U.S. patent application number 12/099876 was filed with the patent office on 2008-08-07 for system and method for determining tissue characteristics.
Invention is credited to Anant Agrawal, Shabbir Bambot, Mark L. Faupel, Andrew Fordham, Keith D. Ignotz.
Application Number | 20080188736 12/099876 |
Document ID | / |
Family ID | 46299848 |
Filed Date | 2008-08-07 |
United States Patent
Application |
20080188736 |
Kind Code |
A1 |
Bambot; Shabbir ; et
al. |
August 7, 2008 |
SYSTEM AND METHOD FOR DETERMINING TISSUE CHARACTERISTICS
Abstract
A method and apparatus are provided that interrogate, receive,
and analyze full emission spectra for at least one fluorescence
excitation wavelength and for at least one reflectance measurement
to determine tissue characteristics. The method includes
illuminating a first portion of a target tissue with optical
energy, forming a first image of the target tissue, illuminating a
second portion of the target tissue with optical energy, performing
spectroscopic measurements on optical energy reflected and/or
emitted by the target tissue upon illumination of the second
portion of the target tissue with optical energy, and determining
tissue characteristics of the target tissue based on the results of
the spectroscopic measurements. The apparatus and system include a
base unit having illumination, detection and control sub-units, the
illumination sub-unit providing illumination optical energy for
illuminating a target tissue and the detection sub-unit detecting
tissue characteristics of a target tissue, a separate tissue
interface unit, and a pathway coupling the base unit and the tissue
interface unit. The system and apparatus may also include a tissue
interface unit configured to perform spectroscopic measurements on
a target tissue, a docking unit configured to support the tissue
interface when not in use, the docking unit including an
illumination source and a processor that processes spectrographic
measurements results received from the tissue interface unit, and a
pathway coupling the docking unit and the tissue interface
unit.
Inventors: |
Bambot; Shabbir; (Suwanee,
GA) ; Faupel; Mark L.; (Alpharetta, GA) ;
Agrawal; Anant; (Atlanta, GA) ; Ignotz; Keith D.;
(Duluth, GA) ; Fordham; Andrew; (Sugar Hill,
GA) |
Correspondence
Address: |
Michael B. Lasky;Altera Law Group, LLC
1700 U.S. Bank Plaza South, 220 South Sixth Street
Minneapolis
MN
55402
US
|
Family ID: |
46299848 |
Appl. No.: |
12/099876 |
Filed: |
April 9, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10647222 |
Aug 26, 2003 |
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12099876 |
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10611917 |
Jul 3, 2003 |
7006220 |
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10647222 |
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10603597 |
Jun 26, 2003 |
6975899 |
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10611917 |
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10446857 |
May 29, 2003 |
6870620 |
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10603597 |
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10337687 |
Jan 8, 2003 |
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10446857 |
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PCT/US02/06350 |
Mar 1, 2002 |
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10337687 |
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09786781 |
Mar 9, 2001 |
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PCT/US02/06350 |
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09700538 |
Nov 16, 2000 |
6590651 |
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09786781 |
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09533817 |
Mar 24, 2000 |
6577391 |
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09700538 |
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09434518 |
Nov 5, 1999 |
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09533817 |
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PCT/US99/20646 |
Sep 10, 1999 |
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09434518 |
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PCT/US99/10947 |
May 19, 1999 |
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PCT/US99/20646 |
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Current U.S.
Class: |
600/407 |
Current CPC
Class: |
G01N 21/474 20130101;
G01N 21/64 20130101; A61B 5/0071 20130101; A61B 5/444 20130101;
G01N 21/21 20130101; G01N 2021/6484 20130101; A61B 2562/164
20130101; A61B 5/0088 20130101; A61B 5/0075 20130101; A61B 5/0084
20130101; G01N 21/49 20130101; A61B 5/0091 20130101; A61B 5/4312
20130101; A61B 5/6843 20130101; G01N 21/6486 20130101 |
Class at
Publication: |
600/407 |
International
Class: |
A61B 6/00 20060101
A61B006/00 |
Claims
1. An apparatus for determining tissue characteristics, comprising:
a base unit comprising illumination, detection and control
sub-units, the illumination sub-unit providing illumination optical
energy for illuminating a target tissue and the detection sub-unit
detecting tissue characteristics of a target tissue; a separate
tissue interface unit; and a pathway coupling the base unit and the
tissue interface unit.
2. The apparatus according to claim 1, wherein the pathway is
configured to deliver optical energy from the base unit to the
tissue interface unit and to deliver collected optical energy
reflected and/or emitted by the target tissue from the tissue
interface unit to the base unit.
3. The apparatus according to claim 2, wherein the pathway
comprises an illumination pathway and a collection pathway, wherein
the illumination pathway is configured to deliver optical energy
from the base unit to the tissue interface unit and the collection
pathway is configured to deliver collected optical energy reflected
and/or emitted by a target tissue from the tissue interface unit to
the base unit.
4. The apparatus according to claim 1, wherein the tissue interface
unit comprises a tube having a pathway configured to deliver
optical energy received from the base unit to a target tissue and
to receive collected optical energy reflected and/or emitted by the
target tissue.
5. The apparatus according to claim 4, wherein the tube pathway
comprises an illumination pathway and a collection pathway, wherein
the illumination pathway is configured to deliver optical energy
received from the base unit to the target tissue and the collection
pathway is configured to receive collected optical energy reflected
and/or emitted by the tissue.
6. The apparatus according to claim 5, wherein the illumination
pathway and collection pathway comprise at least one optical
fiber.
7. The apparatus according to claim 4, wherein the tissue interface
unit further comprises an illumination source and a second
illumination pathway configured to deliver illumination optical
energy from the illumination source of the tissue interface unit to
the target tissue.
8. The apparatus according to claim 7, further comprising an
imaging device and an image pathway configured to deliver image
optical energy reflected off the target tissue to the imaging
device.
9. (canceled)
10. The apparatus according to claim 4, wherein the tissue
interface unit comprises a base structure, the tube being
configured to be attachable to the base structure.
11-23. (canceled)
24. A tissue interface unit for use in an apparatus for determining
tissue characteristics, comprising: a tube; a first pathway in
optical communication with the tube and configured to deliver
optical energy received from a base unit to a target tissue and to
receive collected optical energy reflected and/or emitted by the
target tissue; an illumination source; and a second pathway in
optical communication with the tube and configured to deliver
illumination optical energy from the illumination source to the
target tissue.
25. The apparatus according to claim 24, further comprising: an
imaging device; and a third pathway configured to deliver optical
energy reflected from the target tissue to the imaging device.
26. (canceled)
27. The apparatus according to claim 24, wherein the first pathway
comprises an illumination pathway and a collection pathway, wherein
the illumination pathway is configured to deliver optical energy
received from the base unit to the target tissue and the collection
pathway is configured to receive collected optical energy reflected
and/or emitted by the target tissue.
28-30. (canceled)
31. A method of detecting tissue characteristics, comprising:
illuminating a first portion of a target tissue with optical
energy; forming a first image of the target tissue; illuminating a
second portion of the target tissue with optical energy; performing
spectroscopic measurements on optical energy reflected and/or
emitted by the target tissue upon illumination of the second
portion of the target tissue with optical energy; and determining
tissue characteristics of the target tissue based on the results of
the spectroscopic measurements.
32. (canceled)
33. The method of claim 31, wherein illuminating a first portion of
a target tissue with optical energy comprises illuminating a first
portion of a target tissue with optical energy from a first
illumination source and illuminating a second portion of the target
tissue with optical energy comprises illuminating a second portion
of the target tissue with optical energy with a second illumination
source.
34. The method of claim 33, further comprising: forming a second
image of the target tissue using the optical energy reflected
and/or emitted by the target tissue upon illumination with the
optical energy from the second illumination source.
35-37. (canceled)
38. The method of claim 31, wherein illuminating a first portion of
a target tissue with optical energy comprises flood illuminating
the first portion of the target tissue, and wherein the second
portion of the target tissue is divided into a plurality of
detection points arranged in columns and illuminating a second
portion of the target tissue with optical energy comprises
illuminating the plurality of detection points one column at a
time.
39. A method of detecting tissue characteristics, comprising:
dividing an area of target tissue into a plurality of detection
points arranged in columns; illuminating the plurality of detection
points one column at a time; performing spectroscopic measurements
on optical energy reflected and/or emitted by the target tissue;
and determining tissue characteristics of the target tissue based
on the results of the spectroscopic measurements.
40. (canceled)
41. The method of claim 39, wherein the plurality of detection
points cover substantially the entire cervix.
42. The method of claim 39, wherein the plurality of detection
points cover an area of approximately 25 mm in diameter.
43-44. (canceled)
45. The method of claim 39, wherein the plurality of detection
points are illuminated using a probe positioned a predetermined
distance from the target tissue.
46-63. (canceled)
Description
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The invention relates to an apparatus and methods for
determining tissue characteristics of, for example, biological
tissue.
SUMMARY OF THE INVENTION
[0002] The present invention, according to its various embodiments,
provides for a method and apparatus that interrogates, receives and
analyzes full emission spectra for at least one fluorescence
excitation wavelength and for at least one reflectance measurement
to determine tissue characteristics.
[0003] Additional advantages, objects, and features of the
invention will be set forth in part in the description which
follows and in part will become apparent to those having ordinary
skill in the art upon examination of the following or may be
learned from practice of the invention. The objects and advantages
of the invention may be realized and attained as particularly
pointed out in the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] The invention will be described in detail with reference to
the following drawings, in which like reference numerals refer to
like elements, and wherein:
[0005] FIG. 1A is a schematic side view of a tissue interface unit
of a system for determining tissue characteristics according to one
embodiment of the invention;
[0006] FIG. 1B is a schematic diagram of a base unit of a system
for determining tissue characteristics according to one embodiment
of the invention;
[0007] FIG. 1C is a schematic diagram of a tube according to one
embodiment of the invention having a clear annulus at a distal end
thereof;
[0008] FIG. 2 is a front view of an end plate of a body structure
of the tissue interface unit of FIG. 1A;
[0009] FIG. 3 shows an exemplary arrangement of illumination
optical fibers on an end plate of a body structure of a tissue
interface unit according to one embodiment of the invention;
[0010] FIG. 4 shows an exemplary arrangement of bundles of optical
fibers located at one end of an illumination pathway adjacent an
illumination unit according to one embodiment of the invention;
[0011] FIG. 5 shows an exemplary columnar arrangement of
illumination optical fibers on an end plate of a body structure of
a tissue interface unit according to one embodiment of the
invention;
[0012] FIG. 6 is a chart of exemplary spectrographic measurements
to be taken to determine tissue characteristics according to one
embodiment of the invention;
[0013] FIGS. 7A and 7B are schematic drawings of a system for
determining tissue characteristics according to another embodiment
of the invention;
[0014] FIG. 8A is a schematic drawing of a docking unit of a system
for determining tissue characteristics according to another
embodiment of the invention,
[0015] FIG. 8B is a schematic drawing of a system interface and
controller of a system for determining tissue characteristics
according to another embodiment of the invention;
[0016] FIG. 9 is a front view of a tissue interface unit of a
system for determining tissue characteristics according to another
embodiment of the invention;
[0017] FIG. 10 is a side perspective view of the tissue interface
unit of a system for determining tissue characteristics according
to another embodiment of the invention;
[0018] FIG. 11 is a side view of a tissue interface unit of a
system for determining tissue characteristics according to another
embodiment of the invention;
[0019] FIG. 12 is a front perspective view of a tissue interface
unit of a system for determining tissue characteristics according
to another embodiment of the invention;
[0020] FIG. 13 is a schematic drawing showing an exemplary
arrangement of detection points on a subject tissue;
[0021] FIG. 14 is a drawing schematically showing how measurements
of columns of detection points are sequentially taken across a
subject tissue according to one embodiment of the invention;
[0022] FIG. 15 is a drawing schematically showing an exemplary
arrangement of a column of detection points on a CCD camera
according to the invention;
[0023] FIG. 16 is a drawing schematically showing the projection of
an image across a CCD camera according to the invention;
[0024] FIG. 17 is a drawing schematically showing an image of a
left side of a cervix projected onto a CCD camera according to the
invention;
[0025] FIG. 18 is a drawing schematically showing an image of a
right side of a cervix projected onto a CCD camera according to the
invention;
[0026] FIG. 19 is an exemplary arrangement of detection points for
a cervix according to the invention;
[0027] FIG. 20A is a schematic drawing of an illumination or target
end of a fiber optic bundle;
[0028] FIG. 20B is a schematic drawing of a collection end of the
fiber optic bundle of FIG. 20A, illustrating a collection approach
according to the invention;
[0029] FIG. 21 is a schematic drawing of a setup for absolute
calibration of a system embodying the invention;
[0030] FIGS. 22-23 are tables of instrument settings for each of
eight software driven measurements that account for each of eight
column positions on a target; and
[0031] FIG. 24 is a table of instrument settings for measurements
made in three sets using a different excitation and emission
wavelength for each set.
DETAILED DESCRIPTION OF INVENTION
[0032] Before the present systems, methods and apparatus are
disclosed and described, it is to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only and is not intended to be limiting. It must be
noted that, as used in the specification and the appended claims,
the singular forms "a", "an" and "the" include plural referents
unless the context clearly dictates otherwise.
[0033] Ranges may be expressed herein as from "about" or
"approximately" one particular value and/or to "about" or
"approximately" another particular value. When such a range is
expressed, another embodiment comprises from the one particular
value and/or to the other particular value. Similarly, when values
are expressed as approximations, by use of the antecedent "about,"
it will be understood that the particular value forms another
embodiment.
[0034] Various embodiments of the present invention include
systems, methods and apparatus that may be utilized to determine
tissue characteristics by applying and measuring optical energy,
including but not limited to visible, infrared and/or UV light. It
should be understood that the term "illumination" according to the
invention means "to give optical energy to", the term optical
energy again, including but not limited to visible, infrared and/or
UV light.
[0035] In several embodiments, the present invention comprises a
base unit, a tissue interface unit and a pathway that couples the
base unit and the tissue interface unit. In one particular
embodiment, the present invention is comprised of a tissue
interface unit that is optically and electronically coupled to a
base unit, as shown in FIGS. 1A-1B.
[0036] FIG. 1A is a schematic side view drawing of a tissue
interface unit according to an embodiment of the present invention.
The tissue interface unit 70 includes a base structure 80. The base
structure 80 may include a handle 74 attached thereto and
configured to be graspable by a user; however, other configurations
may also be appropriate.
[0037] A tube 72 may be configured to be removably attachable to
the base structure 80. The tube 72 functions as a barrier to
exclude, for example, room light. The tube 72 is not necessarily
tubular or cylindrical in shape; other configurations may also be
appropriate.
[0038] The tube 72 connects to base structure 80 via plate 80b. An
end face 80a of plate 80b is shown in FIG. 2. The end face 80a
contains at least one opening for respective pathways 73a, 73b,
73c, 73d. These pathways are connected to and selectively share the
tube 72 in such a way that no interference occurs between the
respective pathways. For example, illumination pathway 73b delivers
to a subject tissue illumination energy or light received from the
base unit 20 alone illumination pathway 44. The collection pathway
73c receives energy or light reflected and/or emitted by a subject
tissue and guides it to collection pathway 60, which guides the
collected light to the base unit 20.
[0039] The tissue interface unit 70 may further include an
illumination source 76 and a second illumination pathway 73d.
Additionally, the tissue interface unit 70 may include an imaging
device 78 and an imaging pathway 73a. The imaging device could take
the form of a digital camera, or a CCD based imaging device,
although other imaging devices could also be used. The second
illumination pathway 73d delivers illumination energy or light from
the illumination source 76 to the subject tissue. This illumination
energy or light is reflected off the subject tissue as image energy
or light. The image energy or light is received into the imaging
pathway 73a where it is directed to an imaging device 78. The
imaging device is then used to provide a user with an image of all
or a portion of the subject tissue.
[0040] The second illumination pathway 73d and the imaging device
78 comprise the imaging channel (not shown). The imaging device 78
allows the user to position the distal end 72a of the tube 72 in
the proper and otherwise desired contact with the tissue and to
verify that such contact has been accomplished. Moreover, the
imaging channel allows the user to acquire a digital or other image
of the tissue with the help of the imaging device 78. This image
can serve as an additional visual tissue diagnosis tool.
[0041] The tissue interface unit 70 may also contain various lens
assemblies (not shown) that direct optical energy from the
illumination pathways 73b, 73d onto the subject tissue, and that
direct energy or light from the subject tissue into the collection
pathway 73c and the imaging pathway 73a. For example, the various
lens assemblies may comprise a set of achromatic lens doublets. The
matched set of achromatic lens doublets may be provided in each
pathway. The doublets are generally those commonly used in the art,
such as a BK7/SF2 glass biconvex/planoconcave combination available
off the shelf from Edmund Scientific, OptoSigma and Melles Griot;
although other lenses may also be appropriate. The material of the
lenses may be used to limit irradiation and collection in the UV to
a desired wavelength range, such as for example a minimum
wavelength of approximately 350 nm wavelength range. According to
embodiments of the present invention, the lenses may provide
magnification/demagnification in the excitation/collection paths,
respectively.
[0042] The tube 72 can function to fix the lens assemblies a
predetermined distance from the subject tissue. In addition, if the
subject tissue is surrounded by the end 72a of the tube 72, the
tube can function to exclude ambient optical energy from
illuminating the subject tissue. The tube makes contact with the
tissue setting the focal distance so the tissue to lens distance is
correct.
[0043] The illumination pathway 73b may include, for example, a
custom designed bundle of optical fibers. In one example, 52
optical fibers approximately 2 meters long, having a numerical
aperture (NA) of approximately 0.12, and having a core diameter of
approximately 100 .mu.m is utilized to form the illumination
pathway 73b. This fiber bundle may be only part of the illumination
pathway. The illumination pathway may also have lenses. According
to one embodiment, the tube 72 comprises a clear annulus 72b at a
distal end thereof opposite to an end plate 72c that allows the
tube 72 to be attached, removably according to certain embodiments,
to the base structure 80, as shown in FIG. 1C. Contact of the tube
72 to the surface of the tissue will be visible through the annulus
72b, which provides the user with visual confirmation that the tube
72 is properly positioned.
[0044] One exemplary arrangement of optical fibers is illustrated
in FIG. 3. The tissue end of the optical fiber bundle is held in
the tissue interface unit 70 behind a pair of achromatic lens
doublets (not shown). At the tissue end, the optical fibers 21 are
arranged as shown in FIG. 3, in 8 columns 22. At the opposite end
of the illumination pathway 44, the optical fibers 21 for each
column 22 shown in FIG. 3 may be collected into a separate bundle
23a, as shown in FIG. 4. This means that there will be eight
bundles 23 of optical fibers 21 at the opposite end of the
illumination pathway. When constructed in this manner, if optical
energy is fed into a single bundle 23a at a time, a single column
22 of optical fibers 21 will illuminate the target tissue, as
discussed below in detail.
[0045] The collection pathway 73c may be, for example, another
custom designed coherent bundle of optical fibers. In one example,
several thousand, e.g. 5000, optical fibers that were approximately
2 meters long, having a NA of approximately 0.12, and having a core
diameter of approximately 50 .mu.m were arranged in an
approximately 5-mm diameter aperture, in a coherent fashion, to
provide a one to one image transfer from the tissue interface unit
to the detection sub-unit of the base unit. The tissue end of the
bundle of optical fibers is held in the tissue interface unit
behind a pair of achromatic lens doublets. Since one column of
spots is illuminated on the tissue, for example, cervix, at a time,
as is later discussed, returned radiation from the same column is
transferred by the coherent bundle to the detection sub-unit of the
base unit. This returned radiation, which will be arranged in a
column of spots, acts as a virtual vertical slit that is then
spectrally resolved in the horizontal dimension by the detection
sub-unit of the base unit, as is later discussed.
[0046] As mentioned above, some embodiments of the device may
include an illumination device 76 and image detector 78. Together,
these items allow the device operator to obtain a real-time image
of the target tissue, which can help to properly orient the tissue
interface unit with respect to the target tissue. These items are
not required in all embodiment of the invention, and could be
completely eliminated. In other embodiments of the invention, these
items could be replaced with a sighting mechanism which simply
allows the device operator to look down the tube 72 to view the
target tissue.
[0047] In embodiments of the invention that include an illumination
device 76 and imaging device 78, the illumination source 76 may be,
for example, a 4.25V or 2 W halogen lamp manufactured by Welch
Allyn, Inc. in Skeneateles, N.Y. This exemplary lamp has an
integrated parabolic reflector that projects the optical energy
onto the tissue and provides a uniform illumination on the tissue.
The imaging device 78 may be, for example, a 1/4'' format Panasonic
color board camera with 480 horizontal TV lines. This camera has a
C mount adaptor, into which a focusing lens doublet may be mounted.
The camera may be mounted offset from the illumination and
collection pathways due to space constraints, and the image
transfer accomplished using a pair of reflectors 78a.
[0048] The tissue interface unit may be designed in conjunction
with a vaginal speculum configured for insertion into a patient's
vagina during the examination procedure. The unit is held fixed
with respect to the vaginal speculum (not shown) according to
certain embodiments. However, according to other embodiments, the
unit may be used without such a speculum.
[0049] Prior to conducting tissue measurements, some embodiments of
the instrument may be calibrated by making one or more measurements
on a disposable calibration target 78a that mounts on the distal
tissue end of the tube 72. This disposable calibration target could
be used to take a reference or a calibration measurement, or
possibly both. Moreover, in various embodiments, these measurements
may be a reflectance and/or fluorescent measurements.
[0050] FIG. 1B is a schematic diagram of a base unit according to
one embodiment of the invention. The base unit 20 according to the
invention is small enough to be portable or mobile. For example,
the base unit 20 could be provided on a movable cart (not
shown).
[0051] The base unit 20 comprises an illumination sub-unit 30, a
detection sub-unit 50 and a control sub-unit 45.
[0052] The illumination sub-unit 30 includes an illumination source
32. For example, the illumination source may be a 175 W short arc
Xe lamp provided with an integrated parabolic reflector, which
produces a near collimated beam. Such a lamp is manufactured by ORC
lighting products, a division of PerkinElmer Optoelectronics
(Azusa, Calif.). Other lamps may also be appropriate. In addition,
the illumination source 32 could also take the form of one or more
lasers or LEDs. The illumination source 32 may be housed inside a
fan cooled heat sink assembly (not shown) to limit dissipation of
heat to the illumination sub-unit's other components.
[0053] Optically coupled to the illumination source 32 is an
illumination filter wheel 38. The illumination filter wheel 38
provides for selective wavelength filtering and may be motorized.
For example, the illumination filter wheel may be an eight-position
filter wheel manufactured by ISI Systems (Santa Barbara, Calif.).
An example of filters that could be used in one embodiment of the
invention are listed in FIG. 6. The illumination filter wheel is
mounted within the illumination sub-unit 30, as shown in FIG. 1B,
and the control unit 45 selects the appropriate filter to be
brought into the light path.
[0054] A cold mirror 34 may be provided between the illumination
source 32 and the illumination filter wheel 38. In another
embodiment of the invention, an IR absorbing glass/filter may be
used instead of a cold mirror. A near collimated light beam from
the illumination source 32 is directed through the filter. For
example, in one embodiment of the invention, Applicants utilized a
KGI glass filter available off the shelf from Melles Griot. The
filter transmitted wavelengths in the range of approximately
340-700 nm. Because of its high absorption of IR wavelengths, the
filter helps protect downstream components from excessive heat and
also minimizes stray light in the detection sub-unit.
[0055] The illumination sub-unit 30 may also include a safety
shutter 36, in particular where a continuously operating
illumination source is utilized. In such a case, illumination would
only be allowed into the unit and through to the tissue for the
duration of the spectroscopic measurements, even though the
illumination source would be continuously operating. Software in
the control unit 45 would control actuation of the normally closed
shutter.
[0056] The illumination sub-unit 30 may also include a focusing
lens 40, for example, a single approximately 28 mm diameter,
approximately 100 mm FL, plano-convex lens. The focusing lens 40
focuses the illumination optical energy or light onto the
illumination pathway 44.
[0057] A mask 42, motorized using an encoded stepper motor (not
shown) and controlled by the control sub-unit 45, may be provided
at an entrance to the illumination pathway 44. The mask 42 is used
to control the optical energy so that the optical energy will only
pass into certain portions of the illumination pathway, for
example, into certain ones of the optical fibers, at any given
time. The mask 42 blocks the illumination optical energy from
entering the remaining portions of the illumination pathway, for
example, certain remaining optical fibers.
[0058] By way of an example, one embodiment of the illumination
sub-unit end 23 of the illumination pathway 44 is shown in FIG. 4.
As previously discussed, it has a collection of eight bundles 23a
of optical fibers, where the optical fibers in each bundle 23a
corresponding to different respective columns 22 of individual
optical fibers at the tissue end 80a of the illumination pathway
44, as shown in FIG. 5. Thus, the optical fibers in bundle number 1
at the illumination sub-unit end of the illumination pathway 44, as
shown in FIG. 4, correspond to the optical fibers 21 arranged in
column 1 of the tissue end 80a, as shown in FIG. 5.
[0059] The mask 42 has a single hole (not shown) that can be
selectively aligned with only a single bundle 23a of the optical
fibers shown in FIG. 4. The control sub-unit 45 will control
movement of the mask 42 so that each bundle 23, in turn, is
illuminated. This will cause the illumination optical energy to be
emitted from one of the columns 22 shown in FIG. 5, and as the mask
42 moves, different ones of the columns 22 of optical fibers will
illuminate the target tissue.
[0060] The detection sub-unit 50 may comprise a re-imaging device
52, a collection filter wheel 54, a spectrograph 56 and a CCD
camera 58. The collection filter wheel 54 is optically coupled to
the spectrograph and holds a plurality of filters (not shown) for
filtering the collected optical energy before it is sent into the
spectrograph 56. Exemplary filters for multiple spectral
measurements are listed in FIG. 6. Filtering can be used to reduce
artifacts due to reflected excitation from the target tissue. When
attempting to measure fluorescent emissions from the target tissue,
which have a very low amplitude, a reduction in the reflected
excitation energy or light amount is quite helpful. The insertion
of filters, however, can change the light path between the optical
fibers and the spectrograph entrance slit.
[0061] The collected optical energy, which has traveled through,
for example, optical fibers to the detection sub-unit, is re-imaged
at the entrance slit of the spectrograph 56 by a re-imaging device
52, such as, for example, an FC-446-30 from Roper Scientific-Acton
Research (Action Mass.), which does this without introducing
chromatic aberrations and astigmatism. Such a re-imaging device may
include a spacer (not shown) which allows insertion of a motorized
collection filter wheel, such as, for example, an FA-448-2 filter
wheel also from Roper Scientific--Acton Research. The re-imaging
device permits simple, straightforward insertion of the filter
wheel.
[0062] The collection pathway 60, which may be, for example, a
coherent bundle of optical fibers 60, which carries optical energy
collected from the target tissue, is placed at the entrance of the
re-imaging assembly. At any given time, the illumination pathway
44, which may be, for example, optical fibers, will only illuminate
a column of positions on the target tissue. Thus, optical energy
collected into the collection pathway 60 will only be from
approximately the same column of positions on the target tissue.
The result is that, at any given time, the optical energy entering
the spectrograph 56 from the return optical fibers 60, will be
arranged in a virtual vertical slit.
[0063] The spectrograph 56 takes the vertical slit of returned
optical energy, and resolves the optical energy into different
wavelengths by separating the energy or light in the horizontal
direction. The result is an energy or light pattern having two
dimensions, wherein the vertical dimension corresponds to different
positions on the target tissue, and wherein the horizontal
dimension corresponds to different wavelengths. The two dimensional
energy or light pattern is then recorded on a camera, for example,
a CCD camera 58.
[0064] The spectrograph may be, for example, a customized,
approximately 300 mm focal length, f#4, Czerny-Turner configuration
spectrograph, such as the SpectraPro SP-306I, manufactured by Roper
Scientific-Acton Research (Acton Mass.). According to one
embodiment of the invention, the grating of the spectrograph has
the following specifications: [0065] Grooves/mm: 100 nm/mm [0066]
Dispersion: 32 nm/mm [0067] Blaze angle: 1 17' [0068] Field of
view: 365 nm
[0069] The camera may be a CCD camera, for example, a
thermoelectrically cooled CCD camera, such as the NTE/CCD-512SB
manufactured by Roper Scientific-Princeton Instruments (Princeton,
N.J.) with a SITE 512.times.512, square format, approximately 24 m
pixel, back illuminated detector, along with the ST-133 high speed
DMA serial interface controller. The A/D converter in the
controller allows a 1.0 MHZ A/D scan rate. However, other types of
cameras commonly known to those skilled in the art may be used.
[0070] In one embodiment, the control unit 45 is a
software/hardware package comprised of an instrument control
section, a graphical user interface, and data storage capabilities.
For example, a compact PC with adequate ports and bays to
accommodate the requisite interfaces and PCI cards may be used for
this purpose. The control unit 45 provides control over actuation
of the illumination and collection filter wheels 38, 54, the safety
shutter 36, the camera shutter (not shown), the camera controller
(not shown), data conversion and transfer to the PC (not shown),
the spectrograph grating adjust motor (not shown), the imaging
camera 68 and corresponding illumination source 32 and the stepper
motor (not shown) for the motorized mask. Control is provided
according to a schedule template that can be modified by the
user.
[0071] In addition, the software may provide graphical feedback to
the user showing images (video and spectroscopy) that are used to
make real time determinations of measurement adequacy. The program
stores the measured data, which may include tissue particulars,
measurement particulars and/or images. The measured data for each
tissue can then be downloaded and stored in a portable recording
medium (not shown) such as a magnetic or optical disk.
[0072] The above described embodiment, which includes a
spectrograph for spectrally resolving the light returning from the
target tissue, is but one way to accomplish the spectral
resolution. In other embodiments of the invention, other devices
such as prisms or transmissive gratings, for example, could be
utilized to spectrally resolve light returning from a location on a
target tissue into different wavelengths. Yet, even further, other
devices known to those of ordinary skill in the art could be
utilized. For purposes of discussion and example only, a
spectrograph will be discussed as the spectrally resolution
device.
[0073] In addition, in some embodiments of the device, it may prove
more advantageous to take measurements at a plurality of locations
on a target tissue to measure a single narrow wavelength band of
returned light during a first measurement cycle. Another
measurement cycle could then be conducted at the same locations on
the target tissue for one or more different wavelength bands.
[0074] Furthermore, in the embodiment described above, the
illumination light was conveyed to the target tissue such that it
sequentially illuminated several different columns of positions on
the target tissue. In other embodiments of the invention, the
illuminated positions on the target tissue need not be illuminated
in a column arrangement. In fact, it some embodiments of the
invention, it may be advantageous to arrange the optical fibers
such that each sequential illumination and measurement cycle
measures the characteristics of widely separated locations across
the target tissue. Once all measurements have been taken, the
measurement results could be re-combined by the device operating
software to present an image indicative of the target tissue
characteristics. A device configured in this manner would greatly
reduce the occurrence of cross-talk between illuminated
positions.
[0075] The systems, methods and apparatus according to the present
invention use the hyperspectral imaging approach discussed by J.
Marno in "Hyperspectral imager will view many colors of earth,"
Laser Focus World, August 1996, p. 85. This involves measuring
intensities of optical energy emitted from tissue at high spectral
and spatial resolution.
[0076] Systems, methods and apparatuses embodying the present
invention should be designed to ensure that, as between measurement
speed, spectral resolution, and spatial resolution, the most
important characteristics are measured with the highest resolution
in the shortest possible time period.
[0077] In order to obtain spectra free of environmental or system
artifacts, one approach would be to calibrate the system embodied
by the present invention. The calibration procedures are as
follows: (1) provide an absolute scale to the intensity
measurements at each wavelength; (2) provide an absolute wavelength
scale; (3) correct for fluctuations in lamp intensity and spectral
shifts; (4) correct for spectrograph/grating performance
limitations due to stray light; (5) correct for background light;
(6) correct for noise; and/or (7) correct for variance and temporal
changes in optical properties, spectral transmittance, reflectance
lenses and fibers. Providing an absolute scale to the intensity
measurements at each wavelength calibrates the detection elements
of the system and provides an absolute scale to the intensity
measurements. This will also allow identification of performance
variations in the source and detection system.
[0078] With respect to noise, there exists categories of potential
noise that might typically occur with measurements comes from
several possible sources. Without limitation, they include shot
noise, instrument noise, clinical noise, and physiological
noise.
[0079] Shot noise is equal to {square root over (I)} and refers to
the inherent natural variation of the incident photon flux.
Photoelectrons collected by a CCD exhibit a Poisson distribution
which have this square root relationship between signal and
noise.
[0080] Instrument noise includes several individual noise types
classified according to their sources such as CCD noise including
the read noise and dark noise and dependent on the A/D transfer
rates and the temperature of the CCD, respectively. Additional
sources of instrument noise include, without limitation,
variability in lamp intensity, variability in the transmittance of
optical components such as fibers filters and lenses, and
variability in the transmittance of fibers due to fiber
bending.
[0081] Clinical noise is the noise that arises from the clinical
measurement procedure such as the distance/angle between the target
tissue and the device, presence of blood and mucus as well as
patient/device movement.
[0082] Physiological noise is the non-diagnostic natural
variability of the biochemical and morphological properties of
tissue. The physiological noise can be one of the most challenging
to address. To alleviate this noise source is to normalize or
compare the intensities measured at any tissue site with the
intensity from a `clinically normal` site. The normal site is
identified using simple tests such as the maximum or minimum
intensity or intensity ratio.
[0083] The signal to noise ratio of a measuring device is
simply
SNR = I .sigma. ( I ) ##EQU00001##
where I is the measured signal intensity, and .sigma.(I) is the
noise or standard deviation of the measured intensity. We have
taken steps to ensure that signal corruption in our device from the
cumulative effects of these noise sources is reduced or eliminated.
The specific steps include: [0084] A. Obtaining a high enough
signal intensity such that the noise in the measurement in
dominated by the shot noise. The shot noise is an inherent property
of the CCD response and given that it increases as {square root
over (I)} with increase in I, its proportion as a percentage of I
decreases with increase in I. At a high value of I the contribution
of shot noise is negligible. We have attempted, as listed below, to
reduce other noise sources to a value below that of shot noise i.e.
the instrument operates in the shot noise dominated regime; [0085]
B. Keeping the temperature and the A/D transfer rate at the lowest
optimum, thus minimizing read and dark noise; [0086] C. Measuring
the lamp power simultaneously with the tissue measurement. The
tissue measurement is then normalized by this measured lamp
intensity. This removes/corrects for the noise in the measured
intensity due to variability in lamp intensity and variability in
the transmittance of optical components such as fibers, filters and
lenses; [0087] D. Using ratios of intensities at different
wavelengths rather than straight intensities since this method
internally corrects for changes in transmittance and also corrects
for variations in light coupling due to changes in the way the
target tissue is oriented with respect to the light beam. This
method is limited to transmittance changes that do not vary across
the spectrum; and [0088] E. Optimizing the clinical procedure to
minimize the clinical noise. This includes an adequate tissue
cleaning procedure and keeping the device weight and shape
conducive to holding it without significant motion artifact.
[0089] Next, the horizontal dimension of the CCD, measured in pixel
number is used to mark the wavelength of the measured intensity. A
wavelength number is assigned to each pixel. Establishing these
absolute scales contribute to the calibration of the present
invention.
[0090] Calibration standards may include those commonly used by
ones skilled in the art. For example, spectral irradiance standards
may utilize a NIST traceable Quartz Tungsten halogen lamp for
wavelengths greater than approximately 400 nm. For wavelengths less
than approximately 400 nm, a NIST traceable Deuterium lamp may be
used. Wavelength calibration standards may include, without
limitation, mercury lamps and NRCC traceable Erbium Oxide lamps.
With respect to the former, these lamps have narrow, discrete
spectral lines over UV and visible wavelengths that provide a
metric for wavelength calibration. For example, for diffuse
reflectance standards, a NIST traceable Spectralon.TM. from
LabSphere, Inc. (North Sutton, N.H.) may be utilized. The
reflectance of these standards is highly lambertian over their
spectral range. They also have a spectrally flat reflectance
profile, i.e. the percent of radiation reflected at each wavelength
(within the usable wavelength range) is constant. For diffuse
fluorescence standards, ones such as those produced by LabSphere,
Inc. may be used. These standards are also made of Spectralon.TM.
and one further embedded with inorganic fluorophores that provide a
highly stable, reproducible fluorescence.
[0091] In addition to absolute scale, calibration must correct for
variances and potential external and/or internal interferences.
Fluctuations in lamp intensity and spectral shifts may need to be
corrected for, since arc lamps such as the ones used according to
certain embodiments of the present invention are known to display
fluctuations in energy output based on lamp life, duration of use
and ambient conditions. Since the present invention determines
tissue characteristics based on intensity measurements, such
variations should be taken into consideration and accounted for by
appropriate calibration. Similarly, it is helpful to correct for
stray light that may result from the inability of a monochromator
grating to perfectly separate light of different wavelengths.
Grating efficiency, inadequate baffling and the use of short
optical path lengths needed to make a compact instrument all
contribute to stray light and therefore, should also be accounted
for by appropriate calibration. In addition to stray light,
background light may also be a factor to consider. Light leakage
into the system that results in erroneously higher intensities must
be measured and subtracted.
[0092] Finally, in addition to absolute scales and internal and/or
external light factors, calibration of the present invention may
also include accounting for dark noise and variance and temporal
changes in optical properties, spectral transmittance, reflectance
of lenses and fibers. With respect to dark noise, this issue
primarily arises as a result of thermal, non-thermal and readout
noise characteristics of the CCD detector. Although embodiments of
the invention use a PET cooled detector, the noise can be
significant and needs to be subtracted out. With respect to factors
effecting optical properties, spectral transmittance, reflectance
of lenses and fibers, each spot/location of light projected on the
tissue varies in intensity. This variance may be due to the axial
position of the spot and small differences in individual fibers and
mask apertures. The intensities of the spots/locations may change
with time due to changes in alignment and component
degradation.
[0093] The present invention utilizes at least one calibration
during its operation. One type of calibration is before the initial
operation of a device embodying the invention or when the device
needs maintenance and/or repair. This will be referred to as
pre-operative calibration. Pre-operative calibration may comprise
an absolute calibration protocol and a wavelength protocol.
[0094] Absolute calibration applies irradiance standards to
establish performance benchmarks and to provide an absolute scale
to the intensities measured. The irradiance standards allow the
coupling of known intensity levels into fibers or apertures. A
schematic diagram of a setup for performing calibration is shown in
FIG. 21, where 300 designates an aperture mask, 301 designates a
light source, and 302 designates a black absorbing material. The
aperture mask 300 shown may be replaced with an excitation fiber
bundle, where the light is coupled into fibers at one end of the
bundle. The light emerging from the other side of these apertures
or the other end of the fiber bundle can be imaged by the detection
system and the measured intensity calibrated against the known
intensity to arrive at a correction factor which will be further
taught below.
[0095] To calibrate wavelengths, wavelength calibrations are used.
The light source 301, such as a calibrated mercury arc lamp, is
positioned between a focusing lens (not shown) and the mask 300 in
FIG. 21 while the arc lamp is off or the safety shutter is closed
to ensure only illumination from the mercury lamp enters the
system. A reflectance target is held before the sight tube, taking
care to seal off and prevent room light from entering the system.
The columns of illuminated spots are spectrally resolved on the
CCD. The known natural peaks of the mercury spectrum, when the
embodiment is a mercury lamp, are captured and are used for
calculating a wavelength scale for each image. A set of eight
software driven measurements that account for each of the eight
column positions on the target, are made as show in the table of
FIG. 22 using the instrument settings indicated for each
measurement.
[0096] In addition to, or alternatively, the present invention can
be calibrated prior to each measurement. This calibration will be
referred to as "operative calibration". This calibration corrects
for both short-term system, intermediate and long-term
fluctuations, such as lamp degradation, for example. The method
that performs this calibration may be embodied in a software
program using the instrument settings listed in the tables of FIGS.
23 and 24.
[0097] The operative calibration comprises a reflectance
calibration, a fluorescence calibration, and a background and dark
noise calibration. The reflectance calibration may, according to
certain embodiments, comprise of positioning the Spectralon.TM.
diffuse reflectance target before the sight tube so as to exclude
room light from the system. A series of measurements given the
instrument settings listed in the table of FIG. 23 are made. During
a fluorescence calibration, the Spectralon.TM. (or other
comparable) fluorescence target is positioned before the sight tube
taking care to exclude room light or other superfluous light from
the system. A series of measurements given the instrument settings
listed in the table of FIG. 24 are made according to one embodiment
of the present invention. According to this embodiment, the
measurements may be made in sets of three where each set may use a
different excitation and emission wavelength selected by choosing a
different filter set.
[0098] Finally, background and dark noise calibration may be
incorporated into the fluorescence and reflectance and calibrations
above as well as into each subject target tissue/area measurement.
According to certain embodiments, the first measurement of each
sequence of 8+1 measurements in the tables of FIGS. 23 and 24 is a
background measurement where the safety shutter is held closed.
This measurement accounts for the error that may be caused due to
room light and/or other electronic noise sources that may result in
the CCD reading an intensity signal. This type of result may be
defined as background noise and is subtracted from each of the
calibration and tissue measurements.
[0099] The data collected from pre-operative and/or operative
calibrations are used to calculate a set of correction factors for
absolute calibration as follows:
C(f,.lamda.)=T(f,.lamda.)/M(f,.lamda.)
[0100] where f is the position/spot number or aperture location in
the target area and .lamda. is the wavelength (.about.400-700 nm).
T(f, .lamda.) is the true intensity from the standard coupled into
the aperture at least one wavelength, and M(f, .lamda.) is the
intensity measured by the system from that aperture at that at
least one wavelength. All spectra acquired with the same detection
system can then be multiplied point-for-point by these correction
factors in order to eliminate effects of the non-uniform response
(spectral and spatial) of the detection system.
[0101] In calibrating wavelengths, the measured spectrum of a
mercury light source contains sharp peaks which correspond to the
spectral lines of the source. The wavelength of each corresponding
spectral line can be assigned to the pixel number along the
horizontal axis of the CCD for each position of the peak. With two
or more peaks present in the spectrum, a linear interpolation is
then used to determine the wavelength values for all the
pixels.
[0102] For operative calibration, the protocol comprises a
reflectance intensity calibration, a fluorescence intensity
calibration, and a stray light or other superfluous light
calibration. Intensity calibration measurements for reflectance
spectra are performed by normalizing the spectrum measured from
each spot on a tissue with the spectrum measured from the same spot
on the reflectance calibration target. This is done after
subtracting the background light from each measurement. This
procedure eliminates any error from spot-to-spot variations in
excitation intensity and can be expressed as follows:
R(f,.lamda.)={[R.sub.S(f,.lamda.)-B.sub.S(f,.lamda.)]/[R.sub.R(f,.lamda.-
)-B.sub.R(f,.lamda.)]}*T.sub.R(f,.lamda.),
[0103] where R.sub.S(f, .lamda.) is the reflected intensity
spectrum measured from the subject target area and R.sub.R(f,
.lamda.) is the reflected intensity spectrum measured from a
reference whose true reflectance T.sub.R(f, .lamda.) is known. This
true reflectance is provided by a diffuse reflectance standard
whose reflectance is substantially constant for all wavelengths
used in the system taught by the present invention.
[0104] B.sub.S(f, .lamda.) is the background measurement
corresponding to the tissue reflectance measurement, e.g. tissue
background measurement taken using the same instrument settings as
the tissue measurement, but with the safety shutter closed.
B.sub.R(f, .lamda.) is the background measurement corresponding to
the reference measurement. With these measurements, a meaningful
estimate of tissue reflectance R(f, .lamda.) may be obtained.
[0105] For fluorescence spectra, intensity calibration involves
normalizing the fluorescence spectrum from each location on the
target area by the fluorescence intensity from the same location
when measuring on the fluorescence calibration target. Then, either
the integral or the peak of each position's intensity spectrum may
be used to normalize spectrum using the following formula:
F(f,.lamda.)=[F.sub.S(f,.lamda.)-B.sub.S(f,.lamda.)]/[F.sub.R(f,.nu.)-B.-
sub.R(f,.lamda.)]
[0106] where F.sub.S(f, .lamda.) is the fluorescence spectrum
measured on subject target area and B.sub.S(f, .lamda.) is the
corresponding background measurement taken using the same
instrument settings as the subject target area measurement but with
the safety shutter closed, F.sub.R(f, .lamda.) is the measurement
on the fluorescence reflectance standard, B.sub.R(f, .lamda.) is
the corresponding background measurement, and F(f, .lamda.) is the
corrected fluorescence spectrum.
[0107] With respect to stray light or superfluous light
calibration, correcting each fluorescence spectrum for the stray
light output of the excitation monochromator involves subtracting
the stray light spectrum reflected from the tissue from the
measured fluorescence spectrum of the tissue. This correction
employs the principle that the absolute reflectance (as a function
of wavelength) is independent of the spectrum used for
illumination. This principle can be expressed as an extension of
the immediately preceding equation as follows:
{R.sub.S[I.sub.1(f,.lamda.)]-B.sub.S[I.sub.1(f,.lamda.)]}/{R.sub.R[I.sub-
.1(f,.lamda.)]-B.sub.R[I.sub.1(f,.lamda.)]}={R.sub.S[I.sub.2(f,.lamda.)]}/-
{R.sub.R[I.sub.2(f,.lamda.)]-B.sub.R[I.sub.2(f,.lamda.)]}.
[0108] Here, I.sub.1 is the standard, broadband output of the
illumination system used to measure reflectance of tissue, for
example, and L is the stray/superfluous light of the illumination
system that accompanies the monochromatic excitation used for
tissue fluorescence measurements. Thus, tissue calibration may be
achieved by normalizing this procedure with the standard
reflectance. The result is a calibration factor, as follows:
{R.sub.S[I.sub.1(f,.lamda.)-B.sub.S[I.sub.1(f,.lamda.)]]}/{R.sub.R[I.sub-
.1(f,.lamda.)-B.sub.R[I.sub.1(f,.lamda.)]]}
[0109] which when multiplied by the stray/superfluous light
spectrum measured on the standard from supposedly monochromatic
excitation gives the stray/superfluous light inadvertently measured
along with tissue fluorescence. This is illustrated by rearranging
the equation such that:
R.sub.S[I.sub.2(f,.lamda.)]=({R.sub.S[I.sub.1(f,.lamda.)-B.sub.S[I.sub.1-
(f,.lamda.)]]}/{R.sub.R[I.sub.1(f,.lamda.)-B.sub.R[I.sub.1(f,.lamda.)]]})*-
{R.sub.R[I.sub.2(f,.lamda.)]-B.sub.R[I.sub.2(f,.lamda.)]]}.
[0110] R.sub.R[I.sub.2(f, .lamda.)] and the corresponding
B.sub.R[I.sub.2(f, .lamda.)] are measured in a similar way as
discussed in the previous section for intensity calibration of
fluorescence spectra. The reflectance standard is illuminated with
monochromatic light (and associated stray light), and the
measurement focuses on wavelengths at which stray light is present
(i.e. longer than the excitation wavelength) rather than the
excitation bandwidth. R.sub.R[I.sub.2(f, .lamda.)] is then
subtracted from the measured fluorescence spectrum.
[0111] After the present invention has been calibrated, the tube 72
of the tissue interface unit 70 may be first inserted into the
patient's vagina so that the end of the tube is immediately
adjacent, or covering the patient's cervix. The cervix is then
illuminated by the illumination source 76. Collected optical energy
transmitted and/or reflected from the tissue is directed to the
imaging device 78, which, in this embodiment, is located in the
tissue interface unit 70. The imaging device 78 sends a video
signal that is viewed with a computer or video monitor (not shown).
Thus, the imaging device 78 provides the user with a view of the
patient's cervix, which assists the physician in properly aligning
and situating the tube 72 with respect to the patient's cervix. The
imaging device 78 may also be used to capture still images of the
cervix, which may be digitally stored and used for later data
analysis.
[0112] The tube 72 is appropriately placed such that a good view of
the subject target area can be seen through the imaging device 78,
the tissue interface unit is fixed in place relative to the subject
target area. At this point, a still picture of the subject target
area may be taken with the imaging device. The illumination device
76 is then turned off, and the spectroscopic measurements are
started. As described above, a series of measurement cycles would
be conducted. During each measurement cycle, a column of positions
on the subject target area would be illuminated, and the light
returning from the subject target area would be detected by the
detection sub-unit. During each measurement cycle, the spectrograph
would spectrally resolve the column of positions into a
two-dimensional image that is captured by the camera 58. Each two
dimensional image would be arranged such that one axis is
indicative tissue position, and the other perpendicular axis would
be indicative of wavelength. The two dimensional images recorded
during the measurement cycles would then be recorded and analyzed
by the device operating software in the control sub-unit 45.
[0113] FIGS. 7A and 7B are schematic drawings of a system for
determining tissue characteristics according to another embodiment
of the invention. The system 110 includes a tissue interface unit
170, which may be configured as a handheld probe-type unit, and a
docking unit 120. The tissue interface unit 170 and the docking
unit 120 communicate with each other via communication pathway 177,
which may comprise one or more optical fibers or other type of
signal cable.
[0114] The docking unit 120 may include a stand or cradle 119 for
docking or holding the tissue interface unit 170 when not in use.
The docking unit 120 may also include one or more pathways 182 for
outputting or receiving signals to or from additional system
components, such as a image recording device, such as a VCR or
other type image recording device 183 or monitor 184, such as a
color TV monitor (shown in FIG. 7B).
[0115] As shown in FIG. 5A, the docking unit 120 may further
include a processor 190, a power supply 191, an illumination source
132 and an illumination source controller 132a. The docking unit
120 may also include a light guide (not shown), such as a liquid
light guide that guides optical energy from the illumination
source, for example, into an optical fiber or other type cable to
be delivered to the tissue interface unit 170.
[0116] As shown in FIG. 7B, the tissue interface unit 170 includes
illumination pathways 173b, 173d, which may comprise a single or
multiple pathways. These pathways 173b, 173d may include one or
more light guides 130 that receive optical energy from the
illumination source 132 disposed in the docking unit via
communication pathway 177b. The tissue interface unit may also
include an illumination lens assembly 131 and an illumination
aperture/filter 131a that provides for selective wavelength
filtering and a shutter function, also shown in FIG. 7B.
[0117] The tissue interface unit 170 further includes a collection
pathway 173c, which guides optical energy reflected and/or emitted
by a subject tissue to a device for making spectroscopic
measurements 175. The device for making spectroscopic measurements
175 may include a diffraction grating 157, a camera 158, and camera
controller 158a. The camera and camera controller may be, for
example, a CCD camera controlled by a CCD camera circuit card
assembly. The spectroscopic measurements may be sent to the
processor 190 disposed within the docking unit 120 via
communication pathway 177a for processing. According to one
embodiment of the invention, the system is capable of detecting
reflectance information between approximately 360 nm and 660 nm at
a resolution and fluorescence information at 2 or 3 wavelength
bands. According to various embodiments, the resolution and
wavelength bands can range from 2 nm to 30 nm. According to one
embodiment, the resolution is at 20 nm as are the wavelength bands.
Each frame of data is transferred from the tissue interface unit to
the docking unit for processing.
[0118] The collection pathway 173c may include a shutter 156 that
blocks out illumination optical energy when spectroscopic
measurements are not being made, a filter 159 that provides for
selective filtering of wavelengths not of interest, and a
collection lens assembly 155.
[0119] The tissue interface unit 170 may further include an imaging
pathway 173a that guides reflected optical energy to an imaging
device 187. The image pathway 173a may also include a lens assembly
178b. The imaging device 187 comprises, for example, camera 178 and
camera controller 178a. The camera and camera controller may be,
for example, a video camera and video camera controller, or any
similar type image recording device. The video imaging channel
according to one embodiment may have a resolution of 300 TV lines
(NTSC analog output for video recording and display) with fixed
magnification and focus, a field of view of approximately 25 mm,
and a depth of field of approximately +/-5 mm. The imaging device
187 allows a user to view the subject tissue in order to position
the tissue interface unit 170 with respect to the subject tissue.
The tissue interface unit 170 may include a monitor, or may
communicate with a separate monitoring device to permit viewing of
the tissue by a user. Additionally, the tissue interface unit 170
may include a user interface (not shown) that provides for entry of
patient information, for example.
[0120] The tissue interface unit further includes a power monitor
199 and a system interface and controller 195, as shown in FIG. 7B.
As shown in FIG. 8B, according to one embodiment of the invention,
the system interface and controller 195 includes a data interface
unit 503 that controls the exchange of data signals between the
tissue interface unit 170 and the docking unit 120. The system
interface and controller 195 may further include a discrete
interface unit 504 that controls the system's respective power and
switches, and an analog interface unit 505 that controls the
systems interface with an external image recording device 183. The
system interface and controller 195 may also include a shutter
controller 502 that controls operation of shutter 159 and an
illumination aperture/filter controller 501 that controls operation
of the motor of the illumination filter.
[0121] An example of one embodiment of a hand-held tissue interface
unit according to the invention is shown in side view in FIG. 11.
The tissue interface unit 170 includes housing 186, a handle 174
configured to be graspable by a user, a tube 172 that delivers
illumination optical energy to a subject tissue, and optical energy
reflected and/or emitted by the subject tissue to the viewing
device and/or the spectroscopic measurement device, and a liquid
light guide 130 that guides optical energy received from a docking
unit 120 into the tube 172. The tube 172 may be removable, as
discussed below, and may be disposable. As shown in FIG. 12, the
tissue interface unit 170 may also include a heat sink 199 that
maintains the tissue interface unit within an acceptable
temperature range.
[0122] FIG. 9 is a front view of a tissue interface unit according
to the invention without outer casing 186, and handle 174. FIG. 10
is a side perspective view of the tissue interface unit of FIG. 9
without outer casing 186 and tube 172. As shown in FIGS. 9 and 10,
the tube 172 connects to the base structure 180 via a plate 180b.
The plate 180b has an endface 180a. The endface 180a includes
openings for illumination pathways 173b, 173d, collection pathway
173c and imaging pathway 173a. These pathways share tube 172 in
such a way that no interference occurs between pathways. Tube 172
may be attached to endface 180a by some type of attachment means
180c, as shown in FIG. 9.
[0123] In an embodiment of the invention configured to detect
tissue characteristics of a patient's cervix, the tube 172 of the
tissue interface unit 170 may be first inserted into the patient's
vagina so that the end of the tube is immediately adjacent,
circumscribing or covering the patient's cervix. The cervix is then
illuminated by the illumination source 132 via illumination pathway
173d. Collected optical energy transmitted and/or reflected from
the tissue is directed to the imaging device 187, which is located
in the tissue interface unit 170. The imaging device 187 sends a
video signal that is viewed with a computer or video monitor. Thus,
the imaging device 187 provides the user with a view of the
patient's cervix, which assists the physician in properly aligning
and situating the tube 172 with respect to the patient's cervix.
The imaging device 187 may also be used to capture still images of
the cervix, which may be digitally stored and used for later data
analysis.
[0124] Once the tube 172 is appropriately placed such that a good
view of the cervix can be seen through the imaging device 187, the
tissue interface unit would be fixed with respect to the patient's
cervix. At this point, a still picture of the cervix may be taken
with the imaging device. The image signal is output to the docking
unit or directly to a monitor provided within the tissue interface
unit, or as a separate component. For example, the image, along
with relevant text, could be displayed on a hand-held LCD unit or a
LCD unit attached to the tissue interface unit. The spectroscopic
measurements are then started. The spectroscopic measurement
results are sent to the processor 190 in the docking unit 120 for
processing. For example, the results can be utilized to categorize
the spectroscopic measurement data, and thus the subject tissue, as
"Normal", "Non-Dysplastic", "Low Grade SIL" and "High Grade
SIL."
[0125] The systems, methods and apparatus of the present invention,
may conduct both fluorescence and reflectance spectroscopy using
both visible and UV light or any combination thereof. This is
generally referred to as multimodal spectroscopy. Cervical cancer,
being a form of epithelial dysplasia, provides an ideal target for
diagnosis using the epithelium down to the germinative layer, since
it undergoes minimum absorption and scattering from non-specific
interactions and obtains the largest possible diagnostic
information on its biochemical and morphological state. Other areas
with similar qualities that may serve as comparable targets for
diagnosis include, without limitation, oral cancer and colon
cancer.
[0126] Fluorescence and reflectance spectra may be made at several
locations on the target area by the present invention. Such
locations may be equispaced. Obtaining measurements across the
entire target area, for example, may allow for differential
diagnosis between dysplasia and surrounding tissue depending on the
embodiment.
[0127] Many investigators have pointed to the large biological
variation in the spectroscopic signature of normal tissue. This
natural variation is often higher than the variation seen in the
spectroscopic signatures going from normal to dysplasia tissue in
the same patient, for example. One cannot, therefore, assign an
absolute spectral intensity or signature to disease state. Rather,
all measurements must be normalized or baselined to "normal" tissue
in the same patient, and it is this relative measure or change that
has diagnostic relevance. Given our inability to determine "a
priori" the location of abnormal and normal tissue with certainty,
the logical alternative is to measure substantially the entire
target area.
[0128] A reflectance measurement is made by measuring the intensity
of light returned from the tissue at the same wavelength as that
used to irradiate the tissue. Reflectance measures the
morphological changes associated with dysplasia progression.
Although biochemical changes precede the morphological changes that
occur as a result of the former, in reality, varying degrees of
morphological change accompany the biochemical changes.
Morphological changes appear later in the course of dysplasia
progression and are defined as any change in average cell nuclei,
cell size, cell appearance, cell arrangement, and the presence of
non-native cells. In addition, effects of the host response such as
increased perfusion from angiogenesis result in an overall
difference in tissue appearance.
[0129] The morphological changes add more complexity to the
fluorescence measurement by absorbing and scattering both the
excitation and fluorescent light, thereby altering the true
fluorescence signal. Thus, it is difficult to make a fluorescence
measurement that is truly independent of the effects of scattering
and absorption. At the same time, both measurements provide
information that is partially independent of one another.
[0130] In reflectance spectroscopy, the tissue properties of
absorption and scattering dictate the amount of radiation measured
at the detector. For example, the increased vascularization due to
angiogenesis causes increased blood absorption of visible light.
Light propagating through and re-emitted from tissue is also
strongly affected by light scattering interactions. For example,
dysplasia cells have enlarged nuclei and since nuclei have a
different refractive index from that of the cell cytoplasm, they
serve as efficient light scatters. Thus, dysplasia tissue can
display increased light scattering.
[0131] While the absorption and scattering properties of tissue
correlate quantitatively with disease, by knowing the absorption
and scattering at each site on the tissue the corresponding error
that these effects produce in the fluorescence yields can also be
corrected for. This is the crux of the multimodal spectroscopy
approach. In order to reap this advantage, both measurements must
be made on the same site at the same time so as to ensure nearly
identical conditions.
[0132] The use of near UV and UV wavelengths elicits the
fluorescence and reflectance response of intrinsic markers shown to
be highly indicative of biological and morphological changes caused
by pre-dysplastic conditions in tissue. Accordingly, the systems,
methods and apparatus according to the invention may be configured
to acquire broad absorption and fluorescent spectra (approximately
340 nm to 700 nm). Particular examples of illumination and
collection wavelengths are shown in FIG. 6. Although these
wavelengths have shown promise, the invention is in no way limited
to the use of these wavelengths.
[0133] The measurements are made from a predetermined standoff
distance from the tissue. In one embodiment constructed by the
inventors to detect abnormalities on cervical tissue, the standoff
distance was set to approximately 175 mm (17.5 cm) to the first
optical surface of the tissue. This standoff distance can be
defined by and maintained by the length of the tube 72, 172 on the
tissue interface unit 70, 170.
[0134] In order to capture high-resolution spectral data from
several locations in a short time (hyperspectral imaging) design
compromises are required. By compromising on the spatial resolution
and measurement time, fluorescence and reflectance spectra can be
captured at approximately 10 nm spectral resolution according to
certain embodiments.
[0135] In one embodiment of the invention used to take measurements
on a subject tissue, for example, a cervix, the system uses a
line-scan approach to collect data from a plurality of detection
points. After positioning, measurements are made at, for example,
52, approximately 0.5-mm circular spots nominally separated from
each other by approximately 3.0 mm, as shown in FIG. 5. The subject
tissue is first flooded with illumination optical energy. Optical
energy returned by the subject tissue is fed to a viewing device,
which provides a user with an image of the tissue so that the user
can appropriately position the system with respect to the subject
tissue. Next, a single line or column of points on the tissue is
illuminated with optical energy. According to one embodiment, the
optical energy is illuminated in a range of approximately 340-700
nm. The radiation/light returned from the target tissue is
collected using a coherent fiber bundle. The result is that the
collected optical energy is formed into a virtual slit at the
entrance of the spectrograph. The spectrograph is then used to
spectrally resolve the optical energy. Given the spectral
resolution required, and the dispersion by the spectrograph, in
this embodiment, a single column is measured at any given time. The
system sequentially scans through all eight columns shown in FIG.
5, acquiring both fluorescence and reflectance spectra in a total
time duration of approximately 2 minutes.
[0136] According to another embodiment of the invention, the system
uses a flood illumination approach. The subject tissue is first
flooded with illumination optical energy. Optical energy returned
by the subject tissue is fed to a viewing device, which provides a
user with an image of the tissue so that the user can appropriately
position the system with respect to the subject tissue. After
positioning, the subject tissue is again flooded with illumination
optical energy, for example, in a range of approximately 340-700
nm.
[0137] The optical energy reflected and/or transmitted with respect
to the subject target area is imaged with the help of a set of
optics onto the face of a fiber bundle (target end) as shown in
FIG. 20A. This end of the fiber bundle has fibers arranged at
discrete points, as shown in FIG. 20A, and the light imaged onto
the bundle at these points is transferred via the fibers to the
other end of the bundle, as shown in FIG. 20B. The other end of the
bundle has all of the fibers arranged in a single column. This
column serves as the entrance slit of the spectrograph, which is
then able to spectrally resolve, in the horizontal direction, the
light in this column.
[0138] In another embodiment, the optical energy is directed to the
subject target area with the help of a set of optics that images a
mask of apertures onto the tissue. This is an alternative
embodiment to those embodiments taught and described in FIGS. 4 and
5. The apertures are arranged in a column on the mask. The mask can
be horizontally moved to scan the entire subject target area while
presenting at least one single column of light at the entrance of
the spectrograph at a given instant. The spectrograph is then able
to spectrally resolve, in the horizontal direction according to an
embodiment, the light collected by this column of apertures.
[0139] The optical energy reflected and/or transmitted by the
subject tissue is then collected and directed to a diffraction
grating, which separates the light spectrally. Wavelengths not of
interest may be filtered out. For example, the illumination
wavelength may be filtered out. The collected light is then
reflected onto a device for making spectrographic measurements,
such as a CCD camera and controller.
[0140] As in the previous embodiments, the spectrograph only makes
measurements at a single column 200 of detection points 210 at a
time on a subject tissue 205, as shown in FIG. 13. According to an
embodiment, reflectance measurements and fluorescence measurements
are made at fifty-six points on the cervix with a separation of
approximately 3 mm. However, depending on the embodiment, the
number of points can vary to any number of possible points at a
separation sufficient to avoid optical cross-talk/interference
among the points. Reference numeral 215 represents a center of the
subject tissue, in the case of a cervix this would be the Os.
Measurements for various columns are then sequentially made, as
shown in FIG. 14.
[0141] FIG. 15 schematically shows what would be recorded by a CCD
camera coupled to the output of a spectrograph. The light returning
from a column of locations on the cervix would be spectrally
resolved into different wavelengths that extend away from the
column in a perpendicular direction. In other words, the pixels of
the CCD camera extending to the left and the right of a single
measurement position would received light of different wavelengths
returned from the measurement position. The intensity of the light
received at each pixel is indicative of the intensity at a
particular range of wavelengths. Thus, examining the values
registered at each pixel on the CCD array allows the device to
determine the intensity of the light returned from each position on
the illuminated column of positions at a plurality of different
wavelengths.
[0142] FIG. 16 schematically shows how a series of measurements
would be taken during different measurement cycles. Each
measurement cycle would provide information about the light
returned from a different column of illuminated positions on the
target tissue.
[0143] Note, the spectrograph would separate the light from each
illuminated measurement position 210 into a +1 Order Spectra and a
-1 Order Spectra. Each Spectra would contain essentially the same
spectral information. Thus, when interrogating a column of
positions 210 on the left side of the cervix, as shown in FIG. 17,
the device could utilize the +1 Order Spectra, which illuminates
pixels within the CCD array. When interrogating a column of
positions 210 on the right side of the cervix, as shown in FIG. 18,
the device could utilize the -1 Order Spectra.
[0144] In cases where the entire spectral bandwidth is not
available in either the +1 or the -1 order spectra, appropriate
wavebands from both orders will be combined to form a complete
spectral set.
[0145] FIG. 19 schematically shows the ultimate arrangement of
detection points 210 collected for an entire cervix using this
system.
[0146] The foregoing embodiments and advantages are merely
exemplary and are not to be construed as limiting the present
invention. The present teaching can be readily applied to other
types of apparatuses and applications that may be common to those
of ordinary skill in the art. The description of the present
invention is intended to be illustrative, and not to limit the
scope of the claims. Many alternatives, modifications, and
variations will be apparent to those skilled in the art. In the
claims, means-plus-function clauses are intended to cover the
structures described herein as performing the recited function and
not only structural equivalents but also equivalent structures.
* * * * *