U.S. patent application number 11/116099 was filed with the patent office on 2005-12-08 for subcutaneous analyte sensor.
Invention is credited to Essenpreis, Matthias, Gerber, Martin, Petrich, Wolfgang.
Application Number | 20050271547 11/116099 |
Document ID | / |
Family ID | 25204303 |
Filed Date | 2005-12-08 |
United States Patent
Application |
20050271547 |
Kind Code |
A1 |
Gerber, Martin ; et
al. |
December 8, 2005 |
Subcutaneous analyte sensor
Abstract
Assembly and method for measuring the concentration of an
analyte in a biological matrix. The assembly includes an
implantable optical-sensing element that comprises a body, and a
membrane mounted on the body in a manner such that the membrane and
the body define a cavity. The membrane is permeable to the analyte,
but is impermeable to background species in the biological matrix.
A refractive, element is positioned in the cavity. A light source
transmits light of a first intensity onto the refractive element,
and a light detector receives light of a second intensity that is
reflected from the cavity. A controller device optically coupled to
the detector compares the first and second light intensities, and
relates the intensities to analyte concentration.
Inventors: |
Gerber, Martin; (Carmel,
IN) ; Essenpreis, Matthias; (Fremont, CA) ;
Petrich, Wolfgang; (Bad Schonborn, DE) |
Correspondence
Address: |
Roche Diagnostics Corporation
9115 Hague Road
PO Box 50457
Indianapolis
IN
46250-0457
US
|
Family ID: |
25204303 |
Appl. No.: |
11/116099 |
Filed: |
April 27, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11116099 |
Apr 27, 2005 |
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09810635 |
Mar 16, 2001 |
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6952603 |
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Current U.S.
Class: |
422/82.05 |
Current CPC
Class: |
A61B 5/14532 20130101;
A61B 5/1459 20130101 |
Class at
Publication: |
422/082.05 |
International
Class: |
G01N 021/00 |
Claims
1-32. (canceled)
33. An implantable optical-sensing element suitable for measuring
the concentration of an analyte in a biological matrix, said
optical-sensing element comprising: a body; a membrane mounted on
said body such that said body and said membrane define a cavity for
receiving said analyte, said membrane being substantially permeable
to said analyte, and substantially impermeable to background
species in said biological matrix; and a refractive-element
disposed in said cavity, said refractive element having a
refractive index different from a refractive index of said
analyte.
34. The optical-sensing element of claim 33, wherein said body
comprises two parallel, elongated members, and said refractive
element comprises a plurality of plates, each plate having two
faces, said plates being sequentially arranged between said
elongated members and oriented generally perpendicular to said
elongated members.
35. The optical-sensing element of claim 34, wherein said plates
are integral with said elongated members in a unit-body
construction.
36. The optical-sensing element of claim 33, wherein said membrane
comprises a first membrane, said optical-sensing element further
comprising a second membrane mounted on said body remote from said
first membrane.
37. The optical-sensing element of claim 33, wherein said
refractive element comprises at least one of plates, particles,
beads and powders.
38. The optical-sensing element of claim 33, wherein said
refractive element comprises at least one of a porous fiber, a
porous rod, a convoluted ribbon, and a convoluted fiber.
39. The optical-sensing element of claim 33, wherein the refractive
element has a refractive index within .+-.9% of the refractive
index of said analyte.
40. The optical-sensing element of claim 39, wherein the refractive
index of said refractive element is within .+-.5% of the refractive
index of said analyte.
41. The optical sensing-element of claim 33, wherein the refractive
element has a refractive index between 1.31 and 1.45.
42. The optical-sensing element of claim 33, wherein said
refractive element comprises a moldable plastic.
43. The optical-sensing element of claim 42, wherein said moldable
plastic is poly(undecafluorohexyl acrylate), poly(decamethylene
carbonate), poly(ethylene succinate), poly(ethylene oxide),
poly(trifluoroethylene), poly(hexafluoropropylene), poly(methyl
methacrylate), poly(ethylene), poly(oxy(diethylsilylene)), or
poly(vinyl fluoride).
44. The optical-sensing element of claim 42, wherein said moldable
plastic is poly(methyl methacrylate) or poly(ethylene).
45. The optical-sensing element of claim 33, wherein said membrane
comprises a bipolar membrane having a cation-exchange layer and an
anion-exchange layer.
46. The optical-sensing element of claim 45, wherein said
cation-exchange layer and said anion-exchange layer are bonded
together, said cation-exchange layer comprising a cross-linked
polystyrene sulfonate and said anion-exchange layer comprising a
cross-linked poly(vinyl benzyl trimethyl ammonium chloride).
47. The optical-sensing element of claim 46, wherein said membrane
further comprises a third membrane layer bonded to one of said
cation and anion-exchange layers, said third membrane layer capable
of excluding macrosolutes.
48. The optical-sensing element of claim 47, wherein said third
membrane layer is a regenerated cellulose or polyamide
membrane.
49. The optical-sensing element claim 33, wherein said body
includes a proximal end and a distal end, said distal end of said
body comprising a light-absorbing material.
50. The optical-sensing element of claim 33, wherein said body
includes a proximal end and a distal end, said distal end of said
body comprising a transparent material.
51. The optical-sensing element of claim 33, wherein said body
comprises a moldable plastic.
52. The optical-sensing element of claim 51, wherein said body has
a "U"-shaped or "V"-shaped cross section.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to implantable sensors, and
more specifically, to implantable sensors for monitoring levels of
analytes, such as glucose.
[0002] Several designs for implantable sensors that allow
continuous in vivo monitoring of levels of analytes such as glucose
have been previously described. Many such designs are based on
electrochemical analyte detection principles. As such, they are
prone to inherent signal instability of the sensor, and they
require that chemicals (e.g., enzymes and mediators) be introduced
into the patient's body.
[0003] A second approach involves physical (i.e. reagent-free)
methodology. A review of physical methods for determinations of
glucose in vivo is given in J. D. Kruse-Jarres "Physicochemical
Determinations of glucose in vivo," J. Clin. Chem. Clin. Biochem.
26 (1988), pp. 201-208. Nuclear magnetic resonance (No), electron
spin resonance (ESR), and infrared (IR) spectroscopy are named,
among others, as non-invasive methods. However, none of these
methods has as yet acquired practical significance. Some of them
require large and expensive apparatus, generally unsuitable for
routine analysis and home monitoring of a patient.
[0004] Nearly all of the methods of this second approach are based
on spectroscopic principles. Concerning the optical methods, the
fundamental principle frequently is the interaction of the
irradiated primary light (of a specific wavelength) with the
vibration and rotation states of the molecules undergoing
analytical determination. The basic vibrational and rotational
states of glucose are found in the IR region at wavelengths above
2500 nm. This spectral region is not suitable for invasive
analytical determination of glucose because of the strong
absorption of water, which is present in high concentration in
biological matrices. In the near infra-red (NI) region, the
absorption of water is smaller (the so-called "water transmission
window). The spectral analysis of glucose in this region is based
on absorption by overtones and combination oscillations of the
basic vibrational and rotational states of the glucose molecule
(see the article by Kruse-Jarres cited above and EP-A-0 426
358).
[0005] Developing a practical implantable glucose sensor on the
basis of these principles presents certain problems. These problems
result particularly from the fact that the effective signal (the
change in the absorption spectrum due to a change in glucose
concentration) is generally very small. Sensitivity is always an
issue in absorption measurements because of the difficulty in
observing a small effective signal superimposed on a relatively
much larger background signal. However, in this case the difficulty
is enhanced due to background signals resulting from the spectral
absorption of water. Some attempts have been made to solve this
problem (see e.g., EP-A-0 160 768; U.S. Pat. No. 5,028,787; and WO
93/00856); however, these attempts have not been successful in
providing a practical and functional implantable glucose sensor
based on absorption principles.
[0006] Methods of continuously monitoring glucose based on light
scattering principles have also been described. For instance,
European patent 0 074 428 describes a method and device for the
quantitative determination of glucose by laser light scattering.
The method assumes that glucose particles scatter light rays
transmitted through a test solution, and that the glucose
concentration can be derived from this scattering. The method
requires measurement of the spatial angular distribution of the
transmitted (i.e. forward-scattered) light emerging from a test
cuvette or an investigated part of the body. In particular, the
intensity of the transmitted light is measured in an angular region
in which the change in relation to the glucose concentration is as
large as possible. This intensity is then compared with the
intensity measured for the central ray passing directly through the
sample. For in vivo analytical determination, a transmission
measurement on ear lobes with laser light is exclusively
recommended.
[0007] A second method based on light scattering principles relies
on the measurement of back-scattered light rather than transmitted
(i.e. forward-scattered) light. U.S. Pat. No. 5,551,422 describes a
method for determining glucose concentration in a biological matrix
by performing at least two detection measurements. In each
detection measurement, primary light is irradiated into the
biological matrix through a boundary surface thereof at a defined
radiation site. The light is propagated along a light path within
the biological matrix. An intensity of the light is measured as the
light emerges as secondary light through a defined detection site
of the boundary surface. At least one of the detection measurements
is a spatially resolved measurement of multiply scattered light.
The detection site is located relative to the irradiation site such
that light which was multiply scattered at scattering centers in
the biological matrix is detected. The light paths of the at least
two detection measurements within the biological matrix are
different. Glucose concentration is then derived from the
dependence of the intensity of the secondary light on the relative
positions of the irradiation site and the detection site.
[0008] Additional methods are needed which minimize or eliminate
the effect on light intensity from variations of physical
parameters, such as temperature and/or changes in the
concentrations of background ions, proteins, and organic acids in
the biological matrices, and which minimize the number of light
paths and/or detection measurements required to be performed.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention, in one form thereof, comprises an
assembly for measuring the concentration of an analyte in a
biological matrix. The assembly includes an implantable
optical-sensing element, a source for transmitting light into the
optical-sensing element, and a detector for receiving light emitted
from the optical-sensing element. A signal-processing and computing
element is provided to compare the respective amounts of
transmitted and emitted light, and relate these amounts to the
concentration of the analyte in the biological matrix. The
implantable optical-sensing element comprises a body and a membrane
mounted on the body, such that the membrane and the body define a
cavity. The membrane is substantially permeable to the analyte, and
substantially impermeable to background species in the biological
matrix, such that the analyte is received in the cavity. A
refractive element for the transmitted light is positioned in the
cavity.
[0010] The present invention, in another form thereof, comprises an
implantable optical-sensing element suitable for measuring the
concentration of an analyte in a biological matrix. The
optical-sensing element comprises a body, and a membrane mounted on
the body such that the body and the membrane define a cavity for
receiving the analyte. The membrane is substantially permeable to
the analyte, and substantially impermeable to background species in
the biological matrix, such as large proteins. A refractive element
having a refractive index different from the refractive index of
the analyte is disposed in the cavity.
[0011] The present invention, in yet another form thereof,
comprises an assembly for measuring the concentration of an analyte
in a biological matrix. The assembly comprises an implantable
optical-sensing element comprising a body, and a first
semi-permeable membrane mounted on the body to define a cavity. The
first semi-permeable membrane is permeable to the analyte, and
impermeable to background species in the biological matrix. A
second membrane is mounted on the body remote from the first
membrane to define a second cavity. A first refractive element is
disposed in the first cavity, and a second refractive element is
disposed in the second cavity. A light source provides light into
each of the first and second cavities toward the respective first
and second refractive elements, and a light detector receives light
from each of the first and second cavities. A signal processor and
computer are provided to relate the respective intensities of the
provided light and the received light to the analyte
concentration.
[0012] The present invention, in still another form thereof,
comprises an implantable optical-sensing element suitable for
measuring the concentration of an analyte in a biological matrix.
The optical-sensing element comprises a body and a first
semi-permeable membrane mounted on the body. The first membrane is
permeable to the analyte, and impermeable to background species in
the biological matrix. The first membrane and the body are aligned
to define a first cavity, the first cavity having a first
refractive element disposed therein. A second membrane is mounted
on the body remote from the first membrane. The second membrane and
the body are aligned to define a second cavity isolated from the
first cavity, the second cavity having a second refractive element
disposed therein.
[0013] The present invention, in yet another form thereof,
comprises a method for measuring the concentration of an analyte in
a biological matrix. An optical-sensing element is implanted in the
biological matrix, the optical-sensing element comprising a body
and a semi-permeable membrane mounted on the body, the
semi-permeable membrane being permeable to the analyte and
impermeable to background species in the matrix. The semi-permeable
membrane and the body define a cavity, and a refractive element is
disposed in the cavity. Primary light from a light-emitting source
is introduced into the body of the optical-sensing element, and is
directed toward the refractive element. Secondary light reflected
from the optical-sensing element is collected and transmitted to a
light-detecting device. The intensity of the secondary light is
measured, and the analyte concentration in the biological matrix is
determined by comparing the intensity of the secondary light with
the intensity of the primary light.
[0014] The present invention, in a still further form thereof,
comprises a method for measuring the concentration of an analyte in
a biological matrix. An optical-sensing element is implanted in the
biological matrix, the optical-sensing element comprising a body, a
first membrane mounted on the body, and a second membrane mounted
on the body remote from said first membrane. At least one of the
membranes is permeable to the analyte and impermeable to background
species in the biological matrix. The first and second membranes
define a cavity, and a refractive element is disposed in the
cavity. Primary light from a light-emitting source is transmitted
into the cavity toward the refractive element, and secondary light
reflected from the refractive element is collected and transmitted
to a light-detecting device. The intensity of the secondary light
is measured with the light-detecting device, and the analyte
concentration in the biological matrix is derived therefrom.
[0015] The present invention, in another form thereof, comprises a
method for measuring the concentration of an analyte in a
biological matrix. An optical-sensing element is implanted in the
biological matrix, the optical-sensing element comprising a body, a
first semi-permeable membrane mounted on the body, and a second
semi-permeable membrane mounted on the body remote from the first
semi-permeable membrane. The body and the first membrane define a
cavity having a first refractive element disposed therein, and the
body and the second membrane define a second cavity isolated from
the first cavity and having a second refractive element disposed
therein. Primary light from a light-emitting source is transmitted
into the body, and respective streams of the primary light are
directed into the first cavity toward the first refractive element,
and into the second cavity toward the second refractive element.
Light reflected from the first refractive element is collected and
transmitted to a first channel of a light-detecting device, and
light from the body reflected at the second refractive element is
collected and transmitted to a second channel of the
light-detecting device. The respective intensities of light
collected from each of the first and second channels is measured,
and the concentration of an analyte in the biological matrix is
computed by comparing the intensity of the transmitted light and
the light collected from each of the first and second channels.
[0016] The present invention, in yet another form thereof,
comprises an assembly for monitoring the concentration of an
analyte in a biological matrix. The assembly includes an
implantable optical-sensing element that comprises a body, a
membrane mounted on the body, and a refractive element disposed in
a cavity defined by the membrane and the body. The analyte is
received in the cavity through the membrane, wherein the membrane
is substantially permeable to the analyte of interest and
substantially impermeable to background species in the biological
matrix. One or more light sources provide light of a first
wavelength and a second wavelength into the cavity, the refractive
element in the cavity having a refractive index greater than the
refractive index of the analyte at the first wavelength, and less
than the refractive index of the analyte at the second wavelength.
A detector receives from the cavity an intensity of light at each
of the first and second wavelengths at a first concentration of
said analyte, and receives an intensity of light at each of the
first and second wavelengths at a second concentration of the
analyte. A signal-processing and computing element is optically
coupled to the detector for comparing the intensities of light
received at the first wavelength to the intensities of light
received at the second wavelength, and for relating the intensities
to analyte concentration.
[0017] The present invention, and yet another form thereof,
comprises a method for monitoring a change in the concentration of
an analyte in a biological matrix of a test subject. An
optical-sensing element is implanted in the test subject, the
implantable optical-sensing element comprising a body and a
membrane mounted on the body, wherein the membrane and body define
a cavity for receiving the analyte. The membrane is substantially
permeable to the analyte of interest and substantially impermeable
to background species in the biological matrix. A refractive
element is disposed in the cavity. Light of a first wavelength and
a second wavelength is introduced into the cavity, wherein the
refractive element has a refractive index greater than the
refractive index of the analyte at the first wavelength, and less
than the refractive index of the analyte at the second wavelength.
An intensity of light at each of the first and second wavelengths
is measured at a first concentration of the analyte, and an
intensity of light at each of said first and second wavelengths is
measured at a second concentration of the analyte. The change in
concentration of the analyte is computed by comparing the
intensities of light received at the first wavelength to the
intensities of light received at the second wavelength for each of
the first and second concentrations, and relating the intensities
to changes in analyte concentration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Various other objects, features and attendant advantages of
the present invention will be more fully appreciated as the same
becomes better understood from the following detailed description
when considered in connection with the accompanying drawings in
which like reference characters designate like or corresponding
parts throughout the several views and wherein:
[0019] FIG. 1 shows a side cross-sectional view through the
Y.sub.1Z.sub.1-plane of an optical-sensing element according to a
first embodiment of the present invention;
[0020] FIG. 2, shows a front cross-sectional view through the
X.sub.1Y.sub.1-plane of the optical-sensing element illustrated in
FIG. 1;
[0021] FIG. 3 shows a shows a top cross-sectional view through the
X.sub.1Z.sub.1-plane of the optical-sensing element illustrated in
FIG. 1;
[0022] FIG. 4 shows a side cross-sectional view through the
Y.sub.2Z.sub.2-plane of an optical-sensing element according to a
second embodiment of the present invention;
[0023] FIG. 5 shows a front cross-sectional view through the
X.sub.2Y.sub.2-plane of the optical-sensing element illustrated in
FIG. 4;
[0024] FIG. 6 shows a top cross-sectional view through the
X.sub.2Z.sub.2-plane of the optical-sensing element illustrated in
FIG. 4;
[0025] FIG. 7 shows a side cross-sectional view through the
Y.sub.3Z.sub.3-plane of an optical-sensing element according to a
third embodiment of the present invention;
[0026] FIG. 8 shows a front cross-sectional view through the
X.sub.3Y.sub.3-plane of the optical-sensing element illustrated in
FIG. 7;
[0027] FIG. 9 shows a top cross-sectional view through the
X.sub.3Z.sub.3-plane of the optical-sensing element illustrated in
FIG. 7;
[0028] FIG. 10 shows a side cross-sectional view through the
Y.sub.4Z.sub.4-plane of an optical-sensing element according to a
fourth embodiment of the present invention;
[0029] FIG. 11 shows a top cross-sectional view through the
X.sub.4Y.sub.4-plane of the optical-sensing element illustrated in
FIG. 10;
[0030] FIG. 12 shows a front cross-sectional view through the
X.sub.4Z.sub.4-plane of the optical-sensing element illustrated in
FIG. 10;
[0031] FIG. 13 shows a side cross-sectional view through the
Y.sub.5Z.sub.5-plane of an optical-sensing element according to a
fifth embodiment of the present invention;
[0032] FIG. 14 shows a side cross-sectional view through the
X.sub.5Y.sub.5-plane of the optical-sensing element illustrated in
FIG. 13;
[0033] FIG. 15 shows a top cross-sectional view through the
X.sub.5Z.sub.5-plane of the optical-sensing element illustrated in
FIG. 13;
[0034] FIG. 16 shows a side cross-sectional view through the
Y.sub.6Z.sub.6-plane of an optical-sensing element according to a
sixth embodiment of the present invention;
[0035] FIG. 17 shows a side cross-sectional view through the
X.sub.6Y.sub.6-plane of the optical-sensing element illustrated in
FIG. 16;
[0036] FIG. 18 shows a top cross-sectional view through the
X.sub.6Z.sub.6-plane of the optical-sensing element illustrated in
FIG. 16;
[0037] FIG. 19 shows a side cross-sectional view through the
Y.sub.7Z.sub.7-plane of an optical-sensing element according to a
seventh embodiment of the present invention;
[0038] FIG. 20 shows a side cross-sectional view through the
X.sub.7Y.sub.7-plane of the optical-sensing element illustrated in
FIG. 19;
[0039] FIG. 21 shows a top cross-sectional view through the
X.sub.7Z.sub.7-plane of the optical-sensing element illustrated in
FIG. 19;
[0040] FIG. 22 shows a block diagram of the an opto-electronic
detection and measurement assembly optically coupled to an
optical-sensing element of the type described in embodiments
1-5;
[0041] FIG. 23 shows another block diagram of the an
opto-electronic detection and measurement assembly optically
coupled to an optical-sensing element of the type described in
embodiments 1-5; and
[0042] FIG. 24 shows a block diagram of an opto-electronic
detection and measurement assembly optically coupled to an
optical-sensing element of the type described in embodiments
6-7.
DETAILED DESCRIPTION OF THE INVENTION
[0043] As used herein, the term "biological matrix" denotes a body
fluid or a tissue of a living organism. Biological matrices, to
which the invention relates, are optically heterogeneous, that is,
they contain a large number of substances (e.g., salts, proteins,
and organic acids) which can affect the refractive index.
[0044] As used herein, the term "background species" refers to
analytes such as ions, proteins, and organic acids native to a
biological matrix, or to non-native agents introduced therein, that
are capable of undergoing a change of refractive index
substantially as a result of (1) adequate variations in
concentration in vivo, and (2) a large specific refractive index
increment. "Background species" does not refer to the analyte(s)
being monitored.
[0045] As used herein, the term "refractive element" is used to
refer to an element having a refractive index different from the
refractive index of the medium to be measured.
[0046] As used herein, the term "mMol" denotes the concentration of
a substance in units of millimoles per liter.
[0047] As used herein, the term "n" denotes the refractive index of
a substance.
[0048] The present invention provides an assembly comprising an
implantable optical-sensing element suitable for measuring the
concentration of an analyte in a biological matrix. The function of
the optical-sensing element is to generate changes in light
refraction, which changes are a function of changes in the
concentration of the analyte in the biological matrix. The
optical-sensing element includes a membrane mounted on a body, such
that the membrane and the body define a cavity. The membrane is
substantially permeable to the analyte, thereby permitting the
analyte to pass through the membrane and into the cavity by means
such as diffusion or osmosis, and is substantially impermeable to
background species in the biological matrix.
[0049] The optical-sensing element of the present invention is
stable over extended periods of time, does not require frequent
recalibration, and does not require signal amplification through
enzymatic reactions. The optical-sensing element also minimizes or
eliminates background drift in such measurements due to variations
in physical parameters such as temperature and/or changes in the
concentrations of background ions, proteins, and organic acids that
may be present in the biological matrix.
[0050] An example of an analyte suitable for monitor utilizing the
assembly of the present invention is glucose. It is well known that
a change in concentration of an analyte, such as glucose, in a test
solution results in a change in the refractive index of the
solution. For example, the refractive-index increment of an aqueous
glucose solution .DELTA.n.sub.m for visible wavelengths is
.DELTA.n.sub.m=2.5.times.10.sup- .-5/mMol glucose (see R. C. Weast,
ed., CRC Handbook of Chemistry and Physics, 55.sup.th ed. (CRC,
Cleveland, Ohio 1974), p. D-205), and this relationship is assumed
to be approximately the same over the entire wavelength region
under investigation. In other words, the refractive index of a
solution rises by approximately 2.5.times.10.sup.-5 for an increase
of one mMol in glucose concentration.
[0051] Unfortunately, direct measurement of the glucose
concentration in a biological matrix based on a change in
refractive index is impractical because refractive index is not per
se glucose specific. As shown in Table 1, the presence of certain
background molecules (e.g., organic acids) and ions (e.g., sodium
and chloride) commonly found in biological matrices can
substantially affect the refractive index of the matrix.
1TABLE 1 Concentration (mMol) Substrate Plasma Extracellular
intracellular .DELTA.n.sub.m/mMol glucose 5 5 0 2.5E-05 Na.sup.+
142 144 10 5.0E-06 K.sup.+ 4 4 160 5.0E-06 Ca.sup.2+ 5 3 2 5.0E-06
Mg.sup.2+ 2 2 25 1.3E-05 Cl.sup.- 102 114 2 5.0E-06 HCO.sub.3.sup.-
26 30 10 5.0E-06 PO.sub.4.sup.3- 2 2 100 9.0E-06 SO.sub.4.sup.2- 1
1 20 1.0E-05 organic acids 5 5 0 6.0E-06 (Concentration expressed
in % w/v) Independent concentration changes in these species could
interfere with the glucose measurement and result in drift or
erroneous readings.
[0052] The present invention addresses this problem by providing an
optical-sensing element having a substantially impermeable body
that is enclosed on at least one surface thereof by a
semi-permeable membrane. The semi-permeable membrane is designed to
exclude undesired background molecules and/or ions from
entering/exiting the interior of the body, while allowing the
analyte or analytes of interest to freely diffuse through the
membrane. When the analyte of interest is glucose, the glucose
diffuses through the membrane to equilibrate with tissue glucose
concentration. Background species cannot permeate through the
membrane. For example, proteins can be excluded by using membranes
with adequate pore size (e.g., 30 kD to exclude albumin but enable
glucose diffusion), and ions can be excluded by using a polarized
membrane (.+-.) layer.
[0053] It is preferred to use a bipolar membrane as the
semi-permeable membrane. Bipolar membranes are ion exchange
membranes constructed of two adjoining layers of ion exchangers of
opposite polarity (i.e. a cation-exchange side and an
anion-exchange side). The charge density of these membranes is such
that ions of the same charge as the fixed charges are hindered from
diffusing through the membrane. Bipolar membranes are useful for
isolating one ionic environment from another. These membranes are
highly hydrated, and are thus permeable to non-charged solutes,
such as glucose, which can diffuse from one side to the other.
[0054] Suitable bipolar membranes for use in the present invention
include those produced by Tokuyama Soda (Japan) under the trade
name of NeoSepta, available from Electrosynthesis Company,
Lancaster, N.Y. These membranes are produced for bulk electrolysis
and salt-splitting applications, and thus are mechanically very
stable and rigid. They possess the high charge densities required
for use in the high salt concentrations of biological matrices.
These membranes are approximately 250 um in thickness, and may be
cut to any appropriate size. Thinner membranes of lower ionic
content could also be used. Thinner membranes are advantageous
because they decrease the response time of the sensor and may
provide more accurate results.
[0055] During use, the semi-permeable membrane must be bonded to
the body of the optical-sensing element in a manner that prevents
infusion of solution in or out of the interior of the body except
through the membrane. This bonding may be accomplished by any of
several methods, including heat or ultrasonic bonding, adhesive
bonding with pressure-sensitive adhesives or liquid adhesives such
as cyanoacrylates (e.g., Superglue or Crazyglue), thermoplastic
adhesives such as urethanes or hot-melt adhesives, or photocurable
adhesives. Preferred bonding methods for in vivo applications
include chemical or physical methods such as heat or ultrasonic
bonding.
[0056] Typical commercial bipolar membranes comprise a cross-linked
polystyrene sulfonate for the cation-exchange side bonded to a
crosslinked poly(vinyl benzyl trimethyl ammonium chloride) for the
anion-exchange side. The membranes are typically supplied in a high
concentration (10%) of salt for stabilization, and are equilibrated
with a physiological saline solution (1.15 M NaCl) prior to use in
the optical-sensing element. The bipolar membranes are preferably
cross-linked to an extent that large molecular weight solutes such
as proteins and lipids are also excluded from the membrane, and
concomitantly, from the volume enclosed by the membrane.
[0057] If a thinner bipolar membrane is used to enable a more rapid
response time, it may be desirable to combine the bipolar membrane
with a third membrane layer capable of excluding macrosolutes. Such
a third membrane layer may, for example, be any of the membranes
typically used for dialysis applications, such as regenerated
cellulose or polyamide membranes. The third membrane layer may be
attached to the sensor body, on or around the bipolar membrane,
using any of the methods suitable for attaching the bipolar
membrane. Alternatively, the third membrane layer may be laminated
directly to the bipolar membrane prior to application of the
bipolar-membrane to the sensor body. Moreover, the third membrane
layer may be formed on the bipolar membrane by a casting process,
for example, by dipping the assembled optical-sensing element with
bipolar membrane attached into a solution of a membrane-forming
polymer, and then drying the element under controlled
conditions.
[0058] Bipolar membranes can be formed into hollow fibers in the
same way that membranes for dialysis and microdialysis are
produced, and the membrane-fibers slid over the sensor structure
and attached with any of the above methods.
[0059] The spectroscopic principle relied upon in the present
invention is that light is reflected or refracted at changes in
refractive index. The closer the refractive indices of two
interfacing media, the smaller the specular reflection. When the
refractive indices match, no specular reflection is observable.
Correspondingly, the specular reflection increases in absolute
magnitude as the refractive indices of the two interfacing media
become more disparate. However, the relative change in specular
reflection is largest when the refractive index differential is
small, as discussed in M. Kohl, M. Cope, M. Essenpreis, and D.
Bbcker, Optics Letters, Vol. 19, No. 24, (1994) pp. 2170-2172,
which is incorporated herein by reference in its entirety. Based
upon these competing effects, it has been determined that the
sensitivity of the measurement is optimized when the refractive
index of a refractive element disposed within the body, and the
refractive index of an analyte such as glucose are preferably
within 9%, more preferably within 5%, of each other when the
glucose concentration in the biological matrix is at physiological
levels, i.e., between 4 and 7 mMol.
[0060] When the analyte of interest is glucose, the refractive
element is preferably formed from a material with a refractive
index close to that of a glucose solution at physiological
concentrations (i.e. n=1.38). Preferably, the refractive element is
formed from a moldable plastic having a refractive index between
1.26 and 1.50, more preferably between 1.31 and 1.45. Examples of
suitable plastics include poly(undecafluorohexyl acrylate)
(n-1.36), poly(decamethylene carbonate) (n=1.47), poly(ethylene
succinate), poly(ethylene oxide) (n=1.46), poly(trifluoroethylene)
(n=1.34), poly(hexafluoropropylene) (n=1.31), poly(methyl
methacrylate) (n=1.49), poly(ethylene) (n=1.49),
poly(oxy(diethylsilylene)) (n=1.42), and poly(vinyl fluoride)
(n=1.45). Preferred plastics include poly(methyl methacrylate) and
poly(ethylene).
[0061] A first embodiment of the optical-sensing element of the
invention is illustrated in FIGS. 1-3. The optical-sensing element
includes a body 100, a semi-permeable membrane 110 and a refractive
element 114. The body 100 and membrane 110 are oriented to define a
cavity 112. The refractive element 114 and the analyte or analytes
of interest (not shown) are disposed in the cavity 112. The
semi-permeable membrane 110 is substantially permeable to the
analyte(s), but substantially impermeable to background species in
the biological matrix.
[0062] Preferably, the body 100 of the optical-sensing element has
a generally "U" or "V"-shaped cross-section, and comprises a molded
plastic. The body 100 has a base portion 101 and two opposing side
walls 103. Each of the side walls 103 includes an upper edge 111.
The body 100 has a proximal end 102 and a distal end 104, and is
preferably less than 2 mm in length. A light-transmitting conduit
106, here a single optical fiber, is optically coupled to the
proximal end 102 of the body. Optical coupling between the body and
the conduit can be accomplished by any means known in the art, such
as, for example, using an adhesive to secure the conduit 106 in an
orifice formed in the body 100.
[0063] The refractive element 114 preferably is made from the same
material as the body 100 as part of a single plastic molding
process. In the embodiment of FIGS. 1-3, the refractive element 114
comprises a plurality of substantially parallel, rectangular
plates. The integral, unit-body construction, with bracing by the
rectangular plates, gives the optical-sensing element particular
stability. Preferably, each individual plate of the refractive
element has a thickness less than 10 .mu.m. Each plate has two
faces 115 which function as refractive or reflective surfaces. The
faces 115 may be flat, or alternatively, may be tilted or even
randomly shaped structures (e.g., FIGS. 7, 10 and 13). Tilted
plates may be useful to avoid interferences. When faces such as
those in FIGS. 1-3 are utilized, the faces 115 are oriented such
that each lies in a plane perpendicular to the longitudinal axis of
the body 100, and the faces 115 on adjacent plates are preferably
separated by no more than 10 .mu.m.
[0064] The change in the intensity of light reflected off the
refractive element may be maximized by using a refractive element
114 having faces 115 capable of multiple reflection and/or
refraction in accordance with the Fresnel formulas. This change may
be further maximized by optimizing the refractive index
differential between the analyte and the refractive element 114.
Preferably, the optical-sensing element includes a refractive
element having at least one hundred parallel plates 114 with at
least two hundred faces 115. Most of the plates and faces have been
omitted from FIG. 1 for clarity. By using multiple faces 115, the
intensity of reflected or refracted light corresponding to changes
in refractive index (and therefore to changes in analyte
concentration) can be amplified by a factor of at least 200.
[0065] The body 100 of the optical-sensing element provides a
support structure for the optical-sensing element and should
correspondingly be rigid or semi-rigid. Since the sensing element
is designed to be implanted in living tissue, the construction
material of the body 100 should also be bio-compatible. The distal
end 104 of the body 100 preferably comprises a light absorbing
material 108, although a transparent material may alternatively be
utilized.
[0066] The refractive element 114 can comprise a single structure
or a plurality of structures. No particular shape is required.
Examples of single structures include a porous fiber, a porous rod,
a convoluted ribbon, and a convoluted fiber. The refractive element
may also comprise combinations of the foregoing. Examples of
pluralities of structures include regular or randomly shaped
plates, particles, beads and powders, or combinations of the
foregoing. Regardless of the particular embodiment, the refractive
element preferably provides a plurality of reflective or refractive
faces 115 that interface with the analyte to amplify the reflected
light when compared to light reflected from a single surface.
[0067] A second embodiment of the invention is illustrated in FIGS.
4-6. The body 200 of the optical-sensing element comprises two
parallel, elongated members 203, each having an upper edge 211 and
a lower edge 213. The body is preferably formed of molded plastic
and is dimensioned in similar manner to the embodiment of FIGS.
1-3. The body 200 also includes a proximal end 202 and a distal end
204. A light-transmitting conduit 206, here a single optical fiber,
is sealed in an orifice in the proximal end 202. The distal end 204
preferably comprises a light-absorbing material 208. In this
embodiment, a first semi-permeable membrane 210 is attached to the
top edges 211 of the elongated members 203, and a second
semi-permeable membrane 209 is attached to the bottom edges 213 of
the elongated members 203.
[0068] The elongated members 203 and semi-permeable membranes 209
and 210 define a cavity 212. The cavity contains the analyte of
interest (not shown) and a refractive element 214. The refractive
element comprises a plurality of substantially parallel,
rectangular plates, and the elongated members 203 are held together
with cross-support from the rectangular plates. In other pertinent
respects the numbers and orientation of rectangular plates 214 and
faces 215 are similar to those as described in the previous
embodiment.
[0069] A third embodiment of the invention is illustrated in FIGS.
7-9. In this embodiment, the body 300, base portion 301, side walls
303, light-transmitting conduit 306, light-absorbing material 308,
membrane 310, edges 311, cavity 312, and respective proximal and
distal ends 302 and 304 are as described in the embodiment of FIGS.
1-3. The refractive element 314 comprises a plurality of beads,
which provide a plurality of reflective or refractive surfaces 315.
The composition of the beads is normally not important, as long as
they provide suitable reflective or refractive surfaces. Glass
beads, or beads formed from polymers such as polystyrene, are
particularly suitable. The composition, diameter, and number of the
beads can be varied to achieve a packing arrangement which provides
optimal amplification of light by multiple reflections off the bead
surfaces 315. A similar effect is achieved when refractive powders
are provided in the, cavity in place of the beads.
[0070] A fourth embodiment of the invention is illustrated in FIGS.
10-12. In this embodiment, the body 400, base portion 401, side
walls 403, light-transmitting conduit 406, light-absorbing material
408, membrane 410, edges 411, cavity 412, and respective proximal
and distal ends 402 and 404 are as described in the embodiment of
FIGS. 1-3. The refractive element 414 comprises a convoluted ribbon
or fiber, which provides a plurality of reflective or refractive
surfaces 415. The composition, length, width, and thickness of the
ribbon 414 can be varied to achieve a packing arrangement which
gives optimal amplification of light by multiple reflections off
the surfaces 415. The particular composition of the ribbon or fiber
is normally not important, as long as suitable reflective or
refractive surfaces are provided. Glass or plastic ribbons and
fibers are particularly suitable.
[0071] A fifth embodiment of the invention is illustrated in FIGS.
13-15. In this embodiment, the body 500, base portion 501, side
walls 503, light-transmitting conduit 506, light-absorbing material
508, membrane 510, edges 511, cavity 512, and respective proximal
and distal ends 502 and 504 are as described in the embodiment of
FIGS. 1-3. The refractive element 514 comprises a rod, or fiber,
having a plurality of pores 516. The pores 516 provide a plurality
of reflective or refractive surfaces 515. The rod should have
sufficient porosity so that the interior pores are in contact with
the analyte. The composition of the rod or fiber, as well as the
porosity, pore size and number of pores can be can be varied to
achieve optimal amplification of light by multiple reflections off
the surfaces 515. The particular composition of the rod or fiber is
normally not important, as long as suitable reflective or
refractive surfaces are provided. Glass or plastic rods and fibers
are particularly suitable.
[0072] A sixth embodiment of the invention is illustrated in FIGS.
16-18. The body 600 includes a cross-beam portion 601 and two
opposing side walls 603, and has an ""-shaped cross-section,
preferably manufactured by a plastic molding process. Each of the
side walls 603 includes an upper edge 611 and a lower edge 621. The
cross-beam portion 601 is attached to each side wall 603 between
the upper edge 611 and the lower edge 621. A first semi-permeable
membrane 610 is attached to each upper edge 611 of the side walls
603, thereby defining a first cavity 612. A first
light-transmitting conduit 606, here a single optical fiber, is
sealed in an orifice in the proximal end 602 of the body 600
adjacent the first cavity 612. The distal end 604 of the body 600
preferably comprises a first light-absorbing material 608 adjacent
the first cavity 612. A second semi-permeable membrane 620 is
attached to each lower edge 621 of the opposing walls 603 of the
body 600, thereby forming a second cavity 622 superposed with
respect to the first cavity 612. A second light-transmitting
conduit 616, here a single optical fiber, is sealed in an orifice
in the proximal end 602 of the body 600 adjacent the second cavity
622. The distal end 604 of the body 600 preferably comprises a
second light-absorbing material 618 adjacent the second cavity 622.
The first and second cavities include first and second refractive
elements 614, 624. The refractive elements preferably are made from
the same material as the body 600 and comprise a plurality of
substantially parallel, rectangular plates as before. The first and
second light-absorbing materials, 608 and 618 respectively,
preferably have the same composition. The second semi-permeable
membrane 620 may have the same composition as its counterpart in
the first cavity 612, or a different composition.
[0073] A seventh embodiment of the invention is illustrated in
FIGS. 19-21. The body 700 of the sensing element has a "" shaped
cross-section, preferably manufactured by a plastic molding
process. The body has a base portion 701 and three opposing side
walls 703. Each of the side walls 703 includes an upper edge
711a-711c. The body 700 has a proximal end 702 and a distal end
704, and is preferably less than 2 mm in length. A first
semi-permeable membrane 710 is attached to the upper edge 711a of
one of the outer side walls 703 and to the upper edge 711b of the
inner side wall 703, thereby defining a first cavity 712. A first
light-transmitting conduit 706, here a single optical fiber, is
sealed in an orifice in the proximal end 702 of the body 700
adjacent the first cavity 712. The distal end 704 of the body 700
preferably comprises a first light-absorbing material 708 adjacent
the first cavity 712. The first cavity 712 contains a first
refractive element 714. The first refractive element 714 is
preferably made from the same material as the body 700, and
comprises a plurality of substantially parallel, rectangular
plates.
[0074] A second semi-permeable membrane 720 is attached to the
upper edge 711c of the other outer side wall 703 and to the upper
edge 711b of the inner side wall 703, thereby forming a second
cavity 722. The second cavity 722 is in side-by-side orientation
with respect to the first cavity 712. A second light-transmitting
conduit 716, here a single optical fiber, is sealed in an orifice
in the proximal end 702 of the body 700 adjacent the second cavity
722. The distal end 704 of the body 700 preferably comprises a
second light-absorbing material 718 adjacent the second cavity 722.
The second cavity 722 contains a second refractive element 724. The
second refractive element 724 is preferably made from the same
material as the body 700, and comprises a plurality of
substantially parallel, rectangular plates. The first and second
light-absorbing materials, 708 and 718 respectively, preferably
have the same composition. The second semi-permeable membrane 720
may independently have the same composition as its counterpart in
the first cavity 712, or a different composition.
[0075] The sixth and seventh embodiments of this invention are
particularly useful for simultaneously measuring the concentration
of two different analytes in a biological matrix. This may be
accomplished by choosing respective semi-permeable membranes that
are permeable to different species. For example, the first
semi-permeable membrane could be permeable to analyte A but
impermeable to analyte B, while the second semi-permeable membrane
could be permeable to analyte B but impermeable to analyte A. The
first cavity would then be used to monitor the concentration of
analyte A, while the second cavity would be used to monitor the
concentration of analyte B.
[0076] The sixth and seventh embodiments of this invention may also
be useful for correcting for background changes in the refractive
index of a biological matrix resulting from variations in physical
parameters like temperature. For example, the first semi-permeable
membrane could be permeable to only analyte A, while the second
semi-permeable membrane could be impermeable to all of the
components (analytes) of the biological matrix. The first cavity
would then constitute a sample cell, while the second cavity would
constitute a reference cell. The sample cell could be used to
monitor changes in light resulting from changes in the
concentration of analyte A and physical changes in the environment
of the sensing element. The reference cell could be used to monitor
changes in light intensity resulting solely from physical changes
in the environment of the biological matrix. The differences in
light intensity between the sample and reference cells would then
correlate to the change in refractive index of the biological
matrix due solely to a change in concentration of analyte A.
[0077] Alternatively, the first semi-permeable membrane could be
permeable to analyte A and background species in the biological
matrix, while the second semi-permeable membrane could be permeable
to the background species but impermeable to analyte A. The first
cavity would still constitute a sample cell, while the second
cavity would constitute a reference cell. However, the sample cell
would now be used to monitor changes in light intensity resulting
from changes in the concentration of analyte A, physical changes in
the environment of the sensing element, and changes in the
concentration of the background species. Similarly, the reference
cell would be used to monitor changes in light intensity resulting
from physical changes in the environment of the sensing element and
changes in the concentration of the background species. The
difference in light intensity between the sample and reference
cells would correlate with the change in refractive index of the
biological matrix due to a change in concentration of analyte
A.
[0078] The implantable analyte sensor of the present invention is
designed to optically couple with an opto-electronic detection and
measurement assembly. The opto-electronic detection and measurement
assembly may include the light source for transmitting light from
the light source to the sensing element, or alternatively, the
light source may comprise a separate assembly. The opto-electronic
detection and measurement assembly includes a detector for
receiving light that has been returned or otherwise reflected from
the sensing element. A signal-processing and computing element is
optically coupled to the detector to compare the intensity of the
received light to that of the transmitted light. By using
previously measured reference values, the signal-processing and
computing element converts the differences in light intensity to a
signal relating to analyte concentration. The signal can then be
displayed on a readout device.
[0079] The method does not require spectroscopic measurement at one
or more defined wavelengths, although in certain cases it might be
advantageous to use multiple wavelengths. When measurement at
multiple defined wavelengths is not desired, relatively inexpensive
opto-electronic components, such as light emitting diodes (LED's),
laser diodes, xenon and metal halide lamps, can be used as the
light source.
[0080] A block diagram of an opto-electronic detection and
measurement assembly optically coupled to an optical-sensing
element of the type described in embodiments 1-5 is shown in FIG.
22. The first end 802 of a first light-transmitting conduit 800 is
optically coupled to the proximal end 806 of the body of the
optical-sensing element 808, for example by sealing the end 802 in
an orifice using an adhesive. The second end 804 of the first
light-transmitting conduit 800 is optically coupled to both a
light-emitting source and a light-detecting device. In this
diagram, optical coupling is provided by a beam-splitter 810. The
beam-splitter is preferably tilted such that the angle of incoming
light is equal to the angle of reflected light, and is oriented
such that secondary light emitted from the second end 804 of the
first light-emitting conduit 800 is directed into a second
light-transmitting conduit 814 connected to a light-detecting
device. The light-detecting device can be, for example, a
photomultiplier tube or a photodiode. The beam-splitter 810 is also
oriented such that primary light emitted from a third
light-transmitting conduit 812 connected to the light-emitting
source is directed into the second end 804 of the
light-transmitting conduit 800. The source can emit light either
continuously or in a pulsed mode. Suitable light sources and
detectors can be purchased from Hamamatsu Corporation, Bridgewater
N.J. The light-detecting device is electrically coupled to a
signal-processing and computing element which converts the
secondary light to an electronic signal that can be read in
conventional fashion, such as by visual display on a conventional
readout device. The signal-processing and computing element may
comprise, for example, a conventional controller such as a
software-driven computer.
[0081] Preferably, each of the first, second, and third
light-transmitting conduits, 800, 814, and 812 respectively,
comprises one or more optical fibers. Suitable optical fibers and
optical fiber bundles can be purchased from Polymicro Technologies,
LLC of Phoenix, Ariz. Suitable beamsplitters for optical fibers can
be purchased from Oz Optics LTD. of Carp, Ontario, Canada.
[0082] Another block diagram of an opto-electronic detection and
measurement assembly optically coupled to an optical-sensing
element of the type described in embodiments 1-5 is shown in FIG.
23. In this arrangement, primary light is emitted from a
light-emitting source. The light-emitting source is optically
coupled to the first end 902 of a first light-transmitting conduit
900, for example using a standard SMA connector. The second end 904
of the first light-transmitting conduit 900 is optically coupled to
the proximal end 906 of the body of the optical-sensing element,
for example, by sealing the end 904 in an orifice in the body of
the sensing element. The alignment should be such that the primary
light is directed into the cavity toward the refractive element.
Secondary light resulting from reflection or refraction at the
refractive element is collected in the first end 912 of a second
light-transmitting conduit 910, which is optically coupled to the
proximal end 906 of the body of the optical-sensing element. The
second end of the conduit 914 is optically coupled to a
light-detecting device, for example using an SMA connector. The
light-detecting device can be, for example, a photomultiplier tube
or a photodiode. Preferably, each of the first and second
light-transmitting conduits, 900 and 910 respectively, comprises
one or more optical fibers. The light-detecting device is
electrically coupled to a signal-processing and computing element,
which converts the secondary light to an electronic signal, which
can be displayed on a readout device.
[0083] A block diagram of an opto-electronic detection and
measurement assembly optically coupled to an optical-sensing
element of the type described in embodiments 6-7 is shown in FIG.
24. Primary light is emitted from a light-emitting source. The
light-emitting source is optically coupled to the first end 922 of
a first light-transmitting conduit 920. The second end 924 of the
first light-transmitting conduit 920 is optically coupled to the
proximal end 926 of the body of the optical-sensing element
adjacent the first cavity, in an alignment such that the primary
light is directed into the first cavity toward the first refractive
element. Secondary light resulting from reflection or refraction at
the first refractive element is collected in the first end 942 of a
second light-transmitting conduit 940. The first end 942 of the
second light-transmitting conduit 940 is optically coupled to the
proximal end 926 of the body of the optical-sensing element
adjacent the first cavity, while the second end 944 is optically
coupled to a channel of a light-detecting device. The
light-detecting device can be, for example, a photomultiplier tube
or a photodiode.
[0084] In addition, the light-emitting source is optically coupled
to the first end 932 of a third light-transmitting conduit 930. The
second end 934 of the third light-transmitting conduit 930 is
optically coupled to the proximal end 926 of the body of the
optical-sensing element adjacent the second cavity, in an alignment
such that the primary light is directed into the second cavity
toward the second refractive element. Secondary light resulting
from reflection or refraction at the second refractive element is
collected in the first end 952 of a fourth light-transmitting
conduit 950. The first end 952 of the fourth light-transmitting
conduit 950 is optically coupled to the proximal end 926 of the
body of the optical-sensing element adjacent the second cavity,
while the second end 954 of the fourth light-transmitting conduit
950 is optically coupled to a second channel of the light-detecting
device. Preferably, each of the first, second, third and fourth
light-transmitting conduits, 920, 940, 930, and 950 respectively,
comprises one or more optical fibers. The light-detecting device is
electrically coupled to a signal-processing and computing element,
which converts the secondary light to an electronic signal, which
can be displayed on a readout device.
[0085] The invention further contemplates a method of measuring the
concentration of an analyte in a biological matrix. First, an
optical-sensing element is inserted in the matrix. The
optical-sensing element includes a body, a semi-permeable membrane
and a refractive element as described previously. Next, primary
light is transmitted from a light-emitting source to the body of
the optical-sensing element, and directed into the cavity to the
refractive element. Then, secondary light resulting from the
reflection or refraction of the light at the refractive element is
collected and read by a light-detecting device. The difference in
intensity between the transmitted light and the reflected light is
measured by a standard computing device, and the analyte
concentration in the biological matrix is determined by the
computing device using, for example, an algorithm and calibration
procedure. Such evaluation algorithms and calibration procedures
are well known to those of ordinary skill in the art.
[0086] Once the analyte concentration in the biological matrix has
been derived, the measurement process can be repeated, thereby
allowing for continuous monitoring of the analyte concentration.
Alternatively, the measurement can be made at specific or random
intervals in time. In either case, the results can be displayed
using means known to those of ordinary skill in the art. For
instance, a running graph/chart of the analyte concentration can be
displayed on a monitor. Alternatively, the analyte concentration
can be displayed on a digital readout device or an analog gauge.
Moreover, the electronic signal can be used to trigger an alarm on
an audio device when the analyte concentration is outside a given
range.
[0087] It is a characteristic of the invention that changes in
light intensity returned from the optical sensing component can be
related to changes in the concentration of a specified analyte,
such as glucose, in the biological matrix without the necessity of
spectroscopic measurement at multiple wavelengths. In addition,
there is no requirement that two detection measurements be made,
wherein at least one of the detection measurements is a spatially
resolved measurement of multiply reflected light. All measurements
of light intensity returned from the optical sensing component can
be made at the same spatial location. In addition, the principle
relied on is light reflection, not optical absorption. Thus, in
contrast to previously know spectroscopic methods (particularly NR
spectroscopy), the wavelength is preferably chosen in a region of
the spectrum where absorption of the analyte is relatively low.
[0088] Spectral regions where the absorption of glucose is
relatively low are described, for example, in U.S. Pat. No.
5,551,422. Preferably, the wavelength is between 400 nm and 1300
nm. Other wavelengths outside of this range may be utilized in
suitable cases, provided that interfering species are not
substantially present in the matrix, or if present, are compensated
for by the use of proper reference test samples.
[0089] In contrast to prior techniques, these spectral regions need
not normally be further narrowed to avoid interferences due to
absorption by other components in the biological matrix (e.g.,
hemoglobin), since the semi-permeable membrane excludes such
components from the sensing volume. Likewise, there is no
particular preference for relatively short wavelengths because the
method does not depend on the depth of penetration of light into
the biological matrix.
[0090] In contrast to absorption-based methods for noninvasive
analytical determination of the glucose concentration in a
biological matrix, in the present invention it is generally not
necessary to use narrow-band measurement, due to the minimal
dependence on the measurement wavelength. Thus, relatively
broad-banded light sources (with half-widths larger than 20 nm),
such as light-emitting diodes (LED's) and other semi-conductor
light sources, can be used without the need for subsequent spectral
selection on the primary side or secondary side. This considerably
reduces the cost of the apparatus. This feature makes the apparatus
especially suitable for the continuous monitoring of the glucose
concentration of a diabetic. Even though it is generally not
necessary to use a laser as a primary light source, in some
situations, such as with planar refractive surfaces, laser light
may be utilized if desired. Similarly, it is generally not
necessary to use coherent or polarized light.
[0091] An alternative arrangement to that described above utilizes
one or more light sources that emit light into the cavity at
defined wavelengths in order to exploit the dispersion (i.e.,
wavelength-dependence) of the refractive indices of the refractive
material and/or the analyte. In this arrangement, a light source
emits light having a wavelength .lambda..sub.1 at which the
refractive index of the refractive element n.sub.element is always
greater than the refractive index of the analyte n.sub.analyte.
Another light source emits light having a wavelength .lambda..sub.2
at which the refractive index of the refractive element
n.sub.element is always less than the refractive index of the
n.sub.analyte. The relative index of refraction
n.sub.re1=n.sub.analyte/n- .sub.element at each wavelength is as
follows:
n.sub.re1=1 for .lambda..sub.1, and
n.sub.re1>1 for .lambda..sub.2.
[0092] Alternatively, a single light source that emits light at
multiple wavelengths may be used in combination with a (dichroic)
beam splitter to split the light into separate beams at the desired
wavelengths.
[0093] When the concentration of the analyte changes, for example
increases, n.sub.analyte increases and therefore n.sub.re1
increases for both .lambda..sub.1 and .lambda..sub.2. In this
setting the relative change in the signals caused by .lambda..sub.1
and .lambda..sub.2 is being measured. A relative measurement does
not rely on an absolute calibration and is less affected by
background considerations. Hence this arrangement can be used to
improve the sensitivity and/or the specificity of the method.
[0094] In implementation of this arrangement using multiple
wavelengths, either a single detector or multiple detectors can be
used. For example, when two wavelengths .lambda..sub.1 and
.lambda..sub.2 are used as described above, two separate detectors
can be utilized to receive the signals. One detector would receive
the ".lambda..sub.1-light" and the other would receive the
".lambda..sub.2-light". If desired, a wavelength-dependent dicroic
beam splitter can be used to isolate the proper wavelength from the
reflected light. A controller could then be utilized to analyze the
signals by means such as signal subtraction to yield an
analyte-dependent result. A single detector may also be utilized,
however in this instance, the signals are generally received
alternating in time.
[0095] Suitable light sources for use in this multiple wavelength
approach include multiple independent single light sources each
having a different wavelength. Alternatively, a beam splitter may
be utilized with a single, multichromatic light source to split the
light into separate beams at different, well-defined
wavelengths.
[0096] The sensor could be designed as a transcutaneous sensor,
which uses a light guide to transmit light to: and from the
optical-sensing element. Alternatively, the sensor could be an
integrated device. In this case, the implanted device would
incorporate the light-emitting and optical-sensing elements in a
single element. A fully compatible sensor unit can also include RF
data transmission means and a battery charge.
[0097] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise than as
specifically described herein.
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