U.S. patent number 5,769,792 [Application Number 08/632,018] was granted by the patent office on 1998-06-23 for endoscopic imaging system for diseased tissue.
This patent grant is currently assigned to Xillix Technologies Corp.. Invention is credited to Jaclyn Y-C Hung, Bruno W. Jaggi, Stephen C-T Lam, Calum E. MacAulay, Branko Palcic, Amedeus E. Profio.
United States Patent |
5,769,792 |
Palcic , et al. |
June 23, 1998 |
**Please see images for:
( Certificate of Correction ) ** |
Endoscopic imaging system for diseased tissue
Abstract
Apparatus for imaging diseases in tissue comprising a light
source for generating excitation light that includes wavelengths
capable of generating characteristic autofluorescence for abnormal
and normal tissue. A fiber-optic illuminating light guide is used
to illuminate tissue with light that includes at least the
excitation light thereby exciting the tissue to emit the
characteristic autofluorescence. An imaging bundle collects emitted
autofluorescence light from the tissue. The autofluorescence light
is filtered into spectral bands in which the autofluorescence
intensity for abnormal tissue is substantially different from
normal tissue and the autofluorescence intensity for abnormal
tissue is substantially similar to normal tissue. An optical system
is used to intercept the filtered autofluorescence light to acquire
at least two filtered emitted autofluorescence images of the
tissue. The acquired images are displayed in real time on a display
monitor in such a manner as to delineate abnormal and normal
tissue.
Inventors: |
Palcic; Branko (Vancouver,
CA), MacAulay; Calum E. (Vancouver, CA),
Jaggi; Bruno W. (Vancouver, CA), Lam; Stephen C-T
(Vancouver, CA), Profio; Amedeus E. (Santa Barbara,
CA), Hung; Jaclyn Y-C (Parkville, AU) |
Assignee: |
Xillix Technologies Corp.
(CA)
|
Family
ID: |
27374189 |
Appl.
No.: |
08/632,018 |
Filed: |
April 15, 1996 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
428494 |
Apr 27, 1995 |
5507287 |
|
|
|
82019 |
Jun 23, 1993 |
|
|
|
|
725283 |
Jul 3, 1991 |
|
|
|
|
Current U.S.
Class: |
600/477; 356/318;
600/478 |
Current CPC
Class: |
A61B
5/0071 (20130101); A61B 5/0084 (20130101); G01N
2021/6463 (20130101) |
Current International
Class: |
A61B
5/00 (20060101); A61B 006/00 () |
Field of
Search: |
;128/633,634,664-666
;356/318 ;250/341.1 ;600/310,317,342,473,475-479 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0215772 |
|
Mar 1987 |
|
EP |
|
58-12675 |
|
Jan 1983 |
|
JP |
|
2-22331 |
|
Jun 1983 |
|
JP |
|
2203831 |
|
Oct 1988 |
|
GB |
|
86/02730 |
|
May 1986 |
|
WO |
|
90/10219 |
|
Sep 1990 |
|
WO |
|
90/12536 |
|
Nov 1990 |
|
WO |
|
Other References
Alfano et al., "Fluorescence Spectra from Cancerous and Normal
Human Breast and Lung Tissues," IEEE Journal of Quantum
Electronics, vol. QE-23, No. 10, 1987, pp. 1806-1811. .
Alfano et al., "Laser Induced Fluorescence Spectroscopy from Native
Cancerous and Normal Tissue," IEEE Journal of Quantum Electronics,
vol. QE-20, No. 12, Dec. 1984, pp. 1507-1511. .
Andersson-Engels et al., "Fluorescence Characteristics of
Atherosclorotic Plaque and Malignant Tumors," SPIE, vol. 1426,
1991, pp. 31-43. .
Andersson-Engels et al., "Tissue Diagnostics Using Laser-Induced
Fluorescence," Ber Bunsenges, Phys. Chem., vol. 93, 1989, pp.
335-342. .
Coffey et al., "Evaluation of Visual Acuity During Laser
Photoradiation Therapy of Cancer," Lasers in Surgery and Medicine,
vol. 4, pp. 65-71. .
Cothren et al., "Gastrointestinal Tissue Diagnosis by Laser-Induced
Fluorescence Spectroscopy at Endoscopy," Gastrointestinal
Endoscopy, vol. 36, No. 2, 1990, pp. 105-111. .
Dougherty et al., "Cutaneous Phototoxic Occurrences in Patients
Receiving Photofrin," Lasers in Surgery and Medicine, vol. 10,
1990, pp. 485-488. .
Hayata et al., "Fiberoptic Bronchoscopic Laser Photoradiation for
Tumor Localization in Lung Cancer," Chest, vol. 82, 1982, pp.
10-14. .
Hirano et al., "Photodynamic Cancer Diagnosis and Treatment System
Consisting of Pulse Lasers and an Endoscopic Spectro-Image
Analyzer," Laser in Life Sciences, vol. 3(1), 1989, pp. 1-18. .
Hung et al., "Autofluorescence of Normal and Malignant Bronchial
Tissue," Lasers in Surgery and Medicine, vol. 11, 1991, pp. 99-105.
.
Ikeda, "New Bronichial TV Endoscopy System," Elsevier Science
Publishers B.V. Biomedical Press, 1988. .
Kapadia et al., "Laser-Induced Fluorescence Spectroscopy of Human
Colonic Mucosa," Gastroenterology, vol. 99, 1990, pp. 150-157.
.
Kato et al., "Early Detection of Lung Cancer by Means of
Hematoporphyrin Derivative Fluorescence and Laser Photoradiation,"
Clinics in Chest Medicine, vol. 6, No. 2, 1985, pp. 237-253. .
Kato et al., Photodynamic Diagnosis in Respiratory Tract Malignancy
Using an Excimer Dye Laser System, Journal of Photochemistry and
Photobiology, B:Biology, vol. 6, 1990, pp. 189-196. .
Lam et al., "Fluorescence Detection," Advances in the Diagnosis and
Therapy of Lung Cancer, Blackwell Scientific Publications Inc.
.
Lam et al., "Fluorescence Imaging of Early Lung Cancer," IEEE Eng.
Med. Biology, vol. 12, 1990. .
Lam et al., "Detection of Lung Cancer by Ratio Fluorometry With and
Without Photofrin II," SPIE Proc. vol. 1201, 1990, pp. 561-568.
.
Lam et al., Detection of Early Lung Cancer Using Low Dose Photofrin
II, Chest, vol. 97, 1990, pp. 333-337. .
Lam et al., "Mechanism of Detection of Early Lung Cancer by Ratio
Fluorometry," Lasers in Life Sciences, vol. 4(2), 1991, pp. 67-73.
.
Montan et al., "Multicolor Imaging and Contrast Enhancement in
Cancer-Tumor Localization Using Laser-Induced Fluorescence in
Hematoporphyrin-derivative-bearing Tissue," Optics Letters, vol.
10(2), 1985, pp. 56-58. .
Mullooly et al., "Dihematoporphyrin Ether-Induced Photosensitivity
in Laryngeal Papilloma Patients," Lasers in Surgery and Medicine,
vol. 10, 1990, pp. 349-356. .
Palcic et al., "Development of a Lung Imaging Fluorescence
Endoscope," Proceedings of the 12th Annual Int'l Conference of the
IEEE Engineering in Medicine and Biology Society, vol. 12, No. 1,
1990. .
Palcic et al., "The Importance of Image Quality for Computing
Texture Features in Biomedical Specimens," SPIE Proc., vol. 1205,
1990, pp. 155-162. .
Palcic et al. "Lung Imaging Fluorescence Endoscope: A Device for
Detection of Occult Lung Cancer," Medical Design and Material,
1991. .
Palcic et al., "Lung Imaging Fluorescence Endoscope: Development
and Experimental Prototype," SPIE, vol. 1448, 1991, pp. 113-117.
.
Palcic et al., "Detection and Localization of Early Lung Cancer by
Imaging Techniques," Chest, vol. 99, 1991, pp. 742-743. .
Peak et al., "DNA-to-Protein Crosslinks and Backbone Breaks Caused
by FAR- and NEAR-Ultraviolet and Visible Light Radiations in
Mammalian Cells," Mechanism of DNA Damage and Repair, Implications
for Carcinogenesis and Risk Assessment, 1986, pp. 193-202. .
Profio et al., "Digital Background Subtraction for Fluorescence
Imaging," Medical Physics, vol. 13(5), 1988, pp. 717-727. .
Profio et al., "Endoscopic Fluorescence Detection of Early Lung
Cancer," SPIE, vol. 1426, 1991, pp. 44-46. .
Profio et al., "Fluorometer for Endoscopic Diagnosis of Tumors,"
Medical Physics, vol. 11(4), 1984, pp. 516-520. .
Profio et al., "Laser Fluorescence Bronchoscope for Localization of
Occult Lung Tumors," Medical Physics, vol. 6, 1979, pp. 523-525.
.
Rava et al., "Early Detection of Dysplasia in Colon and Bladder
Tissue Using Laser Induced Fluorescence," SPIE, vol. 1426, 1991,
pp. 68-78. .
Razum et al., "Skin Photosensitivity: Duration and Intensity
Following Intravenous Hematoporphyrin Derivatives, H.sub.p D and
DHE," Photochemistry and Photobiology, vol. 46, No. 5, 1987, pp.
925-928. .
Richards-Kortum et al., "Spectroscopic Diagnosis of Colonic
Dysplasia: Spectroscopic Analysis," Biochemistry and Photobiology,
vol. 53, No. 6, 1991, pp. 777-786. .
Tang et al., "Spectroscopic Differences Between Human Cancer and
Normal Lung and Breast Tissues," Lasers in Surgery and Medicine,
vol. 9, 1989, pp. 290-295. .
Wagnieres et al., "Photodetection of Early Cancer by Laser Induced
Fluorescence of a Tumor-Selective Dye: Apparatus Design and
Realization," SPIE Proc., vol. 1203, 1990, pp. 43-52. .
Wooten et al., "Prospective Study of Cutaneous Phototoxicity After
Systemic Hematoporphyrin Derivative," Lasers in Surgery and
Medicine, vol. 8, 1988, pp. 294-300..
|
Primary Examiner: Smith; Ruth S.
Attorney, Agent or Firm: Christensen, O'Connor, Johnson
& Kindness PLLC
Parent Case Text
RELATED APPLICATIONS
The present application is a continuation of our previous
application Ser. No. 08/428,494, filed Apr. 27, 1995, now U.S.
Patent No. 5,507,287, which was a continuation of application Ser.
No. 08/082,019, filed Jun. 23, 1993, now abandoned which was a
continuation of application Ser. No. 07/725,283, filed Jul. 3,
1991, now abandoned the benefit of the filing date of which is
being claimed under 35 U.S.C. .sctn. 120, and which is herein
incorporated by reference.
Claims
The embodiments of the invention in which an exclusive property or
privilege is claimed are defined as follows:
1. Apparatus for imaging diseases in tissue using autofluorescence
comprising:
a visible light source for generating excitation light that
includes wavelengths that generate characteristic autofluorescence
for abnormal and normal tissue;
means for illuminating tissue with light from the visible light
source that includes at least said excitation light thereby
exciting tissue to emit said characteristic autofluorescence;
collecting means for gathering reflected excitation light and
emitted autofluorescence light from said tissue;
a dichroic mirror positioned to receive the reflected excitation
light and the emitted autofluorescence light gathered by the
collecting means, the dichroic mirror operating to separate the
spectral components of said autofluorescence light into at least a
first spectral band including the reflected excitation light and
the emitted autofluorescence light having wavelengths where an
autofluorescence intensity for abnormal tissue is substantially
different from normal tissue and a second spectral band different
from said first spectral band including the emitted
autofluorescernce light having wavelengths where an
autofluorescence intensity for abnormal tissue is substantially
similar to normal tissue;
a first optical filter positioned to receive the light within the
first spectral band, said first filter operating to remove the
reflected excitation light from light within the first spectral
band;
a second optical filter positioned to receive the light within the
second spectral band;
a first detector array for receiving the autofluorescence light
within the first spectral band and for producing a first
autofluorescence image of the tissue;
a second detector array for receiving the autofluorescence light
within the second spectral band and for producing a second
autofluorescence image of the tissue; and
a color monitor that simultaneously displays the first and second
autofluorescence images.
2. The apparatus of claim 1, in which the visible light source is a
laser.
3. The apparatus of claim 1, in which the visible light source is a
Xenon light source.
4. The apparatus of claim 1, wherein the dichroic mirror has a
cutoff wavelength in the range of 600 nanometers.
5. The apparatus of claim 1, wherein the first optical filter is a
band pass filter having a center frequency of about 500 nanometers
and a band-pass of about .+-.20 nanometers.
6. The apparatus of claim 1, wherein the second optical filter is a
red, long pass filter having a cutoff frequency of 630
nanometers.
7. The apparatus of claim 1, in which the means for illuminating
tissue is a fiber-optic light guide.
8. The apparatus of claim 7, in which the collecting means is an
imaging bundle and a focusing lens disposed within the fiber-optic
light guide.
9. Apparatus for imaging diseases in tissue using autofluorescence
comprising:
a visible light source for generating excitation light that
includes wavelengths that generate characteristic autofluorescence
for abnormal and normal tissue;
means for illuminating tissue with light from the visible light
source that includes at least said excitation light thereby
exciting tissue to emit said characteristic autofluorescence;
collecting means for gathering a reflected excitation light and an
emitted autofluorescence light from said tissue;
means for separating the spectral components of the collected
reflected excitation light and the emitted autofluorescence light
gathered by the collecting means, into at least a first spectral
band including the reflected excitation light and the emitted
autofluorescence light having wavelengths where an autofluorescence
intensity for abnormal tissue is substantially different from
normal tissue and a second spectral band different from said first
spectral band including the emitted autofluorescence light having
wavelengths where an autofluorescence intensity for abnormal tissue
is substantially similar to normal tissue;
a first optical filter positioned to receive the light within the
first spectral band, said first filter operating to remove the
reflected excitation light from light within the first spectral
band;
a second optical filter positioned to receive the light within the
second spectral band;
a first CCD camera for receiving the autofluorescence light within
the first spectral band and for producing a first autofluorescence
image of the tissue;
a second CCD camera for receiving the autofluorescence light within
the second spectral band and for producing a second
autofluorescence image of the tissue; and
a color monitor that simultaneously displays the first and second
autofluorescence image.
10. The apparatus of claim 9, wherein the means for separating the
spectral components of the collected reflected excitation light and
the autofluorescence light into the first and second spectral bands
comprises a dichroic mirror.
11. The apparatus of claim 10, wherein the dichroic mirror has a
cutoff wavelength of nearly 600 nanometers.
12. The apparatus of claim 9, wherein the means for separating the
spectral components of the collected reflected excitation light and
the autofluorescence light into the first and second spectral bands
comprises a prism.
13. The apparatus of claim 9, in which the visible light source is
a laser.
14. The apparatus of claim 9, in which the visible light source is
a Xenon light source.
15. The apparatus of claim 9, wherein the first optical filter is a
band pass filter having a center frequency of about 500 nanometers
and a band-pass of about .+-.20 nanometers.
16. The apparatus of claim 9, wherein the second optical filter is
a red, long pass filter having a cutoff frequency of 630
nanometers.
17. The apparatus of claim 9, in which the means for illuminating
tissue is a fiber-optic light guide.
18. The apparatus of claim 17, in which the collecting means is an
imaging bundle and a focusing lens disposed within the fiber
optic-light guide.
19. Apparatus for imaging diseases in tissue using autofluorescence
comprising:
a visible light source for generating excitation light that
includes wavelengths that generate characteristic autofluorescence
for abnormal and normal tissue;
a fiber optic light guide for illuminating tissue with light from
the visible light source that includes at least said excitation
light thereby exciting tissue to emit said characteristic
autofluorescence;
collecting means for gathering reflected excitation light and
emitted autofluorescence light from said tissue;
a dichroic mirror positioned to receive the reflected excitation
light and the emitted autofluorescence light gathered by the
collecting means, the dichroic mirror operating to separate the
spectral components of said autofluorescence light into at least a
first spectral band including the reflected excitation light and
the emitted autofluorescence light having wavelengths where an
autofluorescence intensity for abnormal tissue is substantially
different from normal tissue and a second spectral band different
from said first spectral band including the emitted
autofluorescence light having wavelengths where an autofluorescence
intensity for abnormal tissue is substantially similar to normal
tissue;
a first optical filter positioned to receive the light within the
first spectral band, said first filter operating to remove the
reflected excitation light from light within the first spectral
band;
a first detector array for receiving the autofluorescence light
within the first spectral band and for producing a first
autofluorescence image of the tissue;
a second detector array for receiving the autofluorescence light
within the second spectral band and for producing a second
autofluorescence image of the tissue; and
a color monitor that simultaneously displays the first and second
autofluorescence image.
20. The apparatus of claim 19, in which the visible light source is
a laser.
21. The apparatus of claim 19, in which the visible light source is
a Xenon light source.
22. The apparatus of claim 21, wherein the dichroic mirror has a
cutoff wavelength in the range of 600 nanometers.
23. The apparatus of claim 22, wherein the first optical filter is
a band pass filter having a center frequency of about 500
nanometers and a band-pass of about .+-.20 nanometers.
24. The apparatus of claim 19, further comprising a second optical
filter positioned to receive the light within the second spectral
band.
25. The apparatus of claim 24, wherein the second filter is a red,
long pass filter having a cutoff frequency of 630 nanometers.
26. The apparatus of claim 19, in which the collecting means is an
imaging bundle and a focusing lens disposed within the fiber-optic
light guide.
27. Apparatus for imaging diseases in tissue using autofluorescence
comprising:
a visible light source for generating excitation light that
includes wavelengths that generaie characteristic autofluorescence
for abnormal and normal tissue;
a fiber optic light guide for illuminating tissue with light from
the visible light source that includes at least said excitation
light thereby exciting tissue to emit said characteristic
autofluorescence;
collecting means for gathering a reflected excitation light and an
emitted autofluorescence light from said tissue;
means for separating the spectral components of the collected
reflected excitation light and the emitted autofluorescence light
gathered by the collecting means, into at least a first spectral
band including the reflected excitation light and the emitted
autofluorescence light having wavelengths where an autofluorescence
intensity for abnormal tissue is substantially different from
normal tissue and a second spectral band different from said first
spectral band including the emitted autofluorescence light having
wavelengths where an autofluorescence intensity for abnormal tissue
is substantially similar to normal tissue;
a first optical filter positioned to receive the light within the
first spectral band, said first filter operating to remove the
reflected excitation light from light within the first spectral
band;
a first CCD camera for receiving the autofluorescence light within
the first spectral band and for producing a first autofluorescence
image of the tissue;
a second CCD camera for receiving the autofluorescence light within
the second spectral band and for producing a second
autofluorescence image of the tissue; and
a color monitor that simultaneously displays the first and second
autofluorescence images.
28. The apparatus of claim 27, wherein the means for separating the
spectral components of the collected reflected excitation light and
the autofluorescence light into the first and second spectral bands
comprises a dichroic mirror.
29. The apparatus of claim 28, wherein the dichroic mirror has a
cutoff wavelength of nearly 600 nanometers.
30. The apparatus of claim 27, wherein the means for separating the
spectral components of the collected reflected excitation light and
the autofluorescence light into the first and secoirid spectral
bands comprises a prism.
31. The apparatus of claim 27, in which the visible light source is
a laser.
32. The apparatus of claim 27, in which the visible light source is
a Xenon light source.
33. The apparatus of claim 32, wherein the first optical filter is
a band pass filter having a center frequency of about 500
nanometers and a band-pass of about .+-.20 nanometers.
34. The apparatus of claim 27, further comprising a second optical
filter positioned to receive the light within the second spectral
band.
35. The apparatus of claim 27, wherein the second optical filter is
a red, long pass filter having a cutoff frequency of 630
nanometers.
36. The apparatus of claim 25, in which the collecting means is an
imaging bundle and a focusing lens disposed within the fiber
optic-light guide.
Description
FIELD OF THE INVENTION
This invention relates to an apparatus for imaging abnormal tissues
in the body to locate and identify areas that are otherwise not
recognizable by white light endoscopy. The invention is
particularly suited for imaging abnormal bronchial tissues to
detect conditions such as inflammation, denudation, dysplasia and
noninvasive early cancer (carcinoma in situ).
BACKGROUND OF THE INVENTIKON
At present, the most effective method for examination of body
cavities in human patients is by endoscopes. For examination of the
air passages of the lung, a flexible endoscope is usually used,
commonly referred to as a bronchoscope. Bronchoscopes, like all
endoscopes, employs visible white light to illuminate the surface
under examination. The illuminating light is brought into the air
passages (bronchi) of the lungs via a fiber-optic illuminating
light guide. The reflected and scattered light from the bronchial
tissues is captured by a projection lens which focuses the image
into the bronchoscope's imaging bundle. The imaging bundle is
composed of several thousand individually wrapped fibers, which
transmit a coherent image to the exterior of the body. This image
is then projected through the ocular of the bronchoscope for human
observation. A color video camera can be attached to the eyepiece
of the bronchoscope such that color images of scattered/reflected
white (broadband) light can be viewed on a color video monitor.
Using a conventional bronchoscope, large invasive cancers can be
readily seen. However, focal inflammation, denudation, dysplasia,
and early lung cancers cannot be readily seen by such an
apparatus.
Several methods have been developed to visualize small early lung
cancers which are difficult to detect by ordinary white light
bronchoscopy. All of these involve the use of tumor localizing
drugs, e.g., Haematoporphyrin derivatives or Porfimer sodium, which
have been shown to be preferentially retained in tumor tissues.
Some of these drugs also fluoresce and their fluorescence can be
detected by non-imaging and imaging devices (A.E. Proflo et al.,
Med Phys. 6:532-535, 1979; A.E. Proflo et al., Med Phys.
11:516-520, 1984; A.E. Profio et al., Med Phys. 13:717-721, 1986;
Y. Hayata et al., Chest 82:10-14, 1982; A. Kato, D.A. Cortese,
Clin. Chest Med 6:237-253, 1985; S. Montan et al., Opt Letters
10:56-58, 1985). The drawback of these techniques is the use of
drugs which may have serious side effects and therefore may not be
appropriate for diagnostic purposes. In addition, the use of
non-imaging devices such as the ratio fluorometer probe (AE. Proflo
et al., Med Phys. 11:516-520, 1984) cannot delineate the exact site
and dimensions of the abnormal areas.
An alternative approach for detecting invasive tumors has been
proposed by Alfano et al. in U.S. Pat. No. 4,930,516, issued Jun.
5, 1990. Alfano discloses a method of detecting cancers on the
basis that the fluorescence spectra of cancerous tissues is
different from normal tissues in that the maximal fluorescence peak
of tumor tissues is blue shifted to lower wavelengths (from 531 nm
to 521 nm). These observations were made based on in vitro
measurements in excised, large (invasive) animal and human tumors
but have not been reported on human tumors in vivo. In addition,
there are no reports of other abnormal tissues such as inflamed or
precancerous tissues. We have measured tissue autofluorescence in
human patients in vivo using different excitation wavelengths
including 405 nm, 442 nm, and 488 nm by a specially designed
optical multichannel analyzer which can be attached to a
conventional bronchoscope. Contrary to the observation by Alfano et
al., we did not find any difference in the shape of the
fluorescence spectrum between normal and tumor tissues using these
excitation wavelengths, in particular, there was no blue shift of
the emission peaks. We observed a significant difference in the
overall fluorescence intensity especially in the green region of
the visible spectrum. A significant but a lesser decrease in the
overall fluorescence intensity was also found in precancerous and
non-cancerous lesions (dysplasia and metaplasia).
The decreased green fluorescence may be attributed to a reduced
level of oxidized form of riboflavin. Riboflavin emits strongly in
the green region and is believed to be predominantly responsible
for the strong green fluorescence in normal human lung tissue. In
the cancerous tissues, much less riboflavin was found (M.A. Pollack
et al., Cancer Res. 2:739-743, 1942) and/or is present in the
reduced state. This may account for the reduced autofluorescence in
premalignant and malignant bronchial tissues.
Tests were conducted revealing examples of such decreased tissue
autofluorescence for dysplastic bronchial tissue, and carcinoma in
situ. It was determined that the main difference between abnormal
and normal tissues is manifested by a greatly reduced fluorescence
intensity in the region of the spectrum from 480 nm-600 nm. At
wavelengths greater than approximately 635 nm, the tissue
autofluorescence is approximately the same between abnormal and
normal tissues. Tests were conducted using excitation light of 442
nm, 405 nm and 488 nm and abnormal tissue results were compared to
normal tissue results. All of these data were obtained in vivo
during standard fiber-optic bronchoscopy using the optical
multichannel analyzer.
Because of the observed large decrease in the emitted fluorescence
without a change in the spectral profile in the abnormal tissues,
methods using rationing of two or more wavelengths that was
originally described by Profio and coworkers and then studied in
patients who have received fluorescent drugs such as Photoflin
(Profo et al., Med Phys. 11:516-520, 1984) generally will not
differentiate abnormal from normal bronchial tissues using
autofluorescence alone.
We have invented and constructed an apparatus which exploits
differences in autofluorescence intensity for the detection and
delineation of the extent of abnormal areas in the human body,
particularly the lung.
SUMMARY OF THE INVENTION
The present invention provides an imaging apparatus that uses
autofluorescence characteristics of tissues to detect and delineate
the extent of abnormal tissues in human patients in vivo. Capture
and analysis of the autofluorescence images is achieved using a
highly sensitive detector such as an image intensified CCD camera.
A pseudo image is generated by sending one image to the red channel
and one image to the green channel of an RGB video monitor. By
capturing the two images simultaneously or sequentially within a
few milliseconds, pseudo image generation in real time can be
achieved. The pseudo images can clearly delineate the diseased
tissue from the surrounding normal tissue.
Accordingly, the present invention provides an apparatus for
imaging diseases in tissue comprising:
a light source for generating excitation light that includes
wavelengths capable of generating characteristic autofluorescence
for abnormal and normal tissues;
means for illuminating tissue with light that includes at least
said excitation light thereby exciting the tissue to emit said
characteristic autofluorescence;
collecting means for gathering emitted autofluorescence light from
said tissue;
means for filtering said autofluorescence light into spectral bands
in which said autofluorescence intensity for abnormal tissue is
substantially different from normal tissue and said
autofluorescence intensity for abnormal tissue is substantially
similar to normal tissue;
optical means for intercepting said filtered autofluorescence light
to acquire at least two filtered emitted autofluorescence images of
the tissue; and
display means for displaying said acquired images in such a manner
as to delineate abnormal and normal tissue.
In a preferred embodiment, the apparatus of the present invention
is used with a standard bronchoscope for imaging abnormal bronchial
tissues.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing aspects and many of the attendant advantages of this
invention will become more readily appreciated as the same becomes
better understood by reference to the following detailed
description, when taken in conjunction with the accompanying
drawings, wherein:
FIGS. 1A to 1D provide examples of autofluorescence spectrums at
selected excitation wavelengths which indicate the difference
between abnormal and normal tissue;
FIG. 2 is a schematic diagram showing the apparatus of the present
invention useful for imaging abnormal lung tissue;
FIG. 3 shows details of the illumination module;
FIG. 4A shows the filtering and optical means of the present
invention in which a single sensitive detector is used to acquire
fluorescence images sequentially;
FIG. 4B shows alternative filtering and optical means m which
fluorescence images are acquired simultaneously using two sensitive
cameras;
FIG. 4C shows a still further filtering and optical means in which
a prism element is incorporated to allow two fluorescence images to
be acquired simultaneously together with a reflected/scattered
excitation light image.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
While the preferred embodiment of the invention has been
illustrated and described, it will be appreciated that various
changes can be made therein without departing from the spirit and
scope of the invention.
FIG. 1 shows examples of decreased tissue autofluorescence for
dysplastic bronchial tissue and carcinoma in situ. The main
difference between abnormal and normal tissues is manifested by a
greatly reduced fluorescence intensity in the region of the
spectrum from 480 nm-600 nm. At wavelengths greater than
approximately 635 nm, the tissue autofluorescence is approximately
the same between abnormal and normal tissues. For the results in
FIGS. 1A and 1B, a 442 nm, Helium Cadmium laser light was used to
excite the tissues. FIG. 1A shows tissue autofluorescence spectra
of normal and dysplastic tissues and FIG. 1B shows a carcinoma in
situ (CIS) lesion compared to the normal tissue of a different
patient. Similar results were found when employing other excitation
light, e.g., 405 nm, FIG. 1C, and 488 nm, FIG. 1D. In both cases
carcinoma in situ patients are compared to their normal lung
tissue. All of these data were obtained in vivo during standard
fiber-optic bronchoscopy using an optical multichannel
analyzer.
The apparatus of the present invention is designed to exploit the
difference in fluorescence intensity in different regions of the
spectrum to identify and delineate abnormal tissue.
The apparatus of the present invention adapted for use in examining
bronchial tissues of the lung in patients is schematically
illustrated in FIG. 2. As such, the apparatus is integrated with a
conventional bronchoscope used for examining bronchial tissue of
the lung.
There is a light source 1 for generating excitation light that
includes wavelengths capable of generating characteristic
autofluorescence spectra for abnormal and normal tissue. The light
source 1 is shown in greater detail in FIG. 3 and preferably
includes a laser light source 7 capable of producing excitation
light at a selected desirable wavelength. A white light source such
as an incandescent Xenon light source 8 can be used for white light
illumination when desired. The laser light source 7 is used to
generate pseudo images derived from tissue autofluorescence while
the white light source is used to generate color images of
reflected/scattered white light.
The light from each light source passes through synchronizing means
that allow for alternate illumination of the tissue by the laser
light and the white light source. In the embodiment illustrated in
FIG. 3, the synchronizing means comprises blocking means in the
form of electronically controlled shutters 9 and 13 associated with
laser light source 7 and Xenon light source 8, respectively. When
shutter 9 is open to allow laser light to pass, shutter 13 is
closed to prevent passage of white light and vice versa. The light
from the laser light source 7 passes through shutter 9 when open, a
mirror with a pin hole 10, and a lens 11 which focuses the laser
light onto means for illuminating the tissue with light comprising
a conventional bronchoscope light guide 12. Light guide 12 conducts
the excitation light to the tissue area under examination. The
tissue, upon illumination with the laser light, emits its
characteristic autofluorescence for abnormal and normal tissue. To
generate regular white light illumination images, shutter 9 is
closed and previously closed shutter 13 is opened to allow the
light from Xenon light source 8 to pass through shutter 13. The
white light is then filtered by a neutral density filter set 14,
reflected by a mirror 15, and passes through a lens 16 which
focuses the light onto bronchoscope light guide 12 after being
reflected off mirror 10 and through lens 11. The neutral density
filter set 14 is used to condition the light from the Xenon source
such that it is of the appropriate intensity for the light sensors
used in the apparatus. Thus the white light conducted to the tissue
illuminates the tissue under examination. Light guide 12 ensures
that the light is evenly dispersed over the area under
examination.
In the present embodiment, the bronchoscope provides the collecting
means to gather images in the form of the bronchoscope lens (not
shown) which collects scattered and reflected light, or emitted
autofluorescence light from within the lung for transmission out of
the body by imaging bundle 2 of the bronchoscope. This collected
light is transmitted to a focusing lens 21 of the bronchoscope
ocular coupled to the imaging bundle.
From the ocular of the bronchoscope, the collected light enters the
image acquisition module 3 which includes means for filtering the
autofluorescence light and optical means for intercepting the
filtered light. Various embodiments of image acquisition module 3
are possible.
FIG. 4A illustrates an image acquisition module that includes
filtering means and optical means that allow for acquisition of
emitted autofluorescence images sequentially. In this embodiment,
the means for filtering the autofluorescence light comprises a
series of filters that are sequentially insertable into the path of
the emitted autofluorescence light to generate a sequence of
filtered autofluorescence images. Filter wheel 18 is provided and
is rotatably mounted beneath the optical means of the image
acquisition module. When laser excitation light 7 is used, it is
necessary to filter the autofluorescence light generated into at
least two spectral bands. In one spectral band, the
autofluorescence intensity for abnormal tissue is substantially
different from that of normal tissue and in the other spectral
band, the autofluorescence intensity is substantially similar to
that of normal tissue. For example, in accordance with the
characteristic spectral bands indicated in FIGS. 1A to 1D for lung
examination, filter wheel 18 would be fitted with two filters. For
laser excitation light of 442 nm or 405 nm, a green filter of
500.+-.20 nm and a red 630 nm long pass filter would be used. The
green filter would filter the autofluorescence light into a
spectral band in which the autofluorescence intensity for abnormal
tissue is substantially different from that of normal tissue while
the red long pass filter would filter the light into a spectral
band in which the autofluorescence intensity is substantially
similar for abnormal and normal tissue. The two filters are mounted
in filter wheel 18 such that each covers one-half of the filter
surface. By rotating filter wheel 18 at an appropriate speed, red
and green filtered autofluorescence images can be captured
sequentially by optical means in the form of a single highly
sensitive detector 17 such as an image intensified CCD camera.
The foregoing image acquisition module also includes additional
optical means for capturing reflected/scattered white light images
when white light source 8 is providing illumination of the tissue.
A movable mirror 20 is provided that is insertable into the path of
the collected light transmitted by ocular lens 21. Mirror 20 is
positionable to deflect white light into a color video camera 22
for acquisition of white light images. Necessarily, the movement of
mirror 20 is controlled such that the mirror deflects the collected
light into video camera 22 only when white light source 8 is
providing illumination. Using white light source 8, color images
can be generated on a color monitor in the same way as in
conventional bronchoscopy. When laser light source 7 is
illuminating the tissue, mirror 20 is removed from the light path
to allow for filtering of the autofluorescence light and subsequent
acquisition by detector 17.
FIG. 4B illustrates an alternative arrangement of image acquisition
module 3 in which the optical means comprises at least two
photodetectors that acquire filtered autofluorescence images
simultaneously. Each photodetector has associated filtering means.
For simultaneous collection of autofluorescence images, filter
wheel 18 of the embodiment of FIG. 4A is replaced by beam splitting
means in the form of a dichroic mirror 24 which allows the red
light >600 nm to pass but reflects the shorter wavelengths. In
this case, additional filters 25 and 26 for exact selection of the
desired autofluorescence light can be employed and the respective
images are focused onto two independent, sensitive photodetectors
such as image intensified CCD cameras 17 and 23. In FIG. 4, filter
25 is a red 630 nm long pass filter to further filter red light
passed by dichroic mirror into a spectral band in which
autofluorescence intensity is substantially similar for normal and
abnormal tissue. Filter 26 is a green filter of 500.+-.20 nm for
filtering the autofluorescence light into a spectral band in which
the autofluorescence intensity for abnormal tissue is substantially
different from that of normal tissue. Images acquired by the image
intensified CCD camera 17 and/or image intensified CCD camera 23
are fed into red and green input channels of an RGB color monitor 5
(FIG. 1).
As in the arrangement of FIG. 4A, reflected/scattered white light
images created by white light source 8 are captured by a color
camera 22 and are displayed directly onto the color monitor for
visualization of the examined site using an identical movable
mirror 20 insertable into the light path whenever white light
source 8 is providing illumination.
FIG. 4C illustrates a further embodiment of an image acquisition
module for use with the apparatus of the present invention. A prism
element 27 is provided that simultaneously splits collected light
into a plurality of directions. By alternating between laser light
source 7 and white light source 8, it is possible to capture
sequentially both autofluorescence images and white light images
within a 33 millisecond cycle time, therefore allowing a view of
white (broadband) light color images and pseudo fluorescence images
at the same time on display means.
A specially developed camera with three photodetectors 28, 29 and
30 is provided. The prism 27 splits the collected light into three
images which are then captured by the three separate detectors.
Photodetectors 28 and 29 comprise CCD imaging devices that are
provided with associated image intensifiers 37 and 38 and
photodetector 30 is a regular CCD imaging device. Each
photodetector has its own filter 32, 33 and 34, respectively, as
well as an x,y,z micropositioner 31. Filters 32 and 33 are the same
as in the previous embodiments: a 500.+-.20 nm green filter 33, and
a 630 nm long pass filter 33. CCD imaging device 30 has an
associated broadband blue filter 34.
As best shown in FIG. 2, associated camera control electronics 4
are such that they generate three image signals, a red signal
produced by red filter 32 and intensified CCD imaging device 28, a
green signal produced by green filter 33 and intensified CCD
imaging device 29 and a blue signal produced by blue filter 34 and
nonintensified CCD imaging device 30.
In all of the above embodiments, one can employ a specially
designed CCD imaging device instead of an image intensified
detector. For example, particularly when a lesser spatial
resolution is required, several pixels of a sensitive scientific
CCD detector can be electronically combined into a single very
large pixel which allows very low signals to be detected.
All or some of the image signals produced by the various image
acquisition modules of the present invention may be displayed
directly on color monitor 5 or processed by image processing means
prior to display. The apparatus of the present invention can switch
between white (broadband) light illumination and laser illumination
in one-thirtieth of a second.
Under laser illumination, the image acquisition module of FIG. 4C
can collect autofluorescence images of the tissue over two selected
areas of the spectra and a blue scattered/reflected excitation
light image all simultaneously. These images can be combined either
visually or mathematically via image processing means to make
distinguishable the various tissue types present in the image. With
white light illumination, the apparatus can collect red, green and
blue reflected/scattered light images so as to make possible a
regular color image of the tissues.
Furthermore, the color image can be combined with the
autofluorescence blue laser illuminated images to enhance the
detection, localization, and delineation of the various
tissues.
For different tissues and/or diseases, a different combination of
filters is employed to enhance the differences between normal and
diseased tissues based on the characteristic emitted
autofluorescence light of the diseased tissue under study.
As shown in FIG. 2, the present invention is preferably provided
with image processing means in the form of an imaging board 35
associated with a computer 6 that controls and coordinates
operation of the apparatus. Imaging board 35 allows images to be
digitally captured if desired. Board 35 acts to digitize the
filtered images provided by the image acquisition modules and
enhance the digitized images by application of transformational
algorithms to produce pseudo computed images in real time for
display on video monitor 5. Alternatively, the digitized images can
be stored in computer memory.
The pixel values in the digitized images can be used to calculate a
value for each image pixel, using a mathematical transformation, so
that all pixels covering the diseased tissue site are clearly
different from those of the normal tissue. This process can be used
to enhance the images, to enable the measurement of the degree of
the disease, and make possible other applications and/or
measurements.
Several mathematical algorithms have been developed that allow the
creation of different computed pseudo images from the digitized
emitted autofluorescence images and scattered/reflected light
images, provided the autofluorescence images are captured over the
spectral areas that are characteristic and appropriate for the
specific tissue disease. Examples of appropriate mathematical
algorithms that can be programmed and applied to the digitized
images include hue, contrast and intensity functions, principal
component decomposition algorithms, logarithm of differences, and
subtraction algorithms, all of which delineate normal tissues from
the diseased tissues.
One transformation which has been reported with tumor localizing
drugs (A.E. Profio, Med Phys. 11:516-520, 1984) was found by us not
to be useful for the imaging method; with the exception of large
invasive cancers, it often fails to reveal the abnormal areas.
In a preferred embodiment of the present invention, digitization of
images and image processing is not required. By employing color
monitor 5 and the human visual system, it is possible to depict
differences between the normal and diseased site as differences in
perceived color.
When using the image acquisition module of FIG. 4B having two
sensitive CCD cameras, one camera feeds the Red channel and the
other feeds the Green channel of the RGB color monitor 5. The red
tissue autofluorescence of the abnormal and normal bronchial
tissues is approximately the same. The green tissue
autofluorescence is dramatically decreased in the abnormal site
compared to normal tissue. Therefore the abnormal site appears much
less green and much more reddish and/or sandy colored compared to
the surrounding normal tissue which looks bright green, as green
fluorescence is much more dominant than red fluorescence in normal
tissue. This preferred embodiment allows visualization of the
diseased sites in real time without any processing of the images
and is therefore very inexpensive.
The same result can be achieved using the single CCD camera and
filter wheel of the image acquisition module of FIG. 4A. In this
case, two sequential red and green fluorescence images must be
electronically combined at video rates to be fed as red and green
input signals for an RGB monitor.
Alternatively, two different spectral bands of tissue
autofluorescence are acquired and interpreted as red and green
signals for color display on a color monitor. This gives excellent
pseudo images of inflamed tissue, dysplastic tissue and
non-invasive cancer; clearly delineating these tissues from normal
tissue. The decrease in diseased tissue autofluorescence,
particularly in the green region, indicates the presence of the
disease as well as the severity of the disease.
If tumor localizing drugs are used, the apparatus of the present
invention can be used to visualize small and large tumors. For
example, for drugs such as Photoflin (Porfimer sodium), the same
filters can be used as the drug emits fluorescence at peak values
of 630 nm and 690 nm. In this case all sites where the drug has
localized will also be clearly delineated from the normal
tissues.
Although the present invention has been described in some detail by
way of example for purposes of clarity and understanding, it will
be apparent that certain changes and modifications may be practiced
within the scope of the appended claims.
* * * * *