WO2010127495A1 - 一种脉冲式超声治疗装置 - Google Patents

一种脉冲式超声治疗装置 Download PDF

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Publication number
WO2010127495A1
WO2010127495A1 PCT/CN2009/071679 CN2009071679W WO2010127495A1 WO 2010127495 A1 WO2010127495 A1 WO 2010127495A1 CN 2009071679 W CN2009071679 W CN 2009071679W WO 2010127495 A1 WO2010127495 A1 WO 2010127495A1
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ultrasonic
ultrasound
treatment
tumor
pulse
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PCT/CN2009/071679
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English (en)
French (fr)
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李澎
张琬
李代贵
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Li Peng
Zhang Wan
Li Daigui
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Application filed by Li Peng, Zhang Wan, Li Daigui filed Critical Li Peng
Priority to PCT/CN2009/071679 priority Critical patent/WO2010127495A1/zh
Priority to PCT/CN2009/075744 priority patent/WO2010127546A1/zh
Publication of WO2010127495A1 publication Critical patent/WO2010127495A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0039—Ultrasound therapy using microbubbles

Definitions

  • the invention relates to an ultrasonic therapeutic device combined with microbubbles, which is applied to the treatment of various clinical solid malignant tumors, and belongs to the technical field of non-invasive ultrasonic therapy.
  • tumor ang iogenes is a new tumor treatment model developed after surgery, radiotherapy and chemotherapy in recent years [4] .
  • interventional vascular embolization therapy can only embolize arteries with larger diameters, and is incapable of collateral circulation.
  • Anti-tumor angiogenesis therapy using chemical or biological agents can directly target tumor neovascularization, but the specificity is not high, and the curative effect is not satisfactory.
  • Tumor physical therapy methods include various interventional thermal ablation, cryotherapy, electrochemistry, etc., all of which directly kill tumor tissue by puncture or surgery, but the side effects are also large.
  • Non-invasive treatment of tumors with ultrasound energy has always been the goal of the industry.
  • Head In the past, although high-intensity ul t rasound (HIFU) represented by thermal ablation of tumors has developed rapidly in the country, it has been successfully applied to the treatment of partial liver cancer, osteosarcoma and uterine fibroids, but HIFU.
  • HIFU high-intensity ul t rasound
  • the equipment is large and expensive, and the operation is complicated.
  • the skin, ribs and surrounding vital organs may be burned, causing serious side effects, and the treatment effect is not satisfactory.
  • the reason is mainly because it uses the thermal effect to ablate the tumor, and it needs to collect ultrasonic energy of up to 5000 - 20000 W/cm 2 in the target area, and generate 65 ⁇ 100 in a few seconds. C high temperature, it is inevitable to damage the normal tissue in the acoustic window. Therefore, it is necessary to find a tumor physiotherapy method with low energy and relatively simple equipment.
  • Ultrasonic cavitation effect refers to a series of kinetic processes in which microbubbles in a liquid generate oscillation, expansion, contraction, and implosion under ultrasonic action, accompanied by transient high temperature, high pressure, shock wave, and discharge. And multiple energy release behaviors such as microfluidics) [ 9 ] is the main physical effect of another ultrasound other than thermal effects. Because it has been previously thought that ultrasonic cavitation is not easy to control, it is not suitable for tumor ultrasound treatment.
  • Hwang et al [9] used microbubble combined with focused ultrasound cavitation damage to achieve damage to rabbit rim vein vascular endothelium, but local intraluminal injection of small doses of thrombin required to cause vascular embolization, pulsed ultrasound used by Hwang There is no time interval between energy, and no intermittent time can be provided for microbubble reperfusion; no microbubbles are used in Cain cavitation studies. Their ultrasound cavitation treatment did not target the ablation of tumor neovascularization Destruction.
  • Ultrasonic cavitation treatment requires ultrasound pulses that emit high peak and negative pressure in the microbubbles in the biological blood circulation, causing transient cavitation of the microbubbles, releasing high-temperature, high-pressure, shock waves, jets and other therapeutic energy forms, and microbubbles are cavitation.
  • intermittent (suspended) ultrasound emission is required to give the microbubbles a certain reperfusion time.
  • the ultrasonic energy must be a low average sound intensity (I SPTA below 10W / cm 2 ), a low working duty cycle energy form.
  • the present invention provides a novel tumor ultrasound treatment method for tumor neovascularization, and a second object of the present invention is to provide a pulsed ultrasound microbubble treatment apparatus for use in the aforementioned treatment method.
  • the pulse type ultrasonic therapeutic apparatus of the present invention comprises: a control circuit and an ultrasonic treatment head.
  • the control circuit includes: a regulated power supply unit, a time shaping adjustment unit, a time base circuit unit, a high voltage DC power supply, a high pulse switching function tube, and an ultrasonic power oscillation unit (Fig. 2).
  • the regulated power supply unit provides a stable power supply for all parts of the unit.
  • the high pulse switching function tube is because it has faster speed, less distortion and higher stability than the conventional low pulse control unit; the high pulse control unit supplies the DC high voltage to the ultrasonic wave by the high pulse, thereby making the ultrasonic power
  • the oscillation depends on the high pulse simulation law provided by the high pulse switching function tube (such as the triode), the oscillation output is given to the ultrasonic energy, and then supplied to the ultrasonic head to realize the high pulse intermittent ultrasonic emission (Fig. 2 ).
  • the power oscillating unit is used to push the piezoelectric wafer to generate therapeutic ultrasound, the principle of which is the inverse piezoelectric effect.
  • the control unit is used to control the form of ultrasonic energy output by the instrument, such as: pulse repetition frequency, intermittent time and pulse width.
  • the waveform transform unit and the time base signal unit are used to transform the therapeutic ultrasound pulse signal into an ideal waveform required for the design.
  • the existing ultrasonic therapeutic apparatus does not have an ultrasonic energy mode specially designed for enhancing microbubble cavitation.
  • the power oscillation control of the conventional ultrasonic therapeutic apparatus uses the oscillation tube base level control to change the oscillation output, and the disadvantage is that when the oscillator output is controlled When the oscillating tube is in the off state, all the devices are in a high potential state at this time, and the component itself is charged and discharged, and the damped oscillation output occurs, and signal smearing occurs.
  • the control on/off state under microsecond control is unknown.
  • the ultrasound treatment head is partially controlled by a circuit to perform pulsed or intermittent pulsed ultrasound.
  • the ultrasound treatment head can be a focus transducer composed of a piezoelectric wafer, an acoustic lens, a focusing medium, and a housing portion; the ultrasonic treatment head can also be a planar ultrasonic transducer composed of a piezoelectric wafer, an acoustic lens, and a housing portion.
  • Ultrasonic energy form Under the control of a high frequency pulsed circuit, the ultrasonic treatment head produces a therapeutic ultrasound pulse.
  • the frequency of the ultrasonic pulse can be varied within ⁇ ⁇ ⁇ 2. 0MHz; the peak sound pressure (including peak negative pressure and peak positive pressure) varies from 0.4 to 15 MPa; the average sound intensity of the acoustic head output (I SPTA ) can single ultrasonic pulse width is adjustable within a range of 10-2500 microseconds; in 0. l ⁇ 10W / cm 2 changes; (? ⁇ 1) emitted ultrasound pulse repetition frequency may be adjustable in a range of 1 to 100.
  • the device of the present invention further includes a microbubble portion, which refers to various commercial ultrasound contrast agent bubbles and therapeutic bubbles that can be used intravenously, for example: SonoVue, Def ini ty, perfluorinated, etc.
  • a microbubble portion refers to various commercial ultrasound contrast agent bubbles and therapeutic bubbles that can be used intravenously, for example: SonoVue, Def ini ty, perfluorinated, etc.
  • Peripheral intravenous injection is used to enter the blood circulation of the human body, cavitation effect occurs under the action of the ultrasonic pulse, and energy forms such as shock waves and microjets are released, and the tumor neovascularization is physically destroyed.
  • the novel tumor ultrasound treatment method for tumor neovascularization comprises the following steps:
  • Flow perfusion information ( Figure 4) provides localization information for ultrasound cavitation blocking tumor neovascularization.
  • Imaging evaluation procedures including: contrast-enhanced ultrasound imaging, CT angiography, and magnetic resonance imaging. Among them, contrast-enhanced ultrasound is the easiest and most economical method. The results of the experiment showed that the tumor blood vessels were almost 100% blocked immediately after treatment by contrast-enhanced ultrasound imaging of the tumor in the treated area (Fig. 4).
  • tumor neovascularization has congenital development defects such as weak wall, high permeability, and lack of elastic fiber layer
  • this treatment can selectively block tumor microvessels, and its mechanism is: tumor vascular physical destruction, tumor Interstitial edema (compression of local tumor blood vessels) and thrombosis.
  • tumor vascular physical destruction tumor Interstitial edema (compression of local tumor blood vessels)
  • thrombosis normal microvessels or larger vessels with more than 2 legs in diameter, the wall is well developed, the structure is tight, and the wall is thick and tough.
  • the treatment has little effect on it, and the experiment has not found a phenomenon of blocking normal blood vessels.
  • the ultrasonic emission intensity of the pulsed ultrasonic therapy method is 1/2000-5000 of high-intensity focused ultrasound, and is more than 2_3W/cm 2 , and ultrasonic cavitation is mainly confined to the lumen of the blood vessel, so The biological effects of blood vessels and other organs are small, thus avoiding side effects.
  • the ultrasound contrast agent is a microbubble suspension.
  • the average size of the microbubbles is between 2-4 microns, which is significantly smaller than the red blood cell size and cannot penetrate the capillary wall into the interstitial space. It is a blood pool developer. Therefore, in a region where the contrast agent is not developed, blood forming components such as red blood cells are more inaccessible.
  • FIG. 1 Comparison of the continuous emission of high intensity focused ultrasound and the intermittent pulsed emission signal of the instrument of the present invention.
  • Figure 2 Circuit block diagram of a pulsed ultrasound therapy device.
  • FIG. 1 Schematic diagram of the planar ultrasound treatment head structure.
  • FIG. 1 Two-dimensional ultrasound image of subcutaneous VX2 tumor; B: VX2 tumor color blood flow image; C: VX2 tumor before treatment with high perfusion phase (white arrow); D: Negative imaging after tumor treatment (white) arrow).
  • Figure 5 Ivans blue dye (EB) perfusion in the VX2 tumor vascular treatment group and the control group in New Zealand white rabbits.
  • Figure A Experimental group tumor tissue (black arrow) EB no perfusion, muscle (white arrow) blue staining;
  • Figure B Control group tumor tissue (black arrow) and muscle (white arrow) were EB blue staining.
  • FIG. 1 Pathological observation of vascular treatment of VX2 tumors in New Zealand white rabbits.
  • the specific experimental procedure was as follows: New Zealand white rabbit VX2 tumor subcutaneous tumor-bearing rabbits were randomly divided into a simple microbubble control group, a simple ultrasound control group and a microbubble ultrasound test group. Ultrasound treatment uses the treatment head to vertically irradiate the tumor area for 5-10 min. The patients underwent routine ultrasonography and contrast-enhanced ultrasound examination before and after treatment. In addition, the microbubble ultrasound group was examined by contrast-enhanced ultrasound at 30 min, 60 min and 24 h after irradiation. Ultrasound angiography of VX2 tumors was rich in blood supply before and after treatment with simple microbubble group and pure ultrasound irradiation group. The difference of angiographic gray value was not significant ( ⁇ 0.05).
  • VX2 tumor angiography was rich in blood supply.
  • the average gray scale value (GSV) was 84. 1 ⁇ 22. 4;
  • ultrasound contrast tumor microvascular perfusion disappeared, negative development, GSV was 15.8 soil 10. 8; a small amount of recovery after 30 minutes, The GSV was 30. 1 soil 21. 3 , 60 min perfusion was further restored, and the GSV was 45. 4 ⁇ 29. 8.
  • the neovascularization of the tumor was completely disappeared, and the difference was significant ( ⁇ 0.01). In each group, no significant changes were found in blood perfusion of normal tissues surrounding the tumor.
  • Evans Blue is a blue dye for blood tracers that binds well to plasma proteins and has a high molecular weight that does not penetrate the vascular wall into the interstitial space.
  • the EB can blue-stain the muscle tissue surrounding the tumor, it cannot enter the tumor tissue; while the control group EB can simultaneously stain the tumor and muscle tissue (Fig. 5).
  • the VX2 tumor of the New Zealand white rabbit in the treatment group only had a surviving cancer cell layer of 0. 5-0. 8mm after 3 days of treatment, and there was still a surviving cancer cell layer of 5 mm or more in the control group (Fig. 6). .
  • the pulsed ultrasonic therapy device provided by the present invention has been described in detail above. The description of the above embodiment is only for helping to understand. The method of the present invention and its core idea; at the same time, for those skilled in the art, according to the idea of the present invention, there will be changes in the specific implementation manner and the scope of application. It is understood to be a limitation of the invention.

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Description

一种脉冲式超声治疗装置
技术领域
本发明涉及一种联合微泡的超声治疗装置，应用于临床各种 实体恶性肿瘤的治疗， 属于非创伤性超声治疗的技术领域。 技术背景
恶性肿瘤是严重威胁人类生命健康的疾病，其治疗一直是医 学界的难点和热点。 目前， 治疗癌症的基本方法有手术、 放疗、 化疗和生物免疫等疗法，但这些治疗手段往往不能满足患者的治 疗要求， 而且手术、 放疗、 化疗创伤性大， 易产生严重的并发症 和副作用， 不仅风险性大， 而且降低了患者的生存质量。 原发性 肝癌等肿瘤对放疗和化疗均不敏感，现有的物理治疗又具有一定 创伤性， 不能反复使用。 故寻找一种非创伤性的肿瘤治疗方法十 分必要。
实体肿瘤的发生、 发展、 侵袭以及转移依赖肿瘤血管生成
( Tumor ang iogenes i s ) , 故以抑制、 栓塞或阻断肿瘤新生血管 为治疗目的的肿瘤 "休眠疗法" 是近年来继手术、 放化疗后发展 起来的一种新的肿瘤治疗模式[4]。 目前， 介入血管栓塞疗法只能 栓塞较大管径的动脉， 对侧枝循环无能为力； 使用化学或生物制 剂抗肿瘤血管生成治疗可以直接作用肿瘤新生血管的靶点，但特 异性不高， 疗效不理想。 肿瘤物理治疗方法包括各种介入性热消 融、 冷冻、 电化学等， 均通过穿刺或者手术直接杀伤肿瘤组织， 但副作用也较大。
利用超声能量非创伤性治疗肿瘤一直是业界追求的目标。 目 前， 尽管以热效应消融肿瘤为代表的高强度聚焦超声 （High intens i ty focused ul t rasound, HIFU )在国内夕卜发展迅速， 已 成功应用于部分肝癌、 骨肉瘤和子宫肌瘤治疗， 但是 HIFU设备庞 大昂贵、 操作复杂， 在肋骨肠道阻挡、 热传导不均勾等情况下可 能烧伤皮肤、 肋骨及周围重要器官， 产生严重的副作用， 治疗效 果并不理想。 就其原因， 主要是因为其利用热效应消融肿瘤， 需 要在靶区聚集高达 5000 - 20000 W/cm2的超声能量， 数秒内产生 65 ~ 100。C高温， 难免损伤到声窗内正常组织。 故寻找一种低能 量、 设备相对简单的肿瘤超声物理治疗方法十分必要。
超声空化效应（cavi tat ion, 注： 空化效应是指液体中微气 泡在超声作用下产生震荡、 膨胀、 收缩以及内爆等一系列动力学 过程， 伴随瞬态高温、 高压、 冲击波、 放电和微射流等多种能量 释放行为） 〔9〕是热效应之外另一种超声的主要物理效应。 由于 既往认为， 超声空化不易控制， 不适合用于肿瘤超声治疗。
近年来，微泡超声造影剂增强的超声空化效应在非创伤性超 声治疗领域中的基础研究十分活跃，但是大多数相关研究主要涉 及药物释放和基因转染，对其空化产生的机械性损伤效应研究不 多[14— 21]。 欧美仅有 Hwang、 Ca in和 Mi l ler等少数几个课题组进行 过该领域的探讨，他们的研究仅涉及到正常血管壁的空化物理损 伤和离体组织标本的超声空化消融， 采用的治疗方法也不尽相 同。 Hwang等 [9]采用微泡联合聚焦超声空化损伤实现了对兔耳缘 静脉血管内皮的损伤， 但是需要局部管腔内注射小剂量凝血酶， 才可能造成血管栓塞， Hwang使用的脉冲式超声能量不存在时间 间歇， 不能为微泡再灌注提供间歇时间； Ca in的空化研究中没有 采用微泡。他们的超声空化治疗均没有针对肿瘤新生血管的消融 破坏。
目前， 尚未见专用微泡超声空化治疗的超声物理治疗仪和本 超声治疗仪发射的超声能量形式报道。超声空化治疗需要针对在 生物血液体循环中的微泡发射高峰值负压的超声脉冲，使微泡产 生瞬态空化， 释放高温、 高压、 冲击波、 射流等治疗能量形式， 微泡被空化破坏后又需要间歇（暂停）超声发射给予微泡一定再 灌注时间。 同时， 为了避免超声热效应产生类似高强度聚焦超声 的热损伤副作用， 超声能量必须是低平均声强 （ ISPTA低于 10W / cm2 ), 低工作占空比的能量形式。 发明内容
为了克服了传统超声治疗的上述缺点，本发明提供一种针对 肿瘤新生血管的新型肿瘤超声治疗方法，本发明的第二目的是提 供一种前述治疗方法采用的脉冲式超声微泡治疗装置。
本发明的脉冲式超声治疗仪包括：控制电路和超声治疗头两 部分。
控制电路部分包括： 稳压电源单元、 时间整形调节单元、 时 基电路单元、 高压直流电源、 高脉冲开关功能管和超声波功率振 荡单元 （图 2 )。
稳压电源单元为装置各部分提供稳定的电源。
所述的高脉冲开关功能管是因为它比传统的低脉冲控制速度 快、 失真小、 稳定性高； 所述的高脉冲控制单元将直流高压通过 高脉冲提供给超声波规律振荡，从而使超声波功率振荡依赖于高 脉冲开关功能管 （如三极管）提供的高脉冲模拟规律， 振荡输出 给超声能量， 再提供给超声头， 实现了高脉冲间歇超声发射（图 2 )。
功率振荡单元用于推动压电晶片产生治疗超声波， 其原理是 逆压电效应。
控制单元用于控制仪器输出的超声波能量形式， 例如： 脉冲 重复频率、 间歇时间和脉冲宽度等。
波形变换单元和时基信号单元用于将治疗超声脉冲信号变换 为设计所需的理想波形。
而现有的超声治疗仪未见专门为增强微泡空化设计的超声能 量方式，传统的超声治疗仪的功率振荡控制采用振荡管基级控制 来改变振荡输出， 其缺点是当控制振荡器输出时， 振荡管处于截 止状态， 此时所有的器件均处于高电位状态， 必然会出现元器件 的自身充放电， 而发生衰减振荡输出， 出现信号拖尾。 在微秒级 控制下出现控制通断状态不明。
超声治疗头部分由电路控制实施脉冲式或者间歇脉冲式超声 发射。 超声治疗头可以是聚焦换能器， 由压电晶片、 声透镜、 聚 焦介质和外壳部分组成； 超声治疗头也可以是平面超声换能器由 压电晶片、 声透镜、 和外壳部分组成。
超声能量形式： 在高频脉冲式电路的控制下， 超声治疗头产 生治疗超声脉冲。 其超声脉冲的频率可以在为 Ι ΟΟΚΗζ ~ 2. 0MHz 内变化； 峰值声压 （包括峰值负压和峰值正压） 在 0. 4 ~ 15MPa 内变化； 声头输出平均声强 （ISPTA ) 可在 0. l ~ 10W / cm2内变化； 超声发射的脉冲重复频率（？1^ )可以在 1 ~ 100内可调； 单个超 声脉冲宽度在 10-2500微秒范围内可调。
本发明装置还包括微泡部分， 微泡指可以静脉使用的各种商 业化超声造影剂 泡和治疗性 泡， 例如： 声诺维 （SonoVue )、 Def ini ty, 全氟显等。 采用经外周静脉注射方式进入人体血液循 环， 在所述超声脉冲的作用下发生空化效应， 释放冲击波、 微射 流等能量形式， 物理破坏肿瘤新生血管。
本发明提供的针对肿瘤新生血管的新型肿瘤超声治疗方法 包括以下步骤：
1、 定位诊断程序， 首先通过经静脉注射诊断剂量的微泡超 声造影剂 （如： 声诺维）， 对肿瘤进行超声造影诊断， 获得肿瘤 的体表定位信息、声窗信息和肿瘤新生血管血流灌注信息（图 4 ), 为超声空化阻断肿瘤新生血管提供的定位信息。
2、 定位治疗程序， 然后， 在经静脉注射所述治疗剂量微泡 的情况下， 对所定位区域进行脉冲式超声照射治疗， 以微泡超声 空化方式物理破坏处于肿瘤新生血管内的高浓度微泡，超声空化 释放高温、 高压、 冲击波和 射流等能量形式。 间歇式超声发射 为微泡再灌注贏得充盈时间， 使超声治疗时， 肿瘤血管内始终处 于高浓度微泡灌注状态 （图 4 )。 治疗时间根据肿瘤大小从 30秒 至 10分钟不等。
3、 影像学评价程序， 包括： 超声造影显像、 CT造影和磁共 振造影等， 其中， 超声造影是最简便易行而又经济的方法。 实验 结果显示， 通过对治疗区域的肿瘤新生血管超声造影， 可以发现 治疗后即刻肿瘤血管几乎 100%被阻断 （图 4 )。
总之， 由于肿瘤新生血管具有管壁薄弱、 通透性高、 缺乏弹 力纤维层等先天性发育缺陷，该治疗方式可以选择性阻断肿瘤新 生微小血管， 其发生机制为： 肿瘤血管物理破坏、 肿瘤组织间水 肿 （压迫局部肿瘤血管） 和血栓形成等。 正常微血管或者直径 2腿以上的较大血管， 管壁发育良好、 结构严密、 管壁厚而坚韧， 一般该治疗方式对其影响微小， 实验未发现有阻断正常血管现 象。 另夕卜， 该脉冲式超声治疗方式的超声发射声强是高强度聚焦 超声的 1/2000-5000, 多在 2_3W/cm2以内， 超声空化又主要被局 限于血管腔内， 故对于大血管和其它脏器产生的生物学效应微 小， 从而避免了副作用产生。
超声造影剂是一种微气泡混悬液，微泡平均在粒径 2-4微米 之间，显著小于红细胞粒径，不能透过毛细血管壁进入组织间隙， 是一种血池显影剂。 因而， 造影剂不显影的区域， 红细胞等血液 有形成分更无法进入。 附图说明
图 1. 高强度聚焦超声的连续式发射和本发明仪器的间歇脉 冲式发射信号对比模式图。
图 2. 脉冲式超声治疗装置电路框图。
图 3. 平面式超声治疗头结构模式图。
图 4. A: 皮下 VX2肿瘤二维超声影像； B: VX2肿瘤彩色血 流影像； C: VX2 肿瘤治疗前造影呈高灌注相 （白箭头）； D: 肿 瘤治疗后造影呈负性显影 （白箭头）。
图 5. 新西兰白兔 VX2肿瘤血管治疗组与对照组伊文思蓝染 料（ EB )灌注情况。 图 A: 实验组肿瘤组织（黑箭头） EB无灌注， 肌肉 （白箭头） 蓝染； 图 B: 对照组肿瘤组织 （黑箭头） 和肌肉 (白箭头） 均 EB蓝染。
图 6. 新西兰白兔 VX2肿瘤血管治疗效果病理观察。 A: 实 验组肿瘤组织中心大量坏死，仅残存 0. 6-0. 8腿的存活癌细胞层 (黑箭头）； B: 对照组肿瘤组织 （白箭头）。 具体实施方式
具体实验过程如下： 新西兰白兔 VX2肿瘤皮下荷瘤兔随机分 为单純微泡对照组， 单純超声对照组和微泡超声实验组。 超声治 疗采用治疗头垂直辐照肿瘤区 5-10min。 各组在治疗前后分别对 肿瘤进行常规超声检查和超声造影检查。 另外， 微泡超声实验组 辐照后在 30min、 60min和 24h行超声造影检查。 单純微泡组和 单純超声辐照组治疗前后 VX2肿瘤超声造影血供丰富，造影灰阶 值差异不显著 （ 〉0. 05 ); 微泡超声实验组治疗前， VX2肿瘤造 影血供丰富， 平均灰阶值 （GSV ) 84. 1 ± 22. 4; 治疗后即刻超声 造影， 肿瘤微小血管灌注消失， 呈负性显影， GSV为 15. 8 土 10. 8 ; 30分钟后有少量恢复， GSV为 30. 1 土 21. 3 , 60min灌注进一步恢 复， GSV为 45. 4 ± 29. 8。 24 小时后， 肿瘤新生血管超声造影灌 注基本消失， 各组差异显著（ < 0. 01 )。 各组中， 肿瘤周边正常 组织血流灌注未发现明显变化。
血液示踪剂评价
伊文思蓝（EB )是一种用于血液示踪剂的为蓝色染料， 能与 血浆蛋白牢固结合， 分子量大， 不能透过血管壁进入组织间隙。 实险证明， 在治疗组， 尽管 EB可以蓝染肿瘤周边的肌肉组织， 但不能进入肿瘤组织； 而对照组 EB则可以同时蓝染肿瘤和肌肉 组织 （图 5 )。
肿瘤治疗效果病理评价
在分组实验中， 治疗组新西兰白兔 VX2肿瘤在治疗后 3天仅 残存 0. 5-0. 8mm不等的存活癌细胞层，对照组则仍存在 5mm以上 的存活癌细胞层 （图 6 )。 综上所述， 以上对本发明所提供的脉冲式超声治疗装置进行 了详细介绍，本文中应用了具体步 4聚对本发明的原理及实施方式 进行了阐述， 以上实施例的说明只是用于帮助理解本发明的方法 及其核心思想； 同时， 对于本领域的一般技术人员， 依据本发明 的思想， 在具体实施方式及应用范围上均会有改变之处， 综上所 述， 本说明书内容不应理解为对本发明的限制。

Claims

权 利 要 求
1. 一种新型脉冲式超声微泡治疗装置， 包括脉冲式超声发射 装置和超声微泡，其特征在于由超声治疗头发射高峰值声压超声 脉冲激发微泡空化破裂， 而获得能够产生治疗效果的空化效应； 其中， 装置发射的超声脉冲为脉冲式或者间歇脉冲式超声发射， 具有极低的发射占空比， 高峰值声压和较低的平均声强。
2. 根据权利要求 1 所述的新型脉冲式超声微泡治疗装置， 其特征是， 由以下部分构成： 稳压电源、 时间整形调节、 时基电 路、 直流高压电源、 高脉冲开关功能管、 超声功率振荡单元和超 声治疗头组成；稳压电源分别将稳压电源信号提供给时间整形调 节和时基电路， 另一端接地； 再由时间整形调节将信号输出给开 关功能管的控制极， 开关功能管一端接直流高电压正电极， 另一 端接超声波功率振荡单元的正电极； 开关功能管和超声波功率振 荡单元相互串联接在高压直流输出两端， 最后由超声波功率振荡 单元输出信号给超声治疗头。
3. 根据权利要求 2所述的新型脉冲式超声微泡治疗装置，其 特征在于， 在超声功率振荡单元上端， 串入一只开关功能管， 以 控制开关的饱和或者截止状态， 以及振荡单元的工作电位， 使超 声波功率振荡依赖于高脉冲控制单元提供的高脉冲模拟规律。
4. 根据权利要求 2所述的新型脉冲式超声微泡治疗装置，其 特征是： 所述超声治疗头是一种聚焦超声换能器， 或是一种平面 超声换能器。
5. 根据权利要求 1-4所述的新型脉冲式超声微泡治疗装置， 其特征是： 装置产生脉冲式或者间歇脉冲式超声发射， 极低的发 射占空比， 高峰值声压和较低的平均声强； 其超声治疗头发射频 率范围在 l OOKHz-2. OMHz , 其每次脉冲式超声发射时间 1-10秒 不等， 两次超声发射之间间歇时间从 0-20秒不等； 其治疗头超 声峰值声压， 包括峰值正压和峰值负压， 在 0. 4-15MPa范围内可 调； 超声发射的脉冲重复频率 （PRF )在 1-100 内可调， 脉冲宽 度在 10-2500微秒范围内可调。
6. 根据权利要求 5 所述的新型脉冲式超声微泡治疗装置超声 治疗头发射频率为 1ΜΗζ、 0. 5MHz或 100KHz。
7. —种采用权利要求 1、 2、 3或 4所述的脉冲式超声治疗仪 的方法是：在联合经外周静脉注射超声微泡每公斤体重 0. 01-0. 5 毫升超声微泡混悬液， 即约每公斤体重 1 X 108 -5 X 109个微泡的 情况下， 超声治疗头对准体内肿瘤部位发射 l OOKHz-2. OMHz的超 声能量， 治疗时间根据肿瘤大小从 30秒至 10分钟， 超声脉冲通 过激发体内肿瘤新生血管内的超声微泡空化，产生针对肿瘤新生 血管的物理破坏和阻断作用。
8. 根据权利要求 7 所述的方法， 其特征是： 超声微泡选自声 诺维 （SonoVue )、 Def ini ty, Opt i soru Imgent和全氟显， 采用 经外周静脉注射方式进入人体。
9. 根据权利要求 7 所述的方法， 其特征是： 产生超声能量形 式的装置可以是各种类型的脉冲式超声治疗仪，或者是一种单純 的超声治疗仪； 或者是将所述的治疗装置整合于超声诊断仪内， 组成诊断治疗一体化的诊断治疗仪器， 利用诊断超声换能器发射 诊断超声用于肿瘤影像监视， 治疗换能器发射治疗超声用于微泡 增强的肿瘤超声治疗。
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