U.S. patent application number 10/384049 was filed with the patent office on 2008-08-21 for method and apparatus for control of skin perfusion for indirect glucose measurement.
Invention is credited to Thomas B. Blank, Alexander D. Lorenz, Marcy Makarewicz, Mutua Mattu, Stephen L. Monfre, Timothy L. Ruchti.
Application Number | 20080200783 10/384049 |
Document ID | / |
Family ID | 31892028 |
Filed Date | 2008-08-21 |
United States Patent
Application |
20080200783 |
Kind Code |
A9 |
Blank; Thomas B. ; et
al. |
August 21, 2008 |
METHOD AND APPARATUS FOR CONTROL OF SKIN PERFUSION FOR INDIRECT
GLUCOSE MEASUREMENT
Abstract
A method and apparatus for noninvasive glucose measurement
measures glucose indirectly from the natural response of tissue to
variations in analyte concentration. The indirect measurement
method utilizes factors affected by or correlated with the
concentration of glucose, such as refractive index, electrolyte
distribution or tissue scattering. Measurement reliability is
greatly improved by stabilizing optical properties of the tissue at
the measurement site, thus blood perfusion rates at the sample site
are regulated. Perfusion is monitored and stabilized by
spectroscopically measuring a control parameter, such as skin
temperature, that directly affects perfusion. The control parameter
is maintained in a range about a set point, thus stabilizing
perfusion. Skin temperature is controlled using a variety of means,
including the use of active heating and cooling elements, passive
devices, such as thermal wraps, and through the use of a heated
coupling medium having favorable heat transfer properties.
Inventors: |
Blank; Thomas B.; (Chandler,
AZ) ; Ruchti; Timothy L.; (Gilbert, AZ) ;
Mattu; Mutua; (Gilbert, AZ) ; Makarewicz; Marcy;
(Chandler, AZ) ; Monfre; Stephen L.; (Gilbert,
AZ) ; Lorenz; Alexander D.; (Chandler, AZ) |
Correspondence
Address: |
GLENN PATENT GROUP
3475 EDISON WAY, SUITE L
MENLO PARK
CA
94025
US
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20040039271 A1 |
February 26, 2004 |
|
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Family ID: |
31892028 |
Appl. No.: |
10/384049 |
Filed: |
March 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09955531 |
Sep 17, 2001 |
6640117 |
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10384049 |
Mar 7, 2003 |
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10349573 |
Jan 22, 2003 |
7039446 |
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10384049 |
Mar 7, 2003 |
|
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60363345 |
Mar 8, 2002 |
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60235369 |
Sep 26, 2000 |
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Current U.S.
Class: |
600/322 ;
600/306 |
Current CPC
Class: |
A61B 2560/0223 20130101;
G01N 21/359 20130101; A61B 5/1455 20130101; A61B 5/1495 20130101;
G01N 21/31 20130101; A61B 5/1491 20130101; G01N 2021/3595 20130101;
G01N 21/33 20130101; A61B 5/14532 20130101; G01N 21/65
20130101 |
Class at
Publication: |
600/322 ;
600/306 |
International
Class: |
A61B 5/00 20060101
A61B005/00 |
Claims
1. A noninvasive method of measuring a tissue analyte, comprising
steps of: stabilizing optical properties of said tissue at a
measurement site; collecting an analytical signal from the tissue,
said collected signal comprising a tissue measurement; extracting
features from the analytical signal indicative of the affect of the
target analyte on the probed tissue; and calculating concentration
of said analyte indirectly by application of a calibration model to
said features.
2. The method of claim 1, wherein said step of stabilizing optical
properties comprises stabilizing perfusion at said measurement
site.
3. The method of claim 2, wherein said step of stabilizing
perfusion comprises: controlling skin temperature at said
measurement site.
4. The method of claim 3, wherein step of controlling skin
temperature at said measurement site comprises any of the steps of:
applying a passive means of temperature control; and applying an
active means of temperature control.
5. The method of claim 4, wherein said passive means of temperature
control comprises a thermal wrap applied by an operator.
6. The method of claim 4, wherein said active means of temperature
control comprises any of: at least one radiative heating element;
at least one conductive heating/cooling element.
7. The method of claim 6, wherein said one or both of said at least
one radiative element and said at least one conductive
heating/cooling element are embodied within a subject interface of
a measurement sensor.
8. The method of claim 3, wherein said step of controlling skin
temperature at said measurement site comprises steps of: providing
a coupling medium; heating a portion of said coupling medium; and
disposing said heated portion of said coupling medium between a
patient interface of patient interface module and said skin at said
measurement site, wherein transfer of thermal energy from said
heated portion of said coupling medium to said skin occurs.
9. The method of claim 8, wherein said coupling medium comprises
any of: silicone oil; mineral oil; and glycerol.
10. The method of claim 8, wherein said coupling medium comprises a
perfluorocarbon liquid.
11. The method of claim 10, wherein said perfluorocarbon liquid
comprises FLUORINERT perfluorocarbon liquid.
12. The method of claim 11, wherein said FLUORINERT perfluorocarbon
liquid comprises one of FC-40 and FC-70.
13. The method of claim 3, wherein skin temperature is controlled
to between approximately 30 and 40 degrees centigrade;
14. The method of claim 13, wherein skin temperature is controlled
to between approximately 30 and 35 degrees centigrade.
15. The method of claim 3, wherein skin temperature is maintained
to within approximately 1 degree centigrade of a set point.
16. The method of claim 15, wherein outermost 100 .mu.m of said
skin is controlled to within approximately 1 degree centigrade of a
set point.
17. The method of claim 1, wherein said analyte comprises
glucose.
18. A noninvasive method of measuring a tissue analyte, comprising
steps of: providing a coupling medium; heating a portion of said
coupling medium; disposing said heated portion of said coupling
medium between a measurement probe and a skin surface at a sampling
site; collecting an analytical signal from the tissue, said
collected signal comprising a tissue measurement; and calculating
concentration of said analyte from said tissue measurement.
19. The method of claim 18, wherein said coupling medium comprises
a perfluorocarbon liquid.
20. The method of claim 19, wherein said perfluorocarbon liquid
comprises FLUORINERT perfluorocarbon liquid.
21. The method of claim 20, wherein said FLUORINERT perfluorocarbon
liquid comprises one of FC-40 and FC-70.
22. The method of claim 18, further comprising a step of:
extracting features from the analytical signal indicative of the
effect of the target analyte on the probed tissue.
23. The method of claim 19, wherein said step of calculating
concentration of said analyte from said tissue measurement
comprises calculating concentration of said analyte indirectly by
application of a calibration model to said features.
24. The method of claim 18, wherein said analyte comprises glucose.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Patent
Application Ser. No. 60/363,345, filed Mar. 8, 2002; and is a
Continuation-in-part of U.S. patent application Ser. No.
09/955,531, filed Sep. 17, 2001, which claims benefit of U.S.
Provisional Patent Application Ser. No. 60/235,369, filed Sep. 26,
2000.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates generally to the field of noninvasive
glucose measurement. More particularly, the invention relates to
control of optical properties of the sampling site to improve
reliability of a noninvasive glucose measurement.
[0004] 2. Background Information
[0005] Diabetes is a chronic disease involving the improper
production and utilization of insulin, a hormone that facilitates
glucose uptake into cells. While a precise cause of diabetes is
unknown, both genetic and environmental factors such as obesity and
lack of exercise appear to play roles. Persons with diabetes have
increased health risk in three broad categories: cardiovascular
heart disease, retinopathy, and neuropathy. Potential disease
complications include heart disease and stroke, high blood
pressure, kidney disease, neuropathy, retinopathy, diabetic
ketoacidosis, skin conditions, gum disease, impotence, and fetal
complications.
Diabetes Prevalence and Trends
[0006] The incidence of diabetes is both common and on the
increase, making the disease a leading cause of death and
disability worldwide. The World Health Organization (WHO) estimates
that diabetes currently afflicts one hundred fifty-four million
people worldwide. Fifty-four million people with diabetes live in
developed countries. The WHO estimates that the incidence of
diabetes will grow to three hundred million by the year 2025. In
the United States, 15.7 million people or 5.9% of the population
are estimated to have diabetes. Within the United States, the
prevalence of adults diagnosed with diabetes increased by six
percent in 1999 and rose by thirty-three percent between 1990 and
1998. This corresponds to approximately eight hundred thousand new
cases every year in America. The estimated total cost to the United
States economy exceeds $90 billion per year. National Institutes of
Health, Diabetes Statistics, Publication No. 98-3926, Bethesda Md.
(1997).
[0007] Long-term clinical studies show that the onset of diabetes
related complications can be significantly reduced through proper
control of blood glucose levels. The Diabetes Control and
Complications Trial Research Group, The effect of intensive
treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus, N
Eng J of Med, 329:977-86 (1993); and 1 U.K. Prospective Diabetes
Study (UKPDS) Group, Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes, Lancet,
352:837-853 (1998); and 1Y. Ohkubo, H. Kishikawa, E. Araki, T.
Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M.
Shichizi, Intensive insulin therapy prevents the progression of
diabetic microvascular complications in Japanese patients with
non-insulin-dependent diabetes mellitus: a randomized prospective
6-year study, Diabetes Res Clin Pract, 28:103-117 (1995).
[0008] A vital element of diabetes management is the
self-monitoring of blood glucose levels in the home environment.
However, current monitoring techniques discourage regular use due
to the inconvenient and painful nature of drawing blood through the
skin prior to analysis. See The Diabetes Control and Complication
Trial Research Group, supra. As a result, noninvasive measurement
of glucose has been identified as a beneficial development for the
management of diabetes. Implantable glucose analyzers eventually
coupled to an insulin delivery system providing an artificial
pancreas are also being pursued.
Glucose Measurement: History, Approaches, and Technologies
[0009] The treatment of diabetes has progressed through several
stages. The combined development of insulin therapy and the
development of devices for the self-monitoring of blood glucose in
the home led to a radical improvement in the lives of individuals
afflicted with diabetes. Self-monitoring of blood glucose has
progressed through multiple stages from early testing that used
urine samples to the current standard of invasive finger stick
samples that are more accurate but somewhat painful. The
development of alternative site glucose measurement technology has
somewhat mitigated the pain aspects, but poses a biohazard.
Alternate site blood glucose concentration levels are also known to
differ from those taken at the fingertip during periods when
glucose concentrations are rapidly changing. The difference is
related to circulatory transport of glucose to peripheral tissues:
Alternate site tissue sites with lower blood perfusion than the
finger will exhibit a delay in the rise and fall of glucose levels
when compared with finger blood glucose.
[0010] Current research is focused on the development of
noninvasive technologies that will totally eliminate the pain
associated with glucose determination and fluid biohazard issues.
Another important area of research involves the combination of
automated glucose measurement and insulin therapy. Progress has
been reported in the research on implantable or full-loop systems
that have been proposed to incorporate both glucose measurement and
control through automated insulin delivery. In the interim, a
device that provides noninvasive, automatic, or (nearly) continuous
measurement of glucose levels would clearly be useful to those
afflicted with diabetes. Various systems have been developed with
this goal in mind. J. Tamada, S. Garg, L. Jovanovic, K. Pitzer, S.
Fermi, R Potts, Noninvasive glucose monitoring comprehensive
clinical results, JAMA, 282:1839-1844 (1999) describe a
minimally-invasive monitoring system reported that provides three
readings of interstitial fluid glucose per hour, each delayed by up
to fifteen minutes due to the sample acquisition process. The
measurement is made through an electrochemical-enzymatic sensor on
a sample of interstitial fluid that is drawn through the skin using
an iontophoresis technique. Other approaches, such as the
continuous monitoring system reported by T. Gross, B. Bode, D.
Einhorn, D. Kayne, J. Reed, N. White and J. Mastrototaro,
Performance evaluation of the Minimed.RTM. continuous glucose
monitoring system during patient home use, Diabetes Technology
& Therapeutics, Vol. 2, Num. 1, (2000) involve the surgical
implantation of a sensor in tissue. Health risks due to sensor
implantation or measurement delay remain as obstacles to
efficacious use of these devices in directing insulin therapy. To
date, a fully noninvasive alternative has not been approved by the
FDA.
Noninvasive Glucose Measurement
[0011] There exist a number of noninvasive approaches for glucose
determination. These approaches vary widely, but have at least two
common steps. First, an apparatus is utilized to acquire a reading
from the body without obtaining a biological sample. Second, an
algorithm is utilized to convert this reading into a glucose
determination.
[0012] A generalized approach to noninvasive glucose measurement
utilizes some form of spectroscopy to acquire the signal or
spectrum from a measurement site on the subject's body. Techniques
include but are not limited to: impedance, Raman, and fluorescence;
as well as techniques using light, from the ultraviolet through the
infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm),
near-IR (700 to 2500 nm or 14,286 to 4000 cm.sup.-1), infrared
(2500 to 14,285 nm or 4000-700 cm.sup.-1)]. A specific near
infrared range for noninvasive glucose determination in diffuse
reflectance mode is about 1100 to 2500 nm or ranges or sets of
ranges therein. K. Hazen, Glucose Determination in Biological
Matrices Using Near-infrared Spectroscopy, doctoral dissertation,
University of Iowa (1995). It is important to note, that these
techniques are distinct from the minimally invasive techniques
listed above in that the sample analyzed is a portion of the human
body in situ, not a biological sample extracted from the human
body.
[0013] Potential sites for the noninvasive measurement have been
identified from the ear lobe, oral mucosa, arm, and eye to the
fingertip. It is important to note that noninvasive techniques do
not have to be based upon spectroscopy. Within the context of the
invention, any device that reads glucose from the body without
penetrating the skin and collecting a biological sample is
classified as a noninvasive glucose analyzer.
[0014] To date, noninvasive glucose measurement has conventionally
employed a direct measurement approach, in which the net analyte
signal due to the absorption of light by glucose in the tissue is
used to calculate the glucose concentration. There exist formidable
challenges to the development of reliable methods of glucose
measurement using a direct approach. Among these challenges are the
size of the glucose signal relative to the spectral background, the
heterogeneity of the sample, the multi-layered structure of the
skin, the rapid variation related to hydration levels, changes in
the volume fraction of blood in the tissue, hormonal stimulation,
temperature fluctuations, and blood analyte levels. Control of the
optical properties of the sample site is essential to the success
of any method of noninvasive glucose measurement using a direct
measurement approach.
Calibration And Utilization Of Noninvasive Glucose Meters
[0015] One noninvasive technology, near-infrared spectroscopy,
provides the opportunity for both frequent and painless noninvasive
measurement of glucose. This approach involves the illumination of
a spot on the body with near-infrared (NIR) electromagnetic
radiation, light in the wavelength range 700 to 2500 nm. The light
is partially absorbed and scattered, according to its interaction
with the constituents of the tissue. The actual tissue volume that
is sampled is the portion of irradiated tissue from which light is
collected and transported to the spectrometer detection system.
Generation of a suitable calibration involves development of a
mathematical relationship between an in vivo near-infrared spectral
measurement and a corresponding reference blood glucose
concentration. The model generation process includes the collection
of a multiplicity of matched spectrum/reference glucose pairs
followed by the calculation of a regression model between the
multiple independent variables contained in each spectral vector
and the associated single dependent reference glucose value.
Reference blood glucose values are typically obtained directly
through the use of measurement tools like the HEMOCUE (YSI, Inc.,
Yellow Springs Ohio) or any other reliable invasive glucose
analyzer.
[0016] The Beer-Lambert Law, equation 1 infra, defines a
proportionality constant between glucose concentration and spectral
light absorbed at a single spectral wavelength in the special case
where no interfering spectral signatures are present. In equation
1, A is the scalar absorbance measurement at a given wavelength of
light, .epsilon. is the molar absorptivity associated with the
molecule of interest at the same given wavelength, b is the
distance (or pathlength) that the light travels through the sample,
and C is the concentration of the molecule of interest (glucose).
A=.epsilon.bC
[0017] A number of interferences do exist for the near-infrared
measurement making the correction for these interferences
necessary. Correction is achieved by using multiple wavelengths in
each spectrum in a multivariate regression model. Such a model is
proven means for compensation of spectral interferences, requiring
some measure of uniqueness in the spectral signature of the
glucose. =C
[0018] In equation 2, boldface type denotes vector variables. The
expression is interpreted as the outer product of the regression
vector k and the absorbance spectrum vector A, consisting of the
absorbance at a multiplicity of selected wavelengths, is equal to
the glucose concentration C of the sample.
[0019] Common multivariate approaches that can be used to solve the
equation 2 for the regression vector k can include partial least
squares (PLS) and principal component regression (PCR).
Nonparametric methods of calibration such as neural networks and
multiple adaptive regression splines (MARS) can also be used to
model an expression analogous to equation 2 in the case where
Beer's law deviations are present and the relation becomes
nonlinear.
[0020] Because every method of glucose measurement has error, it is
beneficial that the primary reference device, which is used to
develop and evaluate noninvasive calibrations for blood glucose, be
as accurate as possible to minimize the uncertainty in the model.
An instrument with a percentage error of five or less is most
desirable. An instrument having a percentage error of up to ten
would be suitable, though the error of the device being calibrated
may increase.
Instrumentation
[0021] Non invasive
[0022] A number of technologies have been proposed for measuring
glucose non-invasively, all of which involve some type of tissue
measurement. Spectroscopy-based noninvasive glucose analyzers
utilize the measured interaction of the tissue sample with
electromagnetic radiation (EMR) or another type of energy input
that leads to an emission of EMR to acquire the signal or spectrum.
Examples include but are not limited to Nuclear Magnetic Resonance
(NMR) spectroscopy, UV, visible near-infrared, mid-infrared, and
far-infrared spectroscopy, tissue impedance spectroscopy, Raman
spectroscopy, and fluorescence spectroscopy. The near infrared
range for noninvasive glucose determination in diffuse reflectance
mode is about 1100 to 2500 nm or ranges therein. Hazen (1995),
supra. It is important to define noninvasive techniques as being
distinct from invasive techniques in that the noninvasive sample is
analyzed in-situ, as opposed to invasively extracting a biological
sample through the skin for analysis. The actual tissue volume that
is sampled is the portion of irradiated tissue from which light is
reflected or transmitted to the spectrometer detection system. All
of these techniques share the common characteristic that, as
secondary calibration methods, they require a calibration, model or
other transformation to convert the measured signal to an estimate
of the glucose concentration using reference measurements based on
a primary method, such as invasive measurements from samples of
venous or capillary blood.
[0023] A number of spectrometer configurations exist for collecting
noninvasive spectra from regions of the body. Typically a
spectrometer has one or more beam paths from a source to a
detector. A light source may include a blackbody source, a
tungsten-halogen source, one or more LED's, or one or more laser
diodes. For multi-wavelength spectrometers a wavelength selection
device may be utilized or a series of optical filters may be
utilized for wavelength selection. Wavelength selection devices
include dispersive elements such as prisms, and gratings of various
types. Nondispersive wavelength selective devices include
interferometers, successive illumination of the elements of an LED
array, and wavelength selective filters. Detectors may be in the
form of one or more single element detectors or one or more arrays
or bundles of detectors. Detector materials are selected to obtain
the desired signal measurement characteristics over the necessary
wavelength ranges. Light collection optics such as fiber optics,
lenses, and mirrors are commonly utilized in various configurations
within a spectrometer to direct light from the source to the
detector by way of a sample.
[0024] The interface of the glucose analyzer to the tissue includes
a patient interface module for directing light into and collecting
light from the tissue measurement site. Optical conduits for
directing and collecting light may include a light pipe, fiber
optics, a focusing lens system, or a light directing mirror
system.
[0025] The scanning of the tissue can be done continuously when
pulsation effects do not affect the tissue area being tested, or
the scanning can be done intermittently between pulses. The
collected signal (near-infrared radiation in this case) is
converted to a voltage and sampled through an analog-to-digital
converter for analysis on a microprocessor based system and the
result displayed.
Related Skin Physiology
[0026] One of the primary functions of cutaneous skin is to provide
a means for thermoregulatory control of body temperature. Blood at
approximately 98.degree. F. is pumped to the outer skin layers to
provide nutrients, is a means for waste removal, and is a mechanism
for thermoregulatory control. In the case of warm ambient
temperatures, heat can be dissipated from the core of the body when
increased blood flow is combined with the cooling effects of sweat
evaporation on the skin surface. In the case of cool ambient
temperatures, heat can also be used to warm a cool skin surface,
but rapid heat loss associated with touching cold objects is
limited by constrictively reducing blood flow to the superficial
tissues. These thermoregulatory mechanisms typically use
constriction or dilation of capillary vessels and the concomitant
variation in blood flow to control the potential for heat transfer
to and from the body. Capillary diameters can vary tenfold during
these processes.
[0027] A tenfold variation in capillary vessel diameter can lead to
substantial changes in the composition and optical properties of
the tissue. Such variation in the measured tissue sample can lead
to poor sampling precision over a sequential series of
measurements. Sample normalization of a varying signal derived from
the heterogeneous, layered structure of skin can be of limited
effectiveness due to spectral nonlinearities imposed by the
compositional variation of the layers and the sequential path of
light through the various layers of skin. Specifically, the
broadband source light is filtered uniquely in the wavelength
domain by each skin layer according to the changing compositions
and varying optical densities that result with a perfusion shift in
the tissue. The result is that the optical sample is destabilized
in a nonlinear manner that is difficult or impossible to normalize
with a high degree of accuracy. It follows that the modeling of
glucose concentration will be most efficacious under the conditions
that variations in the optical properties of the sample are
minimized excepting where changes in the optical properties are a
direct result of glucose variation.
[0028] Accuracy and robustness are improved with thermal control in
the case of either a conventional direct measurement or an indirect
measurement, described below, of blood glucose. Thermally or
mechanically stimulated changes in optical properties will
complicate direct noninvasive glucose determinations. Thermal
perturbations are addressed herein using the knowledge of human
vascular response to heat and cold and by limiting temperature
transients due to skin contact with objects that differ by more
than 5 degrees F. from typical resting skin temperatures of
85-95.degree. F.
DESCRIPTION OF RELATED TECHNOLOGY
[0029] There are a number of issues related to obtaining
representative samples in analytical technologies. Factors
affecting sample stability may be environmental or natural
physiological variation that can arise from variations in sample
site location or time dependent physiologies. Environmental
factors, such as temperature, can affect instrumentation,
electronics, and physiological components. For example, in near-IR
spectroscopy, environmental temperature may affect either or both
of the alignment of a spectrometer and the temperature of the
probing device, which secondarily affects the tissue temperature
upon contact. In the case of noninvasive glucose determination
performed via near-IR spectroscopy, the result of these changes is
a change in the acquired spectra due to the effect of temperature
and pressure on tissue optical properties.
[0030] Furthermore, temperature effects the localized perfusion of
the tissue. The localized perfusion is important for several
reasons. First, vasodilatation of the surface capillaries affects
the amount of blood present near the skin surface. This change can
effect the glucose concentration in the sampled tissue volume.
Second, it has been reported that blood at alternative sites, such
as the forearm, can contain glucose concentrations that are
dampened and/or delayed versus blood in well perfused areas, such
as an artery, vein, or fingertip capillary bed. K. Jungheim, T.
Koschinsky, Glucose Monitoring at the Arm, Diabetes Care,
25:956-960 (2002); and K. Jungheim, T. Koschinsky, Risky delay of
hypoglycemia detection by glucose monitoring at the arm, Diabetes
Care, 24:1303-1304 (2001); and J. Fischer, K. Hazen, M. Welch, L.
Hockersmith, J. Coates, Comparisons of capillary blood glucose
concentrations from the fingertips and the volar aspects of the
left and right forearms, American Diabetes Association, 62.sup.nd
Annual Meeting (Jun. 14, 2002).
[0031] A number of approaches have been utilized to minimize this
lag. For example, M. Rohrscheib, C. Gardner, M. Robinson, Method
and apparatus for noninvasive blood analyte measurement with fluid
compartment equilibration", U.S. Pat. No. 6,240,306 (May 29, 2001)
suggests applying heat to the skin surface to increase perfusion.
The Rohrscheib patent describes elevating localized skin
temperature from 35.degree. C. by at least 5.degree. C. and
preferably by about 7.degree. C. in order to equilibrate the
glucose concentration between the vascular system and skin tissue.
The reported mechanism involves the local dilation of capillaries
to increase blood flow, which results in a partial equalization of
the venous and capillary glucose concentrations. Rohrscheib, et al.
further teach use of vasodilating agents such as nicotinic acid,
methyl nicotinamide, minoxidil, nitroglycerin, histamine,
capsaicin, or menthol to increase local blood flow. While tissue
perfusion can be increased to maximal levels though application of
thermal energy, it has the additional undesirable effect of
destabilizing optical properties of the tissue sample.
[0032] A method and apparatus for sample site temperature
stabilization in conjunction with near-IR based noninvasive glucose
determination has been reported. K. Hazen (1995), supra, pp.
193-249. This method utilizes a heater in thermal contact with the
sampling site, but the methodology is for a direct reading of
glucose and the temperatures are elevated to above forty degrees
centigrade.
[0033] There exists therefore a need in the art for a noninvasive
method of glucose measurement that overcomes the difficulties
inherent in methods based on direct measurement of a net analyte
signal. There further exists a need to maximize the reliability of
such a method by providing a means for controlling and/or
eliminating the fluctuation of optical properties of tissue sample
by stabilizing perfusion of the sample site.
SUMMARY OF THE INVENTION
[0034] The invention provides methods and a system for
non-invasively measuring key constituents and properties of tissue.
A target analyte is measured indirectly based on the natural
response of tissue to variations in analyte concentration. The
indirect method of measuring utilizes factors that are effected by
or correlated with the concentration of glucose, such as the index
of refraction, electrolyte distribution or reduced scattering
coefficient of the bulk tissue. An indirect measurement means that
an ancillary effect due to changes in glucose concentration is
being measured.
[0035] The reliability of the measurement is greatly improved by
stabilizing the optical properties of the tissue at the measurement
site, thus means are provided for regulating blood perfusion rates
at the sample site. In one embodiment, perfusion is monitored and
stabilized by spectroscopically measuring a control parameter, such
as skin temperature, that directly affects perfusion. The control
parameter is maintained in a range about a set point, thus
stabilizing perfusion. Skin temperature is controlled using a
variety of means, including the use of active heating and cooling
elements, passive devices, such as thermal wraps, and through the
use of a heated coupling medium having favorable heat transfer
properties.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 provides a flow diagram of a method for regulating a
control parameter at a tissue measurement site according to the
invention;
[0037] FIG. 2 provides a schematic diagram of a subject interface
module according to the invention; and
[0038] FIG. 3 shows a schematic diagram of an apparatus for
noninvasive glucose determination according to the invention.
DETAILED DESCRIPTION
Indirect Measurement
[0039] A method for indirectly determining a concentration of a
target analyte, such as glucose, non-invasively is described in the
commonly-assigned U.S. patent application Ser. No. 10/xxx,xxx
(SENS0006), the entirety of which is hereby incorporated by
reference as if fully set forth herein. The method takes advantage
of the fact that tissue properties are responsive to and reflect
physiological variations in the tissue related to variations in the
concentration of analyte. An analytical signal is collected at a
sampling site on a subject's body. Features are extracted from the
analytical signals that are indicative of the target analyte on the
sampled tissue. Analyte concentration is calculated indirectly by
applying a calibration model to the features. The extracted
features are reflective of changes in tissue properties, which
themselves are responsive to and reflect physiological variations
in the tissue related to variations in the concentration of
analyte. Thus, indirect measurement measures a target analyte by
measuring an ancillary effect of the target analyte.
[0040] The invention provides a method and apparatus of noninvasive
glucose measurement in which blood perfusion at the sample site is
regulated through regulation of a control parameter that directly
influences perfusion, such as skin temperature. FIG. 1 shows a flow
diagram of a method for noninvasive glucose determination that
includes perfusion control at the sample site. As shown in FIG. 1,
perfusion is controlled through the provision of a feedback loop
that maintains the control parameter within an acceptable range
about a set point. For example, blood perfusion increases rapidly
and is volatile above skin temperatures of 40.degree. C., thus it
is desirable to regulate skin temperature at the sampling site to a
range between approximately 30 and 40.degree. C.; preferably the
skin temperature is controlled between 30 and 35.degree. C. More
preferably, the skin is controlled to within one degree of a
control set-point in a range of 30 to 35.degree. C. The control set
point is established by the environmental conditions and the
patient physiology at the time of a periodic instrument bias
correction. Notably, only the outermost 100 .mu.m of skin
temperature need be controlled, as below this depth the capillary
bed controls the skin temperature. While the invention specifically
provides a method of indirect measurement as described above, the
principle of controlling blood perfusion is also readily applied to
noninvasive measurement approaches in which analyte concentration
is directly determined based on the net analyte signal.
[0041] In the preferred embodiment, local perfusion is monitored
spectroscopically and controlled through regulation of the control
parameter. The invented method generally includes steps of: [0042]
Measuring an analytical signal 101. As shown in FIG. 1, the
analytical signal is a near-infrared absorbance spectrum. However,
the principles of the invention are applicable to other noninvasive
measurement technologies as well. Measurement may be performed
using instrumentation as shown in FIG. 3; [0043] The control
parameter is measured spectroscopically through application of a
first calibration model to the spectral measurement 102, and the
value of the parameter relative to the set point 103 is determined;
[0044] The relative value of the control parameter is evaluated 104
to determine if it is within the acceptable range about the set
point 103; [0045] If the control parameter measurement is
acceptable, a glucose calibration 107 is applied to the spectral
measurement to produce a glucose measurement; [0046] If the control
parameter measurement isn't within an acceptable, an error is
generated, and the value is supplied as an input 105 to an element
106 for regulating the control parameter. The loop is repeated,
with the control parameter being repeatedly evaluated until the
measurement is within the acceptable range.
[0047] One embodiment of the above invention provides a method and
apparatus for minimizing the confounding effects in a noninvasive
spectral measurement attributable to shifts in skin temperature at
the tissue measurement site. Near-infrared measurements of skin
combined with associated skin temperature reference measurements
are used to develop NIR temperature calibrations that require only
NIR tissue scans to predict skin surface temperature. Methods of
developing calibrations for spectral analysis may employ a variety
of multivariate analytical techniques that are well known to those
skilled in the art. NIR skin temperature calibration is made
possible by the known shifting of the 1450 or 1900 nm water band
with variations in skin temperature. The calibration model
incorporates the shift information implicitly in the multivariate
regression coefficients. Temperature measurement and control of
human tissue is important in noninvasive NIR measurement because it
provides a means of simplifying the complex overlapping spectral
effects that inhibit extraction of the analyte signal. The extra
temperature measurement hardware and the associated cost and
complexity are avoided by using NIR temperature measurement.
[0048] Skin temperature at the measurement site is
spectroscopically monitored by calculating temperature values
through the application of a multivariate calibration model that
correlates spectroscopic changes with shifts in skin temperature.
Advantageously, thermal time constants imposed by conventional
temperature sensing devices are eliminated, providing
near-instantaneous temperature readings.
[0049] Temperature control may be either active or passive.
[0050] Passive control is achieved through the selective
application and removal of an occlusive thermal wrap. Active
control is provided by a thermistor applied to the skin in the
vicinity of the measurement site. Active and passive control may be
applied in complementary fashion or they may be used separately. In
a particularly preferred embodiment of the invention, the control
means is incorporated into the measurement instrument, wherein the
calculated skin temperature values provide the feedback in a closed
loop that drives the control device. In an alternate embodiment of
the invention, the temperature values are supplied to an operator,
who then applies active and/or passive control to achieve and
maintain a skin temperature within the target range. By monitoring
skin temperature spectroscopically and employing methods of passive
and/or active control it is possible to reduce the effects of skin
temperature variation on the spectral measurement. Active control
may be by way of a conductive element, as described above, or it
may also be provided by a radiative element.
Non-Spectroscopic Control
[0051] Alternately, perfusion can be controlled in an open-loop
fashion by maintaining skin temperature at a specific set-point, as
shown in FIG. 2. The control of skin temperature is performed
conductively through heating and cooling element 201 included as
part of a patient interface module 200. In one embodiment, the
heating and cooling element may be energy transfer pads.
Alternately, skin temperature is controlled through radiative
energy transfer from an energy source. The system may include means
for monitoring the skin temperature at the measurement site either
spectroscopically or through a temperature probe (not shown).
During use, a noninvasive probe 203 is placed against the skin at
the sample site 204. A coupling medium 205 is employed between the
patient interface 202 and the tissue 204. The coupling medium
serves to facilitate heat transfer between the patient interface
202 and the tissue 204.
Skin Temperature Regulation Using Heated Coupling Medium.
[0052] As previously mentioned, the coupling medium itself may
serve to control skin temperature at the sampling site. Thus, an
embodiment of the invention is possible in which a heated coupling
medium provides the thermal energy to maintain the skin of a
sampling site at or near a set point. A number of compounds are
suitable for use as a coupling medium; for example, silicone oil.
Glycerol and mineral oil could also be used, but they are less
desirable alternatives, in view of the fact that both materials
contain carbon-hydrogen bonds that could interfere with
spectroscopic analysis of an analyte such as glucose.
[0053] A particularly preferred embodiment of the coupling medium
is the perfluorinated liquid FLUORINERT, either FC-40 or FC-70 (3M
COMPANY, ST. PAUL Minn.). While the FLUORINERT functions to reduce
surface reflection variations in the noninvasive 20 measurement,
its heat transfer properties are well suited for use as a thermal
regulator. Because the FLUORINERT comes into contact with skin at
the measurement site, heat can be transferred across the skin if
the temperature of the FLUORINERT differs from that of the
skin.
[0054] Heated FLUORINERT can be used in place of a heated probe
with the advantage of reduced power consumption when compared with
a temperature controlled metal probe contact surface. The advantage
is gained by the rapid heating of small amounts of FLUORINERT just
prior to the measurement. Periodic rapid heating saves power over
continuous heating of the metal heater contact surface thereby
reducing power consumption and lengthening battery life. The use of
heated FLUORINERT also allows for the relocation of the heating
electronics away from the probe for increased safety. The use of
heated FLUORINERT also allows for the heating of the tissue at the
measurement site, which is not heated directly by the probe surface
heater as it is not in contact with the tissue at the measurement
site. During use, a portion of the heated FLUROINERT is disposed
between the patient interface of the probe and the skin surface of
the measurement site. Alternatively, the coupling fluid may be
heated by the source element in embodiments where the source
element is in close proximity to the sampling site.
Instrumentation
[0055] While a variety of sensors or instrument configurations are
suitable for practice of the invention, FIG. 3 provides a schematic
diagram of a preferred embodiment of the sensor. The sensor
includes a radiation source such as a tungsten halogen
near-infrared radiation source 301, a wavelength selection filter
302 passing light in a range of approximately 1150 to 1850 nm;
optional illumination fibers 303 for conveying the source photons
to an in-vivo skin sample 204; an interface 200 to the sample site,
for example, a patient's forearm; detection fibers 306 for
gathering diffusely reflected and transflected radiation from the
skin to a spectrum analyzer 307 that includes, for example a
grating (not shown), and a detector array (not shown) to detect the
radiation; an AD (analog-to-digital) converter 308 for converting
the detected signal to a voltage; and processing means 309 for
converting the voltage into a glucose concentration.
[0056] Although the invention has been described herein with
reference to certain preferred embodiments, one skilled in the art
will readily appreciate that other applications may be substituted
for those set forth herein without departing from the spirit and
scope of the present invention. Accordingly, the invention should
only be limited by the claims included below.
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