WO2012083532A1 - 载药造影微泡的超声控制释放及其监控成像方法及微泡破坏量评价方法 - Google Patents

载药造影微泡的超声控制释放及其监控成像方法及微泡破坏量评价方法 Download PDF

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WO2012083532A1
WO2012083532A1 PCT/CN2010/080119 CN2010080119W WO2012083532A1 WO 2012083532 A1 WO2012083532 A1 WO 2012083532A1 CN 2010080119 W CN2010080119 W CN 2010080119W WO 2012083532 A1 WO2012083532 A1 WO 2012083532A1
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drug
imaging
microbubbles
monitoring
loaded
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English (en)
French (fr)
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万明习
徐姗姗
徐志安
宗瑜瑾
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Xian Jiaotong University
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Xian Jiaotong University
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    • 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
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/481—Diagnostic techniques involving the use of contrast agents, e.g. microbubbles introduced into the bloodstream
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/52—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/5215—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves involving processing of medical diagnostic data
    • A61B8/5223—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves involving processing of medical diagnostic data for extracting a diagnostic or physiological parameter from medical diagnostic data
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasonic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasonic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment

Definitions

  • the invention belongs to the field of ultrasonic diagnosis and treatment, and particularly relates to an ultrasonic control translation and a monitoring imaging method for a drug-loaded contrast microbubble and a microbubble destruction amount evaluation method, which expands the function of the existing all-digital ultrasound imaging system into Ultrasound contrast envelope microbubbles (hereinafter referred to as drug-loaded contrast microbubbles) with drug loading, localized, fixed-point, conformal spatiotemporal control and low-energy coded excitation monitoring imaging.
  • drug-loaded contrast microbubbles Ultrasound contrast envelope microbubbles
  • the drug translation system encapsulates the drug in a carrier, implants or injects it into the body, and achieves drug release by slow degradation or exogenous stimulation induction of the carrier in the body, thereby increasing the concentration of the drug in the local lesion tissue.
  • Ultrasound-guided drug control is more cost-effective, more controllable in time and space, and easier to combine with ultrasound monitoring imaging than drugs released under the energies of magnetic fields, electric fields, and temperature.
  • the monitoring imaging of this process requires monitoring before and after translating without destroying the drug-loaded microbubbles, and has high detection sensitivity for the concentration of ultrasound contrast microbubbles, especially the lower microbubble concentration in deep blood vessels.
  • the coding excitation method widely used in radar is introduced into the ultrasound monitoring imaging before and after drug translation. The advantage is that the peak sound power can be reduced to avoid excessive sound pressure causing the rupture of the drug-loaded microbubbles, while increasing the average sound power to increase the energy of the signal to increase the depth of detection and signal-to-noise ratio of the tissue.
  • the applicant of the present invention implements the above-mentioned fixed-point, localized, and conformal low-intensity focused ultrasound focus control mode for drug-loaded microbubble spatio-temporal control translation and low-energy coding excitation monitoring imaging technology on the existing fully digital ultrasound imaging apparatus, thereby enabling The functions and applications of existing all-digital B-mode devices have undergone fundamental changes.
  • the present invention provides an ultrasonic controlled release of a drug-loaded contrast microbubble and a monitoring imaging method thereof, comprising the following steps:
  • Step 1 Pre-treatment monitoring of the lesion area: ie, the injected drug-loaded angiography Buffering and collection of radio frequency data;
  • Step 3 Select a treatment area for rupture release of the drug-loaded contrast microbubbles according to the size, shape and location characteristics of the lesion area;
  • Step 4 Determine the size, position and number of basic focus units to be synthesized according to the size and position of the selected treatment area
  • Step 6 Start the control pulse according to the excitation delay time obtained in step 5, and synthesize N basic focus units with different sizes and positions to form a conformal focal region matching the selected treatment area, and perform drug-loading contrast microbubbles.
  • the fixed point, partial, and conformal translation Step 7: Monitor the lesion area after drug release, complete a surveillance imaging-loading microbubble break release-monitoring imaging cycle;
  • the monitoring imaging is performed by using a low energy coded excitation mode;
  • the transmission mode uses a pseudo-random m sequence to perform phase modulation transmission on the m sequence;
  • the decoding uses the m+1 sequence; as a preferred embodiment of the present invention, in the step 4, determining the size, location, and number of basic focus units that need to be synthesized. After N, all the array elements of the array transducer are divided into M groups by the size of each basic focus unit, and then the number of each array element is calculated inversely according to the focus diameter formula, and the sum of the number of array elements is not guaranteed. Exceeding the total number of transducer elements;
  • the invention also provides a method for evaluating the amount of damage of microbubbles: comprising the following steps: Step 1: In the monitoring imaging system with low energy coded excitation, m parameter imaging of the collected radio frequency data to obtain a sequence m parametric image;
  • Step 2 Select the region of interest on the m parametric image according to the treatment area, and take the mean or median of the image, representing the average concentration of the scatterers in the region, thereby drawing a TNC curve;
  • Step 3 by subtracting the ordinate corresponding to the front and back time on the TNC curve obtained in step 2, the difference of the m parameter values is obtained;
  • Step 4 Determine the amount of drug release in this area based on the curve to analyze the reduction of drug-loaded contrast microbubbles.
  • the present invention realizes two functions of localized, fixed-point, conformal control translation and low-energy coding excitation monitoring imaging of the ultrasound contrast envelope microbubbles carrying the drug on the existing all-digital ultrasound imaging system, thereby Fundamentally expand the work of existing all-digital diagnostic ultrasound equipment Mode and function;
  • the present invention proposes to implement on the existing all-digital ultrasound imaging system.
  • the conformal focal region reverse synthesis control technique for local and fixed-point drug translation specifically, the treatment region where the drug-loaded microbubbles need to be broken and translated according to the shape, position and size of the lesion, and the synthesis of the conformable coke is determined.
  • the number N and size of the basic focus units required by the domain are divided into N groups of transducer elements, each group is used to synthesize a basic focus unit, and each array is inversely determined according to the focus synthesis theory of the array transducer.
  • the number of array elements of the tuple (guarantee that the number of array elements in each group does not exceed the total number of transducer elements) and the excitation delay time of each array element, and the control delay pulse is started according to the excitation delay time, and each basic focus unit is synthesized at the same time. Finally, a conformal focal region is formed.
  • the basic focus unit can be changed in terms of focus size, focal length and deflection angle, so that the focus can be calculated to have a certain size at a certain depth.
  • the corresponding excitation delay time of each driving array element realizes the positioning of the focus of different sizes on the drug release plane by calling the controlled release pulse having the delay time.
  • the monitoring imaging method of the present invention replaces the traditional monitoring imaging with a low-energy coded excitation emission method.
  • the pseudo-random m-sequence encoding is used to perform phase-modulated emission on the m-sequence.
  • the m-sequence is a sequence of positive and negative levels +a, -a. When it is positive, it is a sine of 0 phase. Waveform, when it is negative, it is a sinusoidal sinusoidal waveform to achieve phase Modulation.
  • the present invention provides a parameter based on the Nakagami statistical model for the drug in the region of interest.
  • the parameter m in the Nakagami statistical model can distinguish different scatterer concentrations, and the parametric m image can reflect the local scatterer concentration distribution of the imaged object.
  • Ultrasound contrast microbubbles act as a scatterer. Therefore, the present invention uses a parametric m image to reflect the distribution of microbubbles in the contrast region.
  • Figure 1 is a timing chart of the operation of the system of the present invention
  • Figure 2 is a flow chart of the operation of the system of the present invention.
  • FIG. 3 is a schematic view showing a specific method for the reverse synthesis of a conformal focal region in the present invention
  • Figure 4 is a schematic diagram showing changes in contrast microbubble concentration in low energy coded contrast imaging and conventional ultrasound contrast imaging modes
  • Fig. 5 is a schematic view showing the method for evaluating the amount of destruction of microbubbles based on m parametric imaging in the present invention. detailed description
  • the invention mainly includes the following three contents:
  • the first aspect provides a system solution for extending the original single diagnostic imaging function of the fully digital ultrasound imaging system to a localized, fixed-point, conformal control translation and low-energy coded excitation monitoring imaging function of the drug-loaded contrast microbubble;
  • a technique for implementing conformal focal region reverse synthesis control for local and fixed-point drug control interpretation on an existing fully digital ultrasound imaging system is developed;
  • a method for evaluating a drug damage amount in a region of interest based on a parameter m in a Nakagami statistical model is provided;
  • the present invention provides a system solution for extending the original single diagnostic imaging function of a fully digital ultrasound imaging system to a localized, fixed-point, conformal control translation and low-energy coded excitation monitoring imaging function for drug-loaded contrast microbubbles.
  • the fully digital ultrasound imaging system of the present invention consists of an ultrasound array transducer, a fully digital ultrasound imaging device, a network connection, and a host PC.
  • the timing of the system's time-sharing work is shown in Figure 1.
  • the system work flow chart is shown in Figure 2.
  • the specific approach is:
  • Step 1 Start the system and initialize the device.
  • Step 2 According to the coded excitation monitoring imaging method, the user performs pre-treatment monitoring on the lesion area: the monitoring imaging emission sequence of the coded excitation is started by the fully digital ultrasound imaging system, and the radio frequency data of the injected drug-loaded contrast microbubbles is collected. Transmission:
  • the delay formula is:
  • T ⁇ ( l - [ l + ( H ⁇ f ) + To , where is the time at which the central element emits a pulse wave or c F
  • F is the focal length
  • n is the number of elements participating in a single shot
  • d is the center distance of the element
  • c is the speed of sound
  • Step 4 The main control PC of the system transmits a command to the imaging device through the network connection, and calls the low-intensity focus controlled release pulse with the above excitation delay time to synthesize each basic focus unit to form a suitable matching with the selected treatment area of the user. Forming focal region, performing fixed-point, partial, and conformal translation of the drug-loaded contrast bubble;
  • Step 5 After the fully digitalized ultrasound imaging device completes the control of the drug-loaded contrast microbubbles, restarts the ultrasound-monitored imaging sequence of the coded excitation, monitors the lesion area after the drug is released, and completes a surveillance imaging-loading microbubble. Fracture translation - monitoring imaging cycle;
  • Step 6 The user judges whether the remaining area of the treatment area needs to be controlled for translation according to the translation and release of the drug-loaded contrast microbubble displayed on the monitoring image, and restarts the focus control pulse if necessary, and moves the transducer if not needed. Enter another imaging plane, repeat the above diagnostic imaging - drug-loaded microbubble rupture - monitoring imaging work process, and finally the master PC calculates the microbubble damage based on the radio frequency data of the monitored image obtained by it, and finally the treatment Conduct an evaluation.
  • the present invention in order to solve the problem of uncontrollable full-field translation of the microbubbles in the ultrasonic single-probe scanning beam or the B-mode scanning imaging plane in the conventional mode, the present invention develops an existing all-digital ultrasound imaging system.
  • a conformal focal region reverse synthesis control technique for realizing local and fixed-point drug translation the user can select the treatment area to be translated and translated according to the shape, position and size of the patient's lesion, and determine the number N and size of the basic focus units needed to synthesize the conformal focal region.
  • the array element of the transducer is divided into M groups, each group is used to synthesize a basic focus unit, and the number of array elements of each array of elements is inversely determined according to the focus synthesis theory of the array transducer (guarantee the number of array elements of each array) Adding no more than the total number of transducer elements and the excitation delay time of each element, the control pulse is started according to the excitation delay time, and each basic focus unit is synthesized at the same time, and finally a conformal focal region is formed.
  • the coding method used in the present invention is a pseudo-random m-sequence, and the internal clock frequency is set to 40 MHz, and each '+' or '-' represents a time length of 25 ns, if the excitation waveform is set to '++++' , the duration of the excitation is 100ns, and if the waveform of the excitation is set to, the excitation duration is 100ns. If the excitation waveform is set to '++++----', the duration of the excitation is 200ns and the frequency of the transducer's transmitted waveform is 5MHz.
  • this decoding method can overcome the DC component interference generated by the m-sequence autocorrelation decoding method, thereby improving the signal-to-noise ratio and penetration depth of the signal.
  • Coded excitation m sequence The longer the code length, the stronger the energy of the signal, the stronger the penetrating power, the lower the sidelobe level produced by decoding, and the lower the signal-to-noise ratio.
  • the array array probe of the all-digital diagnostic ultrasound device used in the present invention has 128 array elements and 256 excitation channels (positive /negative)) imaging depth, focus position, number of scan lines, pulse repetition frequency, etc.;
  • the receiving parameters such as the number of receiving channels, that is, the number of receiving elements (the maximum number of receiving channels provided by the device is 32), the sampling frequency (can be set to 5/10/20/40MHZ), Format of stored data (RF data or video data), data storage memory
  • the present invention also provides a method for evaluating the amount of drug damage in a region of interest based on the parameter m in the Nakagami statistical model, as follows:
  • the statistical model performs statistical analysis on the ultrasonic scattering signal.
  • the parameter m in the Nakagami statistical model is a shape parameter, which determines the shape of the statistical distribution fitting curve. Since the echo envelope statistics obtained by different scattering sub-concentrations have different shapes, The parameter m can be used to distinguish different scatterer concentration distributions, and within a certain range of scatterer concentrations, the parameter m and the scatterer concentration have a good proportional relationship. Therefore, the m-parameter image can be reflected by the parameter m.
  • Ultrasound contrast microbubbles as a kind of scatterer, m parameter images can be used to reflect the distribution of microbubbles in the contrast area.
  • m-parametric images are unaffected by dynamic range, system gain, and time gain compensation
  • m-parametric imaging methods can utilize weaker echo signals.
  • Obtaining the scatterer concentration distribution of the object can reduce the influence of the attenuation to some extent. Therefore, the Time-Nakagami Parameter m Curves (TNC) obtained by using the parameter m is as effective as the Time Intensity Curves TIC in the contrast imaging blood flow perfusion evaluation, and can overcome the attenuation of the tissue.
  • TPC Time-Nakagami Parameter m Curves
  • the invention provides a new method for evaluating the amount of microbubble destruction: in a low-energy coded excitation monitoring imaging system, m-parameter imaging is performed on the collected radio frequency data to obtain a sequence m parametric image, as shown in FIG. 5 . Then, according to the treatment area, the region of interest is selected on the m parametric image, and the mean or median of the image is taken to represent the average concentration of the scatterers in the region, thereby drawing a TNC curve, and the ordinate corresponding to the anteroposterior time on the TNC curve Subtracting, the difference between the obtained m parameter values can qualitatively describe the amount of microbubble reduction between the ultrasound contrast envelope microbubbles between the two monitoring times.
  • the above description is only one embodiment of the present invention, and is not all or the only embodiment. Any equivalent transformation of the technical solution of the present invention by those skilled in the art by reading the specification of the present invention is the present invention. Covered by the claims.

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Description

载药造影微泡的超声控制译放及其监控成像方法及微泡破坏量评价 方法
技术领域
本发明属于超声诊断与治疗领域， 特别涉及一种载药造影微泡的 超声控制译放及其监控成像方法及微泡破坏量评价方法，其将现有全 数字化超声成像系统的功能扩展为兼具有携载药物的超声造影包膜 微泡（以下简称载药造影微泡）局部、 定点、 适形的时空控制译放与 低能量编码激励监控成像两种功能。
背景技术
药物译放系统是将药物包裹在载体中，植入或注入体内， 通过载 体在体内的緩慢降解或外源刺激诱导方法达到药物的译放，增加局部 病灶组织的药物浓度。 近年来寻求一种既能增加药物译放率， 又能对 药物译放过程进行控制，同时还能对药物译放过程进行监控的方法已 经成为一个研究热点。 超声引导下的药物控制译放与磁场、 电场、 温 度等能量形式作用下的药物译放相比具有成本较低、时空可控性较强 以及易于与超声监控成像结合等优点。
在超声诱导微泡破裂药物译放方面， 发展能够定点、 局部、 适形 地进行携载药物的微泡时空控制译放工作模式具有重要意义。而从超 声药物控制译放技术角度看 ,传统模式下在超声单探头的扫描声束内 或 B模式扫描成像平面上载药微泡断裂引起的药物译放是不可控制 的译放， 达不到在空间定点、 局部及适形译放的要求。 因此在本发明 中， 提出利用全数字化超声成像系统合成满足定点、 局部、 适形译放 的低强度聚焦超声焦点控制模式的方法和技术。
与超声控制药物译放技术一样，对译放过程的监控成像研究也是 一个非常重要的问题。对此过程的监控成像要求在不破坏载药微泡的 情况下进行译放前后的监控，同时要对超声造影微泡的浓度尤其是深 部血管内较低的微泡浓度具有高检测灵敏度， 因此在本发明中，把雷 达中广泛应用的编码激励方式引入到药物译放前后的超声监控成像 中。其优势在于可以降低峰值声功率从而避免过高的声压导致载药微 泡的破裂，同时增加平均声功率从而提升信号的能量以增加组织的探 测深度和信噪比。
本发明申请人在现有全数字化超声成像设备上实施上述定点、局 部、适形的低强度聚焦超声焦点控制模式下的载药微泡时空控制译放 和低能量编码激励监控成像技术， 从而使现有全数字化 B 超设备的 功能和应用发生根本性变化。
发明内容
本发明所要解决的技术问题是提供一种载药造影微泡的超声控 制译放及其监控成像方法及微泡破坏量评价方法，在现有全数字化超 声成像系统上利用载药造影微泡实现药物局部、 定点、 适形地译放， 并对药物译放过程进行低能量编码激励监控成像，增加平均声功率从 而提升信号的能量以增加组织的探测深度和信噪比。
为实现上述目的，本发明提供了一种载药造影微泡的超声控制释 放及其监控成像方法， 包括以下步骤：
步骤 1 : 对病灶区域进行治疗前期监控： 即对注入的载药造影啟 泡进行射频数据的釆集和传输；
步骤 2: 观察载药造影微泡是否在病灶区域显影， 如果显影成功 继续步骤 3;
步骤 3: 根据病灶区域的大小、 形状、 位置特征选定载药造影微 泡所需断裂释放的治疗区；
步骤 4: 根据选定的治疗区域的大小及位置确定需要合成的基本 焦点单元的大小、 位置及个数 N;
步骤 5: 计算得到参与合成各基本焦点单元所需阵元的激励延迟 时间；
步骤 6: 按照步骤 5得到的激励延迟时间启动控译脉冲， 同时合 成大小、 位置不同的 N个基本焦点单元， 形成与选定的治疗区域相 匹配的适形焦域， 进行载药造影微泡的定点、 局部、 适形地译放； 步骤 7: 对药物译放后的病灶区域进行监控， 完成一次监控成像 -载药微泡断裂译放 -监控成像周期；
步骤 8: 根据监控图像显示的载药造影微泡断裂译放情况判断是 否需要对治疗区域的剩余区域进行控制译放，如果需要则重新启动聚 焦控译脉冲， 如果不需要则移动换能器进入另一个成像平面， 重复以 上诊断成像-载药微泡断裂译放 -监控成像的工作过程， 最后根据获得 的监控图像的射频数据进行微泡破坏量计算，最后对此次治疗进行评 价。
作为本发明的优选实施例， 所述步骤 1中，监控成像釆用低能量 编码激励发射方式； 作为本发明的优选实施例， 所述步骤 1中，发射方式釆用伪随机 m序列， 对 m序列进行调相发射；
作为本发明的优选实施例， 所述步骤 1中， 解码釆用 m+1序列； 作为本发明的优选实施例， 所述骤 4中， 确定需要合成的基本焦 点单元的大小、 位置及个数 N后， 由各基本焦点单元的大小将阵列 换能器的所有阵元分为 M组， 然后根据焦点直径公式反向计算得到 每组阵元的个数， 保证每组阵元数之和不超过换能器阵元总数；
本发明还提供了一种微泡破坏量评价方法： 包括以下步骤： 步骤 1 : 在低能量编码激励的监控成像系统中， 对釆集的射频数 据进行 m参量成像， 得到序列 m参量图像；
步骤 2: 根据治疗区域在 m参量图像上选择感兴趣区域，取图像 均值或者中值， 代表该区域散射子的平均浓度， 由此绘制出 TNC曲 线；
步骤 3: , 通过对步骤 2得到的 TNC曲线上的前后时间所对应的 纵坐标进行减法运算， 得到 m参量值之差；
步骤 4： 根据曲线分析载药造影微泡的减少量确定该区域的药物 译放量。
本发明载药造影微泡的超声控制译放及其监控成像方法及微泡 破坏量评价方法至少具有以下优点：
第 ―、本发明在现有全数字化超声成像系统上实现携载药物的超 声造影包膜微泡的局部、 定点、适形控制译放与低能量编码激励监控 成像的两种功能，由此从根本上扩展现有全数字化诊断超声设备的工 作模式及功能；
第二、 为了解决传统模式下在超声单探头扫描声束内或 B模式 扫描成像平面上载药微泡不可控制的全场译放问题，本发明提出一种 在现有全数字化超声成像系统上实现局部、定点药物译放的适形焦域 反向合成控制技术， 具体地说， 就是根据病灶形状、 位置、 尺寸选定 载药造影微泡需断裂译放的治疗区域，确定合成该适形焦域所需要的 基本焦点单元的个数 N及大小， 将换能器的阵元划分为 N组， 每组 用于合成一个基本焦点单元，根据阵列式换能器焦点合成理论反求出 每一阵元组的阵元个数（保证各组阵元数相加不超过换能器阵元总 数）及各阵元的激励延迟时间， 按该激励延迟时间启动控译脉冲， 同 时合成各个基本焦点单元， 最终形成适形焦域。依据阵列换能器电子 聚焦原理及其延时公式和焦点直径计算公式，基本焦点单元可以在焦 点大小、 焦距及偏转角度等方面进行改变， 因此可计算得到合成位于 一定深度具有一定尺寸的焦点所对应的各驱动阵元的激励延迟时间， 通过调用具有该延迟时间的控释脉冲实现不同大小的焦点在药物释 放平面上任意位置的定位。
第三、为了克服传统超声监控成像中系统高峰值声压导致的载药 微泡在声场中断裂而药物过早译放等问题，本发明监控成像釆用低能 量编码激励发射方式代替传统监控成像系统上的单脉冲激励发射方 式。 在系统的实现过程中， 釆用伪随机 m序列编码， 对 m序列进行 调相发射， m序列是正负电平 +a, -a的序列波形， 当为正电平时， 为 0相的正弦波形， 当为负电平时， 为 Π相正弦波形， 以此来实现相位 的调制。 在解码过程中， 釆用 m+1序列， 这种解码方式能克服 m序 列自相关解码方式产生的直流的分量，从而提高信号的能量。 编码激 励 m序列码长越长， 信号的能量越强， 穿透力越强， 同时解码产生 的旁瓣水平越低， 信噪比也越低。
第四、为了克服载药造影微泡局部译放后未译放区域内造影微泡 浓度过高所产生的声遮挡效应， 本发明提供一种基于 Nakagami统计 模型中参量 m对感兴趣区域内药物破坏量进行评价的方法。 Nakagami 统计模型中的参量 m可以区分不同的散射子浓度， 参量 m图像可以 反映成像对象的局部散射子浓度分布。 超声造影微泡作为一种散射 子， 因此， 本发明釆用用参量 m图像来反映微泡在造影区域的分布。 附图说明
图 1是本发明系统的工作时序图；
图 2是本发明系统的工作流程图；
图 3是本发明中适形焦域反向合成的具体方法示意图；
图 4 是低能量编码造影成像和常规超声造影成像模式下的造影 微泡浓度变化示意图；
图 5是本发明中基于 m参量成像的微泡破坏量评价方法示意图。 具体实施方式
本发明主要包括以下三个内容：
第一方面，提供将全数字化超声成像系统原有的单一诊断成像功 能扩展为具有载药造影微泡局部、 定点、适形控制译放及低能量编码 激励监控成像功能的系统解决方案； 第二方面， 发展一种在现有全数字化超声成像系统上实现局部、 定点药物控制译放的适形焦域反向合成控制的技术；
第三方面，提供一种基于 Nakagami统计模型中参量 m对感兴趣 区域内药物破坏量进行评价的方法；
下面对上述三个方面的更具体的技术方案和实现方法做详细描 述：
本发明提供了一种将全数字化超声成像系统原有的单一诊断成 像功能扩展为具有载药造影微泡局部、 定点、适形控制译放及低能量 编码激励监控成像功能的系统解决方案。本发明全数字化超声成像系 统由超声阵列式换能器、 全数字化超声成像设备、 网络连接， 以及主 控 PC机组成。 该系统分时工作的时序如图 1所示， 系统工作流程图 如图 2所示， 具体做法是：
步骤 1 : 启动系统， 对设备进行初始化；
步骤 2: 用户根据编码激励监控成像方法， 对病灶区域进行治疗 前期监控：即通过全数字化超声成像系统启动编码激励的监控成像发 射序列， 对注入的载药造影微泡进行射频数据的釆集和传输：
步骤 3: 观察载药造影微泡是否在病灶区域显影， 如果显影成功 继续进行；
步骤 4: 用户根据病灶区域的大小、 形状、 位置等特征并结合实 际情况和治疗方案选定载药造影微泡所需断裂译放的治疗区域； 步骤 5: 系统根据用户选定的治疗区域的大小及位置确定需要合 成的基本焦点单元的大小、位置及个数 N, 再由各基本焦点单元的大 小将阵列换能器的所有阵元分为 M组， 然后根据焦点直径公式反向 计算得到每组阵元的个数 ,保证每组阵元数之和不超过换能器阵元总 数， 所述焦点直径公式为： fVf = 2A4AF / nd， 其中， 是焦距， 是发 射的超声波波长， n是参与一次发射的阵元数， d是阵元的中心距； 步骤 3: 通过阵列换能器电子聚焦原理及其延时公式计算得到每 一阵元组各阵元的激励延迟时间 ， 所述延时公式为：
T = ^(l - [l + (H †f) + To , 其中， 是中心阵元发射脉冲波的时间或是 c F
一个足够大的时间常数， F是焦距， n是参与一次发射的阵元数， d 是阵元的中心距， c是声速；
步骤 4: 系统的主控 PC机通过网络连接传输命令给成像设备， 调用具有以上激励延迟时间的低强度聚焦控释脉冲以合成各基本焦 点单元， 构成与用户选定的治疗区域相匹配的适形焦域， 进行载药造 影 泡的定点、 局部、 适形地译放；
步骤 5:全数字化超声成像设备完成载药造影微泡的控制译放后， 重新启动编码激励的超声监控成像序列，对药物译放后的病灶区域进 行监控， 完成一次监控成像-载药微泡断裂译放 -监控成像周期；
步骤 6: 用户根据监控图像显示的载药造影微泡断裂译放情况判 断是否需要对治疗区域的剩余区域进行控制译放，如果需要则重新启 动聚焦控译脉冲， 如果不需要则移动换能器进入另一个成像平面， 重 复以上诊断成像 -载药微泡断裂译放-监控成像的工作过程， 最后主控 PC根据其获得的监控图像的射频数据进行微泡破坏量计算， 最后对 此次治疗进行评价。 在本发明中，为了解决传统模式下在超声单探头扫描声束内或 B 模式扫描成像平面上载药微泡不可控制的全场译放问题，本发明发展 一种在现有全数字化超声成像系统上实现局部、定点药物译放的适形 焦域反向合成控制技术。 实际应用中， 用户可以根据患者病灶形状、 位置、尺寸选定载药造影微泡需断裂译放的治疗区域， 确定合成该适 形焦域所需要的基本焦点单元的个数 N及大小， 将换能器的阵元划 分为 M组， 每组用于合成一个基本焦点单元， 根据阵列式换能器焦 点合成理论反求出每一阵元组的阵元个数（保证各组阵元数相加不超 过换能器阵元总数）及各阵元的激励延迟时间， 按该激励延迟时间启 动控译脉冲， 同时合成各个基本焦点单元， 最终形成适形焦域。 依据 阵列换能器电子聚焦原理及其延时公式和焦点直径计算公式，基本焦 点单元可以在焦点大小、 焦距及偏转角度等方面进行改变， 因此可计 算得到合成位于一定深度具有一定尺寸的焦点所对应的各驱动阵元 的激励延迟时间，通过调用具有该延迟时间的控译脉冲实现不同大小 的焦点在药物译放平面上任意位置的定位。
请参阅图 3所示，即常规超声造影成像系统与本发明超声造影监 控成像系统对造影微泡浓度影响的示意图， 从图中可以看出： 微泡在 常规超声造影成像系统中的存活时间相较于其在低能量编码激励的 超声造影监控成像系统中的存活时间较短，这是因为常规超声造影成 像中过高的能量使载药造影微泡断裂过早的译放药物。本发明超声造 影监控成像釆用低能量编码激励的发射方式， 其优势在于： 可以降低 峰值声功率， 从而避免过高的声压导致载药微泡的破裂， 同时增加平 均声功率， 提升信号的能量以增加组织的探测深度和信噪比。
本发明釆用的编码方式为伪随机 m序列， 设置内部的时钟频率 为 40MHz, 每个 '+'或者' -'所代表的时间长度为 25ns, 如果激励的波 形设置为' ++++' , 则激励的时长为 100ns , 如果激励的波形设置为 则激励时长为 100ns。 如果激励波形设置为 '++++----' , 则激励 的时长为 200ns, 换能器的发射波形的频率为 5MHz。 本发明伪随机 m序列为 7码长的 m序列的编码序列 1 1 1 -1 1 -1 -1。 在发射的过程 中， 对 m序列进行调相发射， m序列是正负电平 +a, -a的序列波形， 当为正电平时， 为 0相的正弦波形如 '++++ -- ' , 当为负电平时， 为 Π 相正弦波形' -- ++++，， 以此来实现相位的调制。 在解码过程中， 釆 用 m+1序列， 这种解码方式能克服 m序列自相关解码方式产生的直 流分量干扰， 从而提高信号的信噪比和穿透深度。 编码激励 m序列 码长越长， 信号的能量越强， 穿透力越强， 同时解码产生的旁瓣水平 也越低， 信噪比也越低。
关于编码超声造影成像模块的工作流程如下所述：
(1)首先用户选择编码方式， 编码激励的波形已在前面详述；
(2)设置发射参数， 如编码激励的电压值， 每一条扫描线发射所 使用的阵元数（本发明使用的全数字化诊断超声设备的阵列阵探头具 有 128阵元及 256个激励通道（正 /负））成像深度， 焦点位置， 扫描 线数， 脉冲重复频率等；
(3)设置接收参数， 如接收通道数， 即接收的阵元数（设备提供 最大的接收通道数为 32 ), 釆样频率（可设置为 5/10/20/40MHZ ), 存 储数据的格式（射频数据或者视频数据）， 数据存储内存
( 128/256/384M )等；
(4)根据发射参数， 对阵列式换能器进行激励， 发射结束后换能 器转换为接收状态；
(5)根据接收参数的设置， 对组织回波信号进行接收釆集；
(6)对射频信号进行 TGC时间增益补偿和滤波；
(7)对每个通道接收的数据进行延迟叠加实现接收动态聚焦；
(8)对合成之后的射频数据进行解码， 解码选择 m+1序列， 同时 存储解码之后的射频数据， 这里每个射频数据点的大小为 2字节；
(9)对射频数据进行包络检波， 动态压缩， 降釆样等处理；
(10)对上述处理之后的射频数据进行成像， 并进行存储， 每一像 素点的大小为 1字节。
本发明还提供了一种基于 Nakagami统计模型中的参量 m对感兴 趣区域药物破坏量的评价方法， 具体如下：
该统计模型对超声散射信号进行统计分析， Nakagami统计模型 中的参量 m为形状参数， 决定统计分布拟合曲线的形状， 由于不同 的散射子浓度得到的回波包络统计具有不同的形状，因此可以利用参 量 m来区分不同的散射子浓度分布， 而且在一定的散射子浓度范围 内， 参量 m和散射子浓度有很好的正比关系， 因此用参量 m进行成 像， 得到的 m参量图像可以反映成像对象的局部散射子浓度分布。 超声造影微泡作为一种散射子， 可以用 m参量图像来反映微泡在造 影区域的分布。 与常规超声监控成像利用回波幅度进行成像的模式不同， m参量 图像不受动态范围、 系统增益以及时间增益补偿等多种设置的影响， 而且 m参量成像方法可以利用较弱的回波信号来得到对象的散射子 浓度分布， 能够在一定程度上减小衰减带来的影响。 所以利用参量 m 得到的时间 -参量 m曲线（ Time-Nakagami Parameter m Curves, TNC ) 同造影成像血流灌注评价中的时间 -强度曲线（ Time Intensity Curves ) TIC一样有效， 而且可以克服组织的衰减， 声遮挡， 图像灰度与造影 剂浓度的非线性等的影响。
本发明提供了一种新的评价微泡破坏量的方法：在低能量编码激励的 监控成像系统中， 对釆集的射频数据进行 m参量成像， 得到序列 m 参量图像， 如图 5所示， 然后根据治疗区域在 m参量图像上选择感 兴趣区域， 取图像均值或者中值， 代表该区域散射子的平均浓度， 由 此绘制出 TNC曲线，通过对 TNC曲线上的前后时间所对应的纵坐标 进行减法运算， 得到的 m参量值之差可以定性的描述超声造影包膜 微泡在两次监控时间之间的微泡减少量。以上所述仅为本发明的一种 实施方式， 不是全部或唯一的实施方式， 本领域普通技术人员通过阅 读本发明说明书而对本发明技术方案釆取的任何等效的变换，均为本 发明的权利要求所涵盖。

Claims

权利 要求
1. 一种载药造影微泡的超声控制译放及其监控成像方法， 其 特征在于： 包括以下步骤：
步骤 1 : 对病灶区域进行治疗前期监控： 即对注入的载药造影 微泡进行射频数据的釆集和传输；
步骤 2: 观察载药造影微泡是否在病灶区域显影，如果显影成 功继续步骤 3;
步骤 3: 根据病灶区域的大小、 形状、 位置特征选定载药造影 微泡所需断裂释放的治疗区；
步骤 4:根据选定的治疗区域的大小及位置确定需要合成的基 本焦点单元的大小、 位置及个数 N;
步骤 5:计算得到参与合成各基本焦点单元所需阵元的激励延 迟时间；
步骤 6: 按照步骤 5得到的激励延迟时间启动控释脉冲， 同时 合成大小、 位置不同的 N个基本焦点单元， 形成与选定的治疗区 域相匹配的适形焦域， 进行载药造影微泡的定点、 局部、 适形地 译放；
步骤 7: 对药物译放后的病灶区域进行监控， 完成一次监控成 像-载药微泡断裂译放 -监控成像周期；
步骤 8:根据监控图像显示的载药造影微泡断裂译放情况判断 是否需要对治疗区域的剩余微泡进行控制译放， 如果需要则重新 启动聚焦控释脉冲， 如果不需要则移动换能器进入另一个成像平 面， 重复以上诊断成像-载药微泡断裂译放-监控成像的工作过程， 最后根据获得的监控图像的射频数据进行微泡破坏量计算， 最后 对此次治疗进行评价。
2. 如权利要求 1 所述的载药造影微泡的超声控制译放及其监 控成像方法， 其特征在于： 所述步骤 1中， 监控成像釆用低能量编 码激励发射方式。
3. 如权利要求 2所述的载药造影微泡的超声控制译放及其监 控成像方法， 其特征在于： 所述步骤 1中， 发射方式釆用伪随机 m 序列， 对 m序列进行调相发射。
4. 如权利要求 3所述的载药造影微泡的超声控制译放及其监 控成像方法， 其特征在于： 所述步骤 1中， 解码釆用 m+1序列。
5. 如权利要求 1所述的载药造影微泡的超声控制译放及其监 控成像方法， 其特征在于： 所述步骤 4中， 确定需要合成的基本焦 点单元的大小、 位置及个数 N后， 由各基本焦点单元的大小将阵 列换能器的所有阵元分为 M组， 然后根据焦点直径公式和电子聚 焦延迟公式反向计算得到每组阵元的个数和每组阵元的激励延迟 时间， 保证每组阵元数之和不超过换能器阵元总数。
6. 一种微泡破坏量评价方法， 其特征在于： 包括以下步骤： 步骤 1 : 在低能量编码激励的监控成像系统中， 对釆集的射频 数据进行 m参量成像， 得到序列 m参量图像；
步骤 2: 根据治疗区域在 m参量图像上选择感兴趣区域，取图 像均值或者中值，代表该区域散射子的平均浓度，由此绘制出 TNC 曲线；
步骤 3: 通过对步骤 2得到的 TNC曲线上的前后时间所对应的 纵坐标进行减法运算， 得到 m参量值之差；
步骤 4: 根据曲线分析载药造影微泡的减少量确定该区域的药 物译放量。
PCT/CN2010/080119 2010-12-22 2010-12-22 载药造影微泡的超声控制释放及其监控成像方法及微泡破坏量评价方法 Ceased WO2012083532A1 (zh)

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