OCT based method for diagnosis and therapy
United States Patent: 7,510,849
Issued: March 31, 2009
Matthew J. (Somerset, NJ), Shakespeare; Walter Jeffrey (Macungie, PA)
Corporation (Bethlehem, PA)
Appl. No.: 11/040,388
Filed: January 21, 2005
George Washington University's Healthcare MBA
This invention relates to a method of
diagnosing or treating a biological subject, such as a person or animal,
comprising the steps of subjecting at least a microsample of the subject's
tissue to a physiological perturbation and measuring the response of the
microsample to the perturbation using optical coherence tomography (OCT).
In an exemplary embodiment, the concentration of glucose in the
microsample is perturbed, as by providing the subject with a high glucose
drink, and subsequently monitoring at a high sample rate in a microsample
by OCT. Pathology, such as diabetes, can be diagnosed by deviation of the
concentration vs. time response over several cells (micro-oscillation)
from the micro-oscillation in the cells of a healthy subject. Other
applications include diagnosing or treating de-hydration and diseases that
cause changes in the osmolyte concentrations and thus the osmotic pressure
in the cells in tissue.
Description of the
FIELD OF THE INVENTION
The invention pertains to a method of using the signal derived from an
Optical Coherence Tomography (OCT) sensor to monitor or diagnose the
health of a subject or to apply therapeutic treatment. Specifically, the
response of an OCT signal to oscillations in biological tissue over time
in response to physiological perturbations can be used to gauge the health
of the tissue, or the organ, system, or subject to which it belongs.
BACKGROUND OF THE INVENTION
In medicine, the health of a subject is frequently monitored via the
periodicity of certain biological processes. For example an
electrocardiogram measures the periodic impulses of the heart in a wide
variety of diagnostic tests. From this periodic signal the health of the
heart or other organs can be monitored. Another way to assess a subject's
health is to introduce a perturbation in the subject's response and
measure the response to that change. An example is the oral glucose
tolerance test, where the insulin response of a subject is tested by
challenging the subject's body with a high glucose load. The rise and fall
of glucose levels in the blood guides the diagnosis of diabetes.
Optical Coherence Tomography (OCT) is an optical backscatter technique,
analogous to a sonogram, that is used to create high resolution images of
tissues (several microns) at relatively shallow depths (a few mm).
("Optical Coherence Tomography (OCT): A Review", J. M. Schmitt, IEEE
Journal of Selected Topics in Quantum Electronics, July/August 1999, p.
1205). Recently, this technique has been applied to monitor blood glucose.
("Noninvasive Blood Glucose Monitoring With Optical Coherence Tomography,
A pilot Study in Human Subjects", K. Larin, et al., Diabetes Care, vol.
25, no. 12, December 2002, See also: R. O. Esenaliev et al., "Noninvasive
Blood Glucose Monitoring With Optical Coherence Tomography", Diabetes
Care, Volume 25, Number 12, December 2002) and blood oxygenation (oximetry).
("Light absorption of (oxy-)hemoglobin assessed by spectroscopic optical
coherence tomography", D. J. Faber et al., Optics Letters, 2003, pgs.
1436-1438). An OCT method for brain oximetry is disclosed in U.S.
Provisional Patent Application Ser. No. 60/485,761, "Method and Apparatus
for Brain Oximetry", filed by M. J. Schurman on Jul. 9, 2003. The
60/485,761 application is attached hereto.
In these sensor applications the change in the intensity of the reflected
light from the tissue can be related to changes in the tissue being
probed. Such changes can be due, for example, to variations in osmolyte
concentrations, cell volume, or fluid volume surrounding the cells. The
great strength of OCT sensors is that the small light/tissue interaction
volume that they probe provides information on tissue changes at a highly
localized level. Also, OCT measurements can be made continuously, thus
providing a monitoring capability that was previously unavailable. One
example of continuous monitoring, according to the prior art, is
illustrated by FIGS. 1 and 2 (see Original Patent), which show,
respectively, an OCT sensor signal from the skin and a blood glucose
measurement as a function of time using standard assay techniques. In this
test, a healthy subject was given a drink of glucose to induce an insulin
response that serves to reduce the glucose levels in the subject. These
tests are used routinely by doctors in the diagnosis of diabetes, however
it is the macro-response of the human body over a period of three hours
that doctors use to guide diagnosis.
It would be advantageous to have a method and apparatus to observe the
response of the human body to this and other types of stimulus over
shorter time scales.
SUMMARY OF THE INVENTION
This invention relates to a method of diagnosing or treating a biological
subject, such as a person or animal, comprising the steps of subjecting at
least a microsample of the subject's tissue to a physiological
perturbation and measuring the response of the microsample to the
perturbation using optical coherence tomography (OCT). In an exemplary
embodiment, the concentration of glucose in the microsample is perturbed,
as by providing the subject with a high glucose drink, and subsequently
monitoring at a high sample rate in a microsample by OCT. Pathology, such
as diabetes, can be diagnosed by deviation of the concentration vs. time
response over several cells (micro-oscillation) from the micro-oscillation
in the cells of a healthy subject. Other applications include diagnosing
or treating de-hydration and diseases that cause changes in the osmolyte
concentrations and thus the osmotic pressure in the cells in tissue.
High frequency measurements of micro-oscillations can show the local
response, in both frequency and amplitude, of a tissue or organ (such as
skin cells) to a macroscopic perturbation (such as an oral glucose
tolerance test). The oscillatory behavior in time of the scatter
coefficient of tissue, as measured via an OCT sensor, can be used to
determine the health of tissue, organs, and/or human and animal subjects.
The oscillatory signal may also be used to guide treatment, as for
example, to supply insulin to the body in a way that more closely mimics
actual insulin production in the pancreas so as to minimize undesirable
side effects of therapeutic insulin administration.
Micro-oscillations of the scatter coefficient can be due to changes in
osmolyte concentrations (such as glucose), tissue perfusion, cellular
volume change, etc. Such oscillations can be due to natural biorhythms in
the tissues, organ, or subject with deviations from a "normal" signal used
to gauge health. In the case of glucose, levels within the tissue itself
are being observed by the inventive method. These observations are short
time scale representations of the biological processes occurring within
the tissue where the glucose is being taken up and the insulin is
interacting with the glucose in the cells or interstitial fluid. This is
believed to be caused by the osmolality (osmatic pressure) of the cells in
Micro-oscillations can be induced intentionally via external perturbation
(such as an oral glucose tolerance test) or may occur naturally and the
response of the tissue can then be monitored in order to determine the
health of the tissue, organ, or subject. Such perturbations can be on the
macroscopic scale (i.e. subject drinks heavy glucose load such as in the
oral glucose tolerance test) or on the microscopic scale (i.e. local
heating or cooling of the tissue). In all the above cases, the localized
information provided by the OCT sensor is used to monitor the local tissue
scatter coefficient changes. Drinks, intravenous ("IV"), or other
solutions or chemicals introduced into the body, that can cause a change
in the osmolyte levels of tissue cells, can be useful as potential agents
to perturb the tissue biological systems to induce micro-oscillations.
Other potential causes of this type of perturbation include, for example
the post trauma response of the body, post surgery, psychological stress
such as in combat, physical stress such as in running a marathon,
pre-gestational diabetes, fatigue, diet, the aging process, infection,
birth defects, and other conditions that cause a response from the
pancreas. These perturbations can lead to characteristic signatures in the
short time scale micro-oscillations which may be useful in diagnosis of
the respective condition.
It is expected that oscillations detected by the inventive method can
indicate body electrolyte levels as for example, related to various stages
and states of physical activity and exercise. The diagnostic is likely a
sensitive indicator of dehydration and thus also an indicator of
conditions that can cause dehydration.
The OCT sensor can be applied to monitoring the blood glucose levels in
humans and animals to observe, measure and record micro-oscillations of
the signal over short time periods on the order of 10 minutes or less.
Corresponding useful sample rates are less then 5 minutes, and preferably
2 minutes or less. By comparison, the standard blood assay is typically
done at 30 minute sampling intervals. Micro-oscillations, are oscillatory
changes in time of the scattering coefficient of tissue on the physical
scale of tens of microns or over small groups of cells. Micro refers to
the very small physical area of the tissue or surface of the organ of the
subject being measured or to a larger surface area with a shallow depth on
the order of tens of microns (as opposed to the short time scale of the
OCT response). Micro-oscillations can be induced by some perturbation of
the biological system. It is expected that there will be pronounced change
in this signal in response to a perturbation in an unhealthy subject,
especially over short time scales heretofore uninvestigated. Changes are
expected in the amplitude, frequency, and wave shape of the
micro-oscillations in unhealthy subjects.
FIG. 3 (see Original Patent) is an exemplary sketch according to the
inventive technique showing the predicted OCT response of a diabetic
versus a healthy human's skin scattering coefficient to rising glucose
levels. The healthy human shows a rise in scatter coefficient accompanied
by a micro-oscillation whose period (shown as .tau.) is constant
throughout the glucose rise. For the diabetic, no oscillation is apparent.
A diabetic may have an oscillation as well but that period will be vastly
different, or even non-constant in response to changing glucose levels.
The oscillations that are observed from tissue can be used to characterize
the health of the tissue being observed and/or the health of an organ or
system. This may be accomplished in one of three ways. First, the
frequency of the oscillation may relate to the efficiency or health of the
subject under observation. Second, the amplitude of the oscillations may
also relate to the subjects health. Third, the impulse response of the
oscillations to a rapid external perturbation may relate to a tissue or
organ's ability to recover from an external perturbation and reveal more
on the health of the system.
Previous studies have observed relatively slow oscillations on far longer
time scales. In the case of glucose sensitivity, oscillations have been
observed to have a characteristic frequency and amplitude for a given
subject. A typical long time scale oscillation curve of a healthy subject
is shown in FIG. 1.
FIG. 4 (see Original Patent) shows the signal from a healthy human
subject's forearm, in the absence of a large perturbation in the blood
glucose level (i.e. not oral glucose tolerance test). The period of the
micro-oscillation is roughly 10 minutes. Although the sources of these
oscillations are not currently well understood, their magnitude can also
be observed to change as a function of a macro-perturbation.
In FIG. 5 (see Original Patent), the OCT signal as a function of time from
another healthy human subject's forearm can be observed to be rising, due
to a .about.76 mg fructose load given after an overnight fast. Although
the overall rise in the signal is expected (glucose levels in the blood
can be expected to rise in such a case), what is not expected nor
previously observed is the 10 minute micro-oscillations in the data.
Further, it appears that as the overall glucose level rises (as determined
via a rise in the normalized OCT signal) the amplitude of the
micro-oscillations can also be seen to increase. It is this signature
micro-oscillation that can be a fingerprint for the health of a tissue,
organ, system, or subject. In the case of glucose, the insulin response of
a subject may be related to the magnitude and period of the
micro-oscillations, with more random frequency of the swings, or greater
amplitude of the oscillations. These can then be related back to the
insulin response of the person and can be used to diagnose diabetes.
Another application might be to modulate insulin dosing in a diabetic so
that the signal received by the OCT scanner mimics the response seen in a
healthy human. This more cell friendly way of applying therapeutic insulin
treatment can reduce complications and side effects of the disease and
lead to a greater life expectancy of the patient. Specifically, in the
case of continuous insulin administration as for example in an insulin
pump, the micro-oscillations of glucose over time in the interstitial
fluid and as shown by the OCT signal can be applied to the pump control to
more faithfully reproduce the body's own insulin production.
In the case of OCT of the skin, the dominant effect on the signal is due
to glucose changes. However, by modifying the wavelength of the OCT
sensor, the tissue type probed, or modifying the OCT system for
polarization sensitivity (as examples), different physiological changes
can be monitored and their micro-oscillatory response over time may prove
equally as useful in monitoring and/or diagnosing health.
Claim 1 of 13 Claims
1. A method of characterizing a patient's
blood glucose concentrations based on optical coherence tomography, the
method comprising: employing optical coherence tomography to measure light
reflected from a patient's skin tissue at a plurality of depths;
determining a tissue scattering coefficient for a tissue region based on
differences in light reflected at different depths; detecting
micro-oscillations in the tissue scattering coefficient over a time
interval; and relating the micro-oscillations to the patient's blood
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