WO2009006758A1 - Continuous and dynamical acquisition-type imaging system for small animal induced fluorescence molecule imaging - Google Patents

Continuous and dynamical acquisition-type imaging system for small animal induced fluorescence molecule imaging Download PDF

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Publication number
WO2009006758A1
WO2009006758A1 PCT/CN2007/002114 CN2007002114W WO2009006758A1 WO 2009006758 A1 WO2009006758 A1 WO 2009006758A1 CN 2007002114 W CN2007002114 W CN 2007002114W WO 2009006758 A1 WO2009006758 A1 WO 2009006758A1
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Prior art keywords
small animal
imaging
fluorescence
detection
excitation
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English (en)
French (fr)
Inventor
Jing Bai
Xiaolei Song
Gang Hu
Junjie Yao
Zhun Xu
Daifa Wang
Jiachang Ou
Guoliang Huang
Yonghong Zhang
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Tsinghua University
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Tsinghua University
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Priority to CN200780001891A priority Critical patent/CN100593389C/zh
Priority to PCT/CN2007/002114 priority patent/WO2009006758A1/zh
Priority to US12/053,355 priority patent/US20090018451A1/en
Publication of WO2009006758A1 publication Critical patent/WO2009006758A1/zh
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0073—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by tomography, i.e. reconstruction of 3D images from 2D projections
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/037—Emission tomography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2503/00—Evaluating a particular growth phase or type of persons or animals
    • A61B2503/40—Animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/44—Constructional features of apparatus for radiation diagnosis
    • A61B6/4417—Constructional features of apparatus for radiation diagnosis related to combined acquisition of different diagnostic modalities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5229—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image
    • A61B6/5247—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image combining images from an ionising-radiation diagnostic technique and a non-ionising radiation diagnostic technique, e.g. X-ray and ultrasound
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N2021/178—Methods for obtaining spatial resolution of the property being measured
    • G01N2021/1785—Three dimensional
    • G01N2021/1787—Tomographic, i.e. computerised reconstruction from projective measurements

Definitions

  • the present invention relates to an imaging system and an imaging method, and more particularly to a continuous dynamic acquisition type small animal induced fluorescent molecular imaging system and method.
  • the existing small animal in vivo molecular imaging technology mainly includes two kinds of radionuclide imaging and optical imaging. Among them, optical imaging is considered to have great potential due to its advantages such as non-destructive, low equipment cost, variety of probes and mature marking technology. Molecular imaging mode. However, due to the influence of visible or near-infrared light on the depth of tissue penetration, optical imaging has been widely used in in vivo imaging of small animals and has become an important link in the transition from ex vivo experiments to clinical applications.
  • Planar imaging and tomography are included in optical molecular imaging. Compared to planar imaging, it only reflects information about a projection direction. Tomography can reconstruct the three-dimensional distribution of fluorophore concentration by the propagation model of light in biological tissues. According to the classification of fluorescent light sources, optical molecular tomography can be divided into Bioluminescence Tomography (BLT) and Fluorescence Molecular Tomography (FMT). In FMT, the fluorophore molecule absorbs the excitation light of a specific wavelength band incident from the outside, generates an energy level transition, but returns to the ground state after a certain period of time, and emits fluorescence having a wavelength longer than the excitation light.
  • BLT Bioluminescence Tomography
  • FMT Fluorescence Molecular Tomography
  • the intensity of the fluorescent light emitted by the induced fluorophore is related to the intensity of the excited light absorbed by it, the fluorescent signal detected from the surface of the small animal is stronger than that of the BLT, and the different excitation situations provide a rich amount of information for favorable reconstruction.
  • Small animal-induced fluorescence molecular tomography systems have evolved over the past decade. Initially, small animals (usually mice) were placed in a cylindrical imaging cavity, and the measurement signals at different positions were extracted from the surface of the cavity by optical fibers. This early system has many disadvantages and limitations, such as filling matching in the imaging cavity. Liquid, the amount of surface detection data is too small and the spatial resolution of the reconstructed image is low. The subsequent flat panel detection system uses CCD to detect fluorescence. Compared with the fiber collection mode, the sampling rate is improved, and the spatial resolution can reach sub-millimeter level. However, because the projection direction is limited, the resolution in the vertical detection plane direction. Very low and still need to use matching solution.
  • optical imaging systems For small animal in vivo optical imaging systems, there are also dual-mode imaging systems, such as optical imaging combined with X-ray imaging, but most of these systems only achieve planar imaging, but also fail to achieve three-dimensional in two modes.
  • Tomography at the same time, the collection mode of such systems is mostly serial in time, and image information in both modes cannot be acquired at the same time.
  • an object of the present invention is to provide a continuous dynamic concentrating small animal induced fluorescence molecular imaging method and system.
  • a continuous dynamic concentrating small animal induced fluorescent molecular imaging system which comprises: a computer, a small animal rotating platform device, and a fluorescence imaging excitation and detecting device;
  • the small animal rotary platform device comprises a small animal suspension bracket and a rotating electrical machine connecting the brackets;
  • the fluorescence imaging excitation and detection device comprises a fluorescence imaging excitation module and a fluorescence imaging detection module, the fluorescence imaging excitation module comprising an excitation light source and focusing and scanning a control unit, the fluorescence imaging detection module includes a band pass filter and a CCD device;
  • the CCD device is connected to the computer through an interface controller, the rotary motor is connected to the computer through an RS232 interface;
  • the signal is an output signal from the CCD device, and the computer output signal is a rotation control and switching signal for controlling the rotating electrical machine to control the CCD device.
  • a small animal contour acquiring device is added on the same side of the fluorescence imaging excitation module.
  • the detection space surrounding the suspended small animal 360 degrees is divided into four pieces, and the fluorescence imaging excitation module and The detection module occupies two opposite detection spaces, and a lead glass is added in front of the filter of the fluorescence imaging detection module, and a PET imaging detection and processing device is added in the other two detection spaces.
  • PET and fluorescence tomography dual-mode system replacing the space occupied by the PET imaging detection and processing device with an X-ray emission and detection device, forming a dual-mode imaging system for X-CT and induced fluorescence tomography; dividing the detection space into 6 Block, the X-ray emission and detection device, the fluorescence imaging and detection device, and the PET imaging detection and processing device each occupy two 60-degree measurement spaces, which can realize X-CT, induced fluorescence tomography, and PET imaging fusion three-mode imaging system.
  • the present invention includes the following specific steps: injecting a specific fluorescent marker into a living small animal for marking cells or tissues; anesthetizing the small animal and hanging it vertically on the small animal rotating platform by a jig;
  • the small animal rotating platform rotates continuously and continuously at a constant speed.
  • the fluorescence imaging detection module continuously collects signals and sends the collected raw data to the computer. After collecting one week of data, according to the detection field size and imaging requirements, the rotating motor control is small. The animal moves up and down along the axis of rotation.
  • the image aliasing phenomenon is corrected as follows: For each frame image acquired by the CCD device, the excitation light source is a fixed point light source during reconstruction, and the position is an excitation spot actually irradiated onto the surface of the small animal. The center of the displacement generated during the exposure time; each frame of image data corresponding to each body position of the small animal is reconstructed with only the data of the range of 90 degrees in the middle relative to the axis of rotation of the small animal.
  • the fluorescence imaging excitation and detection device is a non-contact, 360 degree panoramic detection system, and the specific steps of collecting data include: the laser light emitted by the excitation light source in the fluorescence imaging laser module is subjected to the focusing and After scanning the control unit, it is irradiated onto the surface of the living small animal and then enters the small animal body; the fluorescent probe labeled with a specific molecule or cell in the living small animal is excited by the excitation light to emit fluorescence, and the fluorescence penetrating from the surface of the small animal reaches the place
  • the fluorescence imaging detection module passes through the band pass filter and reaches the CCD device, and the signal collected by the CCD device is input to the computer.
  • the invention has the following advantages due to the above technical solution: 1. Since the invention adopts the continuous dynamic acquisition mode, the 360-degree full-circumference data around the small animals can be quickly and efficiently obtained, which greatly saves time and increases system detection. Flux improves the convenience of the experiment. 2. Because the small animals in the present invention rotate at a low speed and evenly rotate, the small animals are in a relatively balanced state, which eliminates the organ displacement caused by the conventional stepping acquisition. 3. The control method is simple and convenient due to the low speed uniform rotation mode adopted in the present invention. 4. Since the fluorescence imaging excitation and detection device of the present invention is a non-contact, 360 degree panoramic detection system, the measurement data amount and accuracy are greatly improved, and the experiment brings great convenience. 5. Since the detection method adopted by the present invention can integrate an modal imaging system such as P E T or CT, a multi-mode imaging system can be formed, and a rich, high-resolution multi-modal image information is obtained.
  • modal imaging system such as P E T or CT
  • Figure 2 is a three-dimensional structure diagram of the system of the present invention
  • FIG. 3 is a schematic diagram of an imaging data acquisition process of the present invention
  • Figure 4 is a graph showing the spectral characteristics of the fluorescent probe CY5. 5 and the filter XF3113 (710AF40).
  • FIG. 5 is a schematic diagram showing the relationship between the modified excitation light mode and the measured value in the continuous rotation mode of the present invention.
  • FIG. 6 is a perspective structural view of the present invention with the small animal contour acquisition device.
  • Figure 7 is a schematic diagram of an imaging data acquisition process including a contour acquisition device
  • Figure 8 is a diagram showing the spatial structure distribution of the PET imaging detection and processing device of the present invention.
  • Figure 9 is a three-dimensional structure diagram of a dual-mode integrated imaging system for PET and bio-luminous tomography.
  • Figure 10 is a schematic diagram of imaging data acquisition of PET and bio-luminous tomography dual-mode integrated imaging system. The best way to implement the invention
  • the present invention comprises a computer 1, a small animal rotary table device 2, and a fluorescence imaging excitation and detection device 3.
  • Small animal rotary platform device 2 consists of a small animal suspension bracket and a rotating motor that connects the brackets.
  • the fluorescence imaging excitation and detection device 3 includes a fluorescence imaging excitation module 31 and a fluorescence imaging detection module 32.
  • the fluorescence imaging excitation module 31 includes an excitation light source 311 and a focus and scan control unit 312.
  • the fluorescence imaging detection module 32 includes a band pass filter 321, CCD device 323 (including lens and CCD camera).
  • the excitation source 311 provides an initial energy for the excitation of the fluorescent probe, which can be a combination of a broad spectrum incandescent bulb and a different band filter or a specific band of lasers.
  • the focus is to reduce the area of the spot projected onto the surface of the small animal, and to scan the spot position for controlling the surface of the small animal.
  • the band pass filter 321 filters out excitation light and external disturbance light.
  • the lens in the CCD device 322 has a large numerical aperture, and the CCD camera is externally connected to a circulating water refrigerator to reduce the operating temperature of the chip and reduce dark current noise.
  • the information exchange between the CCD camera and the computer 1 is performed by an interface controller, and the signals collected by the CCD are input to the computer for image reconstruction.
  • the rotating platform in the small animal rotary platform unit is driven by a rotary motor that is connected to the computer 1 via an RS232 interface.
  • the rotary motor is controlled by computer software for horizontal or continuous rotation (adjustable for both step and speed) and vertical displacement.
  • the input signal of the computer 1 is the output signal from the CCD device 322, the output signal is the rotation control and switching signal of the rotating electrical machine, the control of the CCD device 322, and the digital image signal is obtained according to the reconstruction method.
  • the small animal rotary platform device 2 is the core component of the present invention.
  • the upper limb of the small animal is connected to the rotating table of the motor through the clamp, and the animal is in a state of vertical free suspension, and the small adjustment is ensured by the position adjustment check.
  • the central axis of the body of an animal, such as a mouse coincides with the axis of the rotating table.
  • the fluorescence imaging excitation module and the detection module are located on opposite sides of the rotating platform. Get the surrounding small animals 360 without damage
  • the computer 1 controls the rotating motor to drive the small animal to rotate at a constant speed around the long axis of the body, and the CCD device simultaneously performs continuous dynamic acquisition. After collecting the data for one week, the motor can also control the movement of the small animal in the vertical direction (ie, the direction along the axis of rotation) according to the size of the detected field of view and different imaging requirements.
  • the fluorescence imaging excitation and detection device 3 is a non-contact, 360 degree panoramic detection system.
  • the illumination emitted by the excitation light source 311 in the fluorescence imaging laser module 31 is illuminated by the focusing and scanning control unit 312 to the living animals. After the surface, enter the small animal.
  • a fluorescent probe for labeling a specific molecule or cell in a living small animal will emit fluorescence after being excited by the excitation light, and the fluorescence penetrating from the surface of the small animal reaches the fluorescence imaging detecting module 32, and the excitation light is filtered by the band pass filter 321 After the light is disturbed by the outside, the CCD device 322 is reached.
  • the signal collected by the CCD device 322 is input to the computer 1 for image reconstruction to determine the three-dimensional position of the fluorescent probe.
  • the fluorescent probe adopts CY5.
  • the filter adopts the XF3113 (710AF40) filter of OMEGA OPTICAL of the United States (the spectral characteristics of the fluorescent probe CY5.5 and the XF3113 filter are as shown in FIG. 4, wherein The thick solid line represents the XF3113 permeability, the dashed line represents the Cy5. 5 excitation spectrum, and the thin solid line represents the Cy5. 5 fluorescence spectrum.)
  • the CCD uses DU-897 from Andor, UK.
  • a specific fluorescent label is injected into a living small animal to mark cells or tissues;
  • the rotating platform of the hanging animal is controlled by the rotating motor to rotate at a low speed and uniform speed in the vertical direction.
  • the fluorescence imaging excitation module continuously emits the excitation light to the surface of the animal, and the fluorescence imaging detection module continuously collects the signal, and the original is collected. Data is sent to the computer.
  • the rotating motor controls the small animals to move up and down along the rotation axis.
  • the detection device CCD Since the fluorescence signal from the small animal is weak, in order to ensure the detection signal quality such as the signal-to-noise ratio, the detection device CCD requires several seconds of exposure time. If the small animal rotates at a constant speed of 1 degree/s, and the exposure time of the CCD to collect an image is 5 s, the small animal rotates 5 degrees with respect to the body axis during the time when the CCD captures one frame of image, and the excitation light is The position of the spot on the surface of the animal has changed slightly, and the CCD collects the alias of the fluorescent image at different surface positions of the small animal.
  • the excitation light source is approximated as a fixed point light source during reconstruction, and the position is the displacement of the excitation spot actually irradiated onto the surface of the small animal during the exposure time. center of.
  • the fluorescence measurement image after the above-mentioned corrected excitation light position and the corresponding fluorescence measurement image when the small animal continuously rotates at a constant speed are simulated on the computer, respectively, and it is proved that the measurement image data is consistent under a certain rotation speed. Very good. For example, in the case of a rotational speed of 1 degree / s, a measurement image of a cylindrical body similar to the optical properties of biological tissue is simulated in both cases. Taking the first frame image of the small animal starting to rotate, the image is selected to correspond to 210 measurement points of the surface of the small animal at an angle of 90 degrees with respect to the rotation axis (as shown in FIG. 5, wherein the solid line represents the corrected excitation light) The measured value in the case of position, the solid dot represents the measured value in the case of continuous uniform rotation).
  • a small animal contour acquiring device 4 is disposed, which is located on the same side of the fluorescence imaging excitation module 31, and is synchronously acquired when collecting fluorescent images. Measuring the three-dimensional surface contour information of small animals.
  • the three-dimensional surface contour of the small animal can be reconstructed by a back projection method based on a set of photos including 360 degree information of the surface contour of the small animal (the principle of the image data acquisition process after adding the contour acquiring device is shown in Fig. 7).
  • the contour acquiring device 4 in this embodiment is a camera connected to the computer 1.
  • the measurement space of the present invention can also integrate other forms of imaging devices to form an information-rich dual-mode or multi-mode imaging system.
  • a PET imaging detecting and processing device 5 is added to form an induced fluorescence tomography and PET dual-mode imaging system.
  • the fluorescence imaging excitation and detection device 3 and the PET imaging detection and processing device 5 adopt a subspace measurement mode, and two planes orthogonal to the central axis of the rotation platform evenly divide the measurement space around the 360 degrees of the small animal into four blocks, each The block occupies a measurement space of 90 degrees, and the fluorescence imaging excitation module 31 and the fluorescence imaging detection module 32 occupy two opposite 1/4 measurement spaces of (a) and (c), respectively, and the PET imaging detection and location device 5 respectively (b) With (d) two quarters of measurement space.
  • PET imaging detection and processing device 5 is used to detect the emission of nuclei labeled with specific tissues and cells injected into living small animals.
  • the photon pair (generated by the positron formed by the decay of the nuclide and the quenching of electrons in the tissue) includes a scintillation crystal 51 and a position sensitive photomultiplier tube 52 and a magnifying and matching unit 53 three parts.
  • the filter 321 of the fluorescence imaging detection module 32 is required.
  • a set of lead glass 323 is added before.
  • the output of the PET imaging detection and processing device 5 is connected to the computer 1 via a data acquisition card.
  • the PET imaging detecting and processing device 5 light is converted into visible light by the scintillation crystal material 51, and converted into an electrical signal by the position sensitive photomultiplier tube 52.
  • the amplifying and matching unit 53 first performs A/D conversion and amplification on the electrical signal, and then performs a coincidence operation on the arrival time of the pulse signal outputted by the different detection parts according to the circuit system, and finally the output signal is appropriately conditioned and sent to the computer by the acquisition system. deal with.
  • the input signal of the computer 1 is an output signal from the amplification and matching unit 53 of the PET imaging detection and processing device 5 and an output signal from the CCD device 322.
  • the output signal of the computer 1 is to control the rotation control and switching signals of the rotating motor, and amplify the PET.
  • the digital unit is obtained with the matching unit 53 and the control of the CCD device 322, and according to the reconstruction method.
  • the scintillation crystal is 1. 9*1. 9*10rran of LYS0 (lutetium-yttrium oxyorthosilicate, yttrium silicate: yttrium) crystal, and the photomultiplier tube is a position sensitive photomultiplier tube of Hamamatsu R8520.
  • the present invention can perform multi-modal data processing, reconstruction and fusion of living small animals, and realize three-dimensional visualization, and computer software completes device control, data collection and analysis, and image restoration and reconstruction.
  • the present invention adopts a signal acquisition mode of dividing the space and continuously rotating the measured small animal, it is expandable. If the space occupied by the PET imaging detection and processing device 5 is replaced by an X-ray emission and detection device, after reconstruction, the X-CT image of the measured small animal can be obtained synchronously; the 360-degree measurement space around the small animal is equally divided into 6 Block, X-ray emission and detection device, fluorescence imaging and detection device and PET imaging detection and processing device each occupy two 60-degree measurement space, which can realize the fusion of X-CT, induced fluorescence tomography and PET imaging.
  • the modular imaging system can simultaneously obtain high-resolution anatomical information of small animals and functional information related to cellular molecules.
  • the invention can establish a universal detection technology platform integrated with the integrated system of small animal in vivo molecular imaging research, medical application and drug screening with related instruments, and carry out physiological data processing, image reconstruction, image fusion and three-dimensional visualization on the basis of the invention.
  • the work in other aspects lays the foundation for practical application research of small animal in vivo tumor location and cancer cell proliferation.

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Description

一种连续动态采集式小动物诱发荧光分子成像系统及方法 技术领域
本发明涉及一种成像系统及成像方法， 特别是关于一种连续动态采集式小动 物诱发荧光分子成像系统及方法。
背景技术
医学影像技术经历了结构成像、功能成像后，上世纪 90年代开始，随着生物、 和基因技术的发展以及成像技术的提高， 又出现了新的分子影像技术。 在活体生 物体内注入示踪剂或标记物以标记特定分子或细胞， 通过分子影像技术可以得到 与生物体生理或病理过程相关细胞、 基因和分子水平上的信息， 从而为基因功能 定位、 细胞生长发育和突变过程的作用机制、 新药研发等提供有效的信息获取和 分析处理手段。 现有的小动物在体分子影像技术主要包括核素成像和光学成像两 种， 其中光学成像由于具有无损、 设备成本较低、 探针种类多和标记技术较成熟 等优势被认为是很有潜力的分子成像模式。 然而， 受可见光或近红外光在组织的 穿透深度影响， 光学成像广泛应用于小动物在体成像， 已成为从离体实验过渡到 临床应用的一个重要的纽带。
光学分子成像中包括平面成像和断层成像。 相对于平面成像只能反映某个投 影方向的信息， 断层成像通过光在生物组织中的传播模型则可以重建出荧光团浓 度的三维分布信息。 按照荧光光源类型分类， 光学分子断层成像又可以分为自发 荧光断层成像 （Bioluminescence Tomography, BLT) 和诱发荧光分子断层成像 (Fluorescence Molecular Tomography, FMT)。 在 FMT中， 荧光团分子吸收外界 入射的特定波段的激发光， 产生能级跃迁， 但经过一定的时间会返回基态， 并发 出波长长于激发光的荧光。 由于诱发荧光团发出的荧光光强与其吸收的激发光强 度相关， 所以从小动物表面检测到的荧光信号要比 BLT的信号强， 而且不同的激 发情形也提供了丰富的信息量， 有利重建。
过去十年中， 小动物诱发荧光分子断层成像系统经历了几代的发展。 最初是 将小动物 （通常是小白鼠）放入圆柱形的成像腔， 从腔表面用光纤引出不同位置 的测量信号， 这种早期的系统的缺点和限制较多， 如成像腔中需要填充匹配液， 表面的探测数据量太少和重建图像的空间分辨率低等。 随后出现的平板检测系统 使用 CCD来检测荧光， 与光纤釆集模式相比， 提高了采样率， 空间分辨率可达到 亚毫米级， 但是因其投影方向受限， 所以在垂直探测面方向分辨率很低且仍须使 用匹配液。 2007年出现了非接触式、 环绕小动物全周 （360度）检测的 FMT系统， 其避免了成像腔、 光纤和匹配液的使用， 大大地增加了实验的便利性， 该系统将 激发光源和 CCD器件放于动物的对侧， 每次将小动物绕其身体长轴旋转一个小角 度， 然后停下来采集一幅小动物体表某一视场的荧光图像， 根据所采集的一周内 不同投影方向的图像重建荧光团分布， 为了减少惯性带来的器官移位和歪斜， 小 动物旋转速度须小于 5度 /秒， 在小动物缓慢旋转的过程中 CCD处于空闲状态。 因 此， 如果要实现围绕小动物一周的全景采集， 需要花费很长时间。 此外， 由于小 动物成像时需处于麻醉状态， 长时间反复麻醉将会减少小动物的寿命， 不利于连 续观察。
近年来， 多模态集成成像方式和系统由于能从多个角度对被测活体进行观察 和分析， 成为医学成像发展的一个趋势， 它结合不同成像方式， 形成信息丰富、 分辨率高的多模态图像信息源， 并通过配准、 分割和融合， 实现高精度的空间定 位， 提供更为全面的信息， 为研究人员提供帮助。 如医疗器械巨头企业 Siemens GE、 Philips都推出了 PET_CT， 将 PET的功能成像与螺旋 CT 的解剖结构成像融 于一体， 形成优势互补，为肿瘤诊断作出了很大贡献。
对于小动物在体光学成像系统而言， 目前也出现了双模成像系统， 如光学成 像与 X-ray成像结合， 但这类系统大都只实现平面成像， 还未能实现两种模式下 的三维断层成像， 同时， 这类系统的釆集模式在时间上大都是串行的， 无法同时 采集到两种模式下的图像信息。
发明内容
针对上述问题， 本发明的目的是提供一种连续动态釆集式小动物诱发荧光分 子成像方法及系统。
为实现上述目的， 本发明釆取以下技术方案： 一种连续动态釆集式小动物诱 发荧光分子成像系统， 其特征在于： 它包括计算机、 小动物旋转平台装置和荧光 成像激发与检测装置； 所述小动物旋转平台装置包括小动物悬挂支架和连接支架 的旋转电机； 所述荧光成像激发与检测装置包括荧光成像激发模块和荧光成像检 测模块， 所述荧光成像激发模块包括激发光源和聚焦与扫描控制单元， 所述荧光 成像检测模块包括带通滤光片和 CCD器件； 所述 CCD器件通过一接口控制器连接 所述计算机， 所述旋转电机通过 RS232接口连接到所述计算机； 所述计算机输入 信号为来自所述 CCD器件的输出信号， 所述计算机输出信号是控制所述旋转电机 的转动控制及切换信号， 控制所述 CCD器件。
在所述荧光成像激发模块同侧加设一小动物轮廓获取装置。
将环绕悬吊小动物 360度的检测空间分隔为四块， 所述荧光成像激发模块与 检测模块占其中相对的两个分检测空间， 并在所述荧光成像检测模块的所述滤光 片前加设铅玻璃， 在另外的两个检测空间中加设 PET成像检测与处理装置， 构成 PET与荧光断层成像双模系统;将所述 PET成像检测及处理装置所占的空间替换为 X光发射与探测装置， 构成 X-CT和诱发荧光断层成像双模成像系统； 将检测空间 分成 6块， 所述 X光发射与探测装置、 所述荧光成像与检测装置和所述 PET成像 检测及处理装置各占相对的两个 60度的测量空间，可实现 X- CT、诱发荧光断层成 像和 PET成像融合的三模成像系统。
本发明包括如下具体步骤： 将特定的荧光标记物注入活体小动物体内用以标 记细胞或组织； 将小动物麻醉后通过夹具竖直悬挂于所述小动物旋转平台； 所述 旋转电机控制所述小动物旋转平台绕竖直方向连续匀速旋转， 荧光成像检测模块 连续采集信号， 并将采集到的原始数据送入计算机； 采集完一周数据后， 根据检 测视场大小和成像要求， 旋转电机控制小动物沿旋转轴线上下移动。
图像重建时对数据混叠现象进行如下修正： 对所述 CCD器件采集到的每帧图 像， 重建时将所述激发光源为位置固定的点光源， 其位置为实际照射到小动物表 面的激发光斑在曝光时间内所产生的位移的中心； 与小动物各个体位相对应的每 帧图像数据， 重建时只取其相对于小动物旋转轴线的中间 90度范围的数据。
所述荧光成像激发与检测装置为一个非接触式的、 360度全景检测的系统，它 采集数据的具体步骤包括： 所述荧光成像激光模块中的所述激发光源发出的激光 经所述聚焦与扫描控制单元后， 照射到活体小动物的表面后再进入小动物体内； 活体小动物体内标记特定分子或细胞的荧光探针受激发光激发后发出荧光， 从小 动物表面穿透出的荧光到达所述荧光成像检测模块， 经过所述带通滤光片后， 到 达所述 CCD器件， 所述 CCD器件采集到的信号输入到所述计算机。
本发明由于釆取以上技术方案， 具有以下优点： 1、 由于本发明采用连续动态 采集方式， 所以能快速高效地获取环绕小动物 360度的全周数据， 大大节约了时 间， 增加了系统的检测通量， 提高了实验的便利性。 2、 由于本发明中小动物低速 均匀旋转， 所以小动物处于一个相对平衡状态， 消除了传统步进采集时造成器官 移位。 3、 由于本发明中采用的低速匀速旋转方式， 所以控制方法简单方便。 4、 由于本发明中荧光成像激发与检测装置为一个非接触式的、 360度全景检测的系 统， 所以大大提高了测量数据量和准确度， 同时为实验带来了极大的便利性。 5、 由于本发明采取的检测方式可集成 P E T或 CT等模态的成像系统，所以可形成多 模成像系统， 获得丰富的、 分辨率高的多模态图像信息。
附图说明 图 1是本发明总体组成结构框图
图 2是本发明系统组成的立体结构图
图 3是本发明的成像数据获取过程原理图
图 4是荧光探针 CY5. 5与滤光片 XF3113 ( 710AF40 ) 的光谱特性图
图 5是本发明修正激发光方式与连续旋转方式下测量值的关系示意图 图 6是本发明加设小动物轮廓获取装置后的立体结构图
图 7是包含轮廓获取装置的成像数据获取过程原理图
图 8是本发明加设 PET成像检测及处理装置后的空间结构分布图
图 9是 PET与生物自发光断层成像双模一体成像系统的立体结构图
图 10是 PET与生物自发光断层成像双模一体成像系统成像数据获取原理图 实施发明的最佳方式
下面结合附图和实施例， 对本发明进行详细的描述。
如图 1所示，本发明包括计算机 1、小动物旋转平台装置 2和荧光成像激发与 检测装置 3组成。 小动物旋转平台装置 2由小动物悬挂支架和连接支架的旋转电 机组成。荧光成像激发与检测装置 3包括荧光成像激发模块 31和荧光成像检测模 块 32， 荧光成像激发模块 31包括激发光源 311和聚焦与扫描控制单元 312， 荧光 成像检测模块 32包括带通滤光片 321、 CCD器件 323 (包括镜头和 CCD相机）。 激 发光源 311为荧光探针的激发提供初始能量， 它可以是一个广谱的白炽灯泡和不 同波段滤光片的组合或特定波段的激光器。 聚焦与扫描控制单元 312中， 聚焦是 为了缩小投射到小动物体表的光斑面积， 扫描用以控制小动物体表的光斑位置。 在荧光成像检测模块 32中， 带通滤光片 321滤除激发光和外界干扰光。 CCD器件 322中的镜头具有大数值孔径， CCD相机外接循环水致冷机，以降低芯片工作温度， 减小暗电流噪声。 CCD相机与计算机 1的信息交互由一个接口控制器完成， CCD采 集到的信号输入到计算机后进行图像重建。 小动物旋转平台装置中的旋转平台由 旋转电机带动，旋转电机通过 RS232接口连接到计算机 1。旋转电机由计算机软件 控制实现水平步进或连续旋转 （步长与速度均可调节）以及竖直方向的移位。计算 机 1输入信号为来自 CCD器件 322的输出信号， 输出信号为旋转电机的转动控制 及切换信号， 对 CCD器件 322的控制， 以及根据重建方法得到数字图像信号。
如图 2所示， 小动物旋转平台装置 2是本发明的核心部件， 小动物的上肢通 过夹具连接到电机的旋转台面， 动物处于竖直的自由悬挂状态， 通过位置调节校 验保证被测小动物 （如小白鼠） 的身体中心轴线同旋转台面的轴线重合。 荧光成 像激发模块与检测模块位于旋转平台的对侧。为无缺损地获得环绕被测小动物 360 度全景荧光图像， 计算机 1控制旋转电机带动小动物绕其身体长轴以一定速率作 匀速旋转， CCD器件同时进行连续动态采集。采集完一周数据后， 根据检测视场大 小和不同的成像要求， 电机也可以控制小动物作竖直方向（即沿旋转轴线的方向） 的移动。
如图 3所示（宽箭头表示光信号流通， 实线箭头表示电信号流通)， 动物体内 荧光物质受到激发之后， 发出波长较激发光更长的极微弱荧光信号， 荧光穿过小 动物组织被光电器件所检测。荧光成像激发与检测装置 3为一个非接触式的、 360 度全景检测的系统，荧光成像激光模块 31中的激发光源 311发出的徼光经聚焦与 扫描控制单元 312后， 照射到活体小动物的表面后再进入小动物体内。 活体小动 物体内用来标记特定分子或细胞的荧光探针受激发光激发后将发出荧光， 从小动 物表面穿透出的荧光到达荧光成像检测模块 32， 经过带通滤光片 321滤除激发光 和外界干扰光后， 到达 CCD器件 322。 CCD器件 322采集到的信号输入到计算机 1 后进行图像重建， 确定荧光探针的三维位置。本实施例中荧光探针采用 CY5. 5， 滤 光片采用美国 OMEGA OPTICAL公司的 XF3113 (710AF40)滤光片 （荧光探针 CY5. 5 与 XF3113滤光片光谱特性如图 4所示， 其中， 粗实线代表 XF3113通透率， 虚线 代表 Cy5. 5激发光光谱， 细实线代表 Cy5. 5荧光光谱。）来滤除干扰信号， CCD釆 用英国 Andor公司的 DU-897。
本发明具体操作步骤如下：
1、标记准备阶段， 将特定的荧光标记物注入活体小动物体内用以标记细胞或 组织；
2、 固定被测动物， 将小动物麻醉后通过夹具竖直悬挂于旋转平台；
3、数据采集， 悬挂动物的旋转平台由旋转电机控制绕竖直方向作低速匀速旋 转运动， 荧光成像激发模块持续发射激发光至动物表面， 荧光成像检测模块连续 采集信号， 并将采集到的原始数据送入计算机。
4、 采集完一周数据后， 根据检测视场大小和成像要求， 旋转电机控制小动物 沿旋转轴线上下移动。
由于从小动物体内出来的荧光信号较弱， 为保证探测信号质量如信噪比， 检 测器件 CCD需要若干秒的曝光时间。 若小动物以 1度 /s的速度匀速旋转， CCD釆 集一幅图像的曝光时间为 5s， 则在 CCD采集一帧图像的时间里小动物相对于身体 轴心旋转了 5度，激发光在动物表面的光斑位置发生了微小改变， CCD采集到的也 是小动物不同表面位置荧光图像的混叠。 为降低动态采集所产生的数据混叠的影 响， 在图像重建中需进行以下修正： ( 1 )对所述 CCD器件采集到的每帧图像， 重建时将所述激发光源近似为位置 固定的点光源， 其位置为实际照射到小动物表面的激发光斑在曝光时间内所产生 的位移的中心。
(2)与小动物各个体位相对应的每帧图像数据， 重建时只取其相对于小动物 旋转轴线的中间 90度范围的数据， 左右两边数据则舍弃。
为了验证上述修正方法， 分别在计算机上模拟了釆用上述修正激发光位置后 的荧光测量图像和小动物连续匀速旋转时对应的荧光测量图像， 证明在低于一定 转速情况下， 测量图像数据吻合的很好。 例如， 在转速为 1度 /s的情况下， 模拟 了一个圆柱形的且与生物组织光学特性相似的仿体在两种情况下的测量图像。 取 小动物开始旋转的第一帧图像， 选择此幅图像对应于小动物表面的、 相对于旋转 轴线的中间 90度的 210个测量点（如图 5所示， 其中， 实线代表修正激发光位置 情况下的测量值， 实心圆点代表连续匀速旋转情况下测量值）。
如图 6所示， 在上述诱发荧光断层成像的基础上， 加设一小动物轮廓获取装 置 4， 该轮廓获取装置 4位于荧光成像激发模块 31同侧， 在釆集荧光图像时， 同 步获取被测小动物的三维表面轮廓信息。 根据一组包括小动物表面轮廓 360度信 息的照片，用反投影法可重建出小动物的三维表面轮廓 (加设轮廓获取装置后的成 像数据获取过程原理如图 7所示）。本实施例中的轮廓获取装置 4为一连接计算机 1的摄像头。
本发明测量空间还可以集成其他形式的成像装置， 形成信息丰富的双模或多 模的成像系统。
如图 8所示， 在上述诱发荧光断层成像基础上， 加设一 PET成像检测及处理 装置 5，形成一个诱发荧光断层成像和 PET双模成像系统。荧光成像激发与检测装 置 3和 PET成像检测及处理装置 5采用分空间的测量模式， 两个正交于旋转平台 中心轴线的平面将环绕小动物一周 360度的测量空间均匀分隔为四块， 每块占 90 度的测量空间， 荧光成像激发模块 31和荧光成像检测模块 32分别占 (a)与 (c)两 个相对的 1/4测量空间， PET成像检测及处装置 5分别占 (b)与 (d) 两个 1/4的测 量空间。
如图 9、图 10所示（宽箭头表示光信号流通，实线箭头表示电信号流通)， PET 成像检测及处理装置 5用以检测注入活体小动物体内标记特定组织和细胞的核素 所发出的 ^光子对（由核素衰变形成的正电子与组织器官中的电子发生湮灭现象产 生）， 它包括闪烁晶体 51和位置灵敏型光电倍增管 52和放大与符合单元 53三部 分。为防止 ^光子损坏 CCD器件 322，所以需在荧光成像检测模块 32的滤光片 321 前加设一组铅玻璃 323。 PET成像检测及处理装置 5的输出通过数据采集卡连接到 计算机 1。 PET成像检测及处理装置 5中， 光经闪烁晶体材料 51转换为可见光， 再经位置灵敏型光电倍增管 52转化为电信号。 放大和符合单元 53首先对电信号 进行 A/D转换和放大， 然后通过符合电路系统对不同探测处输出的脉冲信号到达 时间作符合运算， 最后输出信号经适当调理后由采集系统送入计算机 1处理。 计 算机 1输入信号为来自经过 PET成像检测及处理装置 5的放大与符合单元 53的输 出信号和来自 CCD器件 322的输出信号， 计算机 1输出信号是控制旋转电机的转 动控制及切换信号， 对 PET放大与符合单元 53和对 CCD器件 322的控制， 以及根 据重建方法得到数字图像信号。 本实施例中闪烁晶体采用 1. 9*1. 9*10rran的 LYS0 ( lutetium-yttrium oxyorthosilicate, 硅酸镥：钇） 晶体， 光电倍增管采用滨 松 R8520的位置灵敏型光电倍增管。
在光学和核素信号检测基础上， 本发明可完成活体小动物多模态数据处理、 重建和融合， 并实现三维可视化， 计算机软件完成设备控制、 数据釆集与分析以 及图像恢复与重建。
由于本发明采用了分空间、 连续旋转被测小动物的信号采集模式， 所以具有 可拓展性。 如将 PET成像检测及处理装置 5所占的空间替换为 X光发射与探测装 置， 经过重建， 可同步得到被测小动物的 X-CT图像； 将小动物周围的 360度测量 空间平均分成 6块， X光发射与探测装置、荧光成像与检测装置和 PET成像检测及 处理装置各占相对的两个 60度的测量空间，即可实现 X- CT、诱发荧光断层成像和 PET成像融合的三模成像系统，可同时得到小动物的高分辨率解剖结构信息和与细 胞分子相关的功能信息。
本发明可以与相关仪器建立一个小动物在体分子影像学研究、 医疗应用和药 物筛选等一体化系统集成的通用检测技术平台， 在此基础上开展生理数据处理、 图像重建、 图像融合与三维可视化等方面的工作， 为小动物在体的肿瘤定位、 癌 细胞扩散等实际应用研究奠定基础。
尽管为说明目的公幵了本发明的具体实施例和附图， 其目的在于帮助理解本 发明的内容并据以实施， 但是本领域的技术人员可以理解： 在不脱离本发明及所 附的权利要求的精神和范围内， 各种替换、 变化和修改都是可能的。 因此， 本发 明不应局限于最佳实施例和附图所公开的内容， 本发明要求保护的范围以权利要 求书界定的范围为准。

Claims

1、一种连续动态采集式小动物诱发荧光分子成像系统， 其特征在于： 它包括 计算机、 小动物旋转平台装置和荧光成像激发与检测装置； 所述小动物旋转平台 装置包括小动物悬挂支架和连接支架的旋转电机； 所述荧光成像激发与检测装置 包括荧光成像激发模块和荧光成像检测模块， 所述荧光成像激发模块包括激发光 源和聚焦与扫描控制单元， 所述荧光成像检测模块包括带通滤光片和 CCD器件； 所述 CCD器件通过一接口控制器权连接所述计算机， 所述旋转电机通过 RS232接口 连接到所述计算机； 所述计算机输入信号为来自所述 CCD器件的输出信号， 所述 计算机输出信号是控制所述旋转电机的转动控制及切换信号，控制所述 CCD器件。
2、 如权利要求 1所述的一种连续动态采集式小动物诱发荧光分子成像系统， 其特征在于： 在所述荧光成像激发模块同侧加设一小动物轮廓获取装置。
求
3、如权利要求 1或 2所述的一种连续动态采集式小动物诱发荧光分子成像系 统， 其特征在于： 将环绕悬吊小动物 360度的检测空间分隔为四块， 所述荧光成 像激发模块与检测模块占其中相对的两个分检测空间， 并在所述荧光成像检测模 块的所述滤光片前加设铅玻璃， 在另外的两个检测空间中加设 PET成像检测与处 理装置， 构成 PET与荧光断层成像双模系统； 将所述 PET成像检测及处理装置所 占的空间替换为 X光发射与探测装置，构成 X-CT和诱发荧光断层成像双模成像系 统； 将检测空间分成 6块， 所述 X光发射与探测装置、 所述荧光成像与检测装置 和所述 PET成像检测及处理装置各占相对的两个 60度的测量空间， 可实现 X - CT、 诱发荧光断层成像和 PET成像融合的三模成像系统。
4、 一种连续动态釆集式小动物诱发荧光分子成像方法， 其特征在于： 它包括 如下具体步骤 -
( 1 )将特定的荧光标记物注入活体小动物体内用以标记细胞或组织；
(2 )将小动物麻醉后通过夹具竖直悬挂于所述小动物旋转平台；
(3 )所述旋转电机控制所述小动物旋转平台绕竖直方向连续匀速旋转， 荧光 成像检测模块连续采集信号， 并将采集到的原始数据送入计算机；
(4)采集完一周数据后， 根据检测视场大小和成像要求， 旋转电机控制小动 物沿旋转轴线上下移动。
5、 如权利要求 4所述的一种连续动态釆集式小动物诱发荧光分子成像方法， 其特征在于： 图像重建时对数据混叠现象进行如下修正：
( 1 )对所述 CCD器件采集到的每帧图像， 重建时将所述激发光源为位置固定 的点光源， 其位置为实际照射到小动物表面的激发光斑在曝光时间内所产生的位 移的中心；
(2)与小动物各个体位相对应的每帧图像数据， 重建时只取其相对于小动物 旋转轴线的中间 90度范围的数据。
6、如权利要求 4或 5所述的一种连续动态采集式小动物诱发荧光分子成像方 法，其特征在于： 所述荧光成像激发与检测装置为一个非接触式的、 360度全景检 测的系统， 它采集数据的具体步骤包括： 所述荧光成像激光模块中的所述激发光 源发出的激光经所述聚焦与扫描控制单元后， 照射到活体小动物的表面后再进入 小动物体内； 活体小动物体内标记特定分子或细胞的荧光探针受激发光激发后发 出荧光， 从小动物表面穿透出的荧光到达所述荧光成像检测模块， 经过所述带通 滤光片后， 到达所述 CCD器件， 所述 CCD器件采集到的信号输入到所述计算机。
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