JP4956206B2 - Ultrasonic diagnostic apparatus, substance introduction apparatus for ultrasonic therapy, and ultrasonic scanning control program - Google Patents

Description

  The present invention relates to a method for introducing a therapeutic substance into a cell using ultrasonic waves, and in particular, an ultrasonic wave is transmitted in the presence of microbubbles to introduce a therapeutic substance such as a gene into the cell by a sonoporation phenomenon. Then, regenerative medicine and gene therapy are performed effectively, or proteins and the like are introduced into cells to perform local therapy.

  Research into methods for introducing genes into cells (gene introduction methods) began with the elucidation of the mechanism of bacterial transformation, followed by gene introduction into yeast and plant cells, and further to animals and plant individuals. It is becoming possible to introduce genes directly. The various introduction methods shown in FIG. 14 have been developed in accordance with the above-mentioned various purposes, and include methods that cannot be used for the purpose of clinical application.

  On the other hand, for clinical applications, the use of viral vectors is the mainstream in terms of gene transfer efficiency. As shown in FIG. 14, there are differences in characteristics depending on the type of virus used in the virus vector method. Currently, it is most often done using retroviral vectors. The viral vector method is overwhelmingly superior among the introduction methods currently known in terms of introduction efficiency. However, strict management and handling are necessary to handle viruses. In particular, viral vectors have recently been reported to significantly improve the efficiency of introduction into cells, but for clinical applications, there are unknown aspects regarding safety, and more careful examination is required.

  As shown in FIG. 14, there are several types of viral vectors. Representative examples include retroviral vectors and adenoviral vectors. Retroviral vectors are the most widely used representative RNA viral vectors, and have high introduction efficiency and low cytotoxicity, but have the restriction that they do not infect non-proliferating cells. Therefore, introduction into cells that do not normally divide, such as nerve cells, hepatocytes, muscle cells, and hematopoietic cells, cannot be used. Further, in terms of safety, mutagenicity due to insertion is a problem. Adenovirus vectors exhibit the highest introduction / expression efficiency among vectors used for gene therapy. It can be expressed directly in individual animals and is used in a wide range of basic research fields. However, the sustained expression is not sufficient. When the protein expressed by the virus vector is foreign, cellular immunity is strongly induced using the protein as an antigen, and the target cell expressing the target gene exhibits an inflammatory image in 1 to 2 weeks and is removed. In addition, the infection range is large and there is no infection specificity. For clinical application, gene expression efficiency in specific organs is not high, and when normal or excessive protein expression is required, large amounts of viral vectors are required and serious side effects may occur. is there.

In addition, as a well-known document relevant to this application, there exist the following, for example.
Journal of the ME Society of Japan BME vol.12, No.2, 1998 Japanese Clinical Volume 56 No.3, 1998 New developments in gene therapy Yodosha 2001

  However, a clinically applicable technique for introducing a gene into a cell has not yet been completed.

  For example, in the virus vector method, the safety for removing the virus toxicity is not established, there is gene introduction in an organ other than the target site, there is no site specificity, an antibody is generated in humans, and the same virus vector is frequently used. There is a problem that it cannot be used, and it cannot be applied clinically yet.

  Further, non-viral vectors have been studied as a safer gene transfer method. For example, there is a method in which naked DNA is directly administered to an animal individual, and clinical studies are being conducted. Naked DNA cannot be introduced at all in cultured cells, but is introduced and expressed in living tissues. However, since the introduction efficiency is small, it is necessary to inject a large amount of genes. The toxicity at the time of large dose administration has an unknown part, and improvement of introduction efficiency to reduce the dose is required.

  The present invention has been made in view of the above circumstances, and an ultrasonic diagnostic apparatus and ultrasonic therapy that can introduce a therapeutic substance into cells more safely by generating sonoporation by ultrasonic transmission. An object of the present invention is to provide a substance introduction device and an ultrasonic scanning control program.

  In order to achieve the above object, the present invention takes the following measures.

According to the first aspect of the present invention, in response to an applied drive signal, first ultrasonic transmission for acquiring an ultrasonic image for each of a plurality of ultrasonic scanning directions in a treatment target region of a subject. Alternatively, the second ultrasonic transmission for generating the sonoporation is performed, and the first echo signal based on the first ultrasonic transmission or the second ultrasonic transmission is performed from each of the ultrasonic scanning directions. Based on an ultrasonic probe having a plurality of ultrasonic transducers for receiving the second echo signal, driving means for supplying the driving signal to each ultrasonic transducer, and the received first echo signal An image generation unit that generates an ultrasonic image, a display unit that displays the generated ultrasonic image, and an evaluation that evaluates the possibility of sonoporation in the treatment target region based on the second echo signal Means, In response to the serial-induced potential evaluation result, said to execute the second ultrasonic transmission to generate the Sonoporation the treated region within the object, control means for controlling the drive means An ultrasonic diagnostic apparatus or an ultrasonic therapeutic substance introduction apparatus.
The invention according to claim 25 is the first for acquiring an ultrasound image for each of a plurality of ultrasound scanning directions in the treatment target region of the subject in response to the drive signal applied to the computer . A second ultrasonic transmission for generating ultrasonic transmission or sonoporation is performed, and the first echo signal or the second ultrasonic wave based on the first ultrasonic transmission from each of the ultrasonic scanning directions. and signal supply function to supply the driving signals to the plurality of ultrasonic transducers for receiving the second echo signal based on the transmission, a drive means for supplying the drive signal to each ultrasonic transducer, the first received based on the first echo signal, an image generating means for generating an ultrasonic image, and display means for displaying the ultrasonic image generated, based on the correlation to the index to the collapse of the bubble which constitutes the contrast agent, Sonoporeshi An evaluation function to evaluate the induced potential down, in response to the evaluation result of the induced potential, run the treated area the second ultrasonic transmission to generate the Sonoporation to in the subject Thus, there is provided a control means for controlling the driving means, an ultrasonic diagnostic apparatus or an ultrasonic therapeutic substance introduction apparatus.

  As described above, according to the present invention, an ultrasonic diagnostic apparatus, an ultrasonic therapeutic substance introduction apparatus, and an ultrasonic apparatus that can introduce a therapeutic substance into cells more safely by generating sonoporation by ultrasonic transmission. A scanning control program can be realized.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. In the following description, components having substantially the same function and configuration are denoted by the same reference numerals, and redundant description will be given only when necessary.

  In the following embodiments, a case where the technical idea of the present invention is applied to an ultrasonic diagnostic apparatus will be described as an example. However, without being bound by this, the technical idea of the present invention is introduced into the living body for the purpose of therapeutic substances (eg, physiologically active substances such as genes, drugs, proteins, etc.) using ultrasound. It is also possible to realize a device (substance introduction device for ultrasonic therapy) whose main purpose is to introduce the substance into the subject itself.

  In addition, for each component according to the present embodiment, in particular, control for realizing an ultrasonic transmission / reception sequence for introducing a therapeutic substance into a subject to be described later, the same processing as that of each component is executed. It can also be realized by installing a software program to be installed in a computer such as a workstation, an ultrasonic diagnostic apparatus having a computer function, etc., and developing these on a memory. At this time, a program capable of causing the computer to execute the technique is stored in a recording medium such as a magnetic disk (floppy (registered trademark) disk, hard disk, etc.), an optical disk (CD-ROM, DVD, etc.), or a semiconductor memory. It can also be distributed.

  FIG. 1 is a configuration diagram of an ultrasonic diagnostic apparatus 10 according to an embodiment of the present invention. The ultrasonic diagnostic apparatus 10 includes an ultrasonic probe 11, a transmission / reception unit 12, an echo signal processor 14, a Doppler processor 15, an application processor 16, a control unit (CPU) 17, a display control unit 18, an evaluation unit 19, a storage unit 20, A transmission / reception I / F 21, an operation unit 22, and a monitor 23 are provided.

  The ultrasonic probe 11 generates ultrasonic waves based on a drive signal from the transmission unit 12 and converts a reflected wave from the subject into an electric signal, a matching layer provided in the piezoelectric vibrator, It has a backing material that prevents the propagation of ultrasonic waves from the piezoelectric vibrator to the rear. When ultrasonic waves are transmitted from the ultrasonic probe 11 to the subject, various harmonic components are generated along with the propagation of the ultrasonic waves due to nonlinearity of the living tissue. The fundamental wave and the harmonic component constituting the transmission ultrasonic wave are back-scattered by the boundary of acoustic impedance of the body tissue, minute scattering, and the like, and are received by the ultrasonic probe 11 as a reflected wave (echo).

  If necessary, the ultrasonic probe 11 is a dedicated probe corresponding to an ultrasonic transmission / reception function (described later) for introducing a therapeutic substance, such as a special probe for high sound pressure, a single probe, a large area probe, and a catheter tip. It may be a probe, a body cavity probe / laparoscope, or the like. Further, the ultrasonic probe 11 may be either a two-dimensional array probe capable of scanning a three-dimensional space or a mechanical probe capable of mechanically rotating or swinging the one-dimensional array probe.

  The transmission / reception unit 12 includes a T / R switch 120, a transmission unit 121, and a reception unit 122.

  The T / R switch 120 switches the connection between the probe and the transmission unit 121 and the reception unit 122 during transmission and reception.

  The transmission unit 121 includes a delay circuit, a pulsar circuit, and the like (not shown). In the pulsar circuit, a rate pulse for forming a transmission ultrasonic wave is repeatedly generated at a predetermined rate frequency fr Hz (period: 1 / fr second). Further, in the delay circuit, a delay time necessary for focusing the ultrasonic wave into a beam shape for each channel and determining the transmission directivity is given to each rate pulse. The transmission unit 121 applies a drive pulse to each transducer so that an ultrasonic beam is formed toward a predetermined scan line at a timing based on the rate pulse.

  The receiving unit 122 includes an amplifier circuit, an A / D converter, an adder, and the like not shown. The amplifier circuit amplifies the echo signal captured via the probe 11 for each channel. In the A / D converter, a delay time necessary for determining the reception directivity is given to the amplified echo signal, and thereafter, an addition process is performed in the adder. By this addition, an ultrasonic echo signal corresponding to a predetermined scan line is generated.

  The echo signal processor 14 performs an envelope detection process on the ultrasonic echo signal received from the receiving unit 122 to generate a B-mode signal or the like corresponding to the amplitude intensity of the ultrasonic echo.

  The Doppler processor 15 performs orthogonal detection processing, autocorrelation processing, etc. on the echo signal received from the receiving unit 122, and moves within the subject based on the Doppler shift component of the ultrasonic echo signal subjected to delay addition processing. The tissue Doppler signal corresponding to the speed, dispersion, and power of the tissue in question is obtained.

  The application processor 16 develops a predetermined program on the memory under the control of the control unit 17, thereby performing functions such as an ultrasonic transmission / reception function for introducing a therapeutic substance, editing of transmission conditions / transmission protocols, which will be described later. Execute.

  The control unit 17 has a function as an information processing apparatus (computer), and controls the operation of the ultrasonic diagnostic apparatus main body statically or dynamically.

  The display control unit 18 generates a B-mode ultrasonic image representing a two-dimensional distribution related to a predetermined slice of the B-mode signal. Further, the display control unit 18 generates a tissue Doppler ultrasound image representing a two-dimensional distribution relating to a predetermined slice of velocity, dispersion, and power value based on the tissue Doppler signal. Further, the display control unit 18 displays an image for monitoring a treatment target region in a process using an ultrasonic transmission / reception function for introducing a therapeutic substance to be described later.

  The evaluation unit 19 performs an evaluation of the possibility of sonoporation induction, evaluation of the fullness of the therapeutic substance, evaluation of the disappearance degree of the bubble, and the like in an ultrasonic transmission / reception function for introducing a therapeutic substance, which will be described later. Here, the sonoporation causes a cavitation phenomenon by destroying microbubbles (contrast agent), and forms a transient perforation in the cell membrane of the subject, so that the inside of the subject's cells. Means a method of introducing a therapeutic substance.

  The storage unit 20 includes a dedicated program for executing ultrasonic transmission / reception for introducing a therapeutic substance, and ultrasonic image data corresponding to each time phase (for example, tissue image data taken in a tissue Doppler mode, a B mode, etc. ) Etc. Note that the ultrasonic image data stored in the storage unit 22 may be so-called raw image data before scan conversion.

  The transmission / reception I / F 21 transmits / receives various data such as image data and patient information data to / from other devices via a network.

  The operation unit 22 is connected to the apparatus main body, and includes a mouse, a trackball, a mode changeover switch, a keyboard for incorporating various instructions from the operator, a region of interest (ROI) setting instruction, various image quality condition setting instructions, and the like. Etc.

  The monitor 23 displays in vivo morphological information and blood flow information as an image based on the video signal from the display control unit 18. Further, when a contrast agent is used, it is displayed as a luminance image or a color image based on a quantitative distribution of the contrast agent, that is, a blood flow or an area where blood is present.

(Ultrasonic wave transmission / reception function for introducing therapeutic substances into the subject)
Next, the ultrasonic transmission / reception function for introducing the therapeutic substance into the subject of the ultrasonic diagnostic apparatus 1 will be described. This function is used to generate sonoporation in a subject using ultrasound and introduce a therapeutic substance into a cell, so that the introduction is more efficiently introduced according to specific conditions and protocols. Sound wave transmission, predetermined index evaluation, monitoring, etc. are executed. Hereinafter, the operation mode according to the ultrasonic transmission / reception function is referred to as a therapeutic substance introduction mode.

  FIG. 2 is a flowchart showing the flow of processing of the ultrasonic diagnostic apparatus in the therapeutic substance introduction mode. As shown in the figure, in this example, each process from step S1 to step S10 is executed. Hereinafter, the contents of each process (step) will be described. It should be noted that the present invention is not limited to the example shown in FIG. 2, and arbitrary modifications are possible depending on the circumstances at the time of introducing the therapeutic substance, for example, omitting a predetermined index evaluation.

[Steps S1 and S2: Visualization of treatment target region and designation of ROI]
First, a site to be treated (for example, a tumor site or a new blood vessel region) is visualized by a CHI mode, a B mode, a Doppler mode, or a composite mode composed of a combination thereof. At this time, a specific contrast agent corresponding to the site to be treated is used. The surgeon sets the treatment target region with the ROI as shown in FIG. 3 by the operation from the operation unit 22 while observing the imaged treatment target site.

[Step S3: Evaluation of the possibility of inducing sonoporation]
Next, the transmission / reception unit 12 transmits an ultrasonic wave for treatment (that is, for introduction of a therapeutic substance) to the treatment target region, and receives an echo signal from the region. The evaluation unit 19 evaluates the possibility of inducing sonoporation in the treatment target region based on the echo signal.

  FIG. 4 is a diagram for explaining an example of sonoporation induction possibility evaluation in the treatment target region. As shown in the figure, the possibility of sonoporation is based on the echo signal (brightness value) from the treatment target region obtained by administering a contrast agent for observing the treatment target region and transmitting ultrasonic waves for treatment. Based on this, it is possible to evaluate by plotting an index correlated with bubble collapse in time series and observing it.

[Step S4: Administration of a therapeutic substance such as a contrast agent or gene]
In step S3, when the evaluation unit 19 evaluates that the index correlated with the bubble collapse exceeds a predetermined threshold, for example, the treatment of the contrast agent and the gene automatically or manually based on the control of the control unit 17 Administration material is administered.

[Steps S5 and S6: Evaluation and determination of the fullness of the therapeutic substance]
Next, the evaluation unit 19 observes the treatment target area in real time in the monitoring mode as shown in FIG. 5 after administration of the dyed image after administration, and temporal changes in echo signals (luminance values) in the treatment target area Is obtained and plotted, and evaluated as the fullness of the therapeutic substance and bubble. Here, the monitoring mode is a mode in which ultrasonic transmission / reception is continuously executed and observed with a low MI value (Mechanical Index value) that does not break the contrast agent.

  Moreover, the evaluation unit 19 determines the timing when the filling of the therapeutic substance and the bubble is most expected based on the time change of the plotted echo signal.

[Step S7: Transmission / monitoring of therapeutic ultrasound]
When the timing at which the filling of the therapeutic substance and the bubble is most expected is determined, the application processor 16 transmits the therapeutic ultrasonic wave in the ROI set as shown in FIG. 6 at that timing. The ultrasonic transmission performed in the therapeutic substance introduction mode is for efficiently generating sonoporation, not for normal image formation. Therefore, it is possible to positively control the transmission condition / transmission protocol as follows, for example.

  First, in the therapeutic substance introduction mode, the shape and transmission timing of the ultrasonic beam are controlled in a specific form in order to efficiently generate sonoporation. For example, the number of repeated transmissions in the same direction, sound pressure / frequency / waveform / number of repeated transmissions for each beam, aperture for each beam, weighting, focal position, transmission delay pattern, waveform of each element, and the like are controlled. Further, in order to generate sonoporation in a wide range, scanning with a wide beam width in the slice direction / scan direction (that is, three-dimensionally) is performed as compared with the image diagnosis mode in which a beam having a thin slice thickness is formed. This can be realized, for example, by shifting the phase of each element and diffusing the beam. Furthermore, the amount of energy can be corrected between regions by changing the transmission time, frequency, and sound pressure according to the depth and attenuation characteristics of each subject.

  7 shows an example of ultrasonic transmission in which the transmission aperture (beam aperture) is converged at a specific part in the treatment target region, and FIG. 8 shows an example of ultrasonic transmission in which the focal position of the beam is shifted in the same direction in the treatment target region. FIG. 9 shows an example of ultrasonic transmission in which the phase of each element is shifted and the beam is diffused.

  Further, in this therapeutic substance introduction mode, it is possible to control the spatial distribution or temporal distribution of the ultrasonic energy density at least in the treatment target region.

  The spatial distribution of the energy density of the ultrasonic wave is, for example, a method of controlling at least one of the scanning line density and pulse repetition frequency (PRF) of the ultrasonic scanning, or shifting the position of the scanning line of the ultrasonic scanning for each frame Thus, control is performed so as to concentrate two-dimensionally or three-dimensionally or evenly or at a specific part. In particular, in the therapeutic substance introduction mode, unlike the normal diagnostic imaging mode, the PRF can be selected without considering the reception time zone. Therefore, it is possible to control the ultrasonic energy density with a higher degree of freedom than in the diagnostic imaging mode.

  In addition, the temporal distribution of the ultrasonic energy density is, for example, at least one of a pulse repetition frequency, a transmission ultrasonic frequency, a sound pressure, a sound field type, a focal point, a scanning line position, and a pulse transmission over time. It can be controlled two-dimensionally or three-dimensionally by a method such as a change (sweep). With such a method, ultrasonic transmission in which the temporal distribution of the ultrasonic energy density is different due to the difference in pulse repetition frequency as shown in FIGS. 10 and 11, and the ultrasonic energy density as shown in FIG. Uniform ultrasonic transmission, ultrasonic transmission that generates a frequency sweep as shown in FIG. 13 can be executed. In particular, the ultrasonic transmission shown in FIG. 12 can realize continuous sonoporation induction, and the ultrasonic transmission shown in FIG. 13 can realize sonoporation induction by gradual microbubble destruction. Image formation is not required in the therapeutic substance introduction mode. Therefore, it is possible to perform a desired time adjustment from a continuous wave to a pulse wave transmission with a desired wave length / PRF. For example, an arbitrary waveform that is not a constant frequency but effective for substance introduction, such as Chirp transmission. Can be selected depending on the target and the substance to be introduced.

  In the therapeutic substance introduction mode, an image for monitoring the transmission status of the treatment target region is acquired at a desired period using a manual operation setting, an ECG trigger interlock, an internal clock, and the like. The ultrasonic transmission condition / transmission protocol for acquiring the image can be set independently of the ultrasonic transmission condition / transmission protocol for introducing the therapeutic substance. The transmission unit 121 performs ultrasonic transmission according to each set condition and the like, and the reception unit 122 discriminates whether the received echo signal is an echo signal for acquiring a monitoring image based on the frequency of the received echo signal. The discriminated echo signal is subjected to predetermined processing in the echo signal processor 14 or the like, and is displayed on the monitor 23 in real time as a monitoring image.

[Step S8: Evaluation of bubble disappearance]
Next, by observing parameters associated with gene introduction into the treatment target region, the bubble extinction degree (treatment substance introduction degree) in the treatment target region is evaluated. For example, it is possible to evaluate the degree of bubble extinction of the contrast medium in the ROI by observing the change in luminance of the treatment target region in the monitoring mode. In addition, when cells die upon introduction of a therapeutic substance, they are evaluated as CHI (Contrast Harmonic Imaging) defect images.

  In addition, it is also possible to evaluate using other modalities, such as a magnetic resonance imaging apparatus, as needed.

[Step S9: Display of Evaluation Results]
The control unit 17 displays the evaluation result of the bubble extinction degree calculated in step S8 on the monitor 23 in a predetermined form. The surgeon can grasp the degree of introduction of the therapeutic substance into the treatment target region by observing the bubble extinction degree.

(Functions such as editing transmission conditions and transmission protocols)
Next, functions such as editing transmission conditions / transmission protocols of the ultrasonic diagnostic apparatus will be described. This function makes it possible to edit, register, read out transmission conditions and transmission protocols.

  The ultrasonic transmission conditions and ultrasonic transmission protocols set and used in the therapeutic substance introduction mode can be registered for each introduced therapeutic substance (gene, protein, in-vivo substance, drug, etc.) or for each purpose of introduction. is there. The registered ultrasonic transmission conditions are stored in the storage unit 20 and used as a database. Further, ultrasonic transmission conditions and ultrasonic transmission protocols acquired from a recording medium such as a DVD, CD-R, MO, and FD or via communication such as the Internet may be further registered and used as a database.

  According to the configuration described above, the following effects can be obtained.

  According to this ultrasonic diagnostic apparatus, a therapeutic substance is introduced into a subject by sonoporation using ultrasonic waves. Therefore, for example, a therapeutic substance can be introduced more safely than when a viral vector is used. In addition, in the introduction of a therapeutic substance using this ultrasonic diagnostic apparatus, gene introduction can be performed limited to the target organ / region, and repeated trials can be performed without antibody reaction. Further, as the introduced substance, not only genes but also physiologically active substances such as proteins and drugs can be adopted. Therefore, unlike virus vectors, substance introduction can be carried out more practically and easily, which can contribute to the spread of substance introduction treatment.

  In addition, according to this ultrasonic diagnostic apparatus, when a therapeutic substance is introduced into a subject using ultrasonic waves, ultrasonic transmission according to specific conditions / protocols is performed so that the introduction is more efficiently introduced. Execute predetermined index evaluation, monitoring, etc. Therefore, the surgeon can realize the substance introduction treatment under suitable conditions without separately performing special settings. As a result, the burden on the operator during treatment can be reduced.

  Note that the present invention is not limited to the above-described embodiment as it is, and can be embodied by modifying the constituent elements without departing from the scope of the invention in the implementation stage.

  (1) For example, when using the present ultrasonic diagnostic apparatus that realizes the sonoporation, it may be combined with a physical method such as electroporation or a biochemical method such as a liposome or a vector.

  (2) The sonoporation used in the above embodiment was generated mainly by cavitation by ultrasonic transmission under microbubble administration. However, the present invention is not limited to this, and cavitation may be generated by administering a cavitation-inducing substance other than the ultrasonic wave alone or other than microbubbles by the same method as in this embodiment.

  In addition, various inventions can be formed by appropriately combining a plurality of components disclosed in the embodiment. For example, some components may be deleted from all the components shown in the embodiment. Furthermore, constituent elements over different embodiments may be appropriately combined.

  As described above, according to the present invention, the problems associated with viral vectors are solved, and a gene transfer technique applicable clinically is provided. Furthermore, it is possible to realize an ultrasonic diagnostic apparatus and an ultrasonic therapeutic substance introduction apparatus that can introduce not only genes but also proteins and drugs as intracellular introduction substances.

FIG. 1 is a configuration diagram of an ultrasonic diagnostic apparatus 10 according to an embodiment of the present invention. FIG. 2 is a flowchart showing a flow of processing when a therapeutic substance is introduced into a subject using the transmission / reception function of the ultrasonic diagnostic apparatus. FIG. 3 is a diagram illustrating an example of a treatment target region (ROI) set in the visualized treatment target region. FIG. 4 is a diagram for explaining an example of sonoporation induction possibility evaluation in the treatment target region. FIG. 5 is a diagram for explaining the concept of the fullness evaluation of the introduced therapeutic substance in the treatment target region. FIG. 6 is a diagram for explaining an example of ultrasonic transmission for efficiently generating sonoporation. FIG. 7 shows an example of ultrasonic transmission for converging the transmission aperture (beam aperture) at a specific site in the treatment target region. FIG. 8 shows an example of ultrasonic transmission in which the focal position of the beam is shifted in the same direction within the treatment target region. FIG. 9 shows an example of ultrasonic transmission in which the phase of each element is shifted and the beam is diffused. FIG. 10 is a diagram for explaining an example of ultrasonic transmission for efficiently generating sonoporation by controlling the pulse repetition frequency. FIG. 11 is a diagram for explaining another example of ultrasonic transmission for efficiently generating sonoporation by controlling the pulse repetition frequency. FIG. 13 is a diagram for explaining an example of ultrasonic transmission for efficiently generating sonoporation by making the ultrasonic energy density uniform over time. FIG. 14 is a diagram for explaining an example of ultrasonic transmission in which the ultrasonic energy density is temporally changed by sweeping the frequency. FIG. 14 is a diagram for explaining a comparison of gene introduction methods into a living body using a Urus vector.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 ... Ultrasound diagnostic apparatus, 11 ... Ultrasonic probe, 12 ... Transmission unit, 13 ... Reception unit, 14 ... B mode processing unit, 15 ... Tissue Doppler processing unit, 17 ... Display control unit, 18 ... Display unit, 20 ... TSI processing unit, 21 ... volume data generation unit, 22 ... storage unit, 23 ... control unit (CPU), 24 ... mapping processing unit, 25 ... input unit 25

Claims (39)

In response to an applied drive signal, for generating a first ultrasonic transmission or sonoporation for acquiring an ultrasonic image for each of a plurality of ultrasonic scanning directions in a treatment target region of a subject . performing a second ultrasonic transmission, a plurality of receiving a first echo signal or the second second echo signals based on ultrasonic transmission based on the first ultrasound transmission from each of the ultrasonic scanning direction An ultrasonic probe equipped with an ultrasonic transducer of
Drive means for supplying the drive signal to each ultrasonic transducer;
Image generating means for generating an ultrasonic image based on the received first echo signal;
Display means for displaying the generated ultrasound image;
Evaluation means for evaluating the possibility of inducing sonoporation in the treatment target region based on the second echo signal;
Control means for controlling the driving means so as to execute the second ultrasonic transmission for generating sonoporation in the treatment target region in the subject in response to the evaluation result of the inducibility When,
An ultrasonic diagnostic apparatus or a substance introduction apparatus for ultrasonic therapy, comprising:   The control means controls the driving means so as to adjust a spatial energy density or a temporal energy density of a transmission ultrasonic wave in the treatment target region in order to generate the sonoporation. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to claim 1.   The control means controls the driving means so that the spatial energy density of the transmission ultrasonic wave is equal in the treatment target area or concentrated on at least a part of the treatment target area. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to claim 2.   4. The ultrasonic diagnostic apparatus or the ultrasonic therapeutic substance introduction according to claim 2, wherein the control means controls the driving means so as to shift a scanning line position in the ultrasonic transmission in units of frames. apparatus.   4. The ultrasonic diagnostic apparatus or the ultrasonic device according to claim 2, wherein the control unit controls the driving unit so that at least one of a scanning line density and a pulse repetition frequency in the ultrasonic transmission changes. 5. Sonic treatment substance introduction device.   The said control means controls the said drive means so that the energy density of a transmission ultrasonic wave may become equal temporally in the said treatment object area | region, or it concentrates on a specific time slot | zone. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus described.   The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to claim 6, wherein the control means controls the driving means so that a frequency of the transmission ultrasonic wave changes with time.   The ultrasonic wave according to claim 1, wherein the control unit controls the driving unit so as to form a transmission ultrasonic wave having a wide beam width in a slice direction / scan direction. Diagnostic device or substance introduction device for ultrasonic therapy.   The control means adjusts at least one of an ultrasonic transmission time, a transmission ultrasonic frequency, and a transmission ultrasonic sound pressure based on at least one of the depth of the treatment target region and the attenuation characteristic for each subject. 9. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to claim 1, wherein the driving means is controlled. The evaluation means evaluates the possibility of inducing sonoporation in the subject using an index that correlates with a contrast agent collapse calculated based on an echo signal from the treatment target region. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to any one of claims 1 to 9. Said evaluating means, on the basis of the temporal change in the intensity of the echo signal from the treated area, the 1 to claim, characterized in that to evaluate the achievement or fullness introducing therapeutic substance in inside of the subject The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to any one of 10. 12. The evaluation means according to claim 1, wherein the evaluation means evaluates the degree of introduction of the therapeutic substance to be introduced into the subject based on a change over time in the intensity of the echo signal from the treatment target region. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus as described in any one of them.   The ultrasonic diagnostic apparatus or the ultrasonic therapeutic substance introduction according to any one of claims 1 to 12, wherein the therapeutic substance is at least one of a gene, a protein, an in-vivo substance, and a drug. apparatus. The ultrasonic probe is
The super probe according to any one of claims 1 to 13, which is one of a special probe for high sound pressure, a single probe, a large-area probe, a probe with a catheter, and an intracavity probe with a laparoscope. Ultrasound diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus. A management means for editing and registering at least one of a transmission condition and a transmission protocol in ultrasonic transmission for generating sonoporation in the subject;
The control means executes control for ultrasonic transmission for generating sonoporation in the subject according to the transmission condition registered by the management means;
15. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to any one of claims 1 to 14.   16. The ultrasonic diagnostic apparatus or the ultrasonic therapeutic substance introduction apparatus according to claim 15, wherein the management means registers at least one of a transmission condition and a transmission protocol for each introduction therapeutic substance or each introduction purpose.   13. The therapeutic substance according to claim 1, wherein the therapeutic substance is a gene, protein, in-vivo substance, or a mixed substance of a drug and a microbubble capable of perfusing the inside of the living body. Ultrasound diagnostic apparatus or substance introduction apparatus for ultrasonic therapy.   The ultrasonic probe is either a two-dimensional array probe capable of scanning a three-dimensional space or a mechanical probe capable of mechanically rotating or swinging the one-dimensional array probe. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to any one of the above.   19. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to claim 18, further comprising a control unit capable of three-dimensionally scanning a subject and setting a treatment target region in a three-dimensional space.   20. The ultrasonic diagnostic apparatus or ultrasonic therapeutic apparatus according to claim 19, further comprising a three-dimensional display means for observation capable of observing a signal from a microbubble in a treatment target region in a three-dimensional space during treatment. Substance introduction device. The subject is, the ultrasonic diagnostic apparatus or ultrasonic therapeutic agent introducing device of any one of claims 1 to 13, characterized in that the organ for transplantation or vascular retrieved from the body. The evaluation means evaluates the possibility of inducing the sonoporation based on an index correlated with the collapse of a bubble of a contrast medium for observing the treatment target region. The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus as described in any one of them . The evaluation means evaluates the possibility of inducing the sonoporation when an index correlated with the collapse of the contrast agent bubble for imaging the treatment target region exceeds a predetermined threshold,
In response to the evaluation result of the inducibility, the control means administers a contrast agent bubble and a therapeutic substance for generating sonoporation in a treatment target region in the subject, and then Controlling the drive means to perform ultrasonic transmission;
The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to claim 22 .   The control means includes: a first transmission frequency in ultrasonic transmission that does not destroy the contrast agent used for the sonoporation; and a second transmission frequency in ultrasonic transmission for generating the sonoporation. Control the drive means differently,
  The image generating means generates the ultrasonic image as a monitoring image based on an echo signal discriminated based on the first transmission frequency among the received echo signals;
  The ultrasonic diagnostic apparatus or ultrasonic therapeutic substance introduction apparatus according to any one of claims 1 to 23. On the computer,
In response to an applied drive signal, for generating a first ultrasonic transmission or sonoporation for acquiring an ultrasonic image for each of a plurality of ultrasonic scanning directions in a treatment target region of a subject . performing a second ultrasonic transmission, a plurality of receiving a first echo signal or the second second echo signals based on ultrasonic transmission based on the first ultrasound transmission from each of the ultrasonic scanning direction A signal supply function for supplying the drive signal to the ultrasonic transducer of
Drive means for supplying the drive signal to each ultrasonic transducer;
Image generating means for generating an ultrasonic image based on the received first echo signal;
Display means for displaying the generated ultrasound image;
Based on an index correlated with the collapse of bubbles constituting the contrast agent, an evaluation function for evaluating the possibility of sonoporation,
Control means for controlling the driving means so as to execute the second ultrasonic transmission for generating sonoporation in the treatment target region in the subject in response to the evaluation result of the inducibility When,
An ultrasonic diagnostic apparatus or a substance introduction apparatus for ultrasonic therapy, comprising:   The control function controls supply of the driving signal so as to adjust a spatial energy density or a temporal energy density of a transmission ultrasonic wave in the treatment target region in order to generate the sonoporation. The ultrasonic scanning control program according to claim 25.   The control function controls the supply of the drive signal so that the spatial energy density of the transmission ultrasonic wave is uniform in the treatment target region or concentrated on at least a part of the treatment target region. The ultrasonic scanning control program according to claim 26.   28. The ultrasonic scanning control program according to claim 26, wherein the control function controls the supply of the drive signal so as to shift a scanning line position in the ultrasonic transmission in units of frames.   28. The ultrasonic scanning control according to claim 26 or 27, wherein the control function controls the supply of the drive signal so that at least one of a scanning line density and a pulse repetition frequency in the ultrasonic transmission changes. program.   The said control function controls supply of the said drive signal so that the energy density of a transmission ultrasonic wave may become equal temporally in the said treatment object area | region, or it concentrates on a specific time slot | zone. Item 26. The ultrasonic scanning control program according to Item 26.   31. The ultrasonic scanning control program according to claim 30, wherein the control function controls the supply of the drive signal so that the frequency of the transmission ultrasonic wave changes with time.   32. The control function according to claim 25, wherein the control function controls the supply of the drive signal so as to form a transmission ultrasonic wave having a wide beam width in the slice direction / scan direction. Ultrasonic scanning control program.   The control function adjusts at least one of an ultrasonic transmission time, a transmission ultrasonic frequency, and a transmission ultrasonic sound pressure based on at least one of the depth of the treatment target region and the attenuation characteristic for each subject. The ultrasonic scanning control program according to any one of claims 25 to 32, wherein the supply of the drive signal is controlled. On the computer,
Characterized in that it further realizes an evaluation function for evaluating the possibility of inducing sonoporation in the subject by using an index correlated with the contrast agent collapse calculated based on an echo signal from the treatment target region, The ultrasonic scanning control program according to any one of claims 25 to 33. On the computer,
The evaluation function for evaluating the degree of reach or fullness of the introduced therapeutic substance in the subject is further realized based on a temporal change in the intensity of the echo signal from the treatment target region. 35. The ultrasonic scanning control program according to any one of items 34 to 34. On the computer,
36. An evaluation function for evaluating the degree of introduction of a substance for introduction treatment into the subject based on a change over time in the intensity of an echo signal from the treatment target region is further realized. The ultrasonic scanning control program as described in any one of these.   The said therapeutic substance further implement | achieves the evaluation function characterized by the substance being at least any one of a gene, protein, a biological substance, and a chemical | medical agent. The ultrasonic scanning control program according to item. On the computer,
Further realizing a management function for editing and registering at least one of a transmission condition and a transmission protocol in ultrasonic transmission for generating sonoporation in the subject,
The control function executes control for ultrasonic transmission for generating sonoporation in the subject according to the transmission condition registered by the management means;
An ultrasonic scanning control program according to any one of claims 25 to 37.   39. The ultrasonic scanning control program according to claim 38, wherein the management function registers at least one of a transmission condition and a transmission protocol for each introduced therapeutic substance or for each introduction purpose.

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