated into 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. It may be injected near the irradiated part of the irradiated part. The liquid feeding means is provided at the distal end of the liquid feeding channel provided in the catheter and the liquid feeding channel. It consists of a fixed inlet, a liquid reservoir connected to the flow path, and a pump for liquid delivery. 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 is irradiated into the blood vessel, and the local blood part where water vapor bubbles start to be generated is replaced with physiological saline. The part to be irradiated and the inlet of the liquid feeding means must be located close to each other. For example, a lumen may be provided in the catheter, and a high-intensity pulsed 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 it is sufficient to use about 1/10 to 1/1000 of the amount of fluid delivered when using an endoscope that injects flash fluid and observes the lumen of blood vessels. . For example, in the method of injecting a flush solution when observing the lumen of a blood vessel with an endoscope, it is necessary to inject a flush solution of 1 to S raLZ seconds, but the amount to be injected in the present invention is about 1 mL / min. Is enough. With this level of liquid delivery, oxygen supply to the periphery can be ensured without obstructing blood flow.

By irradiating the blood vessel with high-intensity pulsed light, the energy density is increased in front of the irradiation portion of the high-intensity pulsed light, and water vapor bubbles are generated in the region, and the bubbles expand in the blood vessel. Push away blood or saline present around the foam. The 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 apparatus 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 is changed, and the vessel wall is continuously expanded. In addition, when the degree of collagen denaturation is strong, the vessel wall dilates permanently. However, it is desirable to avoid excessive heat denaturation because collagen is prone to loosen when the collagen is strongly denatured and the strength of the blood vessel wall may be reduced. In addition, elastin is also involved in vasodilation, and 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 elastin fibers are stretched by further heat denaturation of the collagen fibers. It is fixed as it is. The denaturation of collagen and elastin can measure Young's modulus. Therefore, it is possible to determine appropriate irradiation conditions by measuring the Young's modulus of collagen and elastin by laser irradiation in a model experimental system. The heating temperature of the blood vessel wall with the high-intensity pulsed light is 60 ° C or higher, preferably 80 ° C or higher. High intensity of irradiation The degree of collagen denaturation can be adjusted by the intensity of the pulsed light and the number of irradiations. When the degree of collagen denaturation is low, the dilated vessel wall returns to its original shape over time. In this case, while the vascular wall is expanded and the vascular wall is maintained in the expanded state, a stent may be inserted and placed in the expanded portion to maintain the expanded state. When 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. As the stent, it is preferable to use a self-expandable type (self-expanding type).

 Figure 2 shows the process from the generation to the 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 pectoris or myocardial infarction, and may be applied to a patient having a stenosis rate of 50% or more, preferably 90% or more.

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

It is desirable that the irradiation with high-intensity pulsed light be 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 stops completely, the blood is a non-Newtonian fluid, so the viscosity increases and water vapor bubbles are hardly generated. Therefore, there is an optimal timing when the pulsatile blood flow rate has fallen (before 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, an electrocardiograph and a laser generator are connected electronically, and an electrocardiogram signal is generated through a delay generator so that high-intensity pulsed light is emitted when the pulsatile blood flow decreases. It can be transmitted to the device. The amount of time delay can be determined as appropriate by the combination of an electrocardiograph, a delay generator, and a high-intensity pulsed light generator. A person skilled in the art can also easily determine the timing of 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 relationship between the known cardiac cycle, aortic blood flow velocity and electrocardiogram. . For example, in the case of coronary arteries, little blood flows during systole when the aortic blood flow rate is large, and blood flows during 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 in 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. It 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 invention

 When using the apparatus of the present invention, the high-intensity pulsed light irradiation unit is guided to a blood vessel site to be expanded. The blood vessels to which the device of the present invention is applied are not limited, and can be applied to coronary arteries and 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 radial artery. It can also be inserted from a thin blood vessel. The high-intensity pulsed light irradiation unit of the device of the present invention may be guided to a blood vessel site to be expanded and irradiated with high-intensity pulsed light without closing the blood flow in whole blood. By high-intensity pulsed light irradiation, water vapor bubbles are generated at the end of the irradiated part in the whole blood, and the bubbles expand, expanding and expanding the blood vessel wall. 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 necessary.

Furthermore, the present invention includes a high-intensity pulsed light irradiating means capable of generating water vapor bubbles in a blood vessel, a high-intensity pulsed light generating means, and a high-intensity pulsed light transmitting means. And 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 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. And a step of changing the intensity and the number of irradiations. At this time, the diameter (inner diameter or outer diameter) of the blood vessel to be expanded and the stenosis rate when stenosis is observed are measured in advance, and a high-intensity pulse is used so that the blood vessel can be appropriately expanded based on the measured value. The intensity of light and the number of irradiations should be controlled. Also, once the high-intensity pulsed light is irradiated inside the blood vessel, the blood vessel wall is expanded and how much is expanded. It is possible to monitor the tension and to control the intensity of the high-intensity pulsed light and the number of irradiations so that the necessary expansion can be achieved if the degree of expansion is insufficient.

 The present invention will be specifically described with reference to 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 used for the study. As the blood vessel, the extracted peta carotid artery was used. The size of the isolated porcine carotid artery was 3.5 cm in length and 0.7 mm in outer diameter.

 An optical fiber with a core diameter of 600 / m was inserted into the isolated porcine carotid artery, and Ho: YAG laser (wavelength 2.10 m) was applied with saline or saline using a Ho: YAG laser generator (IH102 (Neek)). Irradiated in blood vessels. 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.

 Figure 3 shows the configuration of the equipment used.

 Changes in the outer diameter of the blood vessel were photographed using a flash lamp (Nisshin Electronics Co., Ltd.) photography.

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

 1. When irradiated 20 times at a light intensity of 3 J / pulse, dilation of blood vessels was observed. In addition, the dilated blood vessels did not return to their original state after the irradiation, and remained in the dilated state for at least 10 minutes.

 A blood vessel with an outer diameter of 4.7 mm was expanded to an outer diameter of 6. lmm by irradiation 20 times (1.3 times). The expanded area (length) was about 13 thighs with respect to the direction of blood flow. Figure 4 shows photographs of blood vessels before laser irradiation, during 20th irradiation, and after 20th irradiation. Fig. 4A shows the state before irradiation, Fig. 4B shows the state during the 20th irradiation, and Fig. 4C shows the state after irradiation. Figure 5 shows HE-stained blood vessel images. Fig. 5A shows a stained image of a blood vessel cross section that was not irradiated with laser light, and Fig. 5B shows a 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.

Figure 6 shows an image observed with a polarizing microscope. Figure 6 A blood not irradiated with laser light It is an observation image of a pipe cross section. Fig. 6B, Fig. 6C and Fig. 6D show the blood irradiated 20 times at an intensity of 0.17 J / pulse, 20 times at an intensity of 0.41 J / pulse, and 20 times at an intensity of 0 · 81 J / pulse, respectively. An observation image of the cross section of the tube is shown.

As shown, when irradiated with light of 0. 41J / pul _se more strength, due to the influence of heat and pressure in the intima side of the vessel wall, the collagen fibers are extended, and is equipped with orientation of the fibers.

 In addition, the mechanical properties of blood vessels were measured by tensile tests on blood vessels irradiated with laser light and blood vessels not irradiated. 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.). Figure 7 shows an overview of the tensile test method. Figure 8 shows the stress-strain diagram of the blood vessel by the tensile test.

After 100 irradiations with an intensity of 0. 8 J / pulse, no difference was observed in the elastin region from the unirradiated blood vessels. 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 slope of the stress-strain line is large is the collagen region where the contribution of collagen is large. Furthermore, irradiated 100 times the strength of 1300J / pul _S e, before the irradiation, immediately after the irradiation, one minute after irradiation was measured variation of the extension of the 3 min and 10 min of the vessel wall. The vessel wall dilation was calculated from the captured images.

 Figure 9 shows the results. In FIG. 9, the vertical axis represents the outer diameter of the blood vessel, 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 100 times of irradiation was performed at an intensity of 1300 J / pulse, the dilated state of the blood vessels was maintained even after 10 minutes. Example 2 Examination of laser-induced water vapor bubbles in intracatheter 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 investigated the effect on the blood vessel wall.

Ho: YAG laser treatment device approved for medical use as YAG laser device (Wavelength 2. Ι μ πι) (IH102, Niek, Tokyo) was prepared. Closed cycle cooling system of primary cooling water cooling and secondary cooling air cooling is integrated. Laser beam core diameter 600 _mu Paiiota, quartz optical fiber one dedicated outer diameter looo wm (fiber guide 600, Martinique, Tokyo) was transmitted. The maximum energy at the output end of the optical fiber was 1300 mJ / pulse, which was higher than the Ho: YAG laser devices # 1 and # 2 above. Repetition frequency, in order to reduce the influence of heat definitive the irradiation target, and a ^{2. 5} Hz is the lowest frequency of the laser device. Full width at half maximum of the laser pulse waveform, the pulse energy at the output end thereof at 400 mJ / pulse, was 170 mu _3. In order to enable timing control of external devices, laser pump flashlight was measured with a silicon photodiode (S2281, Hamamatsu Photonicus, 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 symmetrical about the optical fiber, and the bubble was divided by one 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 a phenomenon with high-speed time resolution. A high-speed camera (FASTCAM capable of shooting 10,000 frames / s at a resolution of 512 x 512 pixels)

APX RS, Phototron, Tokyo). 0. A high-speed camera was installed on a stereomicroscope (SZX7, Olympus, Tokyo) with a 75x objective lens. A thermostatic chamber (260 mm long, 380 mm wide, 160 mm deep) was filled with pure water at 37 ° C, and an optical fiber was installed parallel to the water surface approximately 10 mm below the water surface. An objective lens was installed approximately 15mm above the water surface of the thermostatic bath to photograph the bubbles. Using metal halide lamps (LS-M350, Sumita Optical Glass, Saitama), continuous illumination was performed from approximately 20mm 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 and the shutter speed was set to l / 30000s. The high-speed camera started shooting with a TTL signal from a delay generator (WF1944A, NF circuit block, Yokohama). The bubble size was determined from the photograph taken. An optical fiber of 600 / m was used. The repetition frequency was 2.5 Hz. The laser energy at the output end of the optical fiber was 100-lOOOOmJ / pulse.

As shown in FIG. 10, the present inventors have reported a method of irradiating with one 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 μηι and an outer diameter of 1000 / _tm was used. Place the tip of the optical fiber l-5mm inside from the tip of the catheter (outer diameter: 1.7mm, inner diameter: 1.3mm) of the indwelling needle (Surfflow F & F 16G X 2 _1/2 ", Terumo, Tokyo) The repetition frequency was set to 2.5 Hz, the laser energy at the optical fiber exit end was set to 200 -800 mJ / pulse. The irradiation method in which the tip of the optical fiber is positioned inside xmm from the tip is described as intra-catheter irradiation (xmm).

 Figures 11 to 15 show images taken with a high-speed camera when the Ho: YAG laser device and the optical fiber with a core diameter of 600 / zm are used and the irradiation method is the bare irradiation method and the intra-catheter irradiation method. The result of the photograph of the shape of the bubble was shown. Figure 1 1 shows the laser energy

A bubble shape photograph at each time taken with a high-speed camera at the time of 400 mJ / pulse and bare irradiation is shown. Figure 12 shows a photograph of the bubble shape at the maximum volume when the laser energy is changed by the bare irradiation method. Figure 13 shows a photograph of the shape of the bubble at each time when the laser energy is 400 mJ / pulse and the force is applied within the taper (3 mm). Figure 14 shows the shape of the bubble at the 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 fiber tip is changed. Show photos. For comparison, Fig. 14 also shows a photograph of the shape of bubbles in the bare irradiation method. Figure 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 ram). From Fig. 1 3 and Fig. 1 4 it can be seen that in the case of the intra-catheter irradiation method, the front edge of the bubble has an umbrella shape that wraps around backwards. 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 center axis of the optical fiber is used as the bubble size. Figure 14 From Figure 4, the maximum diameter of the air bubble measured in the direction perpendicular to the central axis of the optical fiber The maximum length in the direction parallel to the optical fiber is 2.7 mm and 3.7 mm, respectively, 3.7 mm for the irradiation method (3 mm) and 3.4 mm for the bare irradiation method. Therefore, the ratio of the length of one direction of the optical fiber to the length in the vertical direction is 0.7 and 1.1, and the shape of the bubble 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. Figure 15 shows the bubble size. When the laser energy is changed to 200, 400, and 800 mJ / pulse, the maximum diameter of the bubble in the direction perpendicular to the central axis of the optical fiber is 2.9 and 3. 7 and 4.5 mm, which increased with increasing laser energy. To compare the dynamics of bubbles due to differences in the distance between the catheter tip and the optical fiber tip, Figure 1 6 and Figure 1 1 and Figure

13 Optical fiber measured with various irradiation methods, such as 1 and 3, showing the time change from the start of laser oscillation of the maximum bubble diameter in the direction perpendicular to the central axis.

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 Ais later than the bare irradiation method. When the distance between the tip of the catheter and the tip of the optical fiber was increased, the time for the bubbles to reach the outside of the catheter was delayed. From Fig. 16, the bare irradiation method starts to generate bubbles with the laser oscillation, but in the intra-catheter irradiation method (5 mm), bubbles are generated outside the catheter when the laser pulse intensity has decreased to 60% of the peak intensity. Appear. Figure 16 shows that the bubble diameter in the direction perpendicular to the central axis of the optical fiber is the largest in the catheter irradiation method (5 mm), depending on the irradiation method. Figure 17 shows the maximum bubble diameter in the direction perpendicular to the central axis of the optical fiber with respect to the laser energy for the bare irradiation method and the intra-catheter irradiation method (three thighs) measured from Figure 12 and Figure 15 Indicates. At the same laser energy, the maximum bubble diameter in the direction perpendicular to the central axis of the optical fiber is 1.1-1.2 times greater in the force-tail 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, compared to the bare irradiation method, bubbles are formed that spread in the vertical direction of the optical fiber. It seems that the bubble shape changes as compared with the bare irradiation method as the tip of the optical fiber is retracted into the catheter because of fluid resistance in the catheter. Bubble diameter in the direction perpendicular to the central axis of the optical fiber The method (5mm) was the largest. Increasing the distance between the tip of the catheter and the tip of the optical fiber delayed the time for the bubbles to reach the outside of the catheter. For example, in the force-tail irradiation method (5 mm), it was 100 μs later than the bare irradiation method (Fig. 1 6). If growth speed of the bubble at Bear irradiation irradiation 400 mJ / pulse, which is 8. 2 X 10- ³ than the slope of Figure 1 6. When bubbles this growth rate is assumed to proceed to the catheter forward inner diameter 1. ³ X 10- 3 m ', the rate at which bubbles interface traveling within the catheter can be calculated and 62m / 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 calculated to be about 80 s, which almost coincides with the 100 s delay described above. In addition to the positional relationship between the optical fiber and the tip of the catheter, it is considered possible to control the shape of the bubble by changing the outer diameter of the optical fiber and the inner diameter of the catheter.

From Fig. 16, it was found that the bubble diameter in the direction perpendicular to the central axis of the optical fiber was 1.1-1. The average acceleration of bubble growth in the direction perpendicular to the center axis of the optical fiber was calculated from the slope of the bubble growth rate curve obtained from Fig. 16. The result was 400 mJ / pulse and 9.1 X lOVs ² for the bare irradiation method. Yes, 400 mJ / pulse, and 1.7 × 10 / s ² for intra-catheter irradiation (3 mm). Compared to the intracatheter irradiation method (3 mra), the bare irradiation method has a larger average acceleration and is considered to have a greater force on the blood vessels. Direct heating of blood vessel wall by laser light

 A report on the effect of direct irradiation of infrared light on the blood vessel wall is as follows. When a rat aortic ring with a 800 nm wavelength titanium sapphire laser was irradiated, heat of 2.5 ° C or more was generated, and the blood vessels contracted. Some have found an 11% increase in tension.

Matsuo et al., Lasers in Medical Science, vol. 15, pp. 181-187, 2000]. Therefore, it is considered that when Ho: YAG laser light is directly applied to the blood vessel wall, heat is generated and blood vessel contraction occurs. Since the density of water in the bubbles is less than 1/1000 that of the liquid, the absorption coefficient is about the same. Compared to the condition in which blood vessels are filled with blood or saline, when bubbles are generated, 2. l / m light propagates in the bubbles [T. G. van Leeuwen et al., Lasers

Surg Med, vol. 11, pp. 26-34, 1991], reaches the blood vessel wall. Figure 1 in 8 The schematic diagram of the estimate of the direct heating of the blood vessel wall by a laser beam is shown. For example, an estimate is made for a blood vessel with an inner diameter of 2 mm (Fig. 18 (i)). If the numerical aperture of the optical fiber is 0.2, all laser light is absorbed by the blood when the blood vessel is filled with blood. From the volume of bubbles in water measured in 4.3, assuming that the blood vessel wall does not expand and estimating the bubbles in the blood vessel, when the laser energy is ⁸ OOmJ / pulse, 8.0 awake from the tip of the optical fiber. Bubbles are generated up to (Fig. 18 C (ii), (i ii)). If the bubble absorption coefficient is 0, the laser beam directly reaches the blood vessel wall ahead of 3.5 mm from the tip of the optical fiber (Fig. 18 (ii i)). The energy irradiated from 3.5 to 8.0 mm from the end 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 the 3rd thigh, which is the length of penetration of water into the water by the Ho: YAG laser light, the fever can be calculated as 6, 4 ° C (Fig. 18). (v)). This exotherm can cause shrinkage.

 In the intra-catheter irradiation method, it takes time for the bubbles to reach the outside of the catheter. For example, in the intra-catheter irradiation method (5 mm), the time at which the bubbles are generated is 100 Z s later than in the bare irradiation method, as shown in FIG. In the bare irradiation method, bubbles begin 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 thought that the laser energy that reaches the blood vessel wall directly from inside the bubble is smaller in the intra-catheter irradiation method. Estimate fever as described above. Intracatheter irradiation (5mm), laser energy

In the case of 400 mJ / pulse, the laser energy after bubble generation outside the catheter is 213 mJ. Of this energy, the energy that reaches outside the catheter is 120 mJ. From the volume of bubbles in the water, assuming that the vessel wall does not expand and estimating the bubbles in the vessel, bubbles are generated up to 4.4 mm from the catheter tip. If the bubble absorption coefficient is 0, the laser beam can directly reach the tip of the catheter or the blood vessel wall ahead of 1.75 mm. The energy irradiated from the catheter tip to 1.75-4. 4mm can be estimated to be about 14mJ. Assuming that all of this energy is absorbed by the vessel wall up to 0.3 mm, which is the length of light penetration of Ho: YAG laser light into water, the fever can be calculated as 0.67 ° C. Therefore, in the bubbles generated by the intra-catheter irradiation method, the Ho: YAG laser light that directly reaches the blood vessel wall is about an order of magnitude smaller than that of the bare irradiation method. Example 3 It is thought that vasoconstriction is small.

1. Dilation of the isolated porcine carotid artery when Ho: YAG laser-induced water vapor bubbles are generated

(1) Measurement of blood vessel outer diameter

Method In this example, physiological saline was used as a perfusate.

 Twenty-four freshly isolated porcine carotid arteries (Tokyo Shibaura Organ, Tokyo) were used. Figure 19 shows the dimensions of the blood vessel cross section measured by cutting out some of all blood vessels. The dimensions of the cross section of the blood vessel were ID: 0.8-2. 5mm, wall thickness: 0.6-0.9mm. When the relationship between the inner and outer diameters of the blood vessel used in this study was determined by the least square method, the correlation coefficient was 0.93 and the following relationship was found.

(Inner diameter) = 1. I X (outer diameter)-1. 9

The unit is mm. Hereinafter, the inner diameter was estimated from the measured outer diameter of the blood vessel using the above formula. A schematic diagram of the experimental system is shown in FIG. When blood vessels are extracted, the tension in the direction of blood flow is released and their dimensions change, so the experiment method of J. Perree et al. [J. Perree et al., Am J Pathol, vol. 163, pp. 1743-1750, 2003] Similarly, the blood vessels were fixed in a state where they were extended 150% in the long axis direction. The blood vessel was warmed and pressurized perfused with physiological saline so that the blood vessel temperature was 37 ° C, the intravascular pressure was 45-90 mmHg, and the flow rate was 75-100 ml / min. In this state, the outer diameter of the blood vessel was 2.6 to 4. 8 and the estimated inner diameter was 0.9 to 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 with a core diameter of 600 / ηι and an outer diameter of 1000 / im. The thermostatic bath was filled with pure water at 37 ° C, and the blood vessel was placed parallel to the water surface at approximately 10 mm below 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 the 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 over 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 obtained from the obtained photograph of the outer shape of the blood vessel, and the inner diameter was calculated from the above formula. result

 Figures 21A and 22A and B show photographs of the blood vessel outline at each time starting from the start of laser oscillation during the first laser irradiation taken with a high-speed camera. Fig. 21 A and B, Fig. 22 A and B are 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. 23 A and Fig. 24 A and B show photographs of the blood vessel outline before, during and after laser irradiation for each number of laser irradiations taken with a high-speed camera. Figures 2 A and 8 and Figure 2 4 A and B show the cases where the bare irradiation method and the intracatheter irradiation method (3 mm) were used, respectively, and the laser energy was 400 mJ / pulse. Figure 2 5, Figure 2 6 to Figure 2 3, Figure 2

The outer diameter of the blood vessel with respect to the distance from the optical fiber of the blood vessel or the tip of the catheter measured from the photograph in 4 is shown. As shown in Figs. 25 and 26, the blood vessel repeatedly expands and contracts with each laser irradiation, but the outer diameter of the blood vessel after a series of laser irradiations is greater than before the irradiation. From Fig. 25, the outer diameter of the blood vessel after irradiation 200 times with the laser energy of 400 mJ / pulse by bare irradiation method is the initial outer diameter in the range of 3.0 mm from the rear of the optical fiber tip to 5.0 mm from the front of the optical fiber. From 1. 5-2. 1 dragon has increased. 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 outer diameter of the blood vessel after irradiation 200 times with laser energy of 400 niJ / pulse by intra-catheter irradiation method (3 mm) is the initial outer diameter in the range of 1.5 mm from the front of the catheter to 6.0 at the front of the catheter. It is increased by 0.4-0.8mm. The position where the outer diameter increased most was 4.3 mm in front of the tip of the force taper. Figure 27 shows the laser energy for the bare irradiation method and the intra-catheter irradiation method (3 mm).

In the position where the blood vessel outer diameter increased most compared to the initial outer diameter after 200 m irradiation at 400 mJ / pulse, the time variation of the blood vessel outer diameter during the first laser irradiation is shown. For catheter irradiation method (3 mm), it is considered that such a degree 50 mu ₃ for bubbles reaching the outside catheter, displacement of assuming bubbles than 50 S after the laser oscillation grows, to the outside of the blood vessel wall Calculate the average speed of (extension). Laser irradiation The average rate of displacement (dilation) to the outside of the first blood vessel wall is 3.7 m / s when using the bare irradiation method and the laser energy is 400 mJ / pulse, irradiation method within the catheter (3 mm), and the laser energy is 400 mJ / pulse. In this case, it was 3.6 m / s, which was similar. Acceleration is obtained from the slope of the rate of displacement (dilation) to the outside of the vessel wall With bare irradiation method, laser energy 400 mJ / pulse, 6.0 X 10 ⁴ m / s ² , in-force irradiation method (3 mm), laser energy 400 mJ / pulse, 3. l X 10 ⁴ m / s ² and the bare irradiation method is about twice as large. Figures 28 to 30 show the blood vessel outer diameter at each laser irradiation number at the position where the blood vessel outer diameter increased the most after 200 laser irradiations compared to the initial outer diameter. The blood vessel outer diameter was normalized by the outer diameter (initial outer diameter) before the first laser irradiation, and the average value (n = 3) was displayed. This value is called the blood vessel outer diameter expansion rate. Figure 28 shows the vascular diameter expansion rate (bear irradiation method, laser energy change) versus the number of laser irradiations. 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 the initial estimated vessel inner diameter. The outer diameter expansion rate is 400 mJ / pulse for 1.4, 800 mJ / pulse for 1.2 and 2 and 400 mJ / pulse are larger. The blood vessel outer diameter finally reached was about 4.9 mm and 5.0 mm, respectively. Figure 29 shows the vascular diameter expansion rate (irradiation method change, laser energy 400 mJ / pulse-constant) with respect to the number of laser irradiations. In the case of the bare irradiation method, the blood vessel outer diameter expansion rate during the 200th pulse was 1.6, and even after irradiation, the blood vessel outer diameter expansion rate was 1.5, which maintained the expansion. At this time, the estimated vessel inner diameter after 200 irradiations was 2.2 times larger than the initial estimated 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 increased to 1.2 times after 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 to the intracatheter irradiation method, the difference between the maximum blood vessel outer diameter during laser irradiation and the blood vessel outer diameter after laser irradiation was small in the bare irradiation method, and dilation was maintained. Figure 30 shows the blood vessel outer diameter expansion rate (intracatheter irradiation method (3 mm), laser energy change) with respect to the number of laser light irradiations. The blood vessel outer diameter expansion rate after 200 laser irradiations was almost the same as 1.2-1. The estimated blood vessel inner diameter at this time was 1.6-1.9 times the initial estimated blood vessel inner diameter. In FIGS. 28 to 30, the blood vessel outer diameter expansion rate increased with the number of irradiations, but was saturated after about 100 irradiations.

(2) Changes in mechanical properties of blood vessels

Method

The Young's modulus was measured at the laser irradiated part of the blood vessel and at the non-irradiated part. As described above, the blood vessel was placed in the perfusion apparatus, and intravascular laser irradiation was performed. Irradiation method is bear irradiation And intra-catheter irradiation (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 with a length of about 3 mm, and use an automatic stage (SGSP33-100 (x), Sigma Kogyo, Tokyo) and a controller (SHOT-202, Sigma Kogyo, Tokyo) Tension was applied 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. It is said that elastin fibers in the low strain region and collagen fibers in the high strain region share the weight of the blood vessel wall [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. 330o-d313, 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 Think of it as Young's modulus.

Result

Figure 31 shows the stress-strain diagram of the laser irradiated area and non-irradiated area 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 hang rate (E _e ) of the collagen fiber were determined. Laser irradiation site and the non-irradiated portion position Young's modulus of elastin fibers in the (E _e) in FIG. 3. 2 shows a laser irradiation site and the non-irradiated portion position Young's modulus of the collagen fibers of the (E _e) in FIG. 3 3. Laser irradiation conditions are irradiation method: bare irradiation method and intra-catheter irradiation method (3 mra), laser energy: 800 mJ / pulse

—Constant, number of laser pulse irradiation: 20 times and 100 times. Both E _e and E _c were larger in the laser irradiated area than in the non-irradiated area. For example, when laser irradiation is performed 100 times with a laser energy of 800 mJ / pulse by the intra-catheter irradiation method (3 mm), E _e of the laser non-irradiated part is 0. HMPa, whereas E _e of the laser irradiated part is _e was 0.59 MPa. When the same irradiation conditions, E _c of the laser non-irradiation sites in pairs to a 0. 86 MPa, E _c of the laser irradiation site was 1. 82 MPa. Among the laser irradiation conditions in this experiment, the maximum E _e at the laser irradiation site occurred when the laser energy was 800 mJ / pulse and 100 times of laser pulses were irradiated by the intra-catheter irradiation method (3 mm). Among the laser irradiation conditions in this experiment, the maximum E _e of the laser irradiation site is due to the bare irradiation method. -The energy was 800mJ / pulse, 100 times of laser pulse irradiation.

2. Expansion effect of Ho: YAG laser induced water vapor bubbles in rabbit aorta: in vivo animal experiments

 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, so 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). 30 mg / kg of pentobarbital sodium was administered from the rabbit's auricular marginal vein, and general anesthesia was applied. Cut the surgically exposed femoral artery and reverse the 4Fr. Sheath (outer diameter: 1.88 mm, inner diameter: 1.58 mm, length: 250 mm) (CS 40P25 TS, Medikit) Inserted and placed into the aorta. This sheath was selected so that bubbles of the same size as the bubbles generated in the catheter of the indwelling needle in the catheter irradiation method were generated. Here, the inner diameter of the rabbit aorta was measured using an intravascular ultrasound (IVUS) and was 2.0-3. 5 mm. An optical fiber (core diameter: 600 _w m, outer diameter: 1000 m) for the check valve port of the sheath was inserted. Irradiation was performed with the tip of the optical fiber positioned 3 mm inside the sheath tip. Hereinafter, this irradiation method is referred to as an intra-sheath irradiation method (3 mm). Laser energy was irradiated 20 times in the descending aorta at lOOmJ / pulse or 200mJ / pulse. Immediately after laser irradiation or one week later, the rabbit was sacrificed, and immediately after the aorta was fixed with 10% formalin perfusion and removed. A blood vessel HE-stained specimen was prepared. result

Fig. 3 4 A and B show rabbit aorta HE-stained specimen images after in vivo laser irradiation. (A) In-sheath irradiation method (3mm), laser energy 100mJ / pulse, immediately after 20 irradiations, (b) (a) control part, (c) In-sheath irradiation method (3mm), laser energy 100mJ / pulse, 20 exposures 1 week later, (d) (c) The control mouth part. In (a), the extension of the elastic lamina is seen compared to (b). In (c) after 1 week, the medial lamellae stretched compared to (d), and the stretched state in (a) was maintained. (A) and (c) both internal bullets The sex plate is not extended. Both (a) and (c) show no vascular dissociation.

3 Considerations

 (1) Principle of vasodilation by Ho: YAG laser-induced water vapor bubbles

 Ho i YAG laser-induced water vapor bubbles expanded the isolated porcine carotid artery to an outer diameter of 1.1-1.5 times the initial outer diameter. The estimated vessel inner diameter at this time was 1.3 to 2.2 times the initial estimated vessel inner diameter. In this chapter, we used healthy blood vessels. However, angioplasty is intended for blood vessels with stenosis, and this result cannot be directly applied to pathological blood vessels. In a short-time caloric warm-type angioplasty, Photo-thermo dynamic balloon angioplasty: PTDBA has been reported to have a good expansion effect at a low pressure of about 2 atm while heating at about 70 ° C for 15s [T Arai et 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 medial elastic plate. Therefore, the increase in E _e after laser irradiation is thought to be due to elastin fiber stretching, although there are differences in vivo and ex vivo. Ie

Ho: YAG Laser-induced water vapor bubbles can stretch and fix elastin fibers on the blood vessel wall. Comparing bare irradiation method and catheter irradiation method 3 2, whereas the E _e of the vessel was performed 100 times irradiated in bare irradiation method is 3.8 times the E _e of the laser non-irradiation site, Intracatheter irradiation has changed significantly by 5.4 times. This suggests that the extension of elastin fibers is almost the same with the force-tail irradiation method. As shown in Example 2, the intra-catheter irradiation method has a larger bubble diameter and growth acceleration in the direction perpendicular to the center axis of the optical fiber than the bare irradiation method. Conceivable. It has been reported that the E _e of a blood vessel expanded by 2 atm while the porcine carotid artery was heated at 70 ° C for 15 s with PTDBA was 0.16 MPa [N. Shimazaki et al., Proc. Of SPIE, vol. 6424, pp. 642424, 2007]. The E _e of the control site has been reported to be 0. llMPa. On the other hand, catheter irradiation at (3 mm), E _e of the lasers energy 800 mJ / pulse, 100 irradiations were vessel was 0. 59 MPa. This At this time, E _{e of the} non-laser irradiated part was 0. HMPa. Comparing these results with the PTDBA report, it is shown that the expansion of the elastin fiber is larger when the Ho: YAG laser-induced water vapor bubbles are expanded than when the PTDBA is expanded. On the other hand, in FIG. 3 3, what causes E _c after the laser irradiation becomes large due to thermal denaturation of collagen fibers and considered Erareru. At Bear irradiation method E _c of the laser energy 800 mJ / pulse, 100 times the blood tube was irradiated 2. 8 MPa, in the catheter irradiation method (3 mm) of the laser energy Honoré ghee 800 mJ / pulse, 100 irradiations were vessels E _e was 1.8 MPa. The E _{c of the} non-laser irradiated part was 1.0 MPa and 0.86 MPa, respectively. Towards the laser beam irradiation vessel by bare irradiation method, the E _c is greater than when the catheter irradiation appears to indicate that the percentage of heat denatured collagen fiber is large. About 70 ° C The excised porcine carotid artery in PTDBA, while performing the heating of the 15s, the E _c of the vessel subjected to expansion 2atm been reported to 1. 9 MPa Rereru [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 catheter UchiTeru archery (3 mm) in was performed in blood vessels and PTDBA subjected to laser irradiation with heating expansion vessel is comparable, Ho: The extended by YAG laser-induced vapor bubbles, elongation 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 and the heat transfer from the bubbles during vasodilation with Ho: YAG laser-induced water vapor bubbles were 6.4 ° C and 0.66 ° C, respectively. Small compared to about 70 ° C heating by PTDBA. Nevertheless, the same degree of thermal denaturation is considered to have been added. The expansion caused by Ho: YAG laser-induced water vapor bubbles may involve the heat generated by the deformation of the vessel wall.

 In summary, Ho: YAG laser-induced water vapor bubbles provide a vasodilator effect. The principle is that 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 It was estimated that the elastin fiber was fixed while stretched due to thermal denaturation of the fiber.

(2) Bubble suitable for vasodilation

For Ho: YAG laser-induced water vapor bubbles, the diameter perpendicular to the central axis of the optical fiber is The maximum is about 4.5 mm, and this defines the upper limit of expandable blood vessel diameter. The sites where vasodilation by Ho: YAG laser-induced water vapor bubbles can be applied are considered to be coronary arteries and knee arteries. Based on the estimated expansion principle above, 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 in the media and collagen fibers. Specifically, bubble diameter, growth acceleration, and heat associated with bubble generation can be controlled by changing the laser energy and irradiation method (bear irradiation method and intra-catheter irradiation method).

 Intracatheter irradiation can reduce risks such as contact of the tip of the optical fiber 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. With regard to the number of irradiations, both the bare irradiation method and the intra-catheter irradiation method saturated the blood vessel dilatation rate after approximately 100 irradiations (see Figures 28 to 30). For example, when laser irradiation is 400 mJ / pulse and 100 times irradiation with bare irradiation method, 1.5, force When laser irradiation is 400 mJ / pulse and irradiation is 100 times with intra-teeter irradiation method (3 mm), 1.3 blood vessels The outer diameter expansion rate is obtained. Therefore, the number of irradiations should be less than 100 to reduce side effects due to excessive heat input.

(3) In vivo vasodilator effect

 In vivo, the rabbit aorta was irradiated 20 times with laser energy lOOmJ / pulse or 200mJ / pulse by intra-sheath irradiation method (3mm). As shown in Fig. 3 4 B, this extension effect persisted even after one week, so an even longer extension effect would be expected.

The bubbles generated in the blood vessel will be discussed based on the results obtained in Example 2. When the laser energy was 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. The volume of bubbles in blood is 1. 03-1.25 times that in water, so the length is 1. 01-1.08 times. Thus, when the lasers energy 200mJ / _P ulse, the diameter of the optical fiber one vertical Direction of air bubbles generated in the blood 2.9 - estimated 3. was lmm and. Similarly, when the laser energy is lOOmJ / pulse, the diameter in the vertical direction of the optical fiber of the bubble generated in the blood is similarly estimated.

1. 5-1. 6mm. The inner diameter of the rabbit aorta was 2.0-3.5 mm, so It is probable that the diameter in the vertical direction was equal to or less than the inner diameter of the blood vessel. Akimoto's Ho: YAG laser-induced vasodilation method using water vapor bubbles can expand without closing the blood flow without using a complicated and expensive paloon catheter. There is a possibility of developing a simple and inexpensive treatment device that can be treated only with a sheath.

 Ho: YAG laser light 200-800mJ / pulse, 200 times in the blood vessel by bare irradiation method and intracatheter irradiation method. The carotid artery had an outer diameter of 1.1-1. From the relationship between the outer diameter and the inner diameter, the quasi-fixed inner diameter was 1.3-2. When irradiation was performed 20 times with lOOmJ / pulse by the intra-sheath irradiation method (3 mm), it was found that the elastic membrane of the media was extended even after one week in the in vivo rabbit aorta. The principle of the vasodilation effect obtained by the 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 bubbles and the pressure of the bubble growth. It was estimated that the elastin fiber was fixed while stretched by heat denaturation. The intracatheter irradiation method has the same expansion rate as the bare irradiation method, and is considered to be safe to use with little influence of light and heat. Ho: YAG Laser-induced water vapor Expansion using air bubbles can be performed 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 into an inexpensive treatment device. Industrial applicability

By using the apparatus of the present invention, the lesioned part of the blood vessel can be accurately and safely expanded 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 to be emitted and the number of irradiations. The holding time can be controlled. 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. The present invention can be used safely and reliably for angioplasty.

 All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

Claims

The scope of the claims

 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 dilating device using high-intensity pulsed light irradiation, including an intensity pulsed light irradiation unit, generating water vapor bubbles in a blood vessel by high-intensity pulsed light irradiation, and expanding the blood vessel wall by the action of the water vapor bubbles.

 2. The vasodilator by high-intensity pulsed light irradiation according to claim 1, wherein pressure and heat are applied to the blood vessel wall by the action of water vapor bubbles, and the orientation of the collagen fibers in the blood vessel wall is aligned.

 3. 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.

 4. The vasodilator according to claim 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 a blood vessel by irradiation with high-intensity pulsed light according to any one of claims 1 to 4, wherein an optical transmission fiber for transmitting high-intensity pulsed light is provided in the catheter. Expansion unit.

 6. 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.

 7. 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.

8. The vasodilator by high-intensity pulsed light irradiation according to any one of claims 1 to 7, which has an X-ray opaque marker near the distal end of the optical transmission fiber.

 9. The vasodilator by high-intensity pulsed light irradiation according to any one of claims 1 to 8, wherein a radiopaque marker is provided near the distal end of the catheter.

 10. The vasodilator by irradiation with high-intensity pulsed light according to any one of claims 1 to 9, which is applied to a stenosis site of a blood vessel to dilate the stenosis site of the blood vessel.

 1 1. The vasodilator by high-intensity pulsed light irradiation according to any one of claims 1 to 10, which can maintain vasodilation for at least 10 minutes.

1 2. The vasodilator by high-intensity pulsed light irradiation according to claim 11, wherein the vasodilation can be permanently maintained.

1 3. The high-intensity pulse light irradiation apparatus 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 / zm.

 14. 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 13.

 15. The vasodilator according to any one of claims 1 to 14, wherein the pulse width of irradiation with high-intensity pulsed light is 50; us to lms.

 16. The blood vessel dilation device according to any one of claims 1 to 15, wherein the blood vessel is dilated by repeating high-intensity pulsed light irradiation at least 25 times and not more than 100 times.

17. The blood vessel dilator according to claim 16, wherein the blood vessel is dilated by repeating high-intensity pulsed light irradiation at least 50 times and not more than 100 times.

 1 8. High-intensity pulsed light irradiation means capable of generating water vapor bubbles in a blood vessel, high-intensity pulsed light generation means, and high-intensity pulsed light transmission means. A method for controlling a vasodilator by irradiating a high-intensity pulsed light that expands a blood vessel wall by expanding the blood vessel wall by the action of the water vapor bubble, and is applied to the size and shape of the water vapor bubble generated in the blood vessel and the blood vessel wall A control method in which, in order to change heat, 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.

 1 9. Including a high-intensity pulsed light irradiation means capable of generating water vapor bubbles in a blood vessel, a high-intensity pulsed light generation means and a high-intensity pulsed light transmission means. A method for controlling a vasodilator by irradiating a high-intensity pulsed light that expands a blood vessel by expanding the blood vessel wall by the action of the water vapor bubbles, the distance between the position of the irradiation part of the high-intensity pulsed light irradiation means and the distal end of the catheter A control method that controls the shape and pressure of the generated steam bubbles by adjusting the pressure.