U.S. patent application number 10/701123 was filed with the patent office on 2004-09-23 for spectral volume microprobe arrays.
This patent application is currently assigned to MediSpectra, Inc.. Invention is credited to Bee, David, Emans, Matthew, Hed, Ze'ev, Kwo, Jennie, Lipson, David, Modell, Mark, Nordstrom, Robert.
Application Number | 20040186382 10/701123 |
Document ID | / |
Family ID | 33458492 |
Filed Date | 2004-09-23 |
United States Patent
Application |
20040186382 |
Kind Code |
A1 |
Modell, Mark ; et
al. |
September 23, 2004 |
Spectral volume microprobe arrays
Abstract
Methods and apparatus are provided for determining a
characteristic of a sample of a material by the interaction of
electromagnetic radiation with the sample. The apparatus includes
an optical assembly and a protective barrier. The optical assembly
sequentially illuminates a plurality of volume elements in the
sample with an intensity distribution in the sample that drops off
substantially monotonically from a first region in a first optical
path and collects electromagnetic radiation emanating from each of
the volume elements. The optical assembly collects the
electromagnetic radiation emanating from each of the volume
elements with a collected distribution that drops off substantially
monotonically from a second region in a second optical path. The
first and second regions at least partially overlap in each of the
volume elements. The optical assembly can be configured as a probe,
to be directed to the evaluation of a sample of a biological
material. A protective barrier can be disposed between the optical
assembly and a body tissue, to prevent contamination of the optical
assembly by said body tissue.
Inventors: |
Modell, Mark; (Natick,
MA) ; Hed, Ze'ev; (Nashua, NH) ; Bee,
David; (Groton, MA) ; Lipson, David; (N.
Andover, MA) ; Kwo, Jennie; (Cambridge, MA) ;
Emans, Matthew; (Boston, MA) ; Nordstrom, Robert;
(Hanover, MA) |
Correspondence
Address: |
TESTA, HURWITZ & THIBEAULT, LLP
HIGH STREET TOWER
125 HIGH STREET
BOSTON
MA
02110
US
|
Assignee: |
MediSpectra, Inc.
Lexington
MA
|
Family ID: |
33458492 |
Appl. No.: |
10/701123 |
Filed: |
November 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10701123 |
Nov 4, 2003 |
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09481762 |
Jan 11, 2000 |
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10701123 |
Nov 4, 2003 |
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09241806 |
Feb 2, 1999 |
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6411835 |
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09241806 |
Feb 2, 1999 |
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08782936 |
Jan 13, 1997 |
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6104945 |
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60115373 |
Jan 11, 1999 |
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Current U.S.
Class: |
600/473 ;
600/476 |
Current CPC
Class: |
A61B 5/0075 20130101;
A61B 5/0068 20130101; A61B 2090/0814 20160201; A61B 5/0084
20130101; A61B 1/00059 20130101; A61B 1/00142 20130101; G01N
21/4795 20130101; A61B 2562/08 20130101; A61B 5/0066 20130101; A61B
5/0071 20130101 |
Class at
Publication: |
600/473 ;
600/476 |
International
Class: |
A61B 006/00 |
Claims
What is claimed is:
1. Apparatus for determining a characteristic of a sample of
material, comprising: a probe, having illuminating optics that
illuminate with electromagnetic radiation a plurality of locations
in the sample; and collecting optics that collect electromagnetic
radiation emanating from each of said locations in the illuminated
sample; a detector that detects the collected electromagnetic
radiation emanating from each of said locations in the illuminated
sample to produce a response representative of said characteristic;
and a barrier disposed external to said probe and disposed between
the sample and said probe, wherein the barrier permits illumination
by the probe and collecting by the collecting optics.
2. Apparatus of claim 1, wherein the sample comprises biological
material.
3. Apparatus of claim 2, wherein the sample exists in continuity
with an in-vivo body tissue.
4. Apparatus according to claim 3, wherein the barrier prevents the
probe from contacting the in-vivo body tissue.
5. Apparatus according to claim 3, wherein the barrier prevents the
probe from contacting a tissue in proximity to the in-vivo body
tissue.
6. Apparatus according to claim 1, wherein the barrier further
comprises a window adapted for transmitting electromagnetic
radiation therethrough without distortion.
7. Apparatus according to claim 6, wherein the window can be
irradiated with electromagnetic radiation without producing a
significant fluorescent response.
8. Apparatus according to claim 1, wherein the probe is rendered
inoperable by an absence of the barrier.
9. Apparatus according to claim 1, wherein the barrier is adapted
for single use.
10. Apparatus according to claim 9, further comprising an
affixation mechanism that attaches the barrier to the probe,
wherein detaching the barrier from the probe prevents a subsequent
use of said barrier.
11. Apparatus according to claim 10, wherein attaching the barrier
to the probe releases a refractive index matching fluid material
capable of filling a space between the barrier and the probe
whereby electromagnetic radiation can pass effectively through the
space and through the barrier, thereby to permit determining the
characteristic of the sample.
12. Apparatus according to claim 9, wherein the probe comprises a
sensor that detects a marker on the barrier indicating an unused
state of the barrier, said sensor generating a signal upon
detection of that marker, and said probe further comprising a
receptor system that receives the signal and activates the probe
upon receipt of the signal.
13. Apparatus according to claim 9, wherein the probe comprises a
sensor that detects a marker on the barrier indicating a previous
use of the barrier, said sensor generating a signal upon detection
of said marker, and said probe further comprising a receptor system
that receives the signal and renders the probe inactive upon
receipt of the signal.
14. Apparatus for determining a characteristic of a sample of
biological material, comprising: a probe having an optical assembly
that sequentially directs a first set of electromagnetic radiation
to a plurality of locations in a sample with an intensity
distribution in the sample that drops off substantially
monotonically from a first region in a first optical path and that
receives a response indicative of a second set of electromagnetic
radiation, said second set comprising electromagnetic radiation
emanating from each of said locations, said optical assembly
collecting said second set of electromagnetic radiation with a
collection distribution that drops off substantially monotonically
from a second region in a second optical path, said first and
second regions at least partially overlapping in each of said
locations, said optical assembly comprising at least one array of
field stops whose dimensions are large compared to a quotient of
wavelength of said electromagnetic radiation divided by a working
numerical aperture of said optical assembly, measured from said
field stops; a detector coupled to said return signal to produce
responses that vary according to said characteristic in each of
said locations; a processor that processes responses produced by
the detector to determine the characteristic of the sample; and a
sheath that covers the probe.
15. Apparatus according to claim 14, wherein the optical assembly
is inoperative in the absence of the sheath.
16. Apparatus according to claim 14, wherein the sample of
biological material exists in continuity with an in-vivo body
tissue.
17. Apparatus according to claim 16, wherein the sheath prevents
the probe from contacting the in-vivo body tissue.
18. Apparatus according to claim 16, wherein the sheath prevents
the probe from contacting a tissue in proximity to the in-vivo body
tissue.
19. Apparatus according to claim 14, wherein the sheath comprises a
window adapted for transmitting electromagnetic radiation.
20. Apparatus according to claim 19, wherein the window is capable
of transmitting electromagnetic radiation without producing
significant fluorescent response.
21. Apparatus according to claim 16, wherein the sheath is adapted
for a single use.
22. Apparatus according to claim 21, wherein the sheath is adapted
for positioning upon the probe in a unique position.
23. Apparatus according to claim 21, wherein the sheath is attached
to the probe, and wherein a detachment of the sheath from the probe
renders the sheath inoperable.
24. Apparatus according to claim 21, wherein the sheath further
comprises a marker bearing data identifying the sheath, and wherein
the probe further comprises a reader to read the data on the
marker, and a processing system to correlate the data on the marker
with an indicator that relates to an unused state of the
sheath.
25. Apparatus according to claim 21, wherein the sheath further
comprises a marker bearing data identifying the sheath, and wherein
the probe further comprises a reader to read the data on the
marker, and an indicator that relates to a previously used state of
the sheath.
26. Apparatus according to claim 21, wherein affixing the sheath to
the probe creates a space therebetween interfering with effective
passage of electromagnetic radiation, and wherein affixing the
sheath to the probe releases a refractive index matching fluid
capable of filling the space, whereby electromagnetic radiation can
pass effectively through the space and through the barrier, thereby
to permit determining the characteristic of the sample.
27. A method for determining a characteristic of a sample of
material by the interaction of electromagnetic radiation with the
sample, comprising the steps of: providing an optical assembly
adapted for positioning in proximity to the sample; providing a
sheath that prevents the optical assembly from contacting the
sample, said sheath being capable of transmitting electromagnetic
radiation; covering the optical assembly with the sheath;
positioning the optical assembly in proximity to the sample;
illuminating with the optical assembly a plurality of locations in
the sample by directing electromagnetic radiation to the sample;
collecting with said optical assembly electromagnetic radiation
emanating from each of the locations in the sample; detecting the
collected electromagnetic radiation emanating from each of said
locations in the illuminated sample to produce a response
representative of said characteristic in each of said locations;
and determining from the response in each of said locations the
characteristic of the sample.
28. The method of claim 27, wherein the sample comprises biological
material.
29. The method of claim 28, wherein the sample exists in continuity
with an in-vivo body tissue.
30. The method of claim 29, wherein the sheath prevents the optical
assembly from contacting a tissue in proximity to the sample of
biological material.
31. The method of claim 30, further comprising the step of
providing a housing that is dimensionally adapted for positioning
in relation to the in-vivo body tissue, whereby the optical
assembly can be positioned in proximity to the sample and wherein
the sheath covers the housing, thereby covering the optical
assembly.
32. The method of claim 29, wherein the sheath is adapted for a
single use.
33. The method of claim 28, further comprising the steps of
identifying an unused state of the sheath, and rendering the
optical assembly operative upon identifying the unused state of the
sheath.
34. A system for determining a characteristic of a biological
tissue, comprising: an optical probe having illuminating optics and
collecting optics; a protective sheath disposed external to the
optical probe and interposed between the biological tissue and the
optical probe, wherein the optical probe is positioned in proximity
to the biological tissue to illuminate a plurality of locations in
the biological tissue and to collect electromagnetic radiation
emanating from said location; a sensor that detects the
electromagnetic radiation emanating from the biological tissue to
produce data corresponding to said electromagnetic radiation; and a
data processor that processes the data produced by the sensor to
determine from said data a characteristic of the biological tissue,
wherein the characteristic of the biological tissue can be related
to the condition of the biological tissue.
35. The system of claim 34, wherein the biological tissue is an
internal body tissue.
36. The system of claim 35, wherein the optical probe is adapted
for insertion within a body lumen, and wherein the protective
sheath is interposed between the optical probe and the wall of the
body lumen to prevent contact of the optical probe with the
wall.
37. The system of claim 35, wherein the internal body tissue is a
tissue of cervix uteri.
38. The system of claim 34, wherein the protective sheath comprises
an optical window capable of transmitting electromagnetic radiation
and a cylindrical sleeve conforming in shape to the optical
probe.
39. The system of claim 38, wherein the optical window comprises a
rigid material.
40. The system of claim 38, wherein the optical window is
positioned on a distal end of the optical probe.
41. The system of claim 34, wherein the protective sheath comprises
an optical lens capable of transmitting electromagnetic radiation
and a cylindrical sleeve conforming in shape to the optical
probe.
42. The system of claim 38, wherein the optical window comprises an
optical filter that transmits optical radiation at a first
wavelength and prevents transmission of optical radiation at a
second wavelength.
43. The system of claim 38, wherein the optical window comprises an
optical polarizer that selects a first state of electromagnetic
polarization for transmission and prevents a second state of
electromagnetic polarization from being transmitted.
44. The system of claim 34, wherein the protective sheath is
adapted for orientation in a preselected position relative to the
optical probe.
45. The system of claim 38, wherein the optical window comprises a
material capable of transmitting electromagnetic radiation without
generating a significant fluorescent response.
46. The system of claim 41, wherein the optical lens comprises a
material capable of transmitting electromagnetic radiation without
generating a significant fluorescent response.
47. The system of claim 42, wherein the optical filter comprises a
material capable of transmitting electromagnetic radiation without
generating a significant fluorescent response.
48. The system of claim 43, wherein the optical polarizer comprises
a material capable of transmitting electromagnetic radiation
without generating a significant fluorescent response.
49. The system of claim 38, wherein the cylindrical sleeve
comprises a heat-shrinkable plastic.
50. A system for controlling use of a diagnostic apparatus,
comprising: a diagnostic apparatus with a probe; a disposable
sheath that covers the probe, thereby preventing contact of the
probe with a body tissue, said disposable sheath comprising an
identifier bearing unique data characterizing the disposable
sheath; a detector that provides a first signal indicative of the
unique data borne by the identifier; and a receiver system that
responds to the first signal, that determines a state of the
disposable sheath and that provides a second signal to the probe
related to the state of the disposable sheath, wherein the second
signal regulates activation of the probe.
51. The system of claim 50, wherein the diagnostic apparatus
further comprises: an optical assembly having illuminating optics
and collecting optics; a detector that detects electromagnetic
radiation and that produces a data set corresponding thereto; and a
processor that processes the data set to provide a diagnosis of the
tissue.
52. The system of claim 50, wherein the unique data comprise data
relating to a previous use of the disposable sheath.
53. The system of claim 50, wherein the unique data comprise data
relating to a mechanical defect of the disposable sheath.
54. The system of claim 50, wherein the unique data comprise data
relating to a diagnostic use of the probe.
55. The system of claim 50, wherein said second signal transmitted
from the receiver system to the probe is capable of activating the
probe.
56. The system of claim 50, wherein said second signal transmitted
from the receiver system to the probe prevents activation of the
probe.
57. The system of claim 50, further comprising a database
containing data entries and a data processor, wherein the data
processor compares the unique data characterizing the disposable
sheath with the data entries in the database.
58. The system of claim 57, wherein the data entries comprise
serial numbers of disposable probes.
59. The system of claim 50, wherein the state of the disposable
sheath is a state of previous use.
60. The system of claim 50, wherein the probe is adapted for
diagnosis of a condition of an internal body tissue.
61. The system of claim 60, wherein the internal body tissue
comprises a tissue of a cervix uteri.
62. A system for controlling the use of a probe, comprising: a
disposable barrier that prevents a contact of a probe with a body
tissue, said probe comprising a sensor capable of recognizing a
state of a disposable barrier, wherein the sensor can signal the
probe upon recognition of the state of the disposable barrier,
thereby to control the use of the probe.
63. The system of claim 62, wherein the sensor can further transmit
to the probe a signal to inactivate the probe.
64. The system of claim 62, wherein the sensor can further transmit
to the probe a signal to activate the probe.
65. The system of claim 62, wherein the state of the disposable
barrier comprises a secure affixation of the disposable barrier to
the probe.
66. The system of claim 62, wherein the state of the disposable
barrier comprises a condition of physical integrity of the
disposable barrier.
67. The system of claim 62, wherein the state of the disposable
barrier comprises a previously used condition of the disposable
barrier.
68. The system of claim 62, wherein the state of the disposable
barrier comprises an unused condition of the disposable
barrier.
69. The system of claim 62, wherein the probe is adapted for
examination of an internal body tissue.
70. The system of claim 69, wherein the internal body tissue
comprises a cervix uteri.
71. A method for controlling activation of a probe for a diagnostic
examination, comprising: providing a probe adapted for the
diagnostic examination; providing a sheath that covers the probe to
prevent contact of the probe with body tissue; providing a sensor
that senses a condition of the sheath, whereby upon determining the
condition of the sheath the sensor transmits a signal to the probe,
said signal being capable of controlling the activation of the
probe; covering the probe with the sheath; sensing with the sensor
the condition of the sheath; and transmitting a signal to control
the activation of the probe for the diagnostic examination.
72. The method of claim 71, wherein the signal prevents the
activation of the probe.
73. The method of claim 72, wherein the condition of the sheath
comprises a previously used state.
74. The method of claim 71, wherein the signal permits the
activation of the probe.
75. The method of claim 74, wherein the condition of the sheath
comprises physical integrity of the sheath.
76. The method of claim 74, wherein the condition of the sheath
comprises an unused state.
77. The method of claim 71, wherein the probe is adapted for the
diagnostic examination of an internal body tissue.
78. The method of claim 77, wherein the internal body tissue
comprises a cervix uteri.
79. A disposable sheath for a probe, comprising: a barrier disposed
external to the probe preventing contact between the probe and a
feature of an environment in proximity to the probe; and a
single-use mechanism, whereby the barrier is prevented from being
reused.
80. The disposable sheath of claim 79, wherein the single-use
mechanism comprises an affixation mechanism whereby the barrier is
attached to the probe and wherein, upon attachment the barrier is
prevented from being reused.
81. The disposable sheath of claim 79, wherein the single-use
mechanism comprises an affixation mechanism whereby the barrier is
attached to the probe and wherein, upon detachment of said barrier
from the probe, the barrier is prevented from being reused.
82. The disposable sheath of claim 79, wherein the single-use
mechanism comprises an interlock system that recognizes a proper
position of the barrier on the probe and that prevents the probe
from being used without the barrier in the proper position.
83. An interlock system, comprising: a first component; a second
component that mates with the first component; and a sensor system
that perceives a proper positioning of the second component in
relation to the first component and that generates a signal to
activate the first component upon perceiving said proper
position.
84. An optical system comprising: a probe having illuminating
optics that direct electromagnetic radiation to a target sample and
collecting optics that collect electromagnetic radiation emitted
from a target sample; and a sheath for covering the probe, said
sheath having a distal tip dimensionally adapted for entering an
orifice too small to permit entry of the probe into said orifice,
wherein the distal tip directs electromagnetic radiation from the
illuminating optics to the target sample and from the target sample
to the collecting optics.
85. The system of claim 84, wherein the distal tip of the sheath is
dimensionally adapted for entering the cervical os.
86. The system of claim 84, wherein the electromagnetic radiation
from the illuminating optics of the probe is directed to the target
sample through a lateral aspect of the distal tip of the disposable
sheath
87. The system of claim 86, further comprising a reflecting prism
located at the distal end of the disposable sheath that deflects
the electromagnetic radiation being directed from the illuminating
optics.
88. A method of making a probe system, comprising: providing an
optical assembly for illuminating a sample and collecting
electromagnetic radiation emanating from the sample; and
positioning a disposable sheath between the optical assembly and
the sample.
89. The method of claim 88, wherein the sample comprises biological
material.
90. The method of claim 89, wherein the sample of biological
material is in continuity with an in-vivo body tissue.
91. The method of claim 90, wherein the disposable sheath prevents
the optical assembly from contacting the in-vivo body tissue.
92. The method of claim 90, wherein the disposable sheath prevents
the optical assembly from contacting a tissue in proximity to the
in-vivo body tissue.
93. The method of claim 88, wherein the disposable sheath further
comprises a window adapted for transmitting electromagnetic
radiation therethrough without distortion of said electromagnetic
radiation.
94. The method of claim 88, wherein the optical assembly is
rendered inoperable by the absence of the disposable sheath.
95. The method of claim 88, wherein the disposable sheath is
adapted for single use.
Description
PRIOR APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application 60/115,373, filed Jan. 11, 1999, and is a
continuation-in-part of U.S. patent application Ser. No. 09/241,806
filed Feb. 2, 1999, this latter Application having been filed as a
continuation-in-part of U.S. patent application Ser. No. 08/782,936
filed January 13, 1997. Both such applications are herein
incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to systems and methods for
providing a barrier to prevent contact of an optical probe from
surrounding features of the environment. More particularly, the
present invention relates to systems and methods for providing a
disposable sheath for a medical apparatus.
BACKGROUND OF THE INVENTION
[0003] An important requirement exists for an instrument that will
provide rapid and automatic diagnostic information, for example of
cancerous and otherwise diseased tissue. In particular, there is a
need for an instrument that would map the extent and stage of
cancerous tissue without having to excise a large number of tissue
samples for subsequent biopsies. In the current art, the medical
profession relies generally on visual analysis and biopsies to
determine specific pathologies and abnormalities. Various forms of
biochemical imaging are used as well. Unique optical responses of
various pathologies are being exploited in attempts to characterize
biological tissue as well. These prior art techniques, however,
contain limitations. pathologies are being exploited in attempts to
characterize biological tissue as well. These prior art techniques,
however, contain limitations.
[0004] For example, performing a tissue biopsy and analyzing the
extracted tissue in the laboratory requires a great deal of time.
In addition, tissue biopsies can only characterize the tissue based
upon representative samples taken from the tissue. This results in
a large number of resections being routinely performed to gather a
selection of tissue capable of accurately representing the sample.
In addition, tissue biopsies are subject to sampling and
interpretation errors. Magnetic resonance imaging is a successful
tool, but is expensive and has serious limitations in detecting
pathologies that are very thin or in their early stages of
development.
[0005] One technique used in the medical field for tissue analysis
is induced fluorescence. Laser induced fluorescence utilizes a
laser tuned to a particular wavelength to excite tissue and to
cause the tissue to fluoresce at a set of secondary wavelengths
that can then be analyzed to infer characteristics of the tissue.
Fluorescence can originate either from molecules normally found
within the tissue, or from molecules that have been introduced into
the body to serve as marker molecules.
[0006] Although the mechanisms involved in the fluorescence
response of biological tissue to UV excitation have not been
clearly defined, the fluorescence signature of neoplasia appears to
reflect both biochemical and morphological changes. The observed
changes in the spectra are similar for many cancers, which suggest
similar mechanisms are at work. For example, useful
auto-fluorescence spectral markers may reflect biochemical changes
in the mitochondria, e.g., in the relative concentration of
nicotinamide adenine dinucleotide (NADH) and flavins. Mucosal
thickening and changes in capillary profusion are structural
effects that have been interpreted as causing some typical changes
in the spectroscopic record.
[0007] The major molecules in biological tissue which contribute to
fluorescence emission under 337 nm near UV light excitation, have
been identified as tryptophan (390 nm emission), chromophores in
elastin (410 nm) and collagen (300 nm), NADH (470 nm), flavins (520
nm) and melanin (540 nm). However, it should be noted that in
tissue, there is some peak shifting and changes in the overall
shape relative to the pure compounds. Accordingly, the sample can
be illuminated with a UV beam of sufficiently short wavelength and
record responses from the above enumerated wavelengths of light in
order to determine the presence of each of above identified
contributions to tissues types.
[0008] It has been further shown that hemoglobin has an absorption
peak between 400 and 540 nm, while both oxyhemoglobin and
hemoglobin have strong light absorption above 600 nm. Blood
distribution may also influence the observed emission spectra of
elastin, collagen, NAD, and NADH. Further compounds present in
tissue which may absorb emitted light and change the shape of the
emitted spectra include myoglobin, porphyrins, and dinucleotide
co-enzymes.
[0009] A general belief is that neoplasia has high levels of NADH
because its metabolic pathway is primarily anaerobic. The inability
of cells to elevate their NAD+: NADH ratio at confluence is a
characteristic of transformed cells related to their defective
growth control. The ratio of NAD+: NADH is an indicator of the
metabolic capability of the cell, for example, its capacity for
glycolysis versus gluconeogenesis. Surface fluorescence has been
used to measure the relative level of NADH in both in vitro and in
vivo tissues. Emission spectra obtained from individual myocytes
produce residual green fluorescence, probably originating from
mitochondrial oxidized flavin proteins, and blue fluorescence is
consistent with NADH of a mitochondrial origin.
[0010] Collagen, NADH, and flavin adenine dinucleotide are thought
to be the major fluorophores in colonic tissue and were used to
spectrally decompose the fluorescence spectra. Residuals between
the fits and the data resemble the absorption spectra of a mix of
oxy-and deoxy-hemoglobin; thus the residuals can be attributed to
the presence of blood.
[0011] Alfano, U.S. Pat. No. 4,930,516, teaches the use of
luminescence to distinguish cancerous from normal tissue when the
shape of the visible luminescence spectra from the normal and
cancerous tissue are substantially different, and in particular
when the cancerous tissue exhibits a shift to the blue with
different intensity peaks. For example, Alfano discloses that a
distinction between a known healthy tissue and a suspect tissue can
be made by comparing the spectra of the suspect tissue with the
healthy tissue. According to Alfano, the spectra of the tissue can
be generated by exciting the tissue with substantially
monochromatic radiation and comparing the fluorescence induced at
least at two wavelengths.
[0012] Alfano, in U.S. Pat. No. 5,042,494, teaches a technique for
distinguishing cancer from normal tissue by identifying how the
shape of the visible luminescence spectra from the normal and
cancerous tissue are substantially different.
[0013] Alfano further teaches, in U.S. Pat. No. 5,131,398, the use
of luminescence to distinguish cancer from normal or benign tissue
by employing (a) monochromatic or substantially monochromatic
excitation wavelengths below about 315 nm, and, in particular,
between about 260 and 315 nm, and, specifically, at 300 nm, and (b)
comparing the resulting luminescence at two wavelengths about 340
and 440 nm.
[0014] Alfano, however, fails to teach a method capable of
distinguishing between normal, malignant, benign, tumorous,
dysplastic, hyperplastic, inflamed, or infected tissue. Failure to
distinguish these entities prevents selecting appropriate
therapies. While the simple ratio, difference and comparison
analysis of Alfano and others have proven to be useful tools in
cancer research and provocative indicators of tissue status, these
have not, to date, enabled a method nor provided means which are
sufficiently accurate and robust to be clinically acceptable for
cancer diagnosis.
[0015] It is understood that the actual spectra obtained from
biological tissues are extremely complex and thus difficult to
resolve by standard peak matching programs, spectral deconvolution
or comparative spectral analysis. Furthermore, spectral shifting
further complicates such attempts at spectral analysis. Last, laser
fluorescence and other optical responses from tissues typically
fail to achieve depth resolution because either the optical or the
electronic instrumentation commonly used for these techniques
entail integrating the signal emitted by the excited tissue over
the entire illuminated tissue volume.
[0016] Rosenthal, U.S. Pat. No. 4,017,192, describes a technique
for automatic detection of abnormalities, including cancer, in
multi-cellular bulk biomedical specimens, which purports to
overcome the problems associated with complex spectral responses of
biological tissues. Rosenthal teaches the determination of optical
responses (transmission or reflection) data from biological tissue
over a large number of wavelengths for numerous samples and then
the correlation of these optical responses to conventional,
clinical results to select test wavelengths and a series of
constants to form a correlation equation. The correlation equation
is then used in conjunction with optical responses at the selected
wavelengths taken on an uncharacterized tissue to predict the
status of this tissue. However, to obtain good and solid
correlations, Rosenthal excises the tissues and obtains in essence
a homogeneous sample in which the optical responses do not include
the optical signatures of underlying tissues. Rosenthal's methods,
therefore, may not be suitable for in vivo applications.
[0017] In studies carried out at the Wellman Laboratories of
Photomedicine, using a single fiber depth integrating probe,
Schomacker has shown that the auto-fluorescence of the signature of
human colon polyps in vivo is an indicator of normality, benign
hyperplasia, pre-cancerous, and malignant neoplasia. See Schomacker
et al., Lasers Surgery and Medicine, 12, 63-78 (1992), and
Gastroenterology 102, 1155-1160 (1992). Schomacker further teaches
using multi-variant linear regression analysis of the data to
distinguish neoplastic from non-neoplastic polyps. However, using
Schomacker's techniques, the observation of mucosal abnormalities
was hindered by the signal from the submucosa, since 87% of the
fluorescence observed in normal colonic tissue can be attributed to
submucosal collagen.
[0018] Accordingly, there is a need for a more effective and
accurate device to characterize specimens, and particularly in vivo
specimens, which will obtain responses from well defined locations
or volume elements within said specimen, and present data
automatically from a relatively large area comprising a plurality
of such locations or volume elements. Furthermore, there is a need
for methods to automatically interpret such data in terms of simple
diagnostic information on said locations or volume elements.
[0019] In U.S. Pat. No. 5,713,364, DeBaryshe et al. teaches the
general principles of obtaining valuable analytical data from a
volume element in a target sample by using spatial filters with
dimensions that are generally larger than the diffraction limits
for the wavelengths of the probing radiation. Such spatial
filtration is obtained by an optical device including an
illumination and a detection system both containing field stops and
the field stops being conjugated to each other via the volume
element to be analyzed, providing in essence a non imaging volume
microprobe.
[0020] While the family of devices described in the aforementioned
application are very useful in the analysis of a plurality of
points within a target sample, there is a need to easily and
automatically obtain such data on a full array of points so as to
convert these data to an artificial image of the analytical
findings over a large area of the sample. This is particularly
important when heterogeneous samples, such as biological samples
are examined with the non imaging volume microprobe. For instance,
when examining tissues to determine the presence or absence of
oncological pathologies, or other pathologies, visual techniques
are followed, in some cases, by the resection of biopsy specimen.
Such techniques are naturally limited in that the physician eye can
only assess the visual appearance of potential pathologies, and the
number of biopsies taken is by necessity limited. The appearance of
pathological tissues does not provide information on the depth of
the pathologies, and cannot provide positive diagnosis of the
pathology. Furthermore, since biopsies are carried out ex vivo, a
time lag between the taking of the biopsy and obtaining its results
cannot be avoided. It would be very useful for physicians to have a
device capable of performing such diagnostic tasks in vivo and to
obtain differential diagnostics (between healthy and pathological
tissues) while performing the examination. This is particularly
important when performing exploratory surgical procedures, but can
be very useful when examining more accessible tissues as well.
[0021] A number of devices have been described in the prior art
relating particularly to confocal microscopy where illumination and
detection arrays are provided. For instance, a confocal scanning
microscope in which mechanical scanning of the illuminating and the
transmitted (or the reflected) beams is avoided is described in
U.S. Pat. No. 5,065,008. A light shutter array is used to provide
synchronous detection of a scanned light beam without the need to
move a photodetector to follow the scanning beam, and each of the
shutters is serving, in essence, as a field stop in the confocal
microscope. In other embodiments, two overlapping arrays of liquid
crystals are used as optical shutter arrays to attempt reduction in
the size of the field stops. As is well known in the art of
confocal microscopy, in order to obtain the desired resolution
afforded by this technique, the dimensions of the field stops need
to be small relative to the diffraction limit of the optical beam
used in the system. Other embodiments also provide for two sets of
field stops, conjugated within the sample, one set for the
illuminating beam and one set for the transmitted or reflected
beam. While this patent teaches the use of electronic scanning of
the illumination and response beams, the illumination intensity and
response signal strength are drastically limited due to the use of
dual liquid crystal optical shutters required to achieve the
pin-hole effect of a scanning confocal microscope.
[0022] Another confocal imaging device is taught in U.S. Pat. No.
5,028,802, where a microlaser array provides a flying spot light
source in a confocal configuration. Similarly U.S. Pat. No.
5,239,178 provides for an illuminating grid for essentially the
same purpose, except that light emitting diodes are used for the
grid's light sources. These approaches, however, are limited to
monochromatic illumination and are usable only with relatively long
wavelengths at which solid state laser diodes and thus microlaser
arrays or light emitting diode arrays are available.
[0023] None of these devices provide for an array of non-imaging
volume microprobes. Accordingly, there is a need for a device
comprising an array of non-imaging volume microprobes in which a
plurality of volume elements in a sample can rapidly be scanned in
order to obtain diagnostic or analytical information over a
relatively large area of the sample without integrating the data
from all the sampled volume elements or locations.
[0024] Where a diagnostic device is to come into contact with body
tissues, there is a further need that its surfaces be insulated
from contact with those tissues in order to avoid contamination.
During sterile procedures, the device can introduce contamination
into body tissues. Furthermore, the device can become contaminated
by contact with the tissues of one patient and transmit that
contamination to another patient. While these problems may be
avoided by sterilizing the diagnostic device before each use, its
delicate optical components may be damaged or incompletely
sterilized by available techniques; furthermore, a sterilization
cycle prior to each use, even if effective, may be costly and
time-consuming.
[0025] As an alternative, some form of barrier may be provided that
is to be interposed between the diagnostic device and the patient's
tissues. In order to avoid the abovementioned problems of
contamination and cross-contamination, however, it is important
that a sterile barrier be applied prior to each use of the
diagnostic device. Sterility may be effected either by sterilizing
the barrier apparatus each time it is used, or by fabricating the
barrier apparatus as a single-use device which is sterile and
disposable. It is furthermore important with a single-use device
that its reuse be prevented so that a fresh sterile insulator is
employed for each patient.
[0026] It is desirable that an apparatus that provides a barrier
insulating the diagnostic device be compatible with the optical
characteristics of the diagnostic device, so that the presence of
the barrier does not impair the diagnostic device's accuracy or
ease of use. Thus, the method used to isolate the probe from the
target tissue must be compatible with the requirement that
excitation beams traveling to the tissue and the optical responses
therefrom be transmitted through the barrier with minimal optical
losses and without signal alteration. When the barrier apparatus is
applied to the diagnostic device, it is further important that the
optical properties of the system remain stable throughout the
diagnostic test, and remain consistent from one test to another. To
ensure these qualities, it is desirable that the barrier be tightly
adherent to the probe during a diagnostic procedure. Tight
adherence of the barrier to the probe will furthermore avoid
accidental detachment between the probe and the sheath during the
procedure, thus preventing this mechanism of contamination.
[0027] It would be further desirable to provide a barrier apparatus
that conforms to the anatomic area in which it is being used. For
example, a differently shaped barrier apparatus may be required for
diagnosing tissues through an endoscope than would be useful for
diagnosing abnormalities of the cervix. One device adapted for the
examination of the cervix uteri may be termed a colpoprobe. A
barrier apparatus shaped to fit over a colpoprobe might have
particular anatomic and optical characteristics. It would be
advantageous, for example, during a colposcopic examination to
provide not only an image of the cervix, but also a set of data
correlated with important tissue variations from the normal state
which cannot be visualized in normal imaging systems. It is
desirable that, since the contemplated use of certain diagnostic
systems such as the colpoprobe includes screening of large
populations, it is important that the systems and their biological
isolation sheaths be easy to use in an error-free manner, and that
the sheath be readily attached and detached from the diagnostic
system rapidly, simply and without mistake. A barrier insulating
the colpoprobe from the tissues of the vagina and the cervix would
advantageously be compatible with both imaging and non-imaging
applications.
[0028] The prior art teaches the uses of an external barrier or
sheath as an alternative to the complete sterilization of a
diagnostic or therapeutic device. For instance, sanitary covers or
specula for tympanic thermometers probes are described in three US
patents issued to O'Hara et al., U.S. Pat. Nos. 4,662,360,
5,516,010 and 5,707,343. However, the covers disclosed in these
patents only fit tympanic thermometers and cover only the tip of
the device, not permitting modification. Furthermore, nothing in
the design of these tympanic thermometers covers prevents their
repeated use.
[0029] As another example, Furukawa et al., in U.S. Pat. Nos.
5,730,701 and 5,860,913, and Katsurada et al., U.S. Pat. No.
5,865,726, teach the use of disposable tips for side view type
endoscope. However, these tips do not provide biological isolation
for anything beyond the tip. Furukawa et al. in U.S. Pat. No.
5,730,701 suggest that the attachment means or locks plastically
deform upon detachment, thus preventing the reuse of the same tip
cover. However, these locking mechanisms merely deform, rather then
break away. Thus reshaping a used disposable tip to the original
shape by manipulation of the locking mechanism is feasible,
permitting the tip's reuse. Furthermore, this feature requires that
the first attempt in affixing the tip to an endoscope's end be
successful; otherwise, the tip cannot be used and will need to be
discarded.
[0030] Yabe et al., in a number of U.S. patents (U.S. Pat. Nos.
5,419,311, 5,458,132, 5,458,133, 5,536,236, 5,545,121 and
5,556,367), describe a variety of endoscope covers that engulf the
whole endoscope. However, these devices are specific to the
particular device, an endoscope with a set of complex features. The
covers themselves are complicated devices, difficult to assemble
over an endoscope and requiring specialized training, making their
use impractical for a screening setting. Furthermore, these covers
include channels for fluids and for air insufflation and are
specifically designed each to fit a specific endoscope design and
specific endoscope functionality. As an example, U.S. Pat. No.
5,536,236 discloses an endoscope cover bearing optical filters
preventing back scattering from laser beams used in endoscopic
procedures through said endoscope. The endoscope cover of the '236
patent is further characterized by an inner surface designed to
hold it in place over the endoscope by friction fitting. As another
example, U.S. Pat. No. 5,545,121, teaches display means that
indicate that the cover has been properly applied to the specific
endoscope for which it is used. U.S. Pat. No. 5,556,367 discloses
the additional feature of adjustable length, whereby the cover may
be lengthened to fit any of a preselected series of endoscopes. As
previously mentioned, each of these covers is intended for a use
with a particular endoscope system. Further, none of these provides
a biological barrier that may be fitted on a simple optical
diagnostic device with great ease by operators with little
training. Nor do these covers provide means that assure that the
same barrier or sheath is not used sequentially on different
patients.
[0031] Chikama in U.S. Pat. Nos. 5,154,166 and 5,159,919 discloses
an endoscope cover made of a rigid material that has a complex
structure including a mating longitudinal groove in the endoscope
anchoring an opposing anchoring projection in the rigid endoscope
cover. This cover has the same shortcomings cited above for the
various endoscope covers taught by Yabe et al.
[0032] Kimura et al. in U.S. Pat. No. 5,695,448 disclose a simple
tubular disposable sheath having at least a distal transparent end
for viewing and special positioning means assuring that the distal
transparent end is within the view range of the endoscope. This
cover, like many of those mentioned above, does not have means for
preventing reuse. Furthermore, no special means are disclosed
whereby the transparent window may transmit not only images of the
target operational area but also accurate optical responses from
target tissues subjected to excitation beams for diagnostic
purposes.
[0033] Williams et al. in U.S. Pat. Nos. 4,237,984 and 5,413,092
describe a sheath-like cover for an endoscope bearing a very thin
lens cover (between 0.002" to 0.010" thick) intended as an
improvement over thicker lens covers for reducing back reflections
of light from the illumination channel into the field of view of
the endoscope. This feature is not adapted for UV-induced
fluorescence systems like those contemplated herein because in
these systems the excitation beam uses wavelengths that differ
markedly from the wavelengths obtained as responses from the
excited tissue, and minor reflections of the excitation beams are
of little importance.
[0034] Saab in U.S. Pat. No. 5,37,734 and Hamlin et al. in U.S.
Pat. No. 5,690,605 disclose rigid tubular structures as disposable
endoscopic sheaths of a configuration inapplicable to the devices
of the present invention. Further, neither patent teaches methods
for preventing reuse.
[0035] Another type of a disposable endoscope cover is taught by
Sidall et al. (U.S. Pat. No. 4,741,326), which describes a sheath
that is manually rolled over the endoscope. The sheath has a
complex structure comprising its distal element. Employing this
device is complicated, so it has not been widely adopted.
Furthermore, the complex distal end has tubular structures attached
thereto that are not suitable for probes such as those disclosed
herein.
[0036] Oneda et al. in U.S. Pat. No. 4,979,498 describe a
disposable light transmitting sleeve disposed about the distal
member of a cervicoscope. This device, however, fails to provide
for means that prevent the reuse of the sleeve, nor does it provide
the special distal-end properties required to optimize the
transmission of the excitation beams to the tissues and reception
by the system of optical responses from said tissues.
[0037] Sinofsky in U.S. Pat. No. 5,773,835 proposes the use of a
casing made of a fluoropolymer, acting as a disposable sheath over
a thin UV illuminator/collector assembly that could be used in
fluorescence analysis of tissue within body cavities. Using such a
material for a sheath may be particularly beneficial when the
optical head provides for diagnostic information by excitation of
target tissue with a UV beam and detection of the fluorescence
response from the tissue, because fluoropolymers have only minimal
autofluorescence. However, the Sinofsky sheath provides no means
that assure that it will not be reused on multiple subjects. Nor
does the Sinofsky sheath provide an optical window adapted for a
plurality of optical functions, as may be required by an optical
probe according to the systems and methods of the present
invention.
[0038] Similarly, Sklandev et al. in U.S. Pat. No. 5,855,551
describe a disposable sheath intended to be used with a probe that
uses both optical and electrical responses from body tissues for
diagnostic purposes. In this device, however, the disposable sheath
itself contains active elements of the diagnostic system such as
light emitting diodes and electrical contacts. Furthermore, this
patent teaches no means for preventing reuse of the disposable
sheath on subsequent patients.
[0039] There is therefore a need in the art to provide for a
disposable biological barrier or sheath compatible with the
particular characteristics of a non-imaging volume microprobe.
There is a need for a sheath that minimizes the fluorescence
response directly from the optical window thereof. In addition, it
would be advantageous to have a sheath adapted for the anatomic
area where the non-imaging volume microprobe would be used.
Furthermore, there is a need for such a sheath constructed to
prevent its reuse. Finally, there is a need to devise a sheath that
is of simple structure, easy to mount and to remove from the
diagnostic instrument.
SUMMARY OF THE INVENTION
[0040] In one embodiment, the present invention may automatically
obtain optical responses from a three dimensional array of volume
elements or locations by providing a plurality of non imaging
volume microprobes in parallel which automatically presents mapping
of the diagnostic information sought, in a plane generally parallel
to the surface of the specimen (the xy plane) and in the z
direction which is generally perpendicular to the xy plane. As used
in this specification, the term "location" refers to any point in
three dimensional space related to the tissue sample. A location
may be a point within the substance of a tissue sample, or it may
be found on the surface of the tissue sample. A location within a
tissue sample may be termed a volume element. In some embodiments,
the systems and methods of the present invention may be used for
the evaluation of any material. To evaluate a material, these
systems and methods may determine a characteristic of the material.
In certain embodiments, the systems and methods of the present
invention are directed to a sample of a biological material. A
biological material is understood to include those materials
derived from or related to unicellular or multicellular biological
organisms. A sample of a biological material may include one or
more than one specimens of the biological material under
investigation. The sample of biological material may be located in
an in vivo system or in an in vitro system. If in vivo, the sample
may be adjacent to other tissues of like or different kinds. The
sample may represent an area of abnormality within a tissue, or the
sample may represent an entire tissue. The tissues comprising an in
vivo system may be surrounded by other adjacent tissues. The
systems and methods of the present invention may be used within a
living organism to examine a body tissue in vivo. A body tissue may
reside or be derived from a human or a non-human Living organism.
Other uses for these systems and methods will be apparent to
ordinary practitioners of the relevant arts. For the purposes of
this specification, the term "patient" refers to anyone undergoing
diagnostic evaluation using certain of the systems and methods
disclosed herein.
[0041] In one embodiment of these disclosed systems and methods,
optical responses from an array of volume elements are further
analyzed to provide visually (namely on a monitor) information
which is not readily available by direct examination of the sample.
This is achieved by, in essence, providing an artificial three
dimensional biochemical map composed from the optical responses, or
more accurately, derivatives of such responses, of each individual
volume element examined in an array, and by further converting
these biochemical data to an artificial pathological image
delineating the nature, extent and depth of pathologies observed.
This is achieved by creating an artificial pathological scale, for
each pathology of interest, by training the instrument to recognize
specific pathologies. In one embodiment, a training set of
specimens on which optical responses with a non imaging volume
microprobe were collected, is subjected to a rigorous laboratory
determination of the pathological state of each of its specimens
and a value is assigned to each specimen on the artificial
pathological scale. A set of linear equations relating to the
responses (or functions of the responses) for each specimen to the
pathological states, is constructed and optimized solutions for the
correlation coefficients sought. These correlation coefficients are
then used to transform responses obtained on unknown specimen to
obtain the pathological state of these unknown specimen.
[0042] The objectives of the instant invention are achieved by
providing an array of optical assemblies each consisting of two
conjugated, or partially conjugated, optical assemblies. In each
such assembly, the first optical assembly is designed to image
selectively a transmitted beam from a light source, or another
source of radiation, within a plurality of selected volume elements
of a sample in a sequential manner. The second optical assembly is
designed to collect light, or radiation emanating from the volume
elements, in the same sequential manner, and transmit the collected
light or radiation to a detector for further analysis of the
interaction of the first transmitted beam with the volume elements.
The first optical assembly includes a first field stop to achieve
selective illumination of a selected volume element, and the second
optical assembly includes a second field stop to restrict
acceptance of said emanating radiation or light into the collection
optics, essentially only from the selected volume element.
Furthermore, a controller is provided to adjust the depth of the
selected volume elements relative to the surface of the sample by
controlling the respective focal points of the two optical
assemblies while keeping them conjugated and having the volume
element as a common conjugation point for both optical
assemblies.
[0043] Sequential illumination of the various volume elements in an
array is desired to assure that only responses from a given volume
element are collected by the optical assembly associated with the
volume element at any given time.
[0044] The sequential illumination of a plurality of volume
elements may be carried out with a variety of devices. In some
embodiments of the invention, an array of optical shutters is
interposed between the light source and the sample, each shutter
serving as either a field stop or an aperture stop for a specific
optical assembly. In some embodiments, a single array of optical
shutters is provided, while in other embodiments two arrays of
optical shutters are provided. In yet another embodiment of the
invention, an array of micromirrors is used to control the
sequential illumination and response collection of the various
volume elements in the sample. In yet another embodiment of the
invention, an arrayed bundle of optical fibers is used to
sequentially illuminate an array of volume elements in the sample
and to collect sequentially responses from the volume elements.
Appropriate movement of the optics so as to probe various depths of
the sample is provided.
[0045] The optical responses from the selected volume elements bear
important information about the volume elements, such as chemistry,
morphology, and in general the physiological nature of the volume
elements. When the sample is spectrally simple, these optical
responses are analyzed by classical spectral techniques of peak
matching, deconvolution or intensity determination at selected
wavelengths. One such system may be the determination of the degree
of homogeneity of a mixture or a solution of a plurality of
compounds. However, when the samples are complex biological
specimens, as mentioned above, the spectral complexity is often too
great to obtain meaningful diagnosis. When such biological
specimens are analyzed for subtle characteristics, we surprisingly
found that the application of correlation transforms to spatially
filtered optical responses obtained from an array of discrete
volume elements, or the use of such transforms in conjunction with
data obtained through non imaging microscopy, yields diagnostically
meaningful results.
[0046] Specifically, we first select a training sample of a
specific target pathology. Such a sample will preferably have at
least 10 specimens. Optical responses are first collected from well
defined volume elements in the specimens and recorded. These
optical responses may be taken with an array microprobe or with a
single volume microprobe device as described in the aforementioned
co-pending application. The same volume elements that have been
sampled with the non imaging volume microprobe are excised and
biopsies (namely cytological analysis of the excised volume
elements) is carried out in a classical pathological laboratory and
the specimens are scored on an arbitrary scale which relates to the
extent of the pathology, C (for instance a specific cancer) being
characterized. These scores, C.sub.j, where C.sub.j is the score
value assigned to the specimen j within the training set, should be
as accurate as possible, and thus an average of a number of
pathologists' scores (determined on the same volume elements, j),
may be used. We now create a set of equations Ga.sub.ic
F(I.sub.ij)=C.sub.j, where i designates a relatively narrow
spectral window (usually between 5 and 50 nm) and thus F(I.sub.ij)
is a specific function of the response intensity or other
characteristics of the spectral response in the window i for volume
element j. The function F is sometimes the response intensity
itself, in that window, namely, F(I.sub.ij)=I.sub.ij, or
F(I.sub.ij)=(dI.sub.ij/d.lambda.), where .lambda. is the median
wavelength in the window i. The factors a.sub.ic, the correlation
transform's coefficients for the pathology C, are now found from
the set of equations created above, by means well known in the
prior art, such as multivariate linear regression analysis or
univariant linear regression analysis. In such analysis, the number
of wavelength windows i required to obtain faithful correlations
between the optical responses and the pathological derivations of
the values C.sub.j, is minimized and the set of correlation
coefficients a.sub.ic for the pathology, C are found. When we now
record the responses (I.sub.ik) (which is a vector in the space of
i optical windows, now minimized to a limited number of discrete
elements) on a sample outside the training set and apply the
transform operator (a.sub.ic) on the vector F(I.sub.ik), namely
obtain the sum Ea.sub.ic F(I.sub.ik)=C.sub.k, we automatically
obtain the score for the target pathology C for the volume element
sampled.
[0047] It should be understood that other statistical tools, such
as principal component regression analysis of the optical
responses, may be used as well. In addition, linear discriminant
analysis (LDA), quadratic discriminant analysis (QDA), or their
weighted average i.e. regularized discriminant analysis (RDA) can
be used. One may also consider using in the correlation transforms,
in lieu of functions of the optical responses at specific
wavelengths, the Fourier transform of the total spectral responses.
Furthermore, while taking the spectral responses from specific
volume elements, these responses may be treated optically through
either a spatial Fourier transform generator (such as a Sagnac
interferometer) or a temporal Fourier transform generator (such as
a Michelson interferometer), and then the data obtained may be used
to create the desired correlation matrices to train the system for
further data acquisition and image generation of the distribution
of possible pathologies.
[0048] Instruments embodying the invention are deemed useful for
obtaining artificial images of some characteristics of turbid
materials, such as biological tissue, plastics, coatings, and
chemical reaction processes, and may offer particular benefits in
analysis of biological tissue, both in vitro and in vivo. To
provide analysis of biological materials located within a living
body, certain embodiments of the present invention may be adapted
to work with existing endoscopes, laparoscopes, or arthroscopes.
The systems and methods of the present invention may be adapted to
work within a body orifice, such as the mouth, the ear canal, or
the vagina. The systems and methods of the present invention may be
adapted to work within a body lumen, such as the colon or the
bladder. The systems and methods of the present invention may be
adapted to work within a body cavity such as the peritoneal or the
pleural cavity. Other adaptations may be envisioned by ordinary
skilled artisans in the field.
[0049] To adapt the invention for diagnostic purposes involving
contact with biological tissues, the diagnostic apparatus may be
provided with a covering to insulate it from contact with
biological tissues. It is an objective of the present invention to
provide a protective sheath for in vivo optical diagnostic systems
that may serve as a biological barrier between patient's tissue and
the optical probe. In one embodiment, the systems and methods of
the invention may provide a barrier disposed external to the
diagnostic probe that separates the probe from any tissue of the
body, including those tissues in continuity with the target tissue
sample and including those tissues adjacent to or in proximity to
the tissue sample. A barrier according to these systems and methods
may insulate a colposcopic probe, for example, from contact with
the tissues of the cervix, vagina and vulva. Other barriers may be
envisioned by practitioners skilled in the relevant arts that will
prevent the probe from contact with relevant body tissues. It is a
further objective in certain embodiments that the biological
barrier be disposable and adapted for a single use. The term
"single use" is understood to comprise the use for a single
diagnostic measurement performed by the probe. It is desirable that
the barrier or disposable sheath be capable of use with only one
patient. As used in only one patient, a unique individual, the
biological barrier may be adapted for a single use or may be
adapted for multiple uses. Systems according to the present
invention are adapted to prevent the use of the probe in more than
one patient.
[0050] It is yet another objective to provide a sheath constructed
to conform to the optical requirements of the diagnostic systems
and methods of the present invention. In one embodiment, such a
sheath advantageously would provide minimal interference with the
optical responses produced by tissues after their excitation by a
beam of electromagnetic radiation produced by a diagnostic system
according to the present invention. In one embodiment, such a
sheath would include an optical window, an optical filter, a lens
or a polarizer capable of being exposed to ultraviolet radiation
without producing a significant fluorescent response.
[0051] It is yet another objective to provide a protective sheath
for a colposcopic optical probe or an optical probe adapted for the
examination of the cervix uteri.
[0052] It is yet another object of the present invention to provide
a sheath which may be mounted and dismounted on the optical probe
with great ease and minimal training. It is an object of the
invention that a sheath be equipped with an affixation mechanism
that also orients the sheath on the probe in a preselected, optimal
direction. It is a further object of the invention that a sheath
possess mechanisms that facilitate the assurance of single use for
the sheath. In one embodiment, a sheath may be provided with a
mechanical affixation mechanism that is suitable only for a single
use. In one embodiment, the affixation mechanism may entail damage
to the attachment apparatus when the sheath is detached from the
probe. In another embodiment, the sheath may be provided with an
identifying marker that may be read by the probe so that the system
may determine that the sheath is suitable for use. An identifying
marker may provide data about the unused state of the sheath or
data about the previous use of the sheath. It is an object of the
present invention that the sheath interact with the probe to
prevent the use of the probe in the absence of an unused sheath. A
probe being used with the barrier may comprise a processing system
that correlates certain data borne by the identifying marker on the
sheath with an indicator that indicates or relates to an unused or
a previously used state of the sheath. The probe to be used with
the barrier may include a receptor system that receives a signal
generated by a sensor on the barrier and that thereupon renders the
probe operable or inoperable, depending upon the type of signal
received. A probe rendered capable of being used may be termed
operable or activated. In one embodiment, the probe may be
inoperable in the absence of an unused sheath. In another
embodiment, an unused sheath may be required for a signal to be
produced that activates the probe. In one embodiment, the invention
may provide a system for controlling use of a diagnostic apparatus
that includes a diagnostic apparatus, a disposable sheath with an
identifier that bears unique data to characterize that particular
disposable sheath, a detector that produces a signal indicative of
the unique data borne by the identifier, and a receiver system that
responds to the signal produced by the detector, that determines
the state of the disposable sheath and that provides a second
signal that regulates activation of the probe. As understood
herein, a signal or any other mechanism that regulates activation
of the probe may activate the probe, may prevent it from being
activated, or may provide any other type of regulation that affects
the use of the probe.
[0053] It is an object of the invention that these systems and
methods include a plurality of interactions between sheath and
probe whereby the integrity of the sheath and its proper use are
assured. In one embodiment, these systems and methods may comprise
a database with which the probe apparatus communicates to determine
the unused state of the sheath. In another embodiment, these
systems and methods may comprise a set of diagnostic tests that
ensure the integrity of the sheath and its proper positioning upon
the probe, or that ensure the proper positioning of the probe with
respect to the patient, or that ensure the proper type of sheath be
placed on the probe.
[0054] It is an object of the invention to provide proper sheaths
for a plurality of anatomic areas where the probe may be used, for
example the cervix and the endocervix.
[0055] The above and other subjects, features and advantages of the
present invention will become apparent from the following
description with reference to the accompanying drawings which
illustrate examples of the present invention.
DESCRIPTION OF THE DRAWINGS
[0056] FIG. 1 is a schematic and generalized block diagram of the
major elements of the present invention.
[0057] FIG. 2 is a block diagram of an embodiment of the invention
with an array of light valves, in which each light valve acts as an
addressable field stop for the illumination and detection
beams.
[0058] FIG. 3 illustrates an embodiment where an array of lenslets
of the same periodicity as the array of light valves acts as an
array of objective lens for both the illumination and detection
beams.
[0059] FIG. 4 and FIG. 4A illustrate embodiments of the invention
in which separate illumination and detection light valves arrays
create arrays of aperture stops, each in conjunction with lens
arrays serving as objectives for the illumination and detection
optics. In FIG. 4A, the detection lens array is replaced with a
single lens.
[0060] FIG. 5 illustrates an embodiment of the invention in which
an array of (deformable) flat micromirrors is used as field stops
and the sequential selection of micromirrors serves to sequentially
illuminate volume elements in a sample.
[0061] FIGS. 6 and 6A show embodiments of the invention in which an
array of (deformable) off axis parabolic mirrors serve as selecting
objectives to sequentially apply excitation beams to various volume
elements and collect the responses from the volume elements.
[0062] FIG. 7 shows an embodiment of the invention in which the
light shutter array is replaced with a fiber switching device to
sequentially illuminate (and obtain responses from) an array of
volume elements in a target sample.
[0063] FIG. 8 illustrates an embodiment having two optical
assemblies, each coupled to its own (excitation and detection)
fiber bundles in which sequential illumination of fibers (and
detection) is practiced to obtain data from an array of volume
elements.
[0064] FIGS. 9 and 10 illustrate embodiments of the invention in
which light shutter arrays are coupled to optical fiber
bundles.
[0065] FIG. 11 is a schematic representation of one of the
embodiments of the invention, including a block diagram of the
control and data processing elements of the system.
[0066] FIG. 12 is a block diagram that illustrates methods of using
volume probe arrays of the invention, particularly in the
diagnostic of various pathologies.
[0067] FIGS. 13A and 13B are bottom and top views, respectively, of
a partial segment of a PVDF based optical shutter array.
[0068] FIG. 14 shows another embodiment of a PVDF based optical
shutter array.
[0069] FIG. 15 is a top view of a micromachined optical shutter
array.
[0070] FIG. 16 shows another embodiment of a micromachined optical
shutter array.
[0071] FIG. 17 is an anatomic cross-sectional view showing an
embodiment of the invention positioned within a body cavity within
the female perineum.
[0072] FIG. 18 shows an embodiment of a disposable sheath
illustrating optical fibers therein.
[0073] FIGS. 19A and B show an embodiment of an optical probe
bearing a protective sheath.
[0074] FIG. 20A shows an embodiment of a disposable sheath disposed
to cover an optical probe; FIG. 20B shows an embodiment of a
disposable sheath in a furled position.
[0075] FIGS. 21A-F show various projections of an embodiment of an
optical probe system with a protective sheath in place.
[0076] FIG. 22 shows schematically an embodiment of an optical
probe covered with a disposable sheath.
[0077] FIGS. 23A-D show embodiments of attachment mechanisms
affixing a flexible portion of a protective sheath to a distal
rigid portion.
[0078] FIG. 24 shows an embodiment of a protective sheath adapted
for application by heat shrinking.
[0079] FIGS. 25A and B show, respectively, an embodiment of a tip
of a probe system adapted for examination of the endocervix, and an
embodiment of a probe system adapted for examination of the
endocervix.
DETAILED DESCRIPTION OF THE INVENTION
[0080] In FIG. 1 we show a generalized schematic volume probe
array, 10, whose function is to collect data from a plurality of
points in a target sample. The system generally includes an
appropriate light source 11, whose light output is conditioned and
may be multiplexed in block 12 to create a plurality of light
sources to be relayed to an array 13 of light valves. These light
valves may act as illuminating field stops or aperture field stops,
and only one valve is open at a given time, thus providing for
sequential illumination of volume elements in sample 19. The light
emanating from each light valve is then directed to a targeted
volume element in the sample 19 with an appropriate illumination
objective 14. In some embodiments, a single objective lens is used,
while in other embodiments, we incorporate an array of objective
microlens having the same periodicity as that of the light valve
array.
[0081] Responses from each targeted volume element in the form of
light emanating from the volume elements, is collected through a
collection optics objective 15 (which in some embodiments may be
the same as the illumination objective and an array of microlens),
and through an array 16 of light valves (which may also be the same
array as the one used for illumination). The responses are then
directed to one or more detectors 17 to determine their optical and
spectral characteristics.
[0082] It should be emphasized that both the illumination optics
and the collection optics each contain a field stop having
dimensions that are relatively large in relation to the average
wavelength of the illuminating radiation, and furthermore, these
field stops are conjugated to each other through the volume element
examined. As a result, a well defined volume element is illuminated
at any time, and the optical response from the element collected
through the field stop of the collection optics is essentially
limited to responses emanating from the volume element.
[0083] A controller 18 is provided to control the sequencing of the
volume elements scanned (in the x,y plane, the plane of the sample)
and to control the depth of the volume elements examined (in the z
direction.)
[0084] In FIG. 2, a simple example of an array volume microprobe
system 20 is shown. The system includes a light source 21. Light
from the light source is condensed with a lens 22 onto an array of
light shutters 24, through a beam splitter 25. In this embodiment,
each element 28 in the light shutter array serves as a field stop
which is being imaged through an objective lens 26 on a sample 27.
The dimensions and shape of the shutters determine the morphology
of volume elements sampled in a manner discussed in detail in U.S.
Pat. No. 5,713,364. In essence, the mean dimension, d, of each
shutter is selected to be larger than the wavelength divided by the
numerical aperture, NA, of the objective or d o 8/NA. Thus the
image of the field stop in the plane of the sample is larger than
the diffraction limited resolution for the wavelength. As a result,
a very large proportion of the light that traverses a given field
stop and is imaged in the sample is within a well-defined volume
element of the sample. Similarly, while the total response to the
illumination is distributed over a very large spatial angle
(essentially 4B steradians), only responses that are emanating from
within the same volume element are imaged back onto the field stop
and reach detector 29, by being reflected on the beam splitter 25
onto a collector lens 23 which concentrates the response onto the
detector 29. This results from the fact that the respective field
stops of the illumination and detection systems are conjugated to
each other via the target volume element. In the embodiment shown
in FIG. 2, both field stops are embodied within the same aperture
(an optical shutter or a light valve 28 within the optical shutter
array).
[0085] In some embodiments, the beam splitter 25 may be a dichroic
mirror, particularly when the light source is a short wavelength
(UV) exciting light source and the responses are fluorescence
responses. In other embodiments, the beam splitter 25 may be a half
silvered mirror which separates the optical path of responses from
the sample from the optical path of the exciting beam, for
instance, when the exciting beam is provided with a broad spectrum
light source, and the responses involve back scattering and
reflections from the sample (and thus mostly the extent of
absorption of the exciting beam in the targeted volume element is
examined).
[0086] The array of light valves, or optical shutters, may be
implemented in a number of different ways. One may use liquid
crystal sandwiched between two electrode arrays (deposited, as is
in the prior art on transparent glass or plastic sheets in the form
of transparent electrodes made of Indium Tin Oxide (ITO) or Tin
Oxide (TO), usually doped with fluorine to provide good areal
conductivity). One may also use films of PDLC (polymer dispersed
liquid crystals) that might be easier to handle and have lower
production costs. Another embodiment contemplated, when the
required scanning is particularly fast, is an array of
ferroelectric elements, each acting as a light valve. Yet another
embodiment of the light valves may involve an array of PVDF
(Polyvinyl-difluoride) bimorphs, each coated to be reflective (or
opaque on both sides) on the side facing the light source and
designed to bend out of the light path so as to create a light
valve. The typical dimensions of the light valve range from a low
of about 20 microns to as much as 1000 microns. The size is
determined primarily by the application, the nature of the sample
analyzed and the particular design of the specific array volume
microprobe utilized. When using the general design of FIG. 2, with
a single large objective lens serving as a common objective to all
the field stops in the array, the space between adjacent light
valves is usually kept as small as possible, so as to provide as
closely spaced as possible scanned volume elements. It should be
understood however that in some embodiments, the spacing is kept
relatively large (as large as the field stop itself) when an image
of the pathology consisting of well spaced discrete points is more
appropriate.
[0087] In operation, the controller 18 keeps one of the light
valves open and adjusts the position of the device so as to image
the field stop at the desired volume element in the sample 27. Once
the general position of the device relative to the sample has been
optimized, the controller causes scanning of the surface of the
specimen in the xy (the plane of the specimen) direction by
sequentially closing an open light valve and opening an adjacent
light valve. The time interval of each light valve in the open
position is a strong function of the intensity of the light source
and the efficiency of collection of the response from each volume
element. In some embodiments, this time interval may be shorter
than a millisecond, while in other embodiments tens to hundreds
milliseconds are required.
[0088] The controller 18 also controls the position of the volume
elements within the sample in the z direction, generally an axis
perpendicular to the plane of the samples. This may be achieved in
a number of ways. For instance, the whole optical assembly may be
moved back and forth in the z direction. In some embodiments, this
translational movement of the image plane of the field stops in the
sample may be achieved by moving the objective alone, or the array
of light valves, or both of these elements simultaneously. The
specific design depends on the particular embodiment of the
device.
[0089] It should be appreciated that since the intensity of
illumination is highest within the volume element probed by the
excitation beam (relative to zones surrounding the volume element),
and that the response detected by the sensor 29 is primarily from
the same volume element (and contains very little illumination
emanating from zones surrounding the volume element), that changing
the position of the volume element within the sample in the z
direction will provide responses from various depths of the sample.
This, in essence allows for analysis, in vivo of tissues at various
depths, as long as the overall absorption of the illuminating beam
by the tissue and the responses to the beam are not excessive.
[0090] In FIG. 3, a slightly different embodiment of an array
volume microprobe 30 of the present invention is shown. The system
includes a light source 31 with appropriate optics (not shown) to
project a common field stop 41 through a condenser lens 32 onto an
addressable shutter array 34. Each element in the addressable
shutter array may be considered an aperture stop which serves to
further limit the spatial distribution of the light impinging on a
sample 37. In lieu of using a large singular objective (as used in
the embodiment described in FIG. 2) to image the field stop on each
volume element in the sample 37, a lens array 36 is interposed
between the shutter array and the sample. The lens array 36
consists of a plurality of microlens 42. The periodicity of the
lens array is exactly the same as that of the shutter array, and
each lens 42 within the lens array 36 corresponds to a light valve
38 within the light shutter array 34. In most embodiments, the
light impinging on the shutter array would be collimated, and the
shutter array would be fixed in position relative to the lens
array. The volume element probed would be at the focal point of the
objective lens within the microlens array, and movement of the
combination of the shutter and lens array in the z direction, may
be used to probe different layers within the sample, as explained
above when describing the array volume microprobe of FIG. 2. One
can, however, conceive of other arrangements where the lens array
and the shutter array are capable of moving independently, and
probing the sample in the z direction is achieved by translation in
the z direction of the lens array alone.
[0091] Light responses to the exciting radiation from the light
source 31 from each of the sampled volume elements are collected
through the same objective elements through which illumination is
effected. The light responses are separated from the illuminating
beam by the beam splitter 35. These responses are then imaged via a
collecting lens 33 onto a collection field stop 43 that restricts
the responses received by a sensor 39 to be essentially only from
the probed volume element. In operation, the controller 18 opens a
given shutter and allows the illumination of a single volume
element. Furthermore, the same light shutter allows optical
responses to the excitation to be recorded by the detector 39. This
is followed by closing the light valve and opening another light
valve, so that sequentially discrete volume elements within the
sample are scanned to obtain optical responses thereof. One may
scan all the desired volume elements in the array in a given x,y
plane and then rescan the array at a different depth (in the z
axis), so as to obtain three dimensional information on the target
sample. One may also choose to operate the array volume microprobe
in such a way that for each pixel, the respective light valve 38 is
kept open, while the controller causes the shutter array together
with the lens array to move in the z direction, thus probing at the
same x,y location volume elements at various depths of the
specimen.
[0092] In yet another embodiment of the array volume microprobe,
the illuminating and detecting optics are each provided with their
own array of optical shutters. In FIG. 4, such an embodiment is
shown schematically. Specifically, the array volume microprobe 50
includes a light source 51, a first field stop 52, a collimating
lens 53, a first shutter array 54, a first objective lens array 55,
beam splitting means 56, a second objective lens array 58, a second
shutter array 59, a second collimating lens 60, a second field stop
61 and a detector 62. Not shown in FIG. 4 are appropriate means to
image the light source 51 and detector 62 onto their respective
field stops 52 and 61. In operation, the light source 51 is imaged
onto the field stop 52, having dimensions that are greater than the
diffraction resolution limits of the exciting radiation. The light
emanating from the field stop 52 is collimated into an essentially
parallel beam that impinges on the back side of the shutter array
54. At any given time, only one of the light valves in the light
shutter array is opened and its corresponding light valve in the
detector shutter array is open. The sequential illumination of an
array of volume elements within the sample, in a manner similar to
that described above, coupled with the synchronous opening of the
appropriate light valve in the detector array, assures that at any
given time, only responses from the probed volume element are
detected. Similarly, scanning in the x,y direction is provided by
controller 18 sequencing the opening and closing of the light
valves in the two shutter arrays in synchronism. It should be
understood that in this embodiment, the two field stops 52 and 61
are conjugated to each other via each of the volume elements 63 in
the sample 57.
[0093] In FIG. 4A, an arrangement essentially identical to that
described in FIG. 4 is shown, except that the array of microlens 58
is replaced with a single large lens 58'. Like elements in FIGS. 4
and 4A have the same reference numbers.
[0094] Yet another embodiment of the invention is illustrated in
FIG. 5, which shows an array volume microprobe 70. The system
includes a light source 71 and a detector 72 having their optical
axes orthogonal to each other and separated by a first beam
splitter 73. The light emanating from the source is condensed onto
an array of field stops 74 with a condenser lens 75 and a second
beam splitter 76. The array of field stops 74 consists of an array
of micromirrors 77 that may be tilted in and out of a plane
generally parallel to the plane of the array. Light reflected from
any one of these mirrors, while in the untilted position, is
reflected back through the second beam splitter 76 and is imaged
onto a sample 79 with an objective lens 77. As shown in FIG. 5,
only one micromirror 78 at any given time is oriented to reflect
light onto the sample. All other micromirrors in the array are
tilted so that light impinging on them is reflected away from the
sample. In FIG. 5, rays 1 and 4 are limiting rays for the total
field, and rays 2 and 3 are limiting rays for a single micromirror.
In operation, the micromirrors 77 are sequentially brought to the
untilted position by the controller 18, and as a result of this
sequential untilting of micromirrors, a sequence of responses from
volume elements in the sample 79 is recorded in the detector 72. An
artificial image from the responses may then be recorded and
displayed. As in prior embodiments, probing of the sample with the
volume microprobe array in the z direction (depth) may be achieved
by either moving the objective lens 77 or the array 74 in the z
direction.
[0095] The control of the tilting mirror is performed by controller
18, and the tilting mechanism may be implemented in a number of
ways well known in the prior art. For instance, the mirrors may be
micromachined in silicon, leaving a cantilever in the middle of the
back of the mirrors. Two opposing electrodes cause the mirror to
tilt about the cantilever due to charging one or the other
electrode with a charge opposing the charge on the mirror itself
Another method of obtaining tilting mirrors is well known in the
art of deformable mirrors, whereby each micromirror is mounted on a
bipolar piezoelectric element.
[0096] Yet another embodiment of the invention, a variation of the
embodiment shown in FIG. 5, is illustrated in FIG. 6. An array
volume microprobe 80 includes a light source 81 from which light is
conditioned to pass through a first field stop (not shown) and
through a lens 82. The light is collimated onto an array of
micromirrors 83. The micromirrors are tiltable as described above.
However, each of the micromirrors is shaped to be an off axis
segment of a paraboloid of revolution having its focal point
tracing an arc of radius which is somewhat larger than the distance
of the array from the sample. The geometry is such that when the
mirrors are untilted (parallel to the plane of the array), the axis
of the paraboloid of revolution (of which the specific mirror is an
off axis segment) is perpendicular to the plane of the array. Thus
a line between the focal point (of the paraboloid of revolution)
and the micromirror is at a predetermined angle to the normal to
the array. The micromirrors may be tilted through that angle so as
to bring the focal point of the paraboloid onto the sample.
[0097] In one embodiment of the invention, the micromirrors are
arranged in alternating right rows 89 and left rows 88 of off-axis
segments of a paraboloid. The right mirrors may be termed the
exciting mirrors and the left mirrors the detecting mirrors. The
focal points of each segment of right rows 89, upon tilting at the
above mentioned angle, resides within the sample at the volume
element 85, and its respective paraboloid axis of revolution is
parallel to the optics axis of the exciting beam, while the tilting
in the opposing direction (at the same angle) of each micromirror
in an adjacent left row causes the focal point of each micromirror
to move to the same volume element (85) in the sample 84, and its
respective paraboloid axis of revolution is parallel with the
optics axis of the detector.
[0098] Thus, all mirrors in right rows 89 are used to excite volume
element 85 in the sample 84 and all left rows 88 are used to
collect responses from volume element 85. In operation, only one
pair of mirrors is tilted at any given time and the axes of all
other mirrors point down toward the sample. As a result, an
exciting beam from the light source 81 is imaged onto the volume
element 85, or more accurately, the first field stop is so imaged,
while light impinging on all other mirrors is scattered away from
the sample in all directions. Similarly, only responses emanating
from the volume element 85 are imaged back onto the second field
stop in front of the detector. As a result, a very high degree of
discrimination is obtained, since the intensity of the exciting
beam decreases very rapidly outside of volume element 85, and
responses from outside volume element 85 are essentially blocked by
the second field stop in front of the detector 87. The controller
18 controls the sequence of tilting each pair of mirrors to obtain
an array of responses from different volume elements in the sample.
The depth of the volume element in the sample is also controlled by
the controller 18 by moving the total array 83 along the z axis
toward or away from sample 84.
[0099] A slightly modified embodiment of the volume probe array
shown in FIG. 6 is presented in FIG. 6A. This embodiment allows for
using each off axis parabolic micromirror both as an excitation and
detection mirror. The system is equivalent to that shown in FIG. 6
and described above, except that the micromirrors of array 83' of
the volume probe array 80' are rotated by 90.degree. to the right
or the left. Thus, in the unrotated position, the axis of
revolution (and thus the optical axis) of each mirror is at
90.degree. to the optical axis of the exciting and detecting
optics. However, when a mirror 89' is rotated by 90.degree. to the
right, its axis of revolution becomes parallel to the axis of the
excitation, and the focal point of the off-axis parabolic
micromirror is in volume element 85'. If an adjacent mirror 88' is
simultaneously rotated 90.degree. to the left, then its axis of
revolution becomes parallel to the detection optics, and its focal
point is in volume element 85'. The volume element 85' is
determined by the overlap of the images of the two field stops, as
explained in detail in U.S. Pat. No. 5,713,364. In this embodiment,
as well as the one shown in FIG. 6, sheared conjugation of the
excitation and detection optics field stops is used to provide for
spatial discrimination of the excitation beam to the target volume
element as well as the spatial discrimination of the detected
responses to be essentially from each volume element. In operation,
the controller 18 causes two adjacent micromirrors (89' and 88') to
be rotated simultaneously as described above and thus provides
excitation of essentially only the desired volume element 85' and
responses which emanate essentially from the volume element
85'.
[0100] An advantage of the embodiment shown in FIG. 6A is that a
higher resolution of volume elements is feasible for the same
density of micromirrors, since each mirror may be used to either
excite a volume element or to collect responses from an adjacent
volume element. This differs from the embodiment shown in FIG. 6,
where all left mirrors may be used only to collect responses and
all right mirrors may be used only to excite volume elements. In
the embodiment of FIG. 6, the tilting of the off-axis paraboloids
of each segment is in a plane perpendicular to the plane of the
array, while in the embodiment of FIG. 6A, the plane of rotation is
parallel to the plane of the array.
[0101] In FIG. 7, yet another embodiment of the invention is shown.
An array microprobe 90 includes an illumination optical assembly
with a light source 91 and a first collimating lens 92, and a
response collection optical assembly having a detector 93 and a
second collimating lens 94. The respective optical axes of the
light source assembly and the detector assembly are at 90.degree.
to each other. A beam splitter 95 is positioned at the intersection
of the exciting and detected beam so as to separate the detected
signal from the excitation signal. A lens 96 is used to focus the
exciting beam into an optical fiber 102 which is interfaced with a
fiber switching element 97. The fiber switching element 97 is
terminated on the opposing side with a plurality of fibers 98, and
the switching element is capable of connecting optically and
sequentially (under the control of the controller 18) the proximal
fiber 102 to any of the fibers 98 in the distal bundle. The ends of
the individual fibers in the bundle are then arranged in an array
99 (this array may be either a linear array or a two dimensional
array). An objective lens 100 then images the respective ends of
the fibers in the fiber bundle onto the specimen. Each individual
fiber end (within the fiber holder) defines a field stop which is
imaged onto the sample. This field stop serves as a field stop to
both the exciting beam and the detected responses from the sample.
As is described in more detail in U.S. Pat. No. 5,713,364, such an
arrangement involves the conjugation of both the exciting and
detected optics via the volume elements in which the field stop is
imaged, and thus provides for spatial discrimination of both the
excitation beam and the responses to be essentially from each
volume element associated with each fiber in the array.
[0102] In operation, the fiber switching element 97 directs the
exciting beam sequentially through all the fibers in the bundle 98.
As a result, a plurality of volume elements in the sample 101
(having a distribution corresponding to the array of fibers in the
bundle 98) are excited sequentially. Responses are collected
through the same field stop (the natural aperture of each fiber
end) and are separated from the exciting beam by the beam splitter
95 to be detected in detector 93. In this manner, one obtains
responses from an array of volume elements that may then be
displayed as an artificial image of the sample. This embodiment has
the advantage that a higher intensity of excitation is feasible,
since the light source is used sequentially by the different fibers
in the bundle.
[0103] In FIG. 8, yet another embodiment of a volume microprobe
array 110 is shown. The device includes two optical assemblies, an
excitation or source assembly 111 and a detector assembly 112. Each
of the assemblies is interfaced to its own individual fiber bundle
113 and 114, respectively. The individual fibers are organized, in
one embodiment, in two rows 116 and 117, respectively, in a fiber
holder 115. When a linear array is desired, the fibers are
organized in two opposing rows, one row consisting of the
excitation fibers in bundle 113 and the other row of detection
fibers in bundle 114. When a two-dimensional array is desired, the
fibers are organized in alternating rows of excitation fibers and
detection fibers, with a small tilt of such rows relative to each
other. The excitation optics 111 includes a light source 118 and
focusing optics 119 that may focus the output of the light source
on each fiber in the bundle 113 sequentially. A rotating mirror 120
is used to index the light source onto the opening apertures of the
fibers in the bundle 113. One should appreciate that the input
aperture of the excitation fibers may be terminated in an
appropriate way to improve collection of the light from the
rotating mirror. Such termination may include, but is not limited
to, flaring of the input end of the fiber, or termination of each
fiber with a small compound parabolic concentrator, as is well
known in the prior art.
[0104] In operation, the controller 18 causes the incremental
rotation of the mirror 120 so as to direct the excitation beam to
fibers in bundle 113 sequentially. This light then emanates through
an excitation field stop at each distal end of the fiber, the field
stop being essentially the aperture of each fiber. These field
stops are imaged onto a sample 124 with objective microlens at the
end of each fiber. The distal ends of both excitation and detection
fibers are terminated into microlenses that serve as objectives.
The excitation and detection fibers may be at a slight angle to
each other, and sheared conjugation of their respective field stops
(fiber apertures) defines the volume elements probed. The volume
elements in the sample will be a mirror image of the fiber
arrangement, namely a row or an array of points, depending on the
organization of the fibers in the fiber holder 115. The distance
between the volume elements may be the same as that between the
fibers in the fiber holder or may differ from the interspacing of
the fibers in the fiber holder, and will depend on the
magnification of a relay lens 125. In some embodiments, one may
allow for movement of the relay lens relative to the fiber holder
so as to provide magnification (or demagnification). However, the
size of each volume element will also be modified somewhat.
[0105] This configuration allows for the sequential illumination of
an array of volume elements in sample 124. An excited volume
element will emit a response to the exciting beam. To ensure that
responses that are essentially emanating only from the desired
volume element are detected, the responses are collected with a
dedicated fiber from bundle 114. The optics are configured such
that the respective field stops of the response fibers (their
natural aperture) are each conjugated to the respective the field
stops of the associated exciting fiber. As a result of this
conjugation (or, more accurately sheared conjugation, since the
exciting and detecting field stops are slightly spaced apart), the
excitation beam has its highest intensity within the sample within
the zone of sheared conjugation (the probed volume element), and
the intensity declines very rapidly outside the volume element.
Furthermore, responses collected by each detection fiber emanate
essentially only from the volume element, and any response
collected from adjacent tissues is very small relative to the
response obtained from the zone of sheared conjugation of the
excitation and detection field stops.
[0106] Since the excitation of the array of volume elements is
carried out sequentially, response will be transmitted through the
fiber bundle 114 sequentially to the detecting optics 112. In a
preferred embodiment of the invention, the response optics include
a receiving rotating mirror 123 which directs (sequentially and in
synchronism with the excitation mirror 120) the responses through a
focusing lens 122 to a detector 121. This assures that stray
responses (namely, responses emanating outside the zone of sheared
conjugation and thus outside the target volume element) and
collected by adjacent fibers, do not reach the detector. In this
manner, as before, spatial discrimination is obtained, and
sequential detection of responses from specific volume elements is
achieved.
[0107] In this embodiment, the use of a beam splitter is avoided,
and only very simple optics are used at the distal end of the
device. Such a device is particularly suitable when a distance
between the sample and the optics (source and detector) is
required, such as in laparoscopic and endoscopic devices. This
embodiment has the additional advantage that higher excitation
energies are feasible, since the light source resources are not
distributed simultaneously over a full array as in some embodiments
described above, and in this respect is similar to the embodiment
shown in FIG. 7 and described above.
[0108] In FIGS. 9 and 10, two additional embodiments of the
invention, which differ from each other only in the position in the
system of the addressable light shutters, are shown. In FIG. 9, a
volume microprobe array 130 that includes a light source 131, a
detector 132, and an optical fiber bundle 133 is shown. The
proximal end of the optical fiber bundle interfaces an addressable
array of optical shutters 134. The optical shutters are under the
control of the controller 18. Each fiber in the bundle 113 is
positioned in an array arrangement that corresponds to the
addressable light shutter array. The light source 131 is coupled to
the light shutter array via a condenser lens 135 and a shutter
array coupling lens 136. As a result, light from the light source
is distributed over the light shutter array, and, when one of the
shutters is in the open position, light is transmitted to the
specific fiber coupled to that specific shutter. At the distal end
of the fiber bundle, the device has objective optics 137 which
essentially images each of the apertures 138 of the fibers on a
sample 139. The distal apertures of the fibers are, in essence,
acting as the excitation and detection field stops for each of the
volume microprobes in the volume microprobe array 130 of this
embodiment. Responses to the exciting signals emitted from volume
elements in the sample are collected by the fibers through the same
objective optics 137 and the same fibers through which excitation
was carried.
[0109] Since the field stops of both the exciting and detecting
optics are conjugated within the volume element probed, the
excitations and responses are limited to the individual volume
elements probed by each fiber. In operation, the light shutter
array is controlled by the controller 18 to sequentially open the
light shutters in front of the fiber bundle sequentially in such as
way that only one fiber is powered at any given time. Thus, by the
synchronous detection of responses from fibers that are coupled to
an open shutter, a full artificial image of pathologies in the
targeted sample may be constructed. As in some of the embodiments
described above, the response is separated from the excitation by a
beam splitter 140 positioned at 450 to the optical axis of the
excitation optics and detection optics.
[0110] In FIG. 10, a similar volume microprobe array 150 is
presented. The essential difference is that a shutter array 154 is
positioned at the distal end of the fiber bundle. This allows for
selecting an array of field stops determined by each of the
apertures within the shutter array rather than by the individual
apertures of the optical fibers.
[0111] In some embodiments of the volume microprobe arrays
described above, a plurality of detectors corresponding to adjacent
full regions of the shutter array are employed. Each detector
accepts responses from a subarray of the light shutter array, and
thus from the sample. In these embodiments, data collection is
accelerated by the simultaneous opening of a light valve in each of
the subarrays in the light shutter array and detecting the response
in their respective detectors. When using this approach, care is
taken to assure that interferences (or noise) from responses
outside each specific region are smaller than a preset value of the
expected response from the sample in each region.
[0112] In several embodiments described above, an array of light
shutters is employed to sequence the excitation of an array of
volume elements in the sample as well as collect responses from the
volume elements. In some embodiments, each shutter serves as an
excitation and detection field stop, while in other embodiments
other optical elements in the system perform the function of the
field stop. Such light shutters are well known in the prior art and
have been used in a number of display devices, whereby the sequence
of opening and closing sets of optical shutters that are back
illuminated provide either a fixed or a time variable image.
[0113] The actual embodiments of such shutters in the prior art may
take many forms. The most widely used light shutter array is an
array of liquid crystal elements having two sheets of polarizer one
each on the front and the back of the array. On each element in the
array, a voltage may be applied. When the voltage is sufficiently
high, the liquid crystal causes rotation of the plane of
polarization of light passing through it. The two polarizers are
oriented in such a way that no light passes through an element when
no voltage is applied. Thus, the polarizers are cross polarized
(their relative orientation is 90.degree., thus the first polarizer
removes all light polarized in one direction, while the second
polarizer blocks the light passing through the then inactive liquid
crystal element). When a sufficiently high voltage is applied, the
plane of polarization of the light passing through the liquid
crystal cell is rotated, so that the second polarizer is
essentially transparent to the light passing through the active
liquid crystal cell. The addressing may be carried out as in the
prior art, either as row and columns, so that only the sum of
voltages applied to both a row and column is sufficient to cause
the desired rotation of polarized light. Since the dimensions of
our light shutters are relatively large and the number of shutters
small relative to the current practice in liquid crystal display,
such addressing is quite sufficient, and cross talk is minimal and
insignificant in view of the strong spatial discrimination due to
the conjugation of the excitation and detection field stops.
[0114] When very large arrays are desired, approaches such as used
in active matrix liquid crystals display (namely the activation of
a pixel through the direct switching of an individual transistor at
each pixel) may be practiced as well.
[0115] In yet another embodiment, the shutter array consists of
ferroelectric elements activated in a manner similar to that of
liquid crystal light shutter arrays. These shutter arrays are
useful when the switching rate desired, namely, the rate of opening
and closing a given light shutter in the array, is faster.
[0116] In yet another embodiment, the light switching medium is a
polymer dispersed liquid crystal (PDLC). In such films, a
dispersion of droplets of liquid crystal is embedded in a polymer
having an index of refraction equal to the field oriented index of
refraction of the liquid crystal dispersion. When no electrical
field is applied, the droplets are randomly oriented and light is
scattered in all directions. Thus the shutter may be considered as
closed. When a sufficiently large electric field is applied to a
PDLC element, the liquid crystal droplets orient themselves with
the field and thus, in the direction of the field, the index of
refraction is essentially constant and light passes through
uninterrupted. Thus the shutter is open.
[0117] In yet another embodiment, essentially electromechanical
shutters are used. Such may be easily implemented with
piezoelectric bimorphs, which when actuated bend out of the path of
the light and when inactive, assume a straight geometry which
blocks light transmission through a given shutter.
[0118] In FIG. 13A a top view of a light shutter array 310 is
shown. This shutter array consists of two main elements, a passive
base element in which an array of perforations 311 and an array 320
of active flags 321 are provided. The passive base may be made of
an appropriate plastic, metal or even silicon. In the present
embodiment, the perforations 311 are about 0.1 mm in diameter and
are spaced on a grid in which the interspace between the
perforations is about 1.0 mm. It should be understood that other
dimensions may be selected without deviating from the teachings of
the invention. The perforations, which are preferentially slightly
conical with their bases at the proximal end and their truncated
apices at the distal end, serve as receptacles for optical fibers,
each having an external diameter of 0.1 mm. In production, such
fibers may first be inserted and cemented in place, and then the
surface of the passive base, with the fibers in place, is optically
polished to ensure that the fibers are flush with the distal
surface of the base and have an acceptable optical finish. The
surface may then be treated with an antireflective coating so as to
minimize optical reflections from the distal ends of the fibers,
and thus improve both the illumination and signal collection
efficiency.
[0119] The array 320 of active flags 321 consists of two sheets of
piezoelectric material, such as polyvinyl difluoride (PVDF) with
metallization on both sides. The two sheets are first cemented
together (for instance with an acrylonitrile compound). Then the
metallization is etched, leaving a pattern of rows of electrodes
323 interconnected with common leads 322 (in rows) on the top side
of the pair of PVDF sheets as shown in FIG. 13A. The electrodes 323
have the same geometry as the flags 321, or may be just a little
smaller than the flags. In FIG. 13B, the bottom side of the array
320 of active flags 321 is shown. The metallization of the bottom
side is etched to provide second electrodes 324 for each flag,
which are interconnected with leads 325 in columns. After both
sides of the paired PVDF sheets have been treated to leave rows of
electrodes on one side and columns of electrodes on the opposite
side, the flags are formed, the electrodes being congruent on both
sides (overlapping but spaced apart by the two sheets of PVDF). The
array of flags 321 is created by punching or etching horseshoe-like
perforations 326 around each of the metallized pairs of opposing
electrodes in the array. It should be apparent to a person trained
in the art that one may choose to first form the flags and then
etch away the excess metallization between the rows and columns of
electrodes.
[0120] In operation, the application of a voltage to a row of top
electrodes 323 through the common lead 322 causes the top half
(formed by the top PVDF sheet) of the flags 321 in that row to
become shorter than in their respective unpowered state, while the
application of a similar voltage (but of opposite polarity) on a
column of bottom electrodes 324 via common lead 325, causes the
bottom half (formed by the bottom PVDF sheet) of the flags 321 in
that column to become elongated relative to their unpowered state.
Assume that the appropriate voltages are applied to a specific row
through conductor 328 and none other, and to a specific column
through conductor 327 and none other. The flag 329, which is the
only flag at that time having both its top and bottom electrodes
powered, has on its top portion a voltage that causes its top half
to shorten and has on its bottom portion a voltage that causes its
bottom half to elongate. As result, flag 329 bends upward and
exposes the perforation under it, allowing illumination to reach
the sample and allowing responses from the sample to reach the
aperture of the optical fiber and thus be transmitted to the
sensor. All other flags in the row powered by the row conductor 328
are devoid of voltage on their respective bottom electrodes, and,
similarly, all other flags powered by the column conductor 327 are
devoid of voltage on their respective top electrodes. Thus, only
the flag 329 powered simultaneously by the row conductor 328 and
the column conductor 327 is forced to bend upward. One may
therefore actuate the flags 321 in a PVDF optical shutter array by
applying an appropriate voltage to a given column and sequentially
apply voltage pulses to the rows, or one may randomly activate a
flag by applying the appropriate voltages to its coordinate row and
column.
[0121] In FIG. 14, a variation of a PVDF based optical shutter
array 330 is shown. PVDF flags 332 are structured in a similar
fashion to the system shown in FIGS. 13a and 13B and described
above. Specifically, two sheets of PVDF are cemented back to back,
and flags 332 are formed with electrodes on both sides connected on
the top side in columns with leads 333 and connected on the bottom
side in rows with leads 334. This assembly is overlayed on a plate
having an array of perforations 331. The flags are oriented at
45.degree. to the main lattice to allow for a greater movement of
the flag. This is important when the fibers have very large
numerical apertures and the beams emanating from the fibers spread
at a high angle, and the collection angles of responses from the
sample are similarly large. The operation of this array follows the
principles described above. In particular, the application of a
driving voltage to a given column and a given row causes the
actuation of the flag on that column and row.
[0122] These are just two examples of embodiments of an optical
shutter array in which the actuation of the optical shutters is
based on movement induced by piezoelectric bimorphs. In another
arrangement, the bimorphs are arranged in rows perpendicular to the
base surface of the array, and each bimorph has a flag (parallel to
the plane of the array and thus perpendicular to the bimorph)
covering its respective perforation in the array. The actuation of
each bimorph causes movement parallel to the array surface rather
than above the surface. This embodiment is somewhat more difficult
to implement, but has the advantage that smaller bending of the
bimorph is required, particularly when the optical fibers used in
the array possess a large numerical aperture.
[0123] In FIG. 15, yet another embodiment of an array of optical
shutters is shown. In this embodiment, the array 340 is best
produced by techniques of micromachining from silicon wafers. While
a certain order of description of the various elements in the array
is followed below, this order is not necessarily the order used in
the micromachining process. Perforations 341, through which optical
fibers are inserted, are provided in an array. In this embodiment,
these perforations are about 0.1 mm in diameter and are spaced on a
grid of 1.0 mm spacing. Each perforation is associated with its own
shutter 342. The shutter 342 consists of a thin flexible arm 343
anchored on one side to the base plate 344 via an axis 345. On the
opposing side of the arm, a flag 346 is provided. The flag is
sufficiently large to cover its respective perforation 341 when the
shutter is in the closed position. Two series of posts 347 and 348
positioned on opposite sides of the arm 343 are connected to
appropriate electrical leads (not shown). Similarly, the shutter
element is connected to its own electrical lead (not shown).
[0124] There a large number of possible variations of this
embodiment, and a few of these variations are described here. In
one embodiment, the total array of optical shutters is manufactured
monolithically from a single wafer. In that case, the arm and flag
are machined to be in the "open" position 349. Otherwise, it
becomes impractical to etch the perforations. In other embodiments,
the array is produced from two pieces cemented together. One piece
may contain the array of arms, and the other piece may contain the
array of perforations. Then it is preferred to have the rest
position of the arms in the closed position. The groups of posts
347 and 348 may be on either of the two wafers, but for practical
reasons it is preferred to produce them on the array of arms. It is
also possible to provide a single well-positioned post for the
group of posts 347 and a single well-positioned post for the group
of posts 348. The choice of the specific design depends on the
dynamic response required from the light shutters in the array.
[0125] The operation of the arm as a light shutter is based on the
electrostatic attraction and repulsion generated by the charging
and discharging of various members of the assembly. In operation,
the arm may be charged, for instance negatively, and the distal
posts 347 may be charged positively to cause the arm to be
attracted to this set of posts. To accelerate this action, the
proximal posts 348 may be charged negatively to cause simultaneous
repulsion of the arm. It should be understood that actual contact
of the moving arm with either group of posts 348 or 347 is not
required. It is preferred to actually avoid such contact and in
order to accomplish this aim, the whole assembly may be treated to
have a thin layer of silicon oxide as an insulation, thus avoiding
such contact.
[0126] To facilitate the driving of the shutter array, it is
preferred to apply the activating voltages in rows and columns, and
only the simultaneous actuation of a given column and a given row
causes opening of the shutter at the intersection of the selected
row and column. This may be achieved in a number of ways. Consider
the case where the device is made of two independent wafers, so
that the rest position of the arm may be in the closed state. Thus,
when no charges are present on the arm, the optical shutter is
closed. Referring again to FIG. 15, apply a pulse charging all the
arms in the first row negatively, and through the pair of leads for
the first column, a positive charge is applied to the posts 347 and
a negative charge is applied to the posts 348. The negatively
charged arm in the first row and the first column is repulsed from
the negatively charged posts 348 and is attracted to the positively
charged posts 347, thus opening the optical shutter previously
covered by the flag 346. The other arms in the first row are
unaffected, since their respective posts 347 and 348 are uncharged.
Similarly, all arms in the first column are uncharged and thus,
despite the fact that the posts 347 and 348 are charged, the arms
do not move, thus leaving the optical shutters closed. When
scanning the whole array, all arms 343 in a given row may be kept
charged and the posts in adjacent columns may be sequentially
charged.
[0127] The return of the arm to its closed position may be achieved
either through the spring forces in the arm or actively by
reversing the charges on the posts 347 and 348. The selection of a
passive return or an active return to the closed position is
determined by the dynamics of the scanning process. When extremely
rapid scanning is desired, reversal of the charges on the posts is
preferred, but when the dynamic response may be slower, mechanical
relaxation to the rest position may be practiced.
[0128] In FIG. 16, another embodiment of a micromachined optical
shutter array is shown. Here, as in FIG. 15, the array may be
monolithically produced or may be assembled from two sub
structures. In the base plate, an array of perforations 361 having
a diameter of about 0.1 mm spaced on a grid whose points have 1.0
mm spacing is provided. The active elements comprise flat arms 362
attached to the base plate with a twistable post around which the
arm may rotate. The distal end of the arm is sufficiently broad to
cover the perforations and thus block the optical path to the
fibers that are mounted within the perforations. While in FIG. 16
arms having their width gradually expanding to cover the
perforation 361 are shown, it should be understood that a narrow
arm 362 terminated by a wide flag at its distal end, sufficient to
cover the perforation, may be provided.
[0129] The proximal end of the arm is terminated with a structure
364 generally perpendicular to the axis of the arm. Two posts 365
protrude from the base plate, positioned somewhat apart from the
structure 364. When the arm is, for instance, charged negatively,
and the posts 365 are charged positively, the electrostatic
attraction causes the arm to rotate and expose the perforation,
thus opening the optical shutter as shown in position 366. Here as
above, the array may be operated by maintaining a given row
(charging the arms 362 in that row) negatively and scanning the
column, which positively charges all pairs of posts 365, to obtain
sequential opening and closing of the optical shutter array. As
above, the elastic properties of silicon may be relied upon to
return the arm to its rest position (through the twisting base 363
spring action), or the charge on the pairs of posts may be reversed
before switching to the next column.
[0130] A variety of light sources may be used in conjunction with
the array volume microprobes of the present invention. For
instance, when the desired responses are fluorescence responses,
one would often use a laser source, such as a nitrogen laser having
a wavelength in the ultraviolet part of the spectrum, such as 337
nanometers. When backscattering as well as absorption in a broader
part of the spectrum is the desired response, the light source is
usually a broad spectrum source such as, but not limited to, a
xenon discharge lamp, a halogen incandescent lamp, or any other
suitable broad spectrum light source. Furthermore, such a light
source may be conditioned with an appropriate filter to homogenize
or otherwise modify the light spectral distribution. The use of
more than a single light source in a given system is also
contemplated. Thus a volume microprobe array may include a UV laser
source to perform fluorescence measurements, as well as a wide band
light source to perform scattering and absorption measurements. A
third light source particularly rich in near infrared radiation may
be included as well. In operation, these light sources may be
directed toward the excitation optical assembly in a predetermined
sequence. For instance, a typical UV laser source would operate in
a pulse mode having a relatively short duration pulse (for instance
under a microsecond) and a slow repetition rate. Thus a lapse time
between excitation of milliseconds or fractions thereof (often done
to avoid overheating of the laser source) is available between
measurements of fluorescence responses. During this lapse time, a
broadband light source may be directed at the excitation optics,
and measurements of the response of the target sample to that
second light source may be detected.
[0131] Furthermore, to obtain additional diagnostic and analytical
information from the volume elements probed, one may obtain Raman
scattering data which provide molecular structural information on
the material probed. The light source or excitation beam may then
be a laser within the visible range of the spectrum. When it is
desired to reduce the fluorescence signal generated with an intense
beam in the visible part of the spectrum (which masks the much
weaker Raman scattering responses), one may use a laser in the far
red or the near infrared part of the spectrum. Such light sources
may be a HeNe laser at 633 nm, or a GaAlAs diode or laser diode at
783 nm or even a Nd:YAG laser at 1064 nm, as well as other near
infrared diodes or laser diodes. In some embodiments of the
invention, when multiple light sources are used, multiple detectors
may be used as well. Each is designed to be optimized for the
spectral response and response intensity anticipated. In such
cases, the timing of the excitation from the plurality of sources
and the responses from their associated detectors is controlled by
the controller 18.
[0132] In FIG. 11, a typical volume microprobe array 170 with its
associated electronic modules and computing modules is shown. The
optical system is similar to that shown in FIGS. 9 and 10 and
described above, except that the beam splitter is positioned at the
distal end of the optical fiber assembly, and in lieu of using the
light shutter array for both the excitation and detection optics,
an array of detectors is used for the spatial discrimination of the
responses, rather than an array of light shutters. Specifically,
the volume microprobe 170 includes a data processing and system
control unit 171 and an optical system 172. The optical system
includes at least one light source 173. Lenses 174 and 175 are
interposed between the light source and a light shutters array 176
so as to image the light source onto the array. Interposed between
lens 174 and 175, a device 176 may be included to condition the
spectral distribution of the light source. Such a device may be a
filter that is designed to modify the normal spectral distribution
of the light source, which may include parts of the spectrum at
intensities that are greater than other parts, and thus normalize
the spectral distribution of the exciting beam. The element 176 may
be a plurality of filters mounted on a rotating filter wheel, so as
to interpose different type of filters (or no filter) in the
exciting beam path.
[0133] Also interposed between the two lens 174 and 175, a second
device 177 may be included to modulate the exciting beam in time
and in intensity. Such a scheme may be used to improve the
signal-to-noise ratio of the detection system by synchronizing the
modulation and detection through an appropriate phase locked
amplifier (not shown), which is part of the electronics system 171
(indicated as control arrows 191 and 193). Similarly the timing of
the light source 173, including the sequencing of a plurality of
light source or the pulse rate and pulse width of a UV laser
source, is also under the control of the controller 201 as
indicated by the control arrow 192. The light shutter array 176 is
coupled to an optical fiber bundle 178 in such a manner that each
fiber within the bundle is coupled to a given light shutter in the
array. The distal ends of the fibers within the bundle 178 are
arranged in the same array configuration as the proximal ends so as
to maintain the same array geometry. The aperture of the individual
optical fiber determines the field stop of the excitation optics in
this embodiment. The light shutters within the array 176 are under
the control of the controller 201 via a control line 200, and in
operation, the controller sequentially opens light shutters so as
to provide an excitation beam sequentially to all fibers in the
array.
[0134] Light emanating from the distal ends of the fibers in the
bundle is imaged onto a sample 185 with objective optics 179. In
the embodiment shown in FIG. 11, a beam driving mirror 184 is
provided, the function of which is to select, within the sample,
the desired area from which an array of volume elements is to be
analyzed. The tilt of the directing mirror 184 is controlled by a
joy stick 187, which may be operated manually, or be under the
control of the controller 201 via control line 196.
[0135] Responses from the target array of volume elements within
the sample 185 are redirected by the directing mirror 184 to the
objective optics 179, and a beam splitter 180 is utilized to
separate the excitation beam from the responses. Since the
illumination of volume elements within the target array is
sequential, at any time, only responses from a given volume element
are received by the detector assembly. The detector assembly
contains an array of detectors 183, and the respective apertures of
each detector element within the array also serve as the field
stops of the detection optics. Since both the excitation optics and
the field stops of the detection optics are conjugated within the
target volume element in the sample, we ensure that detection of
responses emanating essentially only from each volume element are
recorded for each volume element in the sample.
[0136] The detector assembly also contains additional traditional
optical elements, such as a spectral filter 181, whose function is
to eliminate from the responses undesired parts of the spectrum.
For instance, when the excitation beam is a nitrogen laser and the
desired responses are fluorescence emissions, the filter blocks any
reflections of the excitation beam and prevents their registration
as responses. A spectral analyzer 182 is also included to determine
the spectral distribution of the responses. The detector array is
under the control of the controller 201 via a control line 194 so
as to ensure the synchronization of excitation and response
detection from each volume element in the target sample.
[0137] The detector assembly, or in some embodiments a specific
element of the assembly such as an objective lens, may be caused to
move in a direction parallel to the optical axis of the assembly
with a driving mechanism 186 under the control of controller 201
(through control line 197), so as to adjust the z position, or
depth, of the volume elements probed by the array microprobe
system, in a manner similar to that described above.
[0138] Signals from the detector, representing optical responses,
are directed to a signal processing unit 202, which then transfers
the data to an analog to digital converter 203 for further data
conditioning in a data preparation module 204. The data
representing responses (and tagged to assure that the processor
recognizes data from various volume elements, which is achieved
with a control line 199 from the controller 201) are then treated
in a calibrator/scaler 205 to normalize the data. This is achieved
by monitoring the output of the light source and renormalizing data
for variations in the output of the source via line 220.
[0139] The control and data processing unit 171 contains a memory
unit 210 in which calibration and scaling constants 208 are stored
as well as correlation transform matrices 209, as further described
below. Data from the system are converted to diagnostic information
by a computer 211 and displayed, either as diagnostic values or as
artificial maps on a display station 212. The computer has memory
(resident or removable) in which data may be stored and retrieved
for future analysis off line.
[0140] In general, the invention is intended to operate, at least
partially, to record and generally also compile and analyze the
responses it collects. In some low cost embodiments of the instant
invention, only diagnostic prediction of pathologies is provided.
In this case, the system is equipped with a library of correlation
transform vectors or matrices for specific diagnostics, and the
system only registers the signals I.sub.ij (response intensities at
a specific wavelength, i, for a specific volume element j) and
calculates functions F(I.sub.ij) required to provide a diagnostic
score C.sub.j, for an array of volume element j, as is further
described below.
[0141] The output from detector 183 is fed to a data processor 206
after preprocessing in signal processor 202, analog to digital
converter 203 and data preparation module 204. Data processor 206
may process the output from detector 183 or it may store the data
in memory unit 210 for processing at a later time. The computer 211
may also provide the ability to compare a first data set obtained
from detector 183 with a second data set obtained from memory unit
210, or to perform comparative studies of various volume elements
within an array of volume elements measured at any given time, thus
providing for spatial correlation of volume elements within a given
sample. For example, data processor 206 may calculate correlations
between a first data set representative of the material being
probed and a second data set in memory unit 210. In accordance with
a preferred embodiment of this aspect of the invention, the second
data set may be a library of optical response data or a
mathematical model abstracted from such a library, as is more fully
described below.
[0142] Memory unit 210 may be used to store a large body of data
about particular materials. For example, memory unit 210 may store
data concerning the characteristics of light which has interacted
with a particular type of biological tissue, or memory unit 210 may
store data concerning the characteristics of light emitted,
particularly fluorescence, by particular types of biological
tissues in response to excitation by each of a set of wavelengths
of light, or may store such spectra indexed by tissue depth, or
other complex multidimensional spectra derived from a prior set of
observations.
[0143] Memory unit 210 may further store information associating
particular characteristics of light obtained from a biological
tissue sample with a particular diagnosis. For example, the ratio
of light reflected at one wavelength to light reflected at a second
reference wavelength may be associated with cancerous tissue growth
as in certain known observations, or may be associated with a
clinically relevant condition such as a thickening of one layer of
tissue, a precancerous metabolic change, or a malignancy, based on
correlation with the spectral library and previous clinical
characterizations. Thus, correlation with annotated or stored
digitized spectra may provide a diagnostic judgment, even without
the identification of any specific individual spectral features,
such as peaks or absorbance bands, that have been required for
diagnosis in the past.
[0144] While in the embodiments shown herein, for example in FIG.
11, the detector 183 is shown accepting responses from the specimen
after being treated trough a spectral analyzer 182, it should be
clear that the spectral analyzer may be replaced with either a
temporal interferometer (such as a Michelson interferometer) or a
spatial interferometer (such as a Sagnac interferometer). The
resulting interferogram may then provide the Fourier transform of
the optical responses obtained from each volume element probed for
subsequent data analysis as described elsewhere in this
application.
[0145] Similarly, when performing Raman spectroscopy, particularly
when selecting for an excitation beam a source in the near
infrared, where the intensity of the Raman scattering is greatly
reduced, one may impose in the response path, in lieu of an
interferometer, a Hadamard encodement mask consisting of a
multi-slit array, in order to obtain via Hadamard transform of the
data the Raman spectral response of the probed volume elements.
[0146] In the prior art, spectral and chemical analysis of complex
and heterogeneous matrices with good localization of such analysis
was hindered by the inability to limit the response obtained from
such matrices from regions with a high degree of homogeneity. A
large group of microprobes was thus developed to handle this
problem, and indeed, electron microscopes and ion microprobes and
various other devices capable of providing analytical information
exist, both morphological and to some extent chemical (mostly
elemental) on a point by point or even through sections (such as in
the ion microprobe) of a specimen. Unfortunately, these methods all
require the placement of the sample in vacuum and the eventual
destruction of the specimen, and furthermore these methods are not
conducive to the analysis of organic materials. In vivo microprobe
analysis of biological tissue has requirements that are somewhat
different from those of classical microprobes. Particularly, it is
not desired to have a resolution greater than the typical
dimensions of differentiated tissues, but it is required to have
analytical tools that may be operated by personnel without specific
training in the analytical arts, such as physicians, process
control personnel and other professionals. The use of the present
invention allows for microprobing of samples and biological tissues
in vivo, and enables the spatial delineation of compositional,
morphological and pathological features of such specimens. There
are numerous approaches by which the data from such array volume
microprobe may be used, and without limiting the scope of the
instant invention, we describe herein some of these approaches.
[0147] In one embodiment of the present invention, responses from
an array of volume elements, which represent the interactions of
the material within each of said volume elements with the exciting
radiation, or at least contain specific signatures of such
interactions, are presented in terms of received light intensities
for various wavelengths, or as is known in the art, as a spectrum
of the response. A researcher trained in the specific analytical
art may then use these spectra to deduce important information
about each of the volume elements in the array from his knowledge
of the exciting radiation and the modes of interactions of the
radiation with his target material. A variety of analytical tools,
such as software programs designed to conduct spectral peak
fitting, or spectral deconvolution, may be used to further increase
the researcher's basic understanding of such interactions and to
provide the researcher with information on the chemical,
morphological and physiological nature of the target volume
elements in the array, since the responses correspond each to a
specific volume element in the array probed. This in accordance
with basic principles known in the art, except that the data
provided to the researcher are derived from a well-defined volume
element and thus interferences and response weakening due to
parasitic responses and interferences originating outside the
target volume elements no longer hinder the researcher's ability to
differentiate specific features within a largely heterogeneous
sample. Thus, the array volume microprobe of the present invention
may be used to perform classical spectroscopical analysis,
fluorescence analysis, Raman scattering and other parametric or
characterizing analysis which involves the measurement of the
responses of each volume element in the array to a localized
radiation while limiting the observed responses to essentially each
of the volume elements in the array only at any given time.
[0148] In another embodiment of the present invention, directed to
users that do not possess the technical skills to derive meaningful
conclusions from raw responses observed, the system is equipped
with a library of correlation transforms dedicated to the user's
special needs, so that the system is essentially pre-calibrated for
specific analytical tasks. The method of calibrating the array
volume microprobe is further detailed herein. In many of these
diagnostic situations, a physician who is not a trained
spectroscopist views the suspected tissues, and when discoloration
or other morphological abnormalities are present, samples from such
areas are excised and sent to a pathological laboratory for
microscopic examination of the tissues to determine the presence or
lack thereof, as well as the stage, of possible cancer. It would be
extremely useful if, during the visual examination, a diagnostic
scoring to determine the nature of the suspected pathology of the
suspicious target tissue was available, so that immediate action
may be taken, if necessary, and to avoid unnecessary excision of
tissue for biopsies. When calibrated as described below, the array
volume microprobe of the instant invention will enable the
automated diagnostics of such viewed tissues by a physician,
provide an artificial image of the pathology and its extent,
without the need to examine such tissues under the microscope by
another professional pathologist.
[0149] FIG. 12 is a diagram 300 showing the various steps
undertaken in the calibration and then the use of the array volume
microprobe. In order to calibrate an array volume microprobe 301
for a specific pathology, a training set 302 of specimens for the
specific pathology is first selected. The term training set will be
used herein to denote a group of tissue specimens on which very
exacting cytological and pathological determination of the state of
each specimen was conducted in a pathological laboratory, denoted
by the step 303. Furthermore, prior to excision for such biopsies,
each specimen in the training set was subjected, in vivo, to an
exacting study with the microprobe array 301 of the present
invention. For the purpose of this description, let us assume that
the target volume elements in the training set (those tissues that
are later subjected to a pathological laboratory determination of
their respective pathological states) are excited with both a laser
UV source and a broad band white light source. To assure good
spatial correlation between the excised tissues and the volume
elements examined, during calibration, the array is used with only
a single shutter open, or a special single channel non imaging
volume microprobe may be used. Let the intensities of the responses
to the UV and white light excitations of the targeted volume
element within the specimen j be J.sub.uj and I.sub.ij
respectively, where u and i are central wavelengths within spectral
bands of the spectral responses to the UV and to the white light
excitations, respectively. These data are stored in memory (for
instance memory unit 210 in FIG. 11) for future analysis and
determination of the master calibration at step 304. The volume
elements in the training set are excised after recording the
responses obtained with the non imaging volume microprobe, and
pathological determinations of the state of each specimen are
recorded in the form of scores C.sub.j, where j is the identity of
the specimen and C.sub.j is a number selected according to the
specimen state on a monotonic scoring scale, for instance 0 to 10,
where zero denotes normal tissues and 10 fully entrenched and deep
cancerous tissues. Since this training set will calibrate non
imaging volume microprobes for future determinations of the
presence or lack thereof of such pathologies, it is important that
great care is taken at arriving at an objective determination of
the pathological state of the training set. In such cases, the same
samples are examined microscopically by a number of independent
pathologists in a blind experiment, and only those specimens for
which a minimum agreement between the various pathological results
exists, are included in the training set.
[0150] Once the scores C.sub.j of the specimen in the training set
have been carefully determined, and the medical records of the
patients associated with samples (volume element) in the training
set are recorded (more than one volume element per patient may be
included in the training set, however, it is best to include a
variety of patients in a training set for a given pathology), the
values of I.sub.ij and J.sub.uj previously stored in memory unit
210 are used to set up a set of n correlation equations (n would be
the number of volume elements in the training set):
E a.sub.i F(I.sub.ij)+Eb.sub.u F(J.sub.uj)+E c.sub.S
G(M.sub.sj)=C.sub.j (1)
[0151] The bandwidths around the wavelengths i and u of the
responses to white light and UV light, respectively, are usually
between 5 and 50 nm, depending on the spectral resolution
achievable or desirable in the system's detection monochromator or
spectrograph (element 182 in FIG. 11).
[0152] The selection of the functions F depends to some extent on
the nature of responses received. When almost featureless spectral
responses (namely a spectral response which is relatively smooth
and changes slowly with the wavelength) are received, then one
often selects the intensities, or normalized intensities, of the
responses namely, F(I.sub.ij)=I.sub.ij or F(I.sub.ij)=I.sub.ij/K,
respectively, where K is either the maximum response in the
received spectrum or the response at a predetermined wavelength (in
biological tissues, often a response associated with the presence
of water or hemoglobin). When the spectrum expected contains a
number of sharper features, one often may use
F(I.sub.ij)=(dI.sub.ij/d8)I.sub.ij, where 8 is the wavelength. Of
course, it is best to use the same function F for the responses to
both UV excitation J.sub.uj and white light excitation
I.sub.ij.
[0153] The functions G(M.sub.sj) are included to allow for the
impact on the observed responses of the patient's specific "medical
history", and usually includes parameter such as sex, age, race,
and presence or lack thereof of systemic pathologies such as
hypertension, diabetes etc. In many situations, part or all the
coefficient c.sub.S are nil, and these factors have no impact on
the calibration, but in special cases, these factors play a role
and are included here for completeness.
[0154] A computer is now used at step 304 to perform a regression
analysis to minimize the number of wavelengths i and u (and s which
are "artificial wavelengths" representing medical history) used to
obtain a valid correlation and to solve the set of minimized
equations (1) for the correlation constants a.sub.i, b.sub.u (and
c.sub.S). This regression analysis is performed using the n
equations obtained experimentally, using in essence the correlation
constants as unknowns, for which a solution having the best
correlation is sought. The minimization is carried out to extract
those wavelengths at which the responses contain independent
relevant information that correlates the responses I.sub.ij and
J.sub.uj to the scores C.sub.j. It should be appreciated that
during the calibration process, a greater amount of data is
collected than absolutely necessary, and much of these data are
interrelated. To obtain a sufficiently good correlation, only
responses that are independent from each other are necessary, and
thus the process of minimization of spectral responses in equations
(1) is carried out. This minimization will also allow, during
actual diagnostic use of the non imaging volume microprobe, the
taking of a minimal set of responses and thus will accelerate the
procedure.
[0155] The methods used for obtaining the minimal set of
wavelengths and the associated correlation coefficients a.sub.i and
b.sub.u are well known in the prior art and include multivariant
linear regression analysis and univariant linear regression
analysis. Other statistical tools, such as neural networks
analysis, are also available and may be used for this purpose.
[0156] In general, we may term the values I.sub.ij and J.sub.uj the
responses of the volume element to white light and UV excitation,
respectively. As we have mentioned, other responses may be used to
characterize a volume element in a sample. We therefore term all
responses which are responses from volume elements that correlates
with certain pathologies as responses R.sub.ij. As mentioned above,
we found that it is sometimes advantageous to include as part of
the responses R.sub.ij other information about a volume element (or
the volume element's host) which was not determined with the help
of the non imaging volume microprobe but still contributes to
improvement in the correlation between the observed responses and
the pathologies diagnosed. Such information may include general
classification of the subject in which the volume element resides,
such as, but not limited to sex, age, race, other systemic
pathologies and weight. Such information, when its inclusion in the
regression improves the confidence level of the regression, may be
included as additional artificial responses R (in lieu of the
functions G(M.sub.sj)). The index i therefore represents the type
of response obtained, whether it is obtained with the non imaging
microprobe (one or more types of responses as well as the spectral
band from which the response is registered) or by other means.
[0157] The set of equations (I) from which the correlation
coefficients are derived may thus be simplified to be:
Ea.sub.i F(R.sub.ij)=C.sub.j (2)
[0158] For simplicity, the ordered values a.sub.i may be termed the
correlation vector (a) for pathology C, and the ordered responses
R.sub.ij may be termed the response vector (R.sub.j) for volume
element j in the training set. The functional response vector
(F(R.sub.j)) is similarly defined as the ordered functions of the
elements of the responses in the response vectors (R.sub.j).
Similarly, the ordered scores C.sub.j may be termed the pathology
score vector (C) for the training set. The process of calibrating
the array microprobe for a given pathology C consists therefore of
obtaining all the response vectors (R.sub.j) and their
corresponding pathology score vector (C) and from these data, after
generating the functional response vector (F(R.sub.j)), obtaining a
minimal correlation vector (a), which is the calibration vector of
the non imaging volume microprobe. As may be seen, the calibration
is identical to the calibration designed for the non imaging volume
microprobe of U.S. Pat. No. 5,713,364. The calibration for a number
of different pathologies may be stored in a calibration library 305
for future use on unknown specimens. Each microprobe array includes
a correlation engine 307 which may take calibration vectors from
the calibration library 305 and response vectors obtained from the
microprobe array and other sources such as medical records 308 and
reconstruct for the response vector a value C of the observed
pathology. Since in the various embodiments of the invention the
different optical channels representing excitation and responses
from given volume elements are equivalent, a single calibration
(for a given pathology) suffices.
[0159] When we now want to determine the nature and distribution of
a pathology in a target specimen, which is outside the training
set, or an unknown specimen 306, and for simplicity let us term
each such volume element in the array k(x,y,z), delineating its x,
y and z coordinates. The response vectors (R.sub.k(x,y,z)) are
registered by the instrument on the volume element k(x,y,z), and to
the extent that some of the responses R.sub.ik are artificial
responses (such as sex or race as mentioned above), these are
entered into the correlation engine part of the microprobe array
and the score for the pathology for volume element k(x,y,z),
C.sub.k(x,y,z), is predicted by obtaining the product of the
correlation vector (a) found earlier with the functional response
vector (F(R.sub.k(x,y,z))), namely: C.sub.k(x,y,z)=Ea.sub.i
F(R.sub.ik(x,y,z)). Thus the use of the calibrated microprobe array
on an array of volume elements k(x,y,z), whose pathological state
C.sub.k(x,y,z) is unknown, allows for the immediate and automatic
diagnosis of the pathology in volume element k(x,y,z). This
procedure is repeated for all volume elements in the array, and the
set of values C.sub.k(x,y,z) for all volume elements in the array
may now be presented on a display 309, either as numerical values
or as artificial images of the array examined. Normal methods of
three-dimensional image handling and manipulation may thus provide
the physician with an insight as to the nature, extent, severity
and penetration depth of suspected pathologies. This reduces the
number of unnecessary biopsies required and provides the physician
with immediate information on which he may act during the
examination.
[0160] It should be appreciated that the functions
F(R.sub.ik(x,y,z) may be derived from the Fourier Transforms
obtained from the responses, either with a temporal interferometer
such as a Michelson interferometer or with a spatial interferometer
such as a Sagnac interferometer. It is even possible to use the
interferograms themselves in lieu of the Fourier transform
generated from them. Similarly, when probing for molecular
structural information on the probed elements, one uses for the
functions F(R.sub.ik(x,y,z) the values at various wavelengths
obtained from the Hadamard transform of the Raman spectral
response.
[0161] It should be appreciated by persons trained in the art that
microprobe arrays of the invention may be calibrated to diagnose a
plurality of pathologies P.sub.m, where m denotes a specific
pathology. When used in this fashion, the task of calibrating the
instrument for this plurality of pathologies consists as before of
obtaining for a training set j, responses R.sub.ij and pathological
scores P.sub.mj, where i is the bandwidth of the response or the
type of artificial response, j is the volume element or the
specimen in the training set and P.sub.mj is the score for
pathology m on specimen j. During calibration, we obtain a number
of correlation vectors (a.sub.m), each for the specific pathology
m. In operation of the calibrated non imaging volume microprobe,
the correlation vector (a) mentioned above is now replaced with a
correlation matrix {a} whose elements are a.sub.im, the functional
response vector (F(R.sub.k)) for an uncharacterized specimen, k, is
replaced with the matrix {F(R.sub.k)} whose elements are
F(R.sub.imk) and the diagnostic results are given as a vector
(P).sub.k whose elements are P.sub.mk by obtaining the product of
the correlation matrix {a} with the functional response matrix
{F(R.sub.k)}.
[0162] It should also be appreciated that in the practical
embodiment of this method of analysis, the correlation created will
use the same responses (if not all of them at least some of them)
for different pathologies. Thus only a response vector (R.sub.k)
(having elements R.sub.ik) is required, which includes the minimal
set of responses from volume element k to obtain diagnostic scores
P.sub.mk. The matrix {a} may also be termed the correlation
transform matrix, since it transforms one set of measurable (or
observable) values, to another set of numbers or values, which are
the desired pathological scores. This is achieved by multiplying
the correlation transform matrix, {a}, with the vector
(F(R.sub.k)), the functional response vector, to obtain a
transformation of the response vector (R.sub.k) to a diagnostic
score vector (P).sub.k.
[0163] The correlation transform method exploited herein, of
predicting diagnostic or analytic information on an unknown
specimen by correlating optical responses of a training set to
independent determination of the diagnostic or analytic data on the
training set has been shown by Rosenthal to work well on
artificially homogenized samples that are large enough to provide a
set of responses possessing a large signal-to-noise ratio. It is
surprising that the expanded method of the instant invention yields
good correlation on very minuscule volume elements in vivo. In
classical spectroscopy, for instance, as practiced by Alfano,
spectra or optical responses of diseased tissues are compared to
similar spectra or responses of healthy tissues to attempt a
diagnostic reading on the target tissue. This method fails to work
because of the large variations encountered between subjects and
the nature of the tissue examined. When using our correlation
transform approach, we purposefully avoid using comparison of
spectral responses in a target tissue to the responses of any
existing (healthy or pathological) tissue, since no one specific
tissue may represent all the variations encountered between
subjects. Such subject-to-subject variations cause spectral
distortions that invariably weaken the ability of the prior art to
obtain robust diagnostic determination of pathologies. Furthermore,
our inclusion of non optical responses together with optical
responses, as part of the correlation transform algorithm, in
essence builds a completely artificial model (based on the training
set) of the pathology, which by itself is never reproduced in any
one subject or tissue. Finally, this novel approach, coupled with
the spatial filtering of the optical responses to a small volume
element, thus avoiding response integration over heterogeneous
tissues, makes it possible to obtain valuable artificial imaas of
pathologies heretofore not feasible.
[0164] For simplicity of the descriptions provided herein, we
assume that a goal of the method is to calibrate an array volume
microprobe for the diagnosis of the presence or lack thereof of
tissues that are affected by certain pathologies including cancer
and that are accessible to optical visualization, either on the
external skin, or in a body orifice such as the mouth or the
vagina, or in other cavities that are accessible via endoscopes or
laparoscopes, such as the various segments of the gastrointestinal
tract or various organs in the body cavities, such as the thoracic
cage and the peritoneal cavity. In situations where body cavities
are being accessed by endoscopes or laparoscopes, it is important
to provide a system and a method that is adapted for these medical
uses. It is furthermore important to provide systems and methods
adapted for those other medical uses where the hardware probe is
being used for in vivo diagnosis of biological tissues. Since the
hardware probe is able to be placed into contact with biological
tissues, contamination of the optical hardware probe must be
avoided. A disposable probe or a disposable covering for the
optical hardware probe may be particularly advantageous in these
circumstances.
[0165] In one embodiment, an apparatus according to the present
invention may be used to determine a characteristic of a sample of
a biological material in an in vivo situation. In the in vivo
situation, the sample of biological material may exist in
continuity with an in vivo body tissue of a patient. In this
embodiment, a barrier or a disposable sheath may be provided to
prevent the probe from contacting the biological material and from
contacting the in vivo body tissue of the patient in juxtaposition
to which or in proximity to which the sample of biological material
is found. Furthermore, in an embodiment of the apparatus disclosed
herein, a barrier or disposable sheath may prevent the probe from
contacting those tissues that surround the in vivo body tissue
wherein the sample of biological material being examined may be
found. In one embodiment, a barrier or disposable sheath may
entirely cover the probe; in another embodiment, a barrier or
disposable sheath may cover those parts of the probe adapted for
contact with a body tissue of a patient. The term sheath as used
herein is understood to encompass any device that fits over part or
all of the optical hardware probe and that is thereby interposed
between the probe and sample being studied or between the probe and
an in vivo body tissue.
[0166] A disposable device may be designed for a particular
anatomic application. Procedures involving the gastrointestinal
tract, the urinary tract, the peritoneal cavity, the thorax, and
the female reproductive tract are examples of where a disposable
device may be used. It will be especially advantageous to provide
the hardware of the present invention with a disposable cover or
sheath that may be adapted for use on a single patient.
Furthermore, in one embodiment, the probe is constructed so that a
sheath must be in place for the probe to be operable. Certain
mechanisms are described in more detail below for ensuring single
use of a sheath or to ensure that the probe cannot be operated
without a sheath properly positioned to cover it. Other mechanisms
will be readily apparent to those of ordinary skill in these
arts.
[0167] FIG. 17 shows an embodiment of the apparatus of the present
invention adapted for use in examining a tissue of the cervix
uteri. An embodiment of the present invention may be used to
examine either the external cervix or the internal cervical os.
Embodiments of the present invention may be adapted for colposcopic
use. FIG. 17 shows an anatomic partial cross-sectional view of the
female perineum depicting an embodiment of a disposable sheath 400,
here shown in cross-section, positioned within the vagina 408.
Adjacent structures including the bladder 462, the uterus 460, the
rectum 464 and the symphysis pubis 466 are shown here to facilitate
orientation. This figure shows an embodiment in which a disposable
sheath 400 may be provided for an optical hardware probe 402 to
illuminate the cervix 404. Configurations for the sheath 400 may be
adapted to the anatomy of the cervix 404 and vagina 408. The white
light illumination 410 of the cervix 404 for video illumination may
be provided circumferentially. The distance from the distal end 412
of the probe 402 to the cervix 404 may be about 100 mm. The probing
beam 414 of the optical hardware probe 402 may be transmitted
through the disposable protective sheath 400 to strike the cervix
404.
[0168] A simple cylindrical structure may provide an interface
between the distal end of the light transmitting fibers and the
disposable sheath 400 so that light is transmitted to illuminate
the cervix 404. In one embodiment, an end plate (not shown) applied
to the distal end 412 of the hardware probe 402 may be fabricated
of a material designed to minimize the fluorescence emitted from
the plate when the UV excitation beam is applied. An example of a
substance for fabricating the plate is polymethyl methacrylate
(PMMA), although other optical plastics that will minimize
fluorescence may be envisioned by practitioners of ordinary skill
in these arts. The interface between the ring on the optical
hardware probe 402 bearing the optical fiber ends and the
disposable sheath 400 may be made from a silastic transparent
material in the form of a segment of a toroid.
[0169] In an alternative embodiment of a disposable sheath 400, a
light source ring (not shown) is positioned distally just at the
distal end 412 of the hardware probe 402. This embodiment may
include a transparent silastic ring with a 20 degree slanted
toroidal lens. The toroidal structure may have a retracted snap-on
mechanism that fastens the lens to the steel ring of the probe. The
toroidal silastic element may be part of a highly flexible thin
plastic sleeve that has a frontal membrane as its optical window.
The thin plastic sleeve may extend proximally to wrap the hardware
probe. Flexible plastic materials may include thin polyethylene
films shaped conically to facilitate initial wrapping and
tensioning of the frontal film. Other appropriate plastics may be
envisioned by those skilled in these arts.
[0170] A disposable sheath 400 may be attached or fastened to the
hardware optical probe 402. A variety of fastening mechanisms 406
may be envisioned by those skilled in these arts. A fastening
mechanism 406 is understood to comprise those mechanisms and
systems that may affix the disposable sheath 400 to the hardware
optical probe 402. As one example, a simple band latching mechanism
may be employed. Alternatively, a latching mechanism may be
employed that uses a unidirectional latch. As another example, a
plurality of pins or posts may be placed on the hardware probe 402.
These pins or posts are positioned to align the light transmission
fibers in the hardware probe 402 with the corresponding regions in
the disposable sheath 400. A fork-like latch on the proximal part
of the disposable sheath 400 may articulate with the posts so that
once a post is latched into place, it may only be released by
breaking the latch. The disposable sheath 400, according to this
embodiment, cannot be removed from the optical probe 402 and
subsequently replaced on the probe 402 to be used for another
patient. Other embodiments may be envisioned wherein the disposable
probe is adapted for single patient use only. Fastening mechanisms
may be envisioned by those skilled in the art that will confine the
disposable probe to use on a single occasion. A number of other
affixation mechanisms may be devised by those of ordinary skill in
these arts whereby the sheath or barrier may be detachably attached
to the probe and whereby detaching the sheath or barrier prevents a
subsequent use of these devices, thereby ensuring that a sheath or
barrier be used only once. Certain of these affixation mechanisms
are described below, but these descriptions are not intended to
limit the scope of the invention as claimed herein.
[0171] In certain embodiments, the disposable sheath 400 provides a
frontal window of adequate optical quality so as not to alter the
optical signals passing to and from the hardware optical probe 402.
These features furthermore adapt the device for use in a plurality
of medical situations. These features render the device more useful
for medical personnel in a variety of circumstances. The
embodiments disclosed herein are not intended to be limiting,
however. Other embodiments may be envisioned by those of ordinary
skill in the relevant arts.
[0172] FIG. 18 depicts the distal end 448 of one embodiment of a
disposable sheath 440 according to the present invention. In the
depicted embodiment, a bundle of optical fibers 442 may be arranged
in a ring 444 within a disposable sheath 440. The distal end 448 of
the disposable sheath 440 may be designed according to the
selection of the topology of fiber 442 arrangement. As an example,
a ring 444 may be constructed in the sheath 440 with an inner
diameter of 25 mm and an outer diameter may be provided with
gathers or folds that arrange for a particular ordering of the
sleeve around the probe. A sleeve may be made in part from of a
shrink-fitting material so as to conform more closely to the
configuration of the probe. The shrinkage may be achieved either
externally or by passing a small current in an embedded heating
element prior to using the probe. A sleeve may be made of a single
piece of material, or may be made of a plurality of components. A
variety of sleeve arrangements will be readily envisioned by
ordinary skilled artisans in this field.
[0173] The frontal optical window may include a hollow cylindrical
section mating with the optical distal end of the probe in a unique
manner so that only one relative orientation between the probe and
sheath is possible. Other shapes for the frontal optical window may
be envisioned, based on the configuration of the targeted anatomic
area or based on the shape of the underlying probe. An orientation
mechanism on the sheath or on the probe may facilitate the proper
positioning of the sheath on the probe, so that such positioning is
easy and accurate. This orientation mechanism may further permit
the reading of a marker on the sheath bearing identifying or other
data by an appropriate detector, sensor or reader on the probe.
[0174] The selection of the optical polymer used in the rigid
frontal optical window may be related to the sort of diagnostic
evaluation being performed. It is understood that certain materials
have optical characteristics adapted for particular situations. For
instance, in the colposcopic examination using an embodiment of the
probe according to the present invention, excitation of target
tissues with a UV beam is carried out and the fluorescence
responses from the tissues are collected to determine potential
pathologies. In this situation, the optical window of the sheath
may comprise PMMA since this material has no significant
fluorescent response to the excitation beam. For the purposes of
this specification, a fluorescence response is termed significant
when such a response interferes with the accuracy of interpreting
those fluorescence responses collected from and emitted by the
tissues upon being stimulated with the exciting beam. of 28 mm.
This configuration may permit a number of optical fibers 442 to be
placed within the ring 444, each fiber 442 having a diameter of 1
mm. In one embodiment, 78 optical fibers 442 may be placed within
the ring 444 arranged according to this configuration.
Alternatively, spaces may be left between the optical fibers 442 in
an arrangement, or optical fibers 442 may be bundled. Furthermore,
the thickness of the ring 444 of optical fibers 442 may be varied
to accommodate more or fewer fibers 442. In one embodiment, the
distal end 448 of the sheath 440 may be modular and alignable with
the optics of the probe. Other arrangements of the optical fibers
442 in the sheath 440 will be apparent to practitioners of ordinary
skill in the art. For example, a plurality of concentric rings may
be constructed to contain certain of the optical fibers 442 in each
ring 444.
[0175] It is understood that the disposable sheath depicted in
these figures is shown for illustrative purposes only. A plurality
of sheath configurations will be apparent to practitioners in the
art whereby the sheath configuration will be suitable to the
medical use envisioned for the probe. Moreover, sheath
configurations may be designed by artisans of ordinary skill that
will be adapted to the optical specifications of the hardware
probes disclosed herein. These sheaths, in their various
embodiments, will combine advantageously with the optical probe
systems and methods of the present invention to permit application
in a variety of clinical situations, as will be readily understood
by practitioners in these arts.
[0176] In one embodiment, a protective sheath of the instant
invention consists of two major elements, a frontal optical window,
made for instance from cast or molded polymethylmetacrylate (PMMA),
and a generally cylindrical sleeve extending from the frontal
optical window to cover the optical probe, made of a thin flexible
plastic such as polyethylene, the two elements are fastened at the
proximal rim of the frontal optical window. The sleeve component of
a protective sheath may be of any shape appropriate for the
anatomic area, or it may be shaped to fit a particular probe. The
sleeve may be tightly applied or loosely applied to the underlying
probe. The sleeve
[0177] Under other circumstances, obtaining an image, for example
by way of an embedded CCD in the optical probe, may not be as
important as obtaining a very high signal to noise ratio from
fluorescence response. Under these circumstances, the end piece
transmitting the UV excitation beam may be made of a very thin
teflon, or may comprise other fluoroplastics such as THV-200P (a
TFE/HPF/VDF terfluoropolymer from the 3M corporation). These
plastics do not demonstrate a significant fluorescence response
when irradiated with UV.
[0178] The optical window may be combined with other optical
elements, such as an optical lens, an optical filter, or an optical
polarizer. In certain embodiments, the additional optical elements
may be made of materials capable of transmitting electromagnetic
radiation without generating a significant fluorescent
response.
[0179] In some embodiments of the invention, a segment of the
sheath may be provided with a marker that indicates an unused state
of the barrier, and the probe may be equipped with a sensor or a
reader that may detect the marker. In certain embodiments, the
sensor or reader may generate a signal capable of activating the
probe. Under these circumstances, the probe may only be activated
in the presence of a sheath that has not been previously used. In
an alternate embodiment, a segment of the sheath may be provided
with a marker that indicates that the sheath has been previously
used. In this embodiment, the probe is provided with a sensor or
reader that may detect the marker. In certain embodiments, the
sensor or reader may generate a signal capable of activating the
probe. Other arrangements will be apparent to practitioners in
these arts whereby the needs of the medical community to protect
the probe assembly from contamination or cross-contamination may be
met. A system can be arranged to prevent the use of a probe and a
sheath for more than one diagnostic test cycle. A system can be
arranged to prevent the use of the probe and sheath on more than a
single patient, while permitting multiple diagnostic test cycles to
be executed upon the one patient being examined. Arrangements to
confine the use of the probe and sheath may include mechanical,
electronic, computer hardware or computer software systems or
combinations thereof, which will can be readily devised by ordinary
skilled artisans without undue experimentation.
[0180] A plurality of arrangements may be envisioned whereby the
sensor may detect the marker. In one embodiment, the marker may be
placed on an area of the optical window. However, the marker may be
located on any convenient part of the sheath, with the sensor on
the probe located to permit reading it. In one embodiment, the
marker may comprise a serial number of the specific sheath, either
in the form of an actual alpha numeric marking, or in bar code
form. This serial number may be "read" by a special element in the
optical probe and stored in the probe's electronic system. The
serial number may be correlated with other data identifying the
patient being examined. Each time the probe is used to examine a
patient, data is entered to identify the particular patient. In
this embodiment, the serial number of a particular sheath is
associated with a specific patient. Upon detecting the serial
number located on the sheath, the probe may query a database to
determine if the detected serial number is already associated with
a particular patient, an association that indicates a previous use
of the sheath. If previous use of a sheath is discerned, the probe
may be rendered inoperable. If use of the sheath on another patient
is discerned, the probe may be rendered inoperable. Alternatively,
the probe may be rendered operable if no previous use of the sheath
is discerned, or if no previous use of the sheath on another
patient is discerned. The data on the marker may be compared to any
data within a database to determine prior use of the sheath or an
unused state of the sheath. The reader on the probe may alter the
marker to indicate that the sheath bearing it has been used, or may
add data to the marker indicating that the sheath has been used. In
one embodiment, the sensor may alter or deface the data on the
marker after reading it so it cannot be read again by a probe
sensor. A variety of other permutations will be apparent to
practitioners in these arts wherein a sensor on the probe may
interact with a marker on the sheath to determine or to indicate
the used or unused state of the sheath, and furthermore to affect
the activation of the probe depending upon the used or unused state
of the sheath. These features, providing assurance that the same
sheath is not used on different patients, thus avoid the Potential
problems of cross contamination.
[0181] Systems and methods of the present invention may include the
detection of various conditions of the sheath. The condition of the
sheath may be its used or unused state. The condition of the sheath
may be its appropriateness for a particular type of diagnostic
test. For example, a different type of sheath may be useful for
screening evaluations of the cervix than would be useful for more
detailed diagnostic evaluations. The presence of a particular type
of sheath could enable the probe system to perform a specific set
of diagnostic tests. The condition of the sheath may be its
physical integrity, detected through a system incorporated in the
sheath itself. The sheath may permit a self-testing for physical
integrity, the result of which produces a signal that regulates the
activation of the probe. Self-testing may include mechanical,
hydraulic, pneumatic, electronic or any other type of test produced
by the sheath itself or administered to the sheath by a separate
system. The condition of the sheath may be its proper positioning
on the probe or in the desired anatomic region. The positioning of
the sheath relative to the target tissue may be validated by an
orienting system, for example, that produces a signal that must be
received as a precondition for activation of the probe for
diagnostic examination. Other conditions of the sheath may be
determined by an appropriate sensor, with the generation of an
appropriate signal to the probe. Furthermore, the systems of the
present invention may permit the transmission of a number of
signals relating to the condition of the sheath, each one of said
signals having an effect on the regulation of the activation of the
probe.
[0182] The systems described herein to prevent the operation of the
probe without the sheath in place represent embodiments of an
interlock system. In one embodiment, the sheath and the probe may
bear components of an interlock system whereby the proper
positioning of the sheath on the probe is needed for the probe to
be used. An interlock system may incorporate a marker bearing data
pertaining to the particular sheath and a reader incorporated in
the probe assembly so that the reader may read the data pertaining
to the particular sheath and convey a signal to the probe rendering
it operational or inoperative based upon the data the marker bears.
An interlock system according to these systems and methods may
comprise hardware or software circuits preventing the probe from
being used unless a previously unused sheath is properly positioned
upon said probe. An electrical or electronic circuit may be
included in the optical probe system whereby the presence of a
properly positioned probe is needed in order to complete the
circuit and permit activation of the probe assembly. In one
embodiment, the proper positioning of the sheath upon the probe may
release an electrically conductive fluid that would enable the
activation of the probe by, for example, permitting an activation
circuit to be completed or by allowing a signal to be transmitted
to the probe to activate it or to deactivate a system preventing
use of the probe. Proper positioning of the sheath upon the probe
may release an electrically insulating fluid that may block an
inactivation system on the probe, thereby activating it. In another
embodiment, the proper positioning of the sheath upon the probe
includes the positioning of a latch mechanism whereby a fastening
component on the sheath interdigitates with a fastening component
on the probe, thereby completing a circuit or transmitting an
electrical signal that activates the probe. A plurality of other
interlock devices may be envisioned that are adaptable to the
positioning of a sheath on a probe and further adaptable to any
positioning of two components of a device relative to each
other.
[0183] In one embodiment of the systems and methods of the present
invention, at least a portion of the sleeve is made to mate with a
feature of the optical probe. A feature may be disposed upon the
external aspect of the probe, to correspond with an element of the
sleeve. As an example, a recessed groove may be positioned on the
external aspect of the probe, into which a longitudinal bar of
plastic material on the inner surface of the sleeve is pressed
fit.
[0184] In some embodiments of the invention, we also provide for
mechanical prevention of reuse of the disposable sheath. This is
accomplished, for instance by providing physical breakage of at
least a critical part of the sheath upon its removal from the
probe. The element on the sheath that mates with its counterpart on
the probe may be constructed so it will break when detachment of
the sheath takes place, preventing a subsequent attachment of the
sheath to a probe. In certain embodiments, the sleeve material may
be weakened around the mating structure on the sleeve, so that it
tears away at the weakened area when it is detached from the probe.
In yet another embodiment, an index-matching liquid that improves
the interface between the probe's distal end and the sheath's end
optical element, is provided, but may be used only once, thus
creating another safeguard against multiple uses of the same sheath
on a plurality of subjects.
[0185] While the embodiments illustrated herein pertain to a probe
suitable for use in a biological environment, the interlock
mechanisms disclosed in the present specification may be applied to
any system where the mating of a first component with a second
component must be properly performed in order for the first
component to be activated. Furthermore, the systems and methods
disclosed herein may be applied to any disposable sheath that is
applied to a probe to provide a barrier between the probe and a
feature of the environment in proximity to the probe. For example,
a disposable sheath according to these systems and methods may
prevent contact between the probe and a body fluid in a biological
environment. A disposable sheath according to these systems and
methods may prevent contact between the probe and any substance
making up the probe's environment. For example, a probe may be used
to diagnose a tissue immersed in a fixation solution which may have
a damaging effect on the probe if it were to contact the probe. A
disposable sheath may be used to prevent contact between the probe
and the inimical environment. A probe used in industrial settings
may be placed in various environments where contact between the
probe and a feature of the environment might be damaging to the
probe or might interfere with the probe's accuracy. A disposable
sheath as disclosed herein may be used to protect the probe from
such contact. Furthermore, such a disposable sheath may also
comprise a single-use mechanism whereby the single use of the
disposable sheath is assured. A single-use mechanism may include an
affixation mechanism whereby the barrier may be attached to the
probe and whereby, upon detachment, the barrier is prevented from
being re-used. The single-use mechanism may include an interlock
system that recognizes the proper position of the barrier on the
probe and that prevents the probe from being used without the
barrier in the proper position. Other embodiments of the single-use
mechanism may be envisioned by practitioners of ordinary skill in
the relevant arts.
[0186] FIG. 19A shows a perspective view and FIG. 19B shows a
cross-sectional view of an embodiment of an optical probe covered
with a biological isolation barrier or disposable sheath. FIG. 19A
shows generally an embodiment of an optical probe system 500
comprising an optical probe 506 covered with a disposable sheath
502. The sheath 502 is shown here as including two elements, a
rigid distal optical element 504 and a flexible thin sleeve 508
that may be gathered or wrapped at different locations on the probe
506. The term distal, as applied herein to a medical device, is
understood to refer to that aspect of a device closest to the
target tissue being examined; the distal aspect of the device is
generally also furthest away from the operator. That aspect of the
medical device furthest from the target tissue is termed proximal;
the proximal portion of the device is generally also that aspect
closest to the operator. The probe 506 may consist of a cylindrical
body 510 containing certain optical elements, for example a CCD
(not shown) for imaging, or optical wave guides (not shown) to
facilitate transmission of excitation beams to target tissues and
the transmission back of responses from a target tissue to the main
console. Other shapes for the probe and its body may be readily
envisioned by those of ordinary skill in the art. In the depicted
embodiment, diagnostic signals are emitted and received through the
distalmost portion of the disposable sheath 502, here shown as
comprising the rigid distal optical element 504. The rigid distal
optical element 504 itself may be a hollow cylindrical structure
designed to mate with the distal end of the probe 506. The rigid
distal optical element 504 may have at its distal end an optical
window 514. As described further herein, the optical window 514 may
be fabricated in a plurality of shapes and may be provided with
additional optical properties.
[0187] The probe 506 may terminate proximally with a connector 518
that facilitates attachment of the probe 506 with a coupling 520
that provides an electromagnetic connection between the probe 506
and the main instrument console (not shown) of the diagnostic
system. In one embodiment, the connector 518 and the coupling 520
may have both optical and electrical signal terminations and
interconnections allowing for a remote data processing unit to be
used to analyze the raw data generated and accumulated by the
optical probe 506. The remote data processing and analysis units
may also be provided with appropriate displays to present
graphically the results of diagnostic tests carried out on a
patient, and further may be provided with input mechanisms whereby
additional data may be entered into the system pertaining, for
example, to the unique identification of the particular patient
being examined. The data processing facilities of the present
invention may furthermore be in communication with remote data
sources or databases to provide additional information or data sets
to be compared to the data entered into the diagnostic system in
real time or with time delay.
[0188] The sheath 502 may be provided with a proximal fastener 522
and a distal fastener 524 deployed on each side of the coupling 520
and the connector 518. The fasteners may be elastic bands, or
strings within the sheaths, or hook and loop type fasteners (e.g.,
Velcro.TM.), adhesive tapes or glues, or other mechanisms familiar
to ordinary practitioners in the relevant arts.
[0189] The rigid distal optical element 504 may be provided with an
internal ridge 528 that mates with an appropriate groove 544
channeled on the outer aspect of the distal portion of the probe
506. Mating the internal ridge 528 with the corresponding groove
may assure that the sheath 502 is affixed to the probe 506 in a
unique direction, thereby aligning an identifying marker 530 on the
sheath 502 with a reader (not shown) on the probe. FIG. 19B shows a
cross-section of the embodiment depicted in FIG. 19A taken at the
level indicated by the line X-X'. In FIG. 19B, an arrangement of
the optical probe 548 to the rigid optical distal element 542 of
the sheath is shown. In this figure, a tongue 540 is borne on the
inner aspect of the rigid optical distal element 542. A groove 544
is borne on the outer aspect of the probe 548. The insertion of the
tongue 540 in the groove 544 may align a marker 550 disposed on the
inner aspect of the rigid optical distal element 542 with a reader
552 disposed on the outer aspect of the optical probe 548. Other
types of aligning arrangements will be readily apparent to those
ordinary skilled practitioners in these arts, arrangements whereby
a particular alignment of sheath and probe is urged, thereby
permitting the alignment of other elements on the sheath with
corresponding elements on the probe.
[0190] In the depicted embodiment, a marker 530 is shown disposed
on the inner aspect of the rigid distal optical element 504 of the
sheath 506. It is understood that a variety of markers may be
contemplated without departing from the spirit and scope of the
claimed invention, and that a variety of sensors or receptors may
be disposed upon the probe that are adapted for recognizing the
data borne by the marker. In the illustrated embodiment, the marker
530 or the marker 550 is disposed on the edge of the optical
window. The markers 530 and 550 may be a serial number or any other
marker uniquely identifying the specific sheath used with a unique
patient. It is further understood that the markers 530 and 550 and
the reader may be disposed upon any convenient segment of the
sheath and the probe. In one embodiment, the marker may be placed
upon the sleeve so that its data are read into the optical system
prior to inserting the optical probe within the sleeve. In another
embodiment, the marker and the reader may each be positioned on the
lateral aspect of the sheath and the probe respectively. In another
embodiment, the side of the probe may be equipped with an infrared
light emitting diode and an infrared sensor and reflection from a
series of lines printed on the side of the sleeve (such as a bar
code system of marking), which are read by the sensor to identify
the specific sleeve's serial number. A variety of bar code based
markers and reader systems may be used, as will be appreciated by
artisans of ordinary skill in the relevant arts.
[0191] In operation, the markers 530 and 550 may be used to
identify the patient on whom the measurement was taken. This
specific identification number may be permanently stored in the
optical system main console as a number which if seen again by the
probe, will prohibit, or lock out the probe functions.
Alternatively, the data on the marker may be associated in a
database with data identifying the unique patient, so that the
probe bearing that marker may only be used with that particular
patient. In another embodiment, the reader may affect the state of
the data encoded on the marker so that the data are not readable
subsequently. If a probe reads a set of data from a sheath marker
before the probe may be used, the probe may then each time be
placed in contact with a fresh sheath whose data are available for
reading. The marker 530 on the sheath 508 may be read before the
use of the optical probe 508 and before the probe system 500 may be
positioned in contact with a patient's tissue. This may be
accomplished, for instance by requiring the probe to be armed as
"ready" for use in the patient prior to each measurement. In order
to arm the probe and make the probe ready for use, the operator
mounts the sheath upon the probe in the correct position and the
probe then interrogates the marker on the probe to compare the
identifying data contained therein with a database consisting of
all previously used identity numbers, to verify that the number is
indeed an unused number. If the probe system 500 determines that
the marker 530 on the sheath 506 bears previously unread data,
corresponding to a previously unused state, the probe may be armed
and be thereupon made ready for use. This ready state of the probe
may also depend upon the readiness of other system parameters as
well. A display integral with the controls of the system may then
show the cause for "unreadiness" of the probe. Conditions causing
unreadiness of the probe may include previous use of a sheath,
absence of a sheath, malposition of a sheath, mechanical problems
with a sheath or any other condition of the probe system 500 deemed
to interfere with its safe and effective use in the diagnosis of a
patient. The probe system 500 may include conventional circuits to
permit self-testing and self-diagnosing to ascertain the readiness
of various components and functions necessary for safe and
effective accomplishment of the diagnostic intervention. In another
embodiment, in lieu of markings that are optically read as
described above, an RFID (radio frequency identification device)
chip may embedded in each disposable sheath, to be read by an
appropriate transponder in the optical head. It should be clear
that other active semiconductor devices (typically powered by the
probing or querying beam from the transponder) may be used in this
manner as well. Furthermore, passive electromagnetically read
patterns providing coding are feasible as well and are included
within the scope of the present invention.
[0192] A marker on a sheath may also convey information to the
probe about the kind of use for which the sheath is intended. The
kind of sheath employed may be varied depending upon the type of
diagnostic information that is desired. For example, the
colposcopic probe may operate in three independent modalities, and
for each modality, a unique type of disposable sheath is best
suited for that function. The term "colposcopic probe" as used
herein refers to an optical probe system according to the present
invention used for the evaluation of the tissues of the cervix. In
a highly precise modality of use, a colposcopic probe may be used
by highly trained physicians as a device aiding in standard
colposcopy. A sheath employed with the probe as an aid to
colposcopy may be adapted for transmitting both natural images of
the relevant anatomy and signals according to these systems and
methods indicating the presence or absence of particular cervical
pathologies. The sheath may be adapted to the optimal performance
of these functions. The marker on the sheath may convey to the
probe information about the nature of the particular intended use
of the probe. Upon receiving this information, the probe may adjust
for performing the necessary functions.
[0193] In a different modality of use, a colposcopic probe may be
used to carry out "ASCUS Triage." ASCUS is an acronym understood in
the art to stand for "A typical Squamous Cells of Undetermined
Significance". In performing ASCUS triage, image generation of the
cervix is a less important function for the probe and thus another
type of disposable sheath would be used. The marker on the sheath
may inform the probe of the type of test, here ASCUS triage, to be
carried out so that the probe may be adjusted or calibrated
(typically automatically) for this specific function.
[0194] In a different modality of use, the probe may be employed as
a adjunct to the current "Pap Smear" test, intended to examine the
patient's cervix for cellular abnormalities that may require
subsequent detailed analysis, but not intended to provide a
diagnosis of the abnormalities detected. This use for the probe may
be a binary "pass/no pass" test, or a "yes/no" test, typically
carried on by personnel with relatively little medical training.
This use modality of the colposcopic probe may allow for screening
large populations of subjects; only those returning a result of
"yes" or "no pass" are directed to subsequent more detailed
examination by highly trained personnel. Here as well, a sheath
adapted for this screening function may bear a marker with data
"informing" the colposcopic probe of the specific function
("screening") that is going to be carried out, so that the probe
may be adjusted for that specific purpose.
[0195] In this example, the coding marker of the sheath may
identify the test for which the sheath is intended and may
communicate with the probe to ensure that its settings are
compatible with the intended function. If the sheath is used for an
unintended purpose, the interaction of the marker and the reader
may interfere with the activation of the probe, as described above.
A marker may simultaneously bear additional information about the
specific sheath, so that a single use for the sheath may be
ensured, as previously described.
[0196] FIG. 20A shows a lateral view of an embodiment of a
disposable sheath illustrating certain features. In this
illustration a coded area 570 is shown as part of a sheath
apparatus 572. In certain embodiments, the coded area may be a bar
code borne on the inner aspect of the flexible sheath. Other
arrangements may be envisioned whereby the coded area 570 would be
incorporated in the structure of a sheath 578 itself, or displayed
in any other way to make it accessible to a sensor apparatus (not
shown) of the probe. In yet another embodiment, only a sensor is
used and the reading is accomplished by detecting changes in
ambient light reaching the sensor as the sleeve is passed over the
side of the probe, and the coded area 570 imparts such light
modulation then translated into a unique identifier of the specific
sheath used.
[0197] FIG. 20B depicts an embodiment where the sheath apparatus
572 includes a flexible sheath 578 to which a residual stress curl
has been imparted, so that the flexible sheath 578 may be packaged
in the form of a toroid. FIG. 20B further illustrates an embodiment
where the rigid distal element 574 is attached to the flexible
sheath 578, and the flexible sheath 578 may be uncurled to cover
the probe (not shown). In this embodiment, the rigid distal element
574 is first adjusted on the distal end 584 of the optical probe,
using, for instance, two or more indexing pins 580 which fit into
grooves 582 shown with dashed lines in the illustration. The
grooves 582 may also serve to fasten the rigid distal element 574
to the distal end 584 of the optical probe in a bayonet like
fashion. After the elements are secured, the curled sleeve 578 may
be rolled back over the probe. At the conclusion of the procedure,
the sleeve 578 may be rolled back to its original toroidal shape,
assuring that no external surface of the sleeve comes in contact
with the surface of the probe. The indexing grooves 582 and mating
pins 580 also ensure the alignment of the optical path of the
sheath with that of the probe. This arrangement may further align
the optical path of the sheath with that of the probe, and may
serve to align a marker on the sheath with a sensor on the probe as
previously described.
[0198] In another embodiment, shown in FIG. 20A, the flexible
sheath 578, initially packaged in a rolled-up state to be unrolled
over the probe, may be provided at its proximal end with a hollow
termination 588 within which a string 590 is positioned. After
deployment of the sheath 578 onto the optical probe, the string 590
may be pulled tight, to close the proximal end of the sheath and
thereby to ensure that the sheath apparatus 572 does not become
detached from the optical probe during the procedure. In a variant
of this embodiment, the string 590 may be provided with periodic
protrusions or beads 592 that act as ratchets or locks that hold
the cinched purse-string in position. In another variant of this
embodiment, the distal edge of the hollow termination 588 may be
either perforated or weakened along a line of weakness 594.
According to this embodiment, the string 590 is pulled in the
direction of its axis to close the proximal end of the sheath 578,
but after the procedure is completed the string 590 is pulled
strongly in a direction perpendicular to its axis, thus causing
breakage and release of the proximal hollow termination, permitting
the sheath 578 to be rolled distally over the probe. In this
embodiment, the string 590 may be fastened to one end of the hollow
termination 588 so that pulling and breaking the string 590 through
the hollow termination 588 both breaks the hollow termination 588
and provides a point from which the sheath 578 may be pulled off
the probe without contaminating the probe's external surface.
[0199] FIG. 20A further shows that the disposable sheath apparatus
572 is suitable for an optical colposcopic probe wherein the sheath
578 may be attached to the probe by one or more mating elements 568
that may fit within one or more grooves 566 on the probe. According
to one embodiment of these systems and methods, the sheath may be
pulled over the probe in a manner whereby one or more mating
elements 568 disposed on the inner aspect of the sheath 578 may be
aligned over a matching set of grooves 566 on the outer aspect of
the probe. The user thereupon exerts external pressure upon the
mating element 568 to press fit it into the corresponding groove
566. At the end of the procedure, the mating element 568 is
disengaged so that the sheath may be removed and discarded. In some
embodiments, the cross section of the mating element 568 may be
made asymmetric so that pulling it out of its groove causes the
sheath 578 to tear on the weaker side of the mating element along a
tear line 598. This would permit easier removal of the sheath and
would further ensure that no reuse of the disposable sheath would
occur.
[0200] In FIGS. 21A-F are shown various projections of a an
embodiment of an optical probe, 600, and in particular, an
embodiment adapted for use in examining the cervix uteri. Features
of an embodiment of an optical probe adapted for this use have been
disclosed elsewhere herein.
[0201] Specifically, FIG. 21A is a posterior view of an optical
probe system 600 showing the probe handle 604 with a switch 610
visible distally along the handle 604 and with a connector assembly
608 deployed at the proximal end of the handle. It is understood
that the handle 604 may be designed ergonomically to permit secure
grasping by the operator, and it may further be adapted for the
anatomic region being examined. The handle 604 may also bear within
it or on its surface components of the optical probe system 600
related to the specific diagnostic functions of the probe system
600 itself FIG. 21B shows a lateral view of the optical probe
system 600 showing the angulation 624 of the device distal to the
handle 604 to facilitate anatomic access of the distal optical head
602 to the cervix. In this figure, the optical probe itself is
covered by a tightly adherent sheath 618 shown to be cut away
before providing coverage for the distal optical head 602 of the
probe 600. In the illustrated embodiment, an affixation mechanism
612 is shown on the probe, comprising a protrusion and a groove
into which the protrusion may be inserted. In one embodiment, the
protrusion may be provided on the inner aspect of the sheath 618
while the groove is provided on the outer aspect of the probe; the
opposite arrangement is also possible. Either arrangement of groove
and protrusion may comprise an affixation mechanism 612 that
permits the alignment of the sheath 618 on the probe in a
particular predetermined orientation.
[0202] FIG. 21C shows in more detail a switch 610 here shown to be
located on the posterior aspect of the optical probe system 600 at
the angulation of the device. The position of the switch 610 is
selected for ease of use by the operator and may assume any
appropriate position on the device. The presence of a switch 610 is
optional, and other mechanisms for operating the optical probe
system 600 may be envisioned by those of ordinary skill in these
arts. Without being limiting, examples for such a switching
mechanism may include a floor switch or a voice activation
system.
[0203] FIG. 21D shows a cross section of the probe handle 604 taken
along the line X-X', illustrating the oval shape 620 of the handle
604 in the depicted embodiment. This oval shape 620 has the
advantage of facilitating handling of the device and rendering more
consistent the orientation of the probe with respect to the
cervix.
[0204] FIG. 21E shows a top view of an embodiment of an optical
probe system 600. This figure depicts the body 622 of the probe
distal to the angulation (not shown), with the distal optical head
602 located distal thereto. A switch 610 is positioned on the body
622 for convenient operator access.
[0205] FIG. 21F shows an anterior view of an embodiment of an
optical probe system 600, providing an anterior view of the distal
optical head 602. From this perspective, a ring of optical fibers
628 may be seen disposed along the circumference of the distal
optical head. The ring of optical fibers 628 is operably connected
in certain embodiments to structures of the disposable sheath (not
shown) to permit the transmission of light from the ring of optical
fibers 628 through the disposable sheath to reach the tissues of
the patient being examined. This figure further depicts an
affixation system 614 here shown as a linear arrangement disposed
along the anterior aspect of the probe handle 604. It is understood
that a plurality of other affixation systems are encompassed as
embodiments of the claimed invention, and certain of these systems
may be readily envisioned by those of ordinary skill in the
art.
[0206] In FIG. 22, an embodiment of an optical probe system 670 is
shown schematically. The system includes an optical probe 650 and a
protective sheath 652. In the depicted embodiment, the protective
sheath 652 may be formed as a composite of two elements, a frontal
optical quality element 654 and a thin flexible sleeve 658. In
certain embodiments, the protective sheath 652 is disposable and is
intended for a single use. Various mechanisms of attachment between
the sheath 652 and the probe 650 are contemplated by the systems
and methods disclosed herein. For example, in one embodiment, the
flexible sleeve 658 may be provided with a series of internal
protrusions 660 that may be press fit into corresponding slots 666
on the probe 650. Other mechanisms of attachment may be envisioned
by practitioners of ordinary skill in the relevant arts. The
optical quality element 654 may bear at its distal end a window
662. The optical quality element 654 may bear an affixation
mechanism for securing it relative to the distal end of the probe
650. In certain embodiments the window 662 may be flat. In other
embodiments, the window 662 may be shaped to act as an active
optical component integral to the optics of the optical probe
system 670. In yet other embodiments, the window 662 or the optical
quality element 654 may be segmented so that a portion of the
structure is flat (and thus optically passive) while other portions
may be curved, forming, for example, lens segments. Such
embodiments may permit various segments to perform different
optical functions as part of an overall optical probe system 670.
In certain embodiments, the distal optical quality element 654 may
be shaped as a hollow cylinder that mates with a comparably
structured optical head of the probe. It is desirable for the
distal part of the probe and the optical quality element 654 of the
sheath 652 to be similarly shaped so that a close fit between the
two may be achieved. The shape of these structures in cross-section
may be cylindrical, oval or any shape adapted to carrying out the
functions of the optical probe system 670 or adapted to carrying
out a diagnostic evaluation of a particular anatomic site. The
optical quality element 652 may be molded or cast from an optical
plastic, such as PMMA, polystyrene or polycarbonate. These
materials may be used to form the window 662 while other materials
are used to form the optical quality element 652. PMMA is a
particularly advantageous material for these constructions because
it has minimal fluorescence response when illuminated with the UV
excitation beam.
[0207] FIGS. 23A-D show cross-sectional diagrams of embodiments of
attachments by which a flexible part of a protective sheath may be
affixed to a rigid distal part.
[0208] FIG. 23A shows an end piece 700 of a protective sheath
configured as a hollow structure closed at its distal end with a
distal optical window 702. A thin flexible sheath 704 is shown
fastened to the external part of the proximal end of the end piece
700 by a fastening ring 708 that is disposed circumferentially
around the end piece 700. This fastening ring 708 may be "press
fit" onto the proximal end locking the flexible sheath 704 between
it and the end piece 700. Other arrangements may also be
envisioned. For example, a thin threaded area may be provided on
the inner side of the fastening ring 708 that mates with an
opposing thread on the end piece 700, locking an edge of the
flexible sheath 704 therebetween.
[0209] FIG. 23B shows another embodiment of an optical end piece
710 terminated with a lens structure 712 bearing an inner flat
surface 706. The illustrated optical end piece 710 is configured as
a hollow structure shaped to mate with the distal end of the
optical probe. In this embodiment the fastening of the of the
flexible sheath 716 to the optical end piece 710 is achieved with a
toroidal ring 714 that is adapted to fit within a circular
concavity 718 around the circumference of the exterior aspect of
the optical end piece 710, capturing the edge of the flexible
sheath 716 therebetween.
[0210] FIG. 23C shows an embodiment of the sheath system in which a
rigid optical element 720 is fastened to a flexible sheath 722 with
an appropriate adhesive 724. An appropriate adhesive may comprise
various chemical compositions, for example, any of a variety of
cyano-acrylate compounds that are biocompatible. Other adhesive
compounds may be envisioned by practitioners in the relevant arts.
This figure further shows a lens 728 that may serve as the
objective for the optical probe.
[0211] FIG. 23D shows a cross-sectional view of another embodiment
of the distal end of the disposable sheath of the present
invention. In this embodiment, the optical probe 726 is provided
with illuminating fibers 736 arranged circumferentially and
abutting the circular proximal end 732 of the distal optical
element 730 of the disposable sheath system. The bundle of
illuminating fibers 736 may be arranged in a ring within the
optical probe 726 to emerge and terminate at a correlative area of
the optical element 730 of the disposable sheath system. In one
embodiment, the illuminating fibers 736 may terminate at a
circumferential structure on the distal optical element 730 where
the proximal flexible portion (not shown) of the disposable sheath
system is affixed to the distal optical element 730. In one
embodiment, the wall thickness of the distal optical element 730
may be fairly thick (between 0.5 mm and 2.0 mm), so that a wall 734
is formed that may act as an optical waveguide to transmit light
emitted from the illuminating fibers 736 to the distal end of the
distal optical element 730. The wall 734 of the distal optical
element 730 ends as a toroidal segment 738 of an optical waveguide
which acts to direct the light onto the target tissues for better
visualization. FIG. 23D shows a configuration adapted for the
evaluation of the cervix, although other shapes may be envisioned
that would usefully conform to various other anatomical regions.
The end piece 740 of the distal optical element 730 may be shaped
to achieve various optical purposes, for example, acting as an
objective for the probe's optical assembly. In the depicted
embodiment, a space 742 is shown that may contain a bead or other
delivery apparatus for dispensing a fluid. The fluid is released by
the mating of the distal part of the probe with the distal optical
element 730 of the sheath system. The fluid may flow between the
distal part of the probe and the inner aspect of the distal optical
element 730. In one embodiment, the fluid may have an index of
refraction matching that of the elements in the probe and the end
piece 740. In one embodiment, this space 742 may occupy the top
half of the inner distal circumference of the distal optical
element 730. A bead or other container residing in the space 742
may be caused to to break and discharge its fluid, which then
spread downward by capillary forces to fill the space between the
inner aspect of the end piece 740 and the distal end of the optical
probe. Other dispensation systems for a fluid may be readily
envisioned. The presence of a fluid between these two components
may serve a variety of optical functions, for example, reducing
sharply any reflections from the surfaces of the end piece 740.
Other functions for the fluid may be envisioned by ordinary
practitioners in these arts. One advantage of delivering a fluid to
flow between the optical prove and the distal optical element is
the prevention of reuse of the disposable sheath, because the fluid
necessary for the proper functioning of the optical probe system is
discharged from its reservoir upon the mating of a probe with a
sheath, and the fluid may therefore only be used once, with the
mating of a specific sheath with the probe.
[0212] FIG. 24 depicts an embodiment of a disposable sheath 800
provided with a flexible heat shrinkable sleeve 802. In one
embodiment, the shrinkable sleeve 802 may be treated with a heat
source such as a hair drier after being placed upon an optical
probe, thereby to shrink it. In another embodiment, a resistor
pattern 804 may be placed on the disposable sheath 800, for example
by silk screening. With a resistor pattern in place, the sheath 800
may be treated by passing a current into a connector 808 for a
short period of time, thereby heating the sheath 800 and causing
its shrinkage. Shrink-fitting the sheath 800 to the probe after
positioning it thereupon may stabilize the sheath with respect to
the underlying probe. In this way, any necessary alignments between
the sheath 800 and the probe may be established and maintained.
Shrink-fitting may also require a tearing or other destruction of
the sheath 800 to remove it from the probe at the end of a
procedure. A sheath 800 destructively removed may subsequently be
unusable.
[0213] In FIG. 25A is shown yet another embodiment of a disposable
sheath 850 according to the present invention. This embodiment
provides a configuration of its distal optical element 852 adapted
for evaluating pathologies of the endocervix. It is understood
that, since the cervical os is typically closed, examination of its
inner wall is not possible with direct surface viewing. The
illustrated embodiment provides an optical extension 854 for the
distal optical element 852, said optical extension being adapted
for penetrating into the endocervix to permit the acquisition of
diagnostic data for the tissues lining the endocervix. The optical
extension 854 terminates in a distal tip 858 comprising a tapered
end capable of penetrating the usually closed cervical os and
further comprising an optical system adapted for visualization of
the lateral endocervical walls. Certain structures in the optical
extension 854 are shown in more detail in FIG. 25B. FIG. 25B shows
the distal tip 858 of the optical extension with its distalmost
tapered end 862. An optical system 860 within the distal tip 858
comprises a faceted and mirrored cone 864. The cone 864 has a half
angle of 45 degrees. Thus a light beam 866, as shown in FIG. 25A,
impinging on one of the facets of the cone 864 is reflected at a 90
degree angle to the incident light and is thus emitted laterally
from the distal tip 858, as shown by the arrows at 868. In one
embodiment, the number of facets on the faceted cone 864
corresponds to the number of excitation fibers used for the
procedure, a number that typically is less than the number of
fibers used for examining the entire surface of the cervix. It may
be desirable to add an additional objective 870 to focus the
excitation light beams 866 appropriately on the optical system 860
of the optical extension 854: Furthermore, without departing from
the scope of the disclosed invention, skilled practitioners in the
relevant arts may readily envision other optical systems for
directing the illuminating light to the endocervical tissues and
for collecting the light emanating therefrom.
[0214] In one method of operation according to these systems and
methods, the disposable sheath 850 may be mounted on an optical
probe adapted for examination of the cervix uteri. If a disposable
sheath 850 is selected that is adapted for endocervical
examinations, a marker (not shown) on that sheath 850 may be read
by the optical probe. Data from that marker may be input into the
probe system, operating to activate a selected number of excitation
fibers (not shown). In one embodiment, the activated fibers may
provide UV light for excitation. In one embodiment, the excitation
fibers may be activated sequentially, or may be activated as
"opposing pairs" to assure that fluorescence responses from
different spots on the wall of the endocervix are not interfering
with each other. Optical responses from the illuminated tissues may
be collected along the same optical path traced by the excitation
beams, except that the responses are much broader (in essence
lambertian in nature). In this embodiment, the collection optics
for the response may be separate from the excitation optics, or may
be part of the same apparatus as the excitation optics. When
spatial discrimination of an endocervical lesion is less important,
the mirrored cone 864 may be a simple conical structure without
facets.
[0215] Those skilled in the art will know or be able to ascertain
using no more than routine experimentation, many equivalents to the
embodiments and practices described herein. For example, the
systems and methods described herein may be employed with probes
being disposed in body canals, blood vessels, ducts and other body
passages. Additionally, both the probe and sheath may have shapes
other than those shown in the depicted embodiments, and may be made
of any suitable materials. Further, other embodiments may be
realized, wherein the sheath may be formed from one or more than
one components adapted to the optical functions of the probe and
the anatomic location where it will be used. Other shapes of the
sheath may be envisioned that fit the probe appropriately. A number
of mechanisms may be constructed which lend themselves to limiting
sheath use to a single use, some of which have been illustrated
herein. Other mechanisms for ensuring a single use of the sheath
may include affixation mechanisms, marker and reader mechanisms,
fluid dispensing mechanisms, tearing and breaking mechanisms and
other mechanisms adapted for this purpose. Such mechanisms will be
familiar to those of ordinary skill in the relevant arts.
[0216] Furthermore, it is understood that the systems and methods
of the present invention may collect data or may relate to data
pertaining to the examination procedure itself. The system
according to the present invention may measure and record
information about the duration of the procedure, the amount of
energy or other consumable supplies utilized to perform the
procedure, the number of measurements taken during the procedure,
or any other features of the procedure of significance
alternatively, the systems and methods of the present invention may
interface with a database wherein such data are stored. In one
embodiment, the procedure and its duration may be tallied and
correlated with patient information so that an appropriate bill for
the service may be constructed. Billing information may be entered
into a database that can then be accessed by the system to produce
a bill for the particular procedure. In certain embodiments, the
billing information may include a diagnostic or a procedural code
for categorizing the procedure so that a bill bearing this
information may be generated that will then be associated with a
schedule of predetermined fees. Diagnosis according to ICD-9 codes
and procedural terminology according to CPT codes are well-known in
the art. Other codes or categories may be used for organizing a
patient's billing information, so that each procedure according to
these systems and methods will generate an accurate bill. Billing
information may differ from one patient to the next according to
the fee schedules for various managed care organizations and
third-party payors. In one embodiment, the systems and methods of
the present information may comprise the entry of billing
information for a particular patient into a database. The billing
information may then be correlated with data about the procedure
itself or with data about the diagnosis produced in order to
generate an accurate bill.
[0217] Although the embodiments described herein relate to the
application of these systems and methods to the diagnosis and
treatment of medical conditions and to the delivery of health care
services, it is understood that these systems and methods may be
directed to the examination of any target, and that these systems
and methods may furthermore be correlated with systems for
recording data that identifies characteristics of the target so
that outcomes of the examination may be usefully stored in relation
to other data pertaining to the target.
[0218] Accordingly, it will be understood that the invention may be
realized by many different systems that include a barrier or a
sheath, and is not to be limited to the embodiments disclosed
herein, but is to be understood from the following claims, which
are to be interpreted as broadly as allowed under the law.
* * * * *