U.S. patent application number 12/103594 was filed with the patent office on 2008-08-14 for biointerface with macro- and micro-architecture.
This patent application is currently assigned to DexCom, Inc.. Invention is credited to James H. Brauker, Victoria Carr-Brendel, Peter C. Simpson.
Application Number | 20080195232 12/103594 |
Document ID | / |
Family ID | 34886072 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080195232 |
Kind Code |
A1 |
Carr-Brendel; Victoria ; et
al. |
August 14, 2008 |
BIOINTERFACE WITH MACRO- AND MICRO-ARCHITECTURE
Abstract
Disclosed herein are biointerface membranes including a
macro-architecture and a micro-architecture co-continuous with and
bonded to and/or located within at least a portion of the
macro-architecture. The macro- and micro-architectures work
together to manage and manipulate the high-level tissue
organization and the low-level cellular organization of the foreign
body response in vivo, thereby increasing neovascularization close
to a device-tissue interface, interfering with barrier cell layer
formation, and providing good tissue anchoring, while reducing the
effects of motion artifact, and disrupting the organization and/or
contracture of the FBC. The biointerface membranes of the preferred
embodiments can be utilized with implantable devices such as
devices for the detection of analyte concentrations in a biological
sample (for example, from a body), cell transplantation devices,
drug delivery devices, electrical signal delivering or measuring
devices, and/or combinations thereof.
Inventors: |
Carr-Brendel; Victoria; (San
Diego, CA) ; Simpson; Peter C.; (Encinitas, CA)
; Brauker; James H.; (Cement City, MI) |
Correspondence
Address: |
KNOBBE, MARTENS, OLSEN & BEAR, LLP
2040 MAIN STREET, FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Assignee: |
DexCom, Inc.
San Diego
CA
|
Family ID: |
34886072 |
Appl. No.: |
12/103594 |
Filed: |
April 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11055779 |
Feb 9, 2005 |
7364592 |
|
|
12103594 |
|
|
|
|
60544722 |
Feb 12, 2004 |
|
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|
Current U.S.
Class: |
623/23.76 ;
128/899; 600/365; 604/891.1 |
Current CPC
Class: |
A61L 31/10 20130101;
A61L 31/16 20130101; A61L 2300/10 20130101; B33Y 80/00 20141201;
A61L 31/146 20130101 |
Class at
Publication: |
623/23.76 ;
600/365; 128/899; 604/891.1 |
International
Class: |
A61F 2/02 20060101
A61F002/02; A61B 5/145 20060101 A61B005/145; A61M 5/14 20060101
A61M005/14 |
Claims
1. An implantable device, comprising: an implantable body; and a
biointerface membrane covering at least a portion of the body,
wherein the biointerface comprises: a macro-architecture defining a
plurality of interconnected cavities that are greater than or equal
to about 20 microns in at least one dimension; and a
micro-architecture located within at least some of the cavities of
the macro-architecture, wherein the micro-architecture has a
nominal cavity size of less than or equal to about 20 microns.
2. The device of claim 1, wherein the biointerface membrane is
adapted to support tissue ingrowth and to interfere with barrier
cell layer formation.
3. The device of claim 1, wherein the macro-architecture is formed
from at least one of a homopolymer, a copolymer, and a terpolymer
comprising a material selected from the group consisting of
polyurethane, silicone, polyethylene-co-tetrafluoroethylene,
polypropylene, polyvinylchloride, polyvinylidene fluoride,
polybutylene terephthalate, polymethylmethacrylate, polyether ether
ketone, cellulose ester, polysulfone, polyolefin, polyester,
polycarbonate, polytetrafluoroethylene, and combinations
thereof.
4. The device of claim 1, wherein the micro-architecture comprises
at least one of a homopolymer, a copolymer, and a terpolymer
comprising a material selected from the group consisting of
polyethylene-co-tetrafluoroethylene, polyurethane, silicone,
polyethylene, polypropylene, polyvinylchloride, polyvinylidene
fluoride, polyvinylidene difluoride, polybutylene terephthalate,
polymethylmethacrylate, polyether ether ketone, cellulose ester,
polysulfone, polyolefin, nylon, polyacrylonitrile, polyester,
polycarbonate, polytetrafluoroethylene,
expanded-polytetrafluoroethylene, and combinations thereof.
5. The device of claim 1, wherein the macro-architecture comprises
a silicone material having a structure that defines the
cavities.
6. The device of claim 1, wherein the micro-architecture comprises
a silicone material.
7. The device of claim 1, wherein the micro-architecture comprises
a non-woven fibrous material.
8. The device of claim 7, wherein the micro-architecture comprises
expanded-polytetrafluoroethylene.
9. The device of claim 1, wherein the micro-architecture is located
within a portion of the macro-architecture proximal to the
implantable device.
10. The device of claim 1, wherein the micro-architecture is
located throughout substantially all of the cavities of the
macro-architecture.
11. The device of claim 1, wherein the device comprises a glucose
sensor, and wherein the biointerface membrane is located over a
sensing portion of the body.
12. The device of claim 1, wherein the device comprises a
drug-delivery device, wherein the drug delivery device is
configured and arranged to deliver one or more drugs, and wherein
the biointerface membrane is located over a drug-delivering portion
of the body.
13. The device of claim 1, wherein the device comprises a
cell-transplantation device, wherein the cell-transplantation
device is configured to receive one or more cells for
transplantation.
14. An implantable device, comprising: an implantable body and a
biointerface membrane located over at least a portion of the
implantable body, wherein the biointerface membrane comprises a
macro-architecture and a micro-architecture, wherein the
macro-architecture and the micro-architecture are co-continuous and
interconnected, wherein the macro-architecture and the
micro-architecture are configured and arranged to promote
vascularization within the biointerface membrane and to interfere
with barrier cell layer formation, and wherein the biointerface
membrane is configured to facilitate long-term analyte transport in
vivo.
15. The device of claim 14, wherein the first architecture
comprises a plurality of interconnected cavities that are greater
than or equal to about 20 microns in at least one dimension, and
wherein the second architecture is located within at least some of
the cavities of the macro-architecture and has a nominal cavity
size of less than or equal to about 20 microns.
16. An implantable device, comprising: an implantable body and a
biointerface membrane located over at least a portion of the
implantable body, wherein the biointerface comprising comprises: a
first architecture comprising cavities configured and arranged to
facilitate ingrowth of invasive cells and vascular tissue into the
biointerface membrane; and a second architecture comprising
cavities configured and arranged to facilitate ingrowth of invasive
cells into the biointerface membrane while not facilitating
ingrowth of vascular tissue.
17. The device of claim 16, wherein the first architecture
comprises a plurality of interconnected cavities that are greater
than or equal to about 20 microns in at least one dimension, and
wherein the second architecture is located within at least some of
the cavities of the macro-architecture and has a nominal cavity
size of less than or equal to about 20 microns.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
11/055,779 filed, on Feb. 9, 2005, which claims priority to U.S.
Provisional Application No. 60/544,722, filed on Feb. 12, 2004,
which is incorporated herein by reference in its entirety, and is
hereby made a part of this specification.
FIELD OF THE INVENTION
[0002] The preferred embodiments relate generally to biointerface
membranes that can be utilized with implantable devices such as
devices for the detection of analyte concentrations in a biological
sample (for example, from a body), cell transplantation devices,
drug delivery devices, electrical signal delivering or measuring
devices, and/or combinations thereof.
BACKGROUND OF THE INVENTION
[0003] Some 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.
[0004] A disadvantage of conventional implantable devices is that
they often stimulate a local inflammatory response, called the
foreign body response (FBR), which has long been recognized as
limiting the function of implantable devices that require solute
transport. The FBR has been well described in the literature.
[0005] FIG. 1 is a schematic drawing that illustrates a classical
FBR to a conventional implantable device 10 implanted under the
skin. There are three main layers of a FBR. The innermost FBR layer
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 membrane on the implantable device.
The relatively smooth surface of the membrane causes the downward
tissue contracture 21 to translate directly to the cells at the
device-tissue interface 26. The intermediate FBR layer 16 (herein
referred to as the fibrous zone), lying distal to the first layer
with respect to the device, is a wide zone (about 30-100 microns)
composed primarily of fibroblasts 18, contractile fibrous tissue
20. The organization of the fibrous zone, and particularly the
contractile fibrous tissue 20, contributes to the formation of the
monolayer of closely opposed cells due to the contractile forces 21
around the surface of the foreign body (for example, device 10).
The outermost FBR layer 22 comprises loose connective granular
tissue containing new blood vessels 24.
[0006] Over time, this FBR tissue becomes muscular in nature and
contracts around the foreign body so that the foreign body remains
tightly encapsulated. Accordingly, the downward forces 21 press
against the device-tissue interface 26, and without any
counteracting forces, aid in the formation of a barrier cell layer
14 that blocks and/or refracts the transport of analytes 23 (for
example, glucose) across the device-tissue interface 26.
[0007] A consistent feature of the innermost layers 12, 16 is that
they are devoid of blood vessels. This has led to widely supported
speculation that poor transport of molecules across the
device-tissue interface 26 is due to a lack of vascularization near
the interface. See Scharp et al., World J. Surg., 8:221-229 (1984);
and Colton and Avgoustiniatos, J. Biomech. Eng., 113:152-170
(1991).
[0008] The known art purports to increase the local vascularization
in order to increase solute availability. However, it has been
observed that once the monolayer of cells (barrier cell layer) is
established adjacent to a membrane, increasing angiogenesis is not
sufficient to increase transport of molecules such as glucose and
oxygen across the device-tissue interface 26. In fact, the barrier
cell layer blocks and/or refracts the analytes 23 from transport
across the device-tissue interface 26. Materials or membranes
employed in implantable devices are described in Brauker et al.
(U.S. Pat. No. 5,741,330), Seare, Jr. (U.S. Pat. No. 5,681,572),
and Picha (U.S. Pat. No. 5,564,439).
SUMMARY OF THE INVENTION
[0009] There is a need for a membrane for implantation in soft
tissue that supports tissue ingrowth, interferes with and resists
barrier cell layer formation, and allows the transport of analytes
across the membrane long term in vivo.
[0010] Accordingly, in a first embodiment, a biointerface membrane
is provided, including a macro-architecture that defines a
plurality of interconnected cavities that are greater than or equal
to about 20 microns in a longest dimension and a micro-architecture
bonded to and/or located within at least some of the cavities of
the macro-architecture, wherein the micro-architecture includes
elongated strands of material that are less than or equal to about
20 microns in the shortest dimension.
[0011] In an aspect of the first embodiment, the membrane, when
disposed on an implantable device, is adapted to support tissue
ingrowth and to interfere with barrier cell layer formation.
[0012] In an aspect of the first embodiment, the macro-architecture
is formed from homopolymer, copolymer, or terpolymer including a
material selected from the group consisting of polyurethane,
silicone, polyethylene-co-tetrafluoroethylene, polypropylene,
polyvinylchloride, polyvinylidene fluoride, polybutylene
terephthalate, polymethylmethacrylate, polyether ether ketone,
cellulose ester, polysulfones, polyolefin, polyester,
polycarbonate, polytetrafluoroethylene, and combinations
thereof.
[0013] In an aspect of the first embodiment, the micro-architecture
includes a a homopolymer, copolymer, or terpolymer including a
material selected from the group consisting of
polyethylene-co-tetrafluoroethylene, polyurethane, silicone,
polyethylene, polypropylene, polyvinylchloride, polyvinylidene
fluoride, polyvinylidene difluoride, polybutylene terephthalate,
polymethylmethacrylate, polyether ether ketone, cellulose ester,
polysulfones, polyolefin, nylon, polyacrylonitrile, polyesters,
polycarbonates, polytetrafluoroethylene,
expanded-polytetrafluoroethylene, and combinations thereof.
[0014] In an aspect of the first embodiment, the macro-architecture
includes a silicone material having a structure that defines the
cavities.
[0015] In an aspect of the first embodiment, the micro-architecture
includes a silicone material forming the elongated strands.
[0016] In an aspect of the first embodiment, the micro-architecture
includes a non-woven fibrous material.
[0017] In an aspect of the first embodiment, the micro-architecture
includes expanded-polytetrafluorethylene.
[0018] In an aspect of the first embodiment, the micro-architecture
is bonded to and/or located substantially throughout the cavities
of the macro-architecture.
[0019] In a second embodiment, an implantable device is provided,
including a device adapted to be implanted in a body and a
biointerface membrane disposed on the device, the biointerface
membrane including a macro-architecture that has plurality of
interconnected cavities that are greater than or equal to about 20
microns in a longest dimension and a micro-architecture bonded to
and/or located within at least some of the cavities of the
macro-architecture, wherein the micro-architecture includes
elongated strands of material that are less than or equal to about
20 microns in a shortest dimension.
[0020] In an aspect of the second embodiment, the
micro-architecture is bonded to and/or located within a portion of
the macro-architecture proximal to the implantable device.
[0021] In a third embodiment, an implantable glucose sensor is
provided including a glucose sensor and a biointerface membrane
disposed on the sensor, the biointerface membrane including a
macro-architecture that has plurality of interconnected cavities
that are greater than or equal to about 20 microns in a longest
dimension and a micro-architecture bonded to and/or located within
at least some of the cavities of the macro-architecture, wherein
the micro-architecture includes elongated strands of material that
are less than or equal to about 20 microns in a shortest
dimension.
[0022] In a fourth embodiment, a drug-delivery device is provided
including a device adapted to deliver drugs and a biointerface
membrane disposed on the device, the biointerface membrane
including a macro-architecture that has plurality of interconnected
cavities that are greater than or equal to about 20 microns in at
least one dimension and a micro-architecture bonded to and/or
located within at least some of the cavities of the
macro-architecture, wherein the micro-architecture includes
elongated strands of material that are less than or equal to about
20 microns in a shortest dimension.
[0023] In a fifth embodiment, a cell-transplantation device is
provided including cells disposed on a biointerface membrane
including a macro-architecture that has plurality of interconnected
cavities that are greater than or equal to about 20 microns in at
least one dimension and a micro-architecture bonded to and/or
located within at least some of the cavities of the
macro-architecture, wherein the micro-architecture includes
elongated strands of material that are less than or equal to about
20 microns in a shortest dimension.
[0024] In a sixth embodiment, a biointerface membrane is provided
including a macro-architecture that has plurality of interconnected
cavities that are greater than or equal to about 20 microns in at
least one dimension and a micro-architecture bonded to and/or
located within at least some of the cavities of the
macro-architecture, wherein the micro-architecture has a nominal
cavity size of less than or equal to about 20 microns.
[0025] In an aspect of the sixth embodiment, the membrane, when
disposed on an implantable device, includes the macro-architecture
adapted to support tissue ingrowth and to interfere with barrier
cell layer formation.
[0026] In a seventh embodiment, a method for forming a biointerface
membrane including a micro-architecture within a macro-architecture
is provided, the method including: providing a first membrane that
has a macro-architecture including co-continuous cavities and a
solid portion; providing a second membrane that has a
micro-architecture including a fibrous material that is less than
or equal to about 20 microns in the shortest dimension; and
pressing the first and second membranes together such that the
second membrane at least partially exists within the cavities of
the first membrane.
[0027] In an eighth embodiment, a method for forming a biointerface
membrane including a micro-architecture within a macro-architecture
is provided, the method including: placing a plurality of particles
in a mold, wherein at least some of the particles includes a
micro-architecture therein; introducing an uncured polymeric
material in the mold; compressing the mold to create substantial
mutual contact of adjacent particles; curing the polymeric material
to form a solid interconnected matrix between the particles; and
removing the particles from the matrix, whereby the matrix includes
a macro-architecture that includes the micro-architecture located
within at least some of the cavities.
[0028] In a ninth embodiment, a method for forming a biointerface
membrane including a micro-architecture within a macro-architecture
is provided, the method including: etching a first material with a
micro-architecture, including etching continuous pores
substantially corresponding to the micro-architecture; breaking the
etched first material to form micro-porous particles of a size
substantially corresponding to a desired cavity size(s) of the
macro-architecture; placing a plurality of the micro-porous
particles in a mold such that the particles are adjacent other
particles; filling the mold with a second material, wherein the
second material is a substantially uncured polymeric material;
substantially solidifying the polymeric material; and selectively
removing the micro-porous particles.
[0029] In an aspect of the ninth embodiment, the first material is
a semi-conductor material.
[0030] In an aspect of the ninth embodiment the semi-conductor
material is silicon.
[0031] In a tenth embodiment, a biointerface membrane is provided
including a macro-architecture that has plurality of interconnected
cavities that are greater than or equal to about 20 microns in at
least one dimension and a micro-architecture that has plurality of
interconnected cavities that are less than or equal to about 20
microns in at least one dimension, wherein the micro-architecture
is co-continuous with and at least partially super-imposed within
or bonded with a portion of the macro-architecture.
[0032] In an aspect of the tenth embodiment, the membrane including
the macro-architecture supports tissue ingrowth and interferes with
barrier cell layer formation.
[0033] In an eleventh embodiment, a biointerface membrane is
provided including macro-architextures and microarchitectures,
wherein the macro-architectures and the micro-architectures are
co-continuous and interconnected, wherein the macro-architectures
and the micro-architectures, when disposed on an implantable
device, are adapted to promote vascularization within the
biointerface membrane and to interfere with barrier cell layer
formation, and wherein the biointerface membrane is configured to
facilitate long-term analyte transport in vivo.
[0034] In a twelfth embodiment, a biointerface membrane is provided
including a micro-architecture that includes interconnected
cavities with a cavity size of less than or equal to about 20
microns in at least one dimension, and wherein the
micro-architecture is co-continuous with a macro-architecture that
includes interconnected cavities with a cavity size of greater than
or equal to about 20 microns in at least one dimension.
[0035] In a thirteenth embodiment, a biointerface membrane is
provided including a first architecture including cavities
configured to facilitate ingrowth of invasive cells and vascular
tissue into the biointerface membrane and a second architecture
including cavities configured to facilitate ingrowth of invasive
cells into the biointerface membrane while not permitting ingrowth
vascular tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 is schematic diagram of a foreign body response to a
conventional implantable device.
[0037] FIG. 2 is a cross-sectional schematic diagram of a foreign
body response to a biointerface membrane of the preferred
embodiments that includes a micro-architecture within a portion of
a macro-architecture.
[0038] FIG. 3 is a cross-sectional schematic diagram of a
biointerface membrane in one embodiment, wherein a
micro-architecture is located within a portion of a
macro-architecture adjacent to an implantable device.
[0039] FIG. 4 is a cross-sectional schematic diagram of a
biointerface membrane in another embodiment, wherein a
micro-architecture is located within a macro-architecture,
including along the cavity walls of the macro-architecture.
[0040] FIG. 5 is a cross-sectional schematic diagram of a
biointerface membrane in yet another embodiment, wherein the
micro-architecture is super-imposed within a macro-architecture,
both of which can be formed by a molding process in one
embodiment.
[0041] FIG. 6 is a cross-sectional schematic diagram of a
biointerface membrane in yet another embodiment, wherein only a
portion of the macro-architecture includes a micro-architecture
super-imposed within the macro-architecture, both of which can be
formed by a molding process in one embodiment.
[0042] FIG. 7 is a cross-sectional schematic view of a biointerface
membrane in yet another embodiment, wherein the macro- and
micro-architectures are formed as a lattice structure.
[0043] FIG. 8A is a perspective view of an assembled glucose sensor
in one embodiment, including a biointerface membrane of the
preferred embodiments incorporated thereon.
[0044] FIG. 8B is an exploded perspective view of the glucose
sensor of FIG. 8A, showing the body, the sensing membrane, and the
biointerface membrane of the preferred embodiments.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0045] The following description and examples illustrate some
embodiments of the disclosed invention in detail. Those of skill in
the art will recognize that there are numerous variations and
modifications of the disclosed embodiments that are encompassed by
the scope of the invention. Accordingly, the description of a
certain exemplary embodiment should not be deemed to limit the
scope of the present invention.
DEFINITIONS
[0046] In order to facilitate an understanding of the disclosed
invention, a number of terms are defined below.
[0047] The term "biointerface membrane" as used herein is a broad
term and is used in its ordinary sense, including, without
limitation, a permeable membrane that functions as an interface
between host tissue and an implantable device. In preferred
embodiments, the biointerface membrane includes macro- and
micro-architectures.
[0048] The term "barrier cell layer" as used herein is a broad term
and is used in its ordinary sense, including, without limitation, a
part of a foreign body response that forms a cohesive monolayer of
cells (for example, macrophages and foreign body giant cells) that
substantially block the transport of molecules to the implantable
device.
[0049] The term "cell processes" as used herein is a broad term and
is used in its ordinary sense, including, without limitation,
pseudopodia of a cell.
[0050] The term "solid portions" as used herein is a broad term and
is used in its ordinary sense, including, without limitation, a
material having a mechanical structure that demarcates the
cavities, voids, or other non-solid portions.
[0051] The term "substantial" as used herein is a broad term and is
used in its ordinary sense, including, without limitation, a
sufficient amount that provides a desired function. For example, in
the micro-architecture of the preferred embodiments, a sufficient
number of cavities have a size that allows a sufficient number of
inflammatory cells to enter therein, which can include an amount
greater than 50 percent, an amount greater than 60 percent, an
amount greater than 70 percent, an amount greater than 80 percent,
and an amount greater than 90 percent of cavities within a
preferred nominal pore size range.
[0052] The term "co-continuous" as used herein is a broad term and
is used in its ordinary sense, including, without limitation, a
solid portion or cavities interconnected in such a way that an
unobstructed passageway is formed through at least some of the
cavities and/or solid portions interconnected in such a way that
that the solid portions together form a single solid structure,
wherein an unbroken curved line in three dimensions can be drawn
between two sides of a membrane.
[0053] The term "biostable" as used herein is a broad term and is
used in its ordinary sense, including, without limitation,
materials that are relatively resistant to degradation by processes
that are encountered in vivo.
[0054] The term "sensor" as used herein is a broad term and is used
in its ordinary sense, including, without limitation, the component
or region of a device by which an analyte can be quantified.
[0055] 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 can include
naturally occurring substances, artificial substances, metabolites,
and/or reaction products. In some embodiments, the analyte for
measurement by the sensing regions, 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; carnitine; 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, hemoglobin A, hemoglobin S,
hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, 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 .beta.-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; 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, 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 can also constitute
analytes in certain embodiments. The analyte can be naturally
present in the biological fluid, for example, a metabolic product,
a hormone, an antigen, an antibody, and the like. Alternatively,
the analyte can 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 can 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).
[0056] The terms "analyte-measuring device," as used herein is a
broad term and is used in its ordinary sense, including, without
limitation, any mechanism (for example, enzymatic or non-enzymatic)
by which an analyte can be quantified. In one example of a
glucose-measuring device, a membrane contains glucose oxidase that
catalyzes the conversion of oxygen and glucose to hydrogen peroxide
and gluconate:
Glucose+O.sub.2.fwdarw.Gluconate+H.sub.2O.sub.2
[0057] In the above reaction, for each glucose molecule consumed,
there is a proportional change in the co-reactant O.sub.2 and the
product H.sub.2O.sub.2, one can monitor the change in either the
co-reactant or the product to determine glucose concentration, such
as by measuring corresponding reduction or oxidation currents at an
electrochemically reactive surface.
[0058] The term "host" as used herein is a broad term and is used
in its ordinary sense, including, without limitation, mammals,
preferably humans.
[0059] The phrase "continuous analyte sensing" as used herein is a
broad term and is used in its ordinary sense, including, without
limitation, the period in which monitoring of analyte concentration
is continuously, continually, and or intermittently (but regularly)
performed, for example, at a rate from about every 5 seconds to
about every 10 minutes.
[0060] The term "sensing region" as used herein is a broad term and
is used in its ordinary sense, including, without limitation, the
area of an analyte-monitoring device responsible for the detection
of a particular analyte. In one example, 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 sensor 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 sensing membrane affixed to the body and covering the
electrochemically reactive surface. The counter electrode 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) 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 (for example, glucose) level in the biological sample. In
some embodiments, the sensing membrane further comprises an enzyme
domain (for example, an enzyme layer), and an electrolyte phase
(for example, a free-flowing liquid phase comprising an
electrolyte-containing fluid described further below).
[0061] The term "electrochemically reactive surface" as used herein
is a broad term and is used in its ordinary sense, including,
without limitation, the surface of an electrode where an
electrochemical reaction takes place. In the case of the working
electrode, the hydrogen peroxide produced by the enzyme catalyzed
reaction of the analyte being detected reacts creating a measurable
electronic current (for example, detection of glucose utilizing
glucose oxidase produces H.sub.2O.sub.2 peroxide as a by product,
H.sub.2O.sub.2 reacts with the surface of the working electrode
producing two protons (2H.sup.+), two electrons (2e.sup.-) and one
molecule of oxygen (O.sub.2) which produces the electronic current
being detected). In the case of the counter electrode, a reducible
species, for example, O.sub.2 is reduced at the electrode surface
in order to balance the current being generated by the working
electrode.
[0062] The term "sensing membrane" as used herein is a broad term
and is used in its ordinary sense, including, without limitation, a
permeable or semi-permeable membrane that can comprise one or more
domains and constructed of materials of a few microns thickness or
more, which are permeable to reactants and/or co-reactants in
determining the analyte of interest. In one example, the sensing
membrane comprises an immobilized glucose oxidase enzyme, which
enables an electrochemical reaction with glucose and oxygen to
measure a concentration of glucose.
[0063] The term, "unit cells" as used herein, is a broad term and
is used in its ordinary sense, including, without limitation, the
simplest polyhedron that embodies all the structural
characteristics of and by repetition makes up a lattice.
[0064] The term, "lattice" as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, a
regular geometrical arrangement of points or objects over an area
or in space.
[0065] The term "proximal" as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, near to
a point of reference such as an origin or a point of
attachment.
[0066] The term "distal" as used herein, is a broad term and is
used in its ordinary sense, including, without limitation, spaced
relatively far from a point of reference, such as an origin or a
point of attachment.
[0067] In some instances, ranges of preferred dimensions for the
micro-architecture or the macro-architecture are provided. It will
be appreciated that these ranges specifically encompass any
dimensions at increments of 0.5 microns within the cited range. For
example, the range "between about 20 microns and about 1000
microns" includes, but is not limited to, 19.0 microns or less,
19.5 microns, 20.5 microns, 21 microns 21.5 microns, 22 microns
etc. through 1001 microns or more. It will also be appreciated that
the provided ranges refer to preferred embodiments and that the
cavity sizes of the micro-architecture and macro-architecture can
be any dimensions consistent with their intended purpose.
Overview
[0068] Biointerface membranes and their use with implantable
devices in a biological fluid are employed in the preferred
embodiments. For example, the biointerface membranes can be
utilized with implantable devices and methods for monitoring and
determining analyte levels in a biological fluid, such as
measurement of glucose levels for individuals having diabetes. In
some embodiments, the analyte-measuring device is a continuous
device, for example a subcutaneous, transdermal, or intravascular
device. In some embodiments, the device can analyze a plurality of
intermittent blood samples. The analyte-measuring device can use
any method of analyte-measurement, including enzymatic, chemical,
physical, electrochemical, spectrophotometric, polarimetric,
calorimetric, radiometric, or the like.
[0069] Although some of the description that follows is directed at
glucose-measuring devices including the described biointerface
membranes and methods for their use, these biointerface membranes
are not limited to use in devices that measure or monitor glucose.
Rather, these biointerface membranes can be applied to a variety of
devices, including for example, those that detect and quantify
other analytes present in biological fluids (including, but not
limited to, cholesterol, amino acids, and lactate), especially
those analytes that are substrates for oxidase enzymes (U.S. Pat.
No. 4,703,756, which is incorporated herein by reference in its
entirety), cell transplantation devices (U.S. Pat. Nos. 6,015,572,
5,964,745, and 6,083,523, which are incorporated herein by
reference in their entirety), drug delivery devices (U.S. Pat. Nos.
5,458,631, 5,820,589, and 5,972,369, which are incorporated herein
by reference in their entirety) and electrical delivery and/or
measuring devices such as implantable pulse generation cardiac
pacing devices (U.S. Pat. Nos. 6,157,860, 5,782,880, and 5,207,218,
which are incorporated herein by reference in their entirety),
electrocardiogram devices (U.S. Pat. Nos. 4,625,730 and 5,987,352,
which are incorporated herein by reference in their entirety)
electrical nerve stimulating devices (U.S. Pat. Nos. 6,175,767,
6,055,456, and 4,940,065, which are incorporated herein by
reference in their entirety), and in combination with angiogenic
factor gene transfer technology to enhance implantable sensor
function (Klueh U, Dorsky D I, Kreutzer D L. Use of vascular
endothelial cell growth factor gene transfer to enhance implantable
sensor function in vivo. J Biomed Mater Res. 2003 Dec. 15;
67A(4):1072-86, which is incorporated herein by reference in its
entirety), for example. One further example includes not only
utilizing the biointerface membranes for transplanted cells, for
example, transplanted genetically engineered cells of Langerhans,
either allo, auto or xeno geneic in origin, as pancreatic beta
cells to increase the diffusion of nutrients to the islets, but
additionally utilizing a biointerface membrane of the preferred
embodiment on a sensor proximal to the transplanted cells to sense
glucose in the tissues of the patient to monitor the viability of
the implanted cells.
[0070] Implantable devices for detecting analyte concentrations in
a biological system can utilize the biointerface membranes of the
preferred embodiments to interfere with the formation of a barrier
cell layer, thereby assuring that the sensor receives analyte
concentrations representative of that in the vasculature. Drug
delivery devices can utilize the biointerface membranes of the
preferred embodiments to protect the drug housed within the device
from host inflammatory or immune cells that might potentially
damage or destroy the drug. In addition, the biointerface membrane
prevents or reduces the formation of a barrier cell layer that
might interfere with proper dispensing of drug from the device for
treatment of the host. Correspondingly, cell transplantation
devices can utilize the biointerface membranes of the preferred
embodiments to protect the transplanted cells from attack by the
host inflammatory or immune response cells while simultaneously
allowing nutrients as well as other biologically active molecules
needed by the cells for survival to diffuse through the
membrane.
[0071] The materials contemplated for use in preparing the
biointerface membrane also eliminate or significantly delay
biodegradation, which is advantageous for devices that continuously
measure analyte concentrations, deliver drugs, and/or for cell
transplantation devices, for example. As one example, in a
glucose-measuring device, the electrochemically reactive surfaces
are in contact with (or operably connected with) a thin electrolyte
phase, which in turn is covered by a sensing membrane that contains
an enzyme, for example, glucose oxidase, and a polymer system, such
as described in U.S. Published Patent Application 2003/0032874,
which is incorporated herein in its entirety. In this example, the
biointerface membrane (which can additionally include a cell
impermeable domain on one side) covers this sensing membrane and
serves, in part, to protect the sensor from external forces and
factors that can result in biodegradation. By significantly
delaying biodegradation at the device, accurate data can be
collected over long periods of time (for example, months to years).
Correspondingly, biodegradation of the biointerface membrane of
implantable cell transplantation devices and drug delivery devices
can allow host inflammatory, immune cells, and/or immune mediators
to enter these devices, thereby compromising long-term
function.
[0072] Devices and probes that are implanted into subcutaneous
tissue conventionally elicit a foreign body response (FBR), which
forms a foreign body capsule (FBC), as part of the body's response
to the introduction of a foreign material. Namely, implantation of
a device (for example, a glucose sensor) results in an acute
inflammatory reaction resolving to chronic inflammation with
concurrent building of fibrotic tissue such as described in more
detail in the background section, above. Ultimately, a mature FBC
including primarily a contractile fibrous tissue forms around the
device. See Shanker and Greisler, Inflammation and Biomaterials in
Greco RS, ed., "Implantation Biology: The Host Response and
Biomedical Devices" pp 68-80, CRC Press (1994), which is
incorporated herein by reference in its entirety.
[0073] The FBC around conventional implanted devices have been
shown to preclude the transport of analytes across the
device-tissue interface. Thus, continuous long-term analyte
transport in vivo has been conventionally believed to be unreliable
or impossible. For example, because the formation of a FBC isolates
an implantable sensor of the implantable device in a capsule
containing fluid that does not mimic the levels of analytes (for
example, glucose and oxygen) in the body's vasculature, long-term
sensor function was not believed reliable. Additionally, the
composition of a FBC can prevent stabilization of the implantable
device, contributing to motion artifact that also renders
unreliable results.
[0074] In contrast to conventional practice, it has been recognized
that FBC formation is the dominant event surrounding long-term
implantation of any sensor and is preferably managed or manipulated
to support rather than hinder or block analyte transport. It has
been observed that during the early periods following implantation
of an analyte-sensing device, for example a glucose sensing device,
glucose sensors can track glucose changes in vivo, although
significant time delays are typically incurred. However, after a
few days to two or more weeks of implantation, these devices lose
their function. See, for example, U.S. Pat. No. 5,791,344 and Gross
et al. and "Performance Evaluation of the MiniMed Continuous
Monitoring System During Patient home Use," Diabetes Technology and
Therapeutics, (2000) 2(1):49-56, which are incorporated herein by
reference in their entirety, which have reported a glucose oxidase
sensor (that has been approved for use in humans by the Food and
Drug Administration) that functioned well for several days
following implantation but loses function quickly after 3 days.
These results suggest that there is sufficient vascularization and,
therefore, perfusion of oxygen and glucose to support the function
of an implantable glucose sensor for the first few days following
implantation. New blood vessel formation is clearly not needed for
the function of a glucose oxidase mediated electrochemical sensor
implanted in the subcutaneous tissue for at least several days
after implantation.
[0075] After several days, however, it is believed that this lack
of sensor function is most likely due to cells, such as
polymorphonuclear cells and monocytes that migrate to the wound
site during the first few days after implantation (for example,
from the wounding of the tissue during implant). These cells
consume local glucose and oxygen. If there is an overabundance of
such cells, they can deplete the glucose and/or oxygen
concentration before it is able to reach the sensor enzyme layer,
thereby reducing the sensitivity of the device or rendering it
non-functional. Further inhibition of device function may be due to
inflammatory cells (for example, macrophages) that associate (for
example, align at the interface) with the implantable device and
physically block the transport of glucose into the device (for
example, by formation of a barrier cell layer).
[0076] Additionally, these inflammatory cells can biodegrade many
synthetic biomaterials (some of which were, until recently,
considered non-biodegradable). When activated by a foreign body,
tissue macrophages degranulate, releasing hypochlorite (bleach) and
other oxidative species. Hypochlorite and other oxidative species
are known to break down a variety of polymers.
[0077] Some methods for providing close vascularization of
implantable devices using a micro-architecture without the support
of a macro-architecture are described in U.S. Pat. No. 5,741,330 to
Brauker et al., which is incorporated herein by reference in its
entirety.
[0078] There are some advantages associated with biointerface
membranes that have a micro-architecture as defined herein, for
example, inducing close vascular structures, maintaining of rounded
inflammatory cell morphology, preventing of barrier cell layer
formation, and preventing organized fibroblasts and connective
tissue from entering into the membrane. However, there are
additional advantages which can result from employing biointerface
membrane architectures including co-continuous interconnected
macro- and micro-architectures that promote vascularization within
the membrane and interfere with barrier cell layer formation, while
providing a robust, biostable membrane that is suitable for
long-term implantation and long-term analyte transport in vivo.
Biointerface Membranes
[0079] The biointerface membranes of the preferred embodiments
include a macro-architecture and a micro-architecture, wherein the
macro-architecture includes a porous structure with interconnected
cavities, wherein at least some portion of the cavities are
co-continuous with and at least partially filled with and/or bonded
with the micro-architecture that includes a fibrous or other fine
structured material that aids in preventing formation of a barrier
cell layer, for example in pockets in the bottom of the cavities of
the macro-architecture adjacent to the implantable device.
[0080] FIG. 2 is a cross-sectional schematic view of a biointerface
membrane 29 of the preferred embodiments in vivo that has a
micro-architecture 52 located within a macro-architecture 36. In
some embodiments, the macro-architecture 36 includes cavities 40
and a solid portion 38, wherein the cavities 40 are between about
20 and 1000 microns in at least one dimension. In the preferred
embodiment of FIG. 2, the micro-architecture 52 includes elongated
strands of material that are less than about 20 microns in all but
the longest dimension and/or includes a cavity or nominal pore size
from about 0.6 to about 20 microns. In some embodiments, the
elongated strands of material include a cavity or nominal pore size
of about 1, about 3, about 5, about 7, about 9, about 11, about 13,
about 15, or about 18 microns.
[0081] The macro-architecture 36 includes a solid portion 38 and a
plurality of interconnected three-dimensional cavities 40 formed
therein, which are described in more detail below. In general, the
cavities 40 have sufficient size and structure to allow invasive
cells, such as inflammatory cells (for example, macrophages 34) and
blood vessels 48 to partially or completely enter into each cavity
40, and to pass through the interconnected cavities 40 toward the
interface 50 of the implantable device 28. Within the cavities 40
of the macro-architecture 36, forces from the foreign body response
(for example, contractile forces 42 caused by organization of the
fibroblasts 44 and fibrous matrix 46) are disrupted and redirected
to contract around the solid portions 38 that define the cavities
40 and away from the implantable device 28 and/or the
micro-architecture 52 (see co-pending U.S. patent application Ser.
No. 10/647,065, which is incorporated by reference herein in its
entirety). This disruption or re-direction of the tissue
contracture 42 is advantageous because the contractile forces
caused by the downward tissue contracture that can otherwise cause
cells to flatten against the device and occlude the transport of
analytes (see FIG. 1), are instead translated to and/or
counteracted by the forces that contract around the solid portions
38 (for example, throughout the interconnected cavities 40) away
from the implantable device 28 and/or micro-architecture 52.
Subsequently, the re-direction of the contractile tissue throughout
the cavities 40 and around the solid portions 38 of the
macro-architecture 36 aid in anchoring the implantable device 28 in
vivo and thereby reduce motion artifact, which is known to
otherwise create tissue trauma and increased foreign body response.
Additionally, because the micro-architecture is substantially
isolated from the downward forces of tissue contracture, the
micro-architecture substantially maintains its original
architecture that promotes vascularization and prevents barrier
cell formation long term in vivo.
[0082] Although the macro-architecture 36 is associated with the
numerous advantages described above, if used alone (for example,
without a micro-architecture), some circumstances can create an
opportunity for foreign body giant cells to flatten against the
implantable device 28 and potentially create a layer of barrier
cells that can block some or all analyte transport there across. It
can therefore be advantageous to further disrupt the foreign body
response, particularly in the cavities 40 proximal to the
implantable device, such as described in more detail with reference
to the micro-architecture, below.
[0083] The micro-architecture 52 includes a solid portion(s) 54 and
a plurality of interconnected three-dimensional cavities 56 formed
therein. The cavities 56 of the micro-architecture 52 have a
sufficient size and structure to allow some inflammatory cells (for
example, macrophages 34) to partially or completely enter therein
through the cavities 56. The formation of close vascular structures
48 at the device-tissue interface 50 may be dependent on entry of
some inflammatory cells (for example, macrophages 34) into the
cavities 54 of the micro-architecture 52 so that the strands of the
solid portion 54, which define the apertures and cavities 56,
surround the cells. Thus, macrophages 34 and other inflammatory
cells can grow into the micro-architecture 52, maintain a
substantially rounded morphology, and stimulate blood vessels 48 to
form proximal to the surface thereof. By selecting cavities of
appropriate size(s), one can prevent the formation of organized
fibroblasts 46 and connective tissue 42 therein, which aids in
preventing barrier cell layer formation.
[0084] Although the micro-architecture 52 is associated with the
numerous advantages described above, if unprotected, some
circumstances can create crushing and delamination of the
micro-architecture 52 which allows foreign body giant cells to
flatten against the implantable device 28 and potentially create a
barrier layer of cells that can block some or all analyte transport
there across. It can therefore be advantageous to protect and
support the micro-architecture 52 as described herein to prevent
the crushing and delamination that can negate the advantageous
affects of the micro-architecture 52.
[0085] Accordingly, the biointerface membranes of the preferred
embodiments are designed to cover or surround at least a portion of
an implantable device and combine the advantages of the micro- and
macro-architectures including substantially co-continuous
interconnected macro- and micro-architectures that extend from the
host tissue, through the biointerface membrane, to the implantable
device. Preferably, the micro-architecture is located co-continuous
with and at least partially super-imposed within and/or bonded with
a portion of the macro-architecture that is proximal to the
implantable device and is thereby substantially protected from
downward tissue contracture normally caused by a foreign body
response in vivo. Additionally, the micro-architecture is
substantially strengthened (supported) and protected from motion
artifact and other outside influences that can otherwise negatively
affect the micro-architecture if it were unprotected in vivo.
[0086] By combining the macro- and micro-architectures as described
in the preferred embodiments, the combined advantages work together
to manage and manipulate the high-level tissue organization and the
low-level cellular organization of the foreign body response in
vivo, thereby increasing neovascularization close to the
device-tissue interface, preventing barrier cell layer formation,
and providing good tissue anchoring, while reducing the effects of
motion artifact, and disrupting the organization and/or contracture
of the FBC. The result is a robust biointerface suitable for
sustaining long-term analyte transport in vivo. Long-term analyte
transport in vivo allows solutes (for example, oxygen, glucose and
other analytes) to pass through the biointerface membrane with
relative ease and reduced diffusion distance such that the
implantable device can give and/or receive analytes and/or
nutrients between the implant and the host.
[0087] Additionally, it is known in the art that cellular response
differs depending on material characteristics such as components
(for example, cavity size), architecture, and materials. Thus,
while not wishing to be bound by theory it is believed that the
cellular response to differing materials and architectures of some
embodiments of the micro- and macro-architectures can be
advantageous in influencing different types of inflammatory (for
example, macrophages, monokine, leukocyte and cytokine) responses,
thereby modulating the foreign body response to the implanted
biointerface membrane by numerous mechanisms that can result in
better wound healing (for example, good neovascularization).
Macro-Architecture
[0088] The macro-architecture 36 of the preferred embodiments
includes cavities 40 and a solid portion 38, wherein the cavities
are from about 20 to about 1000 microns in at least one dimension.
The cavity size of the macro-architecture 36 provides a
configuration and overall thickness that encourages vascular tissue
ingrowth and disrupts tissue contracture that is believed to cause
barrier cell formation in vivo (as indicated by the blood vessels
48 formed throughout the cavities), while providing a long-term,
robust structure.
[0089] Preferably, the solid portion 38 includes homopolymers,
copolymers or terpolymers of polyurethanes or silicones and,
preferably, is silicone. In some alternative embodiments, the solid
portion 38 can include non-woven fibers constructed of
polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,
polypropylene (PP), polyvinylchloride (PVC), polyvinylidene
fluoride (PVDF), polybutylene terephthalate (PBT),
polymethylmethacrylate (PMMA), polyether ether ketone (PEEK),
polyurethanes, cellulosic polymers, polysulfones, and block
copolymers thereof including, for example, di-block, tri-block,
alternating, random and graft copolymers (block copolymers are
discussed in U.S. Pat. Nos. 4,803,243 and 4,686,044, hereby
incorporated by reference in their entireties). Non-woven fibers
that can be used include polyolefins, polyesters, polycarbonates,
or polytetrafluoroethylene. However, in certain embodiments, the
solid portion 38 can include other materials. Thus, it will be
appreciated that the macro-architecture can be fashioned from any
material suitable for the intended purpose and that the cavities
therein can have any dimensions, which facilitate ingrowth of
invasive cells.
[0090] Numerous methods are contemplated for manufacturing the
macro-architecture 36 in order to create the preferred architecture
(for example, dimensions and overall structure). In some
embodiments, the macro-architecture 36 can be manufactured by
forming a mold made from particles (for example, sugar, salt, or
other natural or synthetic uniform or non-uniform particles),
wherein the particles have shapes and sizes substantially
corresponding to the desired cavity dimensions. Most often, the
particles are made to coalesce or otherwise connect to provide the
desired interconnectivity between the cavities 40. The desired
material for the solid portion can be introduced into the mold
using methods common in the art of polymer processing, for example
injecting, pressing, vacuuming, depositing, or pouring. After the
solid portion material is cured or solidified, the interconnected
particles are then dissolved, melted, etched, or otherwise removed
leaving interconnecting cavities 40 within the solid portion 38. In
such embodiments, sieving can be used to determine the dimensions
of the particles (which substantially correspond to the dimensions
of resulting cavities). In sieving (also known as screening), the
particles can be added to the sieve and then shaken to produce an
"overs" and an "unders." The overs are the particles that remain on
the screen and the unders are the particles that pass through the
screen. Although one example of determining particle size has been
described, other methods known in the art can be utilized, for
example air classifiers (for example, applying opposing air flows
and centrifugal forces to separate particles down to 2 microns) can
be used to determine particle size when particles are smaller than
100 microns.
[0091] Accordingly in some embodiments, the dimensions of the
cavities 40 can be substantially defined by the particle size used
in creating the cavities. In some embodiments, the particles used
to form the cavities can be substantially spherical, thus the
dimensions below substantially describe a diameter of the particle
and/or a diameter of the cavity 40. In some alternative
embodiments, the particles used to form the cavities can be
non-spherical (for example, rectangular, square, diamond, or other
geometric or non-geometric shapes), thus the dimensions below
substantially describe one dimension (for example, shortest,
average, or longest) of the particle and/or cavity 40.
[0092] In some embodiments, a variety of different particle sizes
can be used in the manufacture of the macro-architecture 36. In
some embodiments, the dimensions of the particles can be somewhat
smaller or larger than the dimensions of the resulting cavities due
to dissolution or other precipitation that can occur during the
manufacturing process, for example.
[0093] In some alternative embodiments, other molds can be used in
the place of the particles described above, for example, coral,
self-assembly beads, etched and broken silicon pieces, glass frit
pieces, or the like. In these embodiments, the dimensions of the
mold can be used to define the cavity sizes, by measuring the
cavities of the final product, and/or by other measuring techniques
known in the art (for example, bubble point test).
[0094] In some alternative embodiments, other methods of forming
three-dimensional macro-architecture can be used, for example
holographic lithography, stereolithography, microstereolithography,
electrochemical fabrication, microphotoforming, spatial forming,
microtransfer molding, localized electrochemical deposition,
silicon micromachining, LIGA (Lithography, Electroplating, and
Molding techniques), precision mechanical machining, AMANDA
(combined surface micromachining, molding and diaphragm) process,
or the like, wherein the cavities' sizes are defined and precisely
formed by the lithographic or other such processes to form a
lattice of unit cells, such as described in more detail with
reference to FIG. 7, for example.
[0095] In some alternative embodiments, the macro-architecture 36
is defined using alternative methods, for example, non-woven
materials, woven materials, or other such materials, such as
electrospun, sintered, scattered, melt-blown, and aggregate, and
are manufactured by forming the solid portions without particularly
defining the cavities therebetween. Accordingly, in these
alternative embodiments, structural elements that provide the
three-dimensional conformation can include fibers, strands,
globules, cones or rods of amorphous or uniform geometry that are
smooth or rough. These elements are hereinafter referred to as
"strands." In these embodiments, the solid portion of the
macro-architecture includes a plurality of strands, which generally
define apertures formed by a scaffold of the interconnected
strands. The apertures of the material form a framework of
interconnected cavities. Formed in this manner, the
macro-architecture can be defined by a cavity size of about 20 to
about 1000 microns in at least one dimension.
[0096] Referring still to the macro-architecture 36, a substantial
number of the cavities 40, defined using any of the methods
described above, are greater than or equal to about 20 microns in
one dimension. In some other embodiments, a substantial number of
the cavities are greater than or equal to about 30, 40, 50, 60, 70,
80, 90, 100, 120, 140, 160, 180, 200, 240, 280, 320, 360, 400, 500,
600, or 700 microns in one dimension.
[0097] In some embodiments, a substantial number of the cavities
40, defined using any of the methods described above, are less than
or equal to about 1000 microns in one dimension. In other
embodiments, a substantial number of the cavities are less than or
equal to about 900, 800, 700, 600, 500, 400, 360, 320, 280, 240,
200, 180, 160, 140, 120, or 100 microns in one dimension.
[0098] In one alternative embodiment, wherein a substantial number
of cavities 40 are greater than or equal to about 20 microns in one
dimension, there can be additional cavities that are less than or
equal to about 20 microns in their shortest dimension interspersed
therein. In another alternative embodiment, wherein a substantial
number of cavities are greater than or equal to about 20 microns in
one dimension, cavity dimensions can be gradually increased or
decreased progressively through the layer, including some cavities
that are less than or equal to about 20 microns in one
dimension.
[0099] Regarding the solid portion(s) 38 of the macro-architecture
36, a substantial number of the shortest dimensions are greater
than or equal to about 5 microns and a substantial number of the
longest dimensions are less than or equal to about 2000 microns in
one embodiment. In other embodiments, the solid portion is less
than or equal to about 10 microns in a substantial number of the
shortest dimensions and less than or equal to about 1000 microns in
a substantial number of the longest dimensions. In further
embodiments, the solid portion is less than or equal to about 10
microns in a substantial number of the shortest dimensions and less
than or equal to about 400 microns in a substantial number of the
longest dimensions. However, the solid portion in other embodiments
can have larger or smaller dimensions.
Micro-Architecture
[0100] The micro-architecture 52 of the preferred embodiments is
preferably co-continuous with the macro-architecture and is located
within at least a portion of and/or bonded to the
macro-architecture 36, preferably, proximal to the implantable
device 28. At least some of the cavities 56 of the
micro-architecture 52 have a sufficient size and structure to allow
inflammatory cells 34 to partially or completely enter therein into
the cavities, however in contrast to the macro-architecture, do not
allow extensive ingrowth of vascular and connective tissues 42, 44,
46 within the cavities 56. When the inflammatory cells (for
example, macrophages 34) enter the cavities 56, growth of vascular
structures 48 occurs proximal (for example, from about 0 to about
150 microns) to the interface 50 of the device 28 and host. The
formation of close vascular structures 48 is dependent on entry of
the inflammatory cells into the cavities of the micro-architecture
52 so that the solid portion surrounds the cells. Thus, the
micro-architecture provides an architecture that breaks up the high
level fibrous organization 42, 44, 46 of the foreign body response
and encourages close vascular structures 48 in order to optimize
analyte transport there across. See U.S. Pat. No. 5,741,330 to
Brauker et al. and also Sanders J E, Rochefort J R. Fibrous
encapsulation of single polymer microfibers depends on their
vertical dimension in subcutaneous tissue. J Biomed Mater Res. 2003
Dec. 15; 67A(4):1181-7. Both of the above-cited references
described micro-architectures that are suitable for implementation
of the micro-architecture herein, and are incorporated by reference
in their entirety.
[0101] There are a variety of methods for describing and defining a
micro-architecture 52 that can be used in the preferred
embodiments. These methods depend, for example, on the material,
its method of manufacture, and the technology available to measure
the cavities and solid portion using standard techniques. A variety
of materials can be useful as the micro-architecture 52 in the
preferred embodiments, and thus more than one method for defining
the structure can be suitable, such as described in more detail
below.
[0102] In some embodiments, the micro-architecture includes
non-woven materials, woven materials, or other such materials, such
as electrospun, sintered, scattered, melt-blown and aggregate,
which are manufactured by forming the solid portions without
particularly defining the cavities therebetween. In these
embodiments, for example, the solid portion 54 is formed by
structural elements that provide the three-dimensional
conformation, wherein solid portion 54 can be formed from fibers,
strands, globules, cones or rods of amorphous or uniform geometry
that are smooth or rough. These elements are hereafter referred to
as "strands," and, in some embodiments, consist of a scaffold
composed of strands that are less than 20 microns in all but the
longest dimension. Therefore in these embodiments, the
micro-architecture can be defined by a strand size of less than
about 20 microns in all but the longest dimension and a sufficient
number of cavities of a size and structure to allow inflammatory
cells (for example, macrophages 34) to completely enter therein
through the apertures that define the cavities 56, without
extensive ingrowth of vascular and connective tissues therein. In
these embodiments, not all of the cavities 56 need have a
sufficient size to allow inflammatory cells to enter therein. What
is preferred is that a sufficient number of cavities 56 have a size
that allows a sufficient number of inflammatory cells to enter
therein. Nor is it necessary that all of the strands 54 are less
than 20 microns in all but the longest dimension. The presence of a
sufficient number of strands 54 and cavities 56 of the prescribed
size and architecture creates a sufficient number of vascular
structures 48 proximal the device-tissue interface 50.
[0103] In some alternative embodiments, the micro-architecture can
be characterized, or defined, by standard pore size tests, such as
the bubble point test. In these embodiments, a micro-architecture
can be selected with a nominal pore size from about 0.6 to about
20-micron nominal pore size. In some embodiments, the nominal pore
size is about 1, about 3, about 5, about 7, about 9, about 11,
about 13, about 15, or about 18 microns. It has been found that a
porous polymer membrane having an average nominal pore size of
about 0.6 to about 20 microns functions satisfactorily in creating
a vascular bed within the micro-architecture 52 at the
device-tissue interface 50.
[0104] The term "nominal pore size" in the context of the
micro-architecture 52 in certain embodiments is derived from
methods of analysis common to the membrane trade, such as the
ability of the membrane to filter particles of a particular size,
or the resistance of the membrane to the flow of fluids. Because of
the amorphous, random and irregular nature of most of these
commercially available membranes, the "nominal pore size"
designation may not actually indicate the size or shape of the
apertures and cavities, which in reality have a high degree of
variability. Accordingly, as used herein with reference to the
micro-architecture, the term "nominal pore size" is a
manufacturer's convention used to identify a particular membrane of
a particular commercial source which has a certain bubble point; as
used herein, the term "pore" does not describe the size of the
cavities of the material used in the instant invention. The bubble
point measurement is described, for example, in Pharmaceutical
Technology May 1983 pp. 36 to 42, which is incorporated herein by
reference in its entirety.
[0105] However, in some alternative embodiments, the
micro-architecture of preferred embodiments can be defined by the
actual size of the cavity, wherein the cavities can be formed from
a mold, for example, such as described in more detail with
reference to the macro-architecture, above. However, in the context
of the micro-architecture it is preferable that the majority of the
mold dimensions, whether particles, beads, crystals, coral,
self-assembly beads, etched and broken silicon pieces, glass frit
pieces, or other mold elements that form cavities, are less than
about 20 microns in at least one dimension.
[0106] Accordingly in these alternative embodiments, the dimensions
of the cavities 56 can be substantially defined by the mold (for
example, particle size) used in creating the cavities. In some
embodiments, the particles used to form the cavities can be
substantially spherical, thus the dimensions below substantially
describe a diameter of the particle and/or a diameter of the cavity
56. In some alternative embodiments, the particles used to form the
cavities can be non-spherical (for example, rectangular, square,
diamond, or other geometric or non-geometric shapes), thus the
dimensions below substantially describe one dimension (for example,
shortest, average, or longest) of the particle and/or cavity
56.
[0107] In some alternative embodiments, other methods of forming
three-dimensional micro-architecture can be used, for example
holographic lithography, stereolithography, microstereolithography,
electrochemical fabrication, microphotoforming, spatial forming,
microtransfer molding, localized electrochemical deposition,
silicon micromachining, LIGA (Lithography, Electroplating, and
Molding techniques), precision mechanical machining, AMANDA
(combined surface micromachining, molding and diaphragm) process,
or the like, wherein the cavities sizes are defined and precisely
formed by the lithographic or other such processes to form a
lattice of unit cells, such as described in more detail with
reference to FIG. 7, for example.
[0108] Generally, the micro-architecture of the preferred
embodiments, can be defined by the strand size, the nominal pore
size, the cavity size, and/or the functional configuration that
allows inflammatory cells to enter therein, while discouraging
extensive ingrowth of vascular and connective tissues within the
cavities 56. Therefore, the material used and its method of
manufacture can dictate the definition of the
micro-architecture.
[0109] The material that forms the solid portion 54 of the
micro-architecture 52 can include polytetrafluoroethylene or
polyethylene-co-tetrafluoroethylene. In some alternative
embodiments, the solid portion includes homopolymers, copolymers or
terpolymers of polyurethanes or silicones. In some embodiments, the
solid portion 54 can include fibers constructed of polyethylene,
polypropylene (PP), polyvinylchloride (PVC), polyvinylidene
fluoride (PVDF), polyvinylidene difluoride, polybutylene
terephthalate (PBT), polymethylmethacrylate (PMMA), polyether ether
ketone (PEEK), polyurethanes, cellulosic polymers (for example,
cellulose acetate, cellulose nitrate, mixed esters of cellulose),
polysulfones, and block copolymers thereof including, for example,
di-block, tri-block, alternating, random and graft copolymers
(block copolymers are discussed in U.S. Pat. Nos. 4,803,243 and
4,686,044, hereby incorporated by reference). In some embodiments,
the fibers 54 are comprised of polyolefins, nylon, polysulfone, and
polyacrylonitrile, polyesters, polycarbonates, or
polytetrafluoroethylene. However, in certain embodiments, the solid
portion 54 can include other materials. In one embodiment, the
solid portion 54 includes expanded-polytetrafluoroethylene (ePTFE),
which is a Teflon based material. Thus, it will be appreciated that
the micro-architecture can be fashioned from any material suitable
for the intended purpose and that the cavities therein can have any
dimensions, which allows inflammatory cells to enter therein, while
discouraging extensive ingrowth of vascular and connective
tissues.
[0110] Numerous methods have been contemplated for manufacturing
the micro-architecture 52 in order to create the preferred
architecture (for example, dimensions and overall structure). In
some embodiments, the micro-architecture 52 is manufactured as an
amorphous material such as described with reference to the
macro-architecture 36 above, which can be modified to create the
micro-architecture 52.
[0111] With regard to the overall thickness of the biointerface
membrane of the preferred embodiments, the thickness can be
optimized for decreased time-to-vascularize in vivo that is,
vascular tissue ingrowth can occur somewhat faster with a thinner
biointerface membrane than a biointerface membrane that is
relatively thicker. Decreased time-to-vascularize results in faster
stabilization and functionality of the biointerface in vivo. For
example in a subcutaneous implantable glucose sensor, consistent
and increasing functionality of the device is at least in part a
function of consistent and stable glucose transport across the
biointerface membrane, which is at least in part a function of the
vascularization thereof; thus quicker start-up time and/or
shortened time lag (for example, the diffusion path of the glucose
through the membrane can be reduced) can be accomplished by
decreasing the thickness of the membrane. In general, the thickness
of the biointerface membrane can be from about 20 to about 2000
microns. In some embodiments, the thickness of the biointerface
membrane can be about 30, 40, 50, 60, 70, 80, 90, 100, 120, 140,
160, 180, 200, 240, 280, 320, 360, 400, 500, 600, 700, 800, 900,
1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, or about 1900
microns.
[0112] With regard to the above-described dimensions of the solid
portion, the preferred structure, including the macro- and
micro-architectures has been found to provide the mechanical
strength and overall structural integrity to withstand the natural
biological and mechanical stresses that occur long term in vivo.
The optimum dimensions and overall structural integrity of the
membrane will vary with the parameters of the device that it can
support. For example, if the membrane is employed with a glucose
sensor, the mechanical requirements of the membrane will be greater
for devices having greater overall weight and surface area as
compared to those that are relatively smaller.
[0113] In some embodiments, the biointerface membrane of the
preferred embodiments can comprise an additional bioprotective
layer, formed from the same or different material as the macro-
and/or micro-architectures. The additional layer can be
incorporated as a part of the biointerface membrane and lie
adjacent to the implantable device or can form a part of the
implantable device. In one embodiment, the bioprotective layer
includes a cell impermeable domain that is impermeable to cells,
and is composed of a biostable material. See U.S. Pat. No.
6,702,857, issued Mar. 9, 2004, and entitled "MEMBRANE FOR USE WITH
IMPLANTABLE DEVICES," co-pending U.S. patent application Ser. No.
10/647,065, filed Aug. 22, 2003, and entitled, "POROUS MEMBRANES
FOR USE WITH IMPLANTABLE DEVICES," and co-pending U.S. patent
application Ser. No. 10/695,636, entitled, "SILICONE COMPOSITION
FOR BIOCOMPATIBLE MEMBRANE," each of which are incorporated herein
by reference in their entirety.
Design and Manufacture
[0114] The biointerface membrane of the preferred embodiments is
intended to protect an implantable device from the external
influences in vivo while encouraging tissue ingrowth and allowing
analyte transport. There are numerous methods of designing and
manufacturing these novel biointerface membranes of the preferred
embodiments, a few of which are described below.
[0115] FIG. 3 is a cross-sectional schematic view of a biointerface
membrane 30 in one embodiment, wherein a micro-architecture 52 is
co-continuous with and at least partially super-imposed within
and/or bonded with a portion of a macro-architecture 36 proximal to
an implantable device 28. The macro-architecture 36 shown in FIG. 3
is substantially amorphous, however other structures, including a
uniform, regular, crystalline, lattice, reciprocal lattice,
repeating unit cells, or the like, can be formed from a polymeric
or non-polymeric biocompatible material (for example, silicone). In
one embodiment, an amorphous structure is formed by a method such
as described with reference to co-pending U.S. patent application
Ser. No. 10/647,065, for example, which is incorporated herein by
reference in its entirety.
[0116] In one embodiment, micro-architecture 52 is formed from a
non-woven fibrous material 54, such as ePTFE, which is described
with reference to U.S. Pat. No. 5,741,330 to Brauker et al., for
example, which is incorporated herein by reference in its entirety.
However other methods known in the art for forming the
micro-architecture described herein can be used as is appreciated
by one skilled in the art.
[0117] In one method of manufacturing the biointerface membrane of
FIG. 3, the macro- and micro-architectures are individually formed,
such as described para supra and are pressed and/or adhered
together such that at least a portion of the micro-architecture 52
is disposed within the cavities 40 of the macro-architecture 36,
forming a co-continuous association between the two architectures.
In one alternative embodiment, pressing the micro-architecture in
or on the macro-architecture during curing of the
macro-architecture forms a biointerface membrane wherein the micro-
and macro-architectures are co-continuous and bonded, but the
micro-architecture is not necessarily disposed within the cavities
of the macro-architecture. While not wishing to be bound by theory,
it is believed that the co-continuous association between the
macro- and micro-architectures provide for the combined advantages
described in more detail above.
[0118] The resulting biointerface membrane can then be bonded (for
example, cast, adhered, or otherwise chemically or mechanically
bonded) to the implantable device 28, for example some or all of
the solid portions of the macro-architecture 38 and/or
micro-architecture 54 can be bonded to the implanted device 28. In
this bonded configuration, cellular ingrowth between the
implantable device 28 and the solid portions (38 and/or 54)
proximal to the implantable device 28 can be significantly reduced
or prevented. While not wishing to be bound by theory, it is
believed that reducing or preventing cellular growth between the
biointerface membrane 30 and implantable device 28 reduces or
prevents delamination that can otherwise occur between the layers
when cells are allowed to grow along the cavity walls.
[0119] FIG. 4 is a cross-sectional schematic view of a biointerface
membrane 40 in another embodiment, wherein a micro-architecture 52
is super-imposed within a macro-architecture 36, including along
the walls of the cavities 40 of macro-architecture 36. The
biointerface membrane 55 of this embodiment is formed from
materials (for example, woven or non-woven materials) similar to
those described with reference to FIG. 3, however the
micro-architecture 52 extends along the walls of the cavities 40 of
the macro-architecture 36 in addition to being super-imposed within
the cavities 40 proximal to the implantable device 28. In some
embodiments, the solid portions (38 and/or 54) can be bonded to the
implantable device 28 such as described para supra.
[0120] In one method of manufacturing the biointerface membrane 40
of this embodiment, particles that form the mold for the cavities
40 of the macro-architecture 36 are coated with a non-woven
material 54 to produce the micro-architecture 52 of the preferred
embodiments, prior to pouring the polymeric material into the mold.
However, other methods of producing the biointerface membrane 40 of
this embodiment can be used, for example, particles can be textured
or otherwise provided with the micro-architecture 52 resulting in
the super-imposed structure of FIG. 4.
[0121] While not wishing to be bound by theory, it is believed that
this embodiment provides the advantages described with reference to
FIG. 3, and further provides a micro-architecture adjacent to
cavities walls of the macro-architecture thereby preventing barrier
cell layer formation thereon. In some alternative embodiments, the
cavities of the macro-architecture can be fully filled with
micro-architecture in some embodiments, which is believed to
produce a similarly advantageous result in vivo.
[0122] FIG. 5 is a cross-sectional schematic view of a biointerface
membrane 50 in yet another embodiment, wherein a micro-architecture
52 is super-imposed within a macro-architecture 36, both of which
can be formed by a molding process in some embodiments. One such
embodiment uses a micro-etched three-dimensional structure as a
negative, which is filled with polymer and then the negative
removed using an etchant, solvent, or water, for example.
[0123] In this embodiment, a semi-conductor material, or the like,
is etched with long channels creating a porous material (for
example, porous silicon). The porous material can be etched to any
desired architecture, including dimensions and pattern, as is
appreciated by one skilled in the art. In one exemplary embodiment,
bulk silicon material is etched with a micro-architecture
corresponding to the desired cavity structure 56 of the
micro-architecture 52 such as described in more detail elsewhere
herein.
[0124] This micro-porous material is then broken to form pieces or
particles of the size substantially corresponding to the desired
cavity size(s) 40 of the macro-architecture 36. The particles are
then optionally filtered (if necessary to obtain the proper size
particles), mixed, and then pressed together to make a bed of
interconnecting particles each with a sub-structure. A desired
polymeric material for the solid portions 38 and 54 is then
introduced into the mold using methods common in the art of polymer
processing, for example injecting, pressing, vacuuming, depositing,
or pouring. After curing is complete, the negative can be removed
using a solvent or etchant, for example, depending on the negative
mold material used. The resulting structure is schematically shown
in FIG. 5, including the macro-architecture 36 with the
micro-architecture 52 super-imposed therein.
[0125] Etching of bulk silicon material can be advantageous due to
its relatively low cost and good reproducibility. The channels can
be formed with a high aspect ratio and can extend all the way
through the silicon material. The dimension and amount of negative
space can be changed by optimizing the etch properties of the
material. Additionally, by controlling the fabrication of the
architecture (for example, via etching of semi-conductor material),
the manufacture, characterization, reproducibility, and overall
quality of the biointerface can be regulated and improved.
[0126] In some alternative embodiments binary solvents can be used
to plate out polymeric material, and then the solvents extracted
with water, or the like. The result includes cavernous micro-
and/or macro-architectures with a skin on one side. This
alternative embodiment can be advantageous when the material used
to form the membrane allows the necessary transport of analytes
therethrough. For example in an implantable glucose sensor that
requires the transport of glucose and oxygen therethrough, a
silicone composition such as described in co-pending U.S. patent
application Ser. No. 10/695,636, which is incorporated herein by
reference in its entirety, can be used to form the macro- and
micro-architectures.
[0127] In some additional alternative embodiments, the
macro-architecture is formed using known molding techniques such as
described with reference to manufacture of the macro-architecture
36 supra, however the particles used to form the cavities 40 of the
macro-architecture 36 are embedded with a fibrous material 54 such
that when the particles are dissolved, the remaining fibers form
the micro-structure 52 within the macro-structure 36 of the
biointerface membrane 50. In one exemplary implementation,
Polyethylene Terephthalate (PET) fibers are imbedded in dissolvable
particles, which form the mold around which silicone is poured and
cured. The resulting silicone macro-architecture 36 includes a
fibrous PET micro-architecture 52 within some or all of the
cavities 40 of the silicone 38.
[0128] The embodiment of FIG. 5, including micro-architecture 52
extending substantially fully through the cavities 40 of the
macro-architecture 36, can be advantageous in reducing the
thickness of the biointerface membrane 50, while maintaining a
desired response. A decreased biointerface membrane thickness can
be advantageous in decreasing the diffusion-distance and increasing
time to stabilization, such as described in more detail elsewhere
herein.
[0129] FIG. 6 is a cross-sectional schematic view of a biointerface
membrane 60 in yet another embodiment, wherein only a portion of
the macro-architecture 36 has the micro-architecture 52
super-imposed therein, both of which can be formed by a molding
process, such as described with reference to FIG. 5, above. The
biointerface membrane 60 of this embodiment can be manufactured in
a manner similar to that described above with reference to FIG. 5,
however, when the particles are placed into the mold, a first layer
of porous particles with a sub-structure are placed into the mold,
after which a second layer of non-porous particles without a
sub-structure are placed into the mold. The non-porous particles
can have any structure such as described in more detail above with
reference to the macro-architecture 52. Alternatively, the
non-porous particles can be etched from the same material as the
porous particles, including a size according the desired cavity
size 40 of the macro-architecture 36, however without the porous
structure.
[0130] The resulting structure is shown in FIG. 6, wherein the
lower portion (for example, proximal to the implantable device 28)
of the macro-architecture 36 includes micro-architecture 52
super-imposed therein, and wherein the upper portion (for example,
distal to the implantable device 28) of the macro-architecture 36
does not include a micro-architecture 52 super-imposed therein.
These embodiments (described with reference to FIGS. 5 and 6)
utilize novel molding techniques, which provide advantageous
manufacturing methods that allow the membrane to be substantially
formed in one molding step and optionally directly onto an
implantable device (or membrane that covers the implantable
device).
[0131] FIG. 7 is a cross-sectional schematic view of a biointerface
membrane in yet another embodiment, wherein the macro- and
micro-architectures are formed as a lattice structure. In this
embodiment, the biointerface membrane 70 illustrates the
macro-architecture 36 formed from a uniform lattice of unit cells
that define the cavities 40 therein and the micro-architecture 52
formed from a uniform lattice of unit cells that define the
cavities 56 therein.
[0132] The unit cells that form the solid portion and
interconnected cavities for both macro- and micro-architectures can
be of any three dimensional shape, including, but not limited to,
cube, sphere, rectangular prism, square prism, hexahedron, pyramid,
hexagonal prism, octahedron, rhombicuboctahedron,
dodecadodecahedron, tetrahedron, triangular pyramid, or the like.
The unit cells for both the macro- and micro-architectures can have
uniform, variable, or gradient dimensions.
[0133] These biointerface membranes can be manufactured using a
variety of three-dimensional cutting or building techniques, such
as three-dimensional holographic lithography, stereolithography, or
the like. These manufacturing techniques provide a method by which
the biointerface membranes can be characterized and reproduced with
improved accuracy. While not wishing to be bound by theory, it is
believed that precisely characterizing and reproducing the
biointerface membranes of the preferred embodiments can improve the
quality and control of the biointerface membranes produced.
[0134] In some alternative embodiments (not shown), the macro-
and/or micro-architecture of the preferred embodiments is formed by
electrospinning a polymer, such as polyurethane. This method for
manufacturing non-woven fibers provides mass-producibility with
controlled fiber diameter, material width and thickness. U.S.
Publication No. 2003/0190383, which is incorporated herein by
reference in its entirety, describes one such method. Additionally,
this alternative embodiment can be advantageous in an
implementation wherein the implantable device has a polymer (for
example, polyurethane) outer surface on which the macro- and/or
micro-architecture can directly be electrospun directly onto the
implantable device.
[0135] Other alternative methods used in forming tissue engineering
scaffolds can be employed with the preferred embodiments, including
solvent-casting, particulate-leaching, gas foaming, fiber
meshes/fiber bonding, phase separation, melt molding, emulsion
freeze drying, solution casting, freeze drying, or the like. [See
Sachols et al. "Making tissue engineering scaffolds work. Review on
the Application of Solid Freeform Fabrication Technology to the
Production of Tissue Engineering Scaffolds". European Cells and
Materials Vol. 5. 2003 (pp 29-400), which is incorporated herein by
reference in its entirety.]
[0136] The biointerface membranes of the preferred embodiments can
be implemented with a variety of implantable devices, including
analyte sensors, cell transplantation devices, drug delivery
devices, electrical delivery and/or measuring devices,
electrocardiogram devices, or electrical nerve stimulating devices.
The biointerface membranes are particularly useful in implantable
devices implanted in the subcutaneous space that are concerned with
the transport of analytes across the tissue-device interface, such
as the examples noted above.
[0137] FIGS. 8A and 8B are perspective views of an implantable
glucose sensor in one embodiment. FIG. 8A is a view of the
assembled glucose sensor 80, including sensing and biointerface
membranes incorporated thereon over the electrode assembly. FIG. 8B
is an exploded view of the glucose sensor 80 of FIG. 8A, showing a
body 82, a sensing membrane 86, and a biointerface membrane 88 of
the preferred embodiments, such as described in more detail
above.
[0138] The body 82 is preferably formed from epoxy molded around
the sensor electronics (not shown), however the body can be formed
from a variety of materials, including metals, ceramics, plastics,
or composites thereof. Co-pending U.S. patent application Ser. No.
10/646,333, entitled, "Optimized Device Geometry for an Implantable
Glucose Device" discloses suitable configurations suitable for the
body 82, and is incorporated by reference in its entirety.
[0139] In one preferred embodiment, the sensor 80 is an
enzyme-based sensor, which includes an electrode system 84 (for
example, a platinum working electrode, a platinum counter
electrode, and a silver/silver chloride reference electrode), which
is described in more detail with reference to U.S. Publication No.
2003/0032874, which is incorporated herein by reference in its
entirety. However a variety of electrode materials and
configurations can be used with the implantable glucose sensor of
the preferred embodiments. The top ends of the electrodes are in
contact with an electrolyte phase (not shown), which is a
free-flowing fluid phase disposed between a sensing membrane 86 and
the electrode system 84. In this embodiment, the counter electrode
is provided to balance the current generated by the species being
measured at the working electrode. In the case of a glucose oxidase
based glucose sensor, the species being measured at the working
electrode is H.sub.2O.sub.2. Glucose oxidase catalyzes the
conversion of oxygen and glucose to hydrogen peroxide and gluconate
according to the following reaction:
Glucose+O.sub.2.fwdarw.Gluconate+H.sub.2O.sub.2
[0140] The change in H.sub.2O.sub.2 can be monitored to determine
glucose concentration because for each glucose molecule
metabolized, there is a proportional change in the product
H.sub.2O.sub.2. Oxidation of H.sub.2O.sub.2 by the working
electrode is balanced by reduction of ambient oxygen, enzyme
generated H.sub.2O.sub.2, or other reducible species at the counter
electrode. The H.sub.2O.sub.2 produced from the glucose oxidase
reaction further reacts at the surface of working electrode and
produces two protons (2H.sup.+), two electrons (2e.sup.-), and one
oxygen molecule (O.sub.2).
[0141] In this embodiment, a potentiostat is employed to monitor
the electrochemical reaction at the electroactive surface(s). The
potentiostat applies a constant potential to the working and
reference electrodes to determine a current value. The current that
is produced at the working electrode (and flows through the
circuitry to the counter electrode) is substantially proportional
to the amount of H.sub.2O.sub.2 that diffuses to the working
electrode. Accordingly, a raw signal can be produced that is
representative of the concentration of glucose in the user's body,
and therefore can be utilized to estimate a meaningful glucose
value.
[0142] In some embodiments, the sensing membrane 86 includes an
enzyme, for example, glucose oxidase, and covers the electrolyte
phase. In one embodiment, the sensing membrane 86 generally
includes a resistance domain most distal from the electrochemically
reactive surfaces, an enzyme domain less distal from the
electrochemically reactive surfaces than the resistance domain, and
an electrolyte domain adjacent to the electrochemically reactive
surfaces. However, it is understood that a sensing membrane 86
modified for other devices, for example, by including fewer or
additional domains, is within the scope of the preferred
embodiments. Co-pending U.S. Patent Publication No. 2003.0032874,
which is incorporated herein by reference in its entirety,
describes membranes that can be used in some embodiments of the
sensing membrane 86. In some embodiments, the sensing membrane 86
can additionally include an interference domain that blocks some
interfering species; such as described in the above-cited
co-pending patent application. Co-pending U.S. patent application
Ser. No. 10/695,636, entitled, "SILICONE COMPOSITION FOR
BIOCOMPATIBLE MEMBRANE" also describes membranes that can be used
for the sensing membrane 86 of the preferred embodiments, and is
incorporated herein by reference in its entirety.
[0143] The biointerface membrane 88 includes a biointerface
membrane of the preferred embodiments, including macro- and
micro-architectures such as described in more detail herein, which
covers the sensing membrane and serves to support tissue ingrowth,
interfere with the formation of a barrier cell layer, and protect
the sensitive regions of the sensor 80 from host inflammatory
response. While not wishing to be bound by theory, it is believed
that implantable glucose sensors employing the biointerface
membranes of the preferred embodiments benefit from a variety of
advantages including decreased start-up time due to increased time
to vascularize, decreased time lag of the analyte across the
membrane, reduction or prevention of barrier cell layer formation,
and reliable and constant analyte transport across the biointerface
in vivo.
[0144] In one alternative embodiment, the glucose sensor comprises
a needle-type sensor wherein the electrode system is in the form of
an elongated needle-shaped structure. For example, the working
electrode can comprise a piece of wire and the reference/counter
electrode can comprise a wire (e.g., a flat wire structure)
helically wound around the working electrode. An insulative layer
can be placed between the working and reference/counter electrode.
Those of skill in the art will appreciate other electrode
structures that could be used to form a needle-shaped structure.
The needle-shaped electrode system can be incorporated with one or
more membranes such as described herein including a sensing
membrane and a biointerface membrane of the preferred embodiments.
The biointerface membrane can be deposited onto the needle-shaped
electrode system or the electrode system can be inserted into a
preformed biointerface membrane. For example, a biointerface
membrane is contemplated with a micro-architecture disposed in a
portion of a macro-architecture (periphery, center, or entire
membrane), wherein the needle-type sensor is inserted into the
biointerface membrane within the micro-architecture. Some examples
of a needle-type sensors suitable for use with the biointerface
membrane of the preferred embodiments is described in co-pending
U.S. Provisional Patent Application No. 60/587,787 and U.S.
Provisional Patent Application No. 60/614,683, which are
incorporated herein by reference in their entirety.
[0145] The biointerface membranes described herein can also be
implemented with a variety of known continuous glucose sensors, for
example. In one embodiment, the biointerface membrane is
implemented in conjunction with a continuous glucose sensor that
comprises a subcutaneous sensor such as described with reference to
U.S. Pat. No. 6,579,690 to Bonnecaze et al. and U.S. Pat. No.
6,484,046 to Say et al. In another alternative embodiment, the
continuous glucose sensor comprises a refillable subcutaneous
sensor such as described with reference to U.S. Pat. No. 6,512,939
to Colvin et al. All of the above patents are incorporated in their
entirety herein by reference. In general, the disclosed embodiments
are applicable to a variety of continuous glucose sensor
configurations.
[0146] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in
copending U.S. application Ser. No. 10/685,636 filed Oct. 28, 2003
and entitled, "SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE";
U.S. application Ser. No. 10/648,849 filed Aug. 22, 2003 and
entitled, "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A
GLUCOSE SENSOR DATA STREAM"; U.S. application Ser. No. 10/646,333
filed Aug. 22, 2003 entitled, "OPTIMIZED SENSOR GEOMETRY FOR AN
IMPLANTABLE GLUCOSE SENSOR"; U.S. application Ser. No. 10/647,065
filed Aug. 22, 2003 entitled, "POROUS MEMBRANES FOR USE WITH
IMPLANTABLE DEVICES"; U.S. application Ser. No. 10/633,367 filed
Aug. 1, 2003 entitled, "SYSTEM AND METHODS FOR PROCESSING ANALYTE
SENSOR DATA"; U.S. Publication No. 2003/0032874; U.S. application
Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled "DEVICE AND
METHOD FOR DETERMINING ANALYTE LEVELS"; U.S. Publication No.
2003/0217966; and U.S. Publication No. 2004/0011671, as well as
issued patents including U.S. Pat. Nos. 6,702,857; 6,741,877;
6,558,321; 6,001,067; 4,994,167; and 4,757,022. The foregoing
patent applications and patents are incorporated herein by
reference in their entireties, and are made a part of this
specification.
[0147] All references cited herein are incorporated herein by
reference in their entirety, and are made a part of this
specification. To the extent publications and patents or patent
applications incorporated by reference contradict the disclosure
contained in the specification, the specification is intended to
supersede and/or take precedence over any such contradictory
material.
[0148] The term "comprising" as used herein is synonymous with
"including," "containing," or "characterized by," and is inclusive
or open-ended and does not exclude additional, unrecited elements
or method steps.
[0149] All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification and claims are
to be understood as being modified in all instances by the term
"about." Accordingly, unless indicated to the contrary, the
numerical parameters set forth in the specification and attached
claims are approximations that may vary depending upon the desired
properties sought to be obtained by the present invention. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, each numerical
parameter should be construed in light of the number of significant
digits and ordinary rounding approaches.
[0150] 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.
* * * * *