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WO2008088062A1 - Vasodilatateur - Google Patents

Vasodilatateur Download PDF

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Publication number
WO2008088062A1
WO2008088062A1 PCT/JP2008/050665 JP2008050665W WO2008088062A1 WO 2008088062 A1 WO2008088062 A1 WO 2008088062A1 JP 2008050665 W JP2008050665 W JP 2008050665W WO 2008088062 A1 WO2008088062 A1 WO 2008088062A1
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WO
WIPO (PCT)
Prior art keywords
pulsed light
blood vessel
intensity pulsed
irradiation
catheter
Prior art date
Application number
PCT/JP2008/050665
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English (en)
Japanese (ja)
Inventor
Tsunenori Arai
Eriko Nakatani
Takehiro Iwasaki
Satoru Mori
Original Assignee
Keio University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Keio University filed Critical Keio University
Publication of WO2008088062A1 publication Critical patent/WO2008088062A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B18/26—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor for producing a shock wave, e.g. laser lithotripsy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N2005/0602—Apparatus for use inside the body for treatment of blood vessels

Definitions

  • 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.
  • 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.
  • an expanded balloon catheter which is a catheter with a balloon
  • a lesion such as a stenosis of a blood vessel
  • 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.
  • balloon catheters that can be used with large outer diameters are limited to vessels with a certain thickness such as coronary arteries.
  • pressure was received from the stenosis part of the blood vessel, and the balloon position was displaced from the lesion part.
  • Patent Document 2 Japanese Patent Application Laid-Open No. 09-084879
  • 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.
  • the present invention is as follows.
  • 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.
  • 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 [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.
  • 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.
  • [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.
  • 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
  • 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
  • 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
  • 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. 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.
  • E e Young's modulus
  • 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.
  • 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.
  • 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.
  • the diameter of the catheter sheath portion is 2 ram or less.
  • 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.
  • 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.
  • the apparatus of the present invention may include a marker for monitoring the position of the high-intensity pulsed light irradiation unit.
  • a marker for monitoring the position of the high-intensity pulsed light irradiation unit.
  • 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.
  • 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.
  • one or more radiopaque markers may be provided at the distal end of the catheter, for example.
  • one or more may be provided at the distal end of the optical transmission fiber.
  • 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 ⁇ , preferably 1 ⁇ 5 to 3 ⁇ , more preferably 1.5 to 2.5 ⁇ , and still more preferably a wavelength near the absorption maximum of water (1.9 ⁇ ).
  • the laser is expressed by the element ions that generate the laser and the type of the base material that holds the ions.
  • Ho Ho (holum), Tin (thulium), Er (erbium), Nd belonging to rare earths as elements (Neodymium) and the like, and Ho and Tm are preferable.
  • base materials include YAG, YSGG, and YV0.
  • 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. .
  • Ho YAG laser (oscillation wavelength 2.1 ⁇ )
  • 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 ⁇ 9 ⁇ ) are preferable.
  • laser generators examples 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 .
  • a wavelength in the vicinity of 0.3 to 3 ⁇ ⁇ , preferably 1.5 to 3 ⁇ , more preferably 1.5 to 2.5 ⁇ , 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 ⁇ S to 400 s. The pulse width is shown in full width at half maximum.
  • 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.
  • “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.
  • 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.
  • the direction of irradiation with high-intensity pulsed light is not limited.
  • a plurality of high-intensity pulsed light transmission fibers may be dispersed.
  • the fiber diameter is preferably 100 ⁇ ! ⁇ 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.
  • 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.
  • 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.
  • the inner diameter of the blood vessel is about 3 mm
  • the lateral length of the water vapor bubbles is about 0.3 to 6 mm, preferably 0.3 to 4.5 mm, more preferably 0. 1-3 wake up.
  • 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.
  • 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.
  • irradiation in the state of bare fiber is called a bare irradiation method.
  • 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.
  • 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.
  • a high-intensity pulsed light irradiation part 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. .
  • 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.
  • 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.
  • 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.
  • heat is generated by the high-intensity pulsed light, and the blood vessel wall is expanded and heated at the same time.
  • 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.
  • the degree of collagen denaturation is strong, the vessel wall dilates permanently.
  • 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.
  • 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.
  • a stent may be inserted and placed in the expanded portion to maintain the expanded state.
  • 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.
  • 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.
  • the stent it is preferable to use a self-expandable type (self-expanding type).
  • FIG. 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.
  • 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.
  • Blood flow is a pulsatile flow.
  • 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.
  • 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.
  • 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. .
  • aortic blood flow velocity 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the extracted peta carotid artery was used as the blood vessel.
  • 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.
  • FIG. 3 shows the configuration of the equipment used.
  • FIG. 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
  • 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
  • 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.
  • the collagen fibers are extended, and is equipped with orientation of the fibers.
  • 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.
  • Figure 9 shows the results.
  • the vertical axis represents the outer diameter of the blood vessel
  • 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.
  • Ho: YAG laser treatment device approved for medical use as YAG laser device (Wavelength 2. ⁇ ⁇ ⁇ ) (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.
  • 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.
  • 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.
  • 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.
  • the above-mentioned Ho: YAG laser device an optical fiber having a core diameter of 600 ⁇ and an outer diameter of 1000 / _tm was used.
  • 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
  • FIG. 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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)).
  • 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)).
  • the fever can be calculated as 6, 4 ° C (Fig. 18). (v)). This exotherm can cause shrinkage.
  • the intra-catheter irradiation method it takes time for the bubbles to reach the outside of the catheter.
  • the time at which the bubbles are generated is 100 Z s later than in the bare irradiation method, as shown in FIG.
  • 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.
  • 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.
  • 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.
  • physiological saline was used as a perfusate.
  • 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.
  • the unit is mm.
  • 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.
  • 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]
  • 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.
  • 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 / ⁇ 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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 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).
  • 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.
  • 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.
  • Figure 28 shows the vascular diameter expansion rate (bear irradiation method, laser energy change) versus the number of laser irradiations.
  • 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.
  • 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.
  • the estimated vessel inner diameter after 200 irradiations was 2.2 times larger than the initial estimated vessel inner diameter.
  • 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.
  • the estimated blood vessel inner diameter after 200 irradiations was 1.4 times the initial estimated blood vessel inner diameter.
  • 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.
  • the blood vessel outer diameter expansion rate increased with the number of irradiations, but was saturated after about 100 irradiations.
  • 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.
  • 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.
  • 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.
  • Laser irradiation conditions are irradiation method: bare irradiation method and intra-catheter irradiation method (3 mra), laser energy: 800 mJ / pulse
  • E e and E c were larger in the laser irradiated area than in the non-irradiated area.
  • E e of the laser non-irradiated part is 0. HMPa
  • E e of the laser irradiated part is e was 0.59 MPa.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the extension of the elastic lamina is seen compared to (b).
  • the medial lamellae stretched compared to (d), and the stretched state in (a) was maintained.
  • 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
  • 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.
  • 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.
  • the expansion caused by Ho: YAG laser-induced water vapor bubbles may involve the heat generated by the deformation of the vessel wall.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne un appareil destiné à dilater la paroi vasculaire qui utilise une lumière pulsée de haute intensité. L'invention concerne donc un vasodilatateur qui utilise une exposition à une lumière pulsée de haute intensité, ledit vasodilatateur comprenant un système d'exposition à une lumière pulsée de haute intensité, ledit système étant capable de générer des bulles de vapeur dans une cuve et comprenant une unité de génération d'une lumière pulsée de haute intensité, une unité de transfert d'une lumière pulsée de haute intensité et une unité d'exposition d'une cuve à une lumière pulsée de haute intensité, des bulles de vapeur étant ainsi générées dans la cuve par exposition à la lumière pulsée de haute intensité et la paroi vasculaire étant ainsi expansée et le vaisseau étant dilaté grâce aux bulles de vapeur.
PCT/JP2008/050665 2007-01-17 2008-01-15 Vasodilatateur WO2008088062A1 (fr)

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JP2012085812A (ja) * 2010-10-19 2012-05-10 Tohoku Univ 光ファイバーおよびそれを用いた水中衝撃波発生装置
EP3019238A1 (fr) * 2013-07-10 2016-05-18 Oxys AG Dispositifs et méthodes de distribution d'énergie thérapeutique

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WO2013147334A1 (fr) * 2012-03-27 2013-10-03 (주)루트로닉 Dispositif de chirurgie ophtalmique et méthode de commande associée
KR101451975B1 (ko) * 2013-03-19 2014-10-23 주식회사 루트로닉 레이저 조사 장치와 레이저 조사 방법
US10716508B2 (en) 2015-10-08 2020-07-21 Briteseed, Llc System and method for determining vessel size

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JP2003135606A (ja) * 1994-10-27 2003-05-13 Novoste Corp 血管系治療装置
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JP2004357792A (ja) * 2003-06-02 2004-12-24 Keio Gijuku 高強度パルス光照射により誘起される音圧波による血管再狭窄予防治療用装置
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WO2005063113A1 (fr) * 2003-05-01 2005-07-14 Keio University Appareil de diagnostic ou de traitement intravasculaire utilisant une lumiere pulsee a forte intensite
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012085812A (ja) * 2010-10-19 2012-05-10 Tohoku Univ 光ファイバーおよびそれを用いた水中衝撃波発生装置
EP3019238A1 (fr) * 2013-07-10 2016-05-18 Oxys AG Dispositifs et méthodes de distribution d'énergie thérapeutique
EP3019238A4 (fr) * 2013-07-10 2017-03-29 Oxys AG Dispositifs et méthodes de distribution d'énergie thérapeutique

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