U.S. patent application number 11/109357 was filed with the patent office on 2005-08-25 for implantable biosensor system, apparatus and method.
Invention is credited to Hitchcock, Robert W., Sorenson, James L..
Application Number | 20050183954 11/109357 |
Document ID | / |
Family ID | 33130433 |
Filed Date | 2005-08-25 |
United States Patent
Application |
20050183954 |
Kind Code |
A1 |
Hitchcock, Robert W. ; et
al. |
August 25, 2005 |
Implantable biosensor system, apparatus and method
Abstract
An implantable biosensor assembly and system includes an
enzymatic sensor probe from which subcutaneous and interstitial
glucose levels may be inferred. The assembly may be associated by
direct percutaneous connection with electronics, such as for signal
amplification, sensor polarization, and data download,
manipulation, display, and storage. The biosensor comprises a
miniature probe characterized by lateral flexibility and tensile
strength and has a large electrode surface area for increased
sensitivity. Irritation of tissues surrounding the probe is
minimized due to ease of flexibility and small cross section of the
sensor. Foreign body reaction is diminished due to a
microscopically rough porous probe surface.
Inventors: |
Hitchcock, Robert W.;
(Sandy, UT) ; Sorenson, James L.; (Salt Lake City,
UT) |
Correspondence
Address: |
TRASK BRITT
P.O. BOX 2550
SALT LAKE CITY
UT
84110
US
|
Family ID: |
33130433 |
Appl. No.: |
11/109357 |
Filed: |
April 19, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11109357 |
Apr 19, 2005 |
|
|
|
10401224 |
Mar 26, 2003 |
|
|
|
Current U.S.
Class: |
204/403.01 ;
600/300 |
Current CPC
Class: |
A61B 2560/045 20130101;
A61B 5/14865 20130101; A61B 5/6852 20130101; A61B 5/14532
20130101 |
Class at
Publication: |
204/403.01 ;
600/300 |
International
Class: |
G01N 027/26 |
Claims
What is claimed is:
1. An implantable needle-type biosensor wherein an electric signal
is produced between first and second electrical contacts responsive
to an electrochemical reaction in a body, said biosensor
comprising: an elongate core comprising a plurality of axially
oriented fibers, said elongate core having a distal end and a
proximal end, said distal end being spaced apart in an axial
direction from said proximal end; a working electrode associated
with said distal end; a reference electrode spaced apart from said
working electrode; structure adapted to resist direct physical
contact between said working electrode and said reference
electrode; a first electrically conductive path between said
working electrode and said first electrical contact; and a second
electrically conductive path between said reference electrode and
said second electrical contact.
2. The implantable needle-type biosensor of claim 1, wherein said
working electrode comprises a metal element formed as a wrap about
a portion of said core.
3. The implantable needle-type biosensor of claim 1, wherein said
working electrode comprises a length of a first wire arranged to
circumscribe a plurality of revolutions about said core.
4. The implantable needle-type biosensor of claim 3, wherein said
first wire's diameter is between about 0.001 and about 0.005
inches.
5. The implantable needle-type biosensor of claim 1, wherein said
working electrode comprises a first wire arranged to form a spiral
path.
6. The implantable needle-type biosensor of claim 5, wherein said
spiral path has an axial pitch spacing, between centerlines of a
pair of adjacent wire wraps, sized between about one and about four
diameters of said first wire.
7. The implantable needle-type biosensor of claim 1, wherein said
working electrode is arranged in harmony with said core to form a
reinforced core operable to carry an axial compression load
permitting insertion of a distal tip of said biosensor through an
introducer catheter for placement of said working electrode into
intimate contact with tissue of the body.
8. The implantable needle-type biosensor of claim 1, wherein said
reference electrode is associated with said distal end and
comprises a length of a second wire formed as a wrap about a
portion of said core.
9. The implantable needle-type biosensor of claim 8, further
comprising: a dielectric spacer interposed between said working
electrode and said reference electrode to resist direct physical
contact therebetween.
10. The implantable needle-type biosensor of claim 1, wherein said
core comprises an electrically nonconductive material.
11. The implantable needle-type biosensor of claim 10, wherein said
core comprises a polymer material.
12. The implantable needle-type biosensor of claim 1, further
comprising: a sensor shaft disposed between said working electrode
and a hub, said shaft comprising a cylinder disposed
circumferentially about an axial length of said core proximal to
said working electrode.
13. The implantable needle-type biosensor of claim 1, wherein said
working electrode comprises an exterior coating of a negatively
charged polymer.
14. The implantable needle-type biosensor of claim 13, wherein said
negatively charged polymer comprises sulfonated
polyethersulfone.
15. The implantable needle-type biosensor of claim 1, wherein said
reference electrode and said working electrode are both arranged
for disposition in intimate contact with tissues of a subject.
16. An implantable biosensor, comprising: an introducer cannula
with a lumen extending axially between proximal and distal ends,
said proximal end carrying affixing structure adapted to resist
motion of said proximal end relative to a skin surface of a subject
and further carrying holding structure configured to receive a
probe; said probe structured for sliding installation of a distal
probe end through said lumen, said probe comprising an elongate
core having a distal end spaced apart axially from a proximal end,
a proximal end of said probe being associated with a hub adapted
for attachment to said holding structure; a first electrode
associated with said distal end of said probe; and a second
electrode associated with said distal end of said cannula, said
cannula and said probe being cooperatively structured on assembly
to resist direct physical contact between said first electrode and
said second electrode.
17. The implantable biosensor of claim 16, wherein said reference
and said working electrodes are both arranged for disposition in
intimate contact with tissue of a subject.
18. A method for manufacturing an implantable, needle-type
biosensor probe with a transversely flexible first electrode
effective to resist irritation at a site of implantation in a
subject, the method comprising: providing a core comprising a first
nonconductive material; disposing a first electrode in a
reinforcing path about said core; disposing structure forming a
first electrical conductor between said first electrode and a hub
associated with a proximal end of said probe; and disposing
structure forming a second electrical conductor between a second
electrode and said hub.
19. The method of claim 18, further comprising: forming said first
electrode from a first wire, a diameter of said first wire being
between about 0.001 and about 0.005 inches; and disposing said
first wire in a spiral path about said core.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 10/401,224, filed Mar. 26, 2003, the contents of the entirety
of which are herein incorporated by this reference.
TECHNICAL FIELD
[0002] This invention relates generally to medical devices and
associated methods such as measuring glucose for ongoing diabetes
management. The invention described herein can also be used for
enzymatic determination of other analytes. This invention provides
a particularly useful implantable biosensor.
BACKGROUND OF THE INVENTION
[0003] Heretofore, treatment and management of diabetes has been
undertaken through many and varied techniques. Formerly, glucose in
urine was measured, though recognized as less than adequate due to
the time delay inherent in the metabolism and voiding process.
Currently, the approach predominantly used for self-monitoring of
blood glucose requires periodic pricks of the skin with a needle,
whereby a blood sample is obtained and tested directly to provide
information about blood glucose levels. This information is then
utilized as a basis from which to schedule the administration of
insulin to maintain glucose equilibrium within the patient. Direct
measurement of glucose levels in periodic blood samples from
diabetes patients provides reasonably useful information about
insulin levels at certain selected points in time. However, the
dynamic nature of blood glucose chemistry and the complexity of
factors influencing blood sugar levels render such periodic
information less than optimal.
[0004] The glucose level in the subcutaneous interstitial fluid
very closely approximates the glucose level in the blood, with a
negligible time lag. The variables of patient food selection,
physical activity and insulin dosage, regime and protocol for a
person with diabetes each have a dynamic impact on physiologic
balance within the patient's body that can change dramatically over
a short period of time. If the net result of changes in these
variables and dynamics results in disequilibrium expressed as too
much glucose ("hyperglycemia"), then more insulin is required,
whereas too little glucose ("hypoglycemia") requires immediate
intervention to raise the glucose levels. A deleterious impact on
physiology follows either such disequilibrium.
[0005] Hyperglycemia is the source of most of the long-term
consequences of diabetes, such as blindness, nerve degeneration,
and kidney failure. Hypoglycemia, on the other hand, poses the more
serious short-term danger. Hypoglycemia can occur at any time of
the day or night and can cause the patient to lose consciousness.
Guarding against hypoglycemia may require frequent monitoring of
blood glucose levels and render the skin-prick approach tedious,
painful and, in some cases, impractical. Even diligent patients who
perform finger-sticking procedures many times each day achieve only
a poor approximation of continuous monitoring. Accordingly,
extensive attention has been given to development of improved means
of monitoring patient glucose levels for treatment of diabetes.
[0006] Many efforts to continuously monitor glucose levels have
involved implantable electrochemical biosensors. These amperometric
sensors utilize an immobilized form of the enzyme glucose oxidase
to catalyze the conversion of oxygen and glucose to gluconic acid
and hydrogen peroxide. Such sensors may be used to measure hydrogen
peroxide resulting from the enzymatic reaction. Alternatively,
these glucose oxidase-based biosensors measure oxygen consumption
to infer glucose concentrations.
[0007] Typical implantable, subcutaneous needle-type biosensors are
disclosed in various publications, such as the following examples:
"An Amperometric Needle-type Glucose Sensor Tested in Rats and
Man," by D. R. Matthews, E. Bown, T. W. Beck, E. Plotkin, L. Lock,
E. Gosden, and M. Wickham, which discloses an amperometric
glucose-measuring 25-gauge (0.5 mm diameter) needle-type sensor
using a glucose oxidase and dimethyl ferrocene paste behind a
semipermeable membrane situated over a window in the needle,
"Performance of Subcutaneously Implanted Needle-Type Glucose
Sensors Employing a Novel Trilayer Coating," by Francis Moussy, D.
Jed Harrison, Darryl W. O'Brien, and Ray V. Rajotte, which teaches
a miniature, needle-type glucose sensor utilizing a perfluorinated
ionomer, Nafion, as a protective, biocompatible, outer coating, and
poly(o-phenylenediamine) as an inner coating to reduce interference
by small, electroactive compounds. Glucose oxidase immobilized in a
bovine serum albumin matrix was sandwiched between these coatings.
The entire assembly of a platinum working electrode and an Ag/AgCl
reference electrode was 0.5 mm in diameter and could be inserted
subcutaneously through an 18-gauge needle. Other examples include,
"Needle Enzyme Electrodes for Biological Studies," by S. J.
Churchouse, C. M. Battersby, W. H. Mullen and P. M. Vadgama, which
presents yet another needle enzyme electrode characterized as the
most promising approach to miniaturization for invasive use, "A
Miniaturized Nafion-based Glucose Sensor," by F. Moussy, D. J.
Harrison, and R. V. Rajotte, which, while teaching a high
sensitivity (due in part to greater surface area of the electrode)
needle-type sensor with a spear-shaped point, acknowledges the need
for more protection against abrasion, "Design and In Vitro Studies
of a Needle-Type Glucose Sensor for Subcutaneous Monitoring," by
Dilbir S. Bindra, Yanan Zhang, George S. Wilson, Robert Sternberg,
Daniel R. Thevenot, Dinah Moatti and Gerard Reach, which sets forth
yet another needle-type glucose microsensor having a 26-gauge
(0.45-mm) outside diameter.
[0008] Additional needle-type implantable biosensors are disclosed
in certain United States patent documents. Relevant documents
include: "Subcutaneous Glucose Electrode" to Heller et al., U.S.
Pat. No. 6,329,161 B1; "Subcutaneous Implantable Sensor Set Having
the Capability to Remove Deliver Fluids to an Insertion Site" to
Mastrototaro et al., U.S. Pat. No. 5,951,521; "Transcutaneous
Sensor Insertion Set" to Halili et al., U.S. Pat. No. 5,586,553;
"Transcutaneous Sensor Insertion Set" to Cheney, II et al., U.S.
Pat. No. 5,568,806; "Transcutaneous Sensor Insertion Set" to Lord
et. al., U.S. Pat. No. 5,390,671; and "Implantable Glucose Sensor"
to Wilson et al., U.S. Pat. No. 5,165,407.
[0009] To provide continuous measurement, biosensors can be placed
for extended periods of time in various locations within the body.
One method of placement is percutaneously with an indwelling sensor
having an attached external wire associated with a readout device.
A risk of infection is associated with percutaneous biosensors, and
they must typically be replaced at regular intervals because of the
risk of infection at the insertion site.
[0010] Another problem with implanted sensors is irritation of the
tissues surrounding the implanted biosensors. Such irritation is
typically due, in part, to the lateral rigidity of prior art
biosensors. Related to this problem is the scarring of surrounding
tissue due not only to rigidity but also to abrupt edges associated
with the implants. Scar tissue surrounding reference electrodes of
the prior art is not desirable, but may be tolerated in some cases.
However, scar tissue can be materially detrimental to the sensor
function in the vicinity of the working electrode because it
impedes the diffusion of oxygen and glucose.
[0011] Further, to protect itself against a perceived invader, the
body commonly experiences a foreign body reaction by encapsulating
the implanted biosensors with protein, which may shorten the life
of the implant and adversely affect the accuracy of information
provided. The size of the sensor may also be regarded as a problem;
smaller is better for comfort. Further yet, interfering compounds,
such as, for example, ascorbic acid, and acetaminophen, can reduce
the accuracy of prior art amperometric glucose sensors given the
membranes selected historically to envelop such sensors.
Additionally, the quantity of dissolved oxygen is limited at high
glucose concentrations, thus leading to nonlinear output of sensor
signals at high glucose concentrations.
[0012] A need remains for a sensor including a miniaturized probe
of suitable materials and characteristics that may facilely be
placed percutaneously. A need exists for a miniaturized, albeit
durable, implantable biosensor percutaneously deployable wherein
irritation to tissues surrounding the biosensor is minimized. A
need also exists to achieve a rough exterior of the portion of an
implantable biosensor exposed to surrounding tissue so that foreign
body reaction may be reduced. Similarly, there is a need for a
selected membrane or membrane combination suitable to correction of
nonlinear diffusion of glucose. Further needed is a method of
manufacturing such a miniaturized yet strong and durable
implantable biosensor with resilient flexibility and minimal
surface relief while achieving a microscopically porous
surface.
BRIEF SUMMARY OF THE INVENTION
[0013] The invention includes an implantable needle-type biosensor
wherein an electric signal is produced between first and second
electrical contacts responsive to an electrochemical reaction in a
body. A needle-like probe element is typically inserted through an
introducer cannula into tissues of a subject's body. An implantable
needle element of an exemplary biosensor includes an elongate core
having a distal end spaced apart axially from a proximal end. A
workable core may be formed as a single element, or may include a
plurality of axially oriented fibers arranged in a bundle. Certain
cores are nonconductive to electric current. Workable cores may be
made from natural and synthetic fibers, metal, polymers, and
plastics. Currently preferred cores are made from polymer
material.
[0014] In general, a working electrode is associated with a distal
end of the core. Desirably, the working electrode is arranged to
protrude beyond a distal end of an introducer cannula into intimate
contact with tissue of a subject's body. A reference electrode is
included in abiosensor to produce an electrical signal, in
combination with the working electrode, responsive to the
electrochemical reaction. Structure included in a biosensor is
adapted to resist direct physical contact between the working
electrode and the reference electrode to prevent forming a direct
electrical short between those electrodes.
[0015] A first electrically conductive path exists between the
working electrode and a first electrical contact. Similarly, a
second electrically conductive path exists between the reference
electrode and a second electrical contact. The first and second
electrical contacts typically are associated with a hub operable to
secure a probe in relation to a cannula. A signal may be received
from the first and second contacts for data reduction and
correlation to a physiological state in a body, such as glucose
concentration. In general, the signal is transmitted through a
sensor cable affixed to structure of the hub. A workable sensor
cable includes first and second wires, each wire having a first end
arranged to make respective electrical connections with one of the
first and second electrical contacts, and a second end of each wire
typically being affixed to a sensor module operable to impose a
conditioning signal on the biosensor probe.
[0016] A working electrode can include a metal element (usually
including platinum) formed as a wrap about a portion of the core.
An exemplary working electrode includes a length of a first wire
arranged to circumscribe a plurality of revolutions about the core.
In such an exemplary working electrode, a diameter of the first
wire is between about 0.001 and about 0.005 inch. Desirably, the
first wire is arranged to form a spiral path. Usually, at least a
portion of the core is disposed substantially coaxial with an axis
of the spiral path. A currently preferred spiral path has an axial
spacing, between the centerlines of a pair of adjacent wire wraps,
sized between about one and about two diameters of the first wire.
A larger spacing, up to about five diameters (or even more in some
cases), is also workable, although it is recognized that the
electrode's active surface area decreases with larger pitch
spacing. Typically, the working electrode is arranged to reinforce
the core so as to enable a reinforced core to carry an axial
compression load permitting insertion of a distal tip of the
biosensor through an introducer catheter for placement of the
working electrode into intimate contact with tissue of the
subject's body.
[0017] The reference electrode typically includes a metal element
(usually including silver, and preferably including chlorided
silver) and can also be associated with the distal end of a core. A
reference electrode may alternatively be associated with an
introducer cannula, or some other structure. In the latter case, a
reference electrode may sometimes be recessed into an exterior
surface of the introducer cannula. In any event, it is currently
preferred for a reference electrode to be placed into intimate
contact with tissue of a subject's body. One embodiment of a
reference electrode includes a length of a second wire formed as a
wrap about a portion of the core. Another embodiment of a reference
electrode may be fashioned as a length of wire, wire coil, foil,
film, or coating associated with a cannula.
[0018] A preferred electrode (either working or reference) maybe
characterized as having: an axially interrupted load path between
first and second ends, a maximum equivalent outside diameter, a
minimum equivalent inside diameter, and a surface texture disposed
between the first and second ends that has a radially oriented
component. Such an electrode has a larger reactive surface area and
a lower bending stiffness compared to a hollow cylinder structured
from an equivalent material and having equivalent maximum outside
and minimum inside diameters.
[0019] The core of a biosensor probe according to the instant
invention can function to assist in retraction of the various
components of the biosensor probe. One structure operable to assist
in such retraction includes a plug carried on a distal end of the
core. The plug can be structured as a stopper that is too large to
pass through an electrode. Such a stopper operates to resist
extraction of the core from within a portion of the working
electrode as the biosensor is removed from the subject's body, so
as not to leave a detached portion of the working electrode in the
body. One functional plug is preferably formed, at least in part,
with a polymer coating. Another functional plug can include a
droplet of dielectric adhesive. A functional plug typically forms
an enlargement in a cross-section of the core, with a portion of
the enlargement being disposed distal to the working electrode.
[0020] In probes carrying both working and reference electrodes, a
dielectric spacer is usually interposed between the electrodes to
resist direct physical contact between them. A functional
dielectric spacer can be made from a droplet of dielectric adhesive
bonded to a portion of the core. Such a droplet desirably also is
arranged as a stopper to resist extraction of the core from within
a portion of the reference electrode as a biosensor is removed from
a subject's body, so as not to leave a detached portion of the
reference electrode in the body.
[0021] A probe portion of a biosensor includes a sensor shaft
disposed between the working electrode and the hub. The sensor
shaft generally includes a cylinder disposed circumferentially
about an axial length of the core proximal to the working
electrode. A currently preferred cylinder includes a plurality of
circumferential wrappings of a component wire having a smaller
diameter than a diameter of the formed cylinder. Wrappings forming
the cylinder desirably are closely spaced, or even touching, in an
axial direction along an axis of the cylinder whereby to enable the
shaft to carry an axial compression load effective to install the
biosensor probe portion through an introducer cannula and into a
body. Usually, a dielectric spacer is disposed at a distal end of
the cylinder to resist direct physical contact between the shaft
and an electrode. One such dielectric spacer can be formed from a
droplet, or small quantity, of dielectric adhesive bonded to a
portion of the core.
[0022] Desirably, an exterior coating of a negatively charged
polymer is applied to the working electrode. One operable
negatively charged polymer includes sulfonated polyethersulfone. It
is also sometimes desirable to provide a microscopically roughed-up
outer surface on the coating to enhance biocompatibility of the
biosensor with tissue of the subject's body. Desirable surface
texture is formed by elements having a size of between about 5 and
50 microns. Multifiber cores typically include a plurality of
spaces between the fibers operable to carry glucose oxidase whereby
to enhance a volume of glucose oxidase associated with a working
electrode.
[0023] The instant invention may be embodied broadly as an
implantable biosensor including an introducer cannula and a probe
element. The introducer cannula includes a lumen extending axially
between its proximal and distal ends. The cannula's proximal end
carries affixing structure adapted to resist motion of the proximal
end relative to a skin surface of a subject and further carries
holding structure configured to receive a probe. A distal end of
the cannula carries a first electrode. A probe includes an elongate
core having a distal end spaced apart axially from a proximal end
and is structured for sliding installation, through the cannula
lumen, into a subject. A proximal end of the probe is associated
with a hub adapted to be held by the cannula-holding structure. The
distal end of the probe carries a second electrode. The probe and
cannula are cooperatively structured on assembly to resist direct
physical contact between the first electrode and the second
electrode. Desirably, the first and second electrodes are installed
to be in intimate contact with the tissue of a subject.
[0024] A method for manufacturing an implantable, needle-type
biosensor probe with a transversely flexible first electrode
effective to resist irritation at a site of implantation in a
subject includes the steps of: a) providing a core comprising a
first nonconductive material; b) disposing a first electrode in a
reinforcing path about the core; c) disposing a first electrical
conductor between the first electrode and a hub associated with a
proximal end of the probe; and d) disposing a second electrical
conductor between a second electrode and the hub. The method can
also include the step of: e) forming a stopper carried by the core,
a portion of the stopper being disposed distal to the first
electrode and operable to resist extraction of the core from within
the interior of the electrode, whereby to retain an association
between the core and the electrode to resist leaving a portion of
the electrode in a subject subsequent to removal of the probe.
[0025] Sometimes, step b) includes: forming the first electrode as
an axially interrupted first cylinder having a first length between
a first end and a second end, a maximum equivalent outside
diameter, and a minimum equivalent inside diameter. The first
cylinder desirably includes a surface texture disposed between its
first and second ends that has a radially oriented component so as
to provide a larger reactive surface area and a lower bending
stiffness than a second cylinder having an equivalent maximum
outside diameter and first length. An exemplary electrode having
such conformation can be formed from a wire of between about 0.001
and about 0.005 inch in diameter, with the wire being disposed to
occupy a spiral path about the core.
[0026] In some cases, the method may further include disposing a
second wire circumferentially about the core in a spiral
reinforcing path operable to enhance an axial load-carrying
capability of the core, whereby to form the second electrode.
Typically, the step of applying an insulation to a conductive path
extending proximally from one or both electrodes is further
included. When two electrodes are carried on a core, the method
additionally can include affixing a dielectric element between the
working and the reference electrodes. Such dielectric element
desirably is also adapted to resist extraction of the core from
retention in an electrode, whereby to resist leaving a portion of
that electrode inside a subject subsequent to extraction of the
probe. Generally, the method includes the step of wrapping, or
otherwise disposing, a third wire circumferentially about the core
in a spiral reinforcing path to form a shaft of the probe.
Furthermore, the method includes affixing the hub to a proximal
portion of the shaft.
[0027] Coatings are typically applied in additional steps
subsequent to assembly of basic probe structure. An inner exclusion
membrane is formed in a first coating step by applying a solution,
such as 5% polyethersulfone, to the working electrode. A second
coating step includes applying a solution, such as 1% glucose
oxidase, 0.6% albumin and 0.5% glutaraldehyde, to the working
electrode to form a middle enzymatic membrane. In a third coating
step, a solution, such as 5% polyurethane is applied to both the
working and the reference electrodes to form an outer polymer
membrane. The final polyurethane coating desirably is
microscopically roughed-up by performing a phase inversion
polymerization procedure. In general, a workable phase inversion
polymerization procedure includes immediately dipping the final
polyurethane layer into a water bath to largely rinse away the
miscible solvent soon after the first of the polymer molecules
comprising the 5% solution have begun to bond with the
second-to-last layer. Desirably, the resulting surface includes
protruding particles sized between about 5 and 50 microns.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0028] In the drawings, which illustrate what are currently
regarded as the best modes for carrying out the invention:
[0029] FIG. 1 is a schematic of one configuration of a preferred
embodiment;
[0030] FIG. 2A is a perspective side view in elevation of a first
implantable biosensor according to the present invention;
[0031] FIG. 2B is an enlarged perspective view in elevation of a
probe portion of the implantable biosensor illustrated in FIG.
2A;
[0032] FIG. 2C is a perspective side view in elevation of the
implantable biosensor of FIG. 2A, in a partially assembled
configuration;
[0033] FIG. 2D is a perspective side view in elevation of the
implantable biosensor of FIG. 2A, in an assembled
configuration;
[0034] FIG. 3 is a side view illustrating a stage of construction
of a probe portion of the implantable biosensor of the
invention;
[0035] FIG. 4 is a side view of an assembled but uncoated miniature
probe portion of the biosensor of the invention;
[0036] FIG. 5 is an enlarged cross-sectional side view of a
miniature, flexible probe portion of the implantable biosensor;
[0037] FIG. 6A is a perspective side view in elevation of a second
implantable biosensor according to the present invention;
[0038] FIG. 6B is an enlarged perspective view in elevation with
greater resolution of a portion of the embodiment illustrated in
FIG. 6A;
[0039] FIG. 6C is a perspective view in elevation of the embodiment
of FIG. 6A in a partially assembled configuration; and
[0040] FIG. 6D is a perspective view in elevation of the embodiment
of FIG. 6A in an assembled configuration.
DETAILED DESCRIPTION OF THE INVENTION
[0041] FIG. 1 illustrates a preferred embodiment in which an
implantable biosensor, generally 10, and associated sensor cable 20
are provided. Miniaturized and highly flexible, the biosensor 10
may be placed into a subject subcutaneously through a cannula such
as an introducer catheter 30. The biosensor 10 as illustrated is
associated percutaneously through the sensor cable 20 with a sensor
module 40, which in turn is associated via a module cable 50 with a
Sensor Display Unit ("SDU") 60. The SDU 60 can be structured to be
interactive across SDU cable 70 with computer hardware and other
software, generally 80.
[0042] The foregoing biosensor system may include a single-use
portion and a reusable portion. The single-use portion includes the
introducer catheter 30, the biosensor 10, the sensor cable 20, the
sensor module 40 and the module cable 50. The introducer catheter
30 can generally be regarded as a separate component, although
certain embodiments may incorporate the catheter to carry a portion
of a biosensor probe. The biosensor 10, sensor cable 20, sensor
module 40 and module cable 50 desirably are all permanently affixed
to each other. Module cable 50 typically is removably attached at
disconnect 55 to SDU 60. The SDU 60 and SDU cable 70 may be reused.
When attached to the SDU 60, the SDU cable 70 allows the glucose
information to be downloaded to a personal computer 80 that is
loaded with the sensor download software.
[0043] To install a preferred embodiment of a biosensor 10,
introducer catheter 30 can be inserted into the subcutaneous tissue
of a subject on a supporting needle (not illustrated). The
supporting needle is removed to leave an opening through the
cannula and, typically, a short path extension into the subject's
tissue. Then, the biosensor 10 maybe placed into the introducer
catheter 30 such that a portion of the biosensor 10 protrudes
beyond the introducer catheter 30. The working electrode 100 and
reference electrode 110 of the presently preferred embodiment are
designed to be deployed 3-10 mm into the subcutaneous fatty tissue
of a subject to monitor glucose concentration in the interstitial
fluids. The introducer catheter 30/biosensor 10 assembly, as well
as the sensor module 40, is then generally affixed to the skin (not
shown) via an adhesive patch.
[0044] The biosensor 10 produces a small electrical current that is
proportional to the glucose concentration. This current is
amplified and conditioned by the sensor module 40. The sensor
module 40 also provides a polarization voltage to the working
electrode of the biosensor 10. The amplified signal typically is
interpreted by the SDU 60, which generally calibrates, displays and
stores the glucose data.
[0045] The biosensor 10, as set forth in FIGS. 2A-2D, includes a
sensor shaft 90 with sensor cable 20 extending therefrom, a working
electrode 100, a reference electrode 110 and a hub 120 for
attaching the biosensor 10 to the introducer catheter 30. With
reference to FIG. 2B, the working electrode 100 and reference
electrode 110 are adjacent a first dielectric spacer 130. The
reference electrode 110 and sensor shaft 90 are adjacent a second
dielectric spacer 140. A filament core 150 is visible in FIG. 2B
through a polymer cap 160. The dielectric spacers 130, 140 provide
one arrangement of structure operable to prevent the two electrodes
from shorting together through a direct physical contact between
the electrodes.
[0046] The filament core 150 may include any of a variety of
suitable materials, such as polymeric, ceramic, or flexible
metallic materials, that can sometimes be insulated. One currently
preferred filament core 150, as illustrated in FIG. 3 at an
intermediate stage of construction of a biosensor 10, includes a
plurality of filamentous fibers 170 of a polymeric material bundled
in substantially axial alignment with respect to each other. Fibers
170 forming an exemplary filament core 150 may be formed from
natural or synthetic fibers, and may have round, rectangular,
uniform, or even irregular cross-sections. A desirable core
material will have sufficient tensile strength to aid in extraction
of biosensor elements entrained thereon.
[0047] A desirable flexible filament core 150 forms a biosensor 10
having enhanced transverse flexibility operable to reduce
irritation at the installation location in a subject compared to
rigid needle-type biosensors. A filament core 150 desirably is
structured and arranged in a multistrand configuration to increase
transverse flexibility of biosensor 10. A multistrand core provides
a plurality of strands, each strand having a significantly reduced
cross-section and bending stiffness compared to a solid
cross-section replaced by that core. A plurality of such strands
170 in combination can form a transversely flexible biosensor 10.
For the purpose of this disclosure, a solid copper needle having a
diameter of about 25 gauge is regarded as being transversely
rigid.
[0048] With reference to FIGS. 3 and 4, working wire lead 180
provides structure that forms a conductive path that extends from
the working electrode 100 for electric communication through the
sensor cable 20 (see, FIG. 1). The conductive path can be disposed
among the fibers 170 and extends axially along the sensor shaft 90.
The working electrode 100 of biosensor 10 is typically formed of
platinum, or a platinum compound, and desirably circumscribes the
filament core 150 in the form of continuous working coils,
generally 190. One operable conductive path is formed by a
proximally directed axial extension of a wire formed at its distal
end into working electrode 100.
[0049] The reference electrode 110 in FIG. 4 preferably is formed
from a chlorided silver substrate. A reference electrode 110
typically extends axially along a portion of the filament core 150
and desirably circumscribes the filament core 150 in the form of
continuous reference coils, generally 200. A reference wire lead
210 forms a conductive path that extends from the coils 200 of
reference electrode 110 for electric communication through the
sensor cable 20. An exemplary conductive path can be formed from a
proximally extending portion of reference wire lead 210 forming the
reference electrode 110. The conductive path can be insulated
and/or disposed among the fibers 170. Both the working wire lead
180 and the reference wire lead 210 are typically available for
termination to a distal end of the sensor cable 20 at a hub 120. An
extension to leads 180 and 210 may effectively continue from
electrical contacts, generally located in association with the hub,
to extend along sensor cable 20 and provide electrical contacts at
a proximal end of sensor cable 20.
[0050] The sensor shaft 90, in certain embodiments, is formed as a
cylinder about the filament core 150. One workable cylinder may, at
least in part, be formed of small-diameter stainless steel wire. A
sensor shaft 90 may be arranged, as illustrated, to
circumferentially circumscribe the filament core 150 in the form of
continuous body coils, generally 220. Generally, wire used to form
coils 190, 200, and 220 has a diameter between about 0.001 and
0.005 inch, with about 0.002 inch being currently preferred. The
configuration of coils 190, 200, and 220 desirably lends additional
axial compressive load-carrying capability to the fibers 170 of the
biosensor 10 while maintaining the lateral flexibility of the
highly flexible, sometimes even flaccid, fibers 170, thereby
reducing a tendency toward scarring in surrounding tissue when
implanted.
[0051] While the illustrations generally depict electrodes and
sensor shafts that are substantially cylindrical, such is not a
strict requirement. For instance, a workable core can be formed
having a triangular, square, rectangular, or even other
alternatively shaped cross-section. An electrode or shaft
reinforcement can be wound around such core to form a tube with a
cross-section substantially conforming to that of the core. In
another example, a reinforcing electrode can be applied to a core
having such a noncircular cross-section by way of a coating,
printing, vapor deposition, or other procedure to form a tubular
electrode that may be characterized as providing some "effective"
inner and outer diameters. Furthermore, in some cases, a shaft
reinforcement can be formed from a shrink-fit tubing that
substantially conforms to an underlying core profile.
[0052] The coils 190, 200, and 220 may be relatively less closely
wound (with respect to an axial spacing, or pitch, between
centerlines of adjacent coils) about the fibers 170 in certain
configurations other than embodiments illustrated in this
disclosure. However, an increase in the relative closeness of the
coils 190 and 200 results in an increase in reactive surface area
for the respective electrodes 100, 110, thus enhancing sensitivity
and accuracy of readings obtained from a biosensor 10. Adjacent
coils 220 can be placed abutting one another (with an axial
spacing, or pitch, between centerlines of adjacent coils of one
coil-wire diameter) to maximize axial load-carrying capabilities of
a sensor shaft 90, while still retaining a significant increase in
transverse flexibility, compared to a rigid solid shaft.
[0053] Construction of a biosensor 10, including coils 190, 200,
220 as illustrated, generally enhances the sensor's flexibility and
resistance to damage. Transverse flexibility is greatly increased
over a comparable solid cross-section because the load path is
changed. Both a solid shaft and a cylinder have a cross-section
that carries a bending-induced load along an uninterrupted, axially
directed load path as axial tension and axial compression stress.
Coils provide an axially interrupted load path along a length of
the electrode (or sensor shaft 90). Coil structures cannot carry
bending loads in the same way an uninterrupted surface can. Under
transverse bending of an illustrated biosensor 10, the coils
displace in a shear mode and carry loads as torsion and bending
loading in the coil elements, but the bending load path and
effective displacements are entirely different than those in a
solid shaft. For example, the bending of a coil element is
essentially orthogonal to the bending in the equivalent
uninterrupted surface. The stress induced in the coil element is,
therefore, significantly lower (potentially by orders of magnitude)
than the stress induced in the comparable solid cross-section. A
coil arrangement therefore resists breaking-off of electrode
portions inside a subject and reduces irritation at the
implantation interface.
[0054] An axially interrupted electrode can be formed other than as
a coil structure. For example, a cylinder can be made to provide
circumferential relief, or radially directed cuts, in an
overlapping finger pattern. Such relief can be laser etched from a
continuous cylinder. Alternatively, such pattern can be printed or
etched. The relief also provides a radial component to the
electrode surface, thereby potentially increasing the available
reactive surface area of the electrode.
[0055] Filament core 150 and its associated cap 160 work in harmony
to further resist leaving any broken-off portions of electrode,
such as working electrode 100, behind in a subject when a biosensor
10 is removed from the subject's tissue. Cap 160 desirably is
operable as a stopper forming an interference to resist extraction
of filament core 150 from within an electrode. That is, the stopper
functions to hold an electrode (such as working electrode 100) at a
distal tip end 310 (FIG. 5), placing the working electrode 100 into
compression during withdrawal of a biosensor 10. A cap 160
desirably provides structure sized larger than an inside diameter
of an electrode. Therefore, the cap 160 forms an interference with
the electrode to resist separation of the electrode from the
filament core 150. Certain embodiments of cap 160 may adhere an
electrode, or a portion of an electrode, directly to a filament
core 150. It is within contemplation for a cap 160 to be formed by
melting a distal portion of a filament core 150. The filament core
150 desirably provides a strand of material having sufficient
tensile strength to overcome resistance due to adhesion between
body tissue and portions of a biosensor 10. Therefore, filament
core 150 and cap 160 are relied upon for extraction of the
biosensor 10.
[0056] The electrodes 100 and 110 of the biosensor 10, in a
preferred embodiment, are illustrated in an enlarged view in FIG. 5
to illustrate three layers of membranes. An inner exclusion
membrane 230 is depicted as surrounding and being adjacent to the
working electrode 100. The inner exclusion membrane 230, preferably
formed of polysulfone or sulfonated polyethersulfone, serves to
reduce the sensor artifact that is caused by non-endogenous
electroactive molecules, thus excluding interfering compounds such
as ascorbic acid and acetaminophen. A middle enzymatic membrane 240
surrounds the inner exclusion membrane 230. The middle enzymatic
membrane 240 includes immobilized glucose oxidase enzyme that
converts glucose to hydrogen peroxide to generate a current. An
outer polymer membrane 250 surrounds the middle enzymatic membrane
240, as well as the reference electrode 110, to restrict diffusion
of glucose while allowing the free passage of oxygen. This outer
polymer membrane 250 may be formed of various polymers. One
preferred embodiment of an outer polymer membrane 250 is formed of
polyurethane. A careful approach to material selection for the
membrane layers 230, 240, and 250 facilitates correction of the
nonlinear diffusion of glucose and reduces errors resulting from
interfering electroactive species.
[0057] It can be appreciated that the introducer catheter 30,
typically used in conjunction with a preferred embodiment biosensor
10, provides access from outside the body (not shown) to the tissue
just under the skin layer (not shown). With reference to FIG. 2A,
the biosensor 10 is inserted into and through a lumen 260 of the
introducer catheter 30 to a point at which the polymer cap 160,
working electrode 100 and reference electrode 110 of the biosensor
10 protrude beyond and outside the introducer catheter lumen 260.
Such placement allows the working electrode 100 and reference
electrode 110 to be in communication with the surrounding tissue
(not illustrated).
[0058] With reference to FIGS. 2B and 5, polymer cap 160, located
at a head portion 270 of the biosensor 10, provides a conformal
material that coats the fibers 170 extending beyond the working
electrode 100 and adheres the fibers 170 into the unified filament
cap 160. The working electrode 100, as illustrated, extends along a
leading portion, generally 280, of the biosensor 10. As further
illustrated, the reference electrode 110 extends along the trailing
portion 290. The leading portion 280 and trailing portion 290, as
best illustrated in FIG. 2D, extend beyond the lumen 260 of the
introducer catheter 30 when introduced into a subject. The sensor
shaft 90 may include a tail portion 300 along which the body coils
220 may be located (see, FIG. 4).
[0059] As illustrated in FIG. 5, working electrode 100 includes a
distal tip end, generally 310, and a proximal tip end, generally
320. The distal tip end 310, as illustrated, is associated with the
filament core 150 at or near the head portion 270. The proximal tip
end 320 is associated with the filament core 150 at or near the
trailing portion 290 or tail portion 300 depending upon the
configuration. In one configuration, a reference electrode 110 is
separate from a needle-probe portion of a biosensor. In another
configuration and as illustrated in FIG. 5, a reference electrode
110 is included on the biosensor 10 probe.
[0060] The preferred embodiment 10 illustrates the working
electrode 100 as being structured in the form of coils. However, it
is only necessary that the working electrode 100 be in length
substantially not less than the leading portion 280 when the
leading portion 280 is laterally deflected to a maximum extent.
Such a limitation is operable to resist separation of an
electrically conductive path from the electrode due to bending of
the biosensor. Correspondingly, whereas in a preferred embodiment
the reference electrode 110 is illustrated as being in the form of
coils, in essence a working electrode 110 may be in length
substantially not less than the trailing portion 290 when the
trailing portion 290 is laterally deflected to a maximum
extent.
[0061] FIGS. 6A-6D illustrate an alternative preferred embodiment
of a biosensor, generally indicated at 330, including an introducer
catheter, generally indicated at 340. The biosensor 330 includes a
working electrode, generally 350, typically corresponding in
function, materials, location and other general characteristics
with the working electrode 100. The biosensor 330 further includes
a polymer cap 360, filament core 370, working coils 380, dielectric
spacer 390, head portion, generally 400, leading portion 410, tail
portion 420, hub 430, working electrode lead 440, and body coils
445. Biosensor 330 generally includes membranes and is structured
to provide characteristics and features that in turn generally
correspond to those of the biosensor embodiment 10.
[0062] The introducer catheter 340, like the introducer catheter
30, includes a lumen that may be thought of as an interior cannula
lumen 450. Furthermore, the illustrated introducer catheter 340
presents an advanced end 460 designed for subcutaneous or other
intra-tissue placement, an opposite end, generally 470, and a
cannula wall 480 defining the interior cannula lumen 450 and
comprising an exterior surface 490. The exterior surface 490 and
the interior cannula lumen 450 extend between the advanced end 460
and the opposite end 470. In the biosensor embodiment 330, a
reference electrode 500 is associated with the exterior surface 490
of catheter 340 in the vicinity of the advanced end 460. Electrode
500 may take other forms, such as a film, band, etching, printed or
imprinted layer, or a shell or coating. The interior cannula lumen
450 is of sufficient cross-sectional diameter to pass the biosensor
330. The advanced end 460 and exterior surface 490 of the
introducer catheter 340 are structured and arranged to enable
access of the advanced end 460 into and through subcutaneous or
other subject tissue.
[0063] The opposite end 470 generally includes one or more surfaces
510 useful for adhesively fixing the introducer catheter 340 to the
skin. The hub 430 may be anchored to the opposite end 470 of the
introducer catheter 340. The opposite end 470 may be further
structured and arranged to engage the hub 430, upon advancement of
the biosensor 330 through the interior cannula lumen 450
sufficiently far, so that the alternative working electrode 350
reaches a position extending beyond the advanced end 460. Upon
achievement of such a position, a reference wire lead 520
associated with the hub 430 may be brought into register with the
reference electrode 500 carried by the catheter 340.
[0064] Glucose ("Glu"), in a somewhat restricted manner, and Oxygen
("O.sub.2"), comparatively freely, diffuse from the interstitial
tissues of the subject through the outer polymer membrane 250 (see
FIG. 5) and, in the presence of the glucose oxidase ("GO.sub.x") of
the middle enzymatic membrane 240, produce gluconic acid "GluA")
and hydrogen peroxide ("H.sub.2O.sub.2"). The H.sub.2O.sub.2, upon
interaction with the platinum ("Pt") working electrode 100, which
is typically polarized at approximately 0.7 volts, creates a
current which travels up the working wire lead 180 for processing
through the sensor module 40. A differential signal is generally
measured between the working electrode 100 and the reference
electrode 110 at the sensor module 40, and successively transmitted
to the SDU 60 and ultimately the computer 80.
[0065] In the manufacture of a biosensor 10, a plurality of
filamentous fibers 170 of the filament core 150 are axially aligned
in a bundle and bonded to form the polymer cap 160. The wire
material of a working electrode 100 can be manually or mechanically
wrapped around the filament core 150 beginning at the head portion
270 and continuing proximally across the leading portion 280 to
form the working coils 190 (see FIGS. 4 and 5). An exemplary
working electrode 100 is somewhat cylindrical, about 0.60 inch in
axial length and about 0.015 inch in maximum outside diameter. It
is currently preferred to form an electrode, such as a working
electrode 100, from a wire wound on a spiral path.
[0066] If the biosensor includes a reference electrode 110 adjacent
to, but apart from, the working electrode 100, the reference
electrode 110 can likewise be manually or mechanically wrapped
around the filament core 150 and working wire lead 180. Reference
electrode 110 is structured to occupy a desired axial distance and
desirably forms reference coils 200 electrically communicating with
the reference wire lead 210. Reference wire lead 210 and the
working wire lead 180 extend proximally among the fibers 170. Body
coils 220 are then similarly wrapped around the filament core 150
and leads 180 and 210, terminating at a proximal end, generally
indicated at 305 (FIG. 4).
[0067] A core may also be threaded through preformed electrodes and
dielectric spacers. Certain preferred polymer cores can be heated
and drawn slightly at a distal portion to form an operable needle
to assist in threading the electrodes. In embodiments manufactured
by threading one or more premanufactured electrodes, a conductive
path from the respective electrode(s) is generally insulated prior
to the threading assembly step. The conductive path typically
includes a proximally protruding portion of the wire forming a
coiled electrode. Such proximally directed wire desirably is
disposed among strands of a core for additional insulation.
[0068] The working electrode 100 is next manually or mechanically
dipped in a vertical orientation into at least one coating of 5%
polyethersulfone in the solvent DMAC to form the inner exclusion
membrane 230 and dried to ensure solidification of the coating. Of
course, while reference is made in this disclosure to dipping, it
is to be realized that other procedures operable to apply a coating
(e.g., brushing, spraying, vapor deposition, and the like) are
intended to be encompassed by such language. Successive coatings
may be desirable and accomplished by repeating the application
process.
[0069] The working electrode 100 and filament core 150 are then
manually or mechanically dipped in a vertical orientation into at
least one coating of 1% glucose oxidase, 0.6% albumin and 0.5%
gluteraldehyde in water to form the middle enzymatic membrane 240,
and dried to ensure solidification ofthe coating. As with the inner
exclusion membrane 230, successive coatings may be desirable and
accomplished by repeating the foregoing process. In certain
embodiments, the electrode is assembled onto a filament core 150
before the step of applying glucose oxidase. In that case, the
glucose oxidase can fill in any spaces between the core fibers 170
to increase the volume of glucose oxidase associated with the
electrode. The increased volume of glucose oxidase provides
enhanced sensor stability and shelf life.
[0070] Next, in biosensor configurations such as embodiment 10,
having the working electrode 100 and reference electrode 110
positioned adjacent but separate from each other on the filament
core 150, both the working and reference electrodes 100 and 110 are
manually or mechanically dipped in a vertical orientation into at
least one coating of 5% polyurethane in the solvent tetrahydrofuran
to form the outer polymer membrane 250, and dried to ensure
solidification of the coating. Again, successive coatings may be
desirable and accomplished by repeating the foregoing process.
Successive coatings contemplate use of an approximately 5% solution
in a solvent such as, for example, tetrahydrofuran or methylene
chloride, to allow for solvent drying from liquid to gel to jelly
to a tightly bound conformal coating. The coating materials and
respective number of layers are selected to balance response time,
electrical insulation, biocompatibility and diffusive properties.
For example, a thicker layer increases response time but provides
better insulation. To enhance biocompatibility, the outermost
surface of the final layer can be made microscopically rough by
phase inversion polymerization, i. e., by immediately dipping the
last layer in water to allow the miscible solvent to be largely
rinsed away soon after the first of the fibers comprising the 5%
solution have begun to bond with the second to last layer. Such a
procedure typically results in a surface including projecting
particles that are sized between about 5 and 50 microns.
[0071] If the biosensor is structured to include coterminous
wrapping of both the working and reference electrodes 100, 110,
then the sequence of the foregoing method of manufacturing would be
altered by, prior to coiling, applying the inner exclusion membrane
230, the middle enzymatic membrane 240 and a preliminary outer
polymer membrane 250 coating to the portion of the working
electrode 100 to be coiled, then coiling both the coated working
electrode 100 and the reference electrode 110 over a portion of the
filament core 150 comparable in length to both working and
reference coils 190, 200 when adjacent but separate, and finally
coating both coterminous coiled electrodes 100, 110 as desired.
[0072] The system, apparatus and method of the present invention
provide distinct advantages over prior implantable biosensors.
Thus, reference herein to specific details of the illustrated or
other preferred embodiments is by way of example and not intended
to limit the scope of the appended claims. It will be apparent to
those skilled in the art that modifications of the basic
illustrated embodiments may be made without departing from the
spirit and scope of the invention as recited by the claims.
* * * * *