U.S. patent application number 17/458034 was filed with the patent office on 2021-12-16 for continuous analyte measurement systems and systems and methods for implanting them.
This patent application is currently assigned to ABBOTT DIABETES CARE INC.. The applicant listed for this patent is ABBOTT DIABETES CARE INC.. Invention is credited to Udo Hoss, Phu Le, John Charles Mazza.
Application Number | 20210386334 17/458034 |
Document ID | / |
Family ID | 1000005798568 |
Filed Date | 2021-12-16 |
United States Patent
Application |
20210386334 |
Kind Code |
A1 |
Hoss; Udo ; et al. |
December 16, 2021 |
CONTINUOUS ANALYTE MEASUREMENT SYSTEMS AND SYSTEMS AND METHODS FOR
IMPLANTING THEM
Abstract
Low profile continuous analyte measurement systems and systems
and methods for implantation within the skin of a patient are
provided.
Inventors: |
Hoss; Udo; (Castro Valley,
CA) ; Mazza; John Charles; (Long Beach, CA) ;
Le; Phu; (Dublin, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBOTT DIABETES CARE INC. |
Alameda |
CA |
US |
|
|
Assignee: |
ABBOTT DIABETES CARE INC.
Alameda
CA
|
Family ID: |
1000005798568 |
Appl. No.: |
17/458034 |
Filed: |
August 26, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17092398 |
Nov 9, 2020 |
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17458034 |
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15789942 |
Oct 20, 2017 |
10827954 |
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17092398 |
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12842013 |
Jul 22, 2010 |
9795326 |
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15789942 |
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61227967 |
Jul 23, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/002 20130101;
A61B 2560/0443 20130101; A61B 2562/227 20130101; A61B 5/6833
20130101; A61B 5/7221 20130101; A61B 5/14865 20130101; A61B 5/14532
20130101 |
International
Class: |
A61B 5/145 20060101
A61B005/145; A61B 5/1486 20060101 A61B005/1486 |
Claims
1. An analyte monitoring system, comprising: a base unit configured
to be mounted on a skin surface; an analyte sensor comprising a
proximal portion configured to be positioned within the base unit
and a distal portion configured to be inserted through the skin
surface, wherein the analyte sensor is configured to detect analyte
levels in a bodily fluid of a user; one or more memories comprising
a drift correction factor of the analyte sensor and a
factory-determined sensitivity; a communication link operatively
coupled to the analyte sensor and configured to communicate data
corresponding to the analyte levels; and a receiver unit comprising
a display and configured to receive the data corresponding to the
analyte levels from the communication link; wherein the analyte
monitoring system is configured to determine the analyte levels
using at least the drift correction factor and the
factory-determined sensitivity.
2. The system of claim 1, further comprising a conductive member
positionable within the base unit and in electrical contact with
the analyte sensor.
3. The system of claim 2, wherein the base unit comprises a cradle
therein for receiving and holding the conductive member.
4. The system of claim 3, wherein the conductive member comprises a
conductive core and an insulating shell covering the conductive
core.
5. The system of claim 1, wherein the base unit is configured to
mechanically and electrically couple the analyte sensor with the
communication link.
6. The system of claim 1, wherein the base unit comprises an
adhesive bottom for adhering to the skin surface.
7. The system of claim 1, wherein the base unit comprises an
opening therein through which the distal portion of the analyte
sensor extends.
8. The system of claim 1, wherein the analyte sensor does not
require a user-initiated calibration during in vivo use of the
analyte sensor.
9. The system of claim 1, wherein the drift correction factor is
associated with a sensor manufacturing lot.
10. The system of claim 1, wherein the factory-determined
sensitivity is associated with a sensor manufacturing lot.
11. The system of claim 1, wherein the drift correction factor is
associated with a sensor manufacturing lot and the
factory-determined sensitivity is associated with the sensor
manufacturing lot.
12. The system of claim 1, wherein the communication link
communicates sensor information from the analyte sensor using a
Bluetooth communication protocol.
13. The system of claim 1, wherein the analyte monitoring system is
further configured to determine the analyte levels by transforming
uncalibrated analyte data.
14. The system of claim 13, wherein the uncalibrated analyte data
is transformed with no user intervention.
15. The system of claim 1, further comprising a data processing
unit, wherein the receiver unit is configured to uniquely identify
the data processing unit.
16. The system of claim 15, wherein the data processing unit is
identified using an identification information of the data
processing unit.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 17/092,398 filed Nov. 9, 2020, which is a
continuation of U.S. patent application Ser. No. 15/789,942 filed
Oct. 20, 2017, now U.S. Pat. No. 10,827,954, which is a
continuation of U.S. patent application Ser. No. 12/842,013 filed
Jul. 22, 2010, now U.S. Pat. No. 9,795,326, which claims priority
under 35 U.S.C. .sctn. 119(e) to U.S. Provisional Application No.
61/227,967 filed Jul. 23, 2009, entitled "Continuous Analyte
Measurement Systems and Systems and Methods for Implanting Them",
the disclosures of each of which are incorporated herein by
reference for all purposes.
BACKGROUND
[0002] There are a number of instances when it is desirable or
necessary to monitor the concentration of an analyte, such as
glucose, lactate, or oxygen, for example, in bodily fluid of a
body. For example, it may be desirable to monitor high or low
levels of glucose in blood or other bodily fluid that may be
detrimental to a human. In a healthy human, the concentration of
glucose in the blood is maintained between about 0.8 and about 1.2
mg/mL by a variety of hormones, such as insulin and glucagons, for
example. If the blood glucose level is raised above its normal
level, hyperglycemia develops and attendant symptoms may result. If
the blood glucose concentration falls below its normal level,
hypoglycemia develops and attendant symptoms, such as neurological
and other symptoms, may result. Both hyperglycemia and hypoglycemia
may result in death if untreated. Maintaining blood glucose at an
appropriate concentration is thus a desirable or necessary part of
treating a person who is physiologically unable to do so unaided,
such as a person who is afflicted with diabetes mellitus.
[0003] Certain compounds may be administered to increase or
decrease the concentration of blood glucose in a body. By way of
example, insulin can be administered to a person in a variety of
ways, such as through injection, for example, to decrease that
person's blood glucose concentration. Further by way of example,
glucose may be administered to a person in a variety of ways, such
as directly, through injection or administration of an intravenous
solution, for example, or indirectly, through ingestion of certain
foods or drinks, for example, to increase that person's blood
glucose level.
[0004] Regardless of the type of adjustment used, it is typically
desirable or necessary to determine a person's blood glucose
concentration before making an appropriate adjustment. Typically,
blood glucose concentration is monitored by a person or sometimes
by a physician using an in vitro test that requires a blood sample.
The person may obtain the blood sample by withdrawing blood from a
blood source in his or her body, such as a vein, using a needle and
syringe, for example, or by lancing a portion of his or her skin,
using a lancing device, for example, to make blood available
external to the skin, to obtain the necessary sample volume for in
vitro testing. The fresh blood sample is then applied to an in
vitro testing device such as an analyte test strip, whereupon
suitable detection methods, such as colorimetric, electrochemical,
or photometric detection methods, for example, may be used to
determine the person's actual blood glucose level. The foregoing
procedure provides a blood glucose concentration for a particular
or discrete point in time, and thus, must be repeated periodically,
in order to monitor blood glucose over a longer period.
[0005] Conventionally, a "finger stick" is generally performed to
extract an adequate volume of blood from a finger for in vitro
glucose testing since the tissue of the fingertip is highly
perfused with blood vessels. These tests monitor glucose at
discrete periods of time when an individual affirmatively initiates
a test at a given point in time, and therefore may be characterized
as "discrete" tests. Unfortunately, the fingertip is also densely
supplied with pain receptors, which can lead to significant
discomfort during the blood extraction process. Unfortunately, the
consistency with which the level of glucose is checked varies
widely among individuals. Many diabetics find the periodic testing
inconvenient and they sometimes forget to test their glucose level
or do not have time for a proper test. Further, as the fingertip is
densely supplied with pain receptors which causes significant
discomfort during the blood extraction process, some individuals
will not be inclined to test their glucose levels as frequently as
they should. These situations may result in hyperglycemic or
hypoglycemic episodes.
[0006] Glucose monitoring systems that allow for sample extraction
from sites other than the finger and/or that can operate using
small samples of blood, have been developed. (See, e.g., U.S. Pat.
Nos. 6,120,676, 6,591,125 and 7,299,082, the disclosures of each of
which are incorporated herein by reference for all purposes).
Typically, about one .mu.L or less of sample may be required for
the proper operation of these devices, which enables glucose
testing with a sample of blood obtained from the surface of a palm,
a hand, an arm, a thigh, a leg, the torso, or the abdomen. Even
though less painful than the finger stick approach, these other
sample extraction methods are still inconvenient and may also be
somewhat painful.
[0007] In addition to the discrete, in vitro, blood glucose
monitoring systems described above, at least partially implantable,
or in vivo, blood glucose monitoring systems, which are designed to
provide continuous or semi-continuous in vivo measurement of an
individual's glucose concentration, have been described. See, e.g.,
U.S. Pat. Nos. 6,175,752, 6,284,478, 6,134,461, 6,560,471,
6,746,582, 6,579,690, 6,932,892 and 7,299,082, the disclosures of
each of which are incorporated herein by reference for all
purposes.
[0008] A number of these in vivo systems are based on "enzyme
electrode" technology, whereby an enzymatic reaction involving an
enzyme such as glucose oxidase, glucose dehydrogenase, or the like,
is combined with an electrochemical sensor for the determination of
an individual's glucose level in a sample of the individual's
biological fluid. By way of example, the electrochemical sensor may
be placed in substantially continuous contact with a blood source,
e.g., may be inserted into a blood source, such as a vein or other
blood vessel, for example, such that the sensor is in continuous
contact with blood and can effectively monitor blood glucose
levels. Further by way of example, the electrochemical sensor may
be placed in substantially continuous contact with bodily fluid
other than blood, such as dermal or subcutaneous fluid, for
example, for effective monitoring of glucose levels in such bodily
fluid, such as interstitial fluid.
[0009] Relative to discrete or periodic monitoring using analyte
test strips, continuous monitoring is generally more desirable in
that it may provide a more comprehensive assessment of glucose
levels and more useful information, including predictive trend
information, for example. Subcutaneous continuous glucose
monitoring is also desirable as it is typically less invasive than
continuous glucose monitoring in blood accessed from a blood
vessel.
[0010] Regardless of the type of implantable analyte monitoring
device employed, it has been observed that transient, low sensor
readings which result in clinically significant sensor related
errors may occur for a period of time. For example, it has been
found that during the initial 12-24 hours of sensor operation
(after implantation), a glucose sensor's sensitivity (defined as
the ratio between the analyte sensor current level and the blood
glucose level) may be relatively low--a phenomenon sometimes
referred to as "early signal attenuation" (ESA). Additionally, low
sensor readings may be more likely to occur at certain predictable
times such as during night time use--commonly referred to as "night
time drop outs". An in vivo analyte sensor with lower than normal
sensitivity may report blood glucose values lower than the actual
values, thus potentially underestimating hyperglycemia, and
triggering false hypoglycemia alarms.
[0011] While these transient, low readings are infrequent and, in
many instances, resolve after a period of time, the negative
deviations in sensor readings impose constraints upon analyte
monitoring during the period in which the deviations are observed.
One manner of addressing this problem is to configure the analyte
monitoring system so as to delay reporting readings to the user
until after this period of negative deviations passes. However,
this leaves the user vulnerable and relying on alternate means of
analyte measuring, e.g., in vitro testing, during this time.
Another way of addressing negative deviations in sensor sensitivity
is to require frequent calibration of the sensor during the time
period in which the sensor is used. This is often accomplished in
the context of continuous glucose monitoring devices by using a
reference value after the sensor has been positioned in the body,
where the reference value most often employed is obtained by a
finger stick and use of a blood glucose test strip. However, these
multiple calibrations are not desirable for at least the reasons
that they are inconvenient and painful, as described above.
[0012] One cause of spurious low readings or drop outs by these
implantable sensors is thought to be the presence of blood clots,
also known as "thrombi", formed as a result of insertion of the
sensor in vivo. Such clots exist in close proximity to a
subcutaneous glucose sensor and have a tendency to "consume"
glucose at a high rate, thereby lowering the local glucose
concentration. It may also be that the implanted sensor constricts
adjacent blood vessels thereby restricting glucose delivery to the
sensor site.
[0013] One approach to addressing the problem of drop outs is to
reduce the size of the sensor, thereby reducing the likelihood of
thrombus formation upon implantation and impingement of the sensor
structure on adjacent blood vessels, and thus, maximizing fluid
flow to the sensor. One manner of reducing the size or surface area
of at least the implantable portion of a sensor is to provide a
sensor in which the sensor's electrodes and other sensing
components and/or layers are distributed over both sides of the
sensor, thereby necessitating a narrow sensor profile. Examples of
such double-sided sensors are disclosed in U.S. Pat. No. 6,175,752,
U.S. Patent Application Publication No. 2007/0203407, now U.S. Pat.
No. 7,826,879, and U.S. Provisional Application No. 61/165,499
filed Mar. 31, 2009, the disclosures of each of which are
incorporated herein by reference for all purposes.
[0014] It would also be desirable to provide sensors for use in a
continuous analyte monitoring system that have negligible
variations in sensitivity, including no variations or at least no
statistically significant and/or clinically significant variations,
from sensor to sensor. Such sensors would have to lend themselves
to being highly reproducible and would necessarily involve the use
of extremely accurate fabrication processes.
[0015] It would also be highly advantageous to provide continuous
analyte monitoring systems that are substantially impervious to, or
at least minimize, spurious low readings due to the in vivo
environmental effects of subcutaneous implantation, such as ESA and
night-time dropouts. Of particular interest are analyte monitoring
devices and systems that are capable of substantially immediate and
accurate analyte reporting to the user so that spurious low
readings, or frequent calibrations, are minimized or are non
existent.
[0016] It would also be highly advantageous if such sensors had a
construct which makes them even less invasive than currently
available sensors and which further minimizes pain and discomfort
to the user.
SUMMARY
[0017] Embodiments of the present disclosure include continuous
analyte monitoring systems utilizing implantable or partially
implantable analyte sensors which have a relatively small profile
(as compared to currently available implantable sensors). The
relatively small size of the subject sensors reduce the likelihood
of bleeding and, therefore, minimize thrombus formation upon
implantation and the impingement of the sensor structure on
adjacent blood vessels, and thus, maximizing fluid flow to the
sensor and reducing the probability of ESA or low sensor
readings.
[0018] In certain embodiments, the sensors are double-sided,
meaning that both sides of the sensor's substrate are
electrochemically functional, i.e., each side provides at least one
electrode, thereby reducing the necessary surface area of the
sensor. This enables the sensors to have a relatively smaller
insertable distal or tail portion which reduces the in vivo
environmental effects to which they are subjected. Further, the
non-insertable proximal or external portion of the sensor may also
have a relatively reduced size.
[0019] The subject continuous analyte monitoring systems include a
skin-mounted portion or assembly and a remote portion or assembly.
The skin-mounted portion includes at least the data transmitter,
the transmitter battery, a portion of the sensor electronics, and
electrical contacts for electrically coupling the implanted sensor
with the transmitter. The remote portion of the system includes at
least a data receiver and a user interface which may also be
configured for test strip-based glucose monitoring. The
skin-mounted portion of the system has a housing or base which is
constructed to externally mount to the patient's skin and to
mechanically and electrically couple the implanted sensor with the
transmitter. Removably held or positioned within the housing/base
structure is a connector piece having an electrical contact
configuration which, when used with a double-sided sensor, enables
coupling of the sensor to the transmitter in a low-profile,
space-efficient manner. The skin-mounted components of the system,
including the associated mounting/coupling structure, have
complementary diminutive structures which, along with the very
small sensor, which maximize patient usability and comfort.
[0020] Embodiments further include systems and devices for
implanting the subject analyte sensors within a patient's skin and
simultaneously coupling the analyte monitoring system's external,
skin-mounted unit to the implanted sensor. Certain insertion
systems include at least a manually-held and/or manually-operated
inserter device and an insertion needle which is carried by and
removably coupled to the inserter. In certain of these embodiments,
only the insertion needle is disposable with the inserter or
insertion gun being reusable, reducing the overall cost of the
system and providing environmental advantages. In other
embodiments, the skin-mounted unit and sensor are inserted manually
without the use of an insertion device.
[0021] Embodiments of the subject continuous analyte monitoring
systems may include additional features and advantages. For
example, certain embodiments do not require individual-specific
calibration by the user, and, in certain of these embodiments,
require no factory-based calibration as well. Certain other
embodiments of the continuous analyte monitoring systems are
capable of substantially immediate and accurate analyte reporting
to the user so that spurious low readings, or frequent
calibrations, are minimized or are non-existent.
[0022] The subject analyte sensors usable with the subject
continuous analyte monitoring systems are highly reproducible with
negligible or virtually non-existent sensor-to-sensor variations
with respect to sensitivity to the analyte, eliminating the need
for user-based calibration. Furthermore, in certain embodiments,
the analyte sensors have a predictable sensitivity drift on the
shelf and/or during in vivo use are provided. Computer programmable
products including devices and/or systems that include programming
for a given sensor drift profile may also be provided. The
programming may use the drift profile to apply a correction factor
to the system to eliminate the need for user-based calibration.
[0023] These and other features, objects and advantages of the
present disclosure will become apparent to those persons skilled in
the art upon reading the details of the present disclosure as more
fully described below.
INCORPORATION BY REFERENCE
[0024] The following patents, applications and/or publications are
incorporated herein by reference for all purposes: U.S. Pat. Nos.
4,545,382; 4,711,245; 5,262,035; 5,262,305; 5,264,104; 5,320,715;
5,356,786; 5,509,410; 5,543,326; 5,593,852; 5,601,435; 5,628,890;
5,820,551; 5,822,715; 5,899,855; 5,918,603; 6,071,391; 6,103,033;
6,120,676; 6,121,009; 6,134,461; 6,143,164; 6,144,837; 6,161,095;
6,175,752; 6,270,455; 6,284,478; 6,299,757; 6,338,790; 6,377,894;
6,461,496; 6,503,381; 6,514,460; 6,514,718; 6,540,891; 6,560,471;
6,579,690; 6,591,125; 6,592,745; 6,600,997; 6,605,200; 6,605,201;
6,616,819; 6,618,934; 6,650,471; 6,654,625; 6,676,816; 6,730,200;
6,736,957; 6,746,582; 6,749,740; 6,764,581; 6,773,671; 6,881,551;
6,893,545; 6,932,892; 6,932,894; 6,942,518; 7,041,468; 7,167,818;
and 7,299,082; U.S. Published Application Nos. 2004/0186365, now
U.S. Pat. No. 7,811,231; 2005/0182306, now U.S. Pat. No. 8,771,183;
2006/0025662, now U.S. Pat. No. 7,740,581; 2006/0091006;
2007/0056858, now U.S. Pat. No. 8,298,389; 2007/0068807, now U.S.
Pat. No. 7,846,311; 2007/0095661; 2007/0108048, now U.S. Pat. No.
7,918,975; 2007/0199818, now U.S. Pat. No. 7,811,430; 2007/0227911,
now U.S. Pat. No. 7,887,682; 2007/0233013; 2008/0066305, now U.S.
Pat. No. 7,895,740; 2008/0081977, now U.S. Pat. No. 7,618,369;
2008/0102441, now U.S. Pat. No. 7,822,557; 2008/0148873, now U.S.
Pat. No. 7,802,467; 2008/0161666; 2008/0267823; and 2009/0054748,
now U.S. Pat. No. 7,885,698; U.S. patent application Ser. No.
11/461,725, now U.S. Pat. No. 7,866,026; Ser. Nos. 12/131,012;
12/242,823, now U.S. Pat. No. 8,219,173; Ser. No. 12/363,712, now
U.S. Pat. No. 8,346,335; Ser. Nos. 12/495,709; 12/698,124; and
12/714,439; U.S. Provisional Application Ser. Nos. 61/184,234;
61/230,686; and 61/347,754.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] A detailed description of various aspects, features and
embodiments of the present disclosure is provided herein with
reference to the accompanying drawings, which are briefly described
below. The drawings are illustrative and are not necessarily drawn
to scale, with some components and features being exaggerated for
clarity. The drawings illustrate various aspects and features of
the present disclosure and may illustrate one or more embodiment(s)
or example(s) of the present disclosure in whole or in part. A
reference numeral, letter, and/or symbol that is used in one
drawing to refer to a particular element or feature maybe used in
another drawing to refer to a like element or feature. Included in
the drawings are the following:
[0026] FIG. 1 shows a block diagram of an embodiment of a data
monitoring and management system usable with the continuous analyte
monitoring systems of the present disclosure;
[0027] FIG. 2 shows a block diagram of an embodiment of a
transmitter unit of the data monitoring and management system of
FIG. 1;
[0028] FIG. 3 shows a block diagram of an embodiment of the
receiver/monitor unit of the data monitoring and management system
of FIG. 1;
[0029] FIG. 4 shows a schematic diagram of an embodiment of an
analyte sensor usable with the present disclosure;
[0030] FIGS. 5A and 5B show perspective and cross sectional views,
respectively, of an embodiment of an analyte sensor usable with the
present disclosure;
[0031] FIGS. 6A, 6B and 6C show top, bottom and cross-sectional
side views, respectively, of an embodiment of a two-sided analyte
sensor usable with the present disclosure;
[0032] FIGS. 7A, 7B and 7C show top, bottom and cross-sectional
side views, respectively, of another embodiment of a two-sided
analyte sensor usable with the present disclosure;
[0033] FIGS. 8A and 8B show perspective and top views,
respectively, of one embodiment of a continuous analyte monitoring
system of the present disclosure utilizing a double-sided analyte
sensor;
[0034] FIGS. 9A-9E show various views of another embodiment of a
continuous analyte monitoring system of the present disclosure
utilizing a different double-sided analyte sensor; specifically,
FIG. 9A is a cross-sectional view of the system's control unit,
including the transmitter, on-skin mounting structure, and an
electrical/mechanical connector with an analyte sensor operatively
attached thereto;
[0035] FIG. 9B is an exploded view of the connector and analyte
sensor; FIG. 9C is an exploded, partial cutaway view of the
mechanical/electrical connector and the analyte sensor; FIG. 9D is
a lengthwise cross-sectional view of the cutaway portion of the
connector taken along lines D-D of FIG. 9C; FIG. 9E is a
cross-sectional view of the coupling core, taken along lines E-E of
FIG. 9C, and associated pins of the system's transmitter;
[0036] FIGS. 10A-10F are schematic representations illustrating use
of an insertion system of the present disclosure to insert the
continuous analyte monitoring system of FIGS. 9A-9E on/in the skin
of a patient;
[0037] FIGS. 11A and 11B show side and top views, respectively, of
an insertion needle of the insertion system of FIGS. 10A-10F having
the double-sided analyte sensor of FIGS. 9A-9E operatively nested
therein; and
[0038] FIGS. 12A and 12B are top and bottom perspective views of
another continuous analyte monitoring system of the present
disclosure.
DETAILED DESCRIPTION
[0039] Before the embodiments of the present disclosure are
described, it is to be understood that the present disclosure is
not limited to particular embodiments described, as such may, of
course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting, since the scope of the
present disclosure will be limited only by the appended claims.
[0040] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range, is encompassed within embodiments of
the present disclosure. The upper and lower limits of these smaller
ranges may independently be included in the smaller ranges as also
encompassed within embodiments of the present disclosure, subject
to any specifically excluded limit in the stated range. Where the
stated range includes one or both of the limits, ranges excluding
either or both of those included limits are also included in the
present disclosure.
[0041] Generally, embodiments of the present disclosure relate to
methods and devices for detecting at least one analyte, such as
glucose, in body fluid. Embodiments relate to the continuous and/or
automatic in vivo monitoring of the level of one or more analytes
using a continuous analyte monitoring system that includes an
analyte sensor for the in vivo detection, of an analyte, such as
glucose, lactate, and the like, in a body fluid. Embodiments
include wholly implantable analyte sensors and analyte sensors in
which only a portion of the sensor is positioned under the skin and
a portion of the sensor resides above the skin, e.g., for contact
to a control unit, transmitter, receiver, transceiver, processor,
etc. At least a portion of a sensor may be, for example,
subcutaneously positionable in a patient for the continuous or
semi-continuous monitoring of a level of an analyte in a patient's
interstitial fluid. For the purposes of this description,
semi-continuous monitoring and continuous monitoring will be used
interchangeably, unless noted otherwise. The sensor response may be
correlated and/or converted to analyte levels in blood or other
fluids. In certain embodiments, an analyte sensor may be positioned
in contact with interstitial fluid to detect the level of glucose,
which detected glucose may be used to infer the glucose level in
the patient's bloodstream. Analyte sensors may be insertable into a
vein, artery, or other portion of the body containing fluid.
Embodiments of the analyte sensors of the subject disclosure may be
configured for monitoring the level of the analyte over a time
period which may range from minutes, hours, days, weeks, or
longer.
[0042] FIG. 1 shows a data monitoring and management system such
as, for example, an analyte (e.g., glucose) monitoring system 100
in accordance with certain embodiments. Embodiments of the subject
disclosure are further described primarily with respect to glucose
monitoring devices and systems, and methods of glucose detection,
for convenience only and such description is in no way intended to
limit the scope of the present disclosure. It is to be understood
that the analyte monitoring system may be configured to monitor a
variety of analytes instead of or in addition to glucose, e.g., at
the same time or at different times.
[0043] Analytes that may be monitored include, but are not limited
to, acetyl choline, amylase, bilirubin, cholesterol, chorionic
gonadotropin, creatine kinase (e.g., CK-MB), creatine, creatinine,
DNA, fructosamine, glucose, glutamine, growth hormones, hormones,
ketone bodies, lactate, oxygen, peroxide, prostate-specific
antigen, prothrombin, RNA, thyroid stimulating hormone, and
troponin. The concentration of drugs, such as, for example,
antibiotics (e.g., gentamicin, vancomycin, and the like),
digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may
also be monitored. In those embodiments that monitor more than one
analyte, the analytes may be monitored at the same or different
times.
[0044] The analyte monitoring system 100 includes a sensor 101, a
data processing unit 102 connectable to the sensor 101, and a
primary receiver unit 104 which is configured to communicate with
the data processing unit 102 via a communication link 103. In
certain embodiments, the primary receiver unit 104 may be further
configured to transmit data to a data processing terminal 105 to
evaluate or otherwise process or format data received by the
primary receiver unit 104. The data processing terminal 105 may be
configured to receive data directly from the data processing unit
102 via a communication link which may optionally be configured for
bi-directional communication. Further, the data processing unit 102
may include a transmitter or a transceiver to transmit and/or
receive data to and/or from the primary receiver unit 104 and/or
the data processing terminal 105 and/or optionally the secondary
receiver unit 106.
[0045] Also shown in FIG. 1 is an optional secondary receiver unit
106 which is operatively coupled to the communication link 103 and
configured to receive data transmitted from the data processing
unit 102. The secondary receiver unit 106 may be configured to
communicate with the primary receiver unit 104, as well as the data
processing terminal 105. The secondary receiver unit 106 may be
configured for bi-directional wireless communication with each of
the primary receiver unit 104 and the data processing terminal 105.
As discussed in further detail below, in certain embodiments the
secondary receiver unit 106 may be a de-featured receiver as
compared to the primary receiver, i.e., the secondary receiver may
include a limited or minimal number of functions and features as
compared with the primary receiver unit 104. As such, the secondary
receiver unit 106 may include a smaller (in one or more, including
all, dimensions), compact housing or embodied in a device such as a
wrist watch, arm band, etc., for example. Alternatively, the
secondary receiver unit 106 may be configured with the same or
substantially similar functions and features as the primary
receiver unit 104. The secondary receiver unit 106 may include a
docking portion to be mated with a docking cradle unit for
placement by, e.g., the bedside for nighttime monitoring, and/or a
bi-directional communication device. A docking cradle may recharge
a powers supply.
[0046] Only one sensor 101, data processing unit 102 and data
processing terminal 105 are shown in the embodiment of the analyte
monitoring system 100 illustrated in FIG. 1. However, it will be
appreciated by one of ordinary skill in the art that the analyte
monitoring system 100 may include more than one sensor 101 and/or
more than one data processing unit 102, and/or more than one data
processing terminal 105. Multiple sensors may be positioned in a
patient for analyte monitoring at the same or different times. In
certain embodiments, analyte information obtained by a first
positioned sensor may be employed as a comparison to analyte
information obtained by a second sensor. This may be useful to
confirm or validate analyte information obtained from one or both
of the sensors. Such redundancy may be useful if analyte
information is contemplated in critical therapy-related
decisions.
[0047] The analyte monitoring system 100 may be a continuous
monitoring system or semi-continuous. In a multi-component
environment, each component may be configured to be uniquely
identified by one or more of the other components in the system so
that communication conflict may be readily resolved between the
various components within the analyte monitoring system 100. For
example, unique IDs, communication channels, and the like, may be
used.
[0048] In certain embodiments, the sensor 101 is physically
positioned in and/or on the body of a user whose analyte level is
being monitored. The sensor 101 may be configured to continuously
or semi-continuously sample the analyte level of the user
automatically (without the user initiating the sampling), based on
a programmed intervals such as, for example, but not limited to,
once every minute, once every five minutes and so on, and convert
the sampled analyte level into a corresponding signal for
transmission by the data processing unit 102. The data processing
unit 102 is coupleable to the sensor 101 so that both devices are
positioned in or on the user's body, with at least a portion of the
analyte sensor 101 positioned transcutaneously. The data processing
unit 102 may include a fixation element such as adhesive or the
like to secure it to the user's body. A mount (not shown)
attachable to the user and mateable with the unit 102 may be used.
For example, a mount may include an adhesive surface. The data
processing unit 102 performs data processing functions, where such
functions may include, but are not limited to, filtering and
encoding of data signals, each of which corresponds to a sampled
analyte level of the user, for transmission to the primary receiver
unit 104 via the communication link 103. In one embodiment, the
sensor 101 or the data processing unit 102 or a combined
sensor/data processing unit may be wholly implantable under the
skin layer of the user.
[0049] In certain embodiments, the primary receiver unit 104 may
include a signal interface section including an radio frequency
(RF) receiver and an antenna that is configured to communicate with
the data processing unit 102 via the communication link 103, and a
data processing section for processing the received data from the
data processing unit 102 such as data decoding, error detection and
correction, data clock generation, data bit recovery, etc., or any
combination thereof.
[0050] In operation, the primary receiver unit 104 in certain
embodiments is configured to synchronize with the data processing
unit 102 to uniquely identify the data processing unit 102, based
on, for example, an identification information of the data
processing unit 102, and thereafter, to continuously or
semi-continuously receive signals transmitted from the data
processing unit 102 associated with the monitored analyte levels
detected by the sensor 101. Referring again to FIG. 1, the data
processing terminal 105 may include a personal computer, a portable
computer such as a laptop or a handheld device (e.g., personal
digital assistants (PDAs), telephone such as a cellular phone
(e.g., a multimedia and Internet-enabled mobile phone such as an
iPhone or similar phone), mp3 player, pager, and the like), drug
delivery device, each of which may be configured for data
communication with the receiver via a wired or a wireless
connection. Additionally, the data processing terminal 105 may
further be connected to a data network (not shown) for storing,
retrieving, updating, and/or analyzing data corresponding to the
detected analyte level of the user.
[0051] The data processing terminal 105 may include an infusion
device such as an insulin infusion pump or the like, which may be
configured to administer insulin to patients, and which may be
configured to communicate with the primary receiver unit 104 for
receiving, among others, the measured analyte level. Alternatively,
the primary receiver unit 104 may be configured to integrate an
infusion device therein so that the primary receiver unit 104 is
configured to administer insulin (or other appropriate drug)
therapy to patients, for example, for administering and modifying
basal profiles, as well as for determining appropriate boluses for
administration based on, among others, the detected analyte levels
received from the data processing unit 102. An infusion device may
be an external device or an internal device (wholly implantable in
a user).
[0052] In certain embodiments, the data processing terminal 105,
which may include an insulin pump, may be configured to receive the
analyte signals from the data processing unit 102, and thus,
incorporate the functions of the primary receiver unit 104
including data processing for managing the patient's insulin
therapy and analyte monitoring. In certain embodiments, the
communication link 103 as well as one or more of the other
communication interfaces shown in FIG. 1, may use one or more of:
an RF communication protocol, an infrared communication protocol, a
Bluetooth.RTM. enabled communication protocol, an 802.11x wireless
communication protocol, or an equivalent wireless communication
protocol which would allow secure, wireless communication of
several units (for example, per HIPAA requirements), while avoiding
potential data collision and interference.
[0053] FIG. 2 shows a block diagram of an embodiment of a data
processing unit of the data monitoring and detection system shown
in FIG. 1. User input and/or interface components may be included
or a data processing unit may be free of user input and/or
interface components. Referring to the Figure, the transmitter unit
102 in one embodiment includes an analog interface 201 configured
to communicate with the sensor 101 (FIG. 1), a user input 202, and
a temperature detection section 203, each of which is operatively
coupled to a transmitter processor 204 such as a central processing
unit (CPU). In certain embodiments, one or more
application-specific integrated circuits (ASIC) may be used to
implement one or more functions or routines associated with the
operations of the data processing unit (and/or receiver unit) using
for example one or more state machines and buffers.
[0054] As can be seen in the embodiment of FIG. 2, the sensor 101
(FIG. 1) includes four contacts, three of which are
electrodes--work electrode (W) 210, reference electrode (R) 212,
and counter electrode (C) 213, each operatively coupled to the
analog interface 201 of the data processing unit 102. This
embodiment also shows optional guard contact (G) 211. Fewer or
greater electrodes may be employed. For example, the counter and
reference electrode functions may be served by a single
counter/reference electrode, there may be more than one working
electrode and/or reference electrode and/or counter electrode, etc.
Also shown is a leak detection circuit 214 coupled to the guard
contact (G) 211 and the processor 204 in the transmitter unit 102
of the analyte monitoring system 100. The leak detection circuit
214 in accordance with one embodiment of the present disclosure may
be configured to detect leakage current in the sensor 101 to
determine whether the measured sensor data is corrupt or whether
the measured data from the sensor 101 is accurate. Further shown in
FIG. 2 are a transmitter serial communication section 205 and an RF
transmitter 206, each of which is also operatively coupled to the
transmitter processor 204. Moreover, a power supply 207 such as a
battery is also provided in the transmitter unit 102 to provide the
necessary power for the transmitter unit 102. Additionally, as can
be seen from the Figure, clock 208 is provided to, among others,
supply real time information to the transmitter processor 204. In
one embodiment, a unidirectional input path is established from the
sensor 101 (FIG. 1) and/or manufacturing and testing equipment to
the analog interface 201 of the transmitter unit 102, while a
unidirectional output is established from the output of the RF
transmitter 206 of the transmitter unit 102 for transmission to the
primary receiver unit 104. In this manner, a data path is shown in
FIG. 2 between the aforementioned unidirectional input and output
via a dedicated link 209 from the analog interface 201 to serial
communication section 205, thereafter to the processor 204, and
then to the RF transmitter 206.
[0055] FIG. 3 is a block diagram of an embodiment of a
receiver/monitor unit such as the primary receiver unit 104 of the
data monitoring and management system shown in FIG. 1. The primary
receiver unit 104 may include one or more of: a blood glucose test
strip interface 301 for in vitro testing, an RF receiver 302, an
input 303, a temperature monitor section 304, and a clock 305, each
of which is operatively coupled to a processing and storage section
307. The primary receiver unit 104 also includes a power supply 306
operatively coupled to a power conversion and monitoring section
308. Further, the power conversion and monitoring section 308 is
also coupled to the receiver processor 307. Moreover, also shown
are a receiver serial communication section 309, and an output 310,
each operatively coupled to the processing and storage unit 307.
The receiver may include user input and/or interface components or
may be free of user input and/or interface components.
[0056] In certain embodiments having a test strip interface 301,
the interface includes a glucose level testing portion to receive a
blood (or other body fluid sample) glucose test or information
related thereto. For example, the interface may include a test
strip port to receive a glucose test strip. The device may
determine the glucose level of the test strip, and optionally
display (or otherwise notice) the glucose level on the output 310
of the primary receiver unit 104. Any suitable test strip may be
employed, e.g., test strips that only require a very small amount
(e.g., one microliter or less, e.g., 0.5 microliter or less, e.g.,
0.1 microliter or less), of applied sample to the strip in order to
obtain accurate glucose information, e.g. Freestyle.RTM. and
Precision.RTM. blood glucose test strips from Abbott Diabetes Care
Inc. Glucose information obtained by the in vitro glucose testing
device may be used for a variety of purposes, computations, etc.
For example, the information may be used to calibrate sensor 101
(however, calibration of the subject sensors may not be necessary),
confirm results of the sensor 101 to increase the confidence
thereof (e.g., in instances in which information obtained by sensor
101 is employed in therapy related decisions), etc. Exemplary blood
glucose monitoring systems are described, e.g., in U.S. Pat. Nos.
6,071,391, 6,120,676, 6,338,790 and 6,616,819, and in U.S.
application Ser. No. 11/282,001, now U.S. Pat. No. 7,918,975 and
Ser. No. 11/225,659, now U.S. Pat. No. 8,298,389, the disclosures
of each of which are incorporated herein by reference for all
purposes.
[0057] In further embodiments, the data processing unit 102 and/or
the primary receiver unit 104 and/or the secondary receiver unit
106, and/or the data processing terminal/infusion section 105 may
be configured to receive the blood glucose value from a wired
connection or wirelessly over a communication link from, for
example, a blood glucose meter. In further embodiments, a user
manipulating or using the analyte monitoring system 100 (FIG. 1)
may manually input the blood glucose value using, for example, a
user interface (for example, a keyboard, keypad, voice commands,
and the like) incorporated in the one or more of the data
processing unit 102, the primary receiver unit 104, secondary
receiver unit 106, or the data processing terminal/infusion section
105.
[0058] Additional detailed descriptions are provided in U.S. Pat.
Nos. 5,262,035, 5,262,305, 5,264,104, 5,320,715, 5,593,852,
6,103,033, 6,134,461, 6,175,752, 6,560,471, 6,579,690, 6,605,200,
6,654,625, 6,746,582 and 6,932,894, and in U.S. Published Patent
Application Nos. 2004/0186365, now U.S. Pat. No. 7,811,231 and
2005/0182306, now U.S. Pat. No. 8,771,183, the disclosures of each
of which are incorporated herein by reference for all purposes.
[0059] FIG. 4 schematically shows an embodiment of an analyte
sensor usable in the continuous analyte monitoring systems just
described. This sensor embodiment includes electrodes 401, 402 and
403 on a base 404. Electrodes (and/or other features) may be
applied or otherwise processed using any suitable technology, e.g.,
chemical vapor deposition (CVD), physical vapor deposition,
sputtering, reactive sputtering, printing, coating, ablating (e.g.,
laser ablation), painting, dip coating, etching and the like.
Suitable conductive materials include but are not limited to
aluminum, carbon (such as graphite), cobalt, copper, gallium, gold,
indium, iridium, iron, lead, magnesium, mercury (as an amalgam),
nickel, niobium, osmium, palladium, platinum, rhenium, rhodium,
selenium, silicon (e.g., doped polycrystalline silicon), silver,
tantalum, tin, titanium, tungsten, uranium, vanadium, zinc,
zirconium, mixtures thereof, and alloys, oxides, or metallic
compounds of these elements.
[0060] The sensor may be wholly implantable in a user or may be
configured so that only a portion is positioned within (internal) a
user and another portion outside (external) a user. For example,
the sensor 400 may include a portion positionable above a surface
of the skin 410, and a portion positioned below the skin. In such
embodiments, the external portion may include contacts (connected
to respective electrodes of the second portion by traces) to
connect to another device also external to the user such as a
transmitter unit. While the embodiment of FIG. 4 shows three
electrodes side-by-side on the same surface of base 404, other
configurations are contemplated, e.g., fewer or greater electrodes,
some or all electrodes on different surfaces of the base or present
on another base, some or all electrodes stacked together, some or
all electrodes twisted together (e.g., an electrode twisted around
or about another or electrodes twisted together), electrodes of
differing materials and dimensions, etc.
[0061] FIG. 5A shows a perspective view of an embodiment of an
electrochemical analyte sensor 500 of the present disclosure having
a first portion (which in this embodiment may be characterized as a
major or body portion) positionable above a surface of the skin
510, and a second portion (which in this embodiment may be
characterized as a minor or tail portion) that includes an
insertion tip 530 positionable below the skin, e.g., penetrating
through the skin and into, e.g., the dermal space 520, in contact
with the user's biofluid such as interstitial fluid. Contact
portions of a working electrode 501, a reference electrode 502, and
a counter electrode 503 are positioned on the portion of the sensor
500 situated above the skin surface 510. Working electrode 501, a
reference electrode 502, and a counter electrode 503 are shown at
the second section and particularly at the insertion tip 530.
Traces may be provided from the electrode at the tip to the
contact, as shown in FIG. 5A. It is to be understood that greater
or fewer electrodes may be provided on a sensor. For example, a
sensor may include more than one working electrode and/or the
counter and reference electrodes may be a single counter/reference
electrode, etc.
[0062] FIG. 5B shows a cross sectional view of a portion of the
sensor 500 of FIG. 5A. The electrodes 501, 502 and 503 of the
sensor 500 as well as the substrate and the dielectric layers are
provided in a layered configuration or construction. For example,
as shown in FIG. 5B, in one aspect, the sensor 500 (such as the
sensor 101 FIG. 1), includes a substrate layer 504, and a first
conducting layer 501 such as carbon, gold, etc., disposed on at
least a portion of the substrate layer 504, and which may provide
the working electrode. Also shown disposed on at least a portion of
the first conducting layer 501 is a sensing component or layer 508,
discussed in greater detail below. The area of the conducting layer
covered by the sensing layer is herein referred to as the active
area. A first insulation layer such as a first dielectric layer 505
is disposed or layered on at least a portion of the first
conducting layer 501, and further, a second conducting layer 502
may be disposed or stacked on top of at least a portion of the
first insulation layer (or dielectric layer) 505, and which may
provide the reference electrode. In one aspect, conducting layer
502 may include a layer of silver/silver chloride (Ag/AgCl), gold,
etc. A second insulation layer 506 such as a dielectric layer in
one embodiment may be disposed or layered on at least a portion of
the second conducting layer 509. Further, a third conducting layer
503 may provide the counter electrode 503. It may be disposed on at
least a portion of the second insulation layer 506. Finally, a
third insulation layer 507 may be disposed or layered on at least a
portion of the third conducting layer 503. In this manner, the
sensor 500 may be layered such that at least a portion of each of
the conducting layers is separated by a respective insulation layer
(for example, a dielectric layer). The embodiment of FIGS. 5A and
5B show the layers having different lengths. Some or all of the
layers may have the same or different lengths and/or widths.
[0063] In addition to the electrodes, sensing layer and dielectric
layers, sensor 500 may also include a temperature probe, a mass
transport limiting layer, a biocompatible layer, and/or other
optional components (none of which are illustrated). Each of these
components enhances the functioning of and/or results from the
sensor.
[0064] Substrate 504 may be formed using a variety of
non-conducting materials, including, for example, polymeric or
plastic materials and ceramic materials. (It is to be understood
that substrate includes any dielectric material of a sensor, e.g.,
around and/or in between electrodes of a sensor such as a sensor in
the form of a wire wherein the electrodes of the sensor are wires
that are spaced-apart by a substrate). In some embodiments, the
substrate is flexible. For example, if the sensor is configured for
implantation into a patient, then the sensor may be made flexible
(although rigid sensors may also be used for implantable sensors)
to reduce pain to the patient and damage to the tissue caused by
the implantation of and/or the wearing of the sensor. A flexible
substrate often increases the patient's comfort and allows a wider
range of activities. Suitable materials for a flexible substrate
include, for example, non-conducting plastic or polymeric materials
and other non-conducting, flexible, deformable materials. Examples
of useful plastic or polymeric materials include thermoplastics
such as polycarbonates, polyesters (e.g., Mylar and polyethylene
terephthalate (PET)), polyvinyl chloride (PVC), polyurethanes,
polyethers, polyamides, polyimides, or copolymers of these
thermoplastics, such as PETG (glycol-modified polyethylene
terephthalate).
[0065] In other embodiments, the sensors, or at least a portion of
the sensors, are made using a relatively rigid substrate, for
example, to provide structural support against bending or breaking.
Examples of rigid materials that may be used as the substrate
include poorly conducting ceramics, such as aluminum oxide and
silicon dioxide. One advantage of an implantable sensor having a
rigid substrate is that the sensor 500 may have a sharp point
and/or a sharp edge to aid in implantation of a sensor without an
additional insertion device. It will be appreciated that for many
sensors and sensor applications, both rigid and flexible sensors
will operate adequately. The flexibility of the sensor may also be
controlled and varied along a continuum by changing, for example,
the composition and/or thickness and/or width of the substrate
(and/or the composition and/or thickness and/or width of one or
more electrodes or other material of a sensor).
[0066] In addition to considerations regarding flexibility, it is
often desirable that implantable sensors should have a substrate
which is non-toxic. For example, the substrate may be approved by
one or more appropriate governmental agencies or private groups for
in vivo use.
[0067] Although the sensor substrate, in at least some embodiments,
has uniform dimensions along the entire length of the sensor, in
other embodiments, the substrate has a distal end or tail portion
and a proximal end or body portion with different widths,
respectively, as illustrated in FIG. 5A. In these embodiments, the
distal end 530 of the sensor may have a relatively narrow width.
For in vivo sensors which are implantable into the subcutaneous
tissue or another portion of a patient's body, the narrow width of
the distal end of the substrate may facilitate the implantation of
the sensor. Often, the narrower the width of the sensor, the less
pain the patient will feel during implantation of the sensor and
afterwards.
[0068] For subcutaneously implantable sensors which are designed
for continuous or semi-continuous monitoring of the analyte during
normal activities of the patient, a tail portion or distal end of
the sensor which is to be implanted into the patient may have a
width of about 2 mm or less, e.g., about 1 mm or less, e.g., about
0.5 mm or less, e.g., about 0.25 mm or less, e.g., about 0.15 mm or
less. However, wider or narrower sensors may be used. The proximal
end of the sensor may have a width larger than the distal end to
facilitate the connection between the electrode contacts and
contacts on a control unit, or the width may be substantially the
same as the distal portion.
[0069] The thickness of the substrate may be determined by the
mechanical properties of the substrate material (e.g., the
strength, modulus, and/or flexibility of the material), the desired
use of the sensor including stresses on the substrate arising from
that use, as well as the depth of any channels or indentations that
may be formed in the substrate, as discussed below. The substrate
of a subcutaneously implantable sensor for continuous or
semi-continuous monitoring of the level of an analyte while the
patient engages in normal activities may have a thickness that
ranges from about 50 .mu.m to about 500 .mu.m, e.g., from about 100
.mu.m to about 300 .mu.m. However, thicker and thinner substrates
may be used.
[0070] The length of the sensor may have a wide range of values
depending on a variety of factors. Factors which influence the
length of an implantable sensor may include the depth of
implantation into the patient and the ability of the patient to
manipulate a small flexible sensor and make connections between the
sensor and the sensor control unit/transmitter. A subcutaneously
implantable sensor of FIG. 5A may have an overall length ranging
from about 0.3 to about 5 cm, however, longer or shorter sensors
may be used. The length of the tail portion of the sensor (e.g.,
the portion which is subcutaneously inserted into the patient) is
typically from about 0.25 to about 2 cm in length. However, longer
and shorter portions may be used. All or only a part of this narrow
portion may be subcutaneously implanted into the patient. The
lengths of other implantable sensors will vary depending, at least
in part, on the portion of the patient into which the sensor is to
be implanted or inserted.
[0071] Electrodes 501, 502 and 503 are formed using conductive
traces disposed on the substrate 504. These conductive traces may
be formed over a smooth surface of the substrate or within channels
formed by, for example, embossing, indenting or otherwise creating
a depression in the substrate. The conductive traces may extend
most of the distance along a length of the sensor, as illustrated
in FIG. 5A, although this is not necessary. For implantable
sensors, particularly subcutaneously implantable sensors, the
conductive traces typically may extend close to the tip of the
sensor to minimize the amount of the sensor that must be
implanted.
[0072] The conductive traces may be formed on the substrate by a
variety of techniques, including, for example, photolithography,
screen printing, or other impact or non-impact printing techniques.
The conductive traces may also be formed by carbonizing conductive
traces in an organic (e.g., polymeric or plastic) substrate using a
laser. A description of some exemplary methods for forming the
sensor is provided in U.S. patents and applications noted herein,
including U.S. Pat. Nos. 5,262,035, 6,103,033, 6,175,752 and
6,284,478, the disclosures of each of which are incorporated herein
by reference for all purposes.
[0073] Another method for disposing the conductive traces on the
substrate includes the formation of recessed channels in one or
more surfaces of the substrate and the subsequent filling of these
recessed channels with a conductive material. The recessed channels
may be formed by indenting, embossing, or otherwise creating a
depression in the surface of the substrate. Exemplary methods for
forming channels and electrodes in a surface of a substrate can be
found in U.S. Pat. No. 6,103,033, the disclosure of which is
incorporated herein by reference for all purposes. The depth of the
channels is typically related to the thickness of the substrate. In
one embodiment, the channels have depths in the range of about 12.5
.mu.m to about 75 .mu.m, e.g., about 25 .mu.m to about 50
.mu.m.
[0074] The conductive traces are typically formed using a
conductive material such as carbon (e.g., graphite), a conductive
polymer, a metal or alloy (e.g., gold or gold alloy), or a metallic
compound (e.g., ruthenium dioxide or titanium dioxide). The
formation of films of carbon, conductive polymer, metal, alloy, or
metallic compound are well-known and include, for example, chemical
vapor deposition (CVD), physical vapor deposition, sputtering,
reactive sputtering, printing, coating, and painting. In
embodiments in which the conductive material is filled into
channels formed in the substrate, the conductive material is often
formed using a precursor material, such as a conductive ink or
paste. In these embodiments, the conductive material is deposited
on the substrate using methods such as coating, painting, or
applying the material using a spreading instrument, such as a
coating blade. Excess conductive material between the channels is
then removed by, for example, running a blade along the substrate
surface.
[0075] In certain embodiments, some or all of the electrodes 501,
502, 503 may be provided on the same side of the substrate 504 in
the layered construction as described above, or alternatively, may
be provided in a co-planar manner such that two or more electrodes
may be positioned on the same plane (e.g., side-by side (e.g.,
parallel) or angled relative to each other) on the substrate 504.
For example, co-planar electrodes may include a suitable spacing
there between and/or include dielectric material or insulation
material disposed between the conducting layers/electrodes.
Furthermore, in certain embodiments, one or more of the electrodes
501, 502, 503 may be disposed on opposing sides of the substrate
504. Variations of such double-sided sensors are illustrated in
FIGS. 6 and 7, discussed and described in detail below. In such
double-sided sensor embodiments, the corresponding electrode
contacts may be on the same or different sides of the substrate.
For example, an electrode may be on a first side and its respective
contact may be on a second side, e.g., a trace connecting the
electrode and the contact may traverse through the substrate.
[0076] As noted above, analyte sensors include an
analyte-responsive enzyme to provide a sensing component or sensing
layer 508 proximate to or on a surface of a working electrode in
order to electrooxidize or electroreduce the target analyte on the
working electrode. Some analytes, such as oxygen, can be directly
electrooxidized or electroreduced, while other analytes, such as
glucose and lactate, require the presence of at least one component
designed to facilitate the electrochemical oxidation or reduction
of the analyte. The sensing layer may include, for example, a
catalyst to catalyze a reaction of the analyte and produce a
response at the working electrode, an electron transfer agent to
transfer electrons between the analyte and the working electrode
(or other component), or both.
[0077] In certain embodiments, the sensing layer includes one or
more electron transfer agents. Electron transfer agents that may be
employed are electroreducible and electrooxidizable ions or
molecules having redox potentials that are a few hundred millivolts
above or below the redox potential of the standard calomel
electrode (SCE). The electron transfer agent may be organic,
organometallic, or inorganic. Examples of organic redox species are
quinones and species that in their oxidized state have quinoid
structures, such as Nile blue and indophenol. Examples of
organometallic redox species are metallocenes such as ferrocene.
Examples of inorganic redox species are hexacyanoferrate (III),
ruthenium hexamine etc.
[0078] In certain embodiments, electron transfer agents have
structures or charges which prevent or substantially reduce the
diffusional loss of the electron transfer agent during the period
of time that the sample is being analyzed. For example, electron
transfer agents include, but are not limited to, a redox species,
e.g., bound to a polymer which can in turn be disposed on or near
the working electrode. The bond between the redox species and the
polymer may be covalent, coordinative, or ionic. Although any
organic, organometallic or inorganic redox species may be bound to
a polymer and used as an electron transfer agent, in certain
embodiments the redox species is a transition metal compound or
complex, e.g., osmium, ruthenium, iron, and cobalt compounds or
complexes. It will be recognized that many redox species described
for use with a polymeric component may also be used, without a
polymeric component.
[0079] One type of polymeric electron transfer agent contains a
redox species covalently bound in a polymeric composition. An
example of this type of mediator is poly(vinylferrocene). Another
type of electron transfer agent contains an ionically-bound redox
species. This type of mediator may include a charged polymer
coupled to an oppositely charged redox species. Examples of this
type of mediator include a negatively charged polymer coupled to a
positively charged redox species such as an osmium or ruthenium
polypyridyl cation. Another example of an ionically-bound mediator
is a positively charged polymer such as quaternized poly(4-vinyl
pyridine) or poly(l-vinyl imidazole) coupled to a negatively
charged redox species such as ferricyanide or ferrocyanide. In
other embodiments, electron transfer agents include a redox species
coordinatively bound to a polymer. For example, the mediator may be
formed by coordination of an osmium or cobalt 2,2'-bipyridyl
complex to poly(l-vinyl imidazole) or poly(4-vinyl pyridine).
[0080] Suitable electron transfer agents are osmium transition
metal complexes with one or more ligands, each ligand having a
nitrogen-containing heterocycle such as 2,2'-bipyridine,
1,10-phenanthroline, 1-methyl, 2-pyridyl biimidazole, or
derivatives thereof. The electron transfer agents may also have one
or more ligands covalently bound in a polymer, each ligand having
at least one nitrogen-containing heterocycle, such as pyridine,
imidazole, or derivatives thereof. One example of an electron
transfer agent includes (a) a polymer or copolymer having pyridine
or imidazole functional groups and (b) osmium cations complexed
with two ligands, each ligand containing 2,2'-bipyridine,
1,10-phenanthroline, or derivatives thereof, the two ligands not
necessarily being the same. Some derivatives of 2,2'-bipyridine for
complexation with the osmium cation include, but are not limited
to, 4,4'-dimethyl-2,2'-bipyridine and mono-, di-, and
polyalkoxy-2,2'-bipyridines, such as
4,4'-dimethoxy-2,2'-bipyridine. Derivatives of 1,10-phenanthroline
for complexation with the osmium cation include, but are not
limited to, 4,7-dimethyl-1,10-phenanthroline and mono, di-, and
polyalkoxy-1,10-phenanthrolines, such as
4,7-dimethoxy-1,10-phenanthroline. Polymers for complexation with
the osmium cation include, but are not limited to, polymers and
copolymers of poly(l-vinyl imidazole) (referred to as "PVI") and
poly(4-vinyl pyridine) (referred to as "PVP"). Suitable copolymer
substituents of poly(l-vinyl imidazole) include acrylonitrile,
acrylamide, and substituted or quaternized N-vinyl imidazole, e.g.,
electron transfer agents with osmium complexed to a polymer or
copolymer of poly(l-vinyl imidazole).
[0081] Embodiments may employ electron transfer agents having a
redox potential ranging from about -200 mV to about +200 mV versus
the standard calomel electrode (SCE).
[0082] As mentioned above, the sensing layer may also include a
catalyst which is capable of catalyzing a reaction of the analyte.
The catalyst may also, in some embodiments, act as an electron
transfer agent. When the analyte of interest is glucose, a catalyst
such as a glucose oxidase, glucose dehydrogenase (e.g.,
pyrroloquinoline quinone (PQQ), dependent glucose dehydrogenase or
oligosaccharide dehydrogenase, flavine adenine dinucleotide (FAD)
dependent glucose dehydrogenase, or nicotinamide adenine
dinucleotide (NAD) dependent glucose dehydrogenase) may be used. A
lactate oxidase or lactate dehydrogenase may be used when the
analyte of interest is lactate. Laccase may be used when the
analyte of interest is oxygen or when oxygen is generated or
consumed in response to a reaction of the analyte.
[0083] In certain embodiments, a catalyst may be attached to a
polymer, cross linking the catalyst with another electron transfer
agent which, as described above, may be polymeric. A second
catalyst may also be used in certain embodiments. This second
catalyst may be used to catalyze a reaction of a product compound
resulting from the catalyzed reaction of the analyte. The second
catalyst may operate with an electron transfer agent to electrolyze
the product compound to generate a signal at the working electrode.
Alternatively, a second catalyst may be provided in an
interferent-eliminating layer to catalyze reactions that remove
interferents.
[0084] Certain embodiments include a Wired Enzyme.TM. sensing layer
(such as used in the FreeStyle Navigator.RTM. continuous glucose
monitoring system by Abbott Diabetes Care Inc.) that works at a
gentle oxidizing potential, e.g., a potential of about +40 mV. This
sensing layer uses an osmium (Os)-based mediator designed for low
potential operation and is stably anchored in a polymeric layer.
Accordingly, in certain embodiments the sensing element is redox
active component that includes (1) Osmium-based mediator molecules
attached by stable (bidente) ligands anchored to a polymeric
backbone, and (2) glucose oxidase enzyme molecules. These two
constituents are crosslinked together.
[0085] In certain embodiments, the sensing system detects hydrogen
peroxide to infer glucose levels. For example, a hydrogen
peroxide-detecting sensor may be constructed in which a sensing
layer includes enzymes such as glucose oxidase, glucose
dehydrogenase, or the like, and is positioned proximate to the
working electrode. The sensing layer may be covered by one or more
layers, e.g., a membrane that is selectively permeable to glucose.
Once the glucose passes through the membrane, it may be oxidized by
the enzyme and reduced glucose oxidase can then be oxidized by
reacting with molecular oxygen to produce hydrogen peroxide.
[0086] Certain embodiments include a hydrogen peroxide-detecting
sensor constructed from a sensing layer prepared by crosslinking
two components together, for example: (1) a redox compound such as
a redox polymer containing pendent Os polypyridyl complexes with
oxidation potentials of about +200 mV vs. SCE, and (2) periodate
oxidized horseradish peroxidase (HRP). Such a sensor functions in a
reductive mode; the working electrode is controlled at a potential
negative to that of the Os complex, resulting in mediated reduction
of hydrogen peroxide through the HRP catalyst.
[0087] In another example, a potentiometric sensor can be
constructed as follows. A glucose-sensing layer is constructed by
crosslinking together (1) a redox polymer containing pendent Os
polypyridyl complexes with oxidation potentials from about -200 mV
to +200 mV vs. SCE, and (2) glucose oxidase. This sensor can then
be used in a potentiometric mode, by exposing the sensor to a
glucose containing solution, under conditions of zero current flow,
and allowing the ratio of reduced/oxidized Os to reach an
equilibrium value. The reduced/oxidized Os ratio varies in a
reproducible way with the glucose concentration, and will cause the
electrode's potential to vary in a similar way.
[0088] The components of the sensing layer may be in a fluid or gel
that is proximate to or in contact with the working electrode.
Alternatively, the components of the sensing layer may be disposed
in a polymeric or sol-gel matrix that is proximate to or on the
working electrode. Preferably, the components of the sensing layer
are non-leachably disposed within the sensor. More preferably, the
components of the sensor are immobilized within the sensor.
[0089] Examples of sensing layers that may be employed are
described in U.S. patents and applications noted herein, including,
e.g., in U.S. Pat. Nos. 5,262,035, 5,264,104, 5,543,326, 6,605,200,
6,605,201, 6,676,819 and 7,299,082, the disclosures of each of
which are incorporated herein by reference for all purposes.
[0090] Regardless of the particular components that make up a given
sensing layer, a variety of different sensing layer configurations
may be used. In certain embodiments, the sensing layer covers the
entire working electrode surface, e.g., the entire width of the
working electrode surface. In other embodiments, only a portion of
the working electrode surface is covered by the sensing layer,
e.g., only a portion of the width of the working electrode surface.
Alternatively, the sensing layer may extend beyond the conductive
material of the working electrode. In some cases, the sensing layer
may also extend over other electrodes, e.g., over the counter
electrode and/or reference electrode (or counter/reference is
provided), and may cover all or only a portion thereof.
[0091] In other embodiments the sensing layer is not deposited
directly on the working electrode. Instead, the sensing layer may
be spaced apart from the working electrode, and separated from the
working electrode, e.g., by a separation layer. A separation layer
may include one or more membranes or films or a physical distance.
In addition to separating the working electrode from the sensing
layer the separation layer may also act as a mass transport
limiting layer, and/or an interferent eliminating layer, and/or a
biocompatible layer.
[0092] In certain embodiments which include more than one working
electrode, one or more of the working electrodes may not have a
corresponding sensing layer, or may have a sensing layer which does
not contain one or more components (e.g., an electron transfer
agent and/or catalyst) needed to electrolyze the analyte. Thus, the
signal at this working electrode may correspond to background
signal which may be removed from the analyte signal obtained from
one or more other working electrodes that are associated with
fully-functional sensing layers by, for example, subtracting the
signal.
[0093] Whichever configuration of the sensing component or layer is
employed, at least one factor in minimizing variations in sensor
sensitivity, at least within the same sensor batch or lot (or all
sensors made according to the same specification), is by strictly
maintaining the dimensions (width, length, diameter and thickness)
of the active area, i.e., the area of the working electrode in
contact with the sensing component or layer, from sensor to sensor.
Optimizing sensitivity, including reproducing substantially the
same sensitivity for sensors within a lot or batch of sensors,
reduces and in certain embodiments eliminates the need for sensor
calibration, by the user. Accordingly, sensors that do not require
a user to calibrate, using for example an in vitro test strip or
the like after insertion of the sensor into the body for testing,
are achieved. Examples of sensors for use in one or more
embodiments of the present disclosure can be found in, among
others, U.S. patent application Ser. No. 12/714,439, the disclosure
of which is incorporated herein by reference for all purposes.
[0094] Calibration, when an electrochemical glucose sensor is used,
generally involves converting the raw current signal (nA) into a
glucose concentration (mg/dL). One way in which this conversion is
done is by relating or equating the raw analyte signal with a
calibration measurement (i.e., with a reference measurement), and
obtaining a conversion factor (raw analyte signal/reference
measurement value). This relationship is often referred to as the
sensitivity of the sensor, which, once determined, may then be used
to convert sensor signals to calibrated analyte concentration
values, e.g., via simple division (raw analyte
signal/sensitivity=calibrated analyte concentration). For example,
a raw analyte signal of 10 nA could be associated with a
calibration analyte concentration of 100 mg/dL, and thus, a
subsequent raw analyte signal of 20 nA could be converted to an
analyte concentration of 200 mg/dL, as may be appropriate for a
given analyte, such as glucose, for example.
[0095] There are many ways in which the conversion factor may be
obtained. For example, the sensitivity factor can be derived from a
simple average of multiple analyte signal/calibration measurement
data pairs, or from a weighted average of multiple analyte
signal/calibration measurement data pairs. Further by way of
example, the sensitivity may be modified based on an empirically
derived weighting factor, or the sensitivity may be modified based
on the value of another measurement, such as temperature. It will
be appreciated that any combination of such approaches, and/or
other suitable approaches, is contemplated herein.
[0096] For subcutaneous glucose sensors, calibration at the site of
manufacture, that may be relied upon to calibrate sensor signal for
the useful life of a sensor, presents numerous challenges to the
feasibility. This infeasibility may be based on any of a number of
factors. For example, variations in the within-lot sensitivity of
the analyte sensors and/or variations in sensor drift may be too
great.
[0097] The present disclosure provides sensor embodiments which
attempt to address both the in vivo environmental effects and the
manufacturing-based inconsistencies which can lead to variation in
sensor sensitivity, and/or which obviate the need for any form of
calibration, whether at the factory or by the user, at anytime
prior to or during operative use of the sensor.
[0098] Certain of these sensor embodiments are double-sided, i.e.,
both sides of the sensor's substrate are electrochemically
functional, with each side providing at least one electrode.
Because both sides of the sensor are utilized, the smaller the
necessary surface area required per side to host the electrodes.
This space-efficient construct allows the sensor to be miniaturized
and much smaller than conventional sensors, and, in particular,
have a relatively narrower tail portion, i.e., at least the portion
of a sensor that is constructed to be positioned beneath a skin
surface of a user is miniaturized. A narrower structure reduces
trauma to tissue at the implantation site, thereby reducing
bleeding and the production of thrombi around the sensor. The
smaller structure also minimizes impingement upon adjacent blood
vessels. The smaller width of the sensor allows, in addition to
perpendicular diffusion of the analyte (e.g., glucose), for the
lateral diffusion of analyte molecules towards the active sensing
area. These effects substantially if not completely eliminate
spurious low readings.
[0099] In addition to providing micro tail sections, these
double-sided sensors are designed and configured to be highly
reproducible. Further, they may be fabricated by methods,
techniques and equipment which minimize inconsistencies in the
registration, deposition and resolution of the sensor components,
as described herein.
[0100] Referring now to FIGS. 6A-6C, an example of such a
double-sided sensor in which an implantable portion of the sensor
600, e.g., the distal portion of the sensor's tail section, is
illustrated. In particular, FIGS. 6A and 6B provide top and bottom
views, respectively, of tail section 600 and FIG. 6C provides a
cross-sectional side view of the same taken along lines C-C in FIG.
6A.
[0101] Sensor tail portion 600 includes a substrate 602 (see FIG.
6C) having a top conductive layer 604a which substantially covers
the entirety of the top surface area of substrate 602, i.e., the
conductive layer substantially extends the entire length of the
substrate to distal edge 612 and across the entire width of the
substrate from side edge 614a to side edge 614b. Similarly, the
bottom conductive layer 604b substantially covers the entirety of
the bottom side of the substrate of tail portion 600. However, one
or both of the conductive layers may terminate proximally of distal
edge 612 and/or may have a width which is less than that of
substrate 602 where the width ends a selected distance from the
side edges 614a, 614b of the substrate, which distance may be
equidistant or vary from each of the side edges.
[0102] One of the top or bottom conductive layers, here, top
conductive layer 604a, serves as the sensor's working electrode.
The opposing conductive layer, here, bottom conductive layer 604b,
serves as a reference and/or counter electrode. Where conductive
layer 604b serves as either a reference or counter electrode, but
not both, a third electrode may optionally be provided on a surface
area of the proximal portion of the sensor (not shown). For
example, conductive layer 604b may serve as reference electrode and
a third conductive trace (not shown), present only on the
non-implantable proximal portion of the sensor, may serve as the
sensor's counter electrode.
[0103] Disposed over a distal portion of the length of conducting
layer/working electrode 604a is sensing component or layer 606.
Providing the sensing layer closer to the distal tip of the sensor
places the sensing material in the best position for contact with
the analyte-containing fluid. As only a small amount of sensing
material is required to facilitate electrooxidization or
electroreduction of the analyte, positioning the sensing layer 606
at or near the distal tip of the sensor tail reduces the amount of
material needed. Sensing layer 606 may be provided in a continuous
stripe/band between and substantially orthogonal to the substrate's
side edges 614a, 614b with the overlap or intersection of working
electrode 604a and the sensing layer 606 defining the sensor's
active area. Due to the orthogonal relationship between sensing
layer 606 and conductive layer 604a, the active area has a
rectilinear polygon configuration; however, any suitable shape may
be provided. The dimensions of the active area may be varied by
varying either or both of the respective width dimensions of the
sensing and conducting layers. The width W.sub.S of the sensing
layer 606 may cover the entire length of the working electrode or
only a portion thereof. As the width W.sub.C of the conductive
layer is dictated by the width of the tail portion's substrate in
this embodiment, any registration or resolution inconsistencies
between the conductive layer and the substrate are obviated. In
certain embodiments, the width of the sensing layer W.sub.S is in
the range from about 0.05 mm to about 5 mm, e.g., from about 0.1 mm
to about 3 mm; the width of the conductive layer W.sub.C is in the
range from about 0.05 mm to about 0.6 mm, e.g., from about 0.1 mm
to about 0.3 mm, with the resulting active area in the range from
about 0.0025 mm.sup.2 to about 3 mm.sup.2, e.g., from about 0.01
mm.sup.2 to about 0.9 mm.sup.2.
[0104] Referring again to the electrodes, the same materials and
methods may be used to make the top and bottom electrodes, although
different materials and methods may also be used. With the working
and reference electrodes positioned on opposing sides of the
substrate as in the illustrated embodiment of FIGS. 6A-6C, it is
not additionally inconvenient to use two or more different types of
conductive material to form the respective electrodes as only one
type of conductive material would need to be applied to each side
of the substrate, thereby reducing the number of steps in the
manufacturing process.
[0105] Selection of the conductive materials for the respective
electrodes is based in part on the desired rate of reaction of the
sensing layer's mediator at an electrode. In some instances the
rate of reaction for the redox mediator at the counter/reference
electrode is controlled by, for example, choosing a material for
the counter/reference electrode that would require an overpotential
or a potential higher than the applied potential to increase the
reaction rate at the counter/reference electrode. For example, some
redox mediators may react faster at a carbon electrode than at a
silver/silver chloride (Ag/AgCl) or gold electrode. However, as
Ag/AgCl and gold are more expensive than carbon, it may be desirous
to use the former materials judiciously.
[0106] The sensor embodiment of FIGS. 6A-6C provides such a
construct in which the full-length conductive layers 604a, 604b may
be of a material such as carbon with a secondary layer of
conductive layer 610 of a material such as Ag/AgCl disposed over a
distal portion of bottom conductive layer 604b to collectively form
the sensor's reference electrode. As with sensing layer 606,
conductive material 610 may be provided in a continuous stripe/band
between and substantially orthogonal to the substrate's side edges
614a, 614b. While layer 610 is shown positioned on substrate 602
proximally of sensing layer 606 (but on the opposite side of the
substrate), layer 610 may be positioned at any suitable location on
the tail portion 600 of the reference electrode 604b. For example,
as illustrated in FIGS. 7A-7C, the secondary conductive material
710 of reference electrode 708b may be aligned with and/or distal
to sensing layer 706 with dimensions W.sub.S and W.sub.C.
[0107] Referring again to sensor 600, an insulation/dielectric
layer 608a, 608b is disposed on each side 600a, 600b of the sensor,
over at least the sensor's body portion (not shown), to insulate
the proximal portion of the electrodes, i.e., the portion of the
electrodes which in part remains external to the skin upon
implantation. The top dielectric layer 608a disposed on the working
electrode 604a may extend distally to but preferably not over any
portion of sensing layer 606. Alternatively, as illustrated in
FIGS. 7A-7C, dielectric layer 708a on the working electrode side of
the sensor 700 may be provided prior to sensing layer 706 whereby
the dielectric layer 708a has at least two portions spaced apart
from each other on conductive layer 704a, best illustrated in FIG.
7C. FIG. 7C provides a cross-sectional side view taken along lines
C-C in FIG. 7A. The sensing material 706 is then provided in the
spacing between the two portions.
[0108] As for the dielectric layer on the bottom/reference
electrode side of the sensor, it may extend any suitable length of
the sensor's tail section, i.e., it may extend the entire length of
both of the primary and secondary conductive layers or portions
thereof. For example, as illustrated in FIGS. 6A-6C, bottom
dielectric layer 608b extends over the entire bottom surface area
of secondary conductive material 610 but terminates proximally of
the distal edge 612 of the length of the primary conductive layer
604b. It is noted that at least the ends of the secondary
conductive material 610 which extend along the side edges 614a,
614b of the substrate 602 are not covered by dielectric layer 608b
and, as such, are exposed to the in vivo environment when in
operative use. In contrast, as illustrated in FIGS. 7A-7C, bottom
dielectric layer 708b has a length which terminates proximally of
secondary conductive layer 710 on bottom primary conductive layer
704b along substrate 702. Additional conducting and dielectric
layers may be provided on either or both sides of the sensors, as
described above.
[0109] Finally, one or more membranes, which may function as one or
more of an analyte flux modulating layer and/or an
interferent-eliminating layer and/or biocompatible layer, discussed
in greater detail below, may be provided about the sensor, e.g., as
one or more of the outermost layer(s). In certain embodiments, as
illustrated in FIG. 6C, a first membrane layer 616 may be provided
solely over the sensing component or sensing layer 606 on the
working electrode 604a to modulate the rate of diffusion or flux of
the analyte to the sensing layer. For embodiments in which a
membrane layer is provided over a single component/material, it may
be suitable to do so with the same striping configuration and
method as used for the other materials/components. Here, the
stripe/band of membrane material 616 preferably has a width greater
than that of sensing stripe/band 606. As it acts to limit the flux
of the analyte to the sensor's active area, and thus contributes to
the sensitivity of the sensor, controlling the thickness of
membrane 616 is important. Providing membrane 616 in the form of a
stripe/band facilitates control of its thickness. A second membrane
layer 618, which coats the remaining surface area of the sensor
tail, may also be provided to serve as a biocompatible conformal
coating and provide smooth edges over the entirety of the sensor.
In other sensor embodiments, as illustrated in FIG. 7C, a single,
homogenous membrane 718 may be coated over the entire sensor
surface area, or at least over both sides of the distal tail
portion. It is noted that to coat the distal and side edges of the
sensor, the membrane material would have to be applied subsequent
to singulation of the sensor precursors.
[0110] Based on current sensor fabrication techniques, provision of
the sensor's conductive layers can be accomplished more accurately
than provision of the sensing layers. As such, improving upon the
accuracy of providing the sensing component on the sensor, and
thus, the accuracy of the resulting active area, may significantly
decrease any sensor to sensor sensitivity variability and obviate
the need for calibration of the sensor. Accordingly, the present
disclosure also includes methods for fabricating such analyte
sensors having accurately defined active areas. Additionally, the
methods provide finished sensors which are smaller than currently
available sensors with micro-dimensioned tail portions which are
far less susceptible to the in situ environmental conditions which
can cause spurious low readings.
[0111] In one variation of the subject methods, web-based
manufacturing techniques are used to perform one or more steps in
fabricating the subject sensors, many of the steps of which are
disclosed in U.S. Pat. No. 6,103,033. To initiate the fabrication
process, a continuous film or web of substrate material is provided
and heat treated as necessary. The web may have precuts or
perforations defining the individual sensor precursors. The various
conductive layers are then formed on the substrate web by one or
more of a variety of techniques as described above, with the
working and reference (or counter/reference) electrode traces
provided on opposite sides of the web. As mentioned previously, the
electrode traces may be provided in channels formed in the surface
of the substrate material; however, with the desire to provide a
sensor having a tail portion that has the smallest functional
profile possible, and particularly with the sensor tail having two
functional sides, the use of channels may not be optimal as it
requires a thicker substrate material. Also, as mentioned
previously, a third, optional electrode trace (which may function
as a counter electrode, for example) may be provided on the
proximal body portion of the sensor precursors. The "primary"
conductive traces provided on the area of the tail portions of the
precursor sensors have a width dimension greater than the intended
width dimension of the tail portions of the finalized sensors. The
precursor widths of these conductive traces may range from about
0.3 mm to about 10 mm including widths in range from about 0.5 mm
to about 3 mm, or may be even narrower. The primary conductive
layers are formed extending distally along the tail section of the
sensor precursors to any suitable length, but preferably extend at
least to the intended distal edge of the finalized sensors to
minimize the necessary sensor tail length.
[0112] Next, the sensing layer and secondary conductive layers, if
employed, are formed on the primary conductive layers on the
respective sides of the substrates or substrate web. As discussed,
each of these layers is preferably formed in a stripe or band of
the respective material disposed orthogonally to the length of the
primary conductive layer/sensor tail. With a single, continuous
deposition process, the mean width of the sensing strip is
substantially constant along the substrate webbing, and ultimately,
from sensor to sensor. The secondary conductive layer (e.g.,
Ag/AgCl on the reference electrode), if provided, may also be
formed in a continuous orthogonal stripe/band with similar
techniques. One particular method of providing the various
stripes/band of material on the sensors is by depositing, printing
or coating the sensing component/material by means of an inkjet
printing process (e.g., piezoelectric inkjet as manufactured by
Scienion Inc. and distributed by BioDot Inc.). Another way of
applying these materials is by means of a high precision pump
(e.g., those which are piston driven or driven by peristaltic
motion) and/or footed needle. The respective stripes/bands may be
provided over a webbing of sequentially aligned sensor precursors
prior to singulation of the sensors or over a plurality of
sensors/electrodes where the sensors have been singulated from each
other prior to provision of the one or more stripes/bands.
[0113] With both the sensing and conductive layers/strips having
substantially constant widths and provided substantially orthogonal
to each other, the active area which their intersection forms is
also substantially constant along both the length and width of the
sensor. In such embodiments, the active area (as well as the
intersecting area of the primary and secondary conductive layers
which form the reference electrode) has a rectilinear polygonal
shape which may be easier to provide in a reproducible manner from
sensor to sensor; however, any relative arrangement of the layers
resulting in any suitable active area geometry may be employed.
[0114] The sensor precursors, i.e., the template of substrate
material (as well as the conductive and sensing materials if
provided on the substrate at the time of singulation), may be
singulated from each other using any convenient cutting or
separation protocol, including slitting, shearing, punching, laser
singulation, etc. These cutting methods are also very precise,
further ensuring that the sensor's active area, when dependent in
part on the width of the sensor (i.e., the tail portion of the
substrate), has very accurate dimensions from sensor to sensor.
Moreover, with each of the materials (i.e., the primary and
secondary conductive materials, sensing component, dielectric
material, membrane, etc.) provided with width and/or length
dimensions extending beyond the intended dimensions or boundaries
of the final sensors, issues with resolution and registration of
the materials is minimized if not obviated altogether.
[0115] The final, singulated, double-sided sensor structures have
dimensions in the following ranges: widths from about 500 .mu.m to
about 100 including widths in range from about 300 .mu.m to about
150 .mu.m; tail lengths from about 10 mm to about 3 mm, including
lengths in range from about 6 mm to about 4 mm; and thicknesses
from about 500 .mu.m to about 100 .mu.m including thicknesses in
range from about 300 .mu.m to about 150 .mu.m. As such, the
implantable portions of the sensors are reduced in size from
conventional sensors by approximately 20% to about 80% in width as
well as in cross-section. The reduced size minimizes bleeding and
thrombus formation upon implantation of the sensor and impingement
on adjacent tissue and vessels, thereby minimizing impediment to
lateral diffusion of the analyte to the sensor's sensing component
or sensing layer.
[0116] The substrate web may have precuts or perforations that
provide guidance for the final cut employed to singulate the
precursors. Depending on the layout and orientation of the sensor
precursors, the singulation lines may be at fixed or varying
intervals. For example, if the orientation and spacing of the
sensor precursors are serial and constant over the area of the
substrate material, the singulation lines will typically be at
fixed intervals in all directions. However, where the sensors
having irregular or asymmetrical shapes (e.g., as illustrated in
FIG. 5A) it may be preferential to orient the sensor precursors in
an alternating (e.g., head to toe) or in mirroring (e.g., back to
back) arrangements to minimize the unused substrate material and
any of the sensor materials deposited thereon. Where the
orientation of the sensor precursors is alternating or in a
mirroring arrangement, the singulation lines may not be at fixed
intervals.
[0117] Embodiments include sensor lots having very low variations
in sensitivity of sensors within the lot. Low sensitivity variation
enables sensors that do not require calibration by a user after a
sensor is positioned in the body. Accordingly, in certain
embodiments, sensor lots are provided that have a coefficient of
variation (CV) of about 5% or less, e.g., about 4.5% or less, e.g.,
about 4% or less, e.g., about 3% or less.
[0118] Sensors having predictable sensor in vivo sensitivity and
signal are provided. For example, sensors having predictable shelf
life sensitivity drift (the period of time between manufacture and
use) and predictable in vivo sensitivity drift, including
substantially no shelf and in vivo sensitivity drift, are also
provided. In embodiments in which sensors have drift (e.g., where
the sensor sensitivity drifts an expected percentage over a certain
time), a drift profile is contemplated. This drift profile may be
contemplated by an algorithm of the monitoring system to determine
a drift correction factor that may be applied to sensor signal to
obtain a glucose measurement (mg/dL). Due, at least in part, to the
high reproducibility of the manufacturing process that results in
low manufacturing coefficient of variation (CV), a single drift
correction factor may be used for all sensors of a given sensor
manufacturing lot or batch.
[0119] In certain embodiments, sensor sensitivity may be determined
post-fabrication by the manufacturer at the site of manufacture.
This "factory-determined" sensitivity may then be used in an
algorithm to calibrate sensor signal for the useable lifetime of
the sensor, negating the need for a user to obtain a reference
value, e.g., from a test strip, for calibration. Sensitivity may
include determining the relationship of sensor signal to a
reference such as an in vitro reference (a known glucose level to
which one or more sensors of a sensor lot may be compared).
Sensitivity may include determining a conversion factor as
described herein. In certain embodiments, the determined
sensitivity may be further augmented. For example, one or more
additional factors (e.g., to account for the relationship of blood
to subcutaneous tissue glucose, effect of oxygen, temperature,
etc.) may be contemplated. In any event, a sensitivity value is
determined. Exemplary calibration protocols are described, e.g., in
U.S. Pat. No. 7,299,082, the disclosure of which is incorporated
herein by reference for all purposes.
[0120] Because the sensitivities of each sensor of a given
manufacturing lot are substantially the same according to the
embodiments herein, the factory-determined sensitivity may be
applied to all sensors of such a lot, i.e., a single calibration
algorithm may be used for all the sensors of a given lot. In one
embodiment, the information is programmed or is programmable into
software of the monitoring system, e.g., into one or more
processors. For example, the factory-determined sensitivity may be
provided to a user with a sensor(s) and uploaded to a calibration
algorithm manually or automatically (e.g., via bar code and reader,
or the like). Calibration of sensor signal may then be implemented
using suitable hardware/software of the system.
[0121] A mass transport limiting layer or membrane, e.g., an
analyte flux modulating layer, may be included with the sensor to
act as a diffusion-limiting barrier to reduce the rate of mass
transport of the analyte, for example, glucose or lactate, into the
region around the working electrodes. The mass transport limiting
layers are useful in limiting the flux of an analyte to a working
electrode in an electrochemical sensor so that the sensor is
linearly responsive over a large range of analyte concentrations.
Mass transport limiting layers may include polymers and may be
biocompatible. A mass transport limiting layer may provide many
functions, e.g., biocompatibility and/or interferent-eliminating,
etc.
[0122] A membrane may be formed by crosslinking in situ a polymer,
modified with a zwitterionic moiety and a non-pyridine copolymer
component. The modified polymer may be made from a precursor
polymer containing heterocyclic nitrogen groups. For example, a
precursor polymer may be polyvinylpyridine or polyvinylimidazole.
Embodiments also include membranes that are made of a polyurethane,
or polyether urethane, or chemically related material, or membranes
that are made of silicone, and the like.
[0123] Optionally, another moiety or modifier that is either
hydrophilic or hydrophobic, and/or has other desirable properties,
may be used to "fine-tune" the permeability of the resulting
membrane to an analyte of interest. Optional hydrophilic modifiers,
such as poly(ethylene glycol), hydroxyl or polyhydroxyl modifiers,
may be used to enhance the biocompatibility of the polymer or the
resulting membrane.
[0124] The membrane may also be formed in situ by applying an
alcohol-buffer solution of a crosslinker and a modified polymer
over an enzyme-containing sensing layer and allowing the solution
to cure for about one to two days or other appropriate time period.
The crosslinker-polymer solution may be applied to the sensing
layer by placing a droplet or droplets of the solution on the
sensor, by dipping the sensor into the solution, or the like.
Generally, the thickness of the membrane is controlled by the
concentration of the solution, by the number of droplets of the
solution applied, by the number of times the sensor is dipped in
the solution, or by any combination of these factors. A membrane
applied in this manner may have any combination of the following
functions: (1) mass transport limitation, i.e., reduction of the
flux of analyte that can reach the sensing layer, (2)
biocompatibility enhancement, or (3) interferent reduction.
Exemplary mass transport layers are described in U.S. patents and
applications noted herein, including, e.g., in U.S. Pat. Nos.
5,593,852, 6,881,551 and 6,932,894, the disclosures of each of
which are incorporated herein by reference for all purposes.
[0125] A sensor may also include an active agent such as an
anticlotting and/or antiglycolytic agent(s) disposed on at least a
portion a sensor that is positioned in a user. An anticlotting
agent may reduce or eliminate the clotting of blood or other body
fluid around the sensor, particularly after insertion of the
sensor. Examples of useful anticlotting agents include heparin and
tissue plasminogen activator (TPA), as well as other known
anticlotting agents. Embodiments may include an antiglycolytic
agent or precursor thereof. Examples of antiglycolytic agents are
glyceraldehyde, fluoride ion, and mannose.
[0126] The electrochemical sensors of the present disclosure may
employ any suitable measurement technique, e.g., may detect
current, may employ potentiometry, etc. Techniques may include, but
are not limited to, amperometry, coulometry, and voltammetry. In
some embodiments, sensing systems may be optical, colorimetric, and
the like.
[0127] The subject analyte measurement systems may include an
optional alarm system that, e.g., based on information from a
processor, warns the patient of a potentially detrimental condition
of the analyte. For example, if glucose is the analyte, an alarm
system may warn a user of conditions such as hypoglycemia and/or
hyperglycemia and/or impending hypoglycemia, and/or impending
hyperglycemia. An alarm system may be triggered when analyte levels
approach, reach or exceed a threshold value. An alarm system may
also, or alternatively, be activated when the rate of change, or
acceleration of the rate of change, in analyte level increase or
decrease approaches, reaches or exceeds a threshold rate or
acceleration. A system may also include system alarms that notify a
user of system information such as battery condition, calibration,
sensor dislodgment, sensor malfunction, etc. Alarms may be, for
example, auditory and/or visual. Other sensory-stimulating alarm
systems may be used including alarm systems which heat, cool,
vibrate, or produce a mild electrical shock when activated.
[0128] The subject disclosure also includes sensors used in
sensor-based drug delivery systems. The system may provide a drug
to counteract the high or low level of the analyte in response to
the signals from one or more sensors. Alternatively, the system may
monitor the drug concentration to ensure that the drug remains
within a desired therapeutic range. The drug delivery system may
include one or more (e.g., two or more) sensors, a processing unit
such as a transmitter, a receiver/display unit, and a drug
administration system. In some cases, some or all components may be
integrated in a single unit. A sensor-based drug delivery system
may use data from the one or more sensors to provide necessary
input for a control algorithm/mechanism to adjust the
administration of drugs, e.g., automatically or semi-automatically.
As an example, a glucose sensor may be used to control and adjust
the administration of insulin from an external or implanted insulin
pump.
[0129] Referring now to FIGS. 8A-12B, the continuous analyte
measurement systems illustrated therein are particularly suitable
for use with the double-sided analyte sensors disclosed herein.
These systems include a skin-mounted portion or assembly and a
remote portion or assembly. The skin-mounted portion includes at
least the data transmitter, the transmitter battery and electrical
contacts for electrically coupling the implanted sensor with the
transmitter, and has a housing or base which is constructed to
externally mount to the patient's skin and to mechanically and
electrically couple the implanted sensor with the transmitter.
Removably held or positioned within the housing/base structure is a
connector piece having an electrical contact configuration which,
when used with a double-sided sensor, enables coupling of the
sensor to the transmitter in a low-profile, space-efficient manner.
The remote portion of the system includes at least a data receiver
and a user interface which may also be configured for test
strip-based glucose monitoring. Various embodiments of these
systems and methods of using them are now described in greater
detail.
[0130] FIGS. 8A and 8B illustrate one embodiment of the
skin-mounted portion or assembly 800 of a continuous analyte
monitoring system of the present disclosure. Assembly 800 includes
a connector or base 802 and a transmitter 804 both having
rectangular or square constructs which, when operatively coupled
together, are mounted side-by-side in the same plane on the skin.
The underside of both components has an adhesive layer for securing
to the skin surface. Connector 802 encases a conductive core or
elongated member 806 extending along its length. Conductive core
806 is shown having a cylindrical configuration but may have any
suitable shape. The connector body and conductive core may be made
of any suitable non-conductive and conductive materials,
respectively. To provide a non-rigid or semi-flexible embodiment,
connector body 802 or the portion of it about the conductive core
806 may be made of a flexible or compressible material such as
silicone, etc., and connector core 806 may be made of a conductive
polymeric material, e.g., carbon-doped silicone. The connector 802
and its connector core 806 may be provided in two parts or halves
802a and 802b, whereby the system's analyte sensor 808, here,
having two functional sides 808a and 808b, may be sandwiched
therebetween. Each of the inner ends of core 806 abuts a respective
electrode 814a, 814b of sensor 808. A bracket or fixture 816 may be
employed to clamp together or apply pressure on opposing ends of
the two connector body 802/connector core 806 pieces to ensure a
sufficient, continuous electrical contact between connector core
806 and sensor electrodes 814a, 814b. The body of the connector 802
has hollowed holes or receptacles 810a, 810b within a side thereof
which extend to or within conductive core 806. Holes 810a, 810b are
dimensioned and spaced for receiving corresponding conductive pins
812a, 812b extending from an end 815 of transmitter 804. When the
connector 802 and transmitter 804 are operatively coupled, as
illustrated in FIG. 8B, pins 812a, 812b extend within and are in
electrical communication with conductive core 806, and thus, with
sensor 808. The compressible, non-conductive material of connector
802 provides a substantially hermetic seal between transmitter 804
and sensor 808. The transmitter housing may house a battery (not
shown) for powering the transmitter 804, the sensor 808, and at
least a portion of the system's control electronics, e.g., the data
processing unit, etc.
[0131] FIGS. 9A-9E illustrate another embodiment of the
skin-mounted portion or assembly 900 of a continuous analyte
monitoring system of the present disclosure. With reference to FIG.
9A, assembly 900 includes a transmitter 902 mounted atop a mounting
structure or base 904, the underside of which has an adhesive layer
for securing to the skin surface. Here, transmitter 902 has a round
foot print and a convex, low-profile top surface. The transmitter
housing may house a battery (not shown) for powering the
transmitter 902, the sensor 906, and at least a portion of the
system's control electronics, e.g., the data processing unit, etc.
A raised rim 916 or similar feature on the top surface 912 of base
904 is shaped and dimensioned to securely hold transmitter 902 in a
snap-fit configuration. Base 904 also has a centrally disposed
cradle 908 on its top surface 912 for receiving and snugly holding
a connector 910. As best shown in FIG. 9B, a sidewall of the base
904 has an outwardly extending portion 914 which defines a slit or
keyhole therein to receive a sensor 906 (as well as an insertion
needle, as will be explained below) when operatively held by
connector 910. An aperture (not shown) within the bottom of cradle
908 allows passage of sensor tail 906b upon placement of connector
910 within the cradle 908. Cradle 908 may be sized to compress the
ends of the connector 910 toward each other so as to ensure a
constant electrical connection between the connector 910 and sensor
906.
[0132] As illustrated in FIGS. 9C-9E, connector 910 has a
cylindrical configuration having several concentric layers or
materials: a non-conductive inner member 910a, a conductive
intermediate layer 910b, and an outer dielectric cover or shell
910c. In one embodiment, the cylindrical connector is compliant,
with each of its layers made of compliant material(s) as described
with respect to the embodiment of FIGS. 8A and 8B. The optional
inner member 910a is made of a non-conductive compliant or
substantially rigid material which extends through a hole 906c at
the proximal end 906a of sensor 906 and, thus, acts as an alignment
pin. The terminal ends of the working and reference electrodes of
double-sided sensor 906 form a conductive area or ring 906d about
hole 906c. Conductive ring 906d may be made of gold or another
highly conductive material. The connector's intermediate layer 910b
is made of a compliant conductive material, such as a conductive
polymeric material as described with respect to the embodiment of
FIGS. 8A and 8B, which abuts against both sides of conductive area
906d of the sensor. The outer shell 910c of the connector, which
extends over and insulates each of the conductive ends of the
intermediate layer 910b, is made of a compliant dielectric
material, such as silicone, which ensures that the interconnection
between the transmitter, connector and sensor is hermetically
sealed. On a top surface of outer shell 910c are a pair of bores or
holes 918 for receiving a corresponding pair of pins or plugs 920
extending from the bottom side of transmitter 902. The bores and
pins may have respective mating configurations to ensure a snug fit
and hermetically seal between transmitter 902 and connector 910.
For example, as illustrated in FIG. 9E, bores 918 may have a
stepped configuration and pins 920 may have a conical
configuration. At least the distal tip 922 of each pin 920 is made
of a conductive material, such as gold, to establish electrical
communication between transmitter 902 and sensor 906.
[0133] FIGS. 10A-10F illustrate various steps in a method of the
present disclosure for mounting the continuous analyte monitoring
system's on-skin assembly 900, including implanting sensor 906
within the skin, utilizing an insertion device 1000 of the present
disclosure. However, the sensor/connector may be configured to be
manually inserted/mounted without the use of an insertion
device.
[0134] Insertion device 1000 comprises a body 1002 having a distal
base portion 1008 having a bottom surface configured for placement
on the skin surface 1005. It is noted that the figures show, with
solid drawing lines, components of the insertion device and the
analyte monitoring system that would otherwise not be visible when
positioned or housed within device body 1002 for purposes of
illustration and ease of description. For example, in FIGS.
10A-10C, mounting base 904 of assembly 900 (FIG. 9A) is shown
releasably held within an opening in the bottom surface of device
body 1002. Insertion device 1000 further includes a plunger
mechanism 1004 positioned within the housing 1002 and movable in a
direction perpendicular to the skin surface 1005. The distal end of
the plunger mechanism 1004 carries an insertion needle 1006. The
components of insertion device 1000 are typically formed using
structurally rigid materials, such as metal or rigid plastic.
Preferred materials include stainless steel and ABS
(acrylonitrile-butadiene-styrene) plastic.
[0135] With reference to FIGS. 11A and 11B, the shaft of insertion
needle 1006 may include a longitudinal opening, having a
cross-sectional shape for releasably carrying the forward edge 906e
of the analyte sensor (see FIG. 11B). In particular, the needle
shaft 1006 may be C-, U- or V-shaped to support the sensor and
limit the amount that the sensor may bend or bow during insertion.
The cross-sectional width and height of insertion needle 1006 are
appropriately sized to hold the sensor being inserted. In the
illustrated embodiment, insertion needle 1006 is pointed and/or
sharp at the tip 1012 to facilitate penetration of the skin of the
patient. A sharp, thin insertion needle may reduce pain felt by the
patient upon insertion of the sensor. In other embodiments, the tip
of the insertion needle has other shapes, including a blunt or flat
shape. These embodiments may be particularly useful when the
insertion needle is not intended to penetrate the skin but rather
serves as a structural support for the sensor as the sensor is
pushed into the skin. As such, the sensor itself may include
optional features to facilitate insertion. For example, sensor 906
may have a pointed tail portion 906b to ease insertion. In
addition, the sensor may include a barb (not shown) which helps
retain the sensor in the subcutaneous tissue upon insertion. The
sensor may also include a notch (not shown) that can be used in
cooperation with a corresponding structure (not shown) in the
insertion needle to apply pressure against the sensor during
insertion, but disengage as the insertion needle is removed.
[0136] To commence the sensor insertion/transmitter mounting
procedure, the front edge 906e (see FIGS. 11A and 11B) of sensor
906, which is operatively held within connector 910 (as shown in
FIG. 9B but not evident in the side views provided in FIGS.
10A-10F), is slid into placed within insertion needle 1006. In
turn, the pre-loaded insertion needle 1006 is operatively loaded
onto the distal end of plunger 1004. Mounting base 904 with the
attached connector cradle 908 is then coupled to the bottom end of
insertion body 1002, such as by a snap-fit arrangement that is
releasable upon complete downward displacement of plunger 1004. The
collective assembly is then placed on the target skin surface 1005,
as shown in FIG. 10A. The user 1010 then applies a downward force
on plunger 1004, as shown in FIG. 10B, which force is transferred
against insertion needle 1006 and/or sensor 906 to carry the sensor
906 into the skin 1005 of the patient. The plunger 1004 may be
biased to require a certain amount of force to avoid accidental
depression and to provide for very fast penetration and removal of
the insertion needle from the skin. For example, a cocked or wound
spring, a burst of compressed gas, an electromagnet repelled by a
second magnet, or the like, may be used to provide the biasing
force on plunger 1004. In one embodiment (as shown), the plunger
force is applied to insertion needle 1006, and optionally to sensor
906, to push a portion of both the sensor 906 and the insertion
needle 1006 through the skin 1005 of the patient and into the
subcutaneous tissue. Alternatively, the force may be applied only
to the sensor 906, pushing it into the skin 1005, while the
insertion needle 1006 remains stationary and provides structural
support to the sensor 906. In either embodiment, a hard stop to the
sensor's continued penetration into the skin 1005 is provided when
the connector 910 is seated within cradle 908. Once fully
depressed, plunger 1004 is then released by the user 1010, as
illustrated in FIG. 10C. With the upward spring biased placed on
the plunger, the insertion needle is quickly retracted from the
skin 1005 with sensor 906 remaining in the subcutaneous tissue due
to frictional forces between the sensor and the patient's tissue.
If the sensor includes the optional barb, then this structure may
also facilitate the retention of the sensor within the interstitial
tissue as the barb catches in the tissue. Release of plunger 1004
may also automatically decouple mounting base 904 from insertion
body 1002, or a separate trigger mechanism (not shown) may be
provided on the device to perform such function. The adhesive on
the skin-contacting surface of base 904 retains it in place when
the insertion device 1000 is removed from the skin, as illustrated
in FIG. 10D. The insertion device 1000 is typically manufactured to
be disposable to avoid the possibility of contamination.
Alternatively, the insertion device 1000 may be sterilized and
reused with only the insertion needle being disposable. After
removal of the insertion device 1000 from the skin 1005, the
transmitter 902 may then be manually coupled onto the mounting base
904, as shown in FIG. 10E. Specifically, the conductive pins 920 of
transmitter 902 are positioned within the corresponding holes 918
within connector 910 (see FIG. 9E). In an alternate embodiment, the
insertion device may be configured to mechanically mount the
transmitter 902 which would be pre-mounted to the mounting base
904. In either variation, control electronics (not shown) housed
within transmitter 902 enables monitoring of glucose (or other
target analytes) by sensor 906 and transmission of such analyte
data by transmitter 902 to the remote receiver unit (not shown)
according to the pre-programmed protocols.
[0137] As mentioned previously, a battery may be provided within
the transmitter housing to power the transmitter 902 as well as to
provide the necessary electrical signals to sensor 906. The battery
may be rechargeable/replaceable through a door (not shown) provided
in the transmitter housing. To minimize the size of the on-skin
unit, the battery may be relatively small, having only a
moderately-lasting charge, e.g., about 3-14 days more or less. In
another variation, the battery is not rechargeable or replaceable,
but is disposed of along with the transmitter upon expiration of
the battery charge. As this arrangement is more expensive, having a
battery/transmitter that has a longer-lasting charge, e.g., about 6
months to a year may be necessary; of course, the tradeoff being a
larger unit. Still yet, the transmitter may be extensively reusable
with the battery being disposable along with the sensor upon
expiration of the sensor's useful life, typically, between about 3
to about 14 days, in which case, the battery may be very small to
last only as long as the sensor.
[0138] FIGS. 12A and 12B illustrate top and bottom views,
respectively, of an on-skin mounting unit or base 1050 of another
continuous analyte monitoring system of the present disclosure in
which the battery is provided in the mounting base rather than in
the transmitter. The conductive proximal portion 1054a (i.e., the
electrodes) of an analyte sensor 1054 is positionable or positioned
within a slot or slit 1066 within a side wall of base 1050 with the
tail portion 1054b extending transversely from the base. The
proximal sensor portion 1054a lies between a two-piece electrical
core or connector 1056 which is permanently housed within mounting
unit 1050. The connector has contacts 1056a (see FIG. 12A) which
extend to a top surface 1052 of base 1050 for receiving
corresponding conductive pins of the transmitter (not shown). The
entire base 1050 may be fabricated of a compressible, insulating
material, such as silicone. Features 1064 on opposing sidewalls of
the base aligned with the ends of connector 1056 are compressible
to ensure that connector 1056 maintains continuous electrical
contact with sensor 1054. Such compression features 1064 may
comprise a flexure such as a living hinge or the like. To prevent
any movement of sensor 1054 upon placement within skin tissue, an
optional alignment pin 1058 may be provided through a hole within
proximal sensor portion 1054a. The opposing ends of the alignment
pin 1058 may extend beyond the sidewalls of the base to physically
engage with corresponding features of the transmitter (not shown)
upon coupling with the base unit 1050. Also housed within base unit
1050 is a battery 1060 having high (+) and ground (-) connector
contacts 1060a, 1060b, respectively. As seen in FIG. 12A, the
connector contacts 1056a and battery contacts 1060a, 1060b have
receptacle configurations to matingly receiving corresponding pin
contacts of a transmitter (not shown) when mounted atop mounting
base 1050. As such, electrical communication is established between
sensor 1054 and the transmitter, and power is supplied to the
transmitter and to the on-skin unit as a whole. The coupling
between the transmitter and mounting base may be by way of a
snap-fit arrangement between the pins and receptacles, which also
allows for easy removal when replacing the base unit 1050 upon
expiration of the battery 1060 and/or useful life of the sensor
1054 with the more expensive transmitter component being
reusable.
[0139] All of the on-skin portions of the subject continuous
monitoring systems have a very low-profile configuration. While
certain embodiments have at least one dimension that is extremely
small, other dimensions may be slightly greater to provide the
necessary volume to house the various components of the on-skin
units. For example, an on-skin unit may have a very low height
dimension, but have relatively greater width and length dimensions.
On the other hand, the width/length dimensions may be very small
with the height being relatively greater. The optimal dimensions of
a particular on-skin unit may depend on where on the body the unit
is intended to be mounted. One exemplary set of dimensions for an
on-skin unit of the present disclosure includes a width from about
7.5 to about 8.5 mm, a length from about 10 to about 11 mm, and a
height from about 2.5 to about 3.3 mm.
[0140] Exemplary analyte monitoring systems are described in, for
example, U.S. patent application Ser. No. 12/698,124 entitled
"Compact On-Body Physiological Monitoring Devices and Methods
Thereof" and in U.S. patent application Ser. No. 12/730,193
entitled "Methods of Treatment and Monitoring Systems for Same",
the disclosures of each of which are incorporated herein by
reference for all purposes. Exemplary methods and systems for
inserting a an analyte sensor are described in, for example, U.S.
Pat. No. 6,990,366, U.S. patent application Ser. Nos. 12/698,124,
12/698,129, now U.S. Pat. No. 9,402,544, and U.S. Provisional
Application Nos. 61/238,159, 61/238,483 and 61/249,535, the
disclosures of each of which are incorporated herein by reference
for all purposes.
[0141] Although the subject sensors may be inserted anywhere in the
body, it is often desirable that the insertion site be positioned
so that the on-skin sensor control unit can be concealed. In
addition, it is often desirable that the insertion site be at a
place on the body with a low density of nerve endings to reduce the
pain to the patient. Examples of preferred sites for insertion of
the sensor and positioning of the on-skin sensor control unit
include the abdomen, thigh, leg, upper arm, and shoulder.
[0142] In one embodiment, the subject sensors are injected between
2 to 12 mm into the interstitial tissue of the patient for
subcutaneous implantation. Preferably, the sensor is injected 3 to
9 mm, and more preferably 5 to 7 mm, into the interstitial tissue.
Other embodiments of the present disclosure may include sensors
implanted in other portions of the patient, including, for example,
in an artery, vein, or organ. The depth of implantation varies
depending on the desired implantation target. Sensor insertion
angles usually range from about 10.degree. to about 90.degree.,
typically from about 15.degree. to about 60.degree., and often from
about 30.degree. to about 45.degree.. The construct of the
insertion device, of course, will vary depending on the desired
angle of insertion.
[0143] In one embodiment, a continuous analyte measurement system
may include a base unit configured for mounting on a skin surface,
an analyte sensor comprising two functional sides, a proximal
portion configured for positioning within the base unit and a
distal portion configured for insertion into the skin surface, and
a conductive member positionable within the base unit and in
electrical contact with the two functional sides of analyte
sensor.
[0144] The proximal portion of the analyte sensor may have a planar
configuration and the conductive member may be mechanically and
electrically coupled to the two functional sides of the proximal
portion of the analyte sensor.
[0145] The base unit may be compressible on opposing sides at least
about the conductive member.
[0146] Furthermore, the system may include a component for
compressing the opposing ends of the conductive member.
[0147] In one aspect, the component for compressing may be flexures
on opposing sides of the base unit about the conductive member.
[0148] In another aspect, the component for compressing may be a
clamping fixture positionable on opposing sides of the base unit
about the conductive member.
[0149] In one aspect, the system may include an alignment pin
extending through the proximal portion of the analyte sensor.
[0150] The base unit may be a non-conductive compressible
material.
[0151] The non-conductive compressible material may be
silicone.
[0152] The conductive connector may be a conductive compressible
material.
[0153] The conductive compressible material may be carbon-doped
silicone.
[0154] In a further aspect, the system may include a transmitter
configured for mounting to the base unit in a low-profile manner,
wherein the base unit includes a pair of receptacles for receiving
a corresponding pair of conductive pins of the transmitter, and the
conductive pins contact the conductive member when the transmitter
is operatively mounted to the base unit.
[0155] The transmitter may mount with the base unit in a
side-by-side configuration.
[0156] The transmitter may mount atop the base unit.
[0157] The transmitter may house a battery.
[0158] The base unit may house a battery.
[0159] Moreover, the base unit may include a second pair of
receptacles for receiving a corresponding second pair of conductive
pins of the transmitter, wherein the conductive pins contact the
battery when the transmitter is operatively mounted to the base
unit.
[0160] The base unit may include a cradle therein for receiving and
holding the conductive member.
[0161] The cradle may compress opposing ends of the conductive
member when held within the cradle.
[0162] The conductive member may include a conductive core and an
insulating shell covering the conductive core.
[0163] In one aspect, the conductive member may include a
non-conductive inner member within the conductive core, wherein the
non-conductive inner member extends through an opening in the
analyte sensor.
[0164] The base unit may include an adhesive bottom for adhering to
the skin surface.
[0165] The base unit may include an opening therein through which
the distal end of the analyte sensor extends.
[0166] The distal end of the analyte sensor may extend along a
sidewall of the base unit.
[0167] Regarding methodology, the subject methods may include each
of the mechanical and/or activities associated with use of the
devices described. As such, methodology implicit to the use of the
devices described forms part of the present disclosure. Other
methods may focus on fabrication of such devices. The methods that
may be performed according to embodiments herein and that may have
been described above and/or claimed below, the operations have been
described in selected typographical sequences. However, the
sequences have been selected and so ordered for typographical
convenience and are not intended to imply any particular order for
performing the operations.
[0168] As for other details of the present disclosure, materials
and alternate related configurations may be employed as within the
level of those with skill in the relevant art. The same may hold
true with respect to method-based aspects of the present disclosure
in terms of additional acts as commonly or logically employed. In
addition, though embodiments of the present disclosure have been
described in reference to several examples, optionally
incorporating various features, the present disclosure is not to be
limited to that which is described or indicated as contemplated
with respect to each variation of the present embodiments. Various
changes may be made to the embodiments described and equivalents
(whether recited herein or not included for the sake of some
brevity) may be substituted without departing from the true spirit
and scope of the present disclosure. Any number of the individual
parts or subassemblies shown may be integrated in their design.
Such changes or others may be undertaken or guided by the
principles of design for assembly.
[0169] Also, it is contemplated that any optional feature of the
inventive variations described may be set forth and claimed
independently, or in combination with any one or more of the
features described herein. Reference to a singular item, includes
the possibility that there are plural of the same items present.
More specifically, as used herein and in the appended claims, the
singular forms "a," "an," "said," and "the" include plural
referents unless the specifically stated otherwise. In other words,
use of the articles allow for "at least one" of the subject item in
the description above as well as the claims below. It is further
noted that the claims may be drafted to exclude any optional
element. As such, this statement is intended to serve as antecedent
basis for use of such exclusive terminology as "solely," "only" and
the like in connection with the recitation of claim elements, or
use of a "negative" limitation. Without the use of such exclusive
terminology, the term "comprising" in the claims shall allow for
the inclusion of any additional element--irrespective of whether a
given number of elements are enumerated in the claim, or the
addition of a feature could be regarded as transforming the nature
of an element set forth in the claims. Stated otherwise, unless
specifically defined herein, all technical and scientific terms
used herein are to be given as broad a commonly understood meaning
as possible while maintaining claim validity.
[0170] In all, the breadth of the present disclosure is not to be
limited by the examples provided.
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