JP6470624B2 - Probe for ultrasound-assisted fluorescence imaging - Google Patents

Description

  The present invention modulates fluorescence emitted from a subject to which a fluorescent contrast agent has been administered by local heating using ultrasound, and uses ultrasound-assisted fluorescence to accurately identify a fluorescent site (lesion site). The present invention relates to an imaging probe.

  In the diagnosis and treatment of a lesion site such as a cancer cell, it is important to accurately diagnose the position and range of the lesion site as well as the presence or absence of the lesion site. As one effective diagnostic method for detecting a lesion site, a method using a fluorescent contrast agent such as indocyanine green (hereinafter abbreviated as “ICG”) has been put into practical use. According to this method, if a fluorescent contrast agent that easily accumulates selectively at the lesion site is administered to the examination area, and the portion that emits fluorescence is detected by irradiating excitation light (laser light), the lesion site is detected. can do. For example, in a liver cancer removal operation, ICG is administered by intravenous injection, and laser light is irradiated to check whether cancer cells remain after the operation.

On the other hand, in Patent Document 1 described later, in a fluorescent contrast agent test, various fluorescent contrast agents such as ICG are administered to a mouse that has developed breast cancer, and the skin surface is uniformly irradiated with laser light from outside the body. In addition, it is disclosed that a fluorescent image of a whole body of a mouse is imaged while detecting fluorescence emission from a body surface with a CCD camera.
However, in this detection method, it is necessary to uniformly irradiate the body surface with excitation light. In addition, the fluorescence emitted outside the body surface of the mouse is a blurry fluorescence emitted by the complex synthesis of the multiple scattered fluorescence emitted by the body tissue, and direct light from the part where the fluorescence is actually emitted. is not. Therefore, although the presence or absence of fluorescence can be determined from the scattered fluorescence, it is difficult to detect the fluorescence position (lesion position) with high sensitivity and accuracy. In particular, the influence of scattering is relatively small for cancer cells that are shallow from the body surface, so the position of fluorescence emission can be roughly grasped, but the more the fluorescence emission position is deeper from the body surface, the more the multiple scattering occurs. Since it is strongly influenced, it is very difficult to specify the position where the fluorescence is emitted.

On the other hand, the inventors of the present application proposed the principle of a new “ultrasonic assisted fluorescence imaging method” using the fact that the fluorescence intensity of ICG is attenuated by heating in Non-Patent Document 1 described later. A simple prototyping device that employs is disclosed. The principle of this ultrasonic assisted fluorescence imaging method and the prototype device will be described with reference to the schematic diagram of FIG.
As shown in FIG. 7, an ultrasonic transducer 101 for local heating is disposed immediately above the examination region S of the subject. Although not shown, the ultrasonic transducer 101 is provided with an ultrasonic lens at the exit window so that the ultrasonic wave is converged at one point, and the depth of the convergence position (focal point) can be adjusted. A directional fine mover (Z-direction moving arm) is attached.

  Further, an excitation laser light source 102 is disposed obliquely above the inspection region S, and a light pipe 103 for receiving fluorescence is disposed obliquely upward on the opposite side across the ultrasonic transducer 101. Radiation light M (including fluorescence N) received from the body received by the light pipe 103 is detected as a fluorescence intensity signal by the photomal detector 105 via the spectroscope 104. Further, a moving stage 106 for moving the examination region (subject) S in the XY directions is provided.

  Then, before the start of the fluorescence diagnosis, ICG is administered as a fluorescent contrast agent to the examination region S of the subject including the lesion site (ICG accumulation site) in advance by injection or infusion.

When the excitation light L is irradiated from the laser light source 102 in this state, the scattered light including the fluorescence N of ICG generated in the inspection region S is emitted as the radiated light M, and a part is received by the light pipe 103. Guided to the spectroscope 104, the fluorescence N having a predetermined wavelength caused by the ICG is extracted and detected by the photomultiplier detector 105. The fluorescence intensity detected at this time is the intensity of the fluorescence N that reaches the light pipe 103 after being emitted from the body after being scattered multiple times in the body tissue, and this value is stored as the “reference value T”.
Next, heating is performed by irradiating ultrasonic waves U from the ultrasonic transducer 101 toward the inside of the body, and the ultrasonic energy irradiated at this time is focused at one point (Pinpoint heating ( Local heating) is performed. Note that if local heating is performed and fluorescence detection is performed by the photomultiplier detector 105 while moving the heating position, the temperature at the locally heated position naturally increases. When ICG is present at this heating position, the amount of fluorescent light is greatly attenuated, and the detection intensity at the photomultiplier detector 105 changes to a value attenuated from the “reference value T”. On the other hand, in the position where ICG does not exist, it hardly changes because it originally does not emit fluorescence. Therefore, by monitoring the change (attenuation) of the fluorescence detection intensity of the photomultiplier detector 105 together with the heating position, whether or not ICG is accumulated at the heating position (whether or not ICG is present) can be accurately determined each time. Can be detected.

  Therefore, the presence or absence of ICG at the moved depth position can be accurately detected by moving the heating position in the depth direction (Z direction) and monitoring the fluorescence detection intensity.

  Similarly, by moving the moving stage 106 two-dimensionally in the XY direction and monitoring the detection intensity of fluorescence in the depth direction at each point, the position and range where the ICG exists can be accurately and three-dimensionally. Can be identified.

Japanese Patent Laid-Open No. 2005-220045 2014 “61st JSAP Spring Meeting, Proceedings”, pages 03-136

As described above, the principle of “ultrasonic assisted fluorescence imaging method” described in Non-Patent Document 1 was confirmed to be able to detect the position of a non-invasive ICG accumulation site, that is, a lesion site such as a cancer cell. .
However, in practical use, it is necessary to improve the fluorescence detection sensitivity as much as possible. That is, in the ultrasound assisted fluorescence imaging method, fluorescence emitted outside the body after being scattered multiple times in the body tissue is received and a change in the fluorescence intensity is detected. However, not only is the amount of fluorescent light itself emitted from the ICG itself weak, but also the range of light emitted gradually from the fluorescent light source as it approaches the body surface increases due to multiple scattering, so the light shown in FIG. The amount of light that can be collected by the light receiving surface of the pipe 103 is considerably attenuated compared with the amount of light of the light source ICG. This attenuation becomes more prominent as the position of the ICG becomes deeper from the body surface. Therefore, when detecting cancer cells of liver cancer at a deep biological depth, it is desirable to collect radiation (including fluorescence) from as wide a body surface as possible in order to improve detection sensitivity. .

Also, it is desirable to reduce the influence of scattering by the body tissue as much as possible for the excitation light to reach the ICG accumulation site, so vertical irradiation with a short distance passing through the body is performed rather than obliquely irradiating the body surface. desired. Similarly, it is desirable to receive the emitted fluorescence from a direction perpendicular to the body surface.
Furthermore, with respect to ultrasonic irradiation from the ultrasonic transducer for heating, since it is desired to perform vertical irradiation from directly above the body surface, the above prototype device could not satisfy all these requirements.

  As another problem, it is necessary to improve the operability of measurement by the “ultrasonic assisted fluorescence imaging method”. For example, in the prototype device described above, the moving stage 106 is operated to move the subject in the XY directions. However, for practical use, the subject can be moved in the XY directions without moving the subject. In this case, it is necessary to move in the X and Y directions while keeping the positional relationship between the excitation light source side (laser light source 102) and the fluorescence light receiving side (light pipe 103) constant. For that purpose, it is desirable to construct an integrated probe including the ultrasonic transducer 101.

  Therefore, the present invention devised the arrangement of the ultrasonic transducer, the excitation light source, and the fluorescence light receiving unit to improve the sensitivity of fluorescence detection and to enable accurate detection of the fluorescence position in the deeper part of the living body than before. An object is to provide a probe for assisted fluorescence imaging. Another object of the present invention is to provide an integrated probe for ultrasound-assisted fluorescence imaging.

  The probe for an ultrasound-assisted fluorescence imaging apparatus of the present invention made to solve the above problems includes an excitation light source unit that irradiates excitation light, a light receiving unit that receives radiated light from a subject including fluorescence, and heating. An ultrasonic irradiation unit for irradiating ultrasonic waves for use, an excitation light source unit, the light receiving unit, and the ultrasonic irradiation unit are integrally held, and an external window through which the excitation light, the emitted light, and the ultrasonic wave pass A first coupling that adjusts the optical path so that the optical path of the excitation light and the optical path of the radiated light are coaxially overlapped and passed on the external window side in the probe head. The optical path and the waveguide so that the optical path of the excitation light and the radiated light and the waveguide of the ultrasonic wave are coaxially overlapped and propagated between the first coupling part and the external window And a second coupling part is provided It is to so that.

According to the present invention, the excitation light, the radiation light from the subject, and the ultrasonic wave for heating can be coaxially incident / exited from the external window by providing the first coupling portion and the second coupling portion. Therefore, it is possible to realize an ultrasonic assisted fluorescence imaging probe as an integrated probe head. In addition, excitation light, radiated light, and ultrasonic waves can enter and exit from the vertical direction with respect to the body surface.
Thereby, compared with the conventional incident / exit from the diagonal direction, the influence of scattering of excitation light and radiation | emission light can be reduced, and detection sensitivity can be raised. Further, the integration of the probe can be realized, and the measurement position can be easily moved in the XY directions without moving the subject, so that the operability can be improved.

In the above invention, the first coupling portion is disposed obliquely with respect to the optical path of the excitation light, is formed with a small hole through which the excitation light can pass, and a mirror with a hole that reflects the emitted light. You may do it.
As a result, if the excitation light is allowed to pass through a small hole of the mirror with a hole, it can pass without being absorbed by the mirror with the hole, and the reflected light is reflected by the entire mirror surface other than the small hole and received. Can be led to the department.

In the above invention, a straight tube may be formed in which excitation light is confined and passed through a small hole of the mirror with a hole.
Accordingly, since the excitation light passes through the straight pipe, noise light generated when strong excitation light is scattered by dust or the like present around the perforated mirror can be drastically reduced.

In the above invention, a condensing lens for condensing the emitted light on the light receiving surface of the light receiving unit may be provided between the mirror with a hole and the light receiving unit.
As a result, the area of the mirror with a hole can be increased with respect to the area of the light receiving surface of the light receiving unit, and radiation light from a wide area can be collected, and detection sensitivity can be improved.

In the above invention, the second coupling portion has a container that forms a liquid space filled with a propagation liquid through which the excitation light, the radiated light, and the ultrasonic wave can propagate, and the refractive index of the propagation liquid approximates, And the light which is immersed in the propagation liquid, is disposed obliquely with respect to the optical path through which the excitation light and the radiation light pass coaxially, and transmits the excitation light and the radiation light and reflects the ultrasonic wave You may make it consist of a sound wave coupling member.
By bringing the refractive index of the propagating liquid and the photoacoustic coupling member close to each other, excitation light and radiated light travel straight through the photoacoustic coupling member immersed in the propagating liquid, and ultrasonic waves propagate through the propagating liquid and couple the photoacoustic wave. Reflected by the member. Therefore, by coupling excitation light and radiation light that travels straight in the propagation liquid and ultrasonic waves with the photoacoustic coupling member disposed obliquely, these can be coaxially overlapped to enter and exit.

In the above invention, the photoacoustic coupling member may be a glass plate, and the propagation liquid may be water.
Since the refractive index of the glass plate is close enough to the refractive index of water, the excitation light and the radiated light go straight without being refracted. Moreover, since acoustic impedance differs greatly between glass and water, it reflects ultrasonic waves. Therefore, these combinations can be used as the photoacoustic coupling member and the propagation liquid.

In the above invention, the ultrasonic irradiation unit converges the ultrasonic wave in the depth direction to form a focal point, and has an electronic focusing function for adjusting the depth of the focal point. You may make it consist of a transducer.
The electronic focus function here is used for converging the ultrasonic wave for heating. By using the well-known electronic focus function that is generally adopted in the multi-channel probe of the medical ultrasonic diagnostic apparatus as it is, The heating scan in the depth direction (Z direction) of the convergence point (focal point) can be performed.

In the above invention, a focus mechanism is formed on the ultrasonic wave guide in the probe head by using an ultrasonic lens that converges ultrasonic waves in the depth direction to form a focal point and adjusts the depth of the focal point. You may do it.
Thereby, the convergence point (focal point) in the depth direction can be scanned by the focus mechanism.
Further, in the above invention, an ultrasonic lens for focusing the ultrasonic wave in the depth direction to form a focal point is provided on the ultrasonic wave guide in the probe head, and the probe head is placed on the body surface of the subject. You may make it provide the raising / lowering mechanism to raise / lower with respect to it.

The schematic block diagram which shows one Embodiment of the probe for ultrasonic assist fluorescence imaging of this invention. The figure which shows the irradiation state of excitation light. The figure which shows the detection state of the emitted light containing fluorescence. The figure which shows the modulation | alteration state of the fluorescence by ultrasonic irradiation. The figure which shows an example of the fluorescence intensity distribution of XY direction obtained using the probe of this invention. The figure which shows an example of the fluorescence intensity distribution of the Z direction obtained using the probe of this invention. The schematic diagram which shows the structure of the prototype of an ultrasonic assisted fluorescence imaging method.

Hereinafter, embodiments of the present invention will be described with reference to the drawings.
FIG. 1 is a schematic configuration diagram showing an embodiment of a probe used for ultrasound-assisted fluorescence imaging of the present invention. 2 is a diagram showing an irradiation state of excitation light L for emitting fluorescence, and FIG. 3 is a diagram showing a detection state of radiated light M (including fluorescence N). FIG. 4 is a diagram showing a modulation state of fluorescence by irradiation with the ultrasonic wave U.

  As shown in FIG. 1, the probe 10 for ultrasound-assisted fluorescence imaging has a structure in which an excitation light source unit 11, a light receiving unit 12, and an ultrasonic irradiation unit 13 are fixed to a probe head 14 and integrally held. Yes. The probe head 14 is sized so that the operator can move it by hand. The excitation light source unit 11, the light receiving unit 12, and the ultrasonic wave irradiation unit 13 are controlled by a main body control unit 15 that performs signal processing, control, and calculation.

  The excitation light source unit 11 uses an excitation light source having a wavelength that allows the fluorescent contrast agent administered in the body to emit fluorescence. Specifically, since ICG is used as the fluorescent contrast agent in this embodiment, the semiconductor laser 21 having a wavelength of 783 nm is used. The excitation light L (see FIG. 2) is converted into parallel light by the optical collimator 22 and the optical path diameter is reduced, and passes through a pipe (straight pipe) 37 that penetrates a small hole 36 of a mirror 35 with a hole to be described later. I can do it.

  The light receiving unit 12 is provided with a light pipe 26 serving as a light receiving end face through a band notch filter 25. The band notch filter 25 transmits the fluorescence N (see FIG. 3) near 820 nm of ICG and cuts light caused by the excitation light L. The wavelength component of 750 nm to 800 nm including the excitation light wavelength of 783 nm is used. Is cut. The light component including the fluorescence N condensed on the light receiving end face of the light pipe 26 is sent to the spectroscope 27, the fluorescence N component is dispersed, and the photomultiplier detector 28 detects the fluorescence intensity. The spectroscope 27 and the photomultiplier detector 28 are controlled by the main body control unit 15.

  An ultrasonic transducer 30 for heating is attached to the ultrasonic irradiation unit 13. Since the ultrasonic wave U (see FIG. 4) emitted from the ultrasonic transducer 30 needs to be converged in the body, it is propagated through the focus mechanism by the ultrasonic lens 44. If a model that can perform electronic focus control with a multi-channel or annual transducer that is widely used in medical ultrasonic diagnostic apparatuses is used, the focus mechanism by the ultrasonic lens 44 can be omitted.

The probe head 14 includes a housing having an upper surface, a side surface, and a bottom surface. The excitation light source unit 11 is attached to the upper surface, the light receiving unit 12 is attached to the upper side of the side surface, and the ultrasonic irradiation unit 13 is attached to the lower side of the side surface. 31 is provided.
As shown in FIG. 2, the semiconductor laser 21 of the excitation light source unit 11 is attached so that the excitation light L travels straight down in the probe head 14 and is emitted vertically from the external window 31. In the probe head 14, a first coupling portion 32 and a second coupling portion 33 are disposed on the optical path of the excitation light L. The light receiving unit 12 is disposed on the side of the upper first coupling unit 32, and the ultrasonic irradiation unit 13 is disposed on the side of the lower second coupling unit 33.

  A mirror 35 with a hole is disposed in the first coupling portion 32 so as to be inclined at 45 degrees with respect to the excitation light L. A small hole 36 is formed at the center of the mirror 35 with a hole, and the excitation light L passes through the small hole 36. In this embodiment, a pipe 37 is attached to the small hole 36 so that the excitation light L passes through the pipe 37. This is to prevent scattered light generated when the strong excitation light L is scattered by dust existing on the optical path near the apertured mirror 35 from being directed to the light receiving unit 12 as noise light. The pipe 37 penetrates a window 42 to be described later and is immersed in a propagation liquid (water) 39 in the container 40. If the inside of the probe head 14 is a clean space from which dust is completely removed, the pipe 37 need not be attached.

  The mirror 35 with a hole is attached so that the area of the mirror surface in the probe head 14 is as large as possible. Further, between the mirror 35 with a hole and the light pipe 26, as shown in FIG. 3, the light M reflected from the entire mirror surface of the mirror 35 with a hole (including fluorescence N) is received by the light receiving end face of the light pipe 26. A condensing lens 38 is attached to guide the light. Thus, the combination of the large-area holed mirror 35 and the condenser lens 38 increases the amount of the radiated light M guided to the light pipe 26 to increase the detection sensitivity.

The second coupling part 33 is filled with a propagation liquid 39 through which the excitation light L and the radiation light M propagate coaxially (transmit) and the ultrasonic wave U (see FIG. 4) from the ultrasonic irradiation part 13 can propagate. The container 40 is disposed. And in the propagation liquid 39, the photoacoustic coupling member 41 arrange | positioned so that it may incline at 45 degree | times diagonally with respect to the excitation light L and the emitted light M is immersed.
The propagation liquid 39 and the photoacoustic coupling member 41 are selected so that the refractive index approximates, so that the excitation light L and the radiated light M are hardly refracted by the photoacoustic coupling member 41 and can be transmitted straight. It is. In addition, the photoacoustic coupling member 41 is made of a material that has a significantly different acoustic impedance from the propagation liquid 39 so that the irradiation direction can be bent by reflecting the ultrasonic wave U at the boundary surface with the propagation liquid 39. It is.

As a specific combination that can satisfy these conditions, water having a refractive index of 1.33 and an acoustic impedance of 1.5 × 10 ⁶ Kg / m ² S is used as the propagating liquid 39, and the refractive index is 1. 52, a glass plate having an acoustic impedance of 13.2 × 10 ⁶ Kg / m ² S was used as the photoacoustic coupling member 41. As the propagation liquid 39 other than water, a “refractive index matching liquid” which is a liquid prepared so that the refractive index thereof is equal to the refractive index of glass may be used.

  Of the wall surface of the container 40, the lower surface of the container 40 from which the excitation light L and the emitted light M enter and exit and the ultrasonic wave U exits constitutes the external window 31. The external window 31 is formed of a transparent silicone rubber that can transmit and propagate the excitation light L, the radiation light M, and the ultrasonic wave U. Similarly, the window 42 on the upper surface of the container 40 and the window 43 on the connection surface with the ultrasonic irradiation unit 13 of the container 40 are also formed of transparent silicone rubber, and the excitation light L, the radiation light M, and the ultrasonic wave U are transmitted and transmitted. Propagation is possible.

By providing a focusing mechanism using an ultrasonic lens 44 made of transparent silicone rubber between the container 40 and the ultrasonic transducer 30, the ultrasonic wave U irradiated from the ultrasonic transducer 30 has a desired depth in the body. Converge at. Specifically, the focusing mechanism extends the container 40 toward the ultrasonic lens 44 and is immersed in the propagating liquid 39 so that the ultrasonic lens 44 moves through the propagating liquid 39 according to a control signal from the main body control unit 15. The focus is adjusted by moving.
When the ultrasonic transducer 30 has an electronic focus function, the focus mechanism by the ultrasonic lens 44 can be omitted.

Next, the measurement operation by the probe 10 for an ultrasound assisted fluorescence imaging apparatus will be described.
First, irradiation with excitation light will be described. As shown in FIG. 2, the excitation light L from the semiconductor laser 21 becomes parallel light by the optical collimator 22, propagates through the pipe 37, passes through the first coupling portion 32, and propagates through the second coupling portion 33. Go straight down in (water) 39. The excitation light L reaches the photoacoustic coupling member (glass plate) 41 in the propagating liquid 39, but water and glass have a refractive index close to each other, so they travel straight on the boundary surface, reach the external window 31 directly below, and exit vertically. To do. The excitation light L emitted from the external window 31 is irradiated into the body as it is, and travels in the body as a light component caused by the excitation light L while being scattered in all directions by the body tissue. As the penetration depth in the body increases, the scattering range becomes wider.

  Next, fluorescence detection will be described. As shown in FIG. 3, a part of the light component caused by the excitation light L scattered in the body is again emitted from the body surface after being subjected to multiple scattering. Further, in addition to the light component caused by the excitation light L, when there is a part where the ICG (fluorescent contrast agent) is selectively accumulated (that is, a lesion part) in the body, the excitation light L is present at the ICG accumulation position. Irradiation causes fluorescence N to be emitted. A part of the light component resulting from the fluorescence N is also emitted from the body surface after being subjected to multiple scattering.

When a light component caused by the excitation light L and a light component caused by the fluorescence N are emitted from the body surface, a part of the emitted light is emitted to the probe head 14 by the emitted light M (including the fluorescence N). From the external window 31.
The radiated light M travels straight upward in the probe head 14 while maintaining a thick optical path diameter when entering from the entire surface of the external window 31, and passes through the second coupling portion 33 (propagating liquid 39, photoacoustic coupling member 41, window 42). To Penetrate. Then, the light is reflected on the entire surface of the mirror 35 with holes except for the small holes 36 (pipe 37), and the reflected light is condensed on the light receiving end face of the light pipe 26 by the condenser lens 38. A band notch filter 25 that removes a wavelength of 750 nm to 800 nm is provided immediately before the light pipe 26, whereby a wavelength component caused by the excitation light L included in the radiation light M is removed. Further, a light component (fluorescence N) caused by fluorescence near 820 nm is extracted by the spectroscope 27 and detected by the photomultiplier detector 28.
The fluorescence intensity (light quantity) detected at this time is stored in the main body control unit 15 as the “reference value T”. This reference value T is stored as a base value of signal intensity when fluorescence modulation by ultrasonic heating is applied.

Next, fluorescence modulation by ultrasonic heating will be described.
After storing the reference value T, the semiconductor laser 21 emits the excitation light L as it is, and the state where the light pipe 26 receives the radiated light M (including the fluorescence N) is maintained. Then, as shown in FIG. 4, the ultrasonic wave U for heating is transmitted from the ultrasonic transducer 30. The ultrasonic wave U passes through the focus mechanism of the ultrasonic lens 44 and enters the propagation liquid 39, is reflected by the photosonic coupling member 41, is emitted from the lower external window 31, travels into the body, and the ultrasonic lens 44. It converges to the convergence point (focal point). As a result, the convergence point is heated by the ultrasonic energy.

  When there is no ICG accumulation at the convergence point, the emitted light M (fluorescence N) received by the light pipe 26 remains at the reference value T and hardly changes. On the other hand, when ICG is accumulated at the convergence point, the amount of fluorescence N of the ICG from the convergence point is greatly attenuated by heating. The effect of this attenuation is the attenuation of the fluorescence N in the radiated light M, and the detection intensity of the fluorescence N received through the light pipe 26 is reduced below the reference value T. Therefore, whether or not the ICG is accumulated at the position of the convergence point (the presence of a lesion site) can be determined based on whether or not a change that the detection intensity greatly attenuates from the reference value T appears.

  Thereafter, by scanning the depth of the convergence point with the ultrasonic lens 44 and monitoring the detection intensity, data of a change in the detection intensity of the fluorescence N in the depth direction is collected. This makes it possible to accurately check the position of the ICG accumulation site (lesion site) in the depth direction in a non-invasive manner.

  In the above, the ICG accumulation position detection in the depth direction has been described. However, when the ICG accumulation position detection in the lateral (two-dimensional) direction is performed, the probe head 14 maintains the convergence point of the ultrasonic lens 44 constant. The detection intensity may be monitored while moving in the horizontal direction.

  When it is desired to accurately map the three-dimensional distribution of ICG accumulation positions in the body, the probe head 14 is held on a two-dimensional transport arm (not shown) that moves in the same manner as an XY two-dimensional plotter, for example. By monitoring while controlling the movement of the transfer arm in the XY direction and the scanning in the depth (Z) direction by the ultrasonic lens 44, three-dimensional distribution data of the accumulation position of the ICG can be obtained.

Further, when a heating ultrasonic transducer 30 having a depth direction electronic focus function such as a multi-channel type or an annual type is used, the position of the convergence point in the depth direction is scanned by the electronic focus function. Therefore, the heating position can be easily scanned without using the ultrasonic lens 44.
Further, when the ultrasonic transducer 30 for heating is of a multi-channel type and has a three-dimensional electronic focusing function as well as the depth direction, the position of the convergence point is set in the three-dimensional direction. In this case, the heating position can be three-dimensionally scanned by the three-dimensional electronic focus while the probe head 14 is fixed at one place.

(Example)
Using the ultrasonic-assisted fluorescence imaging probe 10 of the present invention, the distribution of the change rate of the fluorescence intensity when modulation by ultrasonic waves was applied was measured. The results are shown in FIG. 5 and FIG.

FIG. 5 shows measurement results of measuring changes in fluorescence intensity when the ultrasound-assisted fluorescence imaging probe 10 is fixed to a transport arm movable in the XY directions and moved in the XY directions by 2.5 mm. . As a preliminary experiment, a position in the XY plane where ICG does not exist is found in advance, the probe is moved using the fluorescence intensity obtained at that position as a reference value, and fluorescence is emitted by ultrasonic irradiation at the position where ICG is present. The distribution of attenuation (rate of change) is plotted.
As a result, two peaks of change rate clearly appeared in the measurement range used in the experiment. It was also confirmed that this position is certainly a position where ICG exists. That is, the position in the XY direction can be accurately known non-invasively.
For comparison, when the fluorescence intensity distribution in the same region was measured by irradiating only the excitation light without irradiating ultrasonic waves, the whole area was slightly shining due to the scattered light of the excitation light and fluorescence. As a result, it was possible to grasp the presence of light unevenness mainly in two places, and the fluorescence position could not be specified.

FIG. 6 shows the change of fluorescence intensity by fixing the ultrasound-assisted fluorescence imaging probe 10 to a transport arm movable in the Z direction and scanning the depth Z from the body surface in a range of 45 mm to 55 mm in 2 mm increments. The measured measurement results are shown. As for the position in the XY direction, a position where ICG is present in advance is found in a preliminary experiment, and the probe 10 is fixed at that position.
As a result, in the measurement in the depth direction, abrupt attenuation was observed in the vicinity of the depth where ICG was present, and the fluorescence position in the depth direction was clearly known.

As mentioned above, although one Embodiment of this invention was described, it cannot be overemphasized that this invention can be deform | transformed and implemented in the range which does not deviate from the meaning of this invention not only this.
For example, in the above embodiment, the pipe 37 is attached to the first coupling portion 32. However, the pipe 37 may be removed so that the excitation light L passes directly through the small hole 36. As a result, although the scattered light of the excitation light L due to dust increases, a part of the radiated light M (including the fluorescence N) reflected by the holed mirror 35 is blocked by the pipe 37 to the light pipe 26. It can prevent it from reaching it.

  In the embodiment described above, the holed mirror 35 of the first coupling portion 32 is a plane mirror. However, instead of this, if the focal point is adjusted as a concave mirror, the function as the condenser lens 38 can be shared.

  In the above embodiment, the light pipe 26 is arranged on the light receiving end face of the light receiving unit 12, but this is provided for performing optical transmission to the photomultiplier detector 28 located at a position away from the probe 10. If the light receiving element is used as a detector, the light pipe 26 is unnecessary if the detector is integrally attached to the probe.

  In the above embodiment, the focus mechanism using the ultrasonic lens 44 is disposed between the optical wave coupling member 41 and the ultrasonic transducer 30, but instead, the focus mechanism is located closer to the body surface than the optical wave coupling member 41. You may make it provide.

  In the above-described embodiment, the focus mechanism for moving the ultrasonic lens 44 is provided. Instead of this, the ultrasonic lens 44 is not moved, and an elevating mechanism for moving the probe head 14 up and down with respect to the body surface is provided. You may do it. In this case, a standoff by an oil bag (or a water bag) may be interposed between the external window 31 of the container 40 and the body surface.

  The present invention can be used in a diagnostic apparatus using an ultrasonic assisted fluorescence imaging method.

DESCRIPTION OF SYMBOLS 10 Probe for ultrasonic-assisted fluorescence imaging 11 Excitation light source part 12 Light receiving part 13 Ultrasonic irradiation part 14 Probe head 15 Main body control part 21 Semiconductor laser 22 Optical collimator 25 Band notch filter 26 Light pipe 27 Spectrometer 28 Photomultiplier detector 30 Super Acoustic transducer 31 External window 32 First coupling part 33 Second coupling part 35 Mirror with hole 36 Small hole 37 Pipe (straight pipe)
38 Condensing lens 39 Propagating liquid (water)
40 Container 41 Photosonic coupling member 42 Window (upper surface)
43 Windows (connection surface)
44 Ultrasonic lens 101 Ultrasonic transducer 102 Laser light source 103 Light pipe 104 Spectrometer 105 Photomultiplier detector 106 Moving stage L Excitation light M Radiation light N Fluorescence U Ultrasound

Claims (9)

An excitation light source unit for irradiating excitation light;
A light receiving unit for receiving radiation from a subject including fluorescence; and
An ultrasonic irradiation unit that emits ultrasonic waves for heating;
The excitation light source unit, the light receiving unit, and the ultrasonic wave irradiation unit are integrally held, and the excitation light, the emitted light, and a probe head provided with an external window through which the ultrasonic wave passes,
In the probe head,
A first coupling unit that adjusts an optical path so that the optical path of the excitation light and the optical path of the radiated light are coaxially overlapped and passed on the external window side;
The optical path and the waveguide are adjusted between the first coupling portion and the external window so that the optical path of the excitation light and the radiated light and the waveguide of the ultrasonic wave are superimposed and transmitted coaxially. A probe for ultrasound-assisted fluorescence imaging provided with a two-bond portion.   2. The first coupling portion includes a mirror with a hole that is disposed obliquely with respect to the optical path of the excitation light, has a small hole through which the excitation light can pass, and reflects the emitted light. The probe for ultrasonic assisted fluorescence imaging as described.   The ultrasound-assisted fluorescence imaging probe according to claim 2, wherein a straight tube is formed in which excitation light is confined and passed through a small hole of the holed mirror.   The ultrasonic wave according to any one of claims 1 to 3, wherein a condensing lens for condensing the emitted light on a light receiving surface of the light receiving unit is provided between the mirror with a hole and the light receiving unit. Probe for assisted fluorescence imaging. The second coupling part includes a container that forms a liquid space filled with a propagation liquid through which the excitation light, the radiation light, and the ultrasonic wave can propagate.
The refractive index approximates that of the propagating liquid and is immersed in the propagating liquid, and is disposed obliquely with respect to the optical path through which the excitation light and the emitted light pass coaxially. The probe for ultrasonically-assisted fluorescence imaging according to any one of claims 1 to 4, comprising a photoacoustic coupling member that transmits and reflects the ultrasonic wave.   The probe for ultrasonically assisted fluorescence imaging according to claim 5, wherein the photoacoustic coupling member is a glass plate and the propagation liquid is water.   The ultrasonic irradiator comprises an annual type or multi-channel type ultrasonic transducer having an electronic focus function for converging ultrasonic waves in the depth direction to form a focal point and adjusting the depth of the focal point. The probe for ultrasonic assist fluorescence imaging in any one of Claims 1-6.   2. A focus mechanism using an ultrasonic lens that adjusts the depth of focus while forming a focal point by converging ultrasonic waves in the depth direction on the ultrasonic wave guide in the probe head. The probe for ultrasonic-assisted fluorescence imaging in any one of Claims 6.   An elevating mechanism that includes an ultrasonic lens that converges the ultrasonic wave in the depth direction to form a focal point on the ultrasonic wave guide in the probe head, and moves the probe head up and down relative to the body surface of the subject. The ultrasound-assisted fluorescence imaging probe according to any one of claims 1 to 6, further comprising:

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