CN107049252A - A kind of biological magneto-optic sound joint endoscopic imaging method - Google Patents
A kind of biological magneto-optic sound joint endoscopic imaging method Download PDFInfo
- Publication number
- CN107049252A CN107049252A CN201710199118.5A CN201710199118A CN107049252A CN 107049252 A CN107049252 A CN 107049252A CN 201710199118 A CN201710199118 A CN 201710199118A CN 107049252 A CN107049252 A CN 107049252A
- Authority
- CN
- China
- Prior art keywords
- mrow
- msubsup
- mfrac
- msub
- imaging
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000003384 imaging method Methods 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000004088 simulation Methods 0.000 claims abstract description 6
- 230000004927 fusion Effects 0.000 claims description 15
- 230000003068 static effect Effects 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 6
- 238000005259 measurement Methods 0.000 claims description 5
- 230000005284 excitation Effects 0.000 claims description 4
- 238000010895 photoacoustic effect Methods 0.000 claims description 4
- 238000002604 ultrasonography Methods 0.000 claims description 4
- 238000000342 Monte Carlo simulation Methods 0.000 claims description 3
- 230000031700 light absorption Effects 0.000 claims description 3
- 230000006698 induction Effects 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 2
- 230000000877 morphologic effect Effects 0.000 abstract description 2
- 210000001519 tissue Anatomy 0.000 description 73
- 210000004204 blood vessel Anatomy 0.000 description 7
- 239000002245 particle Substances 0.000 description 6
- 230000008021 deposition Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000004422 calculation algorithm Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000005315 distribution function Methods 0.000 description 2
- 238000002592 echocardiography Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000012887 quadratic function Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0093—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0093—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
- A61B5/0095—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy by applying light and detecting acoustic waves, i.e. photoacoustic measurements
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Pathology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- Medical Informatics (AREA)
- Biophysics (AREA)
- Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Acoustics & Sound (AREA)
- Investigating Or Analyzing Materials By The Use Of Ultrasonic Waves (AREA)
Abstract
一种生物磁光声联合内窥成像方法,所述方法在建立多层腔体组织横截面模型的基础上,对腔道内的超声回波成像、光声成像和感应式磁声成像的过程进行数值仿真,得到腔道横截面上组织反射的超声回波信号以及组织产生的光声和磁声信号,然后对三种超声信号进行最优加权求和,得到融合后的联合成像信号。本发明在信号层对超声换能器分时接收的腔体组织反射/散射的超声回波信号以及组织产生的光声信号和磁声信号进行融合,同传统方法相比,本方法得到的联合成像信号可较多地保留组织的形态结构和成分信息,据此重建出的组合图像具有极高的空间分辨率、对比度、灵敏度和对比分辨率,能准确显示腔道壁内各组织的位置、形态及其功能成分。
A biomagnetoacoustic combined endoscopic imaging method, the method is based on the establishment of a multi-layer cavity tissue cross-sectional model, the process of ultrasonic echo imaging, photoacoustic imaging and inductive magnetoacoustic imaging in the cavity Through numerical simulation, the ultrasonic echo signal reflected by the tissue on the cavity cross section and the photoacoustic and magnetoacoustic signals generated by the tissue are obtained, and then the three ultrasonic signals are optimally weighted and summed to obtain the fused joint imaging signal. The present invention fuses the ultrasonic echo signals reflected/scattered by the cavity tissue received by the ultrasonic transducer in time-division and the photoacoustic signal and magnetoacoustic signal generated by the tissue at the signal layer. Compared with the traditional method, the combined Imaging signals can retain more morphological structure and composition information of tissues, and the reconstructed combined images have extremely high spatial resolution, contrast, sensitivity and contrast resolution, and can accurately display the position, Morphology and its functional components.
Description
技术领域technical field
本发明涉及一种对生物腔体组织进行磁光声联合内窥成像的方法,属于医学成像技术领域。The invention relates to a method for performing magneto-optoacoustic combined endoscopic imaging on biological cavity tissue, and belongs to the technical field of medical imaging.
背景技术Background technique
生物光声(photoacoustic,PA)成像是以生物组织的光声效应为物理基础,即组织吸收短脉冲激光进而发热膨胀产生超声波(即光声信号)。感应式磁声(magnetoacoustictomography with magnetic induction,MAT-MI)成像以生物组织的磁声效应为物理基础,即将目标体置于静磁场中,并在与静磁场的相同方向上施加磁脉冲激励,目标体中感应出的涡电流与静磁场作用产生洛伦兹力,带电粒子在洛伦兹力的作用下产生振动,从而发射出超声波,再经过超声探头接收后成像。单一的成像技术不能全面、详尽地描述生物组织的结构和功能信息,而超声(ultrasonic,US)、PA和MAT-MI成像都是以超声波为载体的声学成像技术,且具有互补的特点,可将它们结合起来,进行磁光声(magneto-photo-acoustic,MPA)联合成像。MPA成像综合了光声信号发射阶段超声检测较高的分辨率以及磁声信号检测时较高的分辨率和灵敏度,可对早期病变组织进行精准的定位和功能成分成像。Biophotoacoustic (PA) imaging is based on the photoacoustic effect of biological tissue as the physical basis, that is, the tissue absorbs short-pulse laser light and then heats up and expands to generate ultrasonic waves (ie, photoacoustic signals). Inductive magnetoacoustic tomography (magnetoacoustictomography with magnetic induction, MAT-MI) imaging is based on the magnetoacoustic effect of biological tissues, that is, the target is placed in a static magnetic field, and magnetic pulse excitation is applied in the same direction as the static magnetic field. The action of the eddy current induced in the medium and the static magnetic field produces the Lorentz force, and the charged particles vibrate under the action of the Lorentz force, thereby emitting ultrasonic waves, which are then imaged after being received by the ultrasonic probe. A single imaging technique cannot describe the structural and functional information of biological tissues in a comprehensive and detailed manner. Ultrasonic (US), PA and MAT-MI imaging are all acoustic imaging techniques based on ultrasound, and have complementary characteristics. Combine them for magneto-photo-acoustic (MPA) joint imaging. MPA imaging combines the higher resolution of ultrasonic detection in the photoacoustic signal transmission stage and the higher resolution and sensitivity of magnetoacoustic signal detection, which can accurately locate and image functional components of early lesion tissues.
目前MPA联合成像都是体外成像,即将超声换能器置于生物体四周,在体外接收超声信号。相对于内窥成像,这种方式不能及时有效地对生物腔体组织(如消化道、肠道和血管等)进行观察和诊断。因此研究一种磁光声联合内窥(endoscopic magneto-photo-acoustic,EMPA)成像方法是十分必要的。At present, MPA combined imaging is in vitro imaging, that is, the ultrasonic transducer is placed around the organism to receive ultrasonic signals outside the body. Compared with endoscopic imaging, this method cannot observe and diagnose biological cavity tissues (such as digestive tract, intestinal tract and blood vessels, etc.) in a timely and effective manner. Therefore, it is necessary to study an endoscopic magneto-photo-acoustic (EMPA) imaging method.
发明内容Contents of the invention
本发明的目的在于针对现有技术之弊端,提供一种生物磁光声联合内窥成像方法,以获取高分辨率和灵敏度的生物腔体组织图像,帮助医务人员及时有效地对生物腔体组织进行观察和诊断。The purpose of the present invention is to address the drawbacks of the prior art, to provide a biomagneto-optoacoustic combined endoscopic imaging method to obtain high-resolution and sensitive images of biological cavity tissue, and to help medical staff timely and effectively detect biological cavity tissue Observation and diagnosis.
本发明所述问题是以下述技术方案实现的:Problem described in the present invention is realized with following technical scheme:
一种生物磁光声联合内窥成像方法,所述方法在建立多层腔体组织横截面模型的基础上,对腔道内的超声回波成像、光声成像和感应式磁声成像的过程进行数值仿真,得到腔道横截面上组织反射的超声回波信号以及组织产生的光声和磁声信号,然后对三种超声信号进行最优加权求和,得到融合后的联合成像信号。A biomagnetoacoustic combined endoscopic imaging method, the method is based on the establishment of a multi-layer cavity tissue cross-sectional model, the process of ultrasonic echo imaging, photoacoustic imaging and inductive magnetoacoustic imaging in the cavity Through numerical simulation, the ultrasonic echo signal reflected by the tissue on the cavity cross section and the photoacoustic and magnetoacoustic signals generated by the tissue are obtained, and then the three ultrasonic signals are optimally weighted and summed to obtain the fused joint imaging signal.
上述生物磁光声联合内窥成像方法,所述方法包括以下步骤:The above biomagnetism photoacoustic combined endoscopic imaging method, the method comprises the following steps:
a.建立多层腔体组织横截面模型a. Establish a cross-sectional model of multi-layer cavity tissue
成像导管位于多层腔体组织横截面模型的中心,超声换能器位于成像导管顶端,模型所在的坐标系是θ-l极坐标系,其中坐标原点是成像导管顶端中心,θ是极角,l是极径,水平向右的方向为l轴正方向,忽略超声换能器的孔径效应,将超声换能器看作理想的点探测器,其扫描轨迹为平行于成像平面的圆形轨迹,以模型的中心为起始点,将模型等角度划分为N份,每一份近似为层与层之间平行的多层腔体组织,导管处的成像角度为The imaging catheter is located at the center of the multi-layer cavity tissue cross-section model, and the ultrasonic transducer is located at the top of the imaging catheter. The coordinate system of the model is the θ-l polar coordinate system, where the origin of the coordinates is the center of the top of the imaging catheter, and θ is the polar angle. l is the polar diameter, the horizontal direction to the right is the positive direction of the l-axis, ignoring the aperture effect of the ultrasonic transducer, the ultrasonic transducer is regarded as an ideal point detector, and its scanning trajectory is a circular trajectory parallel to the imaging plane , taking the center of the model as the starting point, divide the model into N parts at equal angles, and each part is approximately a multi-layer cavity tissue parallel to each other, and the imaging angle at the catheter is
θi=360(i-1)/Nθ i =360(i-1)/N
其中i=1,2,…,N,θi对应的成像区域的角度范围为[θia,θib],其中θia=θi-180/N,θib=θi+180/N;Where i=1,2,...,N, the angular range of the imaging area corresponding to θ i is [θ ia ,θ ib ], where θ ia =θ i -180/N, θ ib =θ i +180/N;
b.对成像组织反射的超声回波信号以及组织产生的光声信号和磁声信号进行数值仿真;b. Numerical simulation of the ultrasonic echo signal reflected by the imaging tissue and the photoacoustic signal and magnetoacoustic signal generated by the tissue;
①超声回波信号:①Ultrasonic echo signal:
从腔体中心沿径向发射超声脉冲,根据不同成分组织的声阻抗差异值以及超声探测器的冲激响应,仿真得到组织反射/散射的超声回波信号;Ultrasonic pulses are emitted radially from the center of the cavity, and the ultrasonic echo signals reflected/scattered by the tissue are simulated according to the difference in acoustic impedance of different components of the tissue and the impulse response of the ultrasonic probe;
②光声信号:② Photoacoustic signal:
从腔体中心对周围组织沿径向发射激光脉冲,组织由于光声效应产生光声信号,根据不同成分组织的光吸收系数和散射系数,结合蒙特卡罗模拟和光声波动方程,仿真得到组织产生的光声信号;Laser pulses are emitted radially from the center of the cavity to the surrounding tissue, and the tissue generates photoacoustic signals due to the photoacoustic effect. According to the light absorption coefficient and scattering coefficient of tissues with different components, combined with Monte Carlo simulation and photoacoustic wave equation, the simulation results of tissue generation photoacoustic signal;
③磁声信号:③Magnetoacoustic signal:
沿腔体的轴向施加静磁场和脉冲磁激励,组织由于磁声效应产生磁声信号,根据不同成分组织的电导率,结合磁声波动方程,仿真得到组织产生的磁声信号;Static magnetic field and pulsed magnetic excitation are applied along the axial direction of the cavity, and the tissue generates magnetoacoustic signals due to the magnetoacoustic effect. According to the conductivity of different components of the tissue, combined with the magnetoacoustic wave equation, the magnetoacoustic signal generated by the tissue is simulated;
c.对超声回波信号、光声信号和磁声信号进行融合c. Fusion of ultrasonic echo signal, photoacoustic signal and magnetoacoustic signal
对于成像组织中的角度θi(i=1,2,…,N)、位置r处的超声回波信号光声信号和磁声信号采用下式进行融合:For the angle θ i (i=1,2,…,N) in the imaging tissue, the ultrasonic echo signal at position r photoacoustic signal and magnetoacoustic signal Fusion is performed using the following formula:
其中为超声回波、光声和磁声信号的融合信号,即联合成像信号,W1i、W2i、W3i分别为超声回波、光声和磁声信号的加权因子,且有W1i+W2i+W3i=1。in is the fusion signal of ultrasonic echo, photoacoustic and magnetoacoustic signals, that is, the joint imaging signal, W 1i , W 2i , and W 3i are the weighting factors of ultrasonic echo, photoacoustic and magnetoacoustic signals, respectively, and W 1i +W 2i +W 3i =1.
上述生物磁光声联合内窥成像方法,为了使超声回波、光声和磁声信号的融合信号的均方误差最小,超声回波、光声和磁声信号的加权因子W1i、W2i、W3i应取最优值最优值的计算公式为:The biomagnetoacoustic combined endoscopic imaging method, in order to make the fusion signal of ultrasonic echo, photoacoustic and magnetoacoustic signal The mean square error is the smallest, and the weighting factors W 1i , W 2i , and W 3i of ultrasonic echo, photoacoustic and magnetoacoustic signals should take the optimal value The formula for calculating the optimal value is:
其中k为超声回波、光声和磁声信号的测量次数,为总均方误差最小时超声回波、光声和磁声信号的最优加权因子,为的方差,为的方差,为的方差,RUU为的自相关系数,RUP为和的互相关系数,RPP为的自相关系数,RPM为和的互相关系数,RMM为的自相关系数,RMU为和的互相关系数。where k is the number of measurements of ultrasonic echo, photoacoustic and magnetoacoustic signals, is the optimal weighting factor for ultrasonic echo, photoacoustic and magnetoacoustic signals when the total mean square error is minimized, for Variance, for Variance, for The variance of R UU is The autocorrelation coefficient of R UP is with The cross-correlation coefficient of R PP is The autocorrelation coefficient of RPM is with The cross-correlation coefficient of R MM is The autocorrelation coefficient of R MU is with The correlation coefficient of .
本发明在信号层对超声换能器分时接收的腔体组织反射/散射的超声回波信号以及组织产生的光声信号和磁声信号进行融合,同传统方法相比,本方法得到的联合成像信号可较多地保留组织的形态结构和成分信息,据此重建出的组合图像具有极高的空间分辨率、对比度、灵敏度和对比分辨率,能准确显示腔道壁内各组织的位置、形态及其功能成分。The present invention fuses the ultrasonic echo signals reflected/scattered by the cavity tissue received by the ultrasonic transducer in time-division and the photoacoustic signal and magnetoacoustic signal generated by the tissue at the signal layer. Compared with the traditional method, the combined Imaging signals can retain more morphological structure and composition information of tissues, and the reconstructed combined images have extremely high spatial resolution, contrast, sensitivity and contrast resolution, and can accurately display the position, Morphology and its functional components.
附图说明Description of drawings
下面结合附图对本发明作进一步说明。The present invention will be further described below in conjunction with accompanying drawing.
图1是含有钙化斑块的血管横截面模型示例;Figure 1 is an example of a cross-sectional model of a blood vessel containing calcified plaque;
图2是EMPA成像导管在角度θi处分时接收超声回波信号、光声信号和磁声信号的示意图;Fig. 2 is a schematic diagram of receiving ultrasonic echo signals, photoacoustic signals and magnetoacoustic signals when the EMPA imaging catheter is at an angle θi ;
图3是将图2中角度θi处对应的成像区域近似为多层血管壁组织的示意图。FIG. 3 is a schematic diagram of approximating the imaging region corresponding to the angle θ i in FIG. 2 as multi-layer blood vessel wall tissue.
文中各符号为:θ、l为θ-l平面极坐标系的极角和极径,其中成像导管位于坐标原点(腔体中心),水平向右的方向为l轴正方向;N为腔体横截面模型被等角度分割的份数;θi为第i个成像角度;θia、θib为θi对应的成像区域角度范围的下限和上限,其中i=1,2,…,N;F(r,θ)为超声探测器在位置r、角度θ处采集的超声回波信号;T(r,θ)为成像组织在位置r、角度θ处的声阻抗差异函数;h(r,θ)为超声探测器的点扩散函数,即冲激响应;σr为发射超声波的脉冲宽度;σθ为发射超声波束的宽度;k0为波数;f0为发射超声波的中心频率;G(r,θ)为均值为0、标准差为1的高斯白噪声;E(r,θ)为位置r、角度θ处组织的声阻抗差异值;为角度θi、位置r处采集的超声回波信号,其中i=1,2,…,N;为哈密顿算子;p(r,t)为时刻t、位置r处的声压;c为生物组织中的声速;A(r)为光能量沉积分布函数;β为组织的体积膨胀温度系数;CP为组织的比热容;I(t)为光声成像中入射激光脉冲的强度;(j,k)为组织上的点r在极坐标系θ-l中的坐标;Δθ、Δl为θ轴和l轴上的单位长度;Δt为离散时间间距;n为离散时刻;pn(j,k)为时刻n、位置(j,k)处的声压;vθ n(j,k)和vl n(j,k)为时刻n、位置(j,k)处的质点分别在θ方向和l方向的振动速度;ρ为组织密度;c(j,k)为位置(j,k)处的声速;A(j,k)为位置(j,k)处的光能量沉积值;In为时刻n的激光脉冲强度;cmax为组织中声速的最大值;λmin为超声波的最小波长;为角度θi、位置r处的光声信号,其中i=1,2,…,N;J为感应电流密度;B0为静磁场强度;J(j,k)为位置(j,k)处的感应电流密度;B0(j,k)为位置(j,k)处的静磁场强度;为角度θi、位置r处的磁声信号,其中i=1,2,…,N;k为超声回波、光声和磁声信号的测量次数;RUU为的自相关系数;RPP为的自相关系数;RMM为的自相关系数;RUP为和的互相关系数;RPM为和的互相关系数;RMU为和的互相关系数;为的方差;为的方差;为的方差;W1i、W2i、W3i为超声回波、光声和磁声信号的加权因子;为超声回波、光声和磁声信号的融合信号;为融合信号的总均方误差;为总均方误差的最小值;为总均方误差最小时超声回波、光声和磁声信号的最优加权因子。The symbols in this paper are: θ and l are the polar angle and polar diameter of the θ-l plane polar coordinate system, where the imaging catheter is located at the coordinate origin (the center of the cavity), and the horizontal direction to the right is the positive direction of the l-axis; N is the cavity The number of equiangular divisions of the cross-sectional model; θ i is the i-th imaging angle; θ ia and θ ib are the lower limit and upper limit of the angle range of the imaging area corresponding to θ i , where i=1,2,...,N; F(r, θ) is the ultrasonic echo signal collected by the ultrasonic probe at position r and angle θ; T(r, θ) is the acoustic impedance difference function of the imaging tissue at position r and angle θ; h(r, θ) is the point spread function of the ultrasonic detector, that is, the impulse response; σ r is the pulse width of the emitted ultrasonic wave; σ θ is the width of the emitted ultrasonic beam; k 0 is the wave number; f 0 is the center frequency of the emitted ultrasonic wave; G( r, θ) is Gaussian white noise with a mean of 0 and a standard deviation of 1; E(r, θ) is the difference in acoustic impedance of tissues at position r and angle θ; is the ultrasonic echo signal collected at angle θ i and position r, where i=1,2,...,N; is the Hamiltonian; p(r,t) is the sound pressure at time t and position r; c is the sound velocity in biological tissue; A(r) is the light energy deposition distribution function; β is the volume expansion temperature coefficient of the tissue ; C P is the specific heat capacity of the tissue; I(t) is the intensity of the incident laser pulse in photoacoustic imaging; (j,k) is the coordinate of the point r on the tissue in the polar coordinate system θ-l; Δθ, Δl are θ Δt is the discrete time interval; n is the discrete time; p n (j,k) is the sound pressure at time n and position (j,k); v θ n (j,k) and v l n (j,k) are the vibration velocities of the particle at the time n and the position (j,k) in the θ direction and the l direction respectively; ρ is the tissue density; c(j,k) is the position (j,k) ) at the sound velocity; A(j,k) is the light energy deposition value at the position (j,k); I n is the laser pulse intensity at time n; c max is the maximum sound velocity in the tissue; λ min is the ultrasonic minimum wavelength; is the photoacoustic signal at angle θ i and position r, where i=1,2,…,N; J is the induced current density; B 0 is the static magnetic field strength; J(j,k) is the position (j,k) The induced current density at the position; B 0 (j,k) is the static magnetic field intensity at the position (j,k); is the magnetoacoustic signal at angle θ i and position r, where i=1,2,…,N; k is the number of measurements of ultrasonic echo, photoacoustic and magnetoacoustic signals; R UU is The autocorrelation coefficient of ; R PP is The autocorrelation coefficient of ; R MM is The autocorrelation coefficient of ; R UP is with The cross-correlation coefficient; R PM is with The cross-correlation coefficient of R MU is with The correlation coefficient of for Variance; for Variance; for Variance of ; W 1i , W 2i , W 3i are weighting factors of ultrasonic echo, photoacoustic and magnetoacoustic signals; is the fusion signal of ultrasonic echo, photoacoustic and magnetoacoustic signals; is the total mean square error of the fusion signal; is the minimum value of the total mean square error; is the optimal weighting factor for ultrasonic echo, photoacoustic and magnetoacoustic signals when the total mean square error is minimized.
具体实施方式detailed description
磁光声联合内窥(endoscopic magneto-photo-acoustic,EMPA)成像是用同一个成像系统在生物腔道内部同时进行超声、光声和感应式磁声成像。超声换能器直接在腔道内采集组织反射、散射或者产生的超声波信号,再经计算机对其进行融合后获得组合图像。Endoscopic magneto-photo-acoustic (EMPA) imaging uses the same imaging system to simultaneously perform ultrasound, photoacoustic and inductive magnetoacoustic imaging inside the biological cavity. The ultrasonic transducer directly collects the ultrasonic signal reflected, scattered or generated by the tissue in the cavity, and then the combined image is obtained after fusion by the computer.
一、建立多层腔体组织横截面模型:1. Establish a cross-sectional model of multi-layer cavity tissue:
如附图1所示,以血管横截面模型为例,成像导管位于模型的中心,超声换能器位于成像导管顶端,环绕导管由内向外沿径向依次是血管内腔、粥样硬化斑块(钙化、脂质、纤维或混合斑块)、血管壁内膜/中膜和外膜。模型所在的坐标系是θ-l极坐标系,其中坐标原点是成像导管中心,θ是极角,l是极径,水平向右的方向为l轴正方向。本发明方法忽略超声换能器的孔径效应,将超声探测器(即超声换能器)看作理想的点探测器,其扫描轨迹为平行于成像平面的圆形轨迹。As shown in Figure 1, taking the cross-sectional model of a blood vessel as an example, the imaging catheter is located in the center of the model, and the ultrasonic transducer is located at the top of the imaging catheter. Surrounding the catheter from the inside to the outside along the radial direction are the lumen of the blood vessel and the atherosclerotic plaque. (calcified, lipid, fibrous or mixed plaque), vessel wall intima/media and adventitia. The coordinate system where the model is located is the θ-l polar coordinate system, where the origin of the coordinates is the center of the imaging catheter, θ is the polar angle, l is the polar diameter, and the horizontal direction to the right is the positive direction of the l-axis. The method of the invention ignores the aperture effect of the ultrasonic transducer, and regards the ultrasonic detector (that is, the ultrasonic transducer) as an ideal point detector, and its scanning trajectory is a circular trajectory parallel to the imaging plane.
如附图2所示,以血管模型的中心为起始点,将模型等角度划分为N份,每一份近似为层与层之间平行的多层血管壁组织(如附图3所示)。对模型分别施加超声脉冲、激光脉冲和激励磁场(如附图2所示,包含静磁场与脉冲磁场,其中静磁场的方向与腔体的轴向重合)。导管处的成像角度为As shown in Figure 2, the center of the blood vessel model is taken as the starting point, and the model is divided into N parts at equal angles, and each part is approximately a multi-layered blood vessel wall tissue parallel to each other (as shown in Figure 3) . Ultrasonic pulses, laser pulses, and excitation magnetic fields are respectively applied to the model (as shown in Figure 2, including static magnetic fields and pulsed magnetic fields, where the direction of the static magnetic field coincides with the axial direction of the cavity). The imaging angle at the catheter is
θi=360(i-1)/N (1)θ i =360(i-1)/N (1)
其中i=1,2,…,N。θi对应的成像区域的角度范围为[θia,θib],其中θia=θi-180/N,θib=θi+180/N。where i=1,2,...,N. The angle range of the imaging area corresponding to θ i is [θ ia , θ ib ], where θ ia =θ i −180/N, θ ib =θ i +180/N.
二、仿真腔体组织的超声回波信号:2. Ultrasonic echo signal of simulated cavity tissue:
超声内窥成像是采用超声束在腔道内周向旋转扫描,并通过超声脉冲反射法检测病变组织。生物软组织是有层次的,不同层次的组织成分不同,表现为声学特征参量的差异,超声波在组织中传播时,当遇到不同组织之间的分界面时,会产生反射回波,其中包含了不同组织的位置和结构信息。Ultrasonic endoscopic imaging uses ultrasonic beams to scan in the circumferential direction of the cavity, and detects diseased tissues by ultrasonic pulse reflection. Biological soft tissue has layers, and different layers have different tissue components, which manifest as differences in acoustic characteristic parameters. When ultrasonic waves propagate in tissues, when encountering the interface between different tissues, reflected echoes will be generated, which include Location and structure information of different tissues.
超声探头从腔体横截面模型的中心沿径向发射超声信号,为简化问题,不考虑组织的吸收衰减和高阶回波,则:The ultrasonic probe emits ultrasonic signals radially from the center of the cavity cross-sectional model. To simplify the problem, the absorption attenuation and higher-order echoes of the tissue are not considered, then:
F(r,θ)=h(r,θ)*T(r,θ) (2)F(r,θ)=h(r,θ)*T(r,θ) (2)
其中,F(r,θ)是超声探测器在位置r、角度θ处采集的超声回波信号;h(r,θ)是是超声探测器的点扩散函数,即冲激响应,它是时不变且可分离的,表示为Among them, F(r, θ) is the ultrasonic echo signal collected by the ultrasonic detector at the position r and angle θ; h(r, θ) is the point spread function of the ultrasonic detector, that is, the impulse response, which is the time Invariant and separable, expressed as
式中,σr是发射超声波的脉冲宽度,σθ是发射超声波束的宽度,波数k0=2πf0/c,c是组织中的声速,f0是发射超声波的中心频率。式(2)中的T(r,θ)是成像组织在位置r、角度θ处的声阻抗差异函数:In the formula, σ r is the pulse width of the emitted ultrasonic wave, σ θ is the width of the emitted ultrasonic beam, the wave number k 0 =2πf 0 /c, c is the sound velocity in the tissue, and f 0 is the center frequency of the emitted ultrasonic wave. T(r, θ) in formula (2) is the acoustic impedance difference function of the imaging tissue at position r and angle θ:
T(r,θ)=G(r,θ)*E(r,θ) (4)T(r,θ)=G(r,θ)*E(r,θ) (4)
其中,G(r,θ)是均值为0、标准差为1的高斯白噪声;E(r,θ)是位置r、角度θ处组织的声阻抗差异值,若组织的E值较大,则表明其声阻抗差异较大,产生的回波信号也较强。Among them, G(r, θ) is Gaussian white noise with mean value of 0 and standard deviation of 1; E(r, θ) is the difference value of acoustic impedance of tissue at position r and angle θ. If the E value of tissue is larger, It shows that the difference in acoustic impedance is large, and the echo signal generated is also strong.
由式(2)得到超声探测器在N个角度采集的超声回波信号,将角度θi、位置r处采集的超声回波信号记为(i=1,2,…,N)。The ultrasonic echo signals collected by the ultrasonic probe at N angles can be obtained from formula (2), and the ultrasonic echo signals collected at the angle θ i and position r are recorded as (i=1,2,...,N).
三、仿真短脉冲激光作用于腔体组织产生的光声信号:3. Simulate the photoacoustic signal generated by the short pulse laser acting on the cavity tissue:
从腔体横截面的中心沿径向发射短脉冲激光,根据组织的光吸收系数和散射系数,通过组织内光的蒙特卡罗模拟,获得光能量沉积分布函数。由光声效应导致组织产生的光声信号(其实质是超声波)满足光声波动方程The short-pulse laser is emitted radially from the center of the cavity cross-section, and the light energy deposition distribution function is obtained through Monte Carlo simulation of the light in the tissue according to the light absorption coefficient and scattering coefficient of the tissue. The photoacoustic signal (which is essentially ultrasonic wave) produced by the tissue due to the photoacoustic effect satisfies the photoacoustic wave equation
其中,是哈密顿算子;p(r,t)是时刻t、位置r处的声压;c是生物组织中的声速;A(r)是位置r处的光能量沉积分布;β是组织的体积膨胀温度系数,CP是组织的比热容;I(t)是入射激光脉冲的强度。in, is the Hamiltonian; p(r,t) is the sound pressure at time t and position r; c is the sound velocity in biological tissue; A(r) is the light energy deposition distribution at position r; β is the volume of the tissue The temperature coefficient of expansion, C P is the specific heat capacity of the tissue; I(t) is the intensity of the incident laser pulse.
结合超声波的声压、质点振动速度和组织密度三个物理量之间的关系,采用时域有限差分法对式(5)进行离散化处理得到Combined with the relationship among the three physical quantities of ultrasonic sound pressure, particle vibration velocity and tissue density, the formula (5) is discretized using the time domain finite difference method to obtain
其中,(j,k)是组织上的点r在极坐标系θ-l中的坐标;Δθ和Δl分别是θ轴和l轴的单位长度;Δt是离散时间间距;n是离散时刻;pn(j,k)是时刻n、位置(j,k)处的声压;和是时刻n、位置(j,k)处的质点分别在θ方向和l方向的振动速度;ρ是组织密度;c(j,k)是位置(j,k)处的声速;A(j,k)是位置(j,k)处的光能量沉积值;In是时刻n的激光脉冲强度。Among them, (j,k) is the coordinate of point r on the tissue in the polar coordinate system θ-l; Δθ and Δl are the unit lengths of θ axis and l axis respectively; Δt is the discrete time interval; n is the discrete time; p n (j,k) is the sound pressure at time n and position (j,k); with is the vibration velocity of the particle at time n and position (j, k) in the θ direction and l direction respectively; ρ is the tissue density; c(j, k) is the sound velocity at position (j, k); A(j, k) is the light energy deposition value at position (j,k); In is the laser pulse intensity at time n .
式(6)需满足Courant稳定性条件:Equation (6) needs to satisfy the Courant stability condition:
其中,cmax是组织中声速的最大值;λmin是超声波的最小波长。Among them, c max is the maximum sound velocity in the tissue; λ min is the minimum wavelength of ultrasound.
由式(6)可以得到N个角度的光声信号,将角度θi、位置r处的光声信号记为(i=1,2,…,N)。The photoacoustic signals at N angles can be obtained from formula (6), and the photoacoustic signals at angle θ i and position r are recorded as (i=1,2,...,N).
四、仿真静磁场和脉冲磁场作用于腔体组织产生的磁声信号:4. Simulate the magnetoacoustic signal generated by static magnetic field and pulsed magnetic field acting on cavity tissue:
在MAT-MI成像中,生物组织因受到外界脉冲磁场的激励而产生感应涡流,感应涡流与外界施加的静磁场作用产生洛伦兹力,组织中的带电粒子在洛伦兹力的作用下产生机械振动,并以超声波的形式向外传播,即磁声信号。In MAT-MI imaging, the biological tissue is excited by the external pulsed magnetic field to generate induced eddy current, the induced eddy current interacts with the static magnetic field applied by the outside to generate the Lorentz force, and the charged particles in the tissue are generated under the action of the Lorentz force The mechanical vibration is transmitted outward in the form of ultrasonic waves, that is, magnetoacoustic signals.
为简化起见,将组织近似为理想的均匀流体,忽略其黏性和不可压缩性,其初始状态是静止的,且忽略热交换,假设声波传播过程为绝热过程。基于以上假定,组织产生的磁声信号满足磁声波动方程For the sake of simplicity, the tissue is approximated as an ideal homogeneous fluid, its viscosity and incompressibility are ignored, its initial state is static, and the heat exchange is ignored, and the acoustic wave propagation process is assumed to be an adiabatic process. Based on the above assumptions, the magnetoacoustic signal generated by the tissue satisfies the magnetoacoustic wave equation
其中,p(r,t)是时刻t、位置r处的声压;c是生物组织中的声速;J是感应电流密度,B0是静磁场强度。Among them, p(r,t) is the sound pressure at time t and position r; c is the sound velocity in biological tissue; J is the induced current density, and B 0 is the static magnetic field strength.
式(8)的时域有限差分形式为:The time domain finite difference form of formula (8) is:
其中,(j,k)是组织上的点r在极坐标系θ-l中的坐标;Δθ和Δl分别是θ轴和l轴的单位长度;Δt是离散时间间距;n是离散时刻;pn(j,k)是时刻n、位置(j,k)处的声压;和是时刻n、位置(j,k)处的质点分别在θ方向和l方向的振动速度;ρ是组织密度;c(j,k)是位置(j,k)处的声速;J(j,k)是位置(j,k)处的感应电流密度;B0(j,k)是位置(j,k)处的静磁场强度。Among them, (j,k) is the coordinate of point r on the tissue in the polar coordinate system θ-l; Δθ and Δl are the unit lengths of θ axis and l axis respectively; Δt is the discrete time interval; n is the discrete time; p n (j,k) is the sound pressure at time n and position (j,k); with is the vibration velocity of the particle at time n and position (j, k) in the θ direction and l direction respectively; ρ is the tissue density; c(j, k) is the sound velocity at position (j, k); J(j, k) is the induced current density at position (j,k); B 0 (j,k) is the static magnetic field strength at position (j,k).
式(9)也需满足式(7)中的Courant稳定性条件。由式(9)可以得到N个角度的磁声信号,将角度θi、位置r处的磁声信号记为(i=1,2,…,N)。Formula (9) also needs to satisfy the Courant stability condition in formula (7). The magneto-acoustic signals at N angles can be obtained from formula (9), and the magneto-acoustic signals at angle θ i and position r are recorded as (i=1,2,...,N).
五、融合超声回波、光声信号和磁声信号:5. Fusion of ultrasonic echo, photoacoustic signal and magnetoacoustic signal:
本发明方法在总均方误差最小的条件下,对于成像组织在角度θi(i=1,2,…,N)、位置r处的超声回波信号、光声信号和磁声信号的测量值,以自适应的方式寻找各信号对应的最优加权因子,得到最优的融合结果。具体步骤如下:Under the condition that the total mean square error is minimum, the method of the present invention is used for the measurement of ultrasonic echo signals, photoacoustic signals and magnetoacoustic signals of imaging tissues at angles θ i (i=1, 2,..., N) and positions r Value, find the optimal weighting factor corresponding to each signal in an adaptive way, and get the optimal fusion result. Specific steps are as follows:
设和的测量次数均为k,测量值的方差分别是和具体计算方法如下:Assume with The number of measurements is k, and the variances of the measured values are with The specific calculation method is as follows:
对于和的自相关系数为for with The autocorrelation coefficient of
和的互相关系数为 with The correlation coefficient of
则but
对于和的自相关系数为for with The autocorrelation coefficient of
其中in
和的互相关系数为 with The correlation coefficient of
则but
对于和的自相关系数为for with The autocorrelation coefficient of
和的互相关系数为 with The correlation coefficient of
则but
超声回波、光声和磁声信号的加权因子分别为W1i、W2i和W3i,且满足The weighting factors of ultrasonic echo, photoacoustic and magnetoacoustic signals are W 1i , W 2i and W 3i respectively, and satisfy
W1i+W2i+W3i=1 (19)W 1i +W 2i +W 3i =1 (19)
融合后的信号为The fused signal is
总均方误差为The total mean square error is
通过对式(21)中的多元二次函数求极值,得到总均方误差的最小值By finding the extremum of the multivariate quadratic function in formula (21), the total mean square error is obtained minimum value of
总均方误差最小时,超声回波、光声和磁声信号的最优加权因子分别是:When the total mean square error is minimized, the optimal weighting factors of ultrasonic echo, photoacoustic and magnetoacoustic signals are respectively:
将式(23)代入式(20)即可得到融合后的信号。该融合算法无需有关待融合信号的任何先验知识,只需根据待融合信号的测量值,估计各信号方差的变化,及时调整参与融合的各信号的加权因子,得到均方误差最小的融合信号。融合后信号的均方误差不仅小于单个信号的均方误差,而且融合结果在精度、容错性方面均优于传统的平均值估计算法。Substitute Equation (23) into Equation (20) to get the fused signal. The fusion algorithm does not require any prior knowledge about the signals to be fused, and only needs to estimate the variation of the variance of each signal according to the measured value of the signals to be fused, and adjust the weighting factors of each signal participating in the fusion in time to obtain the fusion signal with the smallest mean square error . The mean square error of the fused signal is not only smaller than the mean square error of a single signal, but also the fusion result is better than the traditional mean estimation algorithm in terms of accuracy and fault tolerance.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710199118.5A CN107049252A (en) | 2017-03-29 | 2017-03-29 | A kind of biological magneto-optic sound joint endoscopic imaging method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710199118.5A CN107049252A (en) | 2017-03-29 | 2017-03-29 | A kind of biological magneto-optic sound joint endoscopic imaging method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107049252A true CN107049252A (en) | 2017-08-18 |
Family
ID=59620896
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710199118.5A Pending CN107049252A (en) | 2017-03-29 | 2017-03-29 | A kind of biological magneto-optic sound joint endoscopic imaging method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107049252A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108703774A (en) * | 2018-06-14 | 2018-10-26 | 华北电力大学(保定) | Joint imaging method and system based on intravascular ultrasound-optoacoustic-OCT |
| CN111829956A (en) * | 2020-07-01 | 2020-10-27 | 华南师范大学 | Photoacoustic endoscopic quantitative tomography method and system based on ultrasonic structural layer guidance |
| CN112023283A (en) * | 2020-08-03 | 2020-12-04 | 西安交通大学 | Annular multi-array ultrasonic passive imaging method and system based on high-order aperture autocorrelation |
| CN112438702A (en) * | 2019-08-29 | 2021-03-05 | 华北电力大学(保定) | Photoacoustic endoscopic imaging method and system for biological cavity |
| CN119321742A (en) * | 2024-12-18 | 2025-01-17 | 江苏霆升科技有限公司 | Bonding detection method and system for ultrasonic transducer |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008062199A3 (en) * | 2006-11-24 | 2008-08-07 | Ucl Business Plc | Imaging method and apparatus |
| WO2009009786A2 (en) * | 2007-07-12 | 2009-01-15 | Board Of Regents, The University Of Texas System | Magneto-motive ultrasound detection of magnetic nanoparticles |
| CN105246414A (en) * | 2013-05-06 | 2016-01-13 | Nkij工程公司 | Magnetic probe system and method of use thereof |
| CN105852814A (en) * | 2016-04-22 | 2016-08-17 | 中国医学科学院生物医学工程研究所 | Magnetic acoustic signal detecting and imaging system based on optical fiber F-P-cavity acoustic sensor |
| CN106023277A (en) * | 2016-05-18 | 2016-10-12 | 华北电力大学(保定) | Magnetic induction magnetoacoustic endoscopic image modeling and simulation method |
-
2017
- 2017-03-29 CN CN201710199118.5A patent/CN107049252A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008062199A3 (en) * | 2006-11-24 | 2008-08-07 | Ucl Business Plc | Imaging method and apparatus |
| WO2009009786A2 (en) * | 2007-07-12 | 2009-01-15 | Board Of Regents, The University Of Texas System | Magneto-motive ultrasound detection of magnetic nanoparticles |
| CN105246414A (en) * | 2013-05-06 | 2016-01-13 | Nkij工程公司 | Magnetic probe system and method of use thereof |
| CN105852814A (en) * | 2016-04-22 | 2016-08-17 | 中国医学科学院生物医学工程研究所 | Magnetic acoustic signal detecting and imaging system based on optical fiber F-P-cavity acoustic sensor |
| CN106023277A (en) * | 2016-05-18 | 2016-10-12 | 华北电力大学(保定) | Magnetic induction magnetoacoustic endoscopic image modeling and simulation method |
Non-Patent Citations (3)
| Title |
|---|
| MIN QU ET AL: "Combined photoacoustic and magneto-motive ultrasound imaging", 《PROC. OF SPIE》 * |
| 徐凯宏等: "《工业工程测试与测控技术》", 31 August 2016 * |
| 马真等: "生物感应式磁声成像的研究现状", 《中国生物医学工程学报》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108703774A (en) * | 2018-06-14 | 2018-10-26 | 华北电力大学(保定) | Joint imaging method and system based on intravascular ultrasound-optoacoustic-OCT |
| CN112438702A (en) * | 2019-08-29 | 2021-03-05 | 华北电力大学(保定) | Photoacoustic endoscopic imaging method and system for biological cavity |
| CN112438702B (en) * | 2019-08-29 | 2022-12-27 | 华北电力大学(保定) | Photoacoustic endoscopic imaging method and system for biological cavity |
| CN111829956A (en) * | 2020-07-01 | 2020-10-27 | 华南师范大学 | Photoacoustic endoscopic quantitative tomography method and system based on ultrasonic structural layer guidance |
| CN111829956B (en) * | 2020-07-01 | 2021-10-01 | 华南师范大学 | Photoacoustic endoscopic quantitative tomography method and system based on ultrasonic structural layer guidance |
| CN112023283A (en) * | 2020-08-03 | 2020-12-04 | 西安交通大学 | Annular multi-array ultrasonic passive imaging method and system based on high-order aperture autocorrelation |
| CN119321742A (en) * | 2024-12-18 | 2025-01-17 | 江苏霆升科技有限公司 | Bonding detection method and system for ultrasonic transducer |
| CN119321742B (en) * | 2024-12-18 | 2025-08-22 | 江苏霆升科技有限公司 | A bonding detection method and system for ultrasonic transducer |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Konofagou et al. | Localized harmonic motion imaging: theory, simulations and experiments | |
| Lizzi et al. | Radiation-force technique to monitor lesions during ultrasonic therapy | |
| Chen et al. | Remote measurement of material properties from radiation force induced vibration of an embedded sphere | |
| Kaproth-Joslin et al. | The history of US: from bats and boats to the bedside and beyond: RSNA centennial article | |
| CN107049252A (en) | A kind of biological magneto-optic sound joint endoscopic imaging method | |
| KR101974580B1 (en) | The laser-induced ultrasonic wave apparatus and the method of generating a image using the same | |
| CN109730722B (en) | Elastic imaging method based on focused ultrasonic acoustic vibration signal | |
| KR20230124893A (en) | Systems and methods for tissue characterization using multi-aperture ultrasound | |
| Barannik et al. | Doppler ultrasound detection of shear waves remotely induced in tissue phantoms and tissue in vitro | |
| Moilanen et al. | Photo-acoustic excitation and optical detection of fundamental flexural guided wave in coated bone phantoms | |
| Hou et al. | Performance assessment of HIFU lesion detection by harmonic motion imaging for focused ultrasound (HMIFU): A 3-D finite-element-based framework with experimental validation | |
| CN111970972B (en) | Acoustic wave field mapped with ultrasound particle velocity estimator | |
| Wakefield et al. | Essential Applications of Musculoskeletal Ultrasound in Rheumatology E-Book: Expert Consult Premium Edition | |
| WO2019087741A1 (en) | Ultrasonic diagnostic device and method for evaluating physical properties of biological tissue | |
| Urban et al. | Harmonic motion detection in a vibrating scattering medium | |
| Yeh et al. | Shear-wave elasticity imaging of a liver fibrosis mouse model using high-frequency ultrasound | |
| Duck | The measurement of exposure to ultrasound and its application to estimates of ultrasound'dose' | |
| Sarvazyan et al. | Potential biomedical applications of non-dissipative acoustic radiation force | |
| Saha et al. | Ultrasound physics & overview | |
| Zhang et al. | In Situ Measurement of Acoustic Attenuation for Focused Ultrasound Ablation Surgery Using a Boiling Bubble at the Focus | |
| Wu et al. | Laser generated leaky acoustic waves for needle visualization | |
| Certon et al. | Low frequency cMUT technology: Application to measurement of brain movement and assessment of bone quality | |
| Martegani et al. | US Physics, Basic Principles, and Clinical Application | |
| Karaböce et al. | Verification of Ultrasound Imaging Phantoms: An Evaluation Study | |
| Schrope et al. | Physical principles of ultrasound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170818 |