WO2022042531A1 - 超声波搭配微气泡辅助的气球导管系统及其血管扩张方法 - Google Patents

超声波搭配微气泡辅助的气球导管系统及其血管扩张方法 Download PDF

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WO2022042531A1
WO2022042531A1 PCT/CN2021/114261 CN2021114261W WO2022042531A1 WO 2022042531 A1 WO2022042531 A1 WO 2022042531A1 CN 2021114261 W CN2021114261 W CN 2021114261W WO 2022042531 A1 WO2022042531 A1 WO 2022042531A1
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balloon catheter
ultrasonic
microbubbles
probe
blood vessel
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PCT/CN2021/114261
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English (en)
French (fr)
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叶秩光
蔡杰羽
李任光
赖俊延
谢宗翰
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清华大学
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Priority to EP21860366.0A priority Critical patent/EP4201481A1/en
Priority to CN202180052272.4A priority patent/CN116056759A/zh
Publication of WO2022042531A1 publication Critical patent/WO2022042531A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B17/22004—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
    • A61B17/22012—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement
    • A61B17/2202—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement the ultrasound transducer being inside patient's body at the distal end of the catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B17/22004—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
    • A61B17/22012—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves in direct contact with, or very close to, the obstruction or concrement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B17/22004—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for using mechanical vibrations, e.g. ultrasonic shock waves
    • A61B2017/22005—Effects, e.g. on tissue
    • A61B2017/22007—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing
    • A61B2017/22008—Cavitation or pseudocavitation, i.e. creation of gas bubbles generating a secondary shock wave when collapsing used or promoted
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22051—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for with an inflatable part, e.g. balloon, for positioning, blocking, or immobilisation
    • A61B2017/22062—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for with an inflatable part, e.g. balloon, for positioning, blocking, or immobilisation to be filled with liquid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22051—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for with an inflatable part, e.g. balloon, for positioning, blocking, or immobilisation
    • A61B2017/22065—Functions of balloons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance
    • A61B2017/22088—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance ultrasound absorbing, drug activated by ultrasound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance
    • A61B2017/22089—Gas-bubbles

Definitions

  • the present application relates to a balloon catheter device; more specifically, it particularly refers to a balloon catheter system assisted by ultrasound and microbubble and a vasodilation method thereof.
  • Atherosclerosis is a common chronic disease in modern society. It compresses blood vessels and causes blood flow to block. In severe cases, it can cause problems such as stroke. Calcification is a type of atherosclerosis and is often considered a marker for the presence of atherosclerosis. When blood vessels are calcified, the walls of blood vessels will harden and lose their due elasticity, resulting in poor vasoconstriction and relaxation. In addition, the phenomenon of excessive calcium deposition on the blood vessel wall can be called vascular calcification. There are many ways to treat atherosclerosis, such as laser or rotational atherectomy. The most common and cheapest method is balloon catheter dilation, which uses water pressure to open the balloon to restore the narrowed blood vessels. When the symptoms are too severe, the balloon often fails to open smoothly and ruptures, resulting in the risk of surgery.
  • the problems to be solved by the present application are: the problem that the balloon catheter cannot be opened in the existing surgical operation; or when the symptoms of calcification are too severe, the balloon cannot be successfully opened and ruptured, thus causing the risk of surgery. .
  • the main purpose of the present application is to provide a balloon catheter system assisted by ultrasound and microbubble, including: a controller; a sensor catheter; a highly focused ultrasonic probe, the highly focused ultrasonic probe and the sensor catheter are connected to the a controller; and a balloon catheter.
  • the secondary purpose of the present application is to utilize a blood vessel dilation method, comprising: providing a sensor catheter into a blood vessel, controlling a highly focused ultrasonic probe to focus on the vascular sclerosis; removing the sensor catheter from the blood vessel, placing a The balloon catheter enters the blood vessel; microbubbles are injected into the balloon catheter, and the highly focused ultrasonic probe is controlled to start working to destroy the calcified point of the sclerotic blood vessel; the balloon catheter is successfully stretched at the sclerotic part of the blood vessel.
  • Young's modulus commonly known as elastic modulus.
  • Pascal is a unit of pressure in the mechanics of materials, and billions of Pascals (GPa) are often used in engineering.
  • GPa Pascals
  • the Young's modulus of calcification in vivo is about 20-40GPa; for refractory calcification, the Young's modulus can reach 35-90GPa, or higher.
  • the present application combines an ultrasonic system with a microbubble and uses the microbubble to generate a cavitation effect.
  • the ultrasonic wave can be used to generate shock waves to break the microbubbles.
  • the present application provides a method for preparing microbubbles.
  • the microbubble preparation process is as follows: the microbubble used is a formula prepared by self-experimentation, and the formula is 1,2-dipalmitoylphosphatidylcholine (1,2- dipalmitoyl-sn-glycero-3-phosphocholine, DPPC), 1,2-distearoyl-Sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000](1,2 -distearoyl-sn-glycero-3-phosph oethanolamine-N-[methoxy(polyethylene glycol)-5000], DSPE-PEG 5000) and 1,2-distearoyl-phosphatidylglycerol (1,2-distearoyl-sn-
  • Another object of the present application is to provide a balloon catheter system assisted by ultrasound and microbubble, including: a controller; a balloon catheter; and at least one ultrasonic transducer probe, which is arranged on the balloon The inside of the catheter, and the ultrasonic transducer probe are connected to the controller.
  • the present application belongs to an externally guided probe, which uses a self-designed special ultrasonic wave pattern to carry out a structural destruction experiment on a vascular calcification model.
  • Another object of the present application is to utilize a blood vessel dilation method, including: providing a balloon catheter to enter the blood vessel; injecting microbubbles into the balloon catheter, and controlling an ultrasonic transducer probe to emit ultrasonic waves, breaking the microbubbles and The shock wave was released; the balloon catheter was successfully opened at the part of the hardened blood vessel.
  • Another object of the present application is to provide a microbubble solution composition, comprising: 1,2-dipalmitoylphosphatidylcholine (DPPC), 1,2-distearoylphosphatidylethanolamine-polyethylene glycol Alcohol (DSPE-PEG 5000) and 1,2-distearoylphosphatidylglycerol (DSPG), 1,2-dipalmitoylphosphatidylcholine: 1,2-distearoylphosphatidylethanolamine-polyethylene glycol
  • DPPC 1,2-dipalmitoylphosphatidylcholine
  • DSPE-PEG 5000 1,2-distearoylphosphatidylglycerol
  • 1,2-dipalmitoylphosphatidylcholine 1,2-distearoylphosphatidylethanolamine-polyethylene glycol
  • the weight ratio of alcohol:1,2-distearoylphosphatidylglycerol is 2.5:1:1, and the above three formulations are dissolved
  • the preferred ratio is 1,2-dipalmitoylphosphatidylcholine (DPPC) 10mg, 1,2-distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG 5000) 4mg, and 1,2- Distearoyl phosphatidyl glycerol (DSPG) 4 mg, the above three formulations were dissolved in chloroform solvent, heated and mixed with shaking.
  • DPPC 1,2-dipalmitoylphosphatidylcholine
  • DSPE-PEG 5000 1,2-distearoylphosphatidylethanolamine-polyethylene glycol
  • DSPG 1,2- Distearoyl phosphatidyl glycerol
  • microbubble solution composition the microbubble composition is lyophilized after being filled with a gas.
  • the gas as described above which is one or more components selected from nitrogen, carbon dioxide, oxygen or fluorocarbons.
  • FIG. 1 is a schematic diagram of a balloon catheter system assisted by ultrasound and microbubble according to an embodiment of the present application.
  • FIG. 2 is a schematic diagram of a balloon catheter system assisted by ultrasound and microbubble according to another embodiment of the present application.
  • FIG. 3 is a flow chart of a blood vessel dilation method according to an embodiment of the present application.
  • FIG. 4 is a flowchart of a blood vessel dilation method according to another embodiment of the present application.
  • Figure 5 Schematic diagram of the experimental architecture of the vascular calcification model of the present application.
  • Fig. 6a and Fig. 6b are schematic diagrams of the special ultrasonic waveform of the present application.
  • Figure 7 Particle size distribution diagram of concentration versus volume for microbubbles prepared in the present application.
  • Figure 8 Results of Feasibility Test A of the Externally Guided Probe of the present application.
  • Figure 9 Quantitative analysis results of the feasibility test A of the externally guided probe of the present application.
  • Figure 10 Results of Feasibility Test B of the Externally Guided Probe of the present application.
  • Figure 11 Architecture diagram of the feasibility test C of the externally guided probe of the present application.
  • Figure 12 3 kinds of tubular calcification models with different thicknesses of the built-in probe ultrasound of the present application.
  • Figure 13 Architecture diagram of the ultrasonic feasibility test of the built-in probe of the present application.
  • Figure 14 Architecture diagram of the ultrasonic feasibility test of the built-in probe of the present application.
  • Figure 15 The ultrasonic feasibility test of the built-in probe of this application - the experimental results of the ultrasonic action time.
  • Figure 17 The ultrasonic feasibility test of the built-in probe of the present application - the experimental results of the concentration of microbubbles.
  • Fig. 19 The test of the ultrasonic structure of the present application in the eggshell experiment.
  • FIG. 20 Experimental results of eggshell experiments.
  • Figure 21 Experimental setup for the biological effects studies of the present application.
  • Figure 22 Experimental results of a pig arterial vascular biological effect experiment.
  • FIG. 1 is a schematic diagram of a balloon catheter system assisted by ultrasonic waves and microbubbles according to one embodiment of the present application
  • FIG. 2 is a schematic diagram of a balloon catheter system assisted by ultrasonic waves and microbubble assistance according to another embodiment of the present application.
  • a balloon catheter system 1 assisted by ultrasound and microbubble includes: a controller 10 ; a sensor catheter 20 ; a highly focused ultrasound probe 30 , the highly focused ultrasound probe 30 and the sensor catheter 20 are connected to the controller 10; and a balloon catheter 40.
  • a balloon catheter system 2 assisted by ultrasound and microbubble includes: a controller 10; a balloon catheter 40; and at least one ultrasonic transducer probe 35, the ultrasonic transducer The transducer probe 35 is disposed inside the balloon catheter 40 , and the ultrasonic transducer probe 35 is connected to the controller 10 .
  • FIG. 3 is a flowchart of a blood vessel dilation method according to an embodiment of the present application.
  • a blood vessel dilation method includes: providing a sensor catheter 20 into a blood vessel, controlling a highly focused ultrasonic probe 30 to focus on the vascular sclerosis; 20 is removed from the blood vessel, a balloon catheter 40 is inserted into the blood vessel; the micro-bubble 45 is injected into the balloon catheter 40, and the highly focused ultrasonic probe 30 is controlled to start working to destroy the calcification point of the hardened blood vessel; the balloon catheter 40 is successfully Stretching in part of the hardened blood vessels.
  • step S310 a sensor catheter is provided into a blood vessel, and a highly focused ultrasonic probe is controlled to focus on the hardened part of the blood vessel.
  • step S320 the sensor catheter is removed from the blood vessel, and a balloon catheter is inserted into the blood vessel.
  • step S330 microbubbles are injected into the balloon catheter, and the highly focused ultrasonic probe is controlled to start working to destroy the calcification points of the hardened blood vessels.
  • step S340 the balloon catheter is successfully stretched at the part of the vascular sclerosis.
  • FIG. 4 is a flowchart of a blood vessel dilation method according to another embodiment of the present application.
  • a blood vessel dilation method includes: providing a balloon catheter 40 to enter the blood vessel; injecting microbubbles 45 into the balloon catheter 40 , and controlling an ultrasonic transducer probe 35 launches ultrasonic waves to break the microbubbles 45 and release shock waves; the balloon catheter 40 is successfully stretched at the part of the vascular sclerosis.
  • step S410 a balloon catheter is provided to enter the blood vessel.
  • step S420 microbubbles are poured into the balloon catheter, and an ultrasonic transducer probe is controlled to emit ultrasonic waves to break the microbubbles and release shock waves.
  • step S430 the balloon catheter is successfully stretched at the part of the vascular sclerosis.
  • gypsum production 10:7 weight ratio of gypsum and water is prepared into slurry, poured into the mold, placed in the oven for 20 minutes to complete curing, and whether the calcified model has a similar Young's mold to the real vascular calcified tissue. number (elasticity), as shown in Table 1 below.
  • the test results show that the Young's modulus of common refractory calcified tissues is about 110-130GPa, so the model made in this experiment can approximate the parameters of refractory calcified tissues.
  • FIG. 5 a schematic diagram of the experimental architecture of the vascular calcification model of the present application.
  • the general in vivo calcification model 50 uses 58.8% plaster (thickness: 3mm), and the Young's modulus is 12.3GPa;
  • the stubborn calcification model 50 is made of 80.6% gypsum (thickness: 3 mm) and has a Young's modulus of 110-130 GPa.
  • phospholipid microbubbles (40.6*10 6 MBs/mL) in the balloon catheter 40, which is treated with 1.5MHz ultrasonic wave 60 (ultrasound insonation) for 30 minutes, and the ultrasonic system is combined with the microbubbles and the microbubbles are used to generate cavitation effects 65 ( cavitation effect).
  • FIG. 6a a schematic diagram of the special ultrasonic waveform of the application.
  • the pressure is 100kPa
  • the duty cycle is 98%.
  • Microbubbles are delivered in close proximity to the inner surface of the balloon.
  • Destruction pulses were then used with a center frequency of 1.5 MHz, a pressure of 800 kPa, and a duty cycle of 2% for cavitation induced by ultrasound and microbubbles.
  • the gypsum was scanned and imaged by 20MHz C-Scan imaging software (C-scan imaging system) before and after ultrasonic treatment to draw the difference map.
  • FIG. 6b for a schematic diagram of a special ultrasonic waveform of the application, at a center frequency of 600 kHz, radiation force pulses are used, the pressure is 15 kPa, and the duty cycle is 99%. , which delivers the phospholipid microbubbles in close proximity to the inner surface of the balloon.
  • Destruction pulses were then used with a center frequency of 600 kHz, a pressure of 150 kPa, and a duty cycle of 1% for cavitation induced by ultrasound and microbubbles.
  • the gypsum was scanned and imaged by 20MHz C-Scan imaging software (C-scan imaging system) before and after ultrasonic treatment to draw the difference map.
  • the preparation process is as follows: the microbubble used is a formula prepared by self-experimentation, and the formula is 1,2-dipalmitoylphosphatidylcholine (DPPC), 1,2-distearoylphosphatidylethanolamine-polyamide
  • DPPC 1,2-dipalmitoylphosphatidylcholine
  • DSPG 1,2-distearoylphosphatidylethanolamine-polyamide
  • the formula of the formula is 1,2-dipalmitoylphosphatidylcholine (DPPC) 10mg, 1,2-distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG 5000) 4mg and 1,2-distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG 5000) 2-Distearoylphosphatidylglycerol (DSPG) 4mg.
  • DPPC 1,2-dipalmitoylphosphatidylcholine
  • DSPE-PEG 5000 1,2-distearoylphosphatidylethanolamine-polyethylene glycol
  • DSPG 2-Distearoylphosphatidylglycerol
  • each sub-packaging tank was filled with 250 ⁇ L, placed in a 65°C water bath, heated and evaporated to dryness, and after 30 minutes, vacuumed until the next day to completely evaporate the solvent.
  • glycerol was dissolved in 20 ml of phosphate buffered saline (PBS), and 800 ⁇ L was added to the aliquoting tank. Take a water bath with 65°C hot water for 5 minutes, then use an ultrasonic oscillator to mix the solution evenly, and use an air pump to pump out the gas dissolved in the water phase. After degassing is completed, octachloropropane (perfluoropropane, C 3 F 8 ) is added, and the sample is shaken for 45 seconds. During the shaking process, lipids will form bubbles containing cavities due to the effect of surface tension. That is, the microbubbles used in this application.
  • PBS phosphate buffered saline
  • FIG. 7 Please refer to FIG. 7 for the particle size distribution diagram of concentration versus volume prepared by the microbubbles of the present application.
  • Probe used 1.5MHz ultrasonic probe.
  • This experiment uses the 1000-fold diluted solution prepared from the microbubbles described above.
  • Group A is an ultrasound group using radiation pulses and microbubbles (abbreviated as: US w/RF+MB, also known as "radiation force group”).
  • US w/RF+MB also known as "radiation force group”
  • Microbubbles are injected into the balloon catheter.
  • Ultrasonic waves with 9,800 cycles of relatively small amplitude are used first to generate a thrust that pushes the microbubbles against the balloon wall.
  • ultrasonic waves with a large amplitude for 200 cycles to generate destructive force the micro-bubble is destroyed by the change of large amplitude, resulting in a cavitation effect, and then a strong shock wave is released to destroy the calcified structure.
  • Group B is the ultrasonic group using microbubbles (abbreviated as: US w/o RF+MB, also known as "non-radiation force group”), and the operation sequence is as follows:
  • Microbubbles are injected into the balloon catheter.
  • This group did not use ultrasonic waves to generate thrust to push the micro-bubbles onto the balloon wall in advance, and only used ultrasonic waves with a large amplitude for 200 cycles to generate destructive force.
  • the micro-bubble was destroyed by the change of large amplitude, thereby generating cavities effect and release a powerful shock wave, destroying the calcification model.
  • Group C is the ultrasound-only group (abbreviated as: US only, also known as “control group”), and the operation sequence is as follows:
  • This group was the control group, only 200 cycles of ultrasonic waves with large amplitude were used throughout the whole process, and the destructive force on the calcification model was tested in the absence of thrust and microbubbles.
  • FIG. 8 Please refer to FIG. 8 for the result of the feasibility test A of the externally guided probe of the present application.
  • the planar vascular calcification model was scanned by 20MHz high-frequency ultrasonic surface before and after the experiment. It can be seen that the radiation force group 801 (A.US w/RF+MB) and the non-radiation force group 802 (B.US w /o RF+MB) and the control group 803 (C.US only), the radiation force group 801 has a better effect.
  • the quantification results of the calcification structure damage in each group of the externally guided probe feasibility test A of the present application showing the damaged area of the calcification model in each group.
  • the damaged area of the radiation force group was 1.4 mm 2
  • the damaged area of the non-radiative force group was 0.8 mm 2 .
  • the radiation force group could increase the calcification damage by 68%. (p ⁇ 0.05).
  • the method proposed in the present application can destroy the calcified structure to assist in the expansion of the balloon catheter.
  • a balloon catheter with a piezoelectric sheet inside will be designed, so that the ultrasonic pulse can be controlled more precisely when the balloon is expanded.
  • Probe used 600kHz ultrasonic probe.
  • microbubbles This experiment uses a 100-fold dilution of the microbubbles prepared above.
  • Group A is an ultrasound group using radiation pulses and microbubbles (abbreviated as: US w/RF+MB, also known as "radiation force group”).
  • US w/RF+MB also known as "radiation force group”
  • Microbubbles are injected into the balloon catheter.
  • Ultrasonic waves with 9,900 cycles of relatively small amplitude are used first to generate a thrust that pushes the microbubbles against the balloon wall.
  • ultrasonic waves with a large amplitude for 100 cycles to generate destructive force the micro-bubble is destroyed by the change of large amplitude, resulting in a cavitation effect, and then a strong shock wave is released to destroy the calcified structure.
  • Group B is the ultrasonic group using microbubbles (abbreviated as: US w/o RF+MB, also known as "non-radiation force group”).
  • US w/o RF+MB also known as "non-radiation force group”
  • Microbubbles are injected into the balloon catheter.
  • This group did not use ultrasonic waves to generate thrust to push the micro-bubbles onto the balloon wall in advance, and only used ultrasonic waves with a large amplitude for 100 cycles to generate destructive force throughout the whole process. effect and release a powerful shock wave, destroying the calcification model.
  • Group C is the ultrasound-only group (abbreviated as: US only, also known as “control group”), and the operation sequence is as follows:
  • This group was the control group, and only 100 cycles of ultrasonic waves with large amplitude were used in the whole process, and the destructive power to the calcification model was tested in the absence of microbubbles.
  • FIG. 10 Please refer to FIG. 10 for the result of the feasibility test B of the externally guided probe of the application.
  • the planar vascular calcification model was scanned by 20MHz high-frequency ultrasonic surface before and after the experiment. It can be seen that the radiation force group 801 (A.US w/RF+MB) and the non-radiation force group 802 (B.US w /o RF+MB) and the control group 803 (C.US only), the radiation force group 801 has a better effect.
  • this experiment tests the tubular calcification model to test whether the experimental design can help to stretch or destroy the tubular calcification model.
  • Mold using the mold made by 3D printing, a ring-shaped general in vivo vascular calcification model (thickness 3mm) was prepared to simulate the superficial calcific sheet, the most common form of calcification in real blood vessels.
  • the balloon catheter 40 was covered with a tubular calcification model 50 in the experimental group (with ultrasound) and the control group (without ultrasound).
  • the balloon catheter 40 is infused with microbubbles.
  • the experimental group applied the above-mentioned ultrasonic 60 special wave pattern designed with the external guided probe feasibility test A, and the action time was 10 minutes.
  • the control group did not receive any ultrasound.
  • the experimental group and the control group were pressurized with water pressure, and the water pressure required for the cylindrical calcification model 50 to be propped up by the balloon until it was ruptured was recorded.
  • the tubular calcification model can be stretched or destroyed under 6 atm water pressure.
  • Control group The tubular calcification model can be stretched or destroyed under 8 atm water pressure.
  • the embodiment of the present application uses a sensor catheter to assist the focus of the ultrasonic wave at the lesion, and its working method is as follows:
  • the sensor catheter enters the blood vessel, and is guided by the sensor catheter to control the ultrasound probe to focus on the lesion.
  • the sensor catheter is removed and the balloon catheter is inserted.
  • the balloon catheter was filled with microbubbles, and ultrasonic waves were applied to destroy the calcified tissue.
  • the balloon catheter is opened and the treatment is completed.
  • the built-in probe ultrasonic structure uses an ultrasonic probe made of a piezoelectric tube (PT120.00, Physik Instrumente) purchased by PI (Ceramic GmbH, Lederhose, Germany), and is tested with a cylindrical calcification model to analyze Whether the result can effectively reduce the water pressure required to expand the balloon.
  • PT120.00 piezoelectric tube
  • PI Ceremic GmbH, Lederhose, Germany
  • Figure 12 three general in vivo vascular calcification models with different thicknesses of 2 mm, 3 mm and 4 mm were used for testing.
  • FIG. 13 Please refer to FIG. 13 for the ultrasonic feasibility test of the built-in probe of the application, and the description is as follows:
  • the vascular calcification models 50 of the control group and the experimental group were placed in water.
  • microbubbles were poured into the experimental group, and put into the piezoelectric tube 55 to start applying the special ultrasonic wave pattern, please refer to Fig. 6a, and applied for 20 minutes.
  • the control group does not put the piezoelectric tube 55 into it.
  • control group and the experimental group were taken out, a balloon catheter was inserted, the water pressure was slowly increased, and the water pressure required for the tubular calcification model 50 to be propped up by the balloon was recorded.
  • Table 3 shows the experimental results of the built-in probe ultrasonic feasibility test-vascular calcification model with different thicknesses:
  • the built-in probe ultrasonic structure uses an ultrasonic probe made of piezoelectric tubes purchased by PI, and is tested with a tubular calcification model to analyze whether the results can effectively reduce the water pressure required for balloon expansion.
  • a 3mm thick stubborn calcification model was used in this experiment for testing.
  • FIG. 14 Please refer to FIG. 14 for the ultrasonic feasibility test of the built-in probe of the application, and the description is as follows:
  • the vascular calcification models 50 of the control group and the experimental group were placed in water.
  • Experimental group The piezoelectric tube 55 was vertically fixed in the vascular calcification model 50, and ultrasound only (US only) or ultrasound plus microbubbles (US+MBs) was administered; control group: ultrasound and microbubbles were not used (Untreated) .
  • microbubbles were injected into the vascular calcification model 50 of the experimental group at a rate of 144 mL/hr, and ultrasonic waves were emitted to act on them with the set parameters.
  • the ultrasonic parameters applied are: frequency 600kHz, pressure: 300kPa, cycles (cycles): 100, pulse repetition frequency (PRF): 1Hz, microbubble concentration: the original concentration of 40*10 9 MBs/ml 100 times dilution, effect Time 10-30 minutes.
  • control group and the experimental group were taken out, a balloon catheter was inserted, the water pressure was slowly increased, and the water pressure required for the tubular calcification model 50 to be propped up by the balloon was recorded.
  • Figure 15 shows the experimental results of the built-in probe ultrasonic feasibility test—ultrasonic action time.
  • the water pressure required for the calcification model of the group without ultrasound and microbubble (Untreated) to be propped up to rupture by the balloon was greater than 12 atm; the calcification model of the group with only ultrasound (US only) was propped up to the rupture by the balloon.
  • the required water pressure is 11 atm; the water pressure required for the calcification model to be propped up by the balloon until it splits is 8.75 atm when combined with ultrasonic waves and micro-bubbles for 10 minutes (US+MBs (10 min));
  • the minute (US+MBs (20min)) calcified model was ballooned to rupture with a water pressure of 7.4 atm.
  • the built-in probe ultrasonic structure uses an ultrasonic probe made of piezoelectric tubes purchased by PI, and is tested with a tubular calcification model to analyze whether the results can effectively reduce the water pressure required for balloon expansion.
  • a stubborn calcification model with a thickness of 3 mm was used for testing.
  • FIG. 14 Please refer to FIG. 14 for the ultrasonic feasibility test of the built-in probe of the application, and the description is as follows:
  • the vascular calcification model 50 is placed in water, and the piezoelectric tube 55 is vertically fixed in the vascular calcification model 50 .
  • microbubbles were injected into the vascular calcification model 50 of the experimental group at a rate of 144 mL/hr, and ultrasonic waves were emitted to act on them with the set parameters.
  • the ultrasonic parameters applied are: frequency 600kHz, pressure: 300kPa, cycles (cycles): 10-1000, pulse repetition frequency (PRF): 1Hz, microbubble concentration: 100-fold dilution of the original concentration of 40* 109 MBs/ml , Action time 20 minutes.
  • the vascular calcification model 50 is taken out, a balloon catheter is inserted, the water pressure is slowly increased, and the water pressure required for the round tubular calcification model 50 to be propped up by the balloon to be ruptured is recorded.
  • Figure 16 shows the experimental results of the built-in probe ultrasonic feasibility test - ultrasonic cycles.
  • the calcification models with 10, 100, 500, and 1000 ultrasonic cycles were propped up by balloons and the required water pressure was greater than 12, 6.63, 8.13, and 9 atm, respectively.
  • the built-in probe ultrasonic structure uses an ultrasonic probe made of piezoelectric tubes purchased by PI, and is tested with a tubular calcification model to analyze whether the results can effectively reduce the water pressure required for balloon expansion.
  • a stubborn calcification model with a thickness of 3 mm was used for testing.
  • FIG. 14 Please refer to FIG. 14 for the ultrasonic feasibility test of the built-in probe of the application, and the description is as follows:
  • the vascular calcification model 50 is placed in water, and the piezoelectric tube 55 is vertically fixed in the vascular calcification model 50 .
  • the microbubbles were injected into the vascular calcification model 50 of the experimental group at a rate of 144 mL/hr, and ultrasonic waves were emitted to act on them with the set parameters.
  • the ultrasonic parameters applied are: frequency 600kHz, pressure: 300kPa, cycles (cycles): 100, pulse repetition frequency (PRF): 1Hz, microbubble concentration: 75 times and 100 times the original concentration of 40*10 9 MBs/ml , 200-fold dilution, and no micro-bubble group, the action time is 20 minutes.
  • the vascular calcification model 50 is taken out, a balloon catheter is inserted, the water pressure is slowly increased, and the water pressure required for the round tubular calcification model 50 to be propped up by the balloon to be ruptured is recorded.
  • Figure 17 shows the experimental results of the built-in probe ultrasonic feasibility test - microbubble concentration.
  • the calcification models of the microbubble concentration of 75-fold, 100-fold, 200-fold dilution, and no microbubble groups were propped up by balloons to the required water pressure of 7.25, 8.2, 9.5 and 11 atm, respectively.
  • the built-in probe ultrasonic structure uses an ultrasonic probe made of piezoelectric tubes purchased by PI, and is tested with a tubular calcification model to analyze whether the results can effectively reduce the water pressure required for balloon expansion.
  • a stubborn calcification model with a thickness of 3 mm was used for testing.
  • FIG. 14 Please refer to FIG. 14 for the ultrasonic feasibility test of the built-in probe of the application, and the description is as follows:
  • the vascular calcification model 50 is placed in water, and the piezoelectric tube 55 is vertically fixed in the vascular calcification model 50 .
  • the microbubbles were injected into the vascular calcification model 50 of the experimental group at a rate of 144 mL/hr, and ultrasonic waves were emitted to act on them with the set parameters.
  • the ultrasonic parameters applied are: frequency 600kHz, pressure: 150kPa, 200kPa, 300kPa, cycles (cycles): 100, pulse repetition frequency (PRF): 1Hz, microbubble concentration: 100 of the original concentration of 40*10 9 MBs/ml Double dilution, the action time is 20 minutes.
  • the vascular calcification model 50 is taken out, a balloon catheter is inserted, the water pressure is slowly increased, and the water pressure required for the round tubular calcification model 50 to be propped up by the balloon to be ruptured is recorded.
  • Figure 18 shows the ultrasonic feasibility test of the built-in probe—the experimental result of ultrasonic pressure.
  • the calcification models with ultrasonic pressures of 150kPa, 200kPa, and 300kPa were propped up by the balloon to the required water pressure of 10.67, 9.33, and 7.88 atm, respectively.
  • the ultrasonic structure uses an ultrasonic probe made of a piezoelectric tube purchased by PI Company, and acts on the egg shell for testing.
  • a shock wave is generated from the inside of the egg shell to observe the effect of the egg shell surface to confirm the effectiveness of the shock wave on the surface of biological calcium. sex.
  • FIG. 19 Please refer to FIG. 19 for the test of the ultrasonic structure of the application in the eggshell experiment, and the description is as follows:
  • An eggshell 70 is prepared, and the piezoelectric tube 55 is mounted on the eggshell in parallel.
  • the microbubbles 45 were poured into the ultrasonic effect area near the eggshell 70 at a speed of 144 mL/hr, and ultrasonic waves were emitted according to the set parameters for effect.
  • the ultrasonic parameters applied are: frequency 600kHz, pressure: 300kPa, cycles (cycles): 100, pulse repetition frequency (PRF): 1Hz, microbubble concentration: 100 times dilution of the original concentration 40*10 9 MBs/ml, the effect Time 20 minutes.
  • the control group used the same ultrasonic parameters, but no microbubbles.
  • the eggshell 70 was stained with Evans Blue to reveal cracks on the surface of the eggshell.
  • the eggshell 70 was observed under a dissecting microscope.
  • Figure 20 is the experimental result of the eggshell experiment. No cracks were found on the eggshell in the control group (US only); obvious cracks were observed in the experimental group (US+MBs(20min)).
  • the ultrasonic structure uses an ultrasonic probe made of piezoelectric tubes purchased by PI, and acts on the inner wall of pig arteries to observe the biological effects of ultrasonic shock waves on the inner wall of arteries.
  • FIG. 21 Please refer to FIG. 21 for the experimental device for the biological effect research of the application, and the description is as follows:
  • the piezoelectric tube 55 is placed in the arterial vessel 75 .
  • microbubbles were perfused into the arterial blood vessels 75 at a rate of 144 mL/hr, and ultrasonic waves were emitted with the set parameters for action.
  • the ultrasonic parameters applied are: frequency 600kHz, pressure: 300kPa, cycles (cycles): 100, pulse repetition frequency (PRF): 1Hz, microbubble concentration: 100 times dilution of the original concentration 40* 109 MBs/ml, the effect Time 20 minutes.
  • the control group used ultrasound only (US only), microbubbles only (MBs only), and neither ultrasound nor microbubbles (Untreated).
  • the piezoelectric tube was taken out, and the arterial blood vessel 75 was sliced to observe whether the inner wall of the blood vessel was damaged under a microscope.
  • Figure 22 shows the experimental results of the pig arterial vascular biological effect experiment. No damage to the inner wall of blood vessels was observed in all groups, indicating that the shock waves generated by ultrasound 60 plus microbubbles would not damage the inner wall of blood vessels.

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Abstract

一种超声波搭配微气泡辅助的气球导管系统（1）及其血管扩张方法，该系统（1）包括：一控制器（10）；一传感器导管（20）；一高度聚焦式超声波探头（30），该高度聚焦式超声波探头（30）及该传感器导管（20）连接于该控制器（10）；以及一气球导管（40）；该血管扩张方法，包括：提供一传感器导管（20）进入一血管，控制一高度聚焦式超声波探头（30）在血管硬化处进行对焦（S310）；将该传感器导管（20）从该血管移出，将一气球导管（40）进入该血管（S320）；将微气泡灌入该气球导管（40），并控制该高度聚焦式超声波探头（30）开始工作破坏硬化血管的钙化点（S330）；顺利将该气球导管（40）在血管硬化的部分位置撑开（S340）。

Description

超声波搭配微气泡辅助的气球导管系统及其血管扩张方法 技术领域
本申请关于一种气球导管设备；更详而言之，特别指一种超声波搭配微气泡辅助的气球导管系统及其血管扩张方法。
背景技术
动脉粥状硬化症是现代社会常见的慢性病，会压缩血管导致血流不通，严重的话会造成中风等问题。钙化是动脉粥状硬化症的一种类型，也常被认为是动脉粥状硬化症存在的标志。当血管钙化会造成血管壁变硬，并失去应有的弹性，使得血管的收缩及舒张的功能变差。并且，血管壁上出现钙有过量沉积的现象，就可称之为血管钙化。一般治疗粥状硬化的方式有很多，例如激光或旋磨术，现行最常见也是最便宜的方法则是气球导管扩张术，利用水压将气球撑开，进而恢复狭窄的血管，然而当硬化的症状太过严重时，常会导致气球无法顺利撑开而破裂，造成手术的风险。
因此我们提出了一个方法可以大大降低这个风险：利用超声波震动微气泡会放出震波的原理，我们将这项技术融合气球导管以治疗血管硬化造成的血管狭窄。经实验发现我们提出的方法可以有效破坏钙化的结构，进而协助气球导管撑开。产品分为内置式探头跟外部引导式探头。
发明内容
本申请所欲解决的问题在于：现有外科手术中气球导管撑不开的问题；或是当钙化的症状太过严重时，常导致气球无法顺利撑开而破裂，因而造成外科手术时的风险。
本申请的主要目的在于，提供一种超声波搭配微气泡辅助的气球导管系统，包括：一控制器；一传感器导管；一高度聚焦式超声波探头，该高度聚焦式超声波探头及该传感器导管连接于该控制器；以及一气球导管。
本申请的次要目的在于，利用一种血管扩张方法，包括：提供一传感器导管进入一血管，控制一高度聚焦式超声波探头在血管硬化处进行对焦；将该传感器导管从该血管移出，将一气球导管进入该血管；将微气泡灌入该气球导管，并控制该高度聚焦式超声波探头开始工作破坏硬化血管的钙化点；顺利将该气球导管在血管硬化的部分位置撑开。
杨氏模数(Young's modulus)，一般称为弹性模量。帕斯卡(Pa)是材料力学中压力的单位，在工程中常使用十亿帕斯卡(GPa)。弹性材料在承受正向应力时会产生正向应变，在形变量没有超过对应材料的一定弹性限度时，得到正向应力与正向应变的比值。一般体内钙化杨氏模数约在20-40GPa左右；对于顽固型钙化，杨氏模数可达35-90GPa，或更高。
对于一般体内钙化(杨氏模数约在20-40GPa)，本实验血管钙化模型采用58.8％的石膏(厚 度：3mm)，杨氏模数为12.3GPa；对于顽固型钙化(杨氏模数约在35-90GPa或更高)，本实验血管钙化模型采用80.6％的石膏(厚度：3mm)，杨氏模数为110-130GPa。因实验的目的是辅助气球导管撑开，目的是运用超声波震动微气泡以辅助气球导管撑开已钙化的血管，故钙化的弹性系数成为本实验在制作血管钙化模型上首要考虑的要素。
在弹性检测上，已知为一种杨氏模数的量测材料检测方式，本实验利用横波探头非破坏性检测法，以确认58.8％石膏的实验模型是否与真正的钙化有相近的杨氏模数。
本申请将超声波系统结合微气泡(microbubble)并运用微气泡产生空穴效应(cavitation effect)。当微气泡被送入血管，并将微气泡吸附于目标位置时，即可使超声波作用，产生震波震碎微气泡。本申请提供一种微气泡的制备方法，微气泡制备流程如下所述：所使用的该微气泡是自行实验调制的配方，配方为1,2-二棕榈酰磷脂酰胆碱(1,2-dipalmitoyl-sn-glycero-3-phosphocholine,DPPC)、1,2-二硬脂酰-Sn-甘油-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)-5000](1,2-distearoyl-sn-glycero-3-phosph oethanolamine-N-[methoxy(polyethylene glycol)-5000],DSPE-PEG 5000)及1,2-二硬脂酰磷脂酰甘油(1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol),DSPG)重量比为DPPC：DSPE-PEG 5000：DSPG＝2.5：1：1)。本实验使用浓度会再稀释1000倍，另也可通过调整成分比例做应用。
本申请的另一目的在于，提供一种超声波搭配微气泡辅助的气球导管系统，包括：一控制器；一气球导管；以及至少一超声波换能器探头，该超声波换能器探头设置于该气球导管内部，以及该超声波换能器探头连接该控制器。
本申请属于外部引导式探头，利用自行设计的超声波特殊波型，对血管钙化模型进行破坏结构实验。
本申请的又一目的在于，利用一种血管扩张方法，包括：提供一气球导管进入该血管；将微气泡灌入该气球导管，并控制一超声波换能器探头发射超声波，击破该微气泡并放出震波；顺利将该气球导管在血管硬化的部分位置撑开。
本申请的又一目的在于，提供一种微气泡的溶液组成物，包含：1,2-二棕榈酰磷脂酰胆碱(DPPC)、1,2-二硬脂酰磷脂酰乙醇胺-聚乙二醇(DSPE-PEG 5000)及1,2-二硬脂酰磷脂酰甘油(DSPG)，1,2-二棕榈酰磷脂酰胆碱：1,2-二硬脂酰磷脂酰乙醇胺-聚乙二醇：1,2-二硬脂酰磷脂酰甘油的重量比为2.5：1：1，将上述三种配方溶于二氯甲烷、三氯甲烷、乙腈、甲醇或乙酸乙酯的一种以上溶剂，经加热并震荡混合。
较佳的比例为1,2-二棕榈酰磷脂酰胆碱(DPPC)10mg、1,2-二硬脂酰磷脂酰乙醇胺-聚乙二醇(DSPE-PEG 5000)4mg、及1,2-二硬脂酰磷脂酰甘油(DSPG)4mg，将上述三种配方溶于三氯甲烷溶剂，经加热并震荡混合。
如上所述的微气泡的溶液组成物，该微气泡的组成物经填充一气体处理后冻干。
如上所述的气体，该气体为氮气、二氧化碳、氧气或碳氟化合物中的一种以上成分。
附图说明
图1：本申请一个实施例的超声波搭配微气泡辅助的气球导管系统示意图。
图2：本申请另一个实施例的超声波搭配微气泡辅助的气球导管系统示意图。
图3：本申请一个实施例的血管扩张方法流程图。
图4：本申请另一个实施例的血管扩张方法流程图。
图5：本申请血管钙化模型实验架构示意图。
图6a及图6b：本申请特殊超声波波形示意图。
图7：本申请微气泡制备的浓度对体积的粒径分布图。
图8：本申请外部引导式探头可行性测试A的结果。
图9：本申请外部引导式探头可行性测试A的量化分析结果。
图10：本申请外部引导式探头可行性测试B的结果。
图11：本申请外部引导式探头可行性测试C架构图。
图12：本申请内置式探头超声波的3种不同厚度的圆管状钙化模型。
图13：本申请内置式探头超声波可行性测试架构图。
图14：本申请内置式探头超声波可行性测试架构图。
图15：本申请内置式探头超声波可行性测试–超声波作用时间的实验结果。
图16：本申请内置式探头超声波可行性测试–超声波周数的实验结果。
图17：本申请内置式探头超声波可行性测试–微气泡浓度的实验结果。
图18：本申请内置式探头超声波可行性测试–超声波压力的实验结果。
图19：本申请超声波架构于蛋壳实验的测试。
图20：蛋壳实验的实验结果。
图21：本申请生物效应研究的实验装置。
图22：猪只动脉血管生物效应实验的实验结果。
符号说明：
1超声波搭配微气泡辅助的气球导管系统；
2超声波搭配微气泡辅助的气球导管系统；
10控制器；
20传感器导管；
30高度聚焦式超声波探头；
35超声波换能器探头；
40气球导管；
45微气泡；
50钙化模型；
55压电管；
60超声波；
65空穴效应；
70蛋壳；
75动脉血管；
801有辐射力组；
802无辐射力组；
803控制组；
S310～S340步骤；
S410～S430步骤。
具体实施方式
下面结合附图和具体实施例对本申请作进一步说明，以使本领域的技术人员可以更好的理解本申请并能予以实施，但所举实施例不作为对本申请的限定。
图1为本申请一个实施例的超声波搭配微气泡辅助的气球导管系统示意图及图2为本申请另一个实施例的超声波搭配微气泡辅助的气球导管系统示意图。请参阅图1，本申请一实施例，一种超声波搭配微气泡辅助的气球导管系统1，包括：一控制器10；一传感器导管20；一高度聚焦式超声波探头30，该高度聚焦式超声波探头30及该传感器导管20连接于该控制器10；以及一气球导管40。
请参阅图2，本申请一实施例，一种超声波搭配微气泡辅助的气球导管系统2，包括：一控制器10；一气球导管40；以及至少一超声波换能器探头35，该超声波换能器探头35设置于该气球导管40内部，以及该超声波换能器探头35连接该控制器10。
图3为本申请一个实施例的血管扩张方法流程图。请参阅图1及图3，本申请一实施例，一种血管扩张方法，包括：提供一传感器导管20进入一血管，控制一高度聚焦式超声波探头30在血管硬化处进行对焦；将该传感器导管20从该血管移出，将一气球导管40进入该血管；将微气泡45灌入该气球导管40，并控制该高度聚焦式超声波探头30开始工作破坏硬化血管的钙化点；顺利将 该气球导管40在血管硬化的部分位置撑开。
请参阅图3，在步骤S310中，提供一传感器导管进入一血管，控制一高度聚焦式超声波探头在血管硬化处进行对焦。
请参阅图3，在步骤S320中，将该传感器导管从该血管移出，将一气球导管进入该血管。
请参阅图3，在步骤S330中，将微气泡灌入该气球导管，并控制该高度聚焦式超声波探头开始工作破坏硬化血管的钙化点。
请参阅图3，在步骤S340中，顺利将该气球导管在血管硬化的部分位置撑开。
图4为本申请另一个实施例的血管扩张方法流程图。请参阅图2及图4，本申请一实施例，一种血管扩张方法，包括：提供一气球导管40进入该血管；将微气泡45灌入该气球导管40，并控制一超声波换能器探头35发射超声波，击破该微气泡45并放出震波；顺利将该气球导管40在血管硬化的部分位置撑开。
请参阅图4，在步骤S410中，提供一气球导管进入该血管。
请参阅图4，在步骤S420中，将微气泡灌入该气球导管，并控制一超声波换能器探头发射超声波，击破该微气泡并放出震波。
请参阅图4，在步骤S430中，顺利将该气球导管在血管硬化的部分位置撑开。
本申请一较佳实施例
实验方法
血管钙化模型-一般体内钙化模型
58.8％的石膏制作：将石膏与水以10：7的重量比例调制成浆，倒入模具后，置于烘箱20分钟完成固化，检测钙化模型是否与真正的血管钙化组织有相近的杨氏模数(弹性)，如下表1。
一般体内钙化模型检测结果：
材料 厚度(mm) 杨氏模数(GPa)
玻璃(标准物) 4.8 82.13
模型1 2.8 12.29
模型2 2.57 12.27
模型3 2.94 20.23
检测结果显示，常见一般体内钙化组织的杨氏模数约为20-40GPa，因此本实验制作的模型已可近似一般体内钙化组织的参数。
血管钙化模型-顽固型钙化模型
80.6％的石膏制作：将石膏与水以25：6的重量比例调制成浆，倒入模具后，静置20分钟完 成固化，检测钙化模型是否与真正的血管钙化组织有相近的杨氏模数(弹性)，如下表2。
顽固型钙化模型检测结果：
材料 厚度(mm) 杨氏模数(GPa)
模型1 3 133.81
模型2 2.6 113.85
模型3 2.6 116.09
检测结果显示，常见顽固型钙化组织的杨氏模数约为110-130GPa，因此本实验制作的模型已可近似顽固型钙化组织的参数。
请参阅图5为本申请血管钙化模型实验架构示意图，为了应用在内置式探头或外部引导式探头，一般体内钙化模型50采用58.8％的石膏(厚度：3mm)，杨氏模数为12.3GPa；顽固型钙化模型50采用80.6％的石膏(厚度：3mm)，杨氏模数为110-130GPa。气球导管40内有磷脂质微气泡(40.6*10 6MBs/mL)，以1.5MHz的超声波60(ultrasound insonation)下处理30分钟，将超声波系统结合微气泡并运用微气泡产生空穴效应65(cavitation effect)。
请参阅图6a为本申请特殊超声波波形示意图，在中心频率1.5MHz下，使用辐射脉冲(radiation force pulses)，压力(pressure)为100kPa，占空比(duty cycles)＝为98％，将磷脂质微气泡送入紧靠气球内表面的位置。
随后使用破坏脉冲，中心频率1.5MHz，压力为800kPa，占空比为2％，用于超声波与微气泡所引致的空穴效应(cavitation)。通过20MHz C-Scan成像软件(C-scan imaging system)对石膏在超声波处理前及超声波处理后做扫描成像，以绘制差异图。
另一实施例为，参阅图6b为本申请特殊超声波波形示意图，在中心频率600kHz下，使用辐射脉冲(radiation force pulses)，压力(pressure)为15kPa，占空比(duty cycles)＝为99％，将磷脂质微气泡送入紧靠气球内表面的位置。
随后使用破坏脉冲，中心频率600kHz，压力为150kPa，占空比为1％，用于超声波与微气泡所引致的空穴效应(cavitation)。通过20MHz C-Scan成像软件(C-scan imaging system)对石膏在超声波处理前及超声波处理后做扫描成像，以绘制差异图。
微气泡制备
其制备流程如下所述：所使用的微气泡是自行实验调制的配方，该配方为1,2-二棕榈酰磷脂酰胆碱(DPPC)、1,2-二硬脂酰磷脂酰乙醇胺-聚乙二醇(DSPE-PEG 5000)及1,2-二硬脂酰磷脂酰甘油(DSPG)重量比为DPPC：DSPE-PEG 5000：DSPG＝2.5：1：1)，制作完成时的平均粒径为2±0.5μm，原始浓度的每毫升数量约为40*10 9MBs/mL，实验用浓度则会稀释再作使用。
本实验该配方的实施方式为1,2-二棕榈酰磷脂酰胆碱(DPPC)10mg、1,2-二硬脂酰磷脂酰乙醇胺-聚乙二醇(DSPE-PEG 5000)4mg及1,2-二硬脂酰磷脂酰甘油(DSPG)4mg。
精秤上述该配方溶于1毫升的三氯甲烷(chloroform)溶剂之中，利用超声波振荡器中加热并震荡混合，使混合均匀呈通明状溶液。
取上述混合溶液移液至1.5mL分装罐中，每个分装罐装填250μL，置于摄氏65度水浴锅内加热蒸干，30分钟后，再抽真空至隔日，使溶剂完全蒸发。
另将0.1克的甘油溶于20毫升的磷酸盐缓冲生理盐水(phosphate buffered saline,PBS)中，取800μL加入分装罐中。以摄氏65度热水进行水浴5分钟，再利用超声波震荡器将溶液混合均匀，利用抽气帮浦将溶于水相中的气体抽掉。经去气(degassing)完成后加入八氯丙烷(perfluoropropane，C 3F 8)，将样品进行震荡，持续45秒，震荡过程中，脂质因为表面张力的作用，会组成含有空腔的气泡，即为本申请所使用的微气泡。
请参阅图7为本申请微气泡制备的浓度对体积的粒径分布图。
实施例1
外部引导式探头可行性测试A
实验架构请参阅图5。本探头是可以移动的，在进行可行性测试，我们只要确认这样的架构可以有效对钙化的结构造成影响即可。因此，我们选用平面式的一般体内血管钙化模型，以确认超声波施打后的结果，实验架构如下：
使用探头：1.5MHz超声波探头。
使用气球导管：血管扩张气球导管。
使用微气泡：本实验使用上述微气泡制备的1000倍稀释溶液。
经过一系列测试，我们设计了一个特殊超声波波形用于验证本架构的可行性，特殊超声波波形请参阅图6a，并将实验组分成三组(A、B、C)，分述如下：
A组为使用辐射脉冲以及微气泡的超声波组(简写为：US w/RF+MB，又称为“有辐射力组”)，操作顺序如下：
气球导管注入微气泡。
施打1.5MHz的超声波，作用时间10分钟。
先使用9800周数(cycles)震幅较小的超声波产生推力，将微气泡推到气球壁上。接续使用200周数(cycles)振幅较大的超声波产生破坏力，借由大震幅的改变破坏微气泡，而产生空穴效应，进而放出强大的震波，破坏钙化的结构。
B组为使用微气泡的超声波组(简写为：US w/o RF+MB，又称为“无辐射力组”)，操作顺 序如下：
气球导管注入微气泡。
施打1.5MHz超声波，作用时间10分钟。
本组未预先使用超声波产生推力将微气泡推到气球壁上，全程仅使用200周数(cycles)振幅较大的超声波产生破坏力，借由大震幅的改变破坏微气泡，进而产生空穴效应并放出强大的震波，破坏钙化模型。
C组为仅施打超声波组(简写为：US only，又称为“控制组”)，操作顺序如下：
施打1.5MHz超声波，作用时间10分钟。
本组为控制组，全程仅使用200周数(cycles)振幅较大的超声波，在无推力与微气泡存在下测试其对钙化模型产生的破坏力。
外部引导式探头可行性测试A，实验结果
请参阅图8为本申请外部引导式探头可行性测试A的结果。平面式的血管钙化模型于实验前及实验后各进行20MHz高频超声波表面扫描，可以看出有辐射力组801(A.US w/RF+MB)与无辐射力组802(B.US w/o RF+MB)及控制组803(C.US only)相比较，有辐射力组801有更好的效果。
以实验前的背景强度作基准值，我们计算实验后与实验前背景强度的差异，以相差10dB的区域的面积，来作为钙化模型受破坏程度的量化指标。请参阅图9，本申请外部引导式探头可行性测试A的各组钙化结构破坏的量化结果，显示各组钙化模型受破坏的面积。有辐射力组受破坏的面积为1.4mm 2，无辐射力组受破坏的面积为0.8mm 2，有辐射力组与无辐射力组相比较，有辐射力组可增加68％的钙化破坏作用(p<0.05)。本申请提出的方法可以破坏钙化结构协助气球导管撑开，对于临床应用上，将设计内部装有压电片的气球导管，以便在气球扩张时可更精确地控制超声波脉冲。
实施例2
外部引导式探头可行性测试B
实验架构请参阅图5。本探头是可以移动的，在进行可行性测试，我们只要确认这样的架构可以有效对钙化的结构造成影响即可。因此，我们选用平面式的一般体内血管钙化模型，以确认超声波施打后的结果，实验架构如下：
使用探头：600kHz超声波探头。
使用微气泡：本实验使用上述微气泡制备的100倍稀释溶液。
经过一系列测试，我们设计了一个特殊超声波波形用于验证本架构的可行性，特殊超声波波形 请参阅图6b，并将实验组分成三组(A、B、C)，分述如下：
A组为使用辐射脉冲以及微气泡的超声波组(简写为：US w/RF+MB，又称为“有辐射力组”)，操作顺序如下：
气球导管注入微气泡。
施打600kHz的超声波，作用时间10分钟。
先使用9900周数(cycles)震幅较小的超声波产生推力，将微气泡推到气球壁上。接续使用100周数(cycles)振幅较大的超声波产生破坏力，借由大震幅的改变破坏微气泡，而产生空穴效应，进而放出强大的震波，破坏钙化的结构。
B组为使用微气泡的超声波组(简写为：US w/o RF+MB，又称为“无辐射力组”)，操作顺序如下：
气球导管注入微气泡。
施打600kHz超声波，作用时间10分钟。
本组未预先使用超声波产生推力将微气泡推到气球壁上，全程仅使用100周数(cycles)振幅较大的超声波产生破坏力，借由大震幅的改变破坏微气泡，进而产生空穴效应并放出强大的震波，破坏钙化模型。
C组为仅施打超声波组(简写为：US only，又称为“控制组”)，操作顺序如下：
施打600kHz超声波，作用时间10分钟。
本组为控制组，全程仅使用100周数(cycles)振幅较大的超声波，在无微气泡存在下测试其对钙化模型产生的破坏力。
外部引导式探头可行性测试B，实验结果
请参阅图10为本申请外部引导式探头可行性测试B的结果。平面式的血管钙化模型于实验前及实验后各进行20MHz高频超声波表面扫描，可以看出有辐射力组801(A.US w/RF+MB)与无辐射力组802(B.US w/o RF+MB)及控制组803(C.US only)相比较，有辐射力组801有更好的效果。
实施例3
外部引导式探头可行性测试C
测试完平面式的血管钙化模型后，本实验测试圆管状钙化模型，测试实验设计是否能帮助撑开或破坏该圆管状钙化模型，制备方法同外部引导式探头可行性测试A，仅替换制作用模具，利用3D打印制作的模具，制备了环状的一般体内血管钙化模型(厚度3mm)，以模拟真实血管中最常见的钙化形式的浅表型钙化(superficial calcific sheet)的状况。
实验架构请参阅图11所示：
实验流程如下：
将实验组(有施打超声波)与控制组(无施打超声波)，分别于气球导管40套上圆管状钙化模型50。
气球导管40注入微气泡。
实验组施打上述同外部引导式探头可行性测试A设计的超声波60特殊波型，作用时间10分钟。控制组未施打任何超声波。
将实验组与控制组用水压加压，纪录圆管状钙化模型50被气球撑至裂开所需的水压。
外部引导式探头可行性测试C，实验结果：
实验组：6atm水压压力下能撑开或破坏圆管状钙化模型。
控制组：8atm水压压力下能撑开或破坏圆管状钙化模型。
通过导管外探头架构可行性测试C实验结果显示，超声波搭配微气泡达成的空穴效应的震波可降低圆管状钙化模型被撑开或破坏的水压压力，即超声波搭配微气泡可有效达成破坏圆管状钙化模型结构的效果。
实施例4
当血管细小，反射信号不强，超声波探头无法顺利找到聚焦点时，本申请实施方式使用一条传感器导管，协助超声波于病灶处的聚焦，其工作方式如下：
传感器导管进入血管，并借由传感器导管的导引，控制超声波探头在病灶处进行聚焦。
传感器导管移出，气球导管进入。
于气球导管中灌入微气泡，施打超声波以破坏钙化组织。
撑开气球导管，完成治疗。
实施例5
内置式探头超声波可行性测试–不同厚度的血管钙化模型
内置式探头超声波架构所使用的是由PI公司(Ceramic GmbH,Lederhose,Germany)购买的压电管(PT120.00,Physik Instrumente)制成的超声波探头，并搭配圆管状钙化模型进行测试，以分析结果是否可有效降低气球撑开所需的水压。请参阅图12，本实验采用了2mm、3mm、4mm的3种不同厚度的一般体内血管钙化模型来进行测试。
实验流程：
请参阅图13为本申请内置式探头超声波可行性测试，说明如下：
将控制组及实验组的血管钙化模型50都置入水中。
将微气泡灌入实验组中，并放入压电管55开始施打超声波特殊波型，请参阅图6a，施打20分钟。控制组则不放入压电管55施打。
将控制组与实验组取出，插入气球导管，缓慢升高水压，纪录圆管状钙化模型50被气球撑至裂开所需的水压。
实验结果：
表3为内置式探头超声波可行性测试-不同厚度的血管钙化模型的实验结果：
  2mm 3mm 4mm
控制组 4atm 7atm 9atm
实验组(超声波) 4atm 4atm 7atm
实施例6
内置式探头超声波可行性测试–超声波作用时间
内置式探头超声波架构所使用的是由PI公司购买的压电管制成的超声波探头，并搭配圆管状钙化模型进行测试，以分析结果是否可有效降低气球撑开所需的水压。另外，为更真实地验证于顽固型钙化组织的效果，本实验采用了3mm厚度的顽固型钙化模型来进行测试。
实验流程：
请参阅图14为本申请内置式探头超声波可行性测试，说明如下：
将控制组及实验组的血管钙化模型50都置入水中。实验组：将压电管55垂直固定于血管钙化模型50中，仅施打超声波(US only)或施打超声波加微气泡(US+MBs)；控制组：不使用超声波及微气泡(Untreated)。
将微气泡以144mL/hr的速度灌入实验组血管钙化模型50中，以设定的参数发射超声波进行作用。施打的超声波参数为：频率600kHz、压力：300kPa、周数(cycles)：100、脉冲重复频率(PRF)：1Hz、微气泡浓度：原始浓度40*10 9MBs/ml的100倍稀释、作用时间10-30分钟。
将控制组与实验组取出，插入气球导管，缓慢升高水压，纪录圆管状钙化模型50被气球撑至裂开所需的水压。
实验结果：
图15为内置式探头超声波可行性测试—超声波作用时间的实验结果。不使用超声波及微气泡的组别(Untreated)的钙化模型被气球撑至裂开所需的水压为大于12atm；仅有超声波的组别(US only)的钙化模型被气球撑至裂开所需的水压为11atm；结合超声波与微气泡、作用10分钟(US+MBs(10min))的钙化模型被气球撑至裂开所需的水压为8.75atm；结合超声波与微气泡、作用20分钟(US+MBs(20min))的钙化模型被气球撑至裂开所需的水压为7.4atm。
实施例7
内置式探头超声波可行性测试–超声波周数
内置式探头超声波架构所使用的是由PI公司购买的压电管制成的超声波探头，并搭配圆管状钙化模型进行测试，以分析结果是否可有效降低气球撑开所需的水压。本实验采用了3mm厚度的顽固型钙化模型来进行测试。
实验流程：
请参阅图14为本申请内置式探头超声波可行性测试，说明如下：
将血管钙化模型50都置入水中，并将压电管55垂直固定于血管钙化模型50中。
将微气泡以144mL/hr的速度灌入实验组血管钙化模型50中，以设定的参数发射超声波进行作用。施打的超声波参数为：频率600kHz、压力：300kPa、周数(cycles)：10-1000、脉冲重复频率(PRF)：1Hz、微气泡浓度：原始浓度40*10 9MBs/ml的100倍稀释、作用时间20分钟。
将血管钙化模型50取出，插入气球导管，缓慢升高水压，纪录圆管状钙化模型50被气球撑至裂开所需的水压。
实验结果：
图16为内置式探头超声波可行性测试–超声波周数的实验结果。超声波周数为10、100、500、1000的钙化模型被气球撑至裂开所需的水压分别为大于12、6.63、8.13与9atm。
实施例8
内置式探头超声波可行性测试–微气泡浓度
内置式探头超声波架构所使用的是由PI公司购买的压电管制成的超声波探头，并搭配圆管状钙化模型进行测试，以分析结果是否可有效降低气球撑开所需的水压。本实验采用了3mm厚度的顽固型钙化模型来进行测试。
实验流程：
请参阅图14为本申请内置式探头超声波可行性测试，说明如下：
将血管钙化模型50都置入水中，并将压电管55垂直固定于血管钙化模型50中。
将微气泡以144mL/hr的速度灌入实验组血管钙化模型50中，以设定的参数发射超声波进行作用。施打的超声波参数为：频率600kHz、压力：300kPa、周数(cycles)：100、脉冲重复频率(PRF)：1Hz、微气泡浓度：原始浓度40*10 9MBs/ml的75倍、100倍、200倍稀释、及无微气泡组，作用时间20分钟。
将血管钙化模型50取出，插入气球导管，缓慢升高水压，纪录圆管状钙化模型50被气球撑至裂开所需的水压。
实验结果：
图17为内置式探头超声波可行性测试–微气泡浓度的实验结果。微气泡浓度为75倍、100倍、200倍稀释、及无微气泡组的钙化模型被气球撑至裂开所需的水压分别为7.25、8.2、9.5与11atm。
实施例9
内置式探头超声波可行性测试–超声波压力
内置式探头超声波架构所使用的是由PI公司购买的压电管制成的超声波探头，并搭配圆管状钙化模型进行测试，以分析结果是否可有效降低气球撑开所需的水压。本实验采用了3mm厚度的顽固型钙化模型来进行测试。
实验流程：
请参阅图14为本申请内置式探头超声波可行性测试，说明如下：
将血管钙化模型50都置入水中，并将压电管55垂直固定于血管钙化模型50中。
将微气泡以144mL/hr的速度灌入实验组血管钙化模型50中，以设定的参数发射超声波进行作用。施打的超声波参数为：频率600kHz、压力：150kPa、200kPa、300kPa、周数(cycles)：100、脉冲重复频率(PRF)：1Hz、微气泡浓度：原始浓度40*10 9MBs/ml的100倍稀释，作用时间20分钟。
将血管钙化模型50取出，插入气球导管，缓慢升高水压，纪录圆管状钙化模型50被气球撑至裂开所需的水压。
实验结果：
图18为内置式探头超声波可行性测试—超声波压力的实验结果。超声波压力为150kPa、200kPa、300kPa的钙化模型被气球撑至裂开所需的水压分别为10.67、9.33与7.88atm。
实施例10
蛋壳实验
超声波架构所使用的是由PI公司购买的压电管制成的超声波探头，并作用于蛋壳进行测试，从蛋壳的内部打出震波，观察蛋壳表面的作用，确认震波在生物钙表面的有效性。
实验流程：
请参阅图19为本申请超声波架构于蛋壳实验的测试，说明如下：
准备一个蛋壳70，将压电管55平行架设于蛋壳上。
实验组将微气泡45以144mL/hr的速度灌入蛋壳70附近的超声波作用区域中，以设定的参数发射超声波进行作用。施打的超声波参数为：频率600kHz、压力：300kPa、周数(cycles)：100、 脉冲重复频率(PRF)：1Hz、微气泡浓度：原始浓度40*10 9MBs/ml的100倍稀释，作用时间20分钟。控制组使用相同的超声波参数，但不使用微气泡。
将蛋壳70以伊文思蓝(Evans Blue)进行染色，以显现蛋壳表面的裂纹。将蛋壳70置于解剖显微镜下观察。
实验结果：
图20为蛋壳实验的实验结果。控制组(US only)未发现蛋壳上有裂纹；实验组(US+MBs(20min))则可观察到明显裂纹。
实施例11
猪只动脉血管生物效应实验
用猪动脉评估超声波的生物效应。超声波架构所使用的是由PI公司购买的压电管制成的超声波探头，并作用于猪只动脉血管内壁，观察超声波的震波在动脉血管内壁的生物效应。
实验流程：
请参阅图21为本申请生物效应研究的实验装置，说明如下：
将压电管55放入动脉血管75中。
实验组(超声波加微气泡，US+MBs)将微气泡以144mL/hr的速度灌入动脉血管75中，以设定的参数发射超声波进行作用。施打的超声波参数为：频率600kHz、压力：300kPa、周数(cycles)：100、脉冲重复频率(PRF)：1Hz、微气泡浓度：原始浓度40*10 9MBs/ml的100倍稀释，作用时间20分钟。控制组为仅使用超声波(US only)，仅使用微气泡(MBs only)，以及既不使用超声波也不使用微气泡(Untreated)。
取出压电管，将动脉血管75进行切片于显微镜下观察血管内壁是否有损伤。
实验结果：
图22为猪只动脉血管生物效应实验的实验结果。所有组别均未观察到血管内壁损伤情形，显示超声波60加微气泡产生的震波不会破坏血管内壁。
以上所述实施例仅是为充分说明本申请而所举的较佳的实施例，本申请的保护范围不限于此。本技术领域的技术人员在本申请基础上所作的等同替代或变换，均在本申请的保护范围之内。本申请的保护范围以权利要求书为准。

Claims (9)

  1. 一种超声波搭配微气泡辅助的气球导管系统，包括：
    一控制器；
    一传感器导管；
    一高度聚焦式超声波探头，该高度聚焦式超声波探头及该传感器导管连接于该控制器；以及
    一气球导管。
  2. 一种血管扩张方法，包括：
    提供一传感器导管进入一血管，控制一高度聚焦式超声波探头在血管硬化处进行对焦；
    将该传感器导管从该血管移出，将一气球导管进入该血管；
    将微气泡灌入该气球导管，并控制该高度聚焦式超声波探头开始工作破坏硬化血管的钙化点；
    将该气球导管在血管硬化的部分位置撑开。
  3. 如权利要求2所述的血管扩张方法，其中该微气泡被送入该血管，并将该微气泡吸附于目标位置时，即可使超声波作用，产生震波震碎微气泡。
  4. 一种超声波搭配微气泡辅助的气球导管系统，包括：
    一控制器；
    一气球导管；以及
    至少一超声波换能器探头，该超声波换能器探头设置于该气球导管内部，以及该超声波换能器探头连接该控制器。
  5. 一种血管扩张方法，包括：
    提供一气球导管进入血管；
    将微气泡灌入该气球导管，并控制一超声波换能器探头发射超声波，击破该微气泡并放出震波；
    将该气球导管在血管硬化的部分位置撑开。
  6. 如权利要求5所述的血管扩张方法，其中运用超声波震动微气泡以辅助气球导管撑开已钙化的血管硬化的部分位置，为通过产生一血管钙化模型进行破坏结构实验。
  7. 一种微气泡的溶液组成物，包含：
    1,2二棕榈酰磷脂酰胆碱(1,2-dipalmitoyl-sn-glycero-3-phosphocholine,DPPC)；
    1,2二硬脂酰磷脂酰乙醇胺-聚乙二醇(1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000],DSPE-PEG 5000)；
    及1,2二硬脂酰磷脂酰甘油(1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol),DSPG)，1,2二棕榈酰磷脂酰胆碱：1,2二硬脂酰磷脂酰乙醇胺-聚乙二醇：1,2二硬脂酰磷脂 酰甘油的重量比为2.5：1：1，将上述三种配方溶于二氯甲烷、三氯甲烷、乙腈、甲醇或乙酸乙酯的一种以上溶剂，经加热并震荡混合。
  8. 如权利要求7所述的微气泡的溶液组成物，该微气泡的溶液组成物经填充一气体处理后冻干。
  9. 如权利要求8所述的气体，该气体为氮气、二氧化碳、氧气或碳氟化合物中的一种以上成分。
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US20130331738A1 (en) * 2012-06-11 2013-12-12 Board Of Trustees University Of Arkansas Compositions and methods for potentiating sonothrombolysis
CN108883204A (zh) * 2016-02-01 2018-11-23 博信生物科技股份有限公司 脂质微泡及其制备方法
CN205548629U (zh) * 2016-03-24 2016-09-07 广州军区广州总医院 一种超声微泡空化溶栓系统
CN110548140A (zh) * 2018-06-01 2019-12-10 叶秩光 带氧微气泡用于制备诱导病变组织血管正常化套组的用途
CN110237256A (zh) * 2019-07-22 2019-09-17 重庆医科大学 一种载n2o微泡及其制备方法与应用

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