JP2006149974A - Vascular restenosis preventive therapeutic apparatus by controlled sound pressure wave induced by irradiation with high strength pulse light - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an apparatus having low invasive property to a patient, which is capable of reducing smooth muscle cells reproducing in a damaged portion of a blood vessel to cause restenosis or suppressing the adhesion of hematopoietic stem cells by a sound pressure wave generated when bubbles shrink and disappear, the bubbles being generated by irradiating the inside of a blood vessel with high-strength pulse light and generating steam bubbles, and also which is capable of adjusting the sound pressure of the sound pressure wave to be induced by adjusting the shape and largeness of the steam bubbles to be generated. <P>SOLUTION: This vascular restenosis preventive therapeutic apparatus reduces the smooth muscle cells reproducing in an operated region after angioplasty by the expansion of a blood vessel by the sound pressure wave induced by irradiation with high-strength pulse light, the generation of the steam bubbles, and the collapse of the steam bubbles. The apparatus generates the steam bubbles where the length of a lateral direction relative to a high-strength pulse light irradiating direction is 50-500% in size with respect to the length of a lengthwise direction, and by which the smooth muscle cells are damaged by sound pressure when the sound pressure wave induced by the collapse of the steam bubbles hits the wall of the blood vessel. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a device for preventing restenosis after percutaneous coronary angioplasty of a narrowed blood vessel by a sound pressure wave induced by high-intensity pulsed light irradiation, and the sound pressure wave is suitable for preventing restenosis. It is related with the controlled apparatus.

  Conventionally, percutaneous coronary angioplasty (PTCA) has been widely performed for patients with angina pectoris and myocardial infarction using balloon dilatation with a balloon catheter. However, in vasodilation using a balloon catheter, the restenosis rate after 3 months was as high as 30-40%. In addition, percutaneous coronary angioplasty by stent placement is also performed. According to this method, although the restenosis rate has decreased to 15 to 35%, there is a problem of in-stent restenosis, and the stent is placed in place. As a result, subsequent retreatment was difficult. In restenosis, the blood vessel wall is damaged by the forced expansion of the blood vessel lumen by the balloon, and in the subsequent healing process, smooth muscle cells migrate and proliferate from the vascular media to the damaged site of the intima, or hematopoietic stem cells adhere. It has been reported that it is caused by adhesion to damaged blood vessels via factors, differentiation and proliferation into smooth muscle cells, and intimal hyperplasia.

  On the other hand, intravascular irradiation therapy (Brachytherapy, JP 9-508038 A), which irradiates the lesion site with an appropriate dose of radiation after balloon expansion to suppress cell growth during the healing process. No. 2001-46532) has been developed.

  However, although radiation therapy is considered to be suitable for the prevention of restenosis in terms of inhibiting the proliferation of smooth muscle cells, side effects caused by damage to the blood vessel wall and surrounding tissues and the need for facilities to handle radiation There was a problem of sex.

  In addition, a method using ultrasonic waves (sonotherapy) has been tried. For example, smooth muscle cells are treated with one or more anti-cytoskeletal agents such as cytochalasin B or cortisin and irradiated with an effective amount of ultrasonic energy to reduce smooth muscle cell migration, survival or adhesion. Although a method for suppressing restenosis has been developed (Japanese Patent Publication No. 2002-502804), there is a problem that administration of an anti-cytoskeleton agent is essential. Furthermore, photodynamic therapy that suppresses neointimal thickening has also been attempted (WO00 / 59505), but it is necessary to administer a PDT drug to the patient in advance, and the time required for the treatment also depends on the patient's time. The burden was also great. Furthermore, a method for preventing restenosis using a dispatch catheter having a drug administration means has been reported.

In these restenosis prevention methods, a catheter is used, but a radiation source is provided at the distal end of the catheter, a heat generating means is provided in the catheter, or a vibration source or drug for generating ultrasonic waves in the catheter. Since it is necessary to arrange a means for locally administering the catheter, the catheter becomes thick and difficult to handle.
JP 7-289557 A Japanese National Patent Publication No. 9-508038 JP 2001-46532 A Japanese National Patent Publication No. 2002-502804 WO00 / 59505 Publication

  The inventors of the present invention have previously developed a device for preventing and treating restenosis that overcomes the drawbacks of the prior art. That is, a blood vessel that causes restenosis due to sound pressure waves generated when high-intensity pulsed light irradiation means irradiates a blood vessel with high-intensity pulsed light to generate water vapor bubbles in the blood vessel and the bubbles contract or disappear. It is a device that can reduce the number of smooth muscle cells that proliferate at the site of injury and suppress the adhesion of hematopoietic stem cells. It can be used in the bloodstream without closing the bloodstream, and the diameter of the portion inserted into the blood vessel is thin. Developed a low-invasive device characterized by the above (Japanese Patent Application No. 2003-157074).

  However, the relationship between the size and shape of water vapor bubbles and the sound pressure waves that can prevent restenosis is unclear, and in order to accurately prevent restenosis, how to generate water bubbles and how much sound pressure waves It was unknown about what to generate. An object of this invention is to provide the apparatus which can control the sound pressure wave which can prevent restenosis exactly.

  As described above, restenosis causes damage to the blood vessel wall due to the forced expansion of the blood vessel lumen by the balloon, and cells, such as smooth muscle cells, migrate and proliferate from the vascular media to the damaged site of the intima during the subsequent healing process. Alternatively, it occurs when hematopoietic stem cells adhere to damaged blood vessels via an adhesion factor, differentiate and proliferate into smooth muscle cells, and hyperplasia of the intima occurs. The present inventors have examined whether or not restenosis can be prevented by inhibiting the proliferation of smooth muscle cells and further preventing the adhesion of hematopoietic stem cells, and water vapor bubbles are generated when laser is irradiated in a liquid. Focusing on the phenomenon in which sound pressure waves are generated when the bubbles contract and disappear, a high-intensity pulsed light irradiation site is provided at the distal end of the blood vessel catheter, and a high-intensity pulsed light such as a laser is irradiated inside the blood vessel. It has been found that pressure waves are generated and the sound pressure waves can inhibit the proliferation of smooth muscle cells and the adhesion of hematopoietic stem cells, thereby preventing restenosis. A device capable of generating water vapor bubbles in a blood vessel is a device that requires means for irradiating high-intensity pulsed light having a certain intensity and wavelength inside the blood vessel, and basically a device that generates high-intensity pulsed light. Only the fiber for transmitting the high-intensity pulsed light and the means for transporting the fiber to the treatment site in the blood vessel are sufficient, and the maximum diameter portion to be inserted into the blood vessel is very small. For this reason, for example, when performing a treatment on a coronary artery, it is not necessary to insert from a thick blood vessel such as a femoral artery blood vessel away from the coronary artery as in the prior art, and it can also be inserted from a thin blood vessel of an arm close to the coronary artery. . The present inventors further examined conditions for generating water vapor bubbles that can generate sound pressure waves that can prevent restenosis more reliably.

That is, the present invention is as follows.
[1] It includes high-intensity pulsed light irradiation means capable of inducing a sound pressure wave in a blood vessel, generates water vapor bubbles in the blood vessel by high-intensity pulsed light irradiation, and generates sound pressure waves induced when the water vapor bubbles collapse An apparatus for preventing and treating vascular restenosis that reduces the number of cells proliferating after angioplasty by vasodilation, the length in the horizontal direction relative to the direction of irradiation with high-intensity pulsed light is longer than the length in the vertical direction A water vapor bubble having a size of 1/2 or more is generated, and the sound pressure wave generated by the collapse of the water vapor bubble hits the blood vessel wall to generate a water vapor bubble that can damage smooth muscle cells. Device for preventing and treating stenosis,
[2] The apparatus for preventing and treating vascular restenosis according to [1], wherein the length of the water vapor bubbles in the transverse direction with respect to the irradiation direction of the high-intensity pulsed light is 50 to 500% of the length in the longitudinal direction.
[3] Furthermore, the apparatus for preventing and treating vascular restenosis according to [1] or [2], wherein the length of the water vapor bubbles in the lateral direction relative to the direction of irradiation with the high-intensity pulsed light is not more than twice the inner diameter of the blood vessel. ,
[4] The apparatus for preventing and treating vascular restenosis according to [3], wherein the transverse length of the water vapor bubbles with respect to the irradiation direction of the high-intensity pulsed light is 10 to 200% of the inner diameter of the blood vessel.
[5] The apparatus for preventing and treating vascular restenosis according to [1], wherein the sound pressure of the sound pressure wave induced by the collapse of water vapor bubbles is 0.1 to 10 MPa in the blood vessel wall;

[6] The vascular restenosis prevention / treatment device according to any one of [1] to [5], further comprising a catheter and a high-intensity pulsed light transmission fiber disposed in the catheter,
[7] The apparatus for preventing and treating vascular restenosis according to [6], wherein the high-intensity pulsed light irradiation means can be inserted into a penetration lumen of a balloon catheter capable of performing percutaneous blood vessel formation by balloon expansion.
[8] The apparatus for preventing and treating vascular restenosis according to [7], wherein the catheter is a balloon catheter capable of performing percutaneous angiogenesis by balloon expansion.
[9] By changing the distance between the catheter tip and the high-intensity pulsed light irradiation part of the high-intensity pulsed light irradiation unit in the direction of high-intensity pulsed light irradiation, the shape of the water-vapor bubble is changed and induced by the collapse of the water-vapor bubble The device for preventing and treating vascular restenosis according to any one of [6] to [8], wherein the sound pressure wave when the sound pressure wave hits the blood vessel wall can be adjusted,

[10] The apparatus for preventing and treating vascular restenosis according to [9], wherein the distance between the distal end portion of the catheter and the high-intensity pulsed light irradiation unit of the high-intensity pulsed light irradiation unit is 1 to 3 mm.
[11] The internal structure of the distal end of the catheter is an internal structure that suppresses the rate at which water vapor bubbles generated by irradiation with high-intensity pulsed light expand in the lateral direction with respect to the direction of irradiation with high-intensity pulsed light. [6] to [8] are generated, which are steam bubbles whose length in the transverse direction relative to the direction is larger than the length in the longitudinal direction, and which have high sound pressure when the sound pressure wave induced by collapse strikes the blood vessel wall. ] For preventing and treating vascular restenosis,
[12] The device for preventing and treating vascular restenosis according to [11], wherein the internal structure of the distal end portion of the catheter has a concavo-convex portion inside the distal end portion,
[13] The apparatus for preventing and treating vascular restenosis according to any one of [1] to [12], wherein the wavelength of the high-intensity pulsed light is in a range where the water absorption coefficient is 10 to 1000 cm ⁻¹ .
[14] The apparatus for preventing and treating vascular restenosis according to any one of [1] to [13], wherein the wavelength of the high-intensity pulsed light is in the range of 0.3 to 3 μm,
[15] The device for preventing and treating vascular restenosis according to [14], wherein the wavelength of the high-intensity pulsed light is in the range of 1.5 to 2.5 μm,

[16] The apparatus for preventing and treating vascular restenosis according to any one of [1] to [15], wherein the high-intensity pulsed light is a pulsed laser,
[17] The apparatus for preventing and treating vascular restenosis according to any one of [1] to [15], wherein the high-intensity pulsed light is pulsed light generated by an optical parametric oscillator (OPO),
[18] The apparatus for preventing and treating vascular restenosis according to [16], wherein the laser is a solid-state laser using rare earth ions,
[19] The apparatus for preventing and treating vascular restenosis according to [18], wherein the laser medium is Ho or Tm, and the laser base material is selected from the group consisting of YAG, YSGG, and YVO.
[20] The apparatus for preventing and treating vascular restenosis according to [19], wherein the laser is a Ho: YAG laser or a Tm: YAG laser, and
[21] The device for preventing and treating vascular restenosis according to any one of [1] to [20], wherein the diameter of the catheter sheath portion to be inserted into the blood vessel is 2 mm or less.

  As shown in the examples, water vapor bubbles are generated by irradiating high-intensity pulsed light in the liquid, and the growth of smooth muscle cells is inhibited by sound pressure waves generated when the bubbles contract or disappear (collapse). At this time, by changing the shape and size of the water vapor bubbles, the size of the sound pressure in the sound pressure blood vessel wall can be adjusted. In particular, the apparatus of the present invention is such that the length of the water vapor bubble in the transverse direction relative to the direction of irradiation with high-intensity pulsed light is at least half the length in the longitudinal direction (direction of irradiation with high-intensity pulsed light). Since the sound pressure of the sound pressure wave propagating in the lateral direction when such a water vapor bubble collapses is increased, it is possible to apply a sound pressure large enough to damage smooth muscle cells to the blood vessel wall. it can. Moreover, in the apparatus of this invention, the magnitude | size and the magnitude | size of a water vapor bubble can be adjusted, and the magnitude | size of the induced sound pressure can also be adjusted. Therefore, a moderate sound pressure can be induced from an extreme sound pressure in a timely manner according to the severity of restenosis predicted in the arteriosclerosis treatment part. The apparatus of the present invention irradiates high-intensity pulsed light at the blood vessel site where the angioplasty was performed, and generates a sound pressure wave, thereby inhibiting the proliferation of smooth muscle cells that migrate and settle in the blood vessel forming part. Thus, vascular restenosis can be prevented.

Hereinafter, the present invention will be described in detail.
The present invention is an apparatus for preventing and treating restenosis using high-intensity pulsed light.

  The apparatus of the present invention includes at least a high-intensity pulsed light irradiation means for irradiating a high-intensity pulsed light into a blood vessel, and a catheter for guiding the high-intensity pulsed light irradiation unit to a percutaneous coronary angioplasty site. May be included. FIG. 1 shows a schematic diagram of the apparatus of the present invention.

  The high-intensity pulsed light irradiation means includes high-intensity pulsed light generation means (high-intensity pulsed light source), means for transmitting high-intensity pulsed light into the blood vessel, means for irradiating the high-intensity pulsed light into the blood vessel, etc. The portion that transmits the intensity pulse light is an optical transmission fiber. The optical transmission fiber of the present invention may be inserted into a penetration lumen in a catheter used for percutaneous angioplasty (PTCA) by balloon expansion so that high-intensity pulsed light reaches the treatment site. In this case, treatment with the treatment apparatus of the present invention is performed immediately after the percutaneous angioplasty by balloon expansion. In addition, an optical fiber for transmitting high-intensity pulsed light is disposed in advance in the balloon catheter used for the above-mentioned percutaneous angioplasty, and after performing percutaneous angioplasty, the balloon is deflated and irradiated with high-intensity pulsed light. The treatment of the present invention may be performed. Therefore, the present invention provides a blood vessel that can prevent vascular restenosis by reducing the number of cells that proliferate in an operation site after performing angioplasty by vasodilation, such as smooth muscle cells, by sound pressure waves induced by irradiation with high-intensity pulsed light. The present invention also includes a balloon catheter for vasodilation including high-intensity pulsed light irradiation means capable of inducing a sound pressure wave therein. Furthermore, the present invention may be a dedicated device for preventing and treating vascular restenosis arranged as a fiber for transmitting high-intensity pulsed light in a catheter. In this case, after angioplasty is performed using a balloon catheter for vasodilation, the balloon catheter for vasodilation is removed from the body, and then vascular restenosis prevention treatment is performed. In the case of a dedicated device, it can also be used to prevent restenosis after angioplasty by stent placement (for example, self-expandable stent). The means for irradiating the high-intensity pulsed light into the blood vessel is provided as a high-intensity pulsed light irradiation unit at the distal end of the optical transmission fiber. The high-intensity pulsed light irradiation unit may be provided with a member such as a prism for changing the pulsed light irradiation angle, but usually no special member is required, and the distal end of the optical fiber is irradiated with high-intensity pulsed light. Can act as a part.

  In the present invention, the sound pressure wave refers to a wave accompanied by pressure fluctuation in a medium. The sound pressure wave is also referred to as an acoustic wave, but in the present invention, the generated acoustic wave may be a shock wave due to the nonlinearity of the medium, and is therefore collectively referred to as a sound pressure wave. In the present invention, the sound pressure wave includes an ultrasonic wave having an audio frequency, an ultrasonic wave having an audio frequency higher than that, and an ultra-low frequency having an audio frequency lower than the audio frequency.

  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 apparatus of the present invention requires only one optical fiber for transmitting high-intensity pulsed light in the catheter, so that the diameter of the catheter can be reduced. For example, the diameter of the catheter sheath portion is 2 mm or less.

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

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

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

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

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

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

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

  In addition, the distal end portion of the optical fiber for transmitting high-intensity pulsed light, that is, the high-intensity pulsed light irradiation part at the tip of the optical fiber is retracted into the catheter rather than the tip of the catheter in order to avoid injury to the blood vessel wall by the tip. Is desirable.

The pulse width of the high intensity pulse light is not limited, but is 10 ns to 1 ms, preferably 100 μs to 400 μs. The pulse width is indicated by the full width at half maximum.
The repetition frequency of the high intensity pulse light is not limited.

  By irradiating the blood vessel with high-intensity pulsed light, the energy density is increased in front of the irradiation part of the high-intensity pulsed light, and water vapor bubbles are generated and expanded (expanded) in the region. A sound pressure wave is generated when collapsing, and propagates from the point of occurrence. FIG. 2 is a diagram showing a process from generation to disappearance of water vapor generated by laser light irradiation. FIG. 3 shows a conceptual diagram of restenosis prevention treatment using the apparatus of the present invention. The water vapor bubbles are particularly effective for preventing restenosis when the shape and size of the water vapor bubbles just before collapsing are constant. In other words, the shape of the water vapor bubbles is such that when 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, the shape of the water vapor bubble spreading in the horizontal direction is more lateral. A large sound pressure wave can be generated. Therefore, the sound pressure wave conducts laterally from the water vapor generation point and more reliably reduces the medial smooth muscle cells present laterally with respect to the water vapor bubbles. On the other hand, if the sound pressure wave is too large, normal cells of normal tissue are also damaged. Therefore, there is a certain range of sound pressure waves suitable for preventing stenosis. Moreover, even if it extends too much in the lateral direction, the blood vessel wall is excessively expanded, and protein fibers such as collagen fibers forming the blood vessel wall are stretched so that they cannot be restored, causing damage to the blood vessel wall. Sometimes. Therefore, the device of the present invention generates a mushroom-shaped or western-less water vapor bubble that spreads in the lateral direction, and is effective in reducing medial smooth muscle cells, but does not significantly damage vascular function. It is a device that can generate water vapor bubbles that generate pressure waves and do not expand the blood vessel wall enough to cause damage to the blood vessel wall. Furthermore, since the peak sound pressure decreases as the distance from the center of the generated bubble increases, it is necessary to generate water vapor bubbles so that a thicker blood vessel induces a stronger sound pressure.

  Furthermore, the larger the arteriosclerotic treatment part, the more smooth muscle cells proliferate after the treatment, and the expected severity of restenosis increases. By adjusting the sound pressure of the sound pressure wave according to the severity of restenosis, normal cell damage can be avoided while accurately damaging smooth muscle cells. The device of the present invention can appropriately adjust the sound pressure strongly or gently depending on the expected severity of restenosis.

  The generated steam bubbles are preferably steam bubbles having a length in the transverse direction with respect to the direction of irradiation with the high-intensity pulsed light that is 1/2 or more of the length in the longitudinal direction. Large steam bubbles are preferred. Furthermore, a water vapor bubble having a size that does not cause excessive damage to the blood vessel wall due to excessive expansion of the blood vessel wall is preferable. Water vapor bubbles having a size of 2 times or less of these are preferable, and water vapor bubbles smaller than the inner diameter of the blood vessel are more preferable.

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

  In order to generate water vapor bubbles that can generate an appropriate sound pressure wave as described above, the positional relationship between the position of the high-intensity pulsed light irradiation means at the distal end of the high-intensity pulsed light transmission means and the distal end of the catheter is adjusted. do it. In addition, 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. Get out. At this time, the shape of water vapor bubbles generated outside the catheter and in the blood vessel can also be adjusted by changing the shape or the like inside the distal end of the catheter. By adjusting the shape of the water vapor bubbles, it is possible to adjust the sound pressure wave generated in the lateral direction, that is, the sound pressure of the sound pressure wave applied to the smooth muscle cells.

  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, a more appropriately shaped water vapor bubble can be generated. A pressure wave can act on the vessel wall. It is desirable that the high-intensity pulsed light irradiation portion at the tip of the optical fiber is located within the catheter 0.5 to 5 mm, preferably 1 to 3 mm, more preferably 1 to 2 mm with respect to the catheter tip. Also, the shape of the water vapor bubble can be adjusted by the shape inside the distal end of the catheter, and as a result, the sound pressure wave can be adjusted. When the high-intensity pulsed light irradiation part is present inside the catheter, water vapor bubbles are generated inside the catheter and go out from the inside of the catheter while expanding. At this time, when the water vapor bubbles go outside the catheter, By suppressing the speed at which the water vapor bubbles expand in the catheter traveling direction, it is possible to suppress the water vapor bubbles from expanding in the catheter traveling direction, and as a result, it is possible to generate water vapor bubbles expanded in the lateral direction. For this purpose, for example, a convex portion that can suppress the expansion of water vapor bubbles in the vertical direction, a groove, or a continuous uneven portion may be provided inside the distal end of the catheter. Further, the structure may be changed at the distal end portion of the catheter so that the inner diameter of the distal end portion increases.

  In addition, even when high-intensity pulsed light of the same intensity is irradiated, the magnitude of the sound pressure wave induced varies depending on the position of the high-intensity pulsed light irradiation part of the optical transmission fiber and the tip of the catheter. . For example, as shown in FIG. 10, as the position of the high-intensity pulsed light irradiation part of the optical transmission fiber 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 higher the same energy. Even when the intensity pulse light is irradiated, the sound pressure of the induced sound pressure wave increases.

  The relationship between the laser energy and the sound pressure in the case where the position of the light irradiation unit in FIG. 10 is changed is an example, and the position of the light irradiation unit is appropriately adjusted depending on the thickness of the catheter or the optical transmission fiber. Sound pressure waves can be generated.

  Moreover, the sound pressure wave changes not only by the positional relationship between the distal end portion of the catheter and the high-intensity pulsed light irradiation unit but also by a combination of the positional relationship and the intensity of the high-intensity pulsed light to be irradiated.

  Therefore, the present invention is generated by changing the intensity of the high-intensity pulsed light to be irradiated, changing the position of the irradiation part of the high-intensity pulsed light and the catheter tip, or changing the internal structure of the catheter distal end. It is an apparatus capable of adjusting the size and / or shape of water vapor bubbles and adjusting the generation of sound pressure waves suitable for restenosis prevention. In addition, the sound pressure of the sound pressure wave can be adjusted as appropriate by changing the wavelength and pulse width of the high-intensity pulsed light.

  Further, if the number of times of irradiation with high-intensity pulsed light is increased, sound pressure waves are also induced many times, which is more effective in damaging smooth muscle cells. The number of irradiations can be appropriately selected depending on the expected severity of restenosis, the thickness of the blood vessel, etc., for example, 1 to 200 times, 1 to 100 times, 1 to 50 times, or 1 to 10 times. is there.

  The sound pressure of the sound pressure wave inhibits the proliferation of smooth muscle cells in the arteriosclerotic treatment part, but does not damage normal cells of the treatment part and the surrounding normal tissue, and varies depending on the blood vessel used, but preferably 0.1 -100 MPa, preferably 0.1-50 MPa, more preferably 0.1-20 MPa, particularly preferably 0.1-10 MPa, most preferably 0.1-4 MPa. If the expected severity of restenosis is low and normal cell damage is avoided, the sound pressure may be lowered, for example, 0.1 to 5 MPa, 0.1 to 4 MPa, 0.1 to 2.5 MPa, or 0.1 to 1 MPa. The sound pressure may be applied to the arteriosclerosis treatment part.

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

  Note that it is desirable that the high-intensity pulsed light irradiation is delayed and synchronized with the pulsation of the blood flow, that is, the pulsating blood flow. Blood flow is a pulsatile flow. When blood flow is flowing, that is, when the kinetic energy (dynamic pressure) of the blood flow is large, the generation of water vapor bubbles affects not only blood pressure (static pressure) but also dynamic pressure. box office. On the other hand, if the blood flow is completely stopped, the blood is a non-Newtonian fluid, so that the viscosity becomes large and water vapor bubbles are hardly generated. Therefore, there is an optimal timing when the pulsatile blood flow rate has decreased (before the blood flow stops). The timing can be detected by setting a delay time specific to the observation blood vessel in the heartbeat information from the electrocardiogram. In this case, the electrocardiogram and the laser generator are electronically connected, and the electrocardiogram signal is passed through the delay generator to the high-intensity pulsed light generator so that the high-intensity pulsed light is emitted when the pulsatile blood flow decreases. Just communicate. How much time delay is applied can be appropriately determined by a combination of an electrocardiograph, a delay generator, and a high-intensity pulsed light generator. A person skilled in the art can easily determine the timing for transmitting a signal such that a high-intensity pulsed light is emitted when the pulsatile blood flow is reduced from the electrocardiograph based on the known relationship between the cardiac cycle, the aortic blood flow rate, and the electrocardiogram. For example, in the case of coronary arteries, blood hardly flows during the systole when the aortic blood flow rate is large, and blood flows during the diastole when the aortic blood flow rate is small. Accordingly, the blood flow velocity of the coronary artery is maximized during the appearance of the P wave after the appearance of the T wave in the electrocardiogram, and the irradiation timing of the high-intensity pulsed light is preferably from the appearance of the P wave to the disappearance of the QRS wave. Furthermore, a pressure sensor or the like is disposed on the catheter of the treatment apparatus of the present invention, and the pulsation of the blood flow is monitored by the sensor so that the high-intensity pulsed light is emitted when the pulsating blood flow decreases. May be. Also in this case, the pressure sensor and the high intensity pulsed light generator are electronically connected, and a signal from the pressure sensor is transmitted to the high intensity pulsed light generator with a delay.

Method of using the device of the present invention The device of the present invention is a device for preventing restenosis of blood vessels after percutaneous angioplasty, and the high-intensity pulsed light irradiation unit of the present invention is used as the percutaneous blood vessel formation. Guide to the site of operation. The target blood vessel of the device of the present invention is not limited, and can be applied to any coronary artery or other smaller blood vessels. However, the angioplasty is usually performed in the common carotid artery and coronary artery. The iliac artery, the superficial femoral artery, and the inferior arteries, and the device of the present invention can also be suitably used for treating these arteries after angioplasty. At this time, when angioplasty is performed by balloon expansion using a balloon catheter having a penetrating lumen, treatment is performed by inserting the high-intensity pulsed light irradiation part of the device of the present invention into the penetrating lumen and carrying it to the treatment site. It can be performed. When the apparatus of the present invention is a dedicated apparatus for preventing restenosis disposed in a dedicated catheter, the catheter of the apparatus of the present invention is removed after the balloon catheter for angioplasty is removed. Is inserted into the blood vessel, and the high-intensity pulsed light irradiation unit reaches the treatment site to perform treatment. In addition, even when angioplasty is performed by stent placement, restenosis prevention treatment can be performed using a dedicated device for restenosis prevention. In the device of the present invention, the portion to be inserted into the blood vessel may be a small diameter catheter including one optical fiber for transmitting high-intensity pulsed light, so that it is not from a large blood vessel such as a femoral artery blood vessel but a thin artery such as a radial artery. It can also be inserted from a blood vessel.

  The high-intensity pulsed light irradiation unit of the apparatus of the present invention may be guided to the percutaneous angioplasty site 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 portion in whole blood, and sound pressure waves are generated when the bubbles contract and disappear. The sound pressure wave propagates through the whole blood, propagates to the blood vessel wall, and reduces the medial smooth muscle cells. At this time, as described above, a small amount of physiological saline or the like may be injected into the portion of the blood vessel irradiated with the high-intensity pulsed light as described above.

  At this time, the shape of water vapor bubbles generated by moving the optical transmission fiber in the catheter and adjusting the position of the high-intensity pulsed light at the fiber tip with respect to the catheter tip or changing the structure inside the catheter distal end The size of the sound pressure wave induced by the collapse of water vapor bubbles and applied to the arteriosclerosis treatment part of the blood vessel wall can be adjusted.

  In order to reduce the number of smooth muscle cells and prevent restenosis after angioplasty, it is common to generate a sound pressure wave by irradiating high-intensity pulsed light after actually performing angioplasty. However, high-intensity pulsed light may be irradiated in advance to generate a sound pressure wave at a site where angioplasty is to be performed before angioplasty. Even if the sound pressure wave is generated before the angioplasty is performed, the smooth muscle cells in that portion can be reduced, and migration and colonization of the smooth muscle cells after the angioplasty at the vascular injury site can be prevented.

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

[Example 1] Measurement of sound pressure of sound pressure wave induced by laser irradiation
Using Ho: YAG laser generator 21 (LASER1-2-3SCHWARTZ (ELECTRO-OPTICS (USA)), Ho: YAG laser (wavelength 2.1Oμm, pulse width 250μs, frequency 2Hz) is irradiated in water and blood, Sound pressure was measured with a needle-type hydrophone (model number NH7020, manufactured by Toray Techno Co., Ltd.) using the laser output and the distance from the end of the optical fiber as parameters.The optical fiber used had an outer diameter of 600 μm and a core diameter of 400 μm. It was.

  At this time, irradiation was performed at an intensity of 0.13 J / pulse, 0.27 J / pulse, or 0.45 J / pulse, and sound pressures at positions of 5 mm, 10 mm, and 15 mm from the center of the generated water vapor bubbles were measured.

  FIG. 4 shows the relationship between the intensity of the irradiation laser (J / pulse), the distance from the center of the bubble (mm), and the peak sound pressure (MPa). As shown in the figure, the peak sound pressure of the generated sound pressure wave is mainly determined by the distance from the center of the bubble, and the sound pressure at a certain point is considered to be inversely proportional to the square of the distance from the center of the bubble.

  When the optical fiber end is 0.45 J / pulse and the distance from the bubble center is 5 mm, a peak sound pressure of 1.5 MPa (about 11000 mmHg) or more is obtained. In Fig. 5, 0.45 J / pulse and the distance from the bubble center is 5 mm. The sound pressure waveform is shown. It was found that the sound pressure in blood was about 30% in water due to the influence of viscosity. From Example 1, it was found that the Ho: YAG laser-induced sound pressure wave gives a smooth controllable injury to smooth muscle cells.

[Example 2] Injury of smooth muscle cells by laser-induced sound pressure waves As shown in Fig. 6, proliferating smooth muscle cells (mouse-derived aortic smooth muscle cells P53LMACO1) were cultured in a 96-well plate and the sound pressure waves were peaked. The pressure (about 1.20, 1.25, 1.46 MPa) and the number of times (1O, 20, 160 times) were changed and applied. The laser beam generator used for generating the sound pressure wave and the laser irradiation conditions were the same as those in Example 1. The dead cell rate was measured by MTT assay 48 hours after application of the sound pressure wave. About 1.20 Mpa, 1O times, about 4%, 1.46 Mpa, about 20% dead cell rate at 20 times, it was possible to damage the smooth muscle cells with good controllability depending on the laser irradiation conditions (FIG. 7). ).

[Example 3] Preventive treatment for restenosis using rabbits A restenosis model was created in which a 2Fr. Balloon catheter was inserted from the femoral artery of a Japanese white rabbit under total anesthesia to scratch the aorta. A 4Fr. Sheath in which an optical fiber was placed in the femoral artery was inserted retrogradely, and laser irradiation was performed on the aorta. FIG. 8 shows a system used in this embodiment. Six weeks later, the mice were sacrificed, and vascular tissue specimens were prepared by Hematoxilin-Eosin (HE) staining to evaluate the therapeutic effect.

  FIG. 9 shows the result. FIG. 9 shows a cross section of a blood vessel wall obtained by cutting and expanding a part of a blood vessel as shown in the figure, with the upper part on the inner membrane side and the lower part on the outer membrane side. Moreover, the arrow in a figure shows an inner elastic board, and a smooth muscle cell proliferates in the intima side from this inner elastic board. Each photograph shows a normal blood vessel, a stenotic model blood vessel, and a laser beam of 0.06 J / pulse irradiated 20 times clockwise from the upper left.

  As shown in the figure, in contrast to Normal which has not been processed at all, in the stenosis model, the intima is thick and smooth muscle cell proliferation is observed. Proliferation was suppressed in the sample irradiated 20 times with 0.06 J / pulse laser light. This result shows that smooth muscle cell proliferation can be suppressed with small irradiation energy.

Example 4
Ho: YAG laser generator 21 (LASER1-2-3SCHWARTZ (ELECTRO-OPTICS (USA)) was used to irradiate Ho: YAG laser (wavelength 2.1Oμm, pulse width 250μs, frequency 2Hz) in water, from the end of the optical fiber Sound pressure was measured using a needle-type hydrophone (model number NH7020, manufactured by Toray Techno Co., Ltd.) at a point 2 mm forward and 3 mm laterally.The optical fiber used had an outer diameter of 600 μm and a core diameter of 400 μm. The laser output was 85 to 570 mJ / pulse, in which case the optical fiber was put into the catheter (sheath) when irradiated using only the optical fiber (free in FIG. 10), and the catheter was inserted from the tip of the optical fiber. The test was carried out when the tip distance was 1 mm, 2 mm, and 3 mm, and the relationship between the position of the optical fiber, laser output, and sound pressure is shown in Fig. 10. As shown in the figure, the tip of the optical fiber was retracted into the catheter several mm. When the distance between the optical fiber tip and the catheter tip is 2 mm or less, a decrease in the sound pressure wave was observed when the laser output was increased, but when the distance was 3 mm, it was not observed up to 600 mJ / pulse. The maximum measured sound pressure was about 4 MPa.When laser was irradiated in a blood vessel with an inner diameter of about 3 mm, the distance from the laser irradiation point to the blood vessel wall was about 1.5 mm, so the maximum sound pressure wave generated Sound pressure is expected to be around 10MPa.

  FIGS. 11 and 12 show the shape of water vapor bubbles generated when a laser of 450 mJ / pulse is irradiated. FIG. 11 shows the case where the laser irradiation fiber is irradiated without being put in the sheath (catheter), and FIG. 12 shows the case where the laser irradiation fiber is put in the sheath, where the fiber tip is within the 3 mm sheath with respect to the sheath tip. This is the case. As shown in the figure, when the tip of the fiber enters the sheath, the generated bubbles have a length in the transverse direction with respect to the laser irradiation direction that is larger than the length in the longitudinal direction, and have a shape similar to a mushroom. The ratio between the vertical length and the horizontal length of the steam bubbles shown in FIG. 11 is 1: 0.8, and the ratio between the vertical length and the horizontal length of the steam bubbles shown in FIG. 12 is 1: 2.

It is the figure which showed the apparatus of this invention. The figure showing the process from generation | occurrence | production to extinction of the water vapor | steam generate | occur | produced by laser beam irradiation is shown. The conceptual diagram of the restenosis prevention treatment by the apparatus of this invention is shown. It is a figure which shows the relationship between the intensity | strength (J / pulse) of irradiation laser, the distance (mm) from the center of a bubble, and peak sound pressure (MPa). The sound pressure waveform at a point 5 mm away from the center of the bubble when a laser intensity of 0.45 J / pulse is used is shown. It is a figure which shows the method of the injury experiment of the smooth muscle cell by a laser induced sound pressure wave. It is a figure which shows the result of the injury experiment of the smooth muscle cell by a laser induced sound pressure wave. It is a figure which shows the method of restenosis prevention treatment using a rabbit. It is a figure which shows the result of the restenosis prevention treatment using a rabbit. It is a figure which shows the relationship between a laser energy and a sound pressure. It is a figure which shows the shape of the water vapor | steam bubble generate | occur | produced when the laser irradiation fiber is not in the catheter. It is a figure which shows the shape of the water vapor | steam bubble generate | occur | produced when the laser irradiation fiber is in the catheter.

Claims (10)

  High-intensity pulsed light irradiation means capable of inducing a sound pressure wave in the blood vessel, generating water vapor bubbles in the blood vessel by high-intensity pulsed light irradiation, and due to blood vessel dilation by the sound pressure wave induced when the water vapor bubbles collapse An apparatus for preventing and treating vascular restenosis that reduces cells proliferating in an operation site after angioplasty is performed, wherein the lateral length with respect to the direction of irradiation with high-intensity pulsed light is 50 to 500 with respect to the longitudinal length. A device for preventing and treating vascular restenosis, which is a size of 50%.   The apparatus for preventing and treating vascular restenosis according to claim 1, wherein the length of the water vapor bubbles in the lateral direction with respect to the irradiation direction of the high-intensity pulsed light is 10 to 200% of the inner diameter of the blood vessel.   The apparatus for preventing and treating vascular restenosis according to claim 1, wherein the sound pressure of the sound pressure wave induced by the collapse of water vapor bubbles is 0.1 to 10 MPa in the blood vessel wall.   The device for preventing and treating vascular restenosis according to any one of claims 1 to 3, further comprising a catheter and a high-intensity pulse light transmission fiber disposed in the catheter.   By changing the distance of the high-intensity pulsed light irradiation part of the high-intensity pulsed light irradiation part of the catheter tip and the high-intensity pulsed light irradiation means, the shape of the water vapor bubble is changed, and the sound pressure wave induced by the collapse of the water vapor bubble The device for preventing and treating vascular restenosis according to claim 4, wherein the sound pressure at the time of hitting the blood vessel wall can be adjusted.   The vascular restenosis prevention and treatment apparatus according to claim 5, wherein the distance between the catheter tip and the high-intensity pulsed light irradiation unit of the high-intensity pulsed light irradiation unit is 1 to 3 mm.   The internal structure of the distal end of the catheter is an internal structure that suppresses the rate at which water vapor bubbles generated by high-intensity pulsed light irradiation expand in the lateral direction with respect to the high-intensity pulsed light irradiation direction. 5. The prevention of vascular restenosis according to claim 4, wherein a water vapor bubble having a direction length longer than a length in the vertical direction and having a high sound pressure when a sound pressure wave induced by a collapse hits a blood vessel wall is generated. Therapeutic device.   The device for preventing and treating vascular restenosis according to claim 7, wherein the internal structure of the distal end portion of the catheter is a structure having an uneven portion inside the distal end portion. The device for preventing and treating vascular restenosis according to any one of claims 1 to 8, wherein the wavelength of the high-intensity pulsed light is in a range where the water absorption coefficient is 10 to 1000 cm- ¹ .   The apparatus for preventing and treating vascular restenosis according to any one of claims 1 to 9, wherein the wavelength of the high-intensity pulsed light is in the range of 0.3 to 3 µm.

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