U.S. patent application number 13/922237 was filed with the patent office on 2014-01-09 for systems and methods for projecting hyperspectral images.
This patent application is currently assigned to Hypermed Imaging, Inc.. The applicant listed for this patent is Hypermed Imaging, Inc.. Invention is credited to Derek Brand, Jenny Freeman, Michael Hopmeier, Svetlana Panasyuk, Kevin Schomacker.
Application Number | 20140012140 13/922237 |
Document ID | / |
Family ID | 38620364 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140012140 |
Kind Code |
A1 |
Freeman; Jenny ; et
al. |
January 9, 2014 |
Systems and Methods for Projecting Hyperspectral Images
Abstract
The invention is directed to methods and systems of
hyperspectral and multispectral imaging of medical tissues. In
particular, the invention is directed to new devices, tools and
processes for the detection and evaluation of diseases and
disorders such as, but not limited to diabetes and peripheral
vascular disease and cancer, that incorporate hyperspectral or
multispectral imaging.
Inventors: |
Freeman; Jenny; (Weston,
MA) ; Panasyuk; Svetlana; (Lexington, MA) ;
Hopmeier; Michael; (Mary Esther, FL) ; Schomacker;
Kevin; (Wayland, MA) ; Brand; Derek; (New
York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hypermed Imaging, Inc. |
Greenwich |
CT |
US |
|
|
Assignee: |
Hypermed Imaging, Inc.
Greenwich
CT
|
Family ID: |
38620364 |
Appl. No.: |
13/922237 |
Filed: |
June 19, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11692131 |
Mar 27, 2007 |
8548570 |
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13922237 |
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11689783 |
Mar 22, 2007 |
8224425 |
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11692131 |
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11396941 |
Apr 4, 2006 |
8374682 |
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11689783 |
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11288410 |
Nov 29, 2005 |
8320996 |
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11396941 |
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11396941 |
Apr 4, 2006 |
8374682 |
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11288410 |
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60785977 |
Mar 27, 2006 |
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60784476 |
Mar 22, 2006 |
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60667677 |
Apr 4, 2005 |
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60785977 |
Mar 27, 2006 |
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60631135 |
Nov 29, 2004 |
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60667678 |
Apr 4, 2005 |
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60732146 |
Nov 2, 2005 |
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Current U.S.
Class: |
600/476 ;
600/407 |
Current CPC
Class: |
A61B 5/445 20130101;
A61B 5/742 20130101; A61B 5/441 20130101; A61B 5/0075 20130101;
G01N 21/314 20130101; A61B 5/14551 20130101; A61B 5/412 20130101;
G01N 21/359 20130101; A61B 5/0059 20130101 |
Class at
Publication: |
600/476 ;
600/407 |
International
Class: |
A61B 5/00 20060101
A61B005/00 |
Claims
1-29. (canceled)
30. A method of displaying information about a region of interest
of a subject, the method comprising: a) resolving light obtained
from the region of interest into a plurality of component spectral
bands; b) constructing a hyperspectral image from the plurality of
component spectral bands; and c) projecting the hyperspectral image
onto the subject.
31. The method of claim 30, the method further comprising applying
a fiducial label to the subject and wherein the projecting
comprises co-registering the hyperspectral image with the fiducial
label.
32. The method of claim 30, wherein the projecting comprises using
information from a calibration pad that includes a diffusely
reflective surface that quantifies an intensity of illumination at
each wavelength represented by the plurality of component spectral
bands to co-register the hyperspectral image with the subject.
33. The method of claim 30, wherein the hyperspectral image is a
pseudo color hyperspectral image.
34. The method of claim 33, wherein the pseudo color hyperspectral
image allows discrimination between tissue types.
35. The method of claim 34, wherein the pseudo color hyperspectral
image allows discrimination of a superficial blood vessel.
36. The method of claim 30, wherein a wavelength range of each
respective component spectral band in the plurality of component
spectral bands is adjacent to the wavelength range of another
component spectral band in the plurality of component spectral
bands.
37. The method of claim 30, wherein each respective component
spectral band in the plurality of component spectral bands has a
bandwidth of less than 50 nm.
38. The method of claim 30, wherein each respective component
spectral band in the plurality of component spectral bands has a
bandwidth that is between 10 nm and 40 nm.
39. The method of claim 30, wherein each respective component
spectral band in the plurality of component spectral bands has a
bandwidth that is between 10 nm and 15 nm.
40. The method of claim 30, wherein each respective component
spectral band in the plurality of component spectral bands has a
bandwidth that is between 5 nm and 12 nm.
41. The method of claim 30, wherein the region of interest of the
subject is a portion of the skin of the subject.
42. The method of claim 30 wherein the light obtained from the
region of interest is in the visible range.
43. The method of claim 30 wherein the light obtained from the
region of interest is in the near-infrared range.
44. The method of claim 30, wherein the region of interest is a
tissue of the subject.
45. The method of claim 44, wherein the tissue comprises an ulcer,
callus, intact skin, hematoma, or superficial blood vessel.
46. An apparatus for displaying information about a region of
interest of a subject, the apparatus comprising: a) a spectral
imager that is configured to resolve light obtained from the region
of interest of the subject into a plurality of component spectral
bands; b) a computer system comprising memory and a processor, the
computer system electrically coupled to the spectral imager, the
memory storing non-transitory instructions for constructing a
hyperspectral image from the plurality of component spectral bands;
and c) a projector, electrically coupled to the computer system,
that is configured to project the hyperspectral image onto the skin
of the subject.
47. The apparatus of claim 46, wherein the apparatus is configured
to co-register the hyperspectral image with a fiducial label on the
subject.
48. The apparatus of claim 46, wherein the apparatus is configured
to use information from a calibration pad that includes a diffusely
reflective surface that quantifies an intensity of illumination at
each wavelength represented by the plurality of component spectral
bands to co-register the hyperspectral image with the subject.
49. The apparatus of claim 46, wherein the hyperspectral image is a
pseudo color hyperspectral image.
50. The apparatus of claim 49, wherein the pseudo color
hyperspectral image allows discrimination between tissue types.
51. The apparatus of claim 50, wherein the pseudo color
hyperspectral image allows discrimination of a superficial blood
vessel.
52. The apparatus of claim 46, wherein a wavelength range of each
respective component spectral band in the plurality of component
spectral bands is adjacent to the wavelength range of another
component spectral band in the plurality of component spectral
bands.
53. The apparatus of claim 46, wherein each respective component
spectral band in the plurality of spectral bands has a bandwidth of
less than 50 nm.
54. The apparatus of claim 46, wherein each respective component
spectral band in the plurality of component spectral bands has a
bandwidth that is between 10 nm and 40 nm.
55. The apparatus of claim 46, wherein each respective component
spectral band in the plurality of component spectral bands has a
bandwidth that is between 10 nm and 15 nm.
56. The apparatus of claim 46, wherein each respective component
spectral band in the plurality of component spectral bands has a
bandwidth that is between 5 nm and 12 nm.
57. The apparatus of claim 46, the memory further storing
non-transitory instructions for displaying the hyperspectral image
on a computer screen.
58. The apparatus of claim 46, wherein the region of interest of
the subject is a portion of the skin of the subject.
59. The apparatus of claim 46, wherein the light obtained from the
region of interest is in the visible range.
60. The apparatus of claim 46, wherein the light obtained from the
region of interest is in the near-infrared range.
61. The apparatus of claim 46, wherein the region of interest is a
tissue of the subject.
62. The apparatus of claim 61, wherein the tissue comprises an
ulcer, callus, intact skin, hematoma, or superficial blood vessel.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 11/692,131 entitled "Hyperspectral Imaging of
Angiogenesis, filed Mar. 27, 2007, which claims priority to U.S.
Provisional Application No. 60/785,977 entitled Hyperspectral
Imaging of Angiogenesis, filed Mar. 27, 2006, and is a continuation
in part of U.S. application Ser. No. 11/689,783 entitled
Hyperspectral Imaging in Diabetes and Peripheral Vascular Disease,
filed Mar. 22, 2007, which claims priority to U.S. Provisional
Patent Application No. 60/784,476 entitled Combinations of
Hyperspectral Imaging Methods with Other Evaluation Methods, filed
Mar. 22, 2006, and is a continuation in part of U.S. application
Ser. No. 11/396,941 entitled Hyperspectral Imaging in Diabetes and
Peripheral Vascular Disease filed Apr. 4, 2006, which claims
priority to U.S. Provisional Application No. 60/667,677 entitled
Hyperspectral Imaging in Diabetes, filed Apr. 4, 2005, and U.S.
Provisional Application No. 60/785,977 entitled Hyperspectral
Imaging of Angiogenesis, filed Mar. 27, 2006. U.S. patent
application Ser. No. 11/692,131 is also a continuation in part to
U.S. application Ser. No. 11/288,410 entitled Medical Hyperspectral
Imaging for Evaluation of Tissue and Tumor filed Nov. 29, 2005,
which claims priority to U.S. Provisional Application No.
60/631,135 entitled Hyperspectral Imaging in Medical Applications,
filed Nov. 29, 2004, U.S. Provisional Application No. 60/667,678
entitled Hyperspectral Imaging in Breast Cancer, filed on Apr. 4,
2005, and U.S. Provisional Application No. 60/732,146 entitled
Hyperspectral Analysis for the Detection of Lymphoma, filed Nov. 2,
2005. All of these provisional and non-provisional applications are
hereby incorporated by reference.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The invention is directed to methods and systems of
hyperspectral and multispectral imaging of biological and medical
tissues. In particular, the invention is directed to new devices,
tools and processes for the detection and evaluation of diseases
and disorders such as diabetes and peripheral vascular disease that
are amenable to diagnosis using hyperspectral/multispectral
imaging.
[0004] 2. Background of the Invention
[0005] Diabetes afflicts an estimated 194 million people worldwide,
affecting 7.9% of Americans (over 21 million people) and 7.8% of
Europeans. Between 85% and 95% of all diabetics suffer from Type 2
diabetes, although nearly 5 million people worldwide suffer from
Type 1 diabetes, affecting an estimated 1.27 million people in
Europe and another 1.04 million people in the United States.sup.1.
Both Type 1 and Type 2 diabetic patients are at higher risk for a
wide array of complications including heart disease, kidney disease
(e.g. nephropathy), ocular diseases (e.g. glaucoma), and neuropathy
and nerve damages to name a few.sup.2. The feet of diabetic
patients are at risk for a wide array of complications, which are
discussed below. Problems with the foot that affect the ambulatory
nature of the patient are not only important from the standpoint of
physical risk, but also convey an emotional risk as well, as these
problems disrupt the fundamental independence of the patient by
limiting his or her ability to walk.
[0006] Peripheral arterial disease (PAD) affects primarily people
older than 55. There are currently 59.3 million Americans older
than 55, and over 12 million of them have symptomatic peripheral
vascular disease. It is estimated that only 20% of all patients
with PAD have been diagnosed at this time. This represents a
dramatically underpenetrated market. Although pharmacologic
treatments for PAD have traditionally been poor, 2.1 million
nevertheless receive pharmacologic treatment for the symptoms of
PAD, and current diagnostic tests are not considered to be very
sensitive indicators of disease progression or response to therapy.
Additionally, 443,000 patients undergo vascular procedures such as
peripheral arterial bypass surgery (100,000) or peripheral
angioplasty (343,000) annually and are candidates for pre and post
surgical testing. One difficulty in diagnosing PAD is that in the
general population, only about 10% of persons with PAD experience
classic symptoms of intermittent claudication. About 40% of
patients do not complain of leg pain, while the remaining 50% have
leg symptoms which differ from classic claudication.
[0007] Relying on medical history and physical examination alone is
unsatisfactory. In one study, 44 percent of PAD diagnoses were
false positive and 19 percent were false negative when medical
history and physical examination alone were used..sup.3 For this
reason, physicians have looked for other means to help in providing
diagnosis. As in the case of diabetic foot disease, current
technologies have fallen short. Nonetheless, patients are
frequently sent to peripheral vascular laboratories for
non-invasive studies. While the test results are known to be
inaccurate, these results do provide some additional information to
physicians for assistance in diagnosis or treatment decisions.
[0008] Another problem faced by physicians is disease of the
peripheral veins. Venous occlusive disease due to incompetent
valves in veins designed to prevent backflow and deep vein
thrombosis results in venous congestion and eventually stasis
ulcers. Approximately 70% of leg ulcers are due to venous
occlusion. Many of these ulcers are found at the medial malleolus.
The foot is generally swollen and the skin near the ulcer site is
brownish in appearance.
Pathology
[0009] Diabetic feet are at risk for a wide range of pathologies,
including microcirculatory changes, peripheral vascular disease,
ulceration, infection, deep tissue destruction and metabolic
complications. The development of an ulcer in the diabetic foot is
commonly a result of a break in the barrier between the dermis of
the skin and the subcutaneous fat that cushions the foot during
ambulation. This, in turn, can lead to increased pressure on the
dermis, resulting in tissue ischemia and eventual death, and
ultimately result in an ulcer..sup.4 There are a number of factors
that weigh heavily in the process of ulceration.sup.5--affecting
different aspects of the foot--that lead to a combination of
effects that greatly increase the risk of ulceration:.sup.6 [0010]
Neuropathy--Results in a loss of protective sensation in the foot,
exposing patients to undue, sudden or repetitive stress. Can cause
a lack of awareness of damage to the foot as it be occurs and
physical defects and deformities.sup.7 which lead to even greater
physical stresses on the foot. It can also lead to increased risk
of cracking and the development of fissures in calluses, creating a
potential entry for bacteria and increased risk of infection..sup.8
[0011] Microcirculatory Changes--Often seen in association with
hyperglycemic damage..sup.9 Functional abnormalities occur at
several levels, including hyaline basement membrane thickening and
capillary leakage. On a histologic level, it is well known that
diabetes causes a thickening of the endothelial basement membrane
which in turn may lead to impaired endothelial cell function.
[0012] Musculoskeletal Abnormalities--Include altered foot
mechanics, limited joint mobility, and bony deformities, and can
lead to harmful changes in biomechanics and gait. This increases
pressures associated with various regions of the foot. Alteration
or atrophy of fat pads from increased pressure can lead to skin
loss or callus, both of which increase the risk of ulceration by
two orders of magnitude. [0013] Peripheral Vascular Disease--Caused
by atherosclerotic obstruction of large vessels resulting in
arterial insufficiency.sup.10 is common in the elderly populations
and is yet more common and severe in diabetics..sup.11 Diabetics
may develop atherosclerotic disease of large-sized and medium-sized
arteries, however, significant atherosclerotic disease of the
infrapopliteal segments is particularly common. The reason for this
is thought to result from a number of metabolic abnormalities in
diabetics, including high LDL and VLDL levels, elevated plasma von
Willebrand factor, inhibition of prostacyclin synthesis, elevated
plasma fibrinogen levels, and increased platelet adhesiveness.
[0014] Venous Disease--Caused by incompetent valves controlling
backflow between the deep veins and the more superficial veins or
thrombosis of the deep veins. Venous occlusions are typically
observed in the elderly who typically presented with swollen lower
extremities and foot ulcers typically at the medial malleolus.
[0015] Previous studies have shown that a foot ulcer precedes
roughly 85% of all lower extremity amputations in diabetic
patients.sup.12, 13 and that 15% of all diabetic patients will
develop a foot ulcer during the course of their lifetimes..sup.14
More than 88,000 amputations performed annually on
diabetics,.sup.15 and roughly an additional 30,000 amputations are
performed on nondiabetics, mostly related to peripheral vascular
disease. Estimations have shown that between 2-6% of diabetic
patients will develop a foot ulcer every year.sup.13, 16 and that
the attributable cost for an adult male between 40 and 65 years old
is over $27,000 (1995 US dollars) for the two years after diagnosis
of the foot ulcer..sup.16 In conjunction with the increased total
costs of care, Ramsey et al showed that diabetic patients incurred
more visits to the emergency room (more than twice as many as
control patients), more outpatient hospital visits (between
2.times. and 3.times. as many as control subjects) and more
inpatient hospital days (between 3.times. and 4.times. as many as
control patients) during the course of an average year.
[0016] Foot pathology is major source of morbidity among diabetics
and is a leading cause of hospitalization. The infected and/or
ischemic diabetic foot ulcer accounts for about 25% of all hospital
days among people with diabetes, and the costs of foot disorder
diagnosis and management are estimated at several billion dollars
annually..sup.16, 17
Current Diagnostic Procedures
[0017] The first step in the assessment of the diabetic foot is the
clinical examination.sup.18, 19. All patients with diabetes require
a thorough pedal examination at least once a year, even without
signs of neuropathy. Evaluation of the diabetic patient with
peripheral vascular disease should include a thorough medical
history, vascular history, physical examination, neurologic
evaluation for neuropathy and a thorough vascular
examination..sup.20
[0018] The next step in the work up of a patient with significant
peripheral vascular or diabetic foot disease is non-invasive
testing..sup.21 Current clinical practice can include ankle
brachial index (ABI), transcutaneous oxygen measurements (TcPO2),
pulse volume recordings (PVR) and laser Doppler flowmetry. All of
these clinical assessments are highly subjective with significant
inter- and intra-observer variability especially in longitudinal
studies. None of these methods are discriminatory for feet at risk,
and none of them provide any information about the spatial
variability across the foot. Doppler ultrasound with B-mode
realtime imaging is typically used to diagnose deep vein thrombosis
while photo and air plethysmography are used to measure volume
refill rates as a means of locating and diagnosing valvular
insufficiency. Currently there is no method to accurately assess
the predisposition to serious foot complications, to define the
real extent of disease or to track the efficacy of therapeutics
over time.
SUMMARY OF INVENTION
[0019] The present invention overcomes the problems and
disadvantages associated with current strategies, techniques,
instrumentation and designs, and provides new tools and methods for
detecting tissue at risk of developing into an ulcer, for detecting
problems with diabetic foot disease, for assessing general tissue
damage and metabolic state, and for evaluating the potential for
wounds to heal.
[0020] One embodiment of the invention is directed to a medical
instrument comprising a first stage optic responsive to
illumination of tissue, a spectral separator, one or more
polarizers, an imaging sensor, a diagnostic processor, a filter
control interface, a general purpose operating module to assess the
state of tissue in diabetic subjects following a set of
instructions, and a calibrator. Preferably, the instrument further
comprises a second stage optic responsive to illumination of
tissue. Preferably, the set of instructions comprises preprocessing
hyperspectral information, building a visual image, defining a
region of interest in tissue, converting the visual image into
units of optical density by taking a negative logarithm of each
decimal base, decomposing a spectra for each pixel into several
independent components, determining three planes for an RGB
pseudo-color image, determining a sharpness factor plane,
converting the RGB pseudo-color image to a
hue-saturation-value/intensity image having a plane, adjusting the
hue-saturation-value/intensity image plane with the sharpness
factor plane, converting the hue-saturation-value/intensity image
back to the RGB pseudo-color image, removing outliers beyond a
standard deviation and stretching image between 0 and 1, displaying
the region of interest in pseudo-colors; and characterizing a
metabolic state of the tissue of interest.
[0021] Preferably, the region of interest is one of a pixel, a
specified region or an entire field of view. Preferably,
determining three planes for an RGB pseudo-color image comprises
one or more characteristic features of the spectra, determining a
sharpness factor plane comprises a combination of the images at
different wavelengths, removing outliers beyond a standard
deviation comprises three standard deviations, displaying the
region of interest in pseudo-colors comprises one of performing one
in combination with a color photoimage of a subject, in addition to
a color photo image of a subject, and projecting onto the tissue of
interest.
[0022] Preferably, defining the color intensity plane as apparent
concentration of one or a mathematical combination of oxygenated
Hb, deoxygenated Hb, and total Hb, oxygen saturation, defining the
color intensity plane as reflectance in blue-green-orange region,
adjusting the hue saturation comprises adjusting a color resolution
of the pseudo-color image according to quality of apparent
concentration of one or a mathematical combination of oxygenated
Hb, deoxygenated Hb, and total Hb, oxygen saturation, adjusting the
hue saturation further comprises one or a combination of reducing
resolution of hue and saturation color planes by binning the image,
resizing the image, and smoothing the image through filtering
higher frequency components out, and further interpolating the
smoothed color planes on a grid of higher resolution intensity
plane.
[0023] Another embodiment of the invention is directed to a method
for assessing the state of tissue of a diabetic subject comprising,
preprocessing hyperspectral information, building a visual image,
defining a region of interest in tissue, converting the visual
image into units of optical density by taking a negative logarithm
of each decimal base, decomposing a spectra for each pixel into
several independent components, determining three planes for an RGB
pseudo-color image, determining a sharpness factor plane,
converting the RGB pseudo-color image to a
hue-saturation-value/intensity image having a plane, adjusting the
hue-saturation-value/intensity image plane with the sharpness
factor plane, converting the hue-saturation-value/intensity image
back to the RGB pseudo-color image, removing outliers beyond a
standard deviation and stretching image between 0 and 1, displaying
the region of interest in pseudo-colors; and characterizing a
metabolic state of the tissue of interest.
[0024] Preferably, the region of interest is one of a pixel, a
specified region or an entire field of view. Preferably,
determining three planes for an RGB pseudo-color image comprises
one or more characteristic features of the spectra, determining a
sharpness factor plane comprises a combination of the images at
different wavelengths, removing outliers beyond a standard
deviation comprises three standard deviations, displaying the
region of interest in pseudo-colors comprises one of performing one
in combination with a color photoimage of a subject, in addition to
a color photo image of a subject, and projecting onto the tissue of
interest.
[0025] Preferably, defining the color intensity plane as apparent
concentration of one or a mathematical combination of oxygenated
Hb, deoxygenated Hb, and total Hb, oxygen saturation, defining the
color intensity plane as reflectance in blue-green-orange region,
adjusting the hue saturation comprises adjusting a color resolution
of the pseudo-color image according to quality of apparent
concentration of one or a mathematical combination of oxygenated
Hb, deoxygenated Hb, and total Hb, oxygen saturation, adjusting the
hue saturation further comprises one or a combination of reducing
resolution of hue and saturation color planes by binning the image,
resizing the image, and smoothing the image through filtering
higher frequency components out, and further interpolating the
smoothed color planes on a grid of higher resolution intensity
plane.
[0026] Another embodiment is directed to quantifying an increase in
the vasculature around a wound, and can be used for comparisons to
adjacent tissue. Embodiments of this invention can be used to
quantify an increase in vasculature as the result of a
proangiogenic agent. Proangiogenic agents include, but are not
limited to, vascular endothelial growth factors (VEGF), epidermal
growth factor (EGF), tumor necrosis factor (TNF-.alpha.),
interleukin-1.alpha., and substance P. Other embodiments quantify a
decrease in vasculature as a result of an antiangiogenic agent.
Antiangiogenic agents include, but are not limited to, angiostatin,
interferon-.alpha., metalloproteinase inhibitors, and other
angiogenesis inhibitor drugs approved by the FDA. Other embodiments
are used to quantify enhanced wound healing due to a proangiogenic
agent. Preferably, enhanced wound healing is quantified due to a
proangiogenic agent in diabetics. More preferably, embodiments are
used to quantify enhanced wound healing in diabetic foot ulcers due
to a proangiogenic agent. Other embodiments are used to quantify
delayed cancer growth due to an antiangiogenic agent. Other
embodiments are directed to quantifying a reduction in cancer size
due to an antiangiogenic agent. Other embodiments are used to
quantify a decrease in cancer growth due to an antiangiogenic
agent. Other embodiments are used to quantify enhanced wound
healing due to negative pressure wound therapy. Other embodiments
are directed to quantifying enhanced wound healing due to
hyperbaric therapy.
[0027] Another embodiment is directed to automatic image
processing/target recognition to highlight regions, tissues, or
issues of interest. Another embodiment is directed to projecting an
image into the field of view of the operator of an apparatus of
this invention in such a way as to provide further useful
information than simply viewing the target tissue unaided would
provide. Other embodiments of this invention are directed to
viewing tissues with an MHSI (multispectral/hyperspectral imaging)
device. Other embodiments are directed to determining the status of
a wound in absolute terms, as well as with respect to other
tissues. Other embodiments are directed to quantifying the
physiologic states of tissue, or of tissue-like compounds.
[0028] Other embodiments and advantages of the invention are set
forth in part in the description, which follows, and in part, may
be obvious from this description, or may be learned from the
practice of the invention.
BRIEF DESCRIPTION OF DRAWINGS
[0029] FIG. 1: Block diagram depicting a portable hyperspectral
imaging apparatus.
[0030] FIG. 2: Basic specifications of the MHSI system.
[0031] FIG. 3: OxyHb and DeoxyHb HSV/I color chart. Schematic
representation of the MHSI display (left) showing the interplay
between the oxyHb and deoxyHb coefficients and describing some of
the potential physiological consequences of values of the MHSI. In
one embodiment, tissues determined to have high oxyhemoglobin and
low deoxyhemoglobin levels (upper left-hand quadrant of FIG. 3) are
displayed in a color located proximal to a first terminal color
(e.g., purple) along a color scale and are faded. These tissues are
provided high oxygen delivery and have low oxygen extraction. The
oxygen delivery in these tissues exceeds the tissue oxygen demand.
These are healthy tissues having the lowest risk for ulceration and
the highest probability of healing. In one embodiment, tissues
determined to have high oxyhemoglobin and high deoxyhemoglobin
levels (upper right-hand quadrant of FIG. 3) are displayed in a
color located proximal to a first terminal color (e.g., purple)
along a color scale and are bright. These tissues are provided high
oxygen delivery and have high oxygen extraction. The balance of
oxygenated blood in these tissues reflects high perfusion and high
metabolic rates. These tissues are at lower risk for ulceration and
have a probable likelihood of healing. In one embodiment, tissues
determined to have low oxyhemoglobin and high deoxyhemoglobin
levels (lower right-hand quadrant of FIG. 3) are displayed in a
color located proximal to a second terminal color (e.g., brown)
along a color scale and are bright. These tissues are provided low
oxygen delivery and have high oxygen extraction. The oxygen demand
in these tissues exceeds the oxygen delivery. These tissues are at
risk for ulceration. In one embodiment, tissues determined to have
low oxyhemoglobin and low deoxyhemoglobin levels (lower left-hand
quadrant of FIG. 3) are displayed in a color located proximal to a
second terminal color (e.g., brown) along a color scale and are
faded. These tissues are provided low oxygen delivery and have low
oxygen extraction, indicating the lowest perfusion. The oxygen
delivery in these tissues exceeds is very low. These tissues have
the highest risk of ulceration.
[0032] FIG. 4: Representative data from dorsal surface of foot
showing individual oxyHb and deoxyHb values and how they can be
used to evaluate regions of the tissue.
[0033] FIG. 5: Representative data from tissue showing sensitivity
of MHSI to drug-induced changes in the vasculature. (left to right)
Visible image of foot surface post iontophoresis (IP),
representative spectra pre and post iontophoresis with
Acetylcholine (IP) showing greater oxyHb levels after IP. Images of
increased oxyHb coefficient ring where IP occurred, image of
deoxyHb, showing little change post IP.
[0034] FIG. 6: Representative data from an ulcer located on the
sole (ulcer 1) and dorsal surface (ulcer 2) of the foot.
[0035] FIG. 7: MHSI information from the soles and dorsal surfaces
of four patients. Each row of images represents data from one
patient. The two columns on the left represent data from the soles
of the feet, while the columns on the right represent data from the
dorsal surfaces of the feet.
[0036] FIG. 8: MHSI image of diabetic foot ulcer with 200 segment
radial profile.
[0037] FIG. 9: MHSI of wounds during healing. The 50-micron
resolution images of a rabbit's ear taken with MHSI (Medical
Hyperspectral Imaging) system (HyperMed, Inc.) over 10 days period.
Reconstructed from MHSI data, shows a part of the observed area
50-by-40 mm, recorded at the baseline on day 1. The black rings
denote location of a future wound--puncture.
[0038] FIG. 10: Obtained as a result of hyperspectral processing,
shows distribution of the oxygenated (oxy) and deoxygenated (deoxy)
hemoglobin in the underlying tissue at the same time. The color hue
represents apparent oxy concentrations, whereas color saturation
(from fade to bright) represents apparent deoxy concentrations.
Both, oxy and deoxy, vary predominantly between 40 and 90 mhsi
units (colorbar to the right). The series of images to the right
show change in a region of interest 17-by-1 7 mm (black box in a)
and b)) over 10 days following the puncture wound initiated at day
1. At day 2, the oxy concentrations increased significantly in the
area as far as 10 mm away from the wound border. By day 5, the
increase in oxygenation became more local (purple area "shrunken"
to about 5 mm) and new microvasculature formed to "feed" the area
in need (red fork-like vessels in the right top corners appearing
in the images for days 5 and 10). By the 10th day, the area of
increased oxy has not changed much, but the peak in oxy amplitude
decreased, suggesting a period of steady healing.
DESCRIPTION OF THE INVENTION
Background of Hyperspectral Imaging
[0039] HSI or hyperspectral imaging is a novel method of "imaging
spectroscopy" that generates a "gradient map" of a region of
interest based on local chemical composition. HSI has been used in
satellite investigation of suspected chemical weapons production
areas.sup.22, geological features.sup.23, and the condition of
agricultural fields.sup.24 and has recently been applied to the
investigation of physiologic and pathologic changes in living
tissue in animal and human studies to provide information as to the
health or disease of tissue that is otherwise unavailable..sup.25
MHSI for medical applications (MHSI) has been shown to accurately
predict viability and survival of tissue deprived of adequate
perfusion, and to differentiate diseased (e.g. tumor) and ischemic
tissue from normal tissue..sup.27
[0040] Spectroscopy is used in medicine to monitor metabolic status
in a variety of tissues. One of the most common spectroscopic
applications is in pulse oximetry, which utilizes the different
oxyhemoglobin {oxyHb) and deoxyhemoglobin (deoxyHb) absorption
bands to estimate arterial hemoglobin oxygen saturation..sup.28 One
of the drawbacks of these systems is that they provide no
information about the spatial distribution or heterogeneity of the
data. In addition, these systems report the ratio of oxyHb and
deoxyHb together thereby losing diagnostic information that can be
garnered by evaluating the state of the individual components. Such
spatial information for the individual components and the ratio is
provided by HSI, which is considered a method of "imaging
spectroscopy", where the multi-dimensional {spatial & spectral)
data are represented in what is called a "hypercube.'" The spectrum
of reflected light is acquired for each pixel in a region, and each
such spectrum is subjected to standard analysis. This allows the
creation of an image based on the metabolic state of the region of
interest (ROI).
[0041] In vivo, MHSI has been used to demonstrate otherwise
unobserved changes in pathophysiology. Specific studies have
evaluated the macroscopic distribution of skin oxygen
saturation,.sup.29 the in-situ detection of tumor during breast
cancer resection in the rat,.sup.27 the determination of tissue
viability following plastic surgery & burns,.sup.30, 31
claudication and foot ulcers in diabetic patients,.sup.32-37, and
applications to shock and lower body negative pressure (LBNP) in
pigs and humans, respectively..sup.38-40 In a skin pedicle flap
model in the rat, tissue that has insufficient oxygenation to
remain viable is readily apparent from local oxygen saturation maps
calculated from hyperspectral images acquired immediately following
surgery; by contrast, clinical signs of impending necrosis do not
become apparent for 12 hours after surgery..sup.41
[0042] Non-invasive measurements of oxygen or blood flow have been
demonstrated previously, with investigators using
thermometry,.sup.42 point diffuse reflectance spectroscopy,.sup.43,
44 and laser Doppler imaging..sup.45 Sheffield et al, have also
reviewed laser Doppler and TcPO.sub.2 measurements and their
specific applications to wound healing..sup.46 While other
techniques have been utilized in both the research lab and the
clinic and have the advantage of a longer experience base, MHSI is
superior to other technologies and can provide predictive
information on the onset and outcomes of diabetic foot ulcers,
venous stasis ulcers and peripheral vascular disease.
[0043] Because MHSI has the ability to show anatomically relevant
information that is useful in the assessment of local, regional and
systemic disease. This is important in the assessment of people
with diabetes and/or peripheral vascular disease. MHSI shows the
oxygen delivery and oxygen extraction of each pixel in the image
collected, These images with pixels ranging from 20 microns to 120
microns have been useful in several ways. In the case of systemic
disease, MHSI shows the effects on the microcirculation of systemic
diabetes, smoking, a variety of medications such as all of the
classes of antihypertensives (ACE inhibitors, ARBs, Beta blockers,
Peripheral arterial and arteriolar dilators), vasodilators (such as
nitroglycerine, quinine, morphine), vasoconstrictors (including
coffee, tobacco, pseudephedrine, Ritalin, epinephrine,
levophedrine, neosynepherine), state of hydration, state of cardiac
function (baseline, exercise, congestive heart failure), systemic
infection or sepsis as well as other viral or bacterial infections
and parasitic diseases. The size of the pixels used is important in
that it is smaller than the spacing of the perforating arterioles
(.about.0.8 mm).sup.47 of the dermis and therefore permits the
visualization of the distribution of mottling or other patterns
associated with the anatomy of the microcirculation and its
responses. In the case of the use of MHSI for regional assessment,
in addition to the above systemic effects at play, the image
delivers information about the oxygen delivery and oxygen
extraction for a particular region as it is influenced by blood
flow through the larger vessels of that region of the body. For
example an image of the top of the foot reflects both the systemic
microvascular status and the status of the large (macrovascular)
vessels supplying the leg. This can reflect atherosclerotic or
other blockage of the vessel, potential injury to the vessel with
narrowing, or spasm of some of the smaller vessels. It can also
reflect other regionalized processes such as neuropathy or venous
occlusion or compromise or stasis. In the case of local disease
MHSI shows the actual effect of the combination of systemic,
regional and local effects on small pieces of tissue. This combines
the effects of systemic and regional effects described above with
the effects of local influences on the tissue including pressure,
neuropathy, localized small vessel occlusion, localized trauma or
wounding, pressure sore, inflammation, and wound healing.
Angiogenesis during wound healing is readily monitored with
MHSI.
[0044] Wounds other than on the foot can be similarly assessed,
such as sacral decubiti, other areas of pressure necrosis,
prosthesis stumps, skin flap tissue before, after or during
surgery, areas of tissue breakdown after surgery, and burn
injuries. In preferred embodiments of this invention, wounds that
are assessed by this invention's imaging methods include wounds due
to acute injuries such as lacerations, burns, bruises, wounds from
high impact traumas, fractures, abrasions, bone dislocations,
transfusion-related acute injuries, etc. Current optical methods
for evaluating tissues for the conditions described above include:
[0045] Laser Doppler (LD)--In early iontophoresis experiments as
well as recent efforts both LD and MHSI data were collected, and
some changes in our images (total hemoglobin) are primarily a
consequence of changes in perfusion which was roughly correlated to
LD. However, important other changes in MHSI images that report
specifically O.sub.2 extraction and tissue metabolism (O.sub.2Sat)
are not related to perfusion or LD readings per-se. Superior
spatial resolution with MHSI, and O.sub.2 extraction information
adds highly important clinical information. [0046] Transcutaneous
PO.sub.2 (TcPO.sub.2)--TcPO.sub.2 data collected in subjects with
peripheral vascular disease and ischemia study as well as in
patients with diabetes both with and without foot ulcers.
TcPO.sub.2 measurements appeared cumbersome, lengthy (.about.20-30
minutes), highly operator dependant, and carried data only from
skin directly under the probe (with little ability to distinguish
the spatial characteristics of the ischemic area). While TcPO.sub.2
has been shown to carry statistically significant information in
terms of quantifying tissue at risk for ulceration,.sup.48
TcPO.sub.2 was not encouraging as a useful clinical device. [0047]
Non-imaging techniques--Techniques such as near-infrared absorption
spectroscopy (NIRS) or TcPO.sub.2, rely on measurements at a single
point in tissue which may not accurately reflect overall tissue
condition or provide anatomically relevant data, and probe
placement on the skin can alter blood flow and cannot deliver
accurate information in the area of an ulcer or directly
surrounding it. Because MHSI is truly remote sensing, data are
acquired at a distance, eliminating probe placement errors and
allowing the investigation of the wound itself, which some
techniques can not accomplish due to infection risk. In short,
analysis of the present invention supports the following
conclusions: [0048] 1. Level of oxygenated hemoglobin in the tissue
of arms and feet of diabetic subjects is lower than the level of
oxygenated hemoglobin in the skin of control subjects. This is a
statistically significant result with separation between diabetics
and controls..sup.36 [0049] 2. Oxyhemoglobin in the arms and feet
of ulcerated subjects is lower than oxyhemoglobin in diabetics
without the ulceration. The strong signal suggests ability to
distinguish diabetics at lower and high risk. [0050] 3. Oxygen
saturation level in the skin of arms and feet of diabetics is lower
than oxygen saturation in the skin of controls. This is at a
statistically significant level allowing separation between
diabetics and controls. [0051] 4. MHSI quantitatively assesses
different areas of tissue metabolism on both dorsal and plantar
foot surfaces of any curvature. [0052] 5. MHSI evaluates state of
tissue as a function of distance away from ulcer to assess the
viability of surrounding tissue, and evaluate the degree of risk of
further ulceration. [0053] 6. MHSI can be classified with a
4-quadrant system to determine the metabolic state of tissue using
oxygen delivery and oxygen extraction: low/low, low/high,
high/high, and high/low. This metric is used in distinguishing
healthy tissue from ulcerated, or from a tissue at risk of
ulceration. [0054] 7. MHSI is a unique visualization method that
produces an image that combines spatial information from three
independent parameters characterizing tissue: oxygenated and
deoxygenated hemoglobin concentrations and light absorption. [0055]
8. MHSI evaluates skin metabolism at high resolution of 20-120
microns per image pixel. [0056] 9. Specific MHSI regions associated
with the margins of the ulcer correlate to inflammation (and/or
infection). [0057] 10. Areas of decreased MHSI indicate tissue at
risk for non-healing, ulcer extension, or primary ulceration.
[0058] 11. MHSI differentiates between regions of tissue associated
with a present foot ulcer on the basis of biomarkers such as oxyHb
and deoxyHb coefficients. [0059] 12. MHSI evaluates temporal
changes in oxygen delivery and extraction to particular areas,
both, on local and systemic scale. The trend in the change of oxyHb
and deoxyHb are used to predict healing status of a wound/ulcer as
well as progression of diabetic complications. [0060] 13. Specific
results from MHSI are indicative of inflamed tissue. [0061] 14.
MHSI examines tissue for gross features that may be indicative of
global risks of complications, such as poor perfusion or the
inability of the microcirculation to react and compensate in
tissue. [0062] 15. MHSI has potential in diagnosing global
microcirculatory insufficiencies and impacting on other
complications of diabetes associated with the microvasculature
besides foot ulcers.
[0063] MHSI is superior to other modalities for assessing the
healing potential of tissue adjacent to ulcers. MHSI provides more
direct measurements of oxyHb and deoxyHb activities of the affected
tissue. Hence, the discrimination is not markedly improved by
adding iontophoresis results to refine prediction as is required
for Laser Doppler to do so. MHSI has significant advantages over
laser Doppler and TcPO.sub.2 measurements. Whereas MHSI is able to
deliver spatially relevant data with high spatial resolution,
TcPO.sub.2 delivers only single point data. Laser Doppler data has
poor spatial resolution and is frequently reported as a single mean
numerical value across the region of interest.
[0064] The major clinical advantage of hyperspectral imaging is the
delivery of metabolic information derived from the tissue's
spectral properties in an easily interpretable image format with
high spatial resolution. This 2-D information allows gradients in
biomarker levels to be assessed spatially. Multiple images taken
over time allow the gradient to be measured temporally. This adds
new dimensions to the assessment of ulceration risk and tissue
healing in that it will allow the physician to target therapy and
care to specific at risk areas much earlier than previously
possible. The reporting of biomarkers such as oxyHb and deoxyHb
levels in tissue individually and in an image format where spatial
distributions can be assessed has not been done before. Typically
the two numbers are combined in a ratio and reported as percent
hemoglobin oxygen saturation (O.sub.2Sat). MHSI has the clear
potential to be developed into a cost effective, easy to use,
turn-key camera-based metabolic sensor given the availability and
relatively low price of components.
[0065] Surprisingly, MHSI information according to this invention
can be used to predict the onset of foot ulcers before there are
clinical indications, and provides early detection, diagnosis, and
quantification of progression of microcirculatory complications
such as neuropathy in diabetic patients. For patients with foot
ulcers, MHSI technology can evaluate the ulcer and surrounding area
to predict whether that will heal or require surgical intervention.
The present invention also provides MHSI that is useful in the
prediction and monitoring of peripheral venous disease including
venous ulcers.
[0066] There are many advantages to using MHSI. Not only does MHSI
provide anatomically relevant spectral information, its use of
spectral data of reflected electro-magnetic radiation
(ultraviolet--UV, visible, near infrared--NIR, and infrared--IR)
provides detailed tissue information. Since different types of
tissue reflect, absorb and scatter light differently, in theory the
hyperspectral cubes contain enough information to differentiate
between tissue types and conditions. MHSI is more robust than
conventional analyses since it is based on a few general properties
of the spectral profiles (slope, offset, water, oxyHb, deoxyHb, and
its ratio) and is therefore flexible with respect to spectral
coverage and not sensitive to a particular light wavelength. MHSI
is faster than conventional analyses because it uses fast image
processing techniques that allow superposition of absorbance,
scattering, and oxygenation information in one pseudo-color image.
Visible MHSI is useful because it clearly depicts oxyHb and deoxyHb
which are important, physiologically relevant biomarkers in a
spatially relevant fashion. Similarly, NIR shows water, oxyHb and
deoxyHb.
[0067] The simplicity of the presented false color images
representing distribution of various chemical species, either
singly or in combination (such as ratioed), or in other more
sophisticated image processing techniques allow for the display of
results in real to near-real time. Another advantage of MHSI is
easy interpretation. Color changes show the different tissue types
or condition, but the distinction is not a yes/no type. MHSI color
scheme allows the surgeon or podiatrist to differentiate between
different tissue types and states. In addition, the color and the
shape of structures depict different composition and level of
viability of the tissue. The data is then represented in a
developed MHSI standard format. OxyHb and deoxyHb are presented in
a format similar to a blood pressure reading that is easy for
physicians to understand. Additionally, a tissue oxygen saturation
value denoted as S.sub.HSIO.sub.2 is also provided.
[0068] MHSI main purposes include 1) expand human capabilities
beyond the ordinary array of senses; 2) expand the human brain
capabilities by pre-analyzing the spectral characteristics of the
observable subject; 3) perform these tasks with real or near-real
time data acquisition. In summary, the aim of MHSI is to facilitate
the diagnosis and assessment of the metabolic state of tissue.
[0069] Results of analysis have to be presented in an easily
accessible and interpretable form. MHSI delivers results in an
intuitive form by pairing MHSI pseudo-color image with a high
quality color picture composed from the same hyperspectral data.
Identification and assessment of a region of interest (ROI) is
easily achieved by flipping between color and MHSI images, and
zooming onto the ROI. The images can be seen on a computer screen
or projector, and/or stored and transported as any other digital
information, and/or printed out. The MHSI image preserves the high
resolution of the hyperspectral imager thereby allowing further
improvement with upgraded hardware.
[0070] Additionally, MHSI transcribes vast 3D spectral information
sets into one image preserving biological complexity via millions
of color shades. The particular color and distinct shape of
features in the pseudo-color image allow discrimination between
tissue types such as ulcers, callus, intact skin, hematoma, and
superficial blood vessels.
[0071] Initially, the algorithm presents oxyHb, deoxyHb and
S.sub.HSIO.sub.2 to the user to conclude characteristics of the
tissue including, but not limited to, discerning whether the tissue
is healing or whether it is at a high risk of ulceration. In
another embodiment, a particular color code contains adequate
information for diagnosis and is presented as such. In one
iteration, MHSI by itself is not a definite decision making
algorithm; it is a tool that a medical professional can use in
order to give a confident diagnosis. In another iteration, MHSI
contains a decision making algorithm that provides the physician
with a diagnosis.
[0072] Due to the complexity of the biological system, medical
personnel desire as much information as possible in order to make
the most-reliable diagnosis. MHSI provides currently unavailable
information to the doctor, preferably to be used in conjunction
with other clinical assessments to provide an accurate diagnosis.
MHSI provides images for further analysis by the user. As more
information is gathered, a spectral library is preferably compiled
to allow MHSI to be a true diagnostic device.
[0073] MHSI is preferably used to quantify medical therapies in
order to measure the effectiveness of new therapeutic agents or
procedures. For example, in wound healing studies, a typical
subject population can be broken down into one of three groups:
those that will heal independent of therapy, those that will not
heal independent of therapy, and the borderline cases that may
benefit from the therapy. MHSI preferably is used to select
borderline subjects for these studies where the treatment if
effective most likely benefits the subject. MHSI is used to
quantify wound progression or prevention in order to identify new
therapeutic agents and to develop individual therapeutic regiments
depending on subject response.
[0074] One embodiment of the invention is directed to a medical
instrument comprising a first-stage optic responsive to
illumination of a tissue, a spectral separator, one or more
polarizers, an imaging sensor, a diagnostic processor, a filter
control interface, and a general-purpose operating module (FIG. 1).
Preferably, the spectral separator is optically responsive to the
first-stage optic and has a control input, the polarizer filters a
plurality of light beams into a plane of polarization before
entering the imaging sensor, the imaging sensor is optically
responsive to the spectral separator and has an image data output,
the diagnostic processor comprises an image acquisition interface
with an input responsive to the imaging sensor and one or more
diagnostic protocol modules wherein each diagnostic protocol module
contains a set of instructions for operating the spectral separator
and for operating the filter control interface, the filter control
interface comprises a control output provided to the control input
of the spectral separator, which directs the spectral separator
independently of the illumination to receive one or more
wavelengths of the illumination to provide multispectral or
hyperspectral information as determined by the set of instructions
provided by the one or more diagnostic protocol module, and the
general-purpose operating module performs filtering and acquiring
steps one or more times depending on the set of instructions
provided by the one or more diagnostic protocol modules.
[0075] The instrument may also comprise a second-stage optic
responsive to illumination of the tissue. Preferably, the one or
more wavelengths of illumination are one or a combination of UV,
visible, NIR, and IR. In preferred embodiments, the multispectral
or hyperspectral information determines one or more of the
metabolic state of tissue to assess areas at high risk of
developing into a foot ulcer or other wounded tissue to assess the
potential of an ulcer or the tissue to heal. Preferred embodiments
include multispectral or hyperspectral information gathered
remotely and noninvasively. Alternatively, an imaging system could
be affixed to a wounded area to track its progress over time. Such
a system could be attached to or embedded in a dressing, skin
covering or a device used to impact wound healing or maintain
tissue integrity such as a vacuum suction system or a bed upon
which a patient is lying or a shoe, boot or offloading device.
[0076] Another embodiment is directed to the set of instructions
comprising: preprocessing the hyperspectral information, building a
visual image, defining a region of interest of the tissue,
converting all hyperspectral image intensities into units of
optical density by taking a negative logarithm of each decimal
base, decomposing a spectra for each pixel into several independent
components, determining three planes for an RGB pseudo-color image,
determining a sharpness factor plane, converting the RGB
pseudo-color image to a hue-saturation-value/intensity (HSV/I)
image having a plane, scaling the hue-saturation-value/intensity
image plane with the sharpness factor plane, converting the
hue-saturation-value/intensity image back to the RGB pseudo-color
image, removing outliers beyond a standard deviation and stretching
image between 0 and 1, displaying the region of interest in
pseudo-colors; and characterizing a metabolic state of the tissue
of interest.
[0077] The region of interest may be a pixel, a group of pixels in
a prespecified region of a prespecified shape or a handoutlined
shape or an entire field of view. Preferably, determining the three
planes for an RGB pseudo-color image comprises one or more
characteristic features of the spectra. Preferably, determining a
sharpness factor plane comprises a combination of the images at
different wavelengths, preferably by taking a ratio of a yellow
plane in the range of about 550-580 nm to a green plane in the
range of about 495-525 nm, or by taking a combination of oxyHb and
deoxyHb spectral components, or by taking a ratio between a
wavelength in the red region in the range 615-710 nm and a
wavelength in the yellow region in the range of about 550-580 nm or
in the orange region in the range of about 580-615 nm. Preferably,
outliers are removed beyond a standard deviation, preferably three
standard deviations. The region of interest is displayed in
pseudo-colors, performed with one of in combination with a color
photo image of a subject, or in addition to a color photo image of
a subject, or by projecting the pseudo-color image onto the
observed surface.
[0078] Another embodiment of the invention is directed to a method
for evaluating DFU or area of tissue at risk comprising
preprocessing the hyperspectral information, building a visual
image, defining a region of interest of the tissue, converting all
hyperspectral image intensities into units of optical density by
taking a negative logarithm of each decimal base, decomposing a
spectra for each pixel into several independent components,
determining three planes for an RGB pseudo-color image, determining
a sharpness factor plane, converting the RGB pseudo-color image to
a hue-saturation-value/intensity (HSV/I) image having a plane,
scaling the hue-saturation-value/intensity image plane with the
sharpness factor plane, converting the
hue-saturation-value/intensity image back to the RGB pseudo-color
image, removing outliers beyond a standard deviation and stretching
image between 0 and 1, displaying the region of interest in
pseudo-colors, and characterizing a metabolic state of the tissue
of interest.
[0079] Another embodiment is directed to a medical instrument
comprising an image projector 81, an illumination source, a remote
control device 82 and a real-time data processing package 85. Such
a system could project the colorized or other kind of image with
relevant information back onto the tissue from which it was taken
to assist the physician in diagnosis and treatment such as wound
debridement. Alternatively, information can be transmitted to the
physician using multiple means, such as a heads-up display.
[0080] Another embodiment is intended to help tell the doctor level
of amputation, safety of debriding tissue, likelihood for tissue to
heal, selection and monitoring of specific therapy including
topical pharmaceuticals, skin-like coverings, vacuum suction
apparatus, systemic pharmaceuticals, adequacy of surgical, stenting
or atherectomy procedure, extension of infection vs inflammation of
tissue to assist in therapy, identification of organism responsible
for local or systemic infection.
[0081] Yet another embodiment can give information about tissue
hydration and potentially information about oxyHb and deoxyHb from
deeper tissue using NIR wavelengths. These can be used as a stand
alone device or as paired with the more standard Visible wavelength
MHSI device as shown in FIG. 2.
[0082] Yet another embodiment can derive and present information
from changes seen radiating from an area of wounded, ulcerated or
otherwise abnormal tissue or from any change in tissue
characteristics over a distance. A "gradient map" thus produced can
be used to generate a diagnosis, predict the capability of the
tissue to heal, define a level for amputation, define the infection
vs inflammation, define areas of ischemia, define areas of tissue
at risk for ulceration etc.
[0083] Another embodiment can involve dividing the region of
interest into radial segments, pie like segments or a combination
of the two or into squares or other geometric shapes and using
these segments to compare and contrast different regions of tissue
in the same field of view or as compared to a similar field of view
on the contralateral extremity or on another part of the body (such
as the forearm, the upper leg, etc.). The radial segments can also
be compared to similar locations at different time points to
demonstrate change over time in response to different therapeutic
interventions, changes in tissue physiology, either local, regional
or systemic due either to progression or remission of disease or of
the effects of topical or systemic medications or therapies.
[0084] Such measurements can be used to evaluate wound healing,
tissue regeneration, angiogenesis, vasculogenesis, arteriogenesis,
infection, inflammation, microvascular disease or alterations, or
other changes in tissue characteristics or physiology associated
with the implementation of negative pressure (vacuum suction
applied to the wound), hyperbaric therapy, grafting of autologuous,
heterograft, xenograft or biological or synthetic skin
substituetes, administration of topical agents including
antibiotics, cleansers, growth factors, surgical intervention,
angioplasty, stenting, atherectomy, laser therapy, vasodilator
therapy, offloading, compression, effects of pressure due to
orthotic or prosthetic, effects of electromagnetic, acupuncture,
massage, infrared, vibration or other therapies.
[0085] Such measurements can be used to quantify an increase in the
vasculature around a wound, and can be used for comparisons to
adjacent tissue. Embodiments of this invention can he used to
quantify an increase in vasculature as the result of a
proangiogenic agent. Proangiogenic agents include, but are not
limited to, vascular endothelial growth factors (VEGF), epidermal
growth factor (EGF), tumor necrosis factor (TNF-.alpha.),
interleukin-1.alpha., and substance P. Other embodiments quantify a
decrease in vasculature as a result of an antiangiogenic agent.
Antiangiogenic agents include, but are not limited to, angiostatin,
interferon-.alpha., metalloproteinase inhibitors, and other
angiogenesis inhibitor drugs approved by the FDA. Other embodiments
are used to quantify enhanced wound healing due to a proangiogenic
agent. Preferably, enhanced wound healing is quantified due to a
proangiogenic agent in diabetics. More preferably, embodiments are
used to quantify enhanced wound healing in diabetic foot ulcers due
to a proangiogenic agent. Other embodiments are used to quantify
delayed wound healing due to an antiangiogenic agent. Other
embodiments are used to quantify a decrease in cancer growth due to
an antiangiogenic agent. Other embodiments are used to quantify
enhanced wound healing due to negative pressure wound therapy.
Other embodiments are directed to quantifying enhanced wound
healing due to hyperbaric therapy.
[0086] Such measurements can be considered as biomarkers
representing tissue oxygen delivery and oxygen extraction, tissue
oxygenation, tissue perfusion, tissue metabolism or other
characteristics correlated with MHSI measurements.
[0087] Such measurements can be used in association with the
implementation of hyperbaric therapy delivered to assist in the
healing of ulceration in diabetic or other foot ulceration, or
other wounds in other parts of the body. In the case of hyperbaric
oxygen therapy, the tissue can be monitored before and at specified
intervals during therapy or continuously during therapy to
determine when the tissue has been adequately modified (oxygenated)
by the therapy or that there has been sufficient change in tissue
metabolism as described by the MHSI measurements of oxyHb, deoxy Hb
or other measured parameters or whether no benefit is being
delivered. MHSI can be used to determine the appropriate duration
of HBO therapy during a given session and as to whether sufficient
benefit has been delivered from a course of therapy that it can
safely be discontinued and that the wound will then be likely to
heal with more standard methods.
[0088] MHSI can be used to determine the capability of tissue to
heal after debridement and hence the relative safety of pursuing
such an approach. Similarly, MHSI can be used to help determine the
lowest level of amputation that can be performed with successful
healing. Similarly MHSI can be used to determine whether elective
surgery to the foot, lower extremity or other body part where
evaluation and or quantitation of perfusion, oxygenation, or tissue
metabolism would assist in determination of the safety of
undertaking such a procedure or the location in which to direct
such a procedure. MHSI can be utilized before debridement,
amputation or other surgery to make this determination or during
debridement, amputation or other surgery to better assess tissue to
improve surgical outcomes.
[0089] Such measurements can be used for the determination of which
patients or which wounds are likely to improve with any of the
above mentioned therapies, which patients or wounds or portions of
wounds are healing or worsening, when a given therapy is sufficient
(this could be during or immediately after application of a therapy
such as hyperbaric therapy or a debridement or a particular
cleansing or pharmaceutical regimen or after a longer course of
several days of therapy such as a vacuum therapy. MHS criteria can
be used to determine when a tissue will accept a skin graft or
benefit from an allograft or other skin replacement.
Systemic or Regional Disease
[0090] One embodiment uses a single system that employs light
wavelengths ranging from the UV through the far infrared portions
of the electromagnetic spectrum, as well as either side of this
range as new technologies are developed allowing for use of a
greater portion of this spectrum (e.g. UV, visible, the near
infrared, short wave infrared, mid infrared or far infrared portion
of the electromagnetic spectrum). Another embodiment uses a system
that uses one or more wavelengths from more than one of these
wavelength regimes. One such system using wavelengths from more
than one of these wavelength groupings is shown in FIG. two. In
other embodiments, a single sensor could be used to collect light
from more than one wavelength regime.
[0091] A portable hyperspectral imaging apparatus according to an
embodiment of the invention is depicted in FIG. 1. Portable
apparatus 10 weighs less than 100 pounds, preferably less than 25
pounds, and more preferably less than 10 pounds. Preferably, the
portable apparatus may be battery operated, have some other form of
portable power source or more preferably, may have a connector
adapted to connect to an existing power source.
[0092] Portable apparatus 10 comprises an optical acquisition
system 36 and a diagnostic processor 38. Optical acquisition system
36 comprises means to acquire broadband data, visible data,
ultraviolet data, infrared data, hyperspectral data, or any
combination thereof. In a preferred embodiment, optical acquiring
means comprises a first-stage imaging optic 40, a spectral
separator 42, a second-stage optic 44, and an imaging sensor 46.
Alternatively, optical acquiring means may be any acquisition
system suited for acquiring broadband data, visible data,
ultraviolet data, infrared data, hyperspectral data, or any
combination thereof. Preferably, one or more polarizers 41, 43 are
included in the acquisition system to compile the light into a
plane of polarization before entering the imaging sensor.
Preferably, a calibrator is also included in the system.
[0093] If the spectral separator 42 does not internally polarize
the light, the first polarizer 43 is placed anywhere in the optical
path, preferably in front of the receiving camera 46. The second
polarizer 41 is placed in front of illuminating lights 20 such that
the incident light polarization is controlled. The incident light
is crossed polarized with the light recorded by the camera 46 to
reduce specular reflection or polarization at different angles to
vary intensity of the reflected light recorded by the camera.
[0094] The illumination is provided by the remote light(s) 20,
various sources tailored or adapted to the need of the instrument,
preferably positioned around the light receiving opening of the
system, or otherwise placed to afford optimal performance. The
light can be a circular array of focused LED lights that emit light
at the particular wavelengths (or ranges) that are used in the
processing algorithm, or in the ranges of wavelengths (e.g.,
visible and/or near-infrared). The circular arrangement of the
light sources provides even illumination that reduces shadowing.
The light wavelength selectivity reduces effect of the observation
on the observing subject. The configuration may also vary depending
on the particular needs and operation of the system.
[0095] Although the preferred embodiment describes the system as
portable, a non-portable system may also be utilized. Preferably,
an optical head is mounted to the wall of the examination room,
more preferably, an overhead light structure is located in the
operating room, or more preferably, the system has a portable table
with an observational window overlooking the operating site.
[0096] The preferred embodiment may also be used as part of another
instrument. For example, as an adjunct to an endoscope.
[0097] The first-stage optic receives light collected from a tissue
sample through a polarizer and focuses the light onto the surface
of the spectral separator. Preferably, the spectral separator is a
liquid crystal tunable filter (LCTF). LCTF 42 is a programmable
filter that sequentially provides light from selected wavelength
bands with small (for example, 7-10 nm) bandwidth from the light
collected from the sample. Second-stage optic 44 receives the
narrow band of light passing through the spectral separator and
focuses the light onto the image sensor 46. The image sensor is
preferably, although not necessarily, a two-dimensional array
sensor, such as a charge-coupled device array (CCD) or CMOS, which
delivers an image signal to the diagnostic processor 38.
[0098] Diagnostic processor 38 includes an image acquisition
interface 50, that has an input responsive to an output of the
image sensor 46 and an output provided to a general-purpose
operating module 54. The general-purpose operating module includes
routines that perform image processing, and that operates and
controls the various parts of the system. The general-purpose
operating module also controls the light source(s) (e.g. LED array)
allowing for switching on and off during measurement as required by
the algorithm. The general-purpose operating module has control
output provided to a filter control interface 52, which in turn has
an output provided to the spectral separator 42. The
general-purpose operating module also interacts with a number of
diagnostic protocol modules 56A, 56B, . . . 54N, and has an output
provided to a video display. The diagnostic process includes
special purpose hardware, general-purpose hardware with
special-purpose software, or a combination of the two. The
diagnostic processor also includes an input device 58, which is
operatively connected to the general-purpose operating module. A
storage device 60 and printer 62 also are operatively connected to
the general-purpose operating module.
[0099] In operation, a portable or semi-portable apparatus is
employed within line of site (or with optical access) of the object
or area of interest, e.g., diabetic foot with or without an ulcer,
or general area of interest. An operator begins by selecting a
diagnostic protocol module using the input device. Each diagnostic
protocol module is adapted to detect particular tissue
characteristics of the target. The diagnostic module could be
specific for diabetes, for peripheral vascular disease, for venous
stasis disease or for a combination of these disease states. As
another example, a screening protocol for feet without ulcers or a
potential for healing protocol for feet with ulcers. In an
alternative embodiment, the apparatus may contain only one
diagnostic module adapted for general medical diagnosis.
[0100] Diagnostic processor 38 responds to the operator's input by
obtaining a series of transfer functions and an image processing
protocol and an image processing protocol from the selected
diagnostic protocol module 56. The diagnostic processor provides
the filtering transfer functions to the spectral separator 42 via
its filter control interface 52 and then instructs the image
acquisition interface 50 to acquire and store the resulting
filtered image from the image sensor 46. The general-purpose
operating module 54 repeats these filtering and acquiring steps one
or more times, depending on the number of filter transfer functions
stored in the selected diagnostic protocol module. The filtering
transfer functions can represent bandpass, multiple bandpass, or
other filter characteristics and can include wavelengths in
preferably the UV, preferably the visible, preferably the NIR and
preferably, the IR electromagnetic spectrum.
[0101] In a preferred embodiment, the light source delivering light
to the target of interest can be filtered as opposed to the
returned light collected by the detector. Thus, a tunable source
delivers the information. Alternatively, both a tunable source and
a tunable detector may be utilized. Such tuning takes the form of
LCTF, acousto-optical tunable filter (AOTF), filter wheels, matched
filters, diffraction gratings or other spectral separators. The
light source may be a tungsten halogen or xenon lamp, but is
preferably a light emitting diode (LED).
[0102] The unique cool illumination provided by the LED prevents
overheating of skin which may result in poor imaging resolution.
Preferably, the LED provides sufficient light while producing no
other physical or physiologic effects such as, for example, minimal
or no increase in skin temperature. This lighting system in
combination with the polarizer allows adequate illumination while
preventing surface glare from internal organs and overheating of
skin. In certain embodiments, illumination can arise from any
source meeting the needs of the device such as, for example, more
passive sources such as room light or from sunlight.
[0103] Once the image acquisition interface 50 has stored images
for all of the image planes specified by the diagnostic protocol
chosen by the operator, the image acquisition interface begins
processing these image planes based on the image processing
protocol from the selected diagnostic protocol module 56N.
Processing operations can include general image processing of
combined images, such as comparing the relative amplitude of the
collected light at different wavelengths, adding amplitudes of the
collected light at different wavelengths, or computing other
combinations of signals corresponding to the acquired planes. The
computed image is displayed on the display 12. Other preferred
embodiments include storing the computed image in the storage
device 60 or printing the computed image out on printer 62.
[0104] In a preferred embodiment, a calibrator is included in the
system. Calibrator has an area colored with a pattern of two (or
more) colors. To optimize use of the calibrator for this particular
application where oxyHb and deoxyHb are important components of the
solution, colors are chosen that have a distinct absorption band in
the wavelength range similar to oxyHb and deoxyHb--preferably in
the range 500-600 nm. The colors are placed into a pattern,
preferably, a checker-board pattern, where 1 out of 4 squares has
color1, and 3 out of 4 squares have color2. Thus, approximately 25%
of the squares are color 1 and 75% of the squares are color2. The
system takes a hypercube being slightly out of focus--that provides
blurring of colors into each pixel. From the spectra for each
pixel, a linear composition of two spectra: one from color1 and
another from color2 are observed. The recorded spectra are
decomposed in a manner similar to a system that decomposes skin
spectra into oxyHb & deoxyHb components. However, in this
instance it takes pure color1 and color2 spectra from library
instead of oxyHb & deoxyHb. Valid calibration reports
concentrations of 75% for color2 and 25% for color1. Results are
similar to skin analysis, where the output is approximately 90% of
oxyHb and 10% of deoxyHb. Other embodiments include but are not
limited to, changes to the pattern, the color concentration &
intensity, and the number of colors.
[0105] In summary, the calibrator simulates the way the biological
mixture (oxyHb+deoxyHb) is observed by using "optical" mixture via
combination of pattern (with known spatial concentrations) and
analog blurring (defocusing--for speed. Defocusing can also be done
in the software through the use of computational filters) in such a
way as to ensure that the entire MHSI system is functioning
correctly and accurately.
[0106] If the correct result is obtained, confirmation of the
lighting distribution and collection throughput, and the wavelength
accuracy of the system given confidence in the spectra (wavelengths
and intensity) that are being collected are provided. This provides
additional assurance that the data recorded off the patient is
acceptable.
[0107] In another preferred embodiment, diagnostic protocol modules
56, printer 62, display 12, or any combination thereof, may be
omitted from portable device 10. In this embodiment, acquired
images are stored in storage device 60 during the medical
procedure. At a later time, these images are transferred via a
communications link to a second device or computer located at a
remote location, for example, hospital medical records, for backup
or reviewing at a later time. This second device can have the
omitted diagnostic protocol modules, printer, display, or any
combination thereof. In another embodiment, the stored images are
transferred from portable device 10, located in the clinic, via a
communications link to a remote second device in real time.
[0108] In a preferred embodiment the system has facility to project
real-time hyperspectral data onto the operation field, region of
interest, or viewing window positioned above the operating site
through use of a Heads Up Display or other suitable technique
allowing the user to overlay the image in a useful manner. Also,
the hyperspectral data can be displayed completely separately for
remote guidance (i.e. on a wall screen for a group of people to
review in real time, or post procedure). The projected information
has precise one-to-one mapping to the illuminated surface (e.g.
wound, operating surface, tissue) and provides the user with
necessary information in efficient and non-distractive way. When
projected onto an overhang viewing window, the images (real-color
and/or pseudo-color) can be zoomed in/out to provide variable
magnification. This subsystem consists of the following elements:
1) image projector 81 with field-of view precisely co-aligned with
the field-of view of the hyperspectral imager, 2) miniature remote
control device 82 which allows the surgeon or podiatrist to switch
the projected image on and off without turning from the site of
debridement and change highlight structure and/or translucency on
the projected image to improve visibility of the features of
interest as well as projected image brightness and intensity, 3) a
real-time data processing package 85 which constructs a projected
image based on hyperspectral data and operator/surgeon input, 4)
optional viewing window 84 positioned above the operating site that
is translucent for real observation or opaque for projecting
pseudo-color solution or higher resolution images.
[0109] The MHSI system consists of three functional modules--a
Spectral Imager (SI), supporting Controller and Power Module (CPM)
and Control and Data Acquisition Computer (CDAC). The MHSI also
includes a thermometer that remotely measures the temperature at
the tissue surface. The Spectral Imager is mounted on suspension
arm which neutralizes device weight and allows for easy positioning
and focusing of the instrument. The suspension arm is attached to
wheeled cart which supports CPM and CDAC as well. This
configuration is very mobile and permits wide range of device
spatial and directional motions.
[0110] FIG. 2 shows the preferred system specifications along with
a diagram of our focusing methodology and the optical design of the
Spectral Imager. In this embodiment, a liquid crystal tunable
filters (LCTF's) was used as the wavelength selector and are
coupled to complementary metal oxide semiconductor (CMOS) imaging
sensors. Fitted with macro lenses and the positional light focusing
system described below, the system has a preferred working focal
length of roughly 1 to 2 feet.
[0111] A major issue in the collection of hyperspectral imaging
data is the position and focusing of the instrument. While our
Spectral Imaging Module is positioned on a ball joint that allows
free rotation and virtually any angle of incidence to the patient,
it is imperative that there be a system in place for targeting the
image to a particular spot on the tissue and ensuring that the
instrument will be at the proper distance from the tissue to
achieve optimal focus. Positioning and focusing with our system are
facilitated by two mirrored collimated light beams or lasers that
cross precisely at the instrument focal plane (FIG. 2), and so
bringing the spectral imaging module into position where the two
light spots overlap on the tissue to insure optimal focus.
[0112] To achieve precisely calibrated images, the system may use a
specially designed calibration pad placed at the focal plane of the
system and measured prior to each patient measurement. The
calibration pad includes a diffusely reflective surface to quantify
the intensity of the illumination at each wavelength and color bars
to validate wavelength accuracy of the system. Calibration data
measured at a preset time such as during maintenance calibrations
can be stored and compared to with each use to decide whether the
system is within specifications and should proceed to patient
measurements.
[0113] To achieve precise co-registration between the hyperspectral
image and the operating surface, the system may use a fiducial
label or target placed in the field of view which the image
registration module can use to perform a self-alignment procedure
before or during the operation as necessary.
[0114] Devices of the present invention allow for the creation and
unique identification of patterns in data that highlight the
information of interest. The data sets in this case may be discrete
images, each tightly bounded in spectra that can then be analyzed.
This is analogous to looking at a scene through various colored
lenses, each filtering out all but a particular color, and then a
recombining of these images into something new. Such techniques as
false color analysis (assigning new colors to an image that don't
represent the true color but are an artifact designed to improve
the image analysis by a human) are also applicable. Optionally,
optics can be modified to provide a zoom function, or to transition
from a micro environment to a macro environment and a macro
environment to a micro environment. Further, commercially available
features can be added to provide real-time or near real-time
functioning. Data analysis can be enhanced by triangulation with
two or more optical acquisition systems. Polarization may be used
as desired to enhance signatures for various targets.
[0115] In addition to having the ability to gather data, the
present invention also encompasses the ability to combine the data
in various manners including vision fusion, summation, subtraction
and other, more complex processes whereby certain unique signatures
for information of interest can be defined so that background data
and imagery can be removed, thereby highlighting features or
information of interest. This can also be combined with automated
ways of noting or highlighting items, areas or information of
interest in the display of the information.
[0116] The hyperspectrally resolved image in the present invention
is comprised of a plurality of spectral bands. Each spectral band
is adjacent to another forming a continuous set. Preferably, each
spectral band having a bandwidth of less than 50 nm, more
preferably less than 30 nm, more preferably less than 20 nm, more
preferably, from about 20-40 nm, more preferably, from about 20-30
nm, more preferably, from about 10-20 nm, more preferably from
about 10-15 nm, and more preferably from about 5-12 nm.
[0117] It is clear to one skilled in the art that there are many
uses for a medical hyperspectral imager (MHSI) according to the
invention. The MHSI offers the advantages of performing the
functions for such uses faster, more economically, and with less
equipment and infrastructure/logistics tail than other conventional
techniques. Many similar examples can be ascertained by one of
ordinary skill in the art from this disclosure for circumstances
where medical personal relies on their visual analysis of the
biological system. The MHSI acts like "magic glasses" to help human
to see inside and beyond.
Algorithm Description
[0118] The embodiment of diabetes algorithm involves the following
steps: [0119] 1. Preprocess the MHSI data. Preferably, by removing
background radiation by subtracting the calibrated background
radiation from each newly acquired image while accounting for
uneven light distribution by dividing each image by the reflectance
calibrator image and registering images across a hyperspectral
cube. [0120] 2. Build a color-photo-quality visual image.
Preferably, by concatenating three planes from the hyperspectral
cube at the wavelengths that approximately correspond to red
(preferably in the range of about 580-800 nm, more preferably in
the range of about 600-700 nm, more preferably in the range of
about 625-675 nm and more preferably at about 650 nm), green
(preferably in the range of about 480-580 nm, more preferably in
the range of about 500-550 nm, more preferably in the range of
about 505-515 nm, and more preferably at about 510 nm), and blue
(preferably in the range of about 350-490 nm, more preferably in
the range of about 400-480 nm, more preferably in the range of
about 450-475 nm, and more preferably at about 470 nm) color along
the third dimension to be scaled for RGB image. [0121] 3. Define a
region of interest (ROI), preferably, where the solution is to be
calculated unless the entire field of view to be analyzed. [0122]
4. Convert all hyperspectral image intensities into units of
optical density. Preferably, by taking the negative logarithm of
the decimal base. FIG. 2 shows examples of spectra taking from
single pixels at different tissue sites within an image. Tissue
sites include connective tissues, oxygenated tissues, muscle,
tumor, and blood. [0123] 5. Decompose the spectra for each pixel
(or ROI averaged across several pixels). Preferably, decompose into
several independent components, more preferably, two of which are
oxyhemoglobin and deoxyhemoglobin. [0124] 6. Determine three planes
for pseudo-color image. Preferably, define the color hue plane as
apparent concentration of oxygenated Hb, or deoxygenated Hb, or
their mathematical combination, e.g. total Hb, oxygen saturation,
etc. Preferably, define the color saturation plane as apparent
concentration of oxygenated Hb, or deoxygenated Hb, or their
mathematical combination, e.g. total Hb, oxygen saturation, etc.
Preferably, define the color intensity (value) plane as reflectance
in blue-green-orange region (preferably in the range of light at
about 450-580 nm). [0125] 7. Adjust the color resolution of the
pseudo-color image according to quality of apparent concentration
of oxygenated Hb, or deoxygenated Hb, or their mathematical
combination, e.g. total Hb, oxygen saturation, etc. Preferably,
reduce resolution of hue, and saturation color planes by binning
the image (e.g. by 2, 3, 4, etc. pixels), or/and by resizing the
image, or/and by smoothing the image through filtering higher
frequency components out. Interpolate the smoothed color planes on
the grid of higher resolution intensity (value) plane. [0126] 8.
Convert hue-saturation-value/intensity (HSV/I) image to
red-green-blue (RGB) image. [0127] 9. Remove outliers in the
resulting image, defining an outlier as color intensity deviating
from a typical range beyond certain number of standard deviations,
preferably three. Stretch the resulting image to fill entire color
intensity range, e.g. between 0 and 1 for a double precision image.
[0128] 10. Display ROI in pseudo-colors, preferably, in combination
with the color photo image of the subject, or preferably, in
addition to the color photo image of the subject, or more
preferably, by projecting the pseudo-color image onto the observed
surface. Additional information can be conveyed through images
portraying the individual coefficients from oxyHb, deoxyHb, slope
and offset coefficients, or any linear or nonlinear combination
such as the oxyhemoglobin to deoxyhemoglobin ratio. [0129] 11.
Characterize the metabolic state of the tissue of interest (e.g.
risk for ulceration, potential to heal). Preferably, by using the
saturation and/or intensity of the assigned color and provide a
qualitative color scale bar.
[0130] As is clear to a person of ordinary skill in the art, one or
more of the above steps in the algorithm can be performed in a
different order or eliminated entirely and still produce adequate
and desired results. Preferably, the set of instructions includes
only the steps of preprocessing the hyperspectral information,
building a visual image, using the entire field of view, converting
all hyperspectral image intensities into units of optical density
by taking a negative logarithm of each decimal base, and
characterizing a metabolic state of the tissue of interest. More
preferably, the set of instructions comprises preprocessing the
hyperspectral information, defining a region of interest of the
tissue, and characterizing a state of the tissue of interest.
[0131] Another preferred embodiment entails reducing the
hyperspectral data in the spectral dimension into a small set of
physiologic parameters involves resolving the spectral images into
several linearly independent images (e.g. oxyhemoglobin,
deoxyhemoglobin, an offset coefficient encompassing multiple
scattering (MS) properties and a slope coefficient) in the visible
regime. Another embodiment determines four images (e.g.
oxyhemoglobin, deoxyhemoglobin, offset/scattering coefficient, and
water absorption) in the near infrared region of the spectrum. As
an example for the visible region of the spectrum, linear
regression fit coefficients c1, c2, c3 and c4 will be calculated
for reference oxy-Hb, deoxy-Hb, and MS spectra, respectively, for
each spectrum (Sij) in an image cube:
{right arrow over (S)}.sub.ij=.parallel.c.sub.1{right arrow over
(OxyHb)}+c.sub.2{right arrow over (DeoxyHb)}+c.sub.3{right arrow
over (Offset+c.sub.4Slope)}.parallel..sub.2
Individual images of the oxyhemoglobin and deoxyhemoglobin
components, the slope and offset or any combination, linear or
nonlinear, of these terms, for example the oxy- to deoxyhemoglobin
ratio, can be presented in addition to producing the pseudo-colored
image to the user. In order to present the MHSI effectively, a
display method was developed that has the potential to convey a
2-dimensional index, and convey the values for both the oxy and
deoxyhemoglobin coefficients independently. The method of
displaying our index uses a color scale, in one iteration this
ranges from purple values (high) to brown values (low) to indicate
the concentration of oxyhemoglobin in the tissue, and a brightness
scale, ranging from very bright (high) to faded (low) associated
with the tissue concentration of deoxyhemoglobin. FIG. 3 summarizes
the display of the MHSI, showing a schematic diagram explaining the
scenarios of low and high oxy and deoxy hemoglobin coefficients as
well as a color scale that indicates a color plat that shows the
vertical color scale and the horizontal brightness scale. By
measuring an MHSI where the oxyhemoglobin component is high and the
deoxyhemoglobin component is low (upper left hand corner of FIG.
3), it could be concluded that that particular area of tissue has
adequate perfusion and oxygenation, and is able to satisfy its
metabolic needs with the oxygen that is being delivered. That this
tissue has the lowest level of risk for ulceration and the highest
probability of healing. If tissue demonstrates a low oxyhemoglobin
level in addition to a low deoxyhemoglobin level (lower left corner
of FIG. 3), this would imply that the tissue was receiving low
total volume of blood. If tissue demonstrates a low oxyhemoglobin
level in addition to a high deoxyhemoglobin level (lower right
corner of FIG. 3) this would imply that the tissue has metabolic
requirements exceeding available oxygen delivery. In both of these
regions there is expected to be a higher risk of ulceration or
difficulties with wound healing. If the tissue has a high
oxyhemoglobin coefficient and also has a high deoxyhemoglobin
content, (lower left corner of FIG. 3) this tissue was receiving a
larger total volume of blood, and that the oxygen extracted from
the blood stream was adequate to support tissue metabolism. This
could be indicative of inflammation. Our technique will uniquely
permit discrimination between each of these disparate physiologic
conditions. For example, if the value is faded purple (upper left
hand quadrant) the tissue has very high oxygenation, as discussed
above, and is very likely to heal. The color map (right) gives an
indication of how the MHSI would be represented in an image
format.
[0132] Described here is hyperspectral imaging for use in the
peripheral vascular and diabetes clinic, designed both to be mobile
for ease of use and to facilitate the most accurate data collection
possible for this project. This system provides fast and precise
measurement of reflectance spectra, and is characterized by high
spatial and spectral resolution, and the ability to process
spectral data in real time. It has been equipped with a turn-key
software interface for the user. Proprietary image registration
software insures image stability when measuring spectra of animated
objects. The system does not rely on external illumination, rather
it contains very efficient internal visible (and NIR in certain
versions) light sources, which allow to achieve high signal to
noise ratios in measured data without putting noticeable heat load
on a biological subject (variations in skin temperature during
acquisition are on the order of 0.1 C).
[0133] All MHSI data were corrected for background and uneven
illumination, and normalized by the integration time. The data were
ratioed to the reflectance of a calibration standard, and negative
decimal logarithm was taken to obtain the absorption data. Images
at all wavelengths were co-registered using proprietary software
developed by HYPERMED to ensure that each pixel represents the same
point on the skin throughout all wavelengths. The spectra were then
deconvolved into four linearly-independent spectral components with
coefficients representing the amount of hemoglobin (both oxyHb and
deoxyHb) in the observed skin. Typically two numbers are presented
x/y wherein x represents oxyHb and y is deoxyHb. The values for x
and y can be taken from a single pixel or from a ROI defined by the
user. In addition the hemoglobin oxygen saturation
(S.sub.HSIO.sub.2), x/(x+y), can be presented for a pixel or a ROI.
FIG. 4 shows examples of tissue with low and high oxyHb and deoxyHb
values corresponding to tissue at risk of ulceration and a wound
that is likely to heal, respectively. Another way of presenting
linearly independent variables is through their sum and difference:
(x+y) and (x-y). The first would be THb, and the second would
"hint" on oxygen extraction--which indicates the kind of Hb that is
predominant at the site.
[0134] Data in the following table represent typical oxyHb,
deoxyHb, and S.sub.HSIO.sub.2 values for two body positions,
forearm and foot, and for various stages of diabetes: nondiabetics,
diabetics without peripheral neuropathy, and diabetics with
peripheral neuropathy. In general, the value for oxyHb and
S.sub.HSIO.sub.2 are lower in the feet of diabetic subjects with
neuropathy compared to the other two groups, a group at high risk
for developing foot ulcers. In addition, the values for oxyHb,
deoxyHb, and S.sub.HSIO.sub.2 depend on body location, that once
calibrated can be accounted for by the diagnostic module.
TABLE-US-00001 MHSI oximetry values at baseline (prior to
iontophoresis of acetylcholine) Site Group (N) Oxy Deoxy
S.sub.HSIO.sub.2 (%) Forearm Control (21) 29 .+-. 7* 41 .+-. 16 42
.+-. 17** Diabetic Non- 20 .+-. 5 44 .+-. 10 32 .+-. 8**
Neuropathic (36) Diabetic 19 .+-. 7 49 .+-. 10 28 .+-. 8**
Neuropathic (51) Dorsum of foot Control (21) 25 .+-. 13 44 .+-. 18
38 .+-. 22 Diabetic Non- 24 .+-. 9 41 .+-. 11 37 .+-. 12
Neuropathic (36) Diabetic 19 .+-. 9*** 45 .+-. 13 30 .+-. 12****
Neuropathic (51) *p < 0.0001 compared to diabetics with and
without neuropathy **p < 0.0001 for all three groups ***p <
0.025 when compared to control and nonneoropathic ****p < 0.027
when compared to control and nonneoropathic
[0135] In summarizing these data, MHSI provides relevant
physiological information at the systemic, regional and local
levels. Forearm data measures systemic microvasculature changes
since the forearm is not affected by macrovasculature or somatic
neuropathy as found in the lower extremities. Dorsal foot
measurements are indicative of microvascular and macrovascular
effects including atherosclerotic changes occurring in large
vessels exacerbated by diabetes. MHSI data from the right and left
lower extremity can be compared to help differentiate the stages of
the damage. Finally, MHSI can be used to find local information
that can be associated to the risk of developing a foot ulcer of
the progression of disease by examining the area around an
ulcer.
[0136] MHSI can not only be used for determining risk of foot
ulceration, but also for determining systemic progression of
diabetic microvascular disease. In one embodiment this is
determined by mean oxyHb, deoxyHb and/or other values for a region
of interest. In another embodiment this is determined by
heterogeneity of oxyHb, deoxyHb and/or other values for a region of
interest. In another embodiment this is determined by the
patterning of oxyHb, deoxyHb and/or other values for a region of
interest. In other embodiments this is determined by changes over a
given time period within a measurement session (between 1
picosecond and one hour preferably between 100 microseconds and 10
minutes and more preferably between 100 microseconds and 15
seconds) and in the mean values or patterns of oxyHb, deoxyHb
and/or other values for a region of interest. These measurements
can be used to determine a diabetes progression index (DPI).
Alternatively, a DPI can be calculated by comparing a MHSI value or
set of values from a single point in time with another point in
time (preferably 1 month to two years, more preferably 2 months to
one year and most preferably 3-6 months)
[0137] Using the active stimulus of acetylcholine as a vasodilator,
and the known effects of this on LD measurements data was derived
in which changes in MHSI could be observed under known alterations
in physiology and compare these with baseline images and with LD
data (FIG. 5). Using data collected from diabetic patients, as well
as previous data from human shock studies and iontophoresis
studies, an algorithm was derived that clearly discriminates
regions vasodilated by iontophoresis and also discriminates ulcer
from non ulcer with a proprietary formula that includes terms for
oxyHb and deoxyHb. This was further developed as a Hyperspectral
Microvascular Index (HMI), which is a metric of tissue physiology
and have explored the use of the MHSI in evaluating tissue of the
foot. In circumstances when an ulcer has been present, tissue was
examined within the ulcer, directly adjacent to the ulcer,
surrounding the ulcer and at various other regions of the foot.
[0138] With the aid of MHSI, a quantitative metric is demonstrated
with superb separation between ulcerated or wounded and
non-ulcerated or wounded tissue. Areas of different tissue
metabolism can be seen with 60 micron (20-120) spatial resolution.
Regions with an increased MHSI associated with the margins of the
ulcer can be seen which correlate to inflammation (and/or
infection). Areas of decreased MHSI can be seen in other areas
which from previous work in ischemia is considered to be tissue at
risk for non-healing, ulcer extension, or primary ulceration. These
data validate the capability of our measurement system to have the
resolution and appropriate range to quantitatively assess different
areas of tissue metabolism on both dorsal and plantar foot surfaces
as well as skin on other body areas or other tissues visible
through endoscopic techniques or at the time of open surgery of the
foot, leg, arm or any other body part including internal organs at
laparoscopy or the retina at retinoscopy. The invention provides
the capability to perform this quantitative assessment on tissue
that demonstrates no visible differences on clinical examination to
the skilled examiner.
[0139] MSHI images have the ability to differentiate between
regions of tissue associated with a present foot ulcer on the basis
of biomarkers such as the oxyHb and deoxyHb coefficients. FIG. 6
shows an ulcer on the sole of the foot of a type 1 diabetic patient
(ulcer 1). From the visible image on the left, little distinguishes
one area of the ulcer from another. However when looking at the
image with the MHSI, there is obvious discriminatory power between
the state of tissue seen in the purple oval, which is likely to
heal, and that surrounded by the black oval, which is tissue at
risk for further ulceration. It is important to note that the skin
on the sole of this patient's feet is highly calloused, with a
thick stratum corneum, but one is still able to differentiate
tissue based on its spectral signatures. Given that the sole of the
foot is often the site of the thickest stratum corneum on the body,
the device works on all naturally or surgically exposed tissue or
tissue otherwise visualized with laparoscopy, endoscopy,
retinoscopy or other visualization techniques. Ulcer 2 was located
on the dorsal surface of the foot, on the patient's big toe (FIG.
6). These images further show the ability to differentiate between
tissue at risk and tissue likely to heal. Additionally, tissue
surrounding a fungal infection on the patient's middle toe (bottom
right-hand corner of the image) has an MHSI that can demonstrate
inflamed or infected tissue.
[0140] In addition to the differentiation of local tissue, tissue
can be examined for gross features indicative of global risks of
complications, such as poor perfusion or the inability of the
microcirculation to react and compensate in tissue. In another
embodiment, iontophoretic application of the vasodilator
acetylcholine (ACH) or nitroprusside was used to stimulate the
vasodilation of the microvasculature on the dorsal surface of the
foot and on the forearm of the patients and measured the reaction
with MHSI (FIG. 7).
[0141] There is potential for hyperspectral imaging in diagnosing
global microcirculatory insufficiencies and impacting other
complications of diabetes associated with the microvasculature
besides foot ulcers. In FIG. 7, hyperspectral measurements from the
feet of four patients, with the first two columns of images showing
the MHSI of the soles of both feet, and the second two columns
showing images of the dorsal surface of both feet after the
application of ACH via iontophoresis. In the first three patients,
an MHSI is seen that is much healthier than that of the fourth
patient. Consequently, the fourth patient had a foot ulcer at the
time of this study and has a previous history of ulceration. While
the contrast between the data from the soles in these patients is
striking, there is complementary information in the data from the
microvascular response shown in the two columns on the right. Note
that the first three patients all have MHSI scores that contain
purple information in response to vasodilation, while the fourth
patient shows what would be considered an MHSF that was indicative
of tissue that was at risk. Microcirculatory changes associated
with the progression of diabetes can also be modified by different
treatment and therapeutic regimens and with the overlay of other
systemic diseases (such as congestive heart failure or
hypertension) or treatments or therapies for systemic diseases.
[0142] To analyze the ulcer data further, ulcer images were divided
into 25 concentric circles 1 mm apart and 8 pie segments forming
200 sectors per ulcer (FIG. 8). A radial profile analysis was
undertaken where the ulcer center was defined at the first visit,
and registered images from subsequent visits to this. OxyHb,
deoxyHb, total-hemoglobin and O.sub.2Sat were calculated for each
sector.
[0143] Each radial pie segment was evaluated for signs of healing,
nonhealing or progression in subsequent visits. MHSI measurements
and clinical healing results were compared. MHSI algorithms were
developed to identify changes associated with ulcer healing,
nonhealing and progression. A primary endpoint evaluated the
specific sectors of tissue around an ulcer that would heal, not
heal or progress. The group estimates for oxyHb, deoxyHb, and
O.sub.2Sat are given in the following table using a linear mixed
effects regression model. Significant differences were seen for
healing for the oxyHb and deoxyHb values. Patients who did not heal
also demonstrated increased heterogeneity in distant foot and in
arm measurements. For the 21 ulcers studied, the algorithm
predicted 6 of 7 ulcers that did not heal and 10 of 14 ulcers that
healed. Conclusion: MHSI identifies microvascular abnormalities in
the diabetic foot and provides early information assist in managing
foot ulceration and predict outcomes in patients with diabetes.
TABLE-US-00002 Group Estimates (.+-.SEM) MHSI Not Healing Healing
p-value OxyHb 36.4 .+-. 2.2 51.9 .+-. 1.8 <.0001 DeoxyHb 34.2
.+-. 1.9 47.8 .+-. 1.6 <.0001 S.sub.HSIO.sub.2 0.51 .+-. 0.01
0.51 .+-. 0.01 0.8646
[0144] MHSI is used to monitor angiogenesis during wound healing.
An example of wound healing in a diabetic rabbit wound model shows
that during the healing process, images of oxyHb and deoxyHb show
patterns that change in shape, area, and amplitude with time.
Similar patterns were noted in experimental models of shock, but
the changes observed for shock occurred on a shorter time scale;
minutes rather than several days as the wound heals. The rabbit's
ears were observed at days 1, 2, 5, and 10. MHSI is ideally suited
for characterization of the local heterogeneity in oxyHb and
deoxyHb and their spatial changes with time. For example, the zone
of hyperemia surrounding a wound as measured by the oxyHb
coefficient decreases with time in wounds that heal (FIG. 9). The
color image (a), reconstructed from MHSI data, shows a part of the
observed area 50-by-40 mm, recorded at the baseline on day 1. The
black rings denote location of a future wound. The pseudocolor
image (b), obtained as a result of hyperspectral processing, shows
distribution of the oxyHb and deoxyHb in the underlying tissue at
the same time. The color hue represents apparent oxyHb
concentrations, whereas color saturation (from fade to bright)
represents apparent deoxyHb concentrations. Both, oxyHb and deoxyHb
vary predominantly between 40 and 90 MHSI units (color bar to the
right). The remaining images to the right show change in a region
of interest 17-by-17-mm (black box in (a) and (b)) over 10 days. At
day 2, the oxy concentrations increased significantly in the area
as far as 10 mm away from the wound border. By day 5, the increase
in oxygenation became more local (purple area, shrunken to about 5
mm) and new microvasculature formed to feed the area in need (red
fork-like vessels in the right top corners appearing in days 5 and
10 images). By the 10.sup.th day, the area of increased oxyHb has
not changed much, but the peak in oxy amplitude decreased,
suggesting a period of steady healing.
[0145] As depicted in FIG. 10, 50-micron resolution images of a
rabbit's ear were taken with MHSI over a ten day period. In FIG.
10(a), the color image was reconstructed from MHSI data, showing a
party of the observed area 50-by-40 mm, recorded at the baseline on
day 1. The pseudo-image (b) was obtained as a result of
hyperspectral processing, showing a distribution of the oxygenated
(oxy) and deoxygenated (deoxy) hemoglobin in the underlying tissue
at the same time.
[0146] Other embodiments and uses of the invention will be apparent
to those skilled in the art from consideration of the specification
and practice of the invention disclosed herein. All references
cited herein, including all publications. U.S. and foreign patents,
and patent and provisional applications, and all publications and
documents cited herein for any reason, are specifically and
entirely incorporated by reference. It is intended that the
specification and examples be considered exemplary only.
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References