U.S. patent application number 11/416346 was filed with the patent office on 2006-10-05 for optimized sensor geometry for an implantable glucose sensor.
Invention is credited to James H. Brauker, Victoria Carr-Brendel, Laura A. Martinson, Paul V. Neale.
Application Number | 20060224108 11/416346 |
Document ID | / |
Family ID | 33101486 |
Filed Date | 2006-10-05 |
United States Patent
Application |
20060224108 |
Kind Code |
A1 |
Brauker; James H. ; et
al. |
October 5, 2006 |
Optimized sensor geometry for an implantable glucose sensor
Abstract
An implantable sensor for use in measuring a concentration of an
analyte such as glucose in a bodily fluid, including a body with a
sensing region adapted for transport of analytes between the sensor
and the bodily fluid, wherein the sensing region is located on a
curved portion of the body such that when a foreign body capsule
forms around the sensor, a contractile force is exerted by the
foreign body capsule toward the sensing region. The body is
partially or entirely curved, partially or entirely covered with an
anchoring material for supporting tissue ingrowth, and designed for
subcutaneous tissue implantation. The geometric design, including
curvature, shape, and other factors minimize chronic inflammatory
response at the sensing region and contribute to improved
performance of the sensor in vivo.
Inventors: |
Brauker; James H.; (San
Diego, CA) ; Carr-Brendel; Victoria; (San Diego,
CA) ; Neale; Paul V.; (San Diego, CA) ;
Martinson; Laura A.; (La Mesa, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
33101486 |
Appl. No.: |
11/416346 |
Filed: |
May 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10646333 |
Aug 22, 2003 |
|
|
|
11416346 |
May 2, 2006 |
|
|
|
60460825 |
Apr 4, 2003 |
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Current U.S.
Class: |
604/66 ; 604/503;
604/504; 604/891.1 |
Current CPC
Class: |
A61B 5/6882 20130101;
A61B 5/0031 20130101; A61B 5/14532 20130101; A61B 5/14546 20130101;
A61B 5/418 20130101; A61B 5/1486 20130101; A61B 5/415 20130101;
A61B 2562/187 20130101 |
Class at
Publication: |
604/066 ;
604/891.1; 604/503; 604/504 |
International
Class: |
A61M 31/00 20060101
A61M031/00; A61K 9/22 20060101 A61K009/22 |
Claims
1. An implantable sensor for use in measuring a concentration of an
analyte in a bodily fluid, the sensor comprising: a body comprising
a sensing region adapted for transport of analytes between the
sensor and the bodily fluid, wherein the sensing region is located
on a curved portion of the body such that when a foreign body
capsule forms around the sensor, a contractile force is exerted by
the foreign body capsule toward the sensing region, wherein the
body comprises a first surface and a second surface, wherein the
sensor region is situated at a position on said first surface
offset from a center point of said first surface, and wherein the
sensor is a subcutaneous sensor suitable for implantation in a soft
tissue of a body.
2. The sensor of claim 1, wherein the sensor comprises a plurality
of sensor regions.
3. The sensor of claim 1, wherein said second surface is flat.
4. The sensor of claim 1, wherein said second surface comprises a
curvature.
5. The sensor of claim 1, wherein t wherein said first surface,
when viewed from a direction perpendicular to a center of said
first surface, has a substantially oval profile.
6. The sensor of claim 1, wherein said first surface, when viewed
from a direction perpendicular to a center of said first surface,
has a substantially circular profile.
7. The sensor of claim 1, wherein the body is substantially
cylindrical defined by a curved lateral surface and two ends.
8. The sensor of claim 1, wherein the body is substantially
cylindrical defined by a curved lateral surface and two ends, and
wherein at least one of said ends comprises the substantially
curved portion on which the sensor region is located.
9. The sensor of claim 1, wherein the second surface comprises
anchoring material thereon for supporting tissue ingrowth.
10. The sensor of claim 1, further comprising a mechanical
anchoring mechanism formed on the body.
11. The sensor of claim 1, wherein said curved portion comprises a
plurality of radii of curvature.
12. The sensor of claim 1, wherein said curved portion comprises a
radius of curvature between about 0.5 mm and about 10 cm.
13. The sensor of claim 1, wherein the body comprises a first major
surface on which said sensing region is located and a second major
surface, and wherein the first and second major surfaces together
account for at least about 40% of the surface area of the
device.
14. The sensor of claim 1, wherein the body comprises a first major
surface on which said sensing region is located and a second major
surface, wherein the first major surface has edges between which a
width of the first major surface can be measured, and wherein the
sensing region is spaced away from the edges by a distance that is
at least about 10% of the width of the first major surface.
15. The sensor of claim 1, and wherein edges of the first major
surface are rounded and transition smoothly away from the first
major surface.
16. The sensor of claim 1, wherein the body defines a surface area,
and wherein between 10% and 100% of the surface area is convexly
curved.
17. The sensor of claim 1, wherein the body comprises plastic.
18. The sensor of claim 17, wherein the plastic is selected from
the group consisting of thermoplastic and thermoset.
19. The sensor of claim 18, wherein the thermoset is selected from
the group consisting of epoxy, silicone, and polyurethane.
20. The sensor of claim 1, wherein the body comprises a material
selected from the group consisting of metal, ceramic, and
glass.
21. The sensor of claim 1, further comprising a porous biointerface
material that covers at least a portion of the sensing region.
22. The sensor of claim 21, wherein the biointerface material
comprises interconnected cavities dimensioned and arranged to
interfere with formation of occlusive cells.
23. The sensor of claim 1, wherein the sensor is a glucose
sensor.
24. A wholly implantable sensor adapted to measure a concentration
of an analyte in a bodily fluid, comprising: a wholly implantable
body comprising a sensing region adapted for transport of analytes
between the sensor and the bodily fluid, wherein the sensing region
is located on a curved portion of a first major surface of said
body, wherein the body further comprises a second major surface,
wherein the sensing region is situated at a position on said first
major surface offset from a center point of said first major
surface, wherein the sensor is a subcutaneous sensor suitable for
implantation in a soft tissue of a body, and wherein said first
surface comprises a porous material thereon for supporting tissue
ingrowth.
25. An implantable sensor adapted to measure a concentration of an
analyte in a bodily fluid, comprising: a body having a first major
surface and, opposite thereto, a second major surface, wherein the
first major surface is generally planar, slightly convex, and has
rounded edges, with a sensor region located on the first major
surface that is spaced away from the rounded edges and offset from
a center point of said first major surface, wherein the first major
surface is sufficiently convex that when a foreign body capsule
forms around the sensor, contractile forces are exerted thereby
generally uniformly towards the sensing region, and wherein the
sensor is a subcutaneous sensor suitable for implantation in a soft
tissue of a body.
Description
[0001] This application is a division of U.S. application Ser. No.
10/646,333 filed Aug. 22, 2003, which claims the benefit of
priority under 35 U.S.C. .sctn. 119(e) to U.S. Provisional
Application No. 60/460,825, filed Apr. 4, 2003, the contents of
which are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to implantable
sensors that measure the concentration of an analyte in a
biological fluid. The sensor geometry optimizes the healing at the
sensor-tissue interface and is less amenable to accidental movement
due to shear and rotational forces than other sensor
configurations.
BACKGROUND OF THE INVENTION
[0003] Implantable analyte sensors that are placed in the
subcutaneous tissue or other soft tissue sites must develop and
sustain a stable biointerface that allows the continuous and timely
transport of analytes across the interface between the tissue and
the device. For example, in the case of a glucose sensor, glucose
must be able to freely diffuse from surrounding blood vessels to a
membrane of the sensor. Glucose sensors may be implanted in the
subcutaneous tissue or other soft tissue. Such devices include
glucose oxidase based amperometric sensors that sense glucose for
weeks, months or longer after implantation.
[0004] While the utility of such devices for glucose sensing has
been demonstrated, the consistency of function for such devices is
not optimal. For a particular device, the sensor may, for example:
1) fail to function (namely, fail to track glucose effectively) in
a stable manner during the first few weeks after implantation; 2)
not work at all during the first few weeks, but subsequently begin
to function in a stable manner; 3) function well during the first
few weeks, lose function, then regain effectiveness or never
recover function; or 4) work immediately, and continue to function
with high accuracy throughout the course of a several month
study.
[0005] Glucose sensors with improved acceptance within the host
tissue and decreased variability of response are required for
reliable functionality in vivo. Accordingly, the present invention
discloses systems and methods for providing this improved
functionality and consistency of analyte sensor in a host.
SUMMARY OF THE INVENTION
[0006] A sensor, especially a sensor suitable for implantation into
soft tissue that provides accurate analyte measurements while
offering consistency of function is highly desirable.
[0007] Accordingly, in a first embodiment an implantable sensor is
provided for use in measuring a concentration of an analyte in a
bodily fluid, the sensor including a body including a sensing
region adapted for transport of analytes between the sensor and the
bodily fluid, wherein the sensing region is located on a curved
portion of the body such that when a foreign body capsule forms
around the sensor, a contractile force is exerted by the foreign
body capsule toward the sensing region.
[0008] In an aspect of the first embodiment, the sensor is a
subcutaneous sensor.
[0009] In an aspect of the first embodiment, the sensor is an
intramuscular sensor.
[0010] In an aspect of the first embodiment, the sensor is an
intraperitoneal sensor.
[0011] In an aspect of the first embodiment, the sensor is an
intrafascial sensor.
[0012] In an aspect of the first embodiment, the sensor is suitable
for implantation in an axillary region.
[0013] In an aspect of the first embodiment, the sensor is suitable
for implantation in a soft tissue of a body.
[0014] In an aspect of the first embodiment, the sensor is suitable
for implantation at the interface between two tissue types.
[0015] In an aspect of the first embodiment, the sensor includes a
plurality of sensor regions.
[0016] In an aspect of the first embodiment, the plurality of
sensor regions are located on curved portions of the body.
[0017] In an aspect of the first embodiment, the body includes a
first major surface and a second major surface, and wherein the
sensing region is located on the first surface, and wherein the
second surface is flat.
[0018] In an aspect of the first embodiment, the body includes a
first major surface and a second major surface, and wherein the
sensing region is located on the first major surface, and wherein
the second major surface includes a curvature.
[0019] In an aspect of the first embodiment, the body includes a
first major surface and a second major surface, and wherein the
sensor region is situated at a position on the first major surface
offset from a center point of the first major surface.
[0020] In an aspect of the first embodiment, the body includes a
first major surface and a second major surface, and wherein the
sensor region is situated on the first major surface approximately
at a center point of the first major surface.
[0021] In an aspect of the first embodiment, the body includes a
first surface and a second surface, and wherein the sensor region
is situated approximately at an apex of the first surface.
[0022] In an aspect of the first embodiment, the body includes a
first surface and a second surface, and wherein the first surface,
when viewed from a direction perpendicular to a center of the first
surface, has a substantially rectangular profile.
[0023] In an aspect of the first embodiment, the body includes a
first surface and a second surface, and wherein the first surface,
when viewed from a direction perpendicular to a center of the first
surface, has a substantially rectangular profile with rounded
corners.
[0024] In an aspect of the first embodiment, the body includes a
first surface and a second surface, and wherein the first surface,
when viewed from a direction perpendicular to a center of the first
surface, has a substantially oval profile.
[0025] In an aspect of the first embodiment, the body includes a
first surface and a second surface, and wherein the first surface,
when viewed from a direction perpendicular to a center of the first
surface, has a substantially circular profile.
[0026] In an aspect of the first embodiment, the body is
substantially cuboidal defined by six faces, eight vertices, and
twelve edges, wherein at least one of the faces includes the
sensing region.
[0027] In an aspect of the first embodiment, at least two of the
faces are substantially curved.
[0028] In an aspect of the first embodiment, at least four of the
faces are substantially curved.
[0029] In an aspect of the first embodiment, all six of the faces
are substantially curved.
[0030] In an aspect of the first embodiment, the edges are
substantially rounded.
[0031] In an aspect of the first embodiment, the vertices are
substantially rounded.
[0032] In an aspect of the first embodiment, the entire body is
curved.
[0033] In an aspect of the first embodiment, the body is
substantially cylindrical defined by a curved lateral surface and
two ends, and wherein the sensor region is located on the lateral
surface.
[0034] In an aspect of the first embodiment, the body is
substantially cylindrical defined by a curved lateral surface and
two ends, and wherein at least one of the ends includes the
substantially curved portion on which the sensor region is
located.
[0035] In an aspect of the first embodiment, the body is
substantially spherical.
[0036] In an aspect of the first embodiment, the body is
substantially ellipsoidal.
[0037] In an aspect of the first embodiment, the body includes a
first surface on which the sensing region is located and a second
surface, and wherein the first surface includes anchoring material
thereon for supporting tissue ingrowth.
[0038] In an aspect of the first embodiment, the second surface is
located opposite the first surface, and wherein the second surface
includes anchoring material thereon for supporting tissue
ingrowth.
[0039] In an aspect of the first embodiment, the second surface is
located opposite the first surface, and wherein the second surface
is substantially smooth and includes a biocompatible material that
is non-adhesive to tissues.
[0040] In an aspect of the first embodiment, the second surface is
curved.
[0041] In an aspect of the first embodiment, a mechanical anchoring
mechanism is formed on the body.
[0042] In an aspect of the first embodiment, the curved portion
includes a plurality of radii of curvature.
[0043] In an aspect of the first embodiment, the curved portion
includes a radius of curvature between about 0.5 mm and about 10
cm.
[0044] In an aspect of the first embodiment, the curved portion
includes a radius of curvature between about 1 cm and about 5
cm.
[0045] In an aspect of the first embodiment, the curved portion
includes a radius of curvature between about 2 cm and about 3
cm.
[0046] In an aspect of the first embodiment, the curved portion
includes a radius of curvature between about 2.5 cm and about 2.8
cm.
[0047] In an aspect of the first embodiment, the sensor includes a
major surface and wherein the curved portion is located on at least
a portion of the major surface.
[0048] In an aspect of the first embodiment, the body further
includes a flat portion adjacent the curved portion.
[0049] In an aspect of the first embodiment, an interface between
the flat portion and the curved portion includes a gradual
transition.
[0050] In an aspect of the first embodiment, the body includes a
first major surface on which the sensing region is located and a
second major surface, and wherein the first and second major
surfaces together account for at least about 40% of the surface
area of the device.
[0051] In an aspect of the first embodiment, the first and second
major surfaces together account for at least about 50% of the
surface area of the device.
[0052] In an aspect of the first embodiment, the body includes a
first major surface on which the sensing region is located and a
second major surface, wherein the first major surface has edges
between which a width of the first major surface can be measured,
and wherein the sensing region is spaced away from the edges by a
distance that is at least about 10% of the width of the first major
surface.
[0053] In an aspect of the first embodiment, the sensing region is
spaced away from the edges by a distance that is at least about 15%
of the width of the first major surface.
[0054] In an aspect of the first embodiment, the sensing region is
spaced away from the edges by a distance that is at least about 20%
of the width of the first major surface.
[0055] In an aspect of the first embodiment, the sensing region is
spaced away from the edges by a distance that is at least about 25%
of the width of the first major surface.
[0056] In an aspect of the first embodiment, the sensing region is
spaced away from the edges by a distance that is at least about 30%
of the width of the first major surface.
[0057] In an aspect of the first embodiment, the spacing of the
sensing region from the edges is true for at least two width
measurements, which measurements are taken generally transverse to
each other.
[0058] In an aspect of the first embodiment, the body includes a
first major surface on which the sensing region is located and a
second major surface, wherein the first major surface is at least
slightly convex.
[0059] In an aspect of the first embodiment, a reference plane may
be defined that touches the first major surface at a point spaced
in from edges of the first major surface, and is generally parallel
to the first major surface, and is spaced away from opposite edges
of the first major surface due to convexity of the first major
surface, and wherein a location of an edge is the point at which a
congruent line or a normal line is angled 45 degrees with respect
to the reference plane.
[0060] In an aspect of the first embodiment, the reference plane is
spaced from the edges a distance that is at least about 3% from the
edges, and not more than 50% of the width.
[0061] In an aspect of the first embodiment, the reference plane is
spaced from the edges a distance that is at least about 3% from the
edges, and not more than 25% of the width.
[0062] In an aspect of the first embodiment, the reference plane is
spaced from the edges a distance that is at least about 3% from the
edges, and not more than 15% of the width.
[0063] In an aspect of the first embodiment, the body includes a
first major surface on which the sensing region is located, and
wherein edges of the first major surface are rounded and transition
smoothly away from the first major surface.
[0064] In an aspect of the first embodiment, the body defines a
surface area, and wherein between 10% and 100% of the surface area
is convexly curved.
[0065] In an aspect of the first embodiment, the body defines a
surface area, and wherein a substantial portion of the surface area
is convexly curved.
[0066] In an aspect of the first embodiment, the body defines a
surface area, and where at least about 90% of the surface area is
convexly curved.
[0067] In an aspect of the first embodiment, the body includes
plastic.
[0068] In an aspect of the first embodiment, the plastic is
selected from the group consisting of thermoplastic and
thermoset.
[0069] In an aspect of the first embodiment, the thermoset is
epoxy.
[0070] In an aspect of the first embodiment, the thermoset is
silicone.
[0071] In an aspect of the first embodiment, the thermoset is
polyurethane.
[0072] In an aspect of the first embodiment, the plastic is
selected from the group consisting of metal, ceramic, and
glass.
[0073] In an aspect of the first embodiment, a porous biointerface
material that covers at least a portion of the sensing region.
[0074] In an aspect of the first embodiment, the biointerface
material includes interconnected cavities dimensioned and arranged
to create contractile forces that counteract with the generally
uniform downward fibrous tissue contracture caused by the foreign
body capsule in vivo and thereby interfere with formation of
occlusive cells.
[0075] In an aspect of the first embodiment, the sensor is a
glucose sensor.
[0076] In a second embodiment, an implantable sensor is provided
for use in measuring a concentration of an analyte in a bodily
fluid, the sensor including: a body including a sensing region on a
major surface of the body, wherein the major surface includes a
continuous curvature substantially across the entire surface such
that when a foreign body capsule forms around the sensor, a
contractile force is exerted by the foreign body capsule toward the
sensing region.
[0077] In a third embodiment, a wholly implantable sensor is
provided to measure a concentration of an analyte in a bodily
fluid, including: a wholly implantable body including a sensing
region adapted for transport of analytes between the sensor and the
bodily fluid, wherein the sensing region is located on a curved
portion of a first surface of the body and wherein the first
surface includes anchoring material thereon for supporting tissue
ingrowth.
[0078] In a fourth embodiment, an implantable sensor is provided to
measure a concentration of an analyte in a bodily fluid, including:
a body having a first major surface and, opposite thereto, a second
major surface, wherein the first major surface is generally planar,
slightly convex, and has rounded edges, with a sensor region
located on the first major surface that is spaced away from the
rounded edges, wherein the first major surface is sufficiently
convex that when a foreign body capsule forms around the sensor,
contractile forces are exerted thereby generally uniformly towards
the sensing region.
[0079] In a fifth embodiment, an implantable sensor is provided for
use in measuring a concentration of an analyte in a bodily fluid,
the sensor including: a body, the body including a sensing region
adapted for transport of analytes between the sensor and the bodily
fluid, wherein the sensing region is located on a curved portion of
the body, and wherein a thermoset material substantially
encapsulates the body outside the sensing region.
[0080] In a sixth embodiment, an implantable sensor for use in
measuring a concentration of an analyte in a bodily fluid, the
sensor including: sensing means for measuring a concentration of
analyte in a bodily fluid; and housing means for supporting the
sensing means, wherein the sensing means is located on a curved
portion of housing means such that when a foreign body capsule
forms around the housing means, a contractile force is exerted by
the foreign body capsule toward the sensing means.
[0081] In a seventh embodiment, an implantable drug delivery device
is provided that allows transport of analytes between the device
and a bodily fluid, the device including: a body including an
analyte transport region adapted for transport of analytes between
the device and the bodily fluid, wherein the transport region is
located on a curved portion of the body such that when a foreign
body capsule forms around the device, a contractile force is
exerted by the foreign body capsule toward the analyte transport
region.
[0082] In an eighth embodiment, an implantable cell transplantation
device is provided that allows transport of analytes between the
device and a bodily fluid, the device including: a body including
an analyte transport region adapted for transport of analytes
between the device and the bodily fluid, wherein the transport
region is located on a curved portion of the body such that when a
foreign body capsule forms around the device, a contractile force
is exerted by the foreign body capsule toward the analyte transport
region.
BRIEF DESCRIPTION OF THE DRAWINGS
[0083] FIG. 1 is an illustration of classical foreign body response
to an object implanted under the skin.
[0084] FIG. 2A is schematic side view of a prior art device that
has a sensing region with an abrupt inside turn, causing a
sub-optimal foreign body response.
[0085] FIG. 2B is a photomicrograph of the foreign body response to
a portion of the device of FIG. 2A, after formation of the foreign
body capsule and subsequent explantation, showing thickened immune
response adjacent to the abrupt inside turn.
[0086] FIG. 3A is a schematic side view of another prior art device
that has flattened surfaces across the entire device, and
particularly across the sensing region, causing sub-optimal foreign
body capsule healing.
[0087] FIG. 3B is a schematic side view of the sensing region of
yet another device that has flattened surfaces across the entire
device, and an inset sensing region, which is an example of another
device that causes sub-optimal foreign body capsule healing in
implantable sensors.
[0088] FIG. 4 is a cross-sectional view of the sensing region of an
analyte sensor in one embodiment of the present invention, wherein
the sensing region is continuously curved, thereby causing
contractile forces from the foreign body capsule to press
downwardly on the sensing region.
[0089] FIG. 5A is a perspective view of an analyte sensor in
another embodiment, including a thin oblong body, a curved sensing
region, and an overall curved surface on which the sensing region
is located, thereby causing contractile forces from the foreign
body capsule to press downward on the sensor head.
[0090] FIG. 5B is the analyte sensor of FIG. 5A shown implanted
with the sensing region adjacent to the fascia underlying the
subcutaneous space, and overlaying adjacent muscle.
[0091] FIG. 5C is an end view of the analyte sensor of FIG. 5A
showing the contractile forces caused by the foreign body
capsule.
[0092] FIG. 5D is a side view of the analyte sensor of FIG. 5A.
[0093] FIG. 6 is a perspective view of sensor geometry in an
alternative embodiment wherein the sensor includes a curved sensor
region and a flat region, wherein the interface between the flat
region and the curved region includes a gradual transition.
[0094] FIG. 7 is a perspective view of sensor geometry in an
alternative embodiment wherein the entire sensor body is
curved.
[0095] FIG. 8 is a perspective view of sensor geometry in an
alternative embodiment including a cylindrical geometry wherein a
plurality of sensing regions are located on the curved lateral
surface of the sensor body.
[0096] FIG. 9A is a perspective view of sensor geometry in an
alternative embodiment including a substantially spherical body
wherein a plurality of sensing regions are located about the
circumference of the sphere.
[0097] FIG. 9B is a perspective view of a sensor geometry in an
alternative embodiment including a substantially spherical body
with a rod extending therefrom.
[0098] FIGS. 10A to 10D are perspective views of a sensor that has
an expandable sensing body in one embodiment. FIGS. 10A and 10C are
views of the sensor with the sensing body in a collapsed state,
FIGS. 10B and 10D are views of the sensor with the sensing body in
an expanded state.
[0099] FIGS. 11A to 11D are perspective views of sensors wherein
one or more sensing bodies are tethered to an electronics body in a
variety of alternative embodiments.
[0100] FIGS. 12A to 12B are perspective views of a sensor in an
alternative embodiment wherein an electronics body is independent
of the sensing bodies in a preassembled state and wherein the
sensing bodies are independently inserted (and operatively
connected) to the electronics body in a minimally invasive
manner.
[0101] FIG. 13A is a side schematic view of an analyte sensor with
anchoring material on a first and second major surface of the
device, including the surface on which the sensing region is
located, wherein the analyte sensor is implanted subcutaneously and
is ingrown with fibrous, vascularized tissue.
[0102] 13B is a side schematic view of an analyte sensor with
anchoring material on a first major surface on which the sensing
region is located, and wherein a second major surface is
substantially smooth.
[0103] FIG. 14A is a graph showing the percentage of functional
sensors from a study of two different sensor geometries implanted
in a host.
[0104] FIG. 14B is a graph showing the average R-value of sensors
from a study of two different sensor geometries implanted in a
host.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0105] The following description and examples illustrate some
exemplary embodiments of the disclosed invention in detail. Those
of skill in the art will recognize that there are numerous
variations and modifications of this invention that are encompassed
by its scope. Accordingly, the description of a certain exemplary
embodiment should not be deemed to limit the scope of the present
invention.
Definitions
[0106] In order to facilitate an understanding of the disclosed
invention, a number of terms are defined below.
[0107] The term "analyte," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, to refer
to a substance or chemical constituent in a biological fluid (for
example, blood, interstitial fluid, cerebral spinal fluid, lymph
fluid or urine) that can be analyzed. Analytes may include
naturally occurring substances, artificial substances, metabolites,
and/or reaction products. In some embodiments, the analyte for
measurement by the sensor heads, devices, and methods is glucose.
However, other analytes are contemplated as well, including but not
limited to acarboxyprothrombin; acylcarnitine; adenine
phosphoribosyl transferase; adenosine deaminase; albumin;
alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),
histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,
tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;
arginase; benzoylecgonine (cocaine); biotinidase; biopterin;
c-reactive protein; carbon dioxide; camitine; carnosinase; CD4;
ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol;
cholinesterase; conjugated 1-.beta.hydroxy-cholic acid; cortisol;
creatine kinase; creatine kinase MM isoenzyme; cyclosporin A;
d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone
sulfate; DNA (acetylator polymorphism, alcohol dehydrogenase, alpha
1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy,
glucose-6-phosphate dehydrogenase, hemoglobinopathies, A,S,C,E,
D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,
Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium
vivax, sexual differentiation, 21-deoxycortisol);
desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus
antitoxin; erythrocyte arginase; erythrocyte protoporphyrin;
esterase D; fatty acids/acylglycines; free 13-human chorionic
gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4);
free tri-iodothyronine (FT3); fumarylacetoacetase;
galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase;
gentamicin; glucose-6-phosphate dehydrogenase; glutathione;
glutathione perioxidase; glycocholic acid; glycosylated hemoglobin;
halofantrine; hemoglobin variants; hexosaminidase A; human
erythrocyte carbonic anhydrase I; 17 alpha-hydroxyprogesterone;
hypoxanthine phosphoribosyl transferase; immunoreactive trypsin;
lactate; lead; lipoproteins ((a), B/A-1, .beta.); lysozyme;
mefloquine; netilmicin; oxygen; phenobarbitone; phenytoin;
phytanic/pristanic acid; progesterone; prolactin; prolidase; purine
nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);
selenium; serum pancreatic lipase; sissomicin; somatomedin C;
specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta
antibody, arbovirus, Aujeszky's disease virus, dengue virus,
Dracunculus medinensis, Echinococcus granulosus, Entamoeba
histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori,
hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease),
influenza virus, Leishmania donovani, leptospira,
measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae,
Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium
falciparum, poliovirus, Pseudomonas aeruginosa, pH, respiratory
syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni,
Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli,
vesicular stomatis virus, Wuchereria bancrofti, yellow fever
virus); specific antigens (hepatitis B virus, HIV-1);
succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH);
thyroxine (T4); thyroxine-binding globulin; trace elements;
transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I
synthase; vitamin A; white blood cells; and zinc protoporphyrin.
Salts, sugar, protein, fat, vitamins and hormones naturally
occurring in blood or interstitial fluids may also constitute
analytes in certain embodiments. The analyte may be naturally
present in the biological fluid, for example, a metabolic product,
a hormone, an antigen, an antibody, and the like. Alternatively,
the analyte may be introduced into the body, for example, a
contrast agent for imaging, a radioisotope, a chemical agent, a
fluorocarbon-based synthetic blood, or a drug or pharmaceutical
composition, including but not limited to insulin; ethanol;
cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants
(nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons,
hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines,
methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState,
Voranil, Sandrex, Plegine); depressants (barbituates, methaqualone,
tranquilizers such as Valium, Librium, Miltown, Serax, Equanil,
Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline,
peyote, psilocybin); narcotics (heroin, codeine, morphine, opium,
meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon,
Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine,
amphetamines, methamphetamines, and phencyclidine, for example,
Ecstasy); anabolic steroids; and nicotine. The metabolic products
of drugs and pharmaceutical compositions are also contemplated
analytes. Analytes such as neurochemicals and other chemicals
generated within the body may also be analyzed, such as, for
example, ascorbic acid, uric acid, dopamine, noradrenaline,
3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),
Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and
5-Hydroxyindoleacetic acid (FHIAA).
[0108] By the terms "evaluated", "monitored", "analyzed", and the
like, it is meant that an analyte may be detected and/or
measured.
[0109] The terms "sensor head" and "sensing region" as used herein
are broad terms and are used in their ordinary sense, including,
without limitation, the region of a monitoring device responsible
for the detection of a particular analyte. In one embodiment, the
sensing region generally comprises a non-conductive body, a working
electrode (anode), a reference electrode, and a counter electrode
(cathode) passing through and secured within the body forming an
electrochemically reactive surface at one location on the body and
an electronic connective means at another location on the body, and
a multi-region membrane affixed to the body and covering the
electrochemically reactive surface. The counter electrode generally
has a greater electrochemically reactive surface area than the
working electrode. During general operation of the sensor a
biological sample (for example, blood or interstitial fluid) or a
portion thereof contacts (directly or after passage through one or
more membranes or domains) an enzyme (for example, glucose
oxidase); the reaction of the biological sample (or portion
thereof) results in the formation of reaction products that allow a
determination of the analyte (e.g., glucose) level in the
biological sample. In preferred embodiments, the multi-region
membrane further comprises an enzyme domain and an electrolyte
phase, namely, a free-flowing liquid phase comprising an
electrolyte-containing fluid described further below. While the
preferred embodiments are generally illustrated by a sensor as
described above, other sensor head configurations are also
contemplated. While electrochemical sensors (including coulometric,
voltammetric, and/or amperometric sensors) for the analysis of
glucose are generally contemplated, other sensing mechanisms,
including but not limited to optochemical sensors, biochemical
sensors, electrocatalytic sensors, optical sensors, piezoelectric
sensors, thermoelectric sensors, and acoustic sensors may be used.
A device may include one sensing region, or multiple sensing
regions. Each sensing region can be employed to determine the same
or different analytes. The sensor region may include the entire
surface of the device, a substantial portion of the surface of the
device, or only a small portion of the surface of the device.
Different sensing mechanisms may be employed by different sensor
regions on the same device, or a device may include one or more
sensor regions and also one or more regions for drug delivery,
immunoisolation, cell transplantation, and the like. It may be
noted that the preferred embodiments, the "sensor head" is the part
of the sensor that houses the electrodes, while the "sensing
region" includes the sensor head and area that surrounds the sensor
head, particularly the area in such proximity to the sensor head
that effects of the foreign body capsule on the sensor head.
[0110] The term "foreign body capsule" or "FBC," as used herein, is
a broad term and is used in its ordinary sense, including, without
limitation, body's response to the introduction of a foreign
object; there are three main layers of a FBC: 1) the innermost
layer, adjacent to the object, is composed generally of
macrophages, foreign body giant cells, and occlusive cell layers;
2) the intermediate FBC layer, lying distal to the first layer with
respect to the object, is a wide zone (e.g., about 30-100 microns)
composed primarily of fibroblasts, contractile fibrous tissue
fibrous matrix; and 3) the outermost FBC layer is loose connective
granular tissue containing new blood vessels. Over time, this FBC
tissue becomes muscular in nature and contracts around the foreign
object so that the object remains tightly encapsulated.
[0111] The term "subcutaneous," as used herein, is a broad term and
is used in its ordinary sense, including, without limitation, under
the skin.
[0112] The term "intramuscular," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
within the substance of a muscle.
[0113] The term "intraperitoneal," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
within the peritoneal cavity, which is the area that contains the
abdominal organs.
[0114] The term "intrafascial," as used herein, is a broad term and
is used in its ordinary sense, including, without limitation,
within the fascia, which is a sheet or band of fibrous tissue such
as lies deep to the skin or forms an investment for muscles and
various other organs of the body.
[0115] The term "axillary region," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
the pyramidal region between the upper thoracic wall and the arm,
its base formed by the skin and apex bounded by the approximation
of the clavicle, coracoid process, and first rib; it contains
axillary vessels, the brachial plexus of nerves, many lymph nodes
and vessels, and loose areolar tissue.
[0116] The term "apex," as used herein, is a broad term and is used
in its ordinary sense, including, without limitation, the uppermost
point; for example the outermost point of a convexly curved
portion.
[0117] The term "cuboidal," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, a
polyhedron composed of six faces, eight vertices, and twelve edges,
wherein the faces.
[0118] The term "convex," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation,
outwardly protuberant; that is, an object is convex if for any pair
of points within the object, any point on the line that joins them
is also within the object. A convex portion is a portion of an
object that is convex in that portion of the object. For example, a
solid cube is convex, but anything that is hollow or has a dent in
it is not convex.
[0119] The term "curvature," "curved portion," and "curved," as
used herein, are broad terms and is used in their ordinary sense,
including, without limitation, one or more arcs defined by one or
more radii.
[0120] The term "cylindrical," as used herein, is a broad term and
is used in its ordinary sense, including, without limitation, a
solid of circular or elliptical cross section in which the centers
of the circles or ellipses all lie on a single line. A cylinder
defines a lateral surface and two ends.
[0121] The term "ellipsoidal," as used herein, is a broad term and
is used in its ordinary sense, including, without limitation,
closed surface of which all plane sections are either ellipses or
circles. An ellipsoid is symmetrical about three mutually
perpendicular axes that intersect at the center.
[0122] The term "spherical," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, a solid
that is bounded by a surface consisting of all points at a given
distance from a point constituting its center.
[0123] The term "anchoring material," as used herein, is a broad
term and is used in its ordinary sense, including, without
limitation, biocompatible material that is non-smooth, and
particularly comprises an architecture that supports tissue
ingrowth in order to facilitate anchoring of the material into
bodily tissue in vivo. Some examples of anchoring materials include
polyester, polypropylene cloth, polytetrafluoroethylene felts,
expanded polytetrafluoroethylene, and porous silicone, for
example.
[0124] The term "mechanical anchoring mechanism," as used herein,
is a broad term and is used in its ordinary sense, including,
without limitation, mechanical mechanisms (e.g., prongs, spines,
barbs, wings, hooks, helical surface topography, gradually changing
diameter, or the like), which aids in immobilizing the sensor in
the subcutaneous space, particularly prior to formation of a mature
foreign body capsule
[0125] The term "biocompatible," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
compatibility with living tissue or a living system by not being
toxic.
[0126] The term "non-adhesive to tissue," as used herein, is a
broad term and is used in its ordinary sense, including, without
limitation, a material or surface of a material to which cells
and/or cell processes do not adhere at the molecular level, and/or
to which cells and/or cell processes do not adhere to the surface
of the material.
[0127] The term "plastic," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation,
polymeric materials that have the capability of being molded or
shaped, usually by the application of heat and pressure. Polymers
that are classified as plastics can be divided into two major
categories: thermoplastic and thermoset.
[0128] The term "thermoplastic," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
polymeric materials such as polyethylene and polystyrene that are
capable of being molded and remolded repeatedly. The polymer
structure associated with thermoplastics is that of individual
molecules that are separate from one another and flow past one
another.
[0129] The term "thermoset," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation,
polymeric materials such as epoxy, silicone, and polyurethane that
cannot be reprocessed upon reheating. During their initial
processing, thermosetting resins undergo a chemical reaction that
results in an infusible, insoluble network. Essentially, the entire
heated, finished article becomes one large molecule. For example,
the epoxy polymer undergoes a cross-linking reaction when it is
molded at a high temperature. Subsequent application of heat does
not soften the material to the point where it can be reworked and
indeed may serve only to break it down.
[0130] The term "substantially," as used herein, is a broad term
and is used in its ordinary sense, including, without limitation,
refers to an amount greater than 50 percent, preferably greater
than 75 percent and, most preferably, greater than 90 percent.
[0131] The term "host," as used herein is a broad term and is used
in its ordinary sense, including, without limitation, both humans
and animals.
[0132] The term "R-value," as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, one
conventional way of summarizing the correlation of data; that is, a
statement of what residuals (e.g., root mean square deviations) are
to be expected if the data are fitted to a straight line by the a
regression.
Overview
[0133] In a preferred embodiment, the sensor heads, devices, and
methods of the preferred embodiments may be used to determine the
level of glucose or other analytes in a host. The level of glucose
is a particularly important measurement for individuals having
diabetes in that effective treatment depends on the accuracy of
this measurement.
[0134] Although the description that follows is primarily directed
at implantable glucose sensors, the methods of the preferred
embodiments are not limited to either electrochemical sensing or
glucose measurement. Rather, the methods may be applied to any
implantable sensor that detects and quantifies an analyte present
in biological fluids (including, but not limited to, amino acids
and lactate), including those analytes that are substrates for
oxidase enzymes (see, e.g., U.S. Pat. No. 4,703,756 to Gough et
al., hereby incorporated by reference), as well as to implantable
sensors that detect and quantify analytes present in biological
fluids by analytical methods other than electrochemical methods, as
described above. The methods may also offer benefits and be
suitable for use with implantable devices, other than sensors, that
are concerned with the transport of analytes, for example, drug
delivery devices, cell transplantation devices, tracking devices,
or any other foreign body implanted subcutaneously or in other soft
tissue of the body, for example, intramuscular, intraperitoneal,
intrafascial, or in the axial region.
[0135] Methods and devices that may be suitable for use in
conjunction with aspects of the preferred embodiments are disclosed
in copending applications including U.S. application Ser. No.
09/916,386 filed Jul. 27, 2001 and entitled "MEMBRANE FOR USE WITH
IMPLANTABLE DEVICES"; U.S. application Ser. No. 09/916,711 filed
Jul. 27, 2001 and entitled "SENSOR HEAD FOR USE WITH IMPLANTABLE
DEVICE"; U.S. application Ser. No. 09/447,227 filed Nov. 22, 1999
and entitled "DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS";
U.S. application Ser. No. 10/153,356 filed May 22, 2002 and
entitled "TECHNIQUES TO IMPROVE POLYURETHANE MEMBRANES FOR
IMPLANTABLE GLUCOSE SENSORS"; U.S. application Ser. No. 09/489,588
filed Jan. 21, 2000 and entitled "DEVICE AND METHOD FOR DETERMINING
ANALYTE LEVELS"; U.S. application Ser. No. 09/636,369 filed Aug.
11, 2000 and entitled "SYSTEMS AND METHODS FOR REMOTE MONITORING
AND MODULATION OF MEDICAL DEVICES"; and U.S. application Ser. No.
09/916,858 filed Jul. 27, 2001 and entitled "DEVICE AND METHOD FOR
DETERMINING ANALYTE LEVELS," as well as issued patents including
U.S. Pat. No. 6,001,067 issued Dec. 14, 1999 and entitled "DEVICE
AND METHOD FOR DETERMINING ANALYTE LEVELS"; U.S. Pat. No. 4,994,167
issued Feb. 19, 1991 and entitled "BIOLOGICAL FLUID MEASURING
DEVICE"; and U.S. Pat. No. 4,757,022 filed Jul. 12, 1988 and
entitled "BIOLOGICAL FLUID MEASURING DEVICE." All of the above
patents and patent applications are incorporated in their entirety
herein by reference.
[0136] Such medical devices, including implanted analyte sensors,
drug delivery devices and cell transplantation devices require
close vascularization and transport of solutes across the
device-tissue interface for proper function. These devices
generally include a biointerface membrane, which encases the device
or a portion of the device to prevent access by host inflammatory
cells, immune cells, or soluble factors to sensitive regions of the
device.
Nature of the Foreign Body Capsule
[0137] Biointerface membranes stimulate a local inflammatory
response, called the foreign body response (FBR) that has long been
recognized as limiting the function of implanted devices that
require solute transport. The FBR has been well described in the
literature.
[0138] FIG. 1 is a schematic drawing that illustrates a classical
foreign body response (FBR) to an object implanted under the skin.
There are three main regions of a FBR. The innermost FBR region 12,
adjacent to the device, is composed generally of macrophages and
foreign body giant cells 14 (herein referred to as the barrier cell
layer). These cells form a monolayer of closely opposed cells over
the entire surface of a microscopically smooth, macroscopically
smooth (but microscopically rough), or microporous (i.e., less than
about 1 .mu.m pore size) membrane. The intermediate FBR region 16
(herein referred to as the fibrous zone), lying distal to the first
region with respect to the device, is a wide zone (about 30-1000
microns) composed primarily of fibroblasts 18, contractile fibrous
tissue 19, and fibrous matrix 20 (shown as empty space, which is
actually filled with this fibrous matrix). It may be noted that the
organization of the fibrous zone, and particularly the contractile
fibrous tissue 19, contributes to the formation of the monolayer of
closely opposed cells due to the contractile forces 21 around the
surface of the foreign body (e.g., membrane 10). The outermost FBR
region 22 is loose connective granular tissue containing new blood
vessels 24 (herein referred to as the vascular zone). Over time,
the foreign body capsule becomes muscular due to differentiation of
fibroblasts into myofibroblasts and contracts around the foreign
body so that the foreign body remains tightly encapsulated.
Sensor Geometry
[0139] It has been observed that the variability of function
observed in implanted sensors may sometimes occur in several
different devices implanted within the same host (e.g., human or
animal). Accordingly, this observation suggests that individual
variability of hosts may not be a significant factor in the
observed variability. Data suggest that a major factor in the
variability is the individual nature of how the surrounding tissue
heals around each device. Accordingly, the present invention
discloses methods and systems for selecting an appropriate geometry
for a device that requires transport of analytes in vivo, such that
the healing of the host tissue around the device is optimized.
Optimizing the host response includes minimizing variability,
increasing transport of analytes, and controlling motion artifact
in vivo, for example.
[0140] FIG. 2A is schematic side view of a prior art device that
has a sensing region with an abrupt inside turn, causing
sub-optimal foreign body response. FIG. 2B is a photomicrograph of
the type of device of FIG. 2A after formation of the foreign body
capsule and subsequent explantation, showing thickened host
response adjacent the abrupt inside turn and lymphocytic
infiltrate.
[0141] Particularly, FIG. 2A depicts a sensor 26 wherein a dome
sensor head 28 incorporating the sensing electrodes 30 or other
sensing devices or means protrudes above a large, flat surface 32
of the device. Particularly noteworthy is the abrupt change in
curvature of an approximately 90-degree turn between the sensor
head 28 and the flat surface 32. Additionally, an O-ring 34
encircles the device to hold a biointerface membrane (not shown)
over the dome sensor head 28 of the device and causes further
discontinuity of the surface between the sensor head and the flat
surface of the sensor body.
[0142] A wide variability in the healing of the tissue adjacent to
the sensor dome of the device is observed. Particularly, the
foreign body capsule is thickest in the area 42 adjacent to the
discontinuous surface (e.g., O-ring and sensor head-sensor body
interface). This thickest portion is a result of tissue contracture
that occurs during the foreign body response, resulting in forces
being applied to the portion of the device interfacing with the
tissue. Notably, because the device of FIG. 2A has an inside turn
where the dome meets the top plate at the O-ring, the forces 40
exerted by contracture pull outwards, and thus away from the
device-tissue interface. This causes inflammation in the region of
the inside turn. Greater tissue trauma and the formation of barrier
cell layers are typically observed adjacent to the region of the
device wherein the dome meets the top plate. It is believed that
outward forces produced by tissue contraction cause wounding in
this site, which stimulates higher levels of inflammation,
resulting in occlusion. It should be noted that this more
"turbulent area" 42 is marked by an increase chronic inflammatory
response which is most occlusive at the discontinuous surface are,
but spreads to include the thickening in sensing area 41 that may
effect the transport of analytes and thus the function of the
sensor in vivo.
[0143] FIG. 2B is a photomicrograph of the foreign body capsule,
after a device having the sensor configuration of FIG. 2A was
explanted from a host. The right side of the photomicrograph shows
a thickening of the tissue response with inflammatory cells present
near the inside turn (within 44). The o-ring 34 was located
approximately as shown by the dashed line, which contributed to the
thickening of the tissue response due to the abruptness of the
surface area. It may be noted that the tissue response thins near
the center of the dome (at 46 (the fold in the section near the
center of the dome is an artifact of sample preparation)). The
electrodes are located within the sensing region 47 as shown on the
photomicrograph, over which occlusive cells extend from the
thickened response 44. That is, the thickening of the tissues in
the "turbulent area", which is the area adjacent to the
discontinuous surfaces at the inside turn, leads to the subsequent
formation of barrier cell layers that may continue over the sensor
head and block the transport of analytes across the device-tissue
interface over time. The nature of the response suggests that
trauma to the tissue may have occurred during or after the initial
wound healing. If trauma occurs during wound healing, complete
healing never occurs and the tissue stays in a hyper-inflammatory
state during the entire course of the implant period.
Alternatively, if trauma occurs subsequent to the initial wound
healing, the wound heals but is re-injured, perhaps repeatedly,
over time. Either of these trauma-induced wounding mechanisms may
lead to improper healing and the growth of occlusive cells at the
biointerface. It may be noted that it is the combination of the
severity of the inside turn and its proximity to the sensing region
that forms the occlusive cell layer, which may cause blockage of
analyte transport to the sensor. In some alternative embodiments,
certain turns (e.g., inside turns or otherwise) on the surface of
the sensor body may not adversely effect the transport of analytes;
for example, turns that are located at a sufficient distance from
the sensing region may not produce a thickened inflammatory host
response adjacent the sensing region and/or turns that are
sufficiently gradual and/or lack abruptness may not adversely
effect the host response adjacent the sensing regions.
[0144] The tissue response resulting in the growth of occlusive
cells as described above tends to occur due to the contraction of
the surrounding wound tissue. It is therefore desirable to ensure
stable wound healing that does not change after the initial
healing. As illustrated by the photomicrograph of FIG. 2B, the
geometry of the device depicted does not favor stable healing
because tissue contracture results in the pulling away of tissues
from the device surface at the junction between the dome and top
plate.
[0145] FIG. 3A is a schematic side view of another prior art device
that has flattened surfaces across the entire device, and
particularly across the sensing region, creating sub-optimal
foreign body capsule healing. In the sensor of FIG. 3A, all
surfaces are flat and all edges and corners are sharp; there is no
curvature or convexity, particularly in the sensing region.
[0146] Consequently, contractile forces 54 pull laterally and
outwardly along the flat surfaces, including the sensing region,
which is the area proximal to the electrodes 52, as the FBC
tightens around the device. Lateral contractile forces 54 caused by
the FBC 50 along the flat surfaces are believed increase motion
artifact and tissue damage due to shear forces 56 between the
device 52 and the tissue. In other words, rather than firmly
holding the tissue adjacent the sensing region with a downward
force against the sensing region (such as will be shown with the
geometry of the present invention), a lateral movement (indicated
by arrow 56) is seen in the tissue adjacent to the sensing region,
causing trauma-induced wounding mechanisms that may lead to
improper healing and the growth of occlusive cells at the
biointerface. This is especially harmful in the sensing region,
which requires substantially consistent transport of analytes,
because it is known that thickening of the FBC from chronic
inflammation and occlusive cells decreases or blocks analyte
transport to the device.
[0147] It may be noted that some prior art devices attempt to
minimize tissue trauma by rounding edges and corners, however the
effects of tissue trauma will still be seen in the flat surfaces
(e.g., sensing region) of the device such as described above,
thereby at least partially precluding function of a device
requiring analyte transport. Similarly, placement of the sensing
region, or a plurality of sensing regions, away from the center of
the device (such as seen in some prior art devices) would not
significantly improve the effects of the lateral contractile forces
along the flat surface of the sensing region(s), because it is the
flat surface, whether at the center and/or off center, that causes
in the occlusive tissue trauma in vivo.
[0148] It may be noted that the thickness of the FBC appears to
increase around the central portion of the device and be thinner
around the ends. It is believed that this phenomenon is due to the
loose and counteracting lateral contractile forces near the center
of the device, while a tighter contractile force near the ends of
the device indicates tighter control of the FBC.
[0149] FIG. 3B is a schematic side view of the sensing region of
yet another prior art device that has flattened surfaces across the
device, however includes an inset sensing region. The device of
FIG. 3B is similar to the device of FIG. 3A, and is another example
of a disadvantageous device due to sub-optimal foreign body capsule
healing. Particularly, the inset portion 58, whether bounded by
sharp or rounded edges, will cause contractile forces 54 of the
foreign body capsule to pull outwardly and laterally. The inset
region of the device will experience increased trauma-induced
wounding mechanisms that may lead to improper healing and the
growth of occlusive cells at the biointerface as compared to FIG.
3A. In other words, both flat and inset (e.g., concave) sensing
regions will cause tissue wounding and chronic inflammatory
response leading to decreased transport of analytes, increased time
lag, and decreased device function.
[0150] In contrast to the prior art, a preferred embodiment of the
present invention provides a sensor geometry that includes a
sensing region adapted for transport of analytes between the sensor
and the bodily fluid, wherein the sensing region is located on a
curved portion of the sensor body such that when a foreign body
capsule forms around the sensor, a contractile force is exerted by
the foreign body capsule toward the sensing region. This
contractile force provides sufficient support to maintain the
foreign body capsule in close proximity to the sensing region
without substantial motion artifact or shearing forces, thereby
minimizing inflammatory trauma, minimizing the thickness of the
foreign body capsule, and maximizing the transport of analytes
through the foreign body capsule. Additionally, the overall design
described herein ensures more stable wound healing, and therefore
better acceptance in the body.
[0151] It may be noted that the disadvantageous outward forces
(e.g., forces 40 as described with reference to FIG. 2A, and forces
54 such as described with reference to FIG. 3B) refer to forces
that cause motion of the foreign body capsule relative to the
device as a whole. In other words, the discontinuity of the surface
on which the sensing region is located creates outward forces of
the FBC as a whole, which unfortunately allows motion of the device
within the FBC. These outside forces 40 create a thickened FBC due
to chronic inflammatory response responsive to motion of the device
within the FBC such as described with reference to FIGS. 2 and 3.
It may be noted however that a biointerface material with
interconnected cavities in at least a portion thereof may be placed
over the sensor head such as described with reference to copending
U.S. patent application Ser. No. 10/647,065 filed Aug. 22, 2003 and
entitled "POROUS MEMBRANE FOR USE WITH IMPLANTABLE DEVICES", which
is incorporated herein in its entirety by reference. This
biointerface material advantageously causes disruption of the
contractile forces caused by the fibrous tissue of the FBC within
the cavities of the biointerface material. Particularly, the
biointerface material includes interconnected cavities with a
multiple-cavity depth, which may affect the tissue contracture that
typically occurs around a foreign body. That is, within the
cavities of the biointerface material, forces from the foreign body
response contract around the solid portions that define the
cavities and away from the device. This architecture of the
interconnected cavities of the biointerface material is
advantageous because the contractile forces caused by the downward
tissue contracture that may otherwise cause cells to flatten
against the device and occlude the transport of analytes, is
instead translated to and/or counteracted by the forces that
contract around the solid portions (e.g., throughout the
interconnected cavities) away from the device. Therefore, the
mechanisms of the present invention (e.g., geometric configurations
described herein) are designed to increase downward forces on the
sensor head in order to decrease motion of the device relative to
the FBC as a whole, which complements the mechanisms of the
biointerface material that causes disruption of the contractile
forces within the biointerface material in order to deflect the
forces toward the solid portions within the biointerface and away
from the device itself, both of which mechanisms work to prevent
the formation of occlusive cells that block analyte transport.
Therefore, a biointerface material such as described above may be
placed over at least a portion (e.g., some or all) of the sensing
region of the devices of the present invention to aid in preventing
the formation of occlusive cells (e.g., barrier cell layer) and
increasing the transport of analytes.
[0152] FIG. 4 is a cross-sectional view of the sensing region of an
analyte sensor in one embodiment, wherein the sensing region is
continuously curved, thereby causing contractile forces from the
foreign body capsule to press downward thereon. The sensing region
is located on an end of sensor that extends longitudinally (not
shown). Particularly, the curved sensor region 70 includes no
abrupt edges or discontinuous surfaces to ensure stable wound
healing. For example, such a device 68 may be cylindrical with a
collet that meets the head, as depicted in FIG. 4. The collet
produces a continuous curvature from the sensor dome 72 to the wall
of the cylinder 73. When this design is employed, tissue
contracture (depicted by the arrows 74) results in forces oriented
in towards the device interface along the entire surface of the
dome (depicted by arrows 76). Thus, the foreign body capsule is
pulled down against the surface of the device. Injury and re-injury
is thereby minimized or even prevented because there are no outward
forces produced by tissue contracture as in the design depicted in
the devices of FIGS. 2 and 3. Improved biointerface healing is
observed for this geometry, as evidenced by improved in vivo
performance. A device with a design similar to that depicted in
FIG. 4 was the subject of animal testing, which is described in
more detail with reference to FIGS. 11A and 11B.
[0153] FIG. 5A is a perspective view of an analyte sensor in
another embodiment, including a thin ellipsoidal geometry, a curved
sensing region, and an overall curved surface on which the sensing
region is located, thereby causing contractile forces from the
foreign body capsule to press downward on the sensor head. FIG. 5B
is the analyte sensor of FIG. 5A shown implanted with the sensing
region adjacent to the muscle fascia underlying the subcutaneous
space. FIG. 5C is an end view of the analyte sensor of FIG. 5A
showing the contractile forces that would be caused by a foreign
body capsule. FIG. 5D is a side view of the analyte sensor of FIG.
5A.
[0154] In this embodiment, the analyte sensor 80 includes the
sensing region 82 located on a curved portion of the sensor body,
and including no abrupt edge or discontinuous surface in the
proximity of the sensing region. Additionally, the overall
curvature of the surface on which the sensing region is located,
including rounded edges, invokes a generally uniform FBC around
that surface, decreasing inflammatory response and increasing
analyte transport at the device-tissue interface 84.
[0155] In one aspect of this embodiment, the sensor geometry
particularly suited for healing at the device-tissue interface 84
when the sensor is implanted between two tissue planes. That is,
the geometry includes a thin, substantially oval sensor, wherein
the sensor head is positioned on one of the major surfaces of the
sensor rather than at the tip, as illustrated in FIG. 4. When
implanted, the sensor is oriented such that the sensor head is
adjacent to the fascia underlying the subcutaneous space.
[0156] Perpendicular forces 88, depicted in FIG. 5C by arrows
pointing down, reduce or eliminate shear forces with the tissue at
the sensor head. While lateral forces 90 may appear to create shear
forces at the sensor head, several features of the sensor mitigate
these forces. For example, the sensor is much thinner and is
immediately adjacent to the fascia, underlying the fat, making it
less prone to movement. As another example, the sensor may be
sutured to the tough fascia, which further prevents lateral forces
from being conveyed to the sensor head; while in other preferred
embodiments, an anchoring material or other method of attachment
may be employed. As yet another example, in order to facilitate
proper healing, the side of the sensor upon which the sensor head
is situated preferably has a curved radius extending from lateral
side to lateral side. As depicted in the side view and end view
(FIGS. 5C and 5D), the sensor head is positioned at the apex of the
radius. When surrounding tissue contracts as it heals, the radius
serves to optimize the forces 88 exerted down onto the curved
surface, especially the forces in the lateral directions 90, to
keep the tissue uniformly in contact with the surface and to
produce a thinner foreign body capsule. The curvature ensures that
the head is resting against the tissue and that when tissue
contraction occurs, forces are generated downward on the head so
that the tissue attachment is maintained. It may be noted that the
downward forces bring the tissue into contact with porous
biointerface materials used for ingrowth-mediated attachment and
for biointerface optimization, such as described above and in
copending U.S. patent application Ser. No. 10/647,065 filed Aug.
22, 2003 and entitled "POROUS MEMBRANE FOR USE WITH IMPLANTABLE
DEVICES". While it is preferable to have a curved radius extending
longitudinally, in certain embodiments it may be acceptable to
incorporate a longitudinally flat surface or longitudinal surface
with another configuration. In a device as depicted in FIG. 5C, the
radius of curvature in the lateral direction is preferably about
2.7 cm.
[0157] It may be noted that any curved surface can be deconvoluted
to a series of radii, as is appreciated by one skilled in the art.
It is generally preferred to have a radius of curvature in the
lateral, longitudinal or other direction of from about 0.5 mm or
less to about 10 cm or more. More preferably the radius of
curvature is from about 1, 2, 3, 4, 5, 6, 7, 8, or 9 mm to about 5,
6, 7, 8, or 9 cm, even more preferably the radius of curvature is
from about 1, 1.25, 1.5, 1.75, 2 or 2.25 cm to about 3, 3.25, 3.5,
3.75, 4, 4.25, 4.5, or 4.75 cm, and most preferably the radius of
curvature is from about 2.5 or 2.6 cm to about 2.7, 2.8, or 2.9 cm.
Radii of curvature in the longitudinal direction are generally
preferred to be larger than those in the lateral direction.
However, in certain embodiments the radii of curvature may be
approximately the same, or smaller in the longitudinal
direction.
[0158] In one embodiment, the preferred shape of the device can be
defined in the context of a reference plane. In such an embodiment,
the device has a first major surface and a second major surface
opposite the first major surface, where the first major surface
includes a sensor. The first and second major surfaces together
preferably account for at least about 40% or 50% of the surface
area of the device. The first major surface has edges between which
a width of the first major surface can be measured, and the sensor
is preferably spaced away from the edges by a distance that is at
least about 10% of the width, and preferably at least about 15%,
20%, 25%, or 30% of the width of the first major surface. It is
understood that the first major surface may have multiple edges and
that multiple widths can be measured, and in the context of the
foregoing, a width should be configured to run from one edge to an
opposite edge. Preferably, spacing of the sensor from the edges
specified above is true for at least two width measurements, which
measurements are taken generally transverse to each other.
[0159] With the sensor situated on the first major surface of the
device, a reference plane can be imagined that is congruent to the
first major surface, which first major surface is preferably at
least slightly convex. This plane, which would then touch the first
major surface at a point spaced in from the edges of the first
major surface, would be generally parallel to the first major
surface and would additionally be spaced away from opposite edges
of the first major surface due to the convex nature of the first
major surface. In preferred embodiments, the reference plane would
be spaced from the edges a distance that is at least about 3%, 4%,
or 5% of the width between those edges, and more preferably 6%, 7%,
8% or more from the edges, but at the same time the distance is
preferably not more than 50%, 40%, or 30% of the width, and may
well be not more than 25%, 20%, or 15% of the width between the
edges. In preferred embodiments, the edges of the first major
surface are rounded, so that they transition smoothly away from the
first major surface. In this situation, the location of the edge
can be configured to be the point at which a congruent line and/or
a normal line would be angled 45 degrees with respect to the
reference plane.
[0160] In preferred embodiments, the sensor body defines a surface
area, and wherein between 10% and 100% of the surface area is
convexly curved. In some preferred embodiments a substantial
portion of the surface area is convexly curved. In one preferred
embodiment, at least about 90% of the surface area is convexly
curved. In other preferred embodiments, 10, 20, 30, 40, 50, 60, 70,
80, 90, or 100% of the surface area is curved.
[0161] FIG. 6 is a perspective view of a sensor geometry in an
alternative embodiment wherein the sensor includes a curved sensor
region and a flat region, wherein the interface between the flat
region and the curved region includes a gradual transition. The
implantable sensor includes a major surface 100 with a curved
portion 102 on which the sensing region 101 is located and a flat
portion 104 adjacent to the curved portion 102. Although the major
surface is not entirely curved in this embodiment, the interface
103 between the curved and flat portions has a gradual transition
and is located sufficiently distal from the sensing region 101
(where the transport of analytes is required) that any chronic
inflammation caused by the turn at the interface 103 will not
likely translate to the sensing region 101. In other words, the
contractile forces 106 from a foreign body capsule that forms
around the sensor in vivo will tend to contract toward the sensing
region 101; although some outward and lateral forces are seen at
the interface 103 and flat surface 104, they are spaced
sufficiently far from the sensing region such that any chronic
inflammatory response will not likely cover the sensing region 101
and block analyte transport. Anchoring material may cover some part
or the majority of the major surface 100, may encircle the
circumference of the sensor body 107, and/or may cover some part or
the entire surface 108 opposite the sensing region, such as
described in more detail elsewhere herein.
[0162] FIG. 7 is a perspective view of a sensor geometry in an
alternative embodiment wherein the entire sensor body is curved.
The implantable sensor has a curvature over the entire surface area
of the sensor body 110. The curvature includes a variety of
different radii at varying locations of the sensor body, and the
contractile forces 112 from a FBC that forms around the sensor in
vivo will tend to contract toward the entire sensor body 110,
including the sensing region 114 on a first major side 116.
Accordingly, this embodiment optimizes foreign body healing by
minimizing the chronic inflammatory response that is otherwise
caused by motion within the FBC. In other words, the FBC holds
tightly to the sensor body 110 to provide optimal control (e.g.,
minimal motion) of the tissues around the sensor geometry, and
particularly around the sensing region 112. It may be noted that
the second major side 118 has a slight curvature that allows the
entire sensor body to be curved. However in some embodiments, the
second major side 118 can be designed flat rather than curved; in
these embodiments, it may be noted that the sensing region is
located on the side opposite the flat surface and there is no
concavity therein or thereon. Anchoring material may cover some
part or a majority of the first major side 116, may encircle the
circumference of the sensor body 117, and/or may cover some part or
the entire second major side 118 opposite the sensing region.
[0163] FIG. 8 is a perspective view of a sensor 120 in an
alternative embodiment including a cylindrical geometry wherein a
plurality of sensors 124 are located on the curved lateral surface
122 of the sensor body. Anchoring material (not shown) may cover at
least some of the non-electrode surface area of the cylindrical
body. The sensor of this embodiment takes advantage of numerous
features described herein, including, but not limited to, the
following advantages.
[0164] As a first noted advantage, the cylindrical geometry of the
sensor body 120 allows for discreet placement within or between
tissue types when the overall surface area-to-volume ratio can be
optimized to provide a maximal surface area with a minimal volume.
That is, although the volume of a sensor often depends on the
necessary electronics within the sensor body, the evolution of
smaller batteries and circuit boards sanctions the design and
manufacture of a cylindrical sensor with minimal volume;
simultaneously, the surface area inherent in a cylindrical geometry
allows for maximal tissue anchoring in vivo (e.g., as compared to a
substantially rectangular or oval structure). In one exemplary
embodiment, an application specific integrated circuit (ASIC) may
be designed to fit within the geometric design of any of the
embodiments disclosed herein to maximize the electronic
capabilities while minimizing volume requirements as compared to
conventional circuit boards. Sensor electronics requirements vary
depend on the sensor type, however one example of electronics for a
glucose sensor is described in more detail with reference to
copending U.S. patent application Ser. No. 10/633,367 filed on Aug.
1, 2003 and entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE
SENSOR DATA," which is incorporated by reference herein in its
entirety.
[0165] As a second noted advantage, the curved lateral surface 122
of the cylindrical structure lends itself to a plurality of sensing
regions 124 (e.g., electrodes) and allows the sensor to sense a
variety of different constituents (e.g., glucose, oxygen,
interferants (e.g., ascorbate, urate, etc.)) using one compact
sensor body.
[0166] As a third noted advantage, when the plurality of sensing
regions 124 are configured to sense the same constituent (e.g.,
glucose) such as shown in FIG. 8, and are spread apart such as
shown in FIG. 8, the likelihood of sensor location adjacent an area
of the FBC that is optimized for transport of analytes is increased
by the amount of increase of the area of the sensing regions 124.
For example, inflammatory host response sometimes forms unevenly,
therefore a distribution and increased surface area of sensing
region(s) increases the likelihood of placement of the sensing
region adjacent an area of minimum inflammatory host response and
maximum transport of analytes to the sensor.
[0167] As a fourth noted advantage, the FBC that forms around the
lateral curved surface 122 will create generally uniform forces 126
toward the sensing region 124 and around the entire lateral
surface. Furthermore, when the ends 128 of the cylindrical sensor
body 120 are designed with a curvature such as shown in the
embodiment of FIG. 8, minimal chronic inflammatory foreign body
response, and further induce a firm, substantially motion-free hold
of the sensor body 120 within the host.
[0168] FIG. 9A is a perspective view of a sensor geometry in an
alternative embodiment including a substantially spherical body.
The spherical sensor body 130a has a plurality of sensing regions
132a that encircle the body. However, in some alternative
embodiments one or more sensing regions may be provided in a
collective location or spread across the surface area of the
sphere. Anchoring material is placed on or around the sensor body;
for example, the anchoring material 136a may encircle the body in a
manner similar to that of the sensing regions 132a. The embodiment
of FIG. 9 takes advantage of numerous features described herein,
including, but not limited to, the following advantages.
[0169] As a first noted advantage, a spherical geometry defines an
optimal surface-to-volume ratio when compared to other geometries
of devices with a comparable volume (e.g., rectangular, oval, and
cylindrical). That is, when volume is a constant, the spherical
geometry will provide an optimal surface area for tissue ingrowth
in vivo in combination with an optimal curvature for uniform
contractile forces from a FBC in vivo as compared to other
geometries.
[0170] As a second noted advantage, entirely curved surface area of
the spherical geometry lends itself to a plurality of sensing
regions (e.g., electrodes) 132a and allows the sensor to sense a
variety of different constituents (e.g., glucose, oxygen,
interferants (e.g., ascorbate, urate, etc.)) using one compact
sensor body 130a.
[0171] As a third noted advantage, when a plurality of sensing
regions 132a that sense the same constituent (e.g., glucose) are
spread apart, the likelihood of finding an area of the FBC that is
optimized for transport of analytes is increased by the amount of
increase of the area of the sensing regions.
[0172] As a fourth noted advantage, the FBC that forms around the
spherical sensor body will create uniform forces 134a toward the
entire surface area, including the sensing regions 132a, which may
therefore be located anywhere on the sensor body. Consequently in
vivo, a sensor body with a curvature such as shown in the
embodiment of FIG. 9A will induce minimal chronic inflammatory
foreign body response, and further induce a firm, substantially
motion-free hold of the sensor body within the host.
[0173] FIG. 9B is a perspective view of a sensor geometry in an
alternative embodiment including a substantially spherical body
with a rod extending therefrom. The spherical sensing body 130b has
a plurality of sensing regions 132b and anchoring material 136b
that encircle (or may be otherwise located on) the body such as
described with reference to FIG. 9A. However, in contrast to the
embodiment of FIG. 9A, a rod 138 is connected to the spherical body
130b and houses some or all of the sensor electronics, which are
described with reference to FIG. 8. The embodiment of FIG. 9B takes
advantage of numerous features described herein, including those
advantages described with reference to FIG. 9A, and further
includes the following advantages.
[0174] The separation of at least some of the electronics between
the sensing body which houses the electrodes, from the rod which
may house, for example a cylindrical battery, allows for
optimization of the sensing body design by minimizing the volume
and/or mass requirements of the sensing body 130b due electronics.
The geometric design of the sphere and rod as shown in FIG. 9B
enables good formation of a FBC because all surfaces, particularly
on the sensing body 130b) are curved, and there are not abrupt or
flat turns or edges; that is, the contractile forces created by the
FBC will be exerted generally uniformly toward at least the sensing
body, and notably toward the sensing region 132b. Additionally, the
sensing regions 132b are optimally located on a curved area that
can be designed with maximum surface area and minimum mass and/or
volume (e.g., some or all sensor electronics account for much of
the mass and/or volume are located within the rod). It may be noted
that in some alternative embodiments, the rod is removably
attachable to the sensing body in vivo such that the electronics
and/or sensing body may be individually removed and replaced (e.g.,
via minimally invasive methods).
[0175] FIGS. 10A to 10D are perspective views of a sensor that has
an expandable sensing body in one embodiment. FIGS. 10A and 10C are
views of the sensor with the sensing body in a collapsed state,
FIGS. 10B and 10D are views of the sensor with the sensing body in
an expanded state. An expandable sensor 140 is advantageous in that
it can be inserted into the subcutaneous space in a minimally
invasive manner (e.g., through a catheter) in its collapsed state.
It may be, for example, less than or equal to about 3 mm in
diameter 142 and may be designed with a guide wire (not shown)
extending through the sensor in some embodiments. Once it has been
delivered into the appropriate site in vivo, the sensing body
expands to an increased surface area.
[0176] The sensor 140 includes a sensing body 144 on which the
sensing region 145 is located and an electronics body 146 in which
the sensor electronics are located such as described with reference
to FIG. 8. In alternative embodiments, some portion of the
electronics may be housed within the sensing body. The sensing body
144 is formed from an elastomeric material and adapted for
expansion using a liquid (e.g., saline or silicone oil). As an
alternative, the sensing body 144 may be formed from a
non-elastomeric material (e.g., polyethylene terephthalate) and
folded for insertion using a catheter (not shown). As another
alternative, the sensing body can be formed from nitinol, or the
like, which may be advantageous due to its ability to self-expand
and memorize its shape long term. In some embodiments, the
expandable sensing body is adapted to fill a particular
subcutaneous pocket without leaving spaces in the subcutaneous
space and without causing pressure necrosis. In one example a metal
framework may be used to hold the sensing body in its expanded
state. The sensing region 145 includes electrodes, which are
connected to the electronics body via a flexible wire or the like
(not shown). Anchoring material 148 encircles (or is otherwise
located on) the sensing body 144 in order to anchor the sensing
body stably in vivo. The sensor electronics portion may be formed
with or without a curvature, with or without anchoring material,
and with or without particular concern for its effect on the
foreign body capsule in vivo as it relates to the sensing body.
Additional advantages of this embodiment correspond to the
advantages described with reference to FIG. 9B due to its
substantially similar configuration in its expanded state.
[0177] FIGS. 11A to 11D are perspective views of sensors wherein
one or more sensing bodies are tethered to an electronics body in a
variety of alternative embodiments. In each of the embodiments, the
sensor 150 includes a sensing body 152 with a sensing region 153
located on a curved portion of the sensing body 152 such that when
a foreign body capsule forms around the sensing body 152, the
foreign body capsule exerts a contractile force toward the sensing
region 153 as described elsewhere herein. Anchoring material 154 is
located on at least a portion of the sensing body 152 in any known
manner such as described elsewhere herein. Furthermore, in each of
these embodiments, the electronics body 156 may include the
majority of the mass of the sensor 150, which is remote from the
sensing body 152. The electronics body 156 is connected to the
sensing body 152 via a tether 158, which may have a variety of
configurations such as described herein. As an alternative to the
tether, the electronics body 156 may be connected to the sensing
body 152 via a wireless RF connection (not shown) such that the
electronics body 156 and the sensing body 152 may be separately
implanted, explanted, monitored, and/or replaced. It may be noted
that in an embodiment that utilizes RF transmission to connect the
sensing body to the electronics body, some electronics are housed
in the sensing body 152 to enable measurement and transmission of
sensor information. Additionally, in some alternative embodiments
of the tethered sensor, at least some of the electronics are housed
within the sensing body.
[0178] In these embodiments wherein the sensing body 152 is
tethered to the electronics body 156, the sensing body 152 can be
easily optimized for surface area, shape, size, geometry, mass,
density, volume, surface area-to-volume, surface area-to-density,
and surface area-to-mass as desired. That is, without the mass,
size, and volume constraints normally imposed by the electronics
portion of a sensor, the sensing body can be optimally designed for
a particular implantation site, function, or other parameter.
Additionally, the electronics body can be formed from any
biocompatible material (e.g., metal, ceramic, or plastic) known in
the art. Additionally, it may be hermetically sealed to protect the
electronic components. The tether 158 may be formed from a
polymeric material or other biocompatible material and encases a
conductive wire (e.g., copper) that connects the electronics within
the electronics body 156 to the electronics portion of the sensing
body 152 (e.g. to electrodes on the sensing region 153).
[0179] This tethered sensor design of these embodiments
advantageously allows for an optimal design of the sensing body
without concern for the effects of the foreign body response caused
by the electronics body. The tether can be design shorter or
longer, and stiffer or more flexible, in order to optimize the
isolation, strain relief, and/or implantation issues.
[0180] FIG. 11A illustrates a tethered sensor 150a includes a
sensing body 152a, a flexible tether 158a, and an electronics body
156a. In this exemplary embodiment, the sensing body 152a is
disk-like with a curved surface on which the sensing region 153a is
located. An anchoring material 154a encircles the sensing body for
anchoring to the tissue. The tether acts as a strain relief,
isolating the adverse effects of the FBC that forms around the
electronics body 156a from the FBC that forms around the sensing
body 152a.
[0181] FIG. 11B illustrates an alternative tethered sensor 150b
that includes a sensing body 152b, a flexible tether 158b, and an
electronics body 156b. In this exemplary embodiment, the sensing
body 152b comprises a cylindrical body with the sensing region 153b
on a curved end. The tether 158b is formed from a flexible material
and may be formed shorter or longer to adapt to an implantation
site. It may be noted that a longer tether may better isolate the
adverse effects of the FBC that forms around the electronics body
156b from the FBC that forms around the sensing body 152b, however
a shorter tether may simplify the implantation considerations.
[0182] FIG. 11C illustrates an alternative tethered sensor 150c
that includes a sensing body 152c, a tether 158c, and an
electronics body 156c. In this exemplary embodiment, the tether may
be formed from a slightly flexible to somewhat rigid material. A
more rigid material may be advantageous in controlling the
positioning of the sensing body 152c in vivo, a more flexible
material may act as a better strain relief in vivo.
[0183] FIG. 11D illustrates an alternative tethered sensor 150d
that includes a plurality of sensing bodies 152d, a tether 158d,
and an electronics body 156d. In this exemplary embodiment, the
plurality of sensing bodies 152d with sensing regions on a curved
portion of the sensing body and anchoring material such as
described elsewhere herein, however may provide additional
advantages including for example, the ability to remotely turn
on/off one or more of the sensing bodies 152c, the ability to
determine which sensing body 152d is performing more optimally
and/or consistently for optimizing accuracy and implantation site,
and the ability to have a "back up" sensing body 152d in the event
one or more of the sensing bodies fails to function as
required.
[0184] FIGS. 12A to 12B are perspective views of a sensor in an
alternative embodiment wherein an electronics body is independent
of the sensing bodies in a preassembled state and wherein the
sensing bodies are independently inserted (and operatively
connected) to the electronics body in a minimally invasive manner.
Particularly, FIG. 12A illustrates the sensor wherein all four
sensing bodies have been inserted and locked within the ports of
the electronics body; FIG. 12B includes a cut-away portion to
illustrate how the sensing body locks into electrical contact
within a port of the electronics body. In this embodiment, the
sensor 160 includes a plurality of independent sensing bodies 162,
also referred to as biointerface probes, and include any necessary
components (e.g., electrodes, biointerface materials, etc.) to
sense an analyte of interest. The sensing bodies 162 further
comprise electrical contacts 164 that allow the sensing bodies to
operatively connect (and lock) within the multiple (optionally
inclined) ports 166 of the electronics body 168. The sensing bodies
162 may be somewhat flexible and configured with a curvature and
anchoring material such as described elsewhere herein.
[0185] In practice, the electronics body 168 may be implanted in
the subcutaneous tissue without particular concern for the design
(e.g., anchoring material, curvature, etc) and its effect on the
formation of a FBC. After the FBC has healed around the electronics
body 168, the sensing bodies 162 can be individually inserted in a
minimally invasive manner (e.g., guide wire introduced with needle
and sheath) as needed. Advantageously, each sensing body 162
functions up to about one year or more in vivo. Accordingly, when a
sensing body fails to function as needed, another sensing body 162
may be inserted into another port 166 of the electronics body
168.
[0186] It may be noted that the sensors of preferred embodiments
may be rigid or flexible, and of any suitable shape, including but
not limited to rectangular, cylindrical, square, elliptical, oval,
spherical, circular, ellipsoidal, ovoid, hourglass, bullet-shaped,
porpoise-nosed, flat sheet, accordion, or any other suitable
symmetrical or irregular shape. Corners may range from sharp to
slightly round, to substantially round. While the sensors of
preferred embodiments are preferably employed to determine the
presence of an analyte, devices of preferred geometries may also be
constructed for drug delivery, immunoisolation, cell
transplantation, and the like. For example, the preferred device
configurations can be suitable for use in fabricating an artificial
pancreas.
[0187] In addition to a simple circular curvature, the curvature
can also be elliptical or parabolic. The curvature can be perfectly
symmetrical about the sensor head, or can possess some degree of
asymmetry. While a true curvature is generally preferred, in
certain embodiments a triangular profile or other polygonal profile
with rounded edges may also be employed. While a smooth surface is
generally preferred, in certain embodiments it may be desired to
incorporate local features, such as bumps, dimples, ridges, and the
like, while maintaining an overall curvature. It is generally
preferred that each surface is convex, or less preferably flat but
not concave. However, in certain embodiments a slightly concave or
recessed surface may be acceptable presuming it is located
sufficiently far from the sensing region that any chronic
inflammatory response will not translate to the area adjacent the
sensor head. The sensor head preferably protrudes above the radius
of curvature or is flush with the radius of curvature. A recessed
sensor head is generally not preferred. However, in certain
embodiments such a configuration may be acceptable.
[0188] The sensor head may be positioned on any convenient location
of on the device. Particularly preferred locations are the
geometric center of a surface of the device, or offset to one side.
In certain embodiments it may be desirable to incorporate multiple
sensor heads on a single device. Such sensor heads may be spaced
apart so as to maximize the distance between the sensor heads, or
grouped together at one location on the device.
Manufacture of Sensor Body
[0189] In a preferred embodiment, the sensor is formed by
substantially entirely epoxy encapsulating the sensor electronics;
that is, the sensor body, outside the sensor head, is comprises an
epoxy resin body. During the manufacture of the sensor body of the
preferred embodiment, the sensitive electronic parts (e.g. battery,
antenna, and circuit board, such as described in copending U.S.
patent application Ser. No. 10/633,367 filed on Aug. 1, 2003 and
entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA")
are substantially entirely encapsulated in epoxy, with the
exception of the sensor head. In some molding processes, the epoxy
body may be formed with a curvature on a portion thereof. After the
epoxy has completely cured, additional curvature may be machined,
milled, laser-etched, or otherwise processed into the epoxy body to
form the final geometric shape. In alternative embodiments, a light
epoxy coating may be applied to the sensitive electronic parts,
after which injection molding or reaction injection molding (RIM)
may be used to form the final shape of the epoxy body. While a
preferred sensor is constructed of epoxy resin, a non-conductive
metal, ceramic or other suitable material may be used.
Anchoring Material & Implantation
[0190] In one embodiment, the entire surface of the sensor is
covered with an anchoring material to provide for strong attachment
to the tissues. In another embodiment, only the sensor head side of
the sensor incorporates anchoring material, with the other sides of
the sensor lacking fibers or porous anchoring structures and
instead presenting a very smooth, non-reactive biomaterial surface
to prevent attachment to tissue and to support the formation of a
thicker capsule. The anchoring material may be selected from the
group consisting of: polyester, polypropylene cloth,
polytetrafluoroethylene felts, expanded polytetrafluoroethylene,
and porous silicone.
[0191] FIG. 13A is a side view of an analyte sensor with anchoring
material on a first and second major surface of the device,
including the surface on which the sensing region is located,
wherein the analyte sensor is implanted subcutaneously and is
ingrown with fibrous, vascularized tissue. FIG. 13B is a side view
of an analyte sensor with anchoring material on a first major
surface on which the sensing region is located, and wherein a
second major surface is substantially smooth.
[0192] While these configurations of anchoring materials are
particularly preferred, other configurations may also be suitable
for use in certain embodiments, including configurations with
different degrees of surface coverage. For example, from less than
about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% to more than about
55, 60, 65, 70, 75, 80, 85, 90, or 95% of the surface of the device
may be covered with anchoring material. The anchoring material may
cover one side, two sides, three sides, four sides, five sides, or
six sides. The anchoring material may cover only a portion of one
or more sides, for example, strips, dots, weaves, fibers, meshes,
and other configurations or shapes of anchoring material may cover
one or more sides. Likewise, while silicone and polyester fibers
are particularly preferred, any biocompatible material capable of
facilitating anchoring of tissue to the device may be employed.
[0193] It may be noted that the optimum amount of anchoring
material that may be used for any particular sensor is dependent
upon one or more of the following parameters: implantation site
(e.g., location in the host), surface area, shape, size, geometry,
mass, density, volume, surface area-to-volume, surface
area-to-density, and surface area-to-mass. For example, a device
with a greater mass as compared to a device with a lesser mass may
require more anchoring material to support the greater mass
differential.
[0194] In preferred embodiments, the sensor of the described
geometry is implanted at the interface between two kinds of tissue,
and is preferably anchored to the more robust tissue type. For
example, the sensor may be placed adjacent to an organ (for
example, a kidney, the liver, or the peritoneal wall), or adjacent
to the fascia below adipose tissue. When implanted in such a
fashion, the sensor geometry minimizes force transference,
permitting non-anchored tissue to move over the smooth surface of
the sensor, thereby minimizing the force transferred to the
underlying tissue to which the sensor is anchored. While it is
generally preferred to anchor the sensor to the more robust tissue
type, in certain embodiments it may be preferred to anchor the
sensor to the less robust tissue type, permitting the more robust
tissue to move over the smooth surface of the sensor. While the
sensor geometries of preferred embodiments are particularly
preferred for use at tissue interfaces, such sensors are also
suitable for use when implanted into a single type of tissue, for
example, muscle tissue or adipose tissue. In such embodiments,
however, the sensor geometry may not confer any benefit, or only a
minimal benefit, in terms of force transference. Other benefits may
be observed, however. In another embodiment, the sensor may be
suspended, with or without sutures, in a single tissue type, or be
placed between two tissue types, and anchoring material covering
substantially the entire surface of the device may be employed.
[0195] In some alternative embodiments, a mechanical anchoring
mechanism, such as prongs, spines, barbs, wings, hooks, helical
surface topography, gradually changing diameter, or the like, may
be used instead of or in combination with anchoring material such
as described herein. For example when an oblong or cylindrical type
sensor is implanted within the subcutaneous tissue, it may tend to
slip along the pocket that was formed during implantation,
particularly if some additional space exists within the pocket.
This slippage can lead to increased inflammatory response and/or
movement of the sensor prior to or during tissue ingrowth.
Accordingly, a mechanical mechanism can aid in immobilizing the
sensor in place, particularly prior to formation of a mature
foreign body capsule. One example of mechanical anchoring means is
shown on FIG. 13B, at 179; however, it should be noted that the
placement and configuration of a mechanical anchoring mechanism is
broad in scope as described herein.
[0196] FIG. 13A illustrates the surface of the sensor 140 in
mechanical contact with the overlying tissue 172, as well as the
underlying muscle fascia 174, due to the ingrowth of the fibrous
tissue and vasculature. In this embodiment, any surface of the
sensor 170 covered with anchoring material 176 is typically ingrown
with fibrous, vascularized tissue 178, which aids in anchoring the
sensor and mitigating motion artifact. It may be noted however,
that in some cases, forces applied laterally to this tissue may be
translated to the sensor, and likewise to the fascia side of the
sensor, causing potential disruption of the interface with the
fascia. Therefore, although the radial profile of the side of the
sensor incorporating the sensor head assists in preventing forces
in the distal subcutaneous tissue from exerting forces on the
sensor head side, which is attached to the muscle fascia by an
anchoring material, complete coverage of the device with anchoring
material may not be preferred in certain embodiments.
[0197] An anchoring material covering the sensor may also make it
difficult to remove the sensor for maintenance, repair, or
permanent removal if its function is no longer necessary. It is
generally difficult to cut down through the surrounding tissue to
the surface of the sensor without also cutting into the anchoring
material and leaving some of it behind in the patient's tissues.
Leaving a portion of the sensor free of anchoring material enables
the sensor to be more easily removed by locating the smooth
surface, grasping the sensor with a holding tool, and then cutting
along the plane of the anchoring material to fully remove the
sensor. In certain embodiments, however, it may be desirable for
the entire surface of the sensor, or a substantial portion thereof,
to be covered with an anchoring material. For example, when
implanted into a single tissue type (subcutaneous adipose tissue,
or muscle tissue), it may be desirable to have anchoring over all
or substantially the entire surface of the sensor. In still other
embodiments, no anchoring at all may be preferred, for example, in
sensors having very small dimensions. One contiguous sheet of
anchoring material can be employed, or two or more different sheets
may be employed, for example, an array of dots, stripes, mesh, or
other suitable configuration of anchoring material.
[0198] FIG. 13B illustrates a preferred embodiment wherein the
surface 180 of the sensor facing away from the muscle fascia 174
(e.g., surface opposite the sensing region) is not covered with
anchoring material, but instead is a smooth, biocompatible material
that is non-adhesive to tissues 182. It is also generally preferred
that the surface 180 facing away from the fascia have a radius of
curvature, although in certain embodiments it may also be
acceptable for the surface to have another shape, for example, a
flat surface. When mechanical force is applied to the overlying
tissue, the force is dissipated in the elastic foreign body
response overlying the sensor, and is not effectively translated
through the sensor to the biointerface with the fascia. This
preferred configuration decreases damage to the biointerface caused
by external forces. Moreover, for sensor removal, the surgeon can
easily find the outermost surface of the sensor without cutting
into it. The outermost aspect of the sensor is surrounded by a
thick foreign body capsule, which substantially frees the sensor
when it is cut free. Once the sensor is located and grasped by the
surgeon, complete removal by careful dissection of the face of the
sensor associated with the fascia can be readily accomplished.
Transference of lateral force around a sensor with anchoring
material covering the entire surface compared to sensors with
anchoring materials covering only the face with the sensor head are
depicted in FIG. 13A and FIG. 13B, respectively.
[0199] In other words, in FIG. 13A, vascular and fibrous tissues
178 intertwine with the anchoring material 176. When a force is
applied to tissue overlying the sensor of FIG. 13A, it may be
translated into the sensor because of the mechanical attachment of
the sensor to the fibrous tissue, which grows into the interstices
of the anchoring material. In contrast, the sensor of FIG. 13B is
smooth on the side opposite the fascia. When mechanical energy is
applied to the overlying tissue, it is not effectively transferred
to the sensor because the tissue is not attached to the sensor nor
intertwined with it.
[0200] It may be noted that the smoothness of the surface of the
device can be measured by any suitable method, for example, by
profilometry as described in U.S. Pat. No. 6,517,571, the contents
of which is hereby incorporated by reference in its entirety.
Measurements are preferably taken from representative areas (for
example, square areas of 500 microns length on each side) of the
smooth surface of the device. A surface is generally considered
"smooth" if it has a smoothness of less than 1.80 microns RMS.
Surfaces with a smoothness greater than or equal to 1.80 microns
RMS are generally considered "rough." In certain embodiments,
however, the cut-off between "rough" and "smooth" may be higher or
lower than 1.80 microns RMS.
[0201] Profilometry measurements can be performed with a Tencor
Profiler Model P-10, measuring samples of square areas of
500-micron length per side. Surface data measurements can be made
using the Tencor Profiler Model P-10 with a MicroHead or
Exchangeable Measurement Head (stylus tip radius of 2.0 microns
with an angle of 60.degree.). Preferred menu recipe settings for
the profilometer are as follows: TABLE-US-00001 Scan length: 500
microns Scan speed: 50 microns/second Sampling rate: 200 Hz No. of
traces: 50 Spacing between traces: 10 microns No. of points/trace:
2000 Point interval: 0.25 microns Stylus force: 5 mg
Range/resolution: 65 microns/0.04 Angstroms Profile type: Peaks and
valleys Waviness filter: 45 mm/1.8 in.
[0202] Cursors can be set at each end of the length of each area to
be sampled, for example, at 0 microns and at 500 microns. Scans can
be performed in the longitudinal direction of tubular samples, or
in any convenient direction for samples of other shapes. A
parameter correlating to roughness of surfaces of the devices of
preferred embodiments is Rq, which is the Root-Mean-Square (RMS)
roughness, defined as the geometric average of the roughness
profile from the mean line measured in the sampling length,
expressed in units of microns RMS.
[0203] The use of an alternative (finer) waviness filter during
profilometry allows for materials that include gross surface
non-uniformities, such as corrugated surfaces made from
microscopically smooth materials.
[0204] In certain embodiments it is preferred that the smooth
surfaces of the device are smooth in their entirety, namely, along
the entire length of the surface. For surfaces of relatively
uniform smoothness along their entire length, surface measurements
are preferably made at three points along the length of the
surface, specifically at points beginning at one fourth, one half
and three fourths of the length of the surface as measured from one
end of device to the other. For surfaces of non-uniform surface
character along their entire length, five samples equally spaced
along the length are preferably considered. The measurements from
these 3-5 sample areas are then averaged to obtain the surface
value for the smooth surface. In other embodiments, however, other
methods of obtaining measurements may be employed.
[0205] An article entitled "Atomic force microscopy for
characterization of the biomaterial interface" describes the use of
AFM for consideration of surface smoothness (Siedlecki and
Marchant, Biomaterials 19 (1998), pp. 441-454). AFM may be usefully
employed for the smoothness evaluation of device surfaces where the
resolution of profilometry is marginally adequate for extremely
smooth surfaces. However, for purposes of the preferred
embodiments, profilometry measurements made using the
above-described Tencor profilometer are generally adequate for
determining the smoothness of the device surface
EXAMPLES
[0206] Weekly infusion studies were conducted for four-weeks to
investigate the effects of sensor geometries of preferred
embodiments on the functional performance of glucose sensors. A
first group of sensors (n=5) included a cylindrical geometry
similar to that described with reference to FIG. 4. A second group
of sensors (n=6) included a thin, oblong geometry similar to that
described with reference to FIG. 5. The functional aspects of each
sensor were constructed in a similar manner, such as described in
Published Patent Application No. 2003/0032874, which is
incorporated herein by reference. The sensors were then implanted
into the subcutaneous tissue in dogs between the fascia and adipose
tissues, and sensor function evaluated by weekly glucose infusion
tests.
[0207] The implantation entailed making a 1-inch incision, then
forming a pocket lateral to the incision by blunt dissection. After
placement of the device with the sensing region facing towards the
fascia, a suture was placed by pulling the connective tissue
together at the end of the device proximal to the incision. It is
believed that the sutures held effectively during wound healing and
device integration with tissues.
[0208] FIG. 14A is a graph showing the percentage of functional
sensors from the two different sensor geometry groups. The x-axis
represents time in weeks; the y-axis represents percentage of
functional sensors for each group during the weekly infusion
studies. It is known that an initial startup period exists for
sensors implanted in the subcutaneous space, between about one and
three weeks, during which delayed sensor functionality may be
related to the amount and speed of tissue ingrowth into the
biointerface, as described with reference to copending U.S. patent
application Ser. No. 10/647,065 filed Aug. 22, 2003 and entitled
"POROUS MEMBRANE FOR USE WITH IMPLANTABLE DEVICES."Interestingly,
both sensor geometries functioned substantially as expected in that
the majority of devices were functional by week four. However, the
sensors of the thin, oblong sensor geometry group showed faster
start-up times as evidenced by a higher percentage of functional
sensors at weeks two and three.
[0209] The delayed start-up of the cylindrical group as compared to
the thin, oblong group is believed to be due to delayed ingrowth of
tissues or lack of ingrowth of tissues, which effects device
function through lack of glucose sensitivity, compromised function
after start-up, low sensitivity, and long time lags. One cause for
this delay of or lack of tissue ingrowth in the cylindrical group
is believed to be the placement of the sensing region on the
device. Particularly, when a sensor is implanted in the
subcutaneous space between two tissue types, such as the adipose
subcutaneous tissue and the fascia, optimal tissue ingrowth may
occur when the sensor is directly adjacent and fully engaged with
the fascia, such as described with reference in FIG. 5B. In
contrast to the sensors of the thin, oblong geometry group, when
the sensors of the cylindrical are implanted in the pocket formed
between the two tissue types, a space may exist adjacent at least a
portion of the sensing region between the two tissue types creating
delayed or lack of tissue ingrowth due to spacing from soft tissue.
Accordingly, it may be advantageous to design the sensing region on
a sensor body such that the entire sensing region is directly
adjacent to the fascia or similar tissue immediately after
implantation.
[0210] Some additional observations may be directly related to the
delayed sensor function in the cylindrical sensors of this study.
For example, the thin, oblong geometry as compared to the
cylindrical geometry does not protrude from the host as much and is
less amenable to accidental bumping or movement, and less available
for patient "fiddling." Thus, it may be inferred that overall
dimensions may effect sensor geometry such that by increasing the
discreetness of the geometry (e.g., mass, shape, dimensions),
sensor functionality may improve. As another example, the thin,
oblong geometry as compared to the cylindrical geometry is less
susceptible to torsion and/or rotational forces, which may create
motion artifact and therefore chronic inflammatory response at the
device-tissue interface. In other words, with the sensor head
oriented down towards the fascia, and nearer to the center of the
sensor, downward pressure on either end is not transferred as shear
force to the sensor head; even if the sensor is moved, the sensor
head more likely remains adjacent to the tissue so that it may heal
in a favorable fashion, unlike the sensors wherein the tip is
positioned on an end of the sensor body, which can leave a space
after lateral movement. From this observation, it may be
hypothesized that surface area-to-volume ratio may effect the
function of the sensor. Particularly, an increased surface
area-to-volume ratio, particularly as a consequence of reducing the
volume of the sensor, may decrease the effects of forces (e.g.,
torsion, rotational, and shearing) caused by behavioral and
environment movement. Similarly, optimization of surface
area-to-mass and surface area-to-density ratios may impact
healing.
[0211] FIG. 14B is a graph showing the average R-value of sensors
from a study of the two different sensor geometries implanted in a
host. The x-axis represents time in weeks; the y-axis represents
average R-value for each group of sensors during each weekly
infusion study. R-values were obtained by correlating sensor output
to the externally derived meter values, and performing a least
squares analysis, such as described with reference to copending
U.S. patent application Ser. No. 10/633,367 filed on Aug. 1, 2003
and entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR
DATA."
[0212] It may be observed that both geometry groups performed with
sufficient accuracy by week three (e.g., greater than 0.79 R-value
constitutes sufficient accuracy in one example). It may also be
observed that the sensors of the thin, oblong group increased in
accuracy and were more consistent than the sensors of the
cylindrical group. It is believed that the slightly improved
performance of the thin, oblong group as compared to the
cylindrical group may be due to a variety of factors, including
those described with reference to FIG. 11A, and additional factors
such as surface area, size, mass, density, volume, surface
area-to-volume, surface area-to-density, and surface
area-to-mass.
[0213] From the observations of the above described study,
optimization of the sensor geometry may additionally include: 1)
density optimization to better correspond to the density of tissue
(e.g., fascia or adipose), 2) surface area-to-volume optimization
by increasing the surface area-to-volume ratio of the sensor, 3)
size optimization by decreasing the overall size, mass, and/or
volume of the sensor, and 4) surface area-to-mass optimization by
increasing the surface area-to-mass ratio of the sensor, for
example.
[0214] Table 1 illustrates additional analysis from the above
described infusion study, including a comparison of average R-value
at week 4 and standard deviation at week 4 for the two groups of
sensors. TABLE-US-00002 TABLE 1 Thin, oblong Cylindrical geometry
with Results of Geometry Geometry with sensor on curved Study
sensor on curved end major surface Average R-value at 0.73 0.87
Week 4 Standard Deviation 0.41 0.08 at Week 4
[0215] As described above with reference to FIG. 11B, the average
R-value at week 4 was better for the thin, oblong group as compared
to the cylindrical group. Additionally the average standard
deviation of the thin, oblong group as compared to the cylindrical
group was much lower, indicating greater consistency and tighter
tolerances with the thin, oblong group. As described above with
reference to FIGS. 11A and 11B, this performance differential may
be due to additional geometric factors such as surface
area-to-volume ratio, size, mass, and surface area-to-density
ratio, for example.
[0216] The above description discloses several methods and
materials of the present invention. This invention is susceptible
to modifications in the methods and materials, as well as
alterations in the fabrication methods and equipment. Such
modifications will become apparent to those skilled in the art from
a consideration of this disclosure or practice of the invention
disclosed herein. Consequently, it is not intended that this
invention be limited to the specific embodiments disclosed herein,
but that it cover all modifications and alternatives coming within
the true scope and spirit of the invention as embodied in the
attached claims. All patents, applications, and other references
cited herein are hereby incorporated by reference in their
entirety.
* * * * *