JP2010005305A - Fluorescence photography method and apparatus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To largely reduce the dose of a fluorescent substance, while photographing a reliable fluorescent image. <P>SOLUTION: A subject 2 to which the fluorescent substance is administered, is continuously irradiated with excitation light from an excitation light output part 14 of a photographing device 10, and also the subject 2 irradiated with the excitation light is continuously photographed by a photographing part 12 to obtain the fluorescent images. Meanwhile the concentration of the fluorescent substance in a living body is measured by a fluorescent substance concentration measuring instrument 50 to obtain concentration information in the living body. When it is discriminated that the measured concentration of the fluorescent substance in the living body is reduced down to the concentration for obtaining the reliable fluorescent image (a first threshold), an image processor 20 outputs an indication to urge the administration of the fluorescent substance so that it reaches the appropriate concentration. Besides, the fluorescent images to be continuously obtained are corrected based on the measured concentration information in the living body to obtain the clear fluorescent images regardless of a concentration change (the change of fluorescent intensity). <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a fluorescence imaging method and apparatus, and more particularly to a technique for acquiring a fluorescence image by continuously imaging a subject to which a fluorescent substance is administered into a living body.

  By injecting a fluorescent substance such as indocyanine green (ICG) into the living body, irradiating excitation light in a specific wavelength region for causing the fluorescent substance to emit light, and photographing the living tissue emitted by the excitation light Attention has been focused on fluorescence imaging for identifying the position of blood vessels and lesions in the body.

  However, there is a problem that the fluorescent substance is metabolized in the body, and as the time passes, the fluorescent substance concentration in the body decreases, and a clear fluorescent image cannot be obtained.

  As a technique considering the fluorescent substance metabolism in the living body, a dose control device for controlling the dose of the fluorescent substance has been proposed (Patent Document 1).

  The dose control device described in Patent Document 1 constantly measures the concentration of the fluorescent substance, and when the concentration falls below a certain value, sends an administration start signal to the automatic administration device or outputs a display prompting administration to the monitor By doing so, stable fluorescence observation is enabled.

Moreover, there exists a thing of patent document 2 as a technique of measuring the density | concentration of ICG noninvasively.
JP 2007-125355 A JP 2001-321362 A

  However, the dose control device described in Patent Document 1 has the following problems.

  1. Since the concentration of the fluorescent substance (dosage of the fluorescent substance) is controlled so that the emission intensity always becomes a peak or a value close to the peak, a large amount of the fluorescent substance is required and costs are increased.

  2. The administration of a large amount of fluorescent substance has an adverse effect on the living body and is not suitable as a harmful reagent.

  The present invention has been made in view of such circumstances, and provides a fluorescence imaging method and apparatus capable of significantly reducing the dose of a fluorescent substance while enabling reliable imaging of fluorescence images. With the goal.

  In order to achieve the above object, the fluorescence imaging method according to claim 1 continuously applies excitation light in a specific wavelength range for causing the fluorescent substance to emit light to a subject to which the fluorescent substance is administered in vivo. A step of irradiating, a step of continuously photographing the subject irradiated with the excitation light by the imaging means, obtaining a fluorescent image, a step of measuring the concentration of the fluorescent substance in the living body, and a desired fluorescence intensity A concentration lower than the appropriate concentration of the fluorescent substance from which the above obtained is obtained, and at least a concentration at which a reliable fluorescent image can be obtained is set as a first threshold, and the measured fluorescent substance in the living body A step of determining whether or not the concentration of the fluorescent substance in the living body has decreased to the first threshold, and each time it is determined that the concentration of the fluorescent substance measured in the living body has decreased to the first threshold, The concentration of the fluorescent substance in the living body It outputs an instruction to prompt the administration of the fluorescent substance to reach every, or is characterized by comprising a step of administering the fluorescent substance automatically.

  That is, the concentration of the fluorescent substance administered into the living body is not always maintained at an appropriate concentration at which a desired fluorescence intensity can be obtained, but the concentration of the fluorescent substance in the living body is lower than the appropriate concentration. Instructing the administration of the fluorescent material so that the concentration of the fluorescent material in the living body reaches the appropriate concentration when the concentration is reduced to a concentration at which at least a reliable fluorescent image can be acquired (first threshold). Or a fluorescent substance is automatically administered. Thereby, although the density | concentration of the fluorescent substance in a living body fluctuates between the said appropriate density | concentration and 1st threshold value, it can maintain the density | concentration which can acquire a fluorescence image with reliability at least, and Therefore, the dose of the fluorescent substance can be greatly reduced as compared with the case where the concentration of the fluorescent substance is always maintained at an appropriate concentration.

  According to a second aspect of the present invention, in the fluorescence photographing method according to the first aspect, the image processing is performed on the fluorescent image continuously photographed by the imaging unit, and the variation in the concentration of the fluorescent substance in the living body is affected. Regardless, the method further includes a step of performing image processing so as to generate a fluorescent image equivalent to the fluorescent image photographed by the imaging unit when the concentration of the fluorescent substance is the appropriate concentration.

  As described above, the concentration of the fluorescent substance in the living body fluctuates between the appropriate concentration and the first threshold value, and as a result, the fluorescent image continuously captured by the imaging unit also changes. Since image processing is performed so as to generate a fluorescent image equivalent to the fluorescent image taken at the time of density, a constant fluorescent image can be maintained.

  The fluorescence imaging method according to claim 1, wherein the image processing step includes a fluorescence image continuously captured by the imaging unit based on the measured concentration of the fluorescent substance in the living body. It is characterized by correcting.

  4. The fluorescence imaging method according to claim 2, wherein the image processing step compares the measured concentration of the fluorescent substance in the living body with the appropriate concentration, and based on the comparison result. Then, the fluorescent image continuously photographed by the imaging means is corrected.

  The concentration of the fluorescent substance in the living body and the emission luminance of the fluorescent substance are in a certain relationship within a certain concentration range. Therefore, the measured fluorescent substance concentration or the measured fluorescent substance concentration is compared with the appropriate concentration. By using the result as an image correction term, it is possible to obtain a clear fluorescent image equivalent to a fluorescent image taken at an appropriate density.

  According to a fifth aspect of the present invention, in the fluorescence imaging method according to any one of the first to fourth aspects, a density that is lower than the first threshold and at which a reliable fluorescent image cannot be obtained And a step of prohibiting photographing of the fluorescent image when it is determined that the measured concentration of the fluorescent substance in the living body has decreased to the second threshold value. It is a feature.

  In particular, when the fluorescent substance is not administered within a predetermined time after the instruction for prompting the administration of the fluorescent substance is output, the concentration of the fluorescent substance in the living body is reduced to the second threshold value, and a reliable fluorescent image is obtained. Can no longer be acquired. In this case, photographing of fluorescent images is prohibited so that diagnosis or the like with inappropriate fluorescent images is not performed.

  6. The fluorescence imaging method according to claim 1, wherein the appropriate density is a density at which a fluorescence intensity of the fluorescent substance is maximized, or a density and a fluorescence intensity of the fluorescent substance. Is the maximum concentration within a range that is substantially proportional.

  The fluorescence imaging method according to any one of claims 1 to 6, wherein the first threshold value is an imaging of a fluorescence image showing a blood vessel from a surface of a living tissue of the subject to a predetermined depth. Is the smallest of the possible concentrations.

  As shown in claim 8, in the fluorescence imaging method according to claim 7, the predetermined depth is about 2 mm. The depth at the time of one incision by endoscopic surgery using an electric knife is about 2 mm. Therefore, if a blood vessel from the surface of the living tissue to a depth of about 2 mm can be confirmed, the operation does not damage the blood vessel. Can do.

  The fluorescence imaging apparatus according to claim 9 continuously irradiates a subject to which a fluorescent substance is administered in a living body, with excitation light in a specific wavelength range for causing the fluorescent substance to emit light at a predetermined time interval. A light source means, an imaging means for photographing a subject irradiated with excitation light by the light source means, a concentration measuring means for measuring the concentration of the fluorescent substance in the living body, and the fluorescent substance for obtaining a desired fluorescence intensity. A first threshold setting means for setting a density that is lower than an appropriate density and at least a reliable fluorescence image can be acquired as a first threshold; and an in vivo measured by the density measuring means First determination means for determining whether or not the concentration of the fluorescent substance has decreased to the first threshold set by the first threshold setting means, and the in vivo measured by the first determination means Fluorescent substance concentration Each time it is determined that the concentration has decreased to the set first threshold value, an instruction for prompting administration of the fluorescent substance so that the concentration of the fluorescent substance in the living body reaches the appropriate concentration is output, or the fluorescence And a means for automatically administering a substance.

  The fluorescence imaging apparatus according to claim 9, wherein the fluorescence imaging apparatus according to claim 9 is an image processing unit that performs image processing on a fluorescence image continuously captured by the imaging unit, the concentration of the fluorescent substance in the living body. Regardless of variation, the image processing device further includes an image processing unit that performs image processing so as to generate a fluorescent image equivalent to the fluorescent image captured by the imaging unit when the concentration of the fluorescent substance is the appropriate concentration. .

  11. The fluorescence imaging apparatus according to claim 10, wherein the image processing unit continuously captures images with the imaging unit based on the concentration of the fluorescent substance in the living body measured by the concentration measuring unit. It is characterized by correcting the fluorescent image.

  In the fluorescence imaging apparatus according to claim 10, the image processing unit is set by the concentration of the fluorescent substance in the living body measured by the concentration measuring unit and the first threshold setting unit. And comparing means for comparing with the first threshold value, and correcting fluorescent images continuously photographed by the imaging means based on the comparison result of the comparing means.

  According to a thirteenth aspect of the present invention, in the fluorescence imaging apparatus according to any one of the ninth to twelfth aspects, a density that is lower than the first threshold and at which a reliable fluorescent image cannot be acquired is set to a first level. A second threshold value setting unit that is set as a second threshold value, and whether or not the concentration of the fluorescent substance in the living body measured by the concentration measurement unit has decreased to the second threshold value set by the second threshold value setting unit And when the second determination means determines that the measured concentration of the fluorescent substance in the living body has decreased to the second threshold value, the fluorescent image is not allowed to be captured. And a photographing prohibiting means.

  As shown in claim 14, in the fluorescence imaging apparatus according to any one of claims 9 to 13, the light source means generates excitation light in a near-infrared wavelength region.

  The fluorescence imaging apparatus according to any one of claims 9 to 14, wherein the first threshold value setting unit is a fluorescence image showing a blood vessel from a surface of a living tissue of the subject to a predetermined depth. The minimum density among the densities that can be photographed is set as the first threshold value.

  According to a sixteenth aspect, in the fluorescence imaging apparatus according to the fifteenth aspect, the predetermined depth is about 2 mm.

  According to the present invention, the fluorescent substance is not administered until the concentration of the fluorescent substance in the living body is reduced to a density (first threshold value) at least capable of acquiring a reliable fluorescent image, and the first threshold value is not provided. Each time it drops, the instruction to prompt the administration of the fluorescent substance to reach the appropriate concentration is output, or the fluorescent substance is automatically administered. Therefore, the concentration of the fluorescent substance in the living body is the appropriate concentration. Can be maintained at least at a concentration at which a reliable fluorescence image can be acquired, and compared with a case where the concentration of the fluorescent substance is always maintained at an appropriate concentration. Thus, the dose of the fluorescent substance can be greatly reduced. Furthermore, even if the concentration of the fluorescent substance is lowered from the appropriate concentration, a clear fluorescent image equivalent to the fluorescent image taken at the appropriate concentration can be obtained by image processing.

  Preferred embodiments of a fluorescence imaging method and apparatus according to the present invention will be described below with reference to the accompanying drawings.

<Principle of fluorescence photography>
In order to obtain information in living tissue using light, it is necessary to avoid light in a wavelength range that is absorbed by the living tissue. As shown in FIG. 1, in the wavelength range of visible light of 700 nm or less, there is absorption of hemoglobin, and in the wavelength range of 1000 nm or more, there is water absorption, so light in this wavelength range cannot be used. Light in the wavelength range of 700 nm to 1000 nm (near infrared range) is referred to as a “biological spectroscopic window” because it passes through living tissue relatively well. In other words, the above-described excitation light in the near infrared region is light that permeates the living tissue relatively well.

  In the present invention, in order to observe and identify the blood vessel and lesion in the living tissue, a fluorescent substance is administered into the living body, and a fluorescence image including the blood vessel and the lesion is irradiated by irradiating near-infrared excitation light. Take a picture. As the angiographic contrast agent, fluorescent reagent ICG (indocyanine green) having an excitation light wavelength of 785 nm and a fluorescence wavelength of 805 nm, and fluorescent reagent Cy7 having an excitation light wavelength of 747 nm and a fluorescence wavelength of 776 nm can be used. The fluorescence wavelength 805 nm is a value in water, and the ICG fluorescence wavelength in blood is around 830 nm.

<Configuration of fluorescence imaging device>
FIG. 2 is a block diagram showing an embodiment of the fluorescence imaging apparatus according to the present invention.

  The fluorescence imaging apparatus 1 mainly includes an imaging device 10 such as an endoscope, an image processing device 20 such as a processor to which the endoscope is connected, a light source unit 30, a display unit 40 such as a monitor, an oximeter, and the like. The fluorescent substance concentration measuring apparatus 50 is configured.

  The imaging apparatus 10 includes an imaging unit 12 including an imaging lens, an imaging device (CCD), and the like, and an excitation light output unit 14 that generates excitation light in the near-infrared wavelength region with respect to the imaging region of the imaging unit 12. I have.

  The light source unit 30 outputs an excitation light control signal to the excitation light output unit 14 in response to an instruction from the image processing apparatus 20, and generates excitation light from the excitation light output unit 14. In the case of an endoscope, excitation light emitted from the light source unit 30 is irradiated to the subject from the illumination lens at the distal end of the endoscope via a light guide in the endoscope.

  The fluorescent substance concentration measuring device 50 measures the concentration of the fluorescent substance administered to the subject 2, and the apparatus described in Patent Document 2 that measures the concentration of the fluorescent substance non-invasively can be applied. The method for measuring the concentration of the fluorescent substance is not limited to the method described in Patent Document 2, and is not limited to the non-invasive measurement method.

  The image processing apparatus 20 controls the light source unit 30 and the imaging of the imaging unit 12, and inputs imaging data of the subject continuously captured by the imaging unit 12. In addition, the concentration information of the fluorescent substance in the living body measured by the fluorescent substance concentration measuring device 50 is input, the input imaging data is subjected to image processing based on the concentration information, and the image processed image data is displayed on the display unit 40. Output. Further, when the measured concentration of the fluorescent substance in the living body falls to a predetermined threshold value set in advance, an instruction for prompting the administration of the fluorescent substance so that the concentration of the fluorescent substance in the living body reaches an appropriate concentration is displayed. Or a voice message is output from a speaker (not shown).

[Image Processing Device 20]
FIG. 3 is a principal block diagram of the image processing apparatus 20.

  The image processing apparatus 20 includes a ROM (EEPROM) 21, a density comparison unit 22, a correction term calculation unit 23, an image generation unit 24, and a main control unit 25.

  The ROM 21 stores in advance concentration information (peak concentration information) of the fluorescent substance in the living body when the fluorescence intensity of the fluorescent substance reaches a peak, and the peak density information is output from the ROM 21 to the concentration comparison unit 22.

  To the other input of the concentration comparison unit 22, the concentration information of the current fluorescent substance in the living body measured by the fluorescent substance concentration measurement device 50 is added, and the concentration comparison unit 22 compares these two input comparison results. (For example, a ratio or difference between two inputs) is output to the correction term calculation unit 23.

  Based on the comparison result input from the concentration comparison unit 22, the correction term calculation unit 23 calculates the excitation light absorption efficiency ratio (the ratio between the excitation light absorption efficiency at the current concentration and the excitation light absorption efficiency at the peak concentration). ) As a correction term of the fluorescence image, and this correction term is output to the image generation unit 24.

  The imaging data is added from the imaging unit 12 to the other input of the image generation unit 24, and the image generation unit 24 corrects the imaging data based on the correction term added from the correction term calculation unit 23, An image equivalent to the image (fluorescence image) taken by the imaging unit 12 when the concentration of the fluorescent substance is the peak concentration is generated.

  The main control unit 25 performs overall control of each part of the apparatus. As described above, the main control unit 25 controls the fluorescent image so that the fluorescent image does not fluctuate even when the concentration of the fluorescent material is reduced. An instruction for prompting or an instruction for prohibiting imaging of a fluorescent image is performed.

  That is, the main control unit 25 sets, as the first threshold value, a density that is lower than the peak density but enables reliable fluorescence image acquisition, and sets the second density for which reliable fluorescence image acquisition is impossible. Threshold value setting means for setting the threshold value as the threshold value, and the first and second threshold values set by the threshold value setting means are stored in the ROM 21.

  The concentration comparison unit 22 outputs the comparison result between the peak concentration information and the current concentration information of the fluorescent substance measured by the fluorescent substance concentration measuring device 50 as described above to the correction term calculation unit 23 and the current fluorescent substance. That the concentration of the current fluorescent substance has decreased to the first threshold or that the concentration has decreased to the second threshold is compared with the set first threshold and the second threshold. If it is determined that the current concentration of the fluorescent material has decreased to the first threshold value, the determination result (instruction for prompting administration of the fluorescent material) is output to the main control unit 25, and the current concentration of the fluorescent material is further increased. If it is determined that the threshold value has decreased to the second threshold value, the determination result (instruction for prohibiting fluorescent image capturing) is output to the main control unit 25.

  The main control unit 25 outputs an instruction signal for prompting the administration of the fluorescent substance to the display unit 40 so that the concentration of the fluorescent substance in the living body reaches an appropriate concentration based on the determination result from the concentration comparison unit 22, or An imaging prohibition signal that prohibits capturing of a fluorescent image is output to the light source unit 30 and the like.

[Relationship between concentration of fluorescent substance and fluorescence intensity]
FIG. 4 is a graph showing the measurement results of fluorescence intensity at IGC concentrations of 0.001 mg / ml, 0.0008 mg / ml, and 0.0006 mb / ml mg / ml in an aqueous solution. Actual fluorescence imaging is performed with ICG in blood, and the relationship between fluorescence peak wavelength and concentration-integrated fluorescence intensity is different from that in aqueous solution, but the concept of correction is the same.

  Here, since the molecular weight of ICG is 774.96, when the concentration of the IGC is converted into the molar concentration, the following [Table 1] is obtained.

  The integrated fluorescence intensity of each concentration of ICG is as shown in [Table 2] below.

  As shown in [Table 1] and [Table 2] above, it can be seen that the molar concentration of ICG and the integrated fluorescence intensity are in a proportional relationship. Therefore, as shown in [Table 3] below, by performing a correction by multiplying the integral fluorescence intensity (corresponding to imaging data output from the imaging unit 12) by an appropriate coefficient according to the molar concentration of ICG, The fluorescence intensity can be made almost equal.

  In the above example of [Table 3], the molar concentration of IGC is 0.0010323113 (mol / L) 0.0010, 0.0007742335 (mol / L) 0.0008 with the molar concentration of IGC 0.0012903892 (mol / L) 0.0013 as the standard (coefficient 1). However, the concentration comparison unit 22 shown in FIG. 3 obtains a coefficient for each concentration information of the fluorescent substance to be measured with reference to the peak concentration information. Further, the image generation unit 24 may multiply the imaging data as it is by the coefficient obtained as described above, or the correction term calculation unit 23 takes into account the spectral sensitivity of the CCD, excitation light, and other correction factors. The correction may be performed using the corrected term.

  Furthermore, as shown in FIG. 5, the concentration of the fluorescent substance and the fluorescence intensity are substantially proportional to each other in the low concentration range, and the fluorescence intensity decreases as the concentration increases due to the influence of concentration quenching or the like.

  In the embodiment shown below, as shown in FIG. 6, at the time of initial administration, the fluorescent substance is administered so that the fluorescence intensity becomes the maximum.

  Further, the maximum concentration within the range in which the concentration of the fluorescent substance and the fluorescence intensity are approximately proportional to each other is set as an appropriate concentration, and the minimum concentration among the concentrations at which a reliable fluorescent image can be acquired is set as the threshold 1. Set.

  Here, the threshold value 1 is a concentration at which a fluorescent image showing a blood vessel from the surface of the living tissue of the subject to a predetermined depth can be taken, and specifically, the depth from the surface of the living tissue is about x seconds. This is the concentration at which the fluorescence of blood vessels at 2 mm cannot be received by the imaging unit 12. x seconds is a time corresponding to a delay time until the administration of the fluorescent substance is instructed and the concentration of the fluorescent substance is increased after the fluorescent substance is actually administered. Moreover, 2 mm is the depth at the time of one incision by endoscopic surgery using an electric knife, and is a depth for ensuring safety at the time of surgery.

  In addition, the maximum density among the densities at which a reliable fluorescent image cannot be acquired is set as the threshold value 2. Specifically, this is the maximum concentration among the concentrations at which the fluorescence of blood vessels at a depth of about 2 mm from the surface of the living tissue cannot be received by the imaging unit 12.

<First Embodiment>
FIG. 7 is a flowchart showing the first embodiment of the fluorescence imaging method according to the present invention.

  A subject to which a fluorescent substance (reagent) has been administered is photographed with fluorescence. First, the reagent concentration in the living body is measured (step S10), and it is determined whether or not the reagent concentration is higher than an appropriate concentration (step S12). ).

  If it is determined that the reagent concentration is higher than the appropriate concentration (in the case of Yes), the process proceeds to step S14, and the captured fluorescent image is output to the monitor without correction. This is because, as shown in FIG. 6, the current reagent concentration is in a region where the relationship between the concentration and the fluorescence intensity cannot be approximated in proportion (high concentration), and correction is difficult because it is not proportional. In addition, since sufficient fluorescence is emitted from the living tissue, no correction is required.

  On the other hand, if the measured reagent concentration is lower than the appropriate concentration, it is further determined whether or not it is higher than the threshold value 1 (step S16). When it is determined that the reagent concentration is higher than the threshold 1 (in the case of Yes), the process proceeds to step S18, where the reagent concentration measured here is compared with an appropriate concentration, and the comparison result is the correction term calculation unit 23 ( 3). Subsequently, the correction term is calculated by the correction term calculation unit 23 and output to the image generation unit 24 (step S20). In the image generation unit 24, the captured fluorescence image is input from the correction term calculation unit 23. The fluorescent image formed by the correction is generated, and the corrected fluorescent image is output to the monitor (step S22). Thereby, even if the reagent concentration is lower than the appropriate concentration, the monitor can display a fluorescent image equivalent to the fluorescent image taken at the appropriate concentration.

  If it is determined in step S16 that the measured reagent concentration is lower than the threshold value 1 (in the case of No), it is further determined whether or not it is higher than the threshold value 2 (step S24). If it is determined that the reagent concentration is higher than the threshold value 2 (in the case of Yes), the process proceeds to step S26, where a message prompting the administration of the fluorescent reagent so that the reagent concentration in the living body becomes an appropriate concentration is monitored. Or a voice message is output from the speaker.

  The user administers the fluorescent reagent to the subject in accordance with the message. However, since the dosage for increasing the reagent concentration from the threshold value 1 to an appropriate concentration differs depending on the body weight of the subject, the dosage is determined in advance. Is preferably calculated in advance.

  On the other hand, when the measured reagent concentration is lower than the threshold value 2 (for example, when administration of the fluorescent reagent is delayed), the process proceeds to step S28, and fluorescence imaging is prohibited. Thereby, it is possible to prevent diagnosis, surgery, etc. from being performed using inappropriate fluorescent images.

  Then, it is determined whether or not an instruction to end fluorescent imaging has been input (step S30). If there is no input to end (in the case of No), the process proceeds to step S10, and the above operation is repeated. Is input (in the case of Yes), the fluorescence imaging process is terminated.

[Metabolic rate of fluorescent reagent (ICG)]
FIG. 8 is a graph plotting blood concentrations 5 minutes, 10 minutes, 15 minutes, and 20 minutes after IGC administration.

  As can be seen from the graph of FIG. 8, the blood concentration of ICG is higher in the early stage (lower in the later stage). Therefore, the lower the limit concentration that can be corrected, the more advantageous it is that it is not necessary to administer the fluorescent reagent for a long time.

[Comparative example]
The blood concentration of ICG decreases with time as shown in [Table 4] below. From the graph shown in FIG. 9, the blood concentration y (mg / dl) can be approximated by the following equation as a function of time x (minutes).

[Equation 1]
y = exp (-0.2 * x)

[Human blood volume]
If the weight of a person is G, the total blood volume A can be approximated by the following equation.

[Equation 2]
A = G / 13 (liter)
This is because the total blood volume is said to be 1/13 of the body weight. Now, assuming a person weighing 62 kg, the total blood volume is 5 liters.

[Total consumption of fluorescent reagent during continuous administration]
When the continuous administration is performed every second, the amount to be administered at one time is the total blood volume × the reduced concentration in one second.
50 (dl) × (1-exp (-0.2 * 1/60)) ≒ 0.16mg
It becomes.

  Assuming that the operation was performed for 30 minutes, the total dose can be obtained from the following formula from one dose × the operation time.

[Equation 3]
0.16 × 60 × 30 ≒ 288mg
[Total consumption of fluorescent reagent according to the present invention]
The amount of ICG decrease at the concentration threshold B is obtained by total blood volume × (initial dose concentration−B).

  Here, if the threshold concentration B is 0.1 mg / dl, the ICG reduction amount at the threshold B can be obtained by the following equation.

[Equation 4]
50 (dl) × (1-0.1) ≒ 45mg
On the other hand, the time to decay to a concentration of 0.1 mg / dl is shown in the graph of FIG.
About -5 x ln (0.1) ≒ 11.5 minutes, and 30 minutes of surgery can be administered twice, so the total ICG dose is
45mg × 2 = 90mg
It becomes.

  Therefore, according to the above comparative example, the total ICG dose according to the present invention can be reduced to about one third of the conventional total ICG dose.

  FIG. 10 is a graph showing the difference in the administration method of the fluorescent reagent between the prior art and the present invention.

  As shown in the figure, in the conventional case, as shown by the broken line, the fluorescent reagent is administered so as to always maintain an appropriate concentration, whereas in the present invention, as shown by the solid line. The fluorescent reagent is not administered during the period from when the concentration is lowered to the threshold value 1, and when the reagent concentration is lowered to the threshold value 1, the fluorescent reagent is administered so as to return to the appropriate concentration at that time.

  According to the present invention, the reagent concentration fluctuates between the appropriate concentration and the threshold value 1, and as a result, the continuously captured fluorescent images also change, but by performing image processing according to the reagent concentration. The fluorescent image equivalent to the fluorescent image taken at the proper density can be maintained.

  When administering a fluorescent reagent as shown in FIG. 10, the dose of the fluorescent reagent is calculated as described in [Total consumption of fluorescent reagent according to the present invention], and the fluorescent reagent of the calculated dose is calculated. Is preferably administered as rapidly as possible to the proper concentration.

  Further, in this embodiment, a case has been described in which a fluorescent reagent is administered by a user (manual) after confirming a message prompting the administration of the fluorescent reagent. However, the present invention is not limited thereto, and is described in Patent Document 1. Automatic administration may be performed using such an automatic administration device. In this case, the automatic administration device automatically inputs a single dose, and gives the automatic administration device the time when the measured in-vivo reagent concentration falls to the threshold 1 as an automatic administration trigger. Administration can be performed.

<Other configuration of fluorescence imaging device>
FIG. 11 is a block diagram showing an embodiment of an endoscope apparatus including a fluorescence imaging apparatus according to the present invention.

  The endoscope apparatus includes an endoscope (laparoscope) 100, a processor 200, a light source device 300, a display unit 40, and a fluorescent substance concentration measuring device 50.

[Laparoscope]
An objective lens 130, an image sensor (CCD) 140, and an illumination lens 150 are disposed at the insertion portion distal end 100A of the laparoscope 100.

  The objective lens 130 forms an image of the subject on the light receiving surface of the CCD 140, and the CCD 140 converts the subject image formed on the light receiving surface into an electric signal by each light receiving element. The CCD 140 of this embodiment is a color CCD in which three primary color red (R), green (G), and blue (B) color filters are arranged for each pixel in a predetermined arrangement (Bayer arrangement, honeycomb arrangement). It is.

  Further, inside the laparoscope 100, a wiring 160 for driving the CCD 140 and taking out the CCD output is provided, and a light guide 170 is provided.

  One end 170 </ b> A of the light guide 170 is connected to the light source device 300 via the LG connector 120, and the other end 170 </ b> B of the light guide 170 faces the illumination lens 150. The light emitted from the light source device 300 is emitted from the illumination lens 150 via the light guide 170 and illuminates the visual field range of the objective lens 130.

  The laparoscope 100 of this embodiment has the same configuration as a general laparoscope except that an infrared cut filter is not provided on the front surface of the CCD 140.

[Processor]
The processor 200 mainly includes a central processing unit (CPU) 210, an analog front end (AFE) 220, an image input controller 222, a normal image processing unit 224, a fluorescence image processing unit 226, an image composition unit 230, a CCD driver 240, a timing. A generator (TG) 242, a character generator (CG) 244, a memory 246, a video output unit 248, an audio processing unit 250, a speaker 252, and an operation unit 254 are configured.

  The CPU 210 has a built-in program ROM, and various data such as a threshold value 1 and a threshold value 2 (FIG. 6) necessary for control are recorded in addition to the control program executed by the CPU 210. The CPU 210 controls each unit by reading a control program recorded in the program ROM into the memory 246 based on an instruction input such as a shooting instruction from the operation unit 254 and sequentially executing the control program. The memory 246 is used as a program execution processing area, a temporary storage area for image data, and various work areas.

  The CPU 210 is added with the concentration information of the fluorescent substance in the living body of the subject measured by the fluorescent substance concentration measuring device 50, and the CPU 210 receives the measured concentration information of the fluorescent substance in the living body and the threshold 1 or Compared with the threshold value 2, if the measured concentration information falls to the threshold value 1, an instruction for prompting the administration of the fluorescent substance is output, and if the measured concentration information falls to the threshold value 2, fluorescent imaging described later is prohibited. (Normal shooting is performed continuously).

  The CCD 140 in the laparoscope 100 outputs the charges accumulated in each pixel as a serial image signal line by line in synchronization with the vertical transfer clock and horizontal transfer clock supplied from the TG 242 via the CCD driver 240. The CPU 210 controls the driving of the CCD 140 by controlling the TG 242.

  The operation unit 254 includes a keyboard, a foot switch, and the like in addition to operation switches such as a power switch and a switch for instructing start and end of photographing.

  The image signal output from the CCD 140 is an analog signal, and this analog image signal is taken into the AFE 220. The AFE 220 includes a correlated double sampling circuit (CDS), an automatic gain control circuit (AGC), and an AD converter (ADC). The CDS removes noise contained in the image signal, the AGC amplifies the noise-removed image signal with a predetermined gain, and the ADC converts the analog image signal into a digital image having a gradation width of a predetermined bit. Convert to signal.

  The image input controller 222 has a built-in line buffer having a predetermined capacity, and stores an image signal for one frame output from the AFE 220. The image signal for one frame accumulated in the image input controller 222 is stored in the memory 246 via the bus 256.

  In addition to the CPU 210, memory 246, and image input controller 222, the normal image processing unit 224, fluorescent image processing unit 226, image composition unit 230, CG244, video output unit 248, and the like are connected to the bus 256. Information can be transmitted and received between each other via a bus 256.

  The image signal for one frame stored in the memory 246 is taken into the normal image processing unit 224 or the fluorescence image processing unit 226 and subjected to necessary image processing. The images processed by the normal image processing unit 224 and the fluorescence image processing unit 226 are combined by the image combining unit 230. Details of the normal image processing unit 224, the fluorescence image processing unit 226, and the image composition unit 230 will be described later.

  The synthesized image synthesized by the image synthesizing unit 230 is converted into a video signal for the display unit 40 by the video output unit 248 and output to the display unit 40.

  In addition, the CG 244 generates a character or the like that prompts the administration of the fluorescent substance according to a command from the CPU 210 and outputs it to the image composition unit 230, and the voice processing unit 250 generates a voice message that prompts the administration of the fluorescent substance according to the command from the CPU 210. Generated from the speaker 252.

[Light source device]
The light source device 300 mainly includes a white light source 310, a rotary filter 320, a diaphragm 330, a condenser lens 340, a motor drive circuit 350, a motor 360, and an automatic light amount adjustment circuit (ALC) 370. It has a function of alternately making excitation light in a specific wavelength region (near infrared region) incident on the light guide 170.

  As the light source 310, for example, a halogen lamp can be used. White light emitted from the halogen lamp has a wavelength range of 400 nm to 1800 nm. The rotary filter 320 transmits only visible light or transmits only near-infrared excitation light according to the rotational position.

  FIG. 12 is a plan view of the rotary filter 320. As shown in the figure, the rotary filter 320 is provided with an infrared cut filter 322 and a near-infrared bandpass filter 324, and the rotary filter 320 has the infrared cut filter 322 positioned in front of the light source 310. In the case where only the visible light (400 nm to 700 nm) is transmitted and the near-infrared bandpass filter (near-infrared BPF) 324 is positioned in front of the light source 310, excitation light in the near-infrared region (for example, , Around 800 nm).

  The motor drive circuit 350 outputs a drive signal to the motor 360, rotates the rotary filter 320 at a speed of 30 times / second, and synchronizes with the vertical synchronization signal from the TG 242 and the infrared cut filter 322 and the near-infrared BPF 324. The phase is controlled so that and are switched.

  The light transmitted through the rotary filter 320 is guided to the end face of the light guide 170 through the diaphragm 330 and the condenser lens 340.

  The ALC 370 controls the diaphragm 330 based on the brightness information of the captured image applied from the CPU 210, and adjusts the amount of light incident on the light guide 170 so that the captured image is maintained at a constant brightness. This prevents halation or the like from occurring.

  When visible light is incident on the light guide 170 by the light source device 300 having the above configuration, the laparoscope 100 can capture a color image (normal image), and when excitation light is incident on the light guide 170, the laparoscope 100 Then, it is possible to take a fluorescent image of a living tissue that emits fluorescence by excitation light.

<Second Embodiment>
The endoscope apparatus having the above configuration alternately captures normal images and fluorescent images. When a fluorescent image is taken, the living tissue is irradiated with near-infrared excitation light as described above.

  FIG. 13 is a flowchart showing a second embodiment of the fluorescence imaging method according to the present invention.

  First, a fluorescent reagent is administered from the vein of the subject (step S100). The administration method of the fluorescent reagent is the same as that in the embodiment shown in FIG.

  Subsequently, the normal image and the fluorescence image are alternately photographed every frame in synchronization with the vertical synchronization signal (VD signal) having a period of 1/60 seconds (step S110). That is, as shown in FIG. 14A, in synchronization with the VD signal, visible light and excitation light are alternately emitted from the light source device 300, and the subject is irradiated through the light guide 170 and the illumination lens 150. As a result, normal image exposure (photographing) and fluorescence image exposure (photographing) are alternately performed by the CCD 140 (FIGS. 14B and 14F).

  When the normal image is exposed, the image signal (normal image) is read from the CCD 140 in synchronization with the next VD signal (FIG. 14C), and then the normal image processing unit shown in FIG. Normal image processing is performed at 224 (FIG. 14D, step S120).

  The normal image processing unit 224 includes a linear matrix circuit, a white balance correction circuit, a gamma correction circuit, a synchronization circuit, and the like, and processes R, G, and B image signals indicating a normal image input by these circuits.

  On the other hand, when the fluorescent image is exposed, the image signal (fluorescent image) is read from the CCD 140 in synchronization with the next VD signal (FIG. 14G), and then the fluorescent image shown in FIG. The processing unit 226 performs fluorescence image processing and blood vessel image generation processing (FIG. 14H, steps S130 and S140).

  The fluorescence image processing unit 226 first processes R, G, and B image signals indicating fluorescence images input by a gamma correction circuit, a synchronization circuit, and the like, and performs R, G, B after the synchronization processing in the synchronization circuit. A luminance signal (a signal having only density information) is generated from the image signal. Subsequently, a blood vessel image is generated from a fluorescent image having only density information.

  FIG. 15 is a flowchart showing blood vessel image generation (blood vessel image extraction) processing in step S140 of FIG.

As shown in FIG. 15, the fluorescence image processed in step S140 is input (step S142). Next, threshold processing is performed on the input fluorescence image with a predetermined threshold value, and density information of pixels (pixels that receive light from a fluorescent tissue that emits fluorescence) having a density equal to or higher than the density set by the threshold value is extracted. A binarized image obtained by binarization is extracted (step S144).

The threshold value is preferably as small as possible within a range in which pixel density information and noise can be distinguished.

  Subsequently, image processing for extracting only the blood vessel image from the extracted density information or binarized image is performed (step S146). For example, a filtering process is performed to delete an image portion or a noise component having a feature amount different from a blood vessel feature amount (elongated continuous shape or the like).

  As shown in FIGS. 14E and 14I, the normal image and the fluorescence image (blood vessel image) subjected to image processing as described above are output in two frames so as to be continuous frames, and are simultaneously output. The normal image and the blood vessel image are output to the image synthesis unit 230 shown in FIG. 11 and synthesized there (step S150).

  16A and 16B are schematic diagrams of a normal image and a blood vessel image output to the image composition unit 230, respectively.

  FIG. 17 is a block diagram showing the internal configuration of the image composition unit 230. As shown in the figure, the image composition unit 230 includes mixers 232 and 234 and a color conversion unit 238.

  A blood vessel image composed of density information is added to the color conversion unit 238, and the color conversion unit 238 performs color conversion so that the blood vessel image to be input has a preset color (for example, red), and is converted. The subsequent blood vessel image is output to the mixer 232. Note that the color conversion unit 238 performs color conversion so as to obtain a gradation (bright red to dark red) corresponding to the density information of the blood vessel image. You may make it do.

  A normal image is added to the other input of the mixer 232, and the mixer 232 synthesizes the normal image and the blood vessel image. In the image synthesis by the mixer 232, a blood vessel image is key-synthesized with a normal image using a binary image corresponding to the blood vessel image (a binary signal indicating a blood vessel image and its background) as a key signal. As a result, the image is synthesized so that only the blood vessel image is pasted on the normal image, and the image is synthesized so that the normal image can be seen in the portion without the blood vessel.

  The synthesized image synthesized in this way is added to the mixer 234. Warning character information (message prompting administration of a fluorescent reagent) is added to the other input of the mixer 234 from the CG 244 as necessary, so that the mixer 234 can synthesize a warning character on the synthesized image.

  Returning to FIG. 13, the composite image synthesized by the image composition unit 230 as described above is output to the display unit 40 via the video output unit 248 and displayed on the display unit 40 (step S160). FIG. 18 shows an example of a monitor screen on which a composite image is displayed.

  In the second embodiment, the normal image and the blood vessel image extracted from the fluorescent image are combined. However, the present invention is not limited to this, and the normal image and the fluorescent image are combined and displayed so as to be displayed side by side. It may be.

  In addition, the fluorescence image changes according to the concentration of the fluorescent reagent, but as described in the first embodiment, the fluorescence image may be corrected according to the concentration of the reagent in the living body. When the blood vessel image is generated by performing the process of extracting the blood vessel, it is only necessary to be able to extract the blood vessel image. Therefore, it is not necessary to correct the fluorescence image according to the reagent concentration.

  Needless to say, the present invention is not limited to the above examples, and various improvements and modifications may be made without departing from the scope of the present invention.

FIG. 1 is a graph showing the relationship between the wavelength of light and the light absorption rate of a living tissue. FIG. 2 is a block diagram showing an embodiment of the fluorescence imaging apparatus according to the present invention. FIG. 3 is a principal block diagram of the image processing apparatus. FIG. 4 is a graph showing the measurement results of fluorescence intensity at IGC concentrations of 0.001 mg / ml, 0.0008 mg / ml, and 0.0006 mb / ml in an aqueous solution. FIG. 5 is a graph showing the relationship between the concentration of the fluorescent substance and the fluorescence intensity. FIG. 6 is a graph used to explain the threshold value set corresponding to the concentration of the fluorescent substance. FIG. 7 is a flowchart showing the first embodiment of the fluorescence imaging method according to the present invention. FIG. 8 is a graph plotting blood concentrations 5 minutes, 10 minutes, 15 minutes, and 20 minutes after IGC administration. FIG. 9 is a semilogarithmic graph showing the relationship between the time after administration of the fluorescent reagent and the blood concentration. FIG. 10 is a graph showing the difference in the administration method of the fluorescent reagent between the prior art and the present invention. FIG. 11 is a block diagram showing an embodiment of an endoscope apparatus including a fluorescence imaging apparatus according to the present invention. FIG. 12 is a plan view of the rotary filter. FIG. 13 is a flowchart showing a second embodiment of the fluorescence imaging method according to the present invention. FIG. 14 is a timing chart of signal processing when the subject is irradiated with visible light and excitation light alternately. FIG. 15 is a flowchart showing a blood vessel image generation (blood vessel image extraction) process. FIGS. 16A and 16B are schematic diagrams of a normal image and a blood vessel image output to the image composition unit, respectively. FIG. 17 is a block diagram showing the internal configuration of the image composition unit. FIG. 18 is a diagram illustrating an example of a monitor screen on which a composite image is displayed.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1 ... Fluorescence imaging device, 2 ... Subject, 10 ... Imaging device, 12 ... Imaging part, 14 ... Excitation light output part, 20 ... Image processing apparatus, 21 ... ROM, 22 ... Concentration comparison part, 23 ... Correction term calculation part , 24 ... Image generation unit, 25 ... Main control unit, 30 ... Light source unit, 40 ... Display unit, 50 ... Fluorescent substance concentration measuring device, 100 ... Laparoscope, 200 ... Processor, 300 ... Light source device

Claims (16)

A step of continuously irradiating a subject to which a fluorescent substance is administered in a living body with excitation light in a specific wavelength range for causing the fluorescent substance to emit light;
A step of continuously photographing the subject irradiated with the excitation light by the imaging means and acquiring a fluorescence image;
Measuring the concentration of the fluorescent substance in the living body;
Setting a concentration that is lower than an appropriate concentration of the fluorescent substance that provides a desired fluorescence intensity, and at least a concentration at which a reliable fluorescence image can be acquired, as a first threshold;
Determining whether the measured concentration of the fluorescent substance in the living body has decreased to the set first threshold;
Each time it is determined that the measured concentration of the fluorescent substance in the living body has decreased to the first threshold value, the administration of the fluorescent substance is urged so that the concentration of the fluorescent substance in the living body reaches the appropriate concentration. Outputting instructions or automatically administering the fluorescent material;
A fluorescence imaging method comprising:   A step of performing image processing on a fluorescent image continuously photographed by the imaging means, regardless of a variation in the concentration of the fluorescent substance in the living body, by the imaging means when the concentration of the fluorescent substance is at the appropriate concentration. The fluorescence imaging method according to claim 1, further comprising a step of performing image processing so as to generate a fluorescence image equivalent to the captured fluorescence image.   The fluorescence imaging method according to claim 2, wherein the image processing step corrects a fluorescence image continuously captured by the imaging unit based on the measured concentration of the fluorescent substance in the living body.   The image processing step compares the measured concentration of the fluorescent substance in the living body with the appropriate concentration, and corrects the fluorescence image continuously photographed by the imaging means based on the comparison result. The fluorescence imaging method according to claim 2, wherein: Setting a concentration that is lower than the first threshold and is not capable of acquiring a reliable fluorescent image as a second threshold;
When it is determined that the measured concentration of the fluorescent substance in the living body has decreased to the second threshold value, prohibiting photographing of the fluorescent image;
The fluorescence imaging method according to claim 1, further comprising:   6. The appropriate concentration is a concentration at which the fluorescence intensity of the fluorescent material is maximized, or a maximum concentration within a range in which the concentration of the fluorescent material and the fluorescence intensity are substantially proportional to each other. The fluorescence imaging method according to any one of the above.   7. The first threshold value according to claim 1, wherein the first threshold value is a minimum density among the densities capable of photographing a fluorescent image showing a blood vessel from a surface of a living tissue of the subject to a predetermined depth. The fluorescence imaging method according to any one of the above.   The fluorescence imaging method according to claim 7, wherein the predetermined depth is about 2 mm. A light source means for continuously irradiating excitation light in a specific wavelength range for emitting a fluorescent substance to a subject to which the fluorescent substance is administered in a living body at a predetermined time interval;
Imaging means for imaging a subject irradiated with excitation light by the light source means;
A concentration measuring means for measuring the concentration of the fluorescent substance in the living body;
First threshold value setting means for setting, as a first threshold value, a concentration that is lower than an appropriate concentration of the fluorescent material that provides a desired fluorescence intensity and that can obtain a fluorescence image with at least reliability. ,
First determination means for determining whether or not the concentration of the fluorescent substance in the living body measured by the concentration measurement means has decreased to a first threshold set by the first threshold setting means;
Each time it is determined by the first determination means that the measured concentration of the fluorescent substance in the living body has decreased to the set first threshold, the concentration of the fluorescent substance in the living body is set to the appropriate concentration. Outputting a command prompting the administration of the fluorescent substance to reach or a means for automatically administering the fluorescent substance;
A fluorescence imaging apparatus comprising:   Image processing means for performing image processing on a fluorescent image continuously photographed by the imaging means, wherein the imaging is performed when the concentration of the fluorescent substance is at the appropriate concentration regardless of a variation in the concentration of the fluorescent substance in the living body. The fluorescence imaging apparatus according to claim 9, further comprising image processing means for performing image processing so as to generate a fluorescence image equivalent to the fluorescence image photographed by the means.   The said image processing means correct | amends the fluorescence image image | photographed continuously by the said imaging means based on the density | concentration of the fluorescent substance in the living body measured by the said density | concentration measuring means. Fluorescence imaging device.   The image processing means includes comparison means for comparing the concentration of the fluorescent substance in the living body measured by the concentration measurement means with the first threshold value set by the first threshold value setting means, and the comparison means The fluorescence imaging apparatus according to claim 10, wherein a fluorescence image continuously captured by the imaging unit is corrected based on a comparison result obtained in step S11. A second threshold value setting means for setting, as a second threshold value, a density that is lower than the first threshold value and incapable of acquiring a reliable fluorescent image;
A second discriminating unit for discriminating whether or not the concentration of the fluorescent substance in the living body measured by the concentration measuring unit has decreased to the second threshold set by the second threshold setting unit;
When it is determined by the second determination means that the measured concentration of the fluorescent substance in the living body has decreased to the second threshold value, photographing prohibiting means for prohibiting photographing of the fluorescent image;
The fluorescence imaging apparatus according to claim 9, further comprising:   The fluorescence imaging apparatus according to claim 9, wherein the light source unit generates excitation light in a near-infrared wavelength region.   The first threshold value setting means sets, as the first threshold value, the minimum density among the densities at which fluorescence images showing blood vessels from the surface of the living tissue of the subject to a predetermined depth can be taken. The fluorescence imaging device according to any one of claims 9 to 14.   The fluorescence imaging apparatus according to claim 15, wherein the predetermined depth is about 2 mm.

Images