U.S. patent application number 11/797403 was filed with the patent office on 2007-11-15 for determination of biological conditions using impedance measurements.
Invention is credited to Peter Aberg, Ingrid Nicander, Stig Ollmar.
Application Number | 20070265512 11/797403 |
Document ID | / |
Family ID | 32469195 |
Filed Date | 2007-11-15 |
United States Patent
Application |
20070265512 |
Kind Code |
A1 |
Ollmar; Stig ; et
al. |
November 15, 2007 |
Determination of biological conditions using impedance
measurements
Abstract
Apparatus and methods for the diagnostics of biological
conditions using impedance measurements are provided wherein an
electrical conducting probe can be placed against a skin surface of
the subject, wherein the probe is made up of a plurality of
electrodes in the form of spikes, the spikes being laterally spaced
apart from each other and being of sufficient length to penetrate
the stratum corneum, passing an electrical current through the
electrodes to obtain a value of impedance for the skin, and
converting the impedance to a concentration of a substance such as
glucose in blood of a subject.
Inventors: |
Ollmar; Stig; (Huddinge,
SE) ; Aberg; Peter; (Lidkoping, SE) ;
Nicander; Ingrid; (Stockholm, SE) |
Correspondence
Address: |
STITES & HARBISON PLLC
1199 NORTH FAIRFAX STREET
SUITE 900
ALEXANDRIA
VA
22314
US
|
Family ID: |
32469195 |
Appl. No.: |
11/797403 |
Filed: |
May 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10682372 |
Oct 10, 2003 |
|
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11797403 |
May 3, 2007 |
|
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60417561 |
Oct 11, 2002 |
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Current U.S.
Class: |
600/347 |
Current CPC
Class: |
A61B 5/444 20130101;
A61B 5/411 20130101; A61B 5/061 20130101; A61B 5/0531 20130101;
A61B 5/14532 20130101; A61B 5/6839 20130101 |
Class at
Publication: |
600/347 |
International
Class: |
A61B 5/053 20060101
A61B005/053 |
Claims
1. A method for the non-invasive determination of the concentration
of a substance (glucose) in blood of a subject, the method
comprising the steps of: (a) placing an electrical conducting probe
against a skin surface of the subject, wherein the probe comprises
a plurality of electrodes, each electrode comprising a spike, the
spikes being laterally spaced apart from each other and being of
sufficient length to penetrate the stratum corneum; (b) passing an
electrical current through the electrodes to obtain a value of
impedance for the skin; and (c) converting the impedance to said
concentration.
2. A method according to claim 1, wherein each spike is at least 10
.mu.m in length.
3. The method of claim 1, wherein the probe comprises three said
electrodes, the spikes of first and second of the electrodes being
laterally spaced a first distance from each other, the spikes of
the first and third electrodes being laterally spaced a second
distance from each other, and wherein and step (b) includes
separately passing an electrical current between the first and
second electrodes and the first and third electrodes to obtain
first and second said values of skin impedance.
4. The method of claim 3, wherein the first and second distances
are different from each other.
5. The method of claim 3, wherein the first distance is between
about 0.1 mm and about 40 mm; or between about 0.1 mm and 30 mm; or
between about 0.1 mm and 25 mm; or between about 0.1 mm and 20 mm;
or between about 0.1 mm and 15 mm; or between about 0.2 mm and 10
mm; or between about 0.2 mm and 8 mm; or between about 0.2 mm and 5
mm; or between about 0.2 mm and 3 mm; or between about 0.2 mm and 2
mm; or between about 0.2 mm and 1.5 mm; or between about 0.2 mm and
1 mm; or between about 0.2 mm and 0.5 mm.
6. The method of claim 5, wherein the second distance is between
about 1 mm and about 50 mm; or between about 1 mm and 40 mm; or
between about 1 mm and 30 mm; or between about 1 mm and 25 mm; or
between about 1 mm and 20 mm; or between about 1 mm and 15 mm; or
between about 1 mm and 10 mm; or between about 1 mm and 9 mm; or
between about 1 mm and 8 mm; or between about 1 mm and 7 mm; or
between about 2 mm and 8 mm; or between about 3 mm and 7 mm; or
between about 4 mm and 7 mm; or between about 4 mm and 6 mm; or
about 5 mm.
7. The method of claim 1, wherein for each electrode, there are at
least two said spikes, or at least three said spikes, or at least
four said spikes, or at least five said spikes, or at least six
said spikes, or at least seven said spikes, or at least eight said
spikes, or at least nine said spikes, or at least ten said spikes,
or at least twelve said spikes, or at least fifteen said spikes, or
at eighteen said spikes, or at least twenty said spikes, or at
least twenty-five said spikes, or at least thirty said spikes, or
at least thirty-five said spikes, or at least fifty said
spikes.
8. The method of claim 1 wherein each said spike is up to 250, or
up to 240, or up to 230, or up to 220, or up to 210, or up to 200,
or up to 190 or up to 180 or up to 170 or up to 160 or up to 150 or
up to 140 or up to 130 or up to 120 or up to 110 or up to 100 .mu.m
in length.
9. The method of claim 1 wherein each said spike is at least 20, or
at least 30 or at least 40 or at least 50, or at least 60 or is at
least 70 or is at least 80 or is at least 90 .mu.m in length.
10. The method of claim 1, wherein each said spike is of sufficient
length to penetrate below the skin surface to the Stratum
Germinativum.
11. The method of claim 1, wherein the outer diameter of each spike
on the electrodes is between about 20 .mu.m and about 50 .mu.m.
12. The method of claim 1, wherein said electrical current has a
frequency of between about 10 Hz and about 10 MHz.
13. The method of claim 12, wherein step (b) is conducted a first
time at a first said frequency, and step (b) is conducted a second
time at a second said frequency.
Description
[0001] This application is a divisional application of U.S.
application Ser. No. 10/682,372, filed Oct. 10, 2003, which claims
priority from U.S. patent application Ser. No. 60/417,561, filed on
Oct. 11, 2002, the contents of all of said applications being
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention is in the field of diagnostics of biological
conditions. In one aspect, the invention involves in vivo
evaluation of the level of a substance in the blood of a subject,
particularly blood glucose levels. In another aspect, the invention
involves diagnosing a diseased condition of the skin of a subject,
particularly the presence of a skin cancer, e.g. basal cell
carcinoma or malignant melanoma, a squamous cell carcinoma or
precursors thereof. In both instances, the determination is based
on skin impedance measurements.
BACKGROUND OF THE INVENTION
[0003] Non-invasive methods of making biological determinations are
generally desirable over invasive techniques that involve the
taking of samples. Non-invasive techniques can be more convenient,
e.g., less painful, involve less risk of infection, etc.
Non-invasive techniques for evaluating blood glucose levels have
been described in the patent literature:
SUMMARY OF THE INVENTION
[0004] A summary of the invention in its various aspects is
provided in the attached claims, bearing in mind that those skilled
in the art will understand that a variety of possible combinations
and subcombinations of the various elements described in the claims
and throughout this specification exist, and all of these
combinations and subcombinations should be considered to be within
the inventors' contemplation though not explicitly enumerated here.
This is also true of the variety of aspects of the processes and
the combinations and subcombinations of elements thereof.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0005] The invention is described in greater detail below, with
reference to the attached figures, in which:
[0006] FIG. 1(a) shows a spiked electrode of the present
invention;
[0007] FIG. 1(b) shows details of the spiked array given as
electron micrograph;
[0008] FIG. 2 shows representative Bode plots of impedance (left
hand axis, kOhms) and phase (right hand axis; degrees) as a
function of frequency number (31 logarithmically distributed
frequencies from 1 kHz to 1 MHz) for subject B. The results shown
in FIG. 2(a) were obtained using a conventional probe and those
shown in FIG. 2(b) were obtained using a spiked electrode. In FIG.
2(a), the lower set of curves shows the magnitude of the impedance
(at various depths) and the corresponding phase is shown by the
upper set of curves. In FIG. 2(b), the phase plots display a local
maximum around frequency number 21;
[0009] FIG. 3 shows the blood glucose level as determined directly
over the course of the tests for each subject. Subject A
(.upsilon.), subject B (.lamda.);
[0010] FIG. 4(a) shows a scatter plot of PCA (principle component
analysis) for each subject (t1 vs. t2) obtained with the spiked
electrode. FIG. 4(b) is a corresponding plot for each subject
obtained with the conventional probe. In both plots, subject A is
to the right and subject B is to the left of the figure;
[0011] FIG. 5(a) shows a scatter plot of measured blood glucose and
index with outliers of subject A obtained with the spiked
electrode. FIG. 5(b) shows the same plot without outliers, readings
number 7, 8, and 13;
[0012] FIG. 6(a) shows a scatter plot of subject B's blood glucose
vs. magnitude of impedance at 1 MHz and depth setting number 5
measured with the spiked electrode with (left) outlier reading
number 10. FIG. 6(b) is the same plot without the outlier;
[0013] FIG. 7 shows a scatter plot of subject B's magnitude at 1
kHz and depth setting number 5 vs. blood glucose;
[0014] FIG. 8 shows representative Bode plots of impedance (left
hand axis; kOhm) and phase angle (right hand axis; degrees) as a
function of frequency (kHz), plotted logarithmically, obtained at
five depth settings using a spiked electrode. In FIG. 8(a), the
results were obtained for a normal skin site of a subject. In FIG.
8(b), the results were obtained from the same subject but a basal
cell carcinoma located near the normal site of FIG. 8(a). In FIG.
8(c), the results were obtained from a normal skin site of another
subject. In FIG. 8(d), the results were obtained from this other
subject but a malignant melanoma located near the normal site of
FIG. 8(c). Each ensemble of curves represents five measured
depths.
[0015] FIG. 9 shows a correlation between blood glucose and values
obtained from impedance measurements taken using a multi-step
inundation method and conventional electrode.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] An apparatus for use according to the present invention can
generally be regarded as a combination of the device described in
international patent application No. PCT/SE 91/00703, published
under WO 92/06634 on Apr. 30, 1992 and the "spiked" electrode
described in international patent application No. PCT/IB 01/00059,
published under WO 01/52731 on Jul. 26, 2001 or in an article
entitled "Micromachined Electrodes for Biopotential Measurements"
published in the Journal of Microelectromechanical Systems 10(1),
pp 10-16, on March 2001 by Griss et al. The electrode used in the
tests described below, however, is a variation of that described by
Griss et al., and is shown if FIGS. 1(a) and 1(b). The probe
includes of a number of electrodes, at least three according to No.
PCT/SE 91/00703, and in the present invention each electrode of the
probe has a spiked surface, which permits measurements to be made
at a variety of skin depths. The probe is illustrated in FIG. 1(b),
the probe being viewed looking down onto its spikes (a bottom plan
view). The probe includes three rectangular areas or bars each bar
containing an array of 35 (7.times.5) spikes. Each bar is 1 mm wide
and 5 mm long. The distance between the closest bars is 0.2 mm, and
the wider between the second and third bars is 1.8 mm. The active
part of the probe is thus about 5.times.5 mm. Each spike has a
length of approximately 150 micrometer, as measured from its base,
and a thickness of approximately 25 micrometer. The spikes are
sharpened cylinders, i.e. are needle-like, and spaced approximately
200 micrometers from each other, center to center. The spikes were
of silicon and covered with gold approximately 2 micrometer thick.
Any material comprising a conductive surface with similar
dimensions would work, but should be selected to be
biocompatible.
[0017] The apparatus, without the spiked probe known as the SciBase
II depth selective spectrometer, may be obtained from SciBase AB of
Huddinge, Sweden. The pin assignment for the probe connector was as
follows: [0018] 1. <START> button [0019] 2. sense (first
electrode illustrated FIG. 1(b); use coaxial (conventional probe)
screen 3. [0020] 3. gnd (for sense) [0021] 4. near exciter (second
(middle) electrode illustrated in FIG. 1(b); use coaxial
(conventional probe) screen 5. [0022] 5. gnd (for near injection).
[0023] 6. gnd. [0024] 7. far exciter (third (right-most) electrode
illustrated in FIG. 1(b); use coaxial (conventional probe) screen
8. [0025] 8. gnd (for far injection). [0026] 9. chassis. [0027] 10.
reserved. [0028] 11. reserved. [0029] 12. gnd. [0030] 13. gnd.
[0031] 14. [0032] 15. charger. Blood Glucose Levels
[0033] Tests were conducted using the foregoing apparatus to
determine the feasibility of using such apparatus in determining
blood glucose levels of human beings. Trials were conducted on two
individuals, subjects A and B. Subject A suffers from atopic
dermatitis, making the subject a relatively poor candidate for a
non-invasive determination involving a skin measurement.
[0034] Tests were thus carried out (i) to assess the correlation
between skin impedance measured using the spiked electrodes and the
blood glucose, and (ii) to compare the glucose correlation of
impedance measured with a conventional probe and the spiked
electrodes.
[0035] Two sites, one on each arm, were marked. One site was used
for the spiked probe and the other for the conventional probe.
Blood glucose levels were measured directly using the Glucometer
Elite (available from Elite Glucometer, Miles Canada, Diagnostics
Division, Division of Bayer). The sites were soaked for 60 seconds
prior to each impedance measurement using 0.9% saline solution and
stopwatch. Impedance was measured using the SciBase II depth
selective spectrometer at 31 logarithmically distributed
frequencies from 1 kHz to 1 MHz at five depth settings, as
described in PCT/SE /00703.
[0036] The correlation between impedance and blood glucose was
evaluated in three steps with increasing complexity of the
regression models. The first step is linear regression between raw
impedance and blood glucose for each frequency, depth setting and
impedance presentation (magnitude, phase, real part, and imaginary
part). The second step is linear regression between indices and
blood glucose. The indices are described in detail below. The last
step is partial least squares regression (PLS) models of full
impedance spectra and glucose levels.
[0037] As indicated in FIG. 2, the magnitude of the impedance
measured with the regular probe (FIG. 2(a)) was found to be much
higher along with the phase, and the characteristic frequency was
lower. Hence, impedance measured with the conventional probe was
significantly different from the spiked electrodes.
[0038] The tests were carried out over about 5 hours. The
electrodes with spikes used to measure impedance of subject B broke
down after approximately 10-11 readings. The glucose levels for
subject A and B, as measured directly, are shown in FIG. 3. The
glucose levels of subject A were generally higher than for subject
B, and the impedance of the two volunteers was also found to be
different, as indicated in FIG. 4. This indicates that it might not
be possible to use one calibration model for these subjects.
[0039] The four indices (MIX, PIX, RIX, and IMIX) were originally
made to normalise impedance spectra of the spectrometer. It was
found that the four indices described a substantial part of the
variations in the impedance spectra and were useful in skin
irritation assessments, but not necessarily in glucose
quantifications. Therefore, new indices, ix, were made using the
frequencies, f, depth settings, d, for all impedance presentations,
X, according to (1). ix .function. ( i , j , k , l , m , n ) = X i
.function. ( f j , d k ) X l .function. ( f m , d n ) .times.
.times. .times. i , k .di-elect cons. 1 .times. .times. .times.
.times. 4 .times. .times. X 1 = Z , X 2 = .theta. , X 3 = Re
.function. ( Z ) , X 4 = Im .function. ( Z ) .times. .times. f i ,
f m .di-elect cons. 1 .times. kHz .times. .times. .times. .times. 1
.times. Mhz .times. .times. d k , d n .di-elect cons. 1 .times.
.times. .times. .times. 5 ( 1 ) ##EQU1##
[0040] Three impedance readings were abnormal and excluded from the
data analysis. Correlation coefficient (R2) of linear regression
between an impedance index of the results obtained with the spiked
electrode and subject A's blood glucose was 70% (n=11). This is
shown in FIG. 5. The new index used in this analysis is based on
only two frequencies, each frequency measured at different depth
settings, and is defined as: ix = Re ( Z 20 .times. kHz , depth
.times. #5 ) Z 500 .times. kHz , depth .times. #3 .times.
##EQU2##
[0041] In the case of the conventional probe, no significant
correlation was found between impedance measured and blood glucose
for subject A.
[0042] In the case of subject B and the results obtained with the
spiked electrode, there was one reading with abnormal impedance.
The measurement was made just before the spiked probe broke down
and it is believed that the impedance of the actual reading was
abnormal because the spiked probe was beginning to malfunction when
the last measurement was made. Linear regression between the
magnitude of the raw impedance at high frequencies and deep depths
and blood glucose showed good correlation, R.sup.2=80% (n=9). See
FIG. 6.
[0043] No significant impedance/glucose correlation was found using
the conventional concentric probe if all the measurements were
included. However, three readings, number 5, 10, and 11, do not
show the same impedance/glucose pattern as the others (FIG. 7). If
these 3 readings are excluded, the correlation coefficient becomes
approximately 95%. If these excluded readings are not considered
outliers (there is nothing abnormal about their impedance or
glucose levels), the correlation between impedance measured with
the regular probe and blood glucose would not be significant.
However, suitable inundation and data exclusion criteria that might
exclude these flawed measurements thus permitting accurate glucose
predictions using the conventional probe at least under certain
conditions.
[0044] The results described herein, summarized in Table 1,
establish the improved correlation between measured skin impedance
and blood glucose levels obtainable using the spiked electrode
described above. It is the experience of the inventors, that a
higher correlation can be achieved using the conventional probe
with optimization of inundation time of the sample site.
TABLE-US-00001 TABLE 1 Summary of the correlation coefficient (R2)
between blood glucose and skin impedance measured with the regular
probe and the spikes. Subject Conventional Probe Spiked Electrode A
Not significant .about.70% B Not significant .about.80%
[0045] It is evident that there was a strong correlation between
skin impedance and blood glucose in this experiment. The
correlation of the two subjects was found more reliable for the
spiked electrodes than the conventional probe.
[0046] The spiked electrodes can improve the glucose correlation by
mitigating factors interfering with the impedance tests and
reducing the stringency of skin inundation in preparing the site
for impedance measurement. Thus the spiked electrodes are likely to
permit glucose determination more reliably in a wider variety of
situations than such determination with a conventional probe.
[0047] The following inundation procedures can be used to improve
results obtained with the conventional probe. Gauze inundation pads
are kept in a closed beaker of 0.9% saline or packaged in a
saturated state. The skin is inundated by holding the gauze pad in
place at the test site for 40 seconds then wiping away any excess
solution before the impedance test, with inundation again 10
additional seconds, wiping away any excess solution before the
second impedance test and impedance test again. This procedure is
repeated until a total of 70 seconds of inundation has been
reached.
[0048] Data are included if at 1 Mhz at depth 1 the kOhms value is
within the range 1.25-1.45. Other frequencies can be used. If more
than one impedance test was within this range, the kOhm value
closest to 1.3 is selected. If the kOhm value is in range and IMIX
at depth one value is between 10.2 and 11.5 then this IMIX value is
accepted. Results obtained over several days are shown in FIG.
9.
[0049] The conditions under which reliable results are obtained
using the probe having spiked electrodes are thus more relaxed than
with the conventional probe. There is thus less likely to be a need
for subjects to use a mild soap, for example, when using the spiked
electrode. It may be possible to obtain reliable results with
tanned or diseased skin (e.g., atopic dermatis) with the spiked
probe where such was not possible with the conventional probe. It
is also likely that use of the same site from measurement to
measurement is less important when using the spiked probe than when
using the conventional probe.
Cancer Diagnosis
[0050] Impedance measurements were similarly taken from subjects
suffering from basal cell carcinoma or malignant melanoma: at a
first site of normal (unaffected skin); and at a second site, of
diseased skin. Results obtained are shown in FIG. 8. A further
description of the approach, in which measurements were obtained
using a conventional probe, is given in Emtestam I, Nicander I,
Stenstrom M, Ollmar S. "Electrical impedance of nodular basal cell
carcinoma: a pilot study", Dermatology 1998; 197: 313-316, and
Kapoor S. "Bioelectric impedance techniques for clinical detection
of skin cancer", (MSc-thesis) University of Missouri-Rolla 2001,
and .ANG.berg P, Nicander I, Holmgren U, Geladi P, Ollmar S.
Assessment of skin lesions and skin cancer using simple electrical
impedance indices. Skin Res Technol 2003; 9: 257-261, and Beetner
DG, Kapoor S, Manjunath S, Zhou X, Stoecker WV. Differentiation
among basal cell carcinoma, benign lesions, and normal skin using
electric impedance. IEEE Trans Biomed Eng 2003; 50: 1020-1025.
[0051] It is desirable to detect and remove skin cancers as early
as possible. As such, precursors of skin cancer, such as, for
example, actinic keratose (a precursor of squamous cell carcinoma)
and dysplastic nevi (a precursor of malignant melanoma), as well as
other lesions that may be mixed up with various cancers unless
surgery and histological evaluation of the catch is made, can be
detected using impedance measurements of the present invention in
the manner described herein.
[0052] The contents of all documents referred to herein are
incorporated into this specification by reference as though such
contents had been reproduced herein in their entirety.
* * * * *