U.S. patent application number 16/028110 was filed with the patent office on 2018-11-08 for membrane for use with implantable devices.
The applicant listed for this patent is DexCom, Inc.. Invention is credited to James H. Brauker, Mark C. Shults, Mark A. Tapsak.
Application Number | 20180317827 16/028110 |
Document ID | / |
Family ID | 25437184 |
Filed Date | 2018-11-08 |
United States Patent
Application |
20180317827 |
Kind Code |
A1 |
Brauker; James H. ; et
al. |
November 8, 2018 |
MEMBRANE FOR USE WITH IMPLANTABLE DEVICES
Abstract
The present invention provides a biointerface membrane for use
with an implantable device that interferes with the formation of a
barrier cell layer including; a first domain distal to the
implantable device wherein the first domain supports tissue
attachment and interferes with barrier cell layer formation and a
second domain proximal to the implantable device wherein the second
domain is resistant to cellular attachment and is impermeable to
cells. In addition, the present invention provides sensors
including the biointerface membrane, implantable devices including
these sensors or biointerface membranes, and methods of monitoring
glucose levels in a host utilizing the analyte detection
implantable device of the invention. Other implantable devices
which include the biointerface membrane of the present invention,
such as devices for cell transplantation, drug delivery devices,
and electrical signal delivery or measuring devices are also
provided.
Inventors: |
Brauker; James H.;
(Coldwater, MI) ; Shults; Mark C.; (Madison,
WI) ; Tapsak; Mark A.; (Bloomsburg, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DexCom, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
25437184 |
Appl. No.: |
16/028110 |
Filed: |
July 5, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14619651 |
Feb 11, 2015 |
10039480 |
|
|
16028110 |
|
|
|
|
14341468 |
Jul 25, 2014 |
9532741 |
|
|
14619651 |
|
|
|
|
12633578 |
Dec 8, 2009 |
8840552 |
|
|
14341468 |
|
|
|
|
10768889 |
Jan 29, 2004 |
7632228 |
|
|
12633578 |
|
|
|
|
09916386 |
Jul 27, 2001 |
6702857 |
|
|
10768889 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/14735 20130101;
A61B 2562/02 20130101; A61L 31/10 20130101; Y10T 428/249921
20150401; A61B 5/14532 20130101; A61L 31/14 20130101; A61B 5/14865
20130101; A61B 5/076 20130101; A61B 5/14546 20130101 |
International
Class: |
A61B 5/1473 20060101
A61B005/1473; A61B 5/07 20060101 A61B005/07; A61B 5/1486 20060101
A61B005/1486; A61L 31/14 20060101 A61L031/14; A61B 5/145 20060101
A61B005/145; A61L 31/10 20060101 A61L031/10 |
Claims
1. A biointerface membrane for use with an implantable device
comprising; a) a first domain distal to said implantable device
wherein said first domain supports tissue ingrowth and interferes
with barrier cell layer formation; and b) a second domain proximal
to said implantable device wherein said second domain is resistant
to cellular attachment and is impermeable to cells and cell
processes.
2. A biointerface membrane according to claim 1 wherein said first
domain is comprised of an open-cell configuration having cavities
and a solid portion.
3. A biointerface membrane according to claim 2 wherein said
open-cell configuration comprises a depth of greater than one
cavity in three dimensions substantially throughout the entirety of
the domain.
4. A biointerface membrane according to claim 2 wherein a
substantial number of said cavities are not less than 20 microns in
the shortest dimension and not more than 1000 microns in the
longest dimension.
5. A biointerface membrane according to claim 2 wherein a
substantial number of said cavities are not less than 25 microns in
the shortest dimension and not more than 500 microns in the longest
dimension.
6. A biointerface membrane according to claim 2 wherein said
cavities and cavity interconnections are formed in layers having
different cavity dimensions.
7. A biointerface membrane according to claim 2 wherein said solid
portion has not less than 5 microns in a substantial number of the
shortest dimensions and not more than 2000 microns in a substantial
number of the longest dimensions.
8. A biointerface membrane according to claim 2 wherein said solid
portion has not less than 10 microns in a substantial number of the
shortest dimensions and not more than 1000 microns in a substantial
number of the longest dimensions.
9. A biointerface membrane according to claim 2 wherein said solid
portion has not less than 10 microns in a substantial number of the
shortest dimensions and not more than 400 microns in a substantial
number of the longest dimensions.
10. A biointerface membrane according to claim 2 wherein said solid
portion comprises silicone.
Description
INCORPORATION BY REFERENCE TO RELATED APPLICATIONS
[0001] Any and all priority claims identified in the Application
Data Sheet, or any correction thereto, are hereby incorporated by
reference under 37 CFR 1.57. This application is a continuation of
U.S. application Ser. No. 14/619,651, filed Feb. 11, 2015, which is
a continuation of U.S. application Ser. No. 14/341,468 filed Jul.
25, 2014, now U.S. Pat. No. 9,532,741, which is a continuation of
U.S. application Ser. No. 12/633,578 filed Dec. 8, 2009, now U.S.
Pat. No. 8,840,552, which is a continuation of U.S. application
Ser. No. 10/768,889 filed Jan. 29, 2004, now U.S. Pat. No.
7,632,228, which is a continuation of U.S. application Ser. No.
09/916,386, filed Jul. 27, 2001, now U.S. Pat. No. 6,702,857. Each
of the aforementioned applications is incorporated by reference
herein in its entirety, and each is hereby expressly made a part of
this specification.
FIELD OF THE INVENTION
[0002] The present invention relates generally to biointerface
membranes that may be utilized with implantable devices such as
devices for the detection of analyte concentrations in a biological
sample, cell transplantation devices, drug delivery devices and
electrical signal delivering or measuring devices. The present
invention further relates to methods for determining analyte levels
using implantable devices including these membranes. More
particularly, the invention relates to novel biointerface
membranes, to sensors and implantable devices including these
membranes, and to methods for monitoring glucose levels in a
biological fluid sample using an implantable analyte detection
device.
BACKGROUND OF THE INVENTION
[0003] One of the most heavily investigated analyte sensing devices
is an implantable glucose sensor for detecting glucose levels in
patients with diabetes. Despite the increasing number of
individuals diagnosed with diabetes and recent advances in the
field of implantable glucose monitoring devices, currently used
devices are unable to provide data safely and reliably for long
periods of time (e.g., months or years) [See, e.g., Moatti-Sirat et
al., Diabetologia 35:224-30 (1992)]. There are two commonly used
types of implantable glucose sensing devices. These types are those
which are implanted intravascularly and those implanted in
tissue.
[0004] With reference to devices that may be implanted in tissue, a
disadvantage of these devices has been that they tend to lose their
function after the first few days to weeks following implantation.
At least one reason for this loss of function has been attributed
to the fact that there is no direct contact with circulating blood
to deliver sample to the tip of the probe of the implanted device.
Because of these limitations, it has previously been difficult to
obtain continuous and accurate glucose levels. However, this
information is often extremely important to diabetic patients in
ascertaining whether immediate corrective action is needed in order
to adequately manage their disease.
[0005] Some medical devices, including implanted analyte sensors,
drug delivery devices and cell transplantation devices require
transport of solutes across the device-tissue interface for proper
function. These devices generally include a membrane, herein
referred to as a cell-impermeable membrane that encases the device
or a portion of the device to prevent access by host inflammatory
or immune cells to sensitive regions of the device.
[0006] A disadvantage of cell-impermeable membranes is that they
often stimulate a local inflammatory response, called the foreign
body response (FBR) that has long been recognized as limiting the
function of implanted devices that require solute transport.
Previous efforts to overcome this problem have been aimed at
increasing local vascularization at the device-tissue interface
with limited success.
[0007] The FBR has been well described in the literature and is
composed of three main layers, as illustrated in FIG. 1. The
innermost FBR layer 40, adjacent to the device, is composed
generally of macrophages and foreign body giant cells 41 (herein
referred to as the barrier cell layer). These cells form a
monolayer 40 of closely opposed cells over the entire surface 48a
of a smooth or microporous (<1.0 .mu.m) membrane 48. The
intermediate FBR layer 42 (herein referred to as the fibrous zone),
lying distal to the first layer with respect to the device, is a
wide zone (30-100 microns) composed primarily of fibroblasts 43 and
fibrous matrix 44. The outermost FBR layer 46 is loose connective
granular tissue containing new blood vessels 45 (herein referred to
as the vascular zone 46). A consistent feature of the innermost
layers 40 and 42 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 47 is due to a lack of
vascularization near interface 47 (Scharp et al., World J. Surg.
8:221-229 (1984), Colton and Avgoustiniatos J. Biomech. Eng.
113:152-170 (1991)).
[0008] Patents by Brauker et al. (U.S. Pat. No. 5,741,330), and
Butler et al. (U.S. Pat. No. 5,913,998), describe inventions aimed
at increasing the number of blood vessels adjacent to the implant
membrane (Brauker et al.), and growing within (Butler et al.) the
implant membrane at the device-tissue interface. The patent of
Shults et al. (U.S. Pat. No. 6,001,067) describes membranes that
induce angiogenesis at the device-tissue interface of implanted
glucose sensors. FIG. 2 illustrates a situation in which some blood
vessels 45 are brought close to an implant membrane 48, but the
primary layer 40 of cells adherent to the cell-impermeable membrane
blocks glucose. This phenomenon is described in further detail
below.
[0009] In the examples of Brauker et al. (supra), and Shults et
al., bilayer membranes are described that have cell impermeable
layers that are porous and adhesive to cells. Cells are able to
enter into the interstices of these membranes, and form monolayers
on the innermost layer, which is aimed at preventing cell access to
the interior of the implanted device (cell impenetrable layers).
Because the cell impenetrable layers are porous, cells are able to
reach pseudopodia into the interstices of the membrane to adhere to
and flatten on the membrane, as shown in FIGS. 1 and 2, thereby
blocking transport of molecules across the membrane-tissue
interface. The known art purports to increase the local
vascularization in order to increase solute availability. However,
the present studies show that once the monolayer of cells (barrier
cell layer) is established adjacent to the membrane, increasing
angiogenesis is not sufficient to increase transport of molecules
such as glucose and oxygen across the device-tissue interface.
[0010] One mechanism of inhibition of transport of solutes across
the device-tissue interface that has not been previously discussed
in the literature is the formation of a uniform barrier to analyte
transport by cells that form the innermost layer of the foreign
body capsule. This layer of cells forms a monolayer with closely
opposed cells having tight cell-to-cell junctions. When this
barrier cell layer forms, it is not substantially overcome by
increased local vascularization. Regardless of the level of local
vascularization, the barrier cell layer prevents the passage of
molecules that cannot diffuse through the layer. Again, this is
illustrated in FIG. 2 where blood vessels 45 lie adjacent to the
membrane but glucose transport is significantly reduced due to the
impermeable nature of the barrier cell layer 40. For example, both
glucose and its phosphorylated form do not readily transit the cell
membrane and consequently little glucose reaches the implant
membrane through the barrier layer cells.
[0011] It has been confirmed by the present inventors through
histological examination of explanted sensors that the most likely
mechanism for inhibition of molecular transport across the
device-tissue interface is the barrier cell layer adjacent to the
membrane. There is a strong correlation between desired device
function and the lack of formation of a barrier cell layer at the
device-tissue interface. In the present studies, devices that were
observed histologically to have substantial barrier cell layers
were functional only 41% of the time after 12 weeks in vivo. In
contrast, devices that did not have significant barrier cell layers
were functional 86% of the time after 12 weeks in vivo.
[0012] Consequently, there is a need for a membrane that interferes
with the formation of a barrier layer and protects the sensitive
regions of the device from host inflammatory response.
SUMMARY OF THE INVENTION
[0013] The biointerface membranes of the present invention
interfere with the formation of a monolayer of cells adjacent to
the membrane, henceforth referred to herein as a barrier cell
layer, which interferes with the transport of oxygen and glucose
across a device-tissue interface.
[0014] It is to be understood that various biointerface membrane
architectures (e.g., variations of those described below) are
contemplated by the present invention and are within the scope
thereof.
[0015] In one aspect of the present invention, a biointerface
membrane for use with an implantable device is provided including;
a first domain distal to the implantable device wherein the first
domain supports tissue ingrowth and interferes with barrier-cell
layer formation and a second domain proximal to the implantable
device wherein the second domain is resistant to cellular
attachment and is impermeable to cells and cell processes.
[0016] In another aspect of the present invention, a biointerface
membrane is provided including the properties of: promoting tissue
ingrowth into; interfering with barrier cell formation on or
within; resisting barrier-cell attachment to; and blocking cell
penetration into the membrane.
[0017] In yet another aspect, a sensor head for use in an
implantable device is provided which includes a biointerface
membrane of the present invention.
[0018] In other aspects, a sensor for use in an implantable device
that measures the concentration of an analyte in a biological fluid
is provided including the biointerface membrane of the present
invention.
[0019] In still another aspect of the present invention, a device
for measuring an analyte in a biological fluid is provided, the
device including the biointerface membrane of the present
invention, a housing which includes electronic circuitry, and at
least one sensor as provided above operably connected to the
electronic circuitry of the housing.
[0020] The present invention further provides a method of
monitoring analyte levels including the steps of: providing a host,
and an implantable device as provided above; and implanting the
device in the host. In one embodiment, the device is implanted
subcutaneously.
[0021] Further provided by the present invention is a method of
measuring analyte in a biological fluid including the steps of:
providing i) a host, and ii) a implantable device as provided above
capable of accurate continuous analyte sensing; and implanting the
device in the host. In one embodiment of the method, the device is
implanted subcutaneously.
[0022] In still another aspect of the present invention, an
implantable drug delivery device is provided including a
biointerface membrane as provided above. Preferably the implantable
drug delivery device is a pump, a microcapsule or a
macrocapsule.
[0023] The present invention further provides a device for
implantation of cells which includes a biointerface membrane as
provided above.
[0024] Also encompassed by the present invention is an electrical
pulse delivering or measuring device, including a biointerface
membrane according to that provided above.
[0025] The biointerface membranes, devices including these
membranes and methods of use of these membranes provided by the
invention allow for long term protection of implanted cells or
drugs, as well as continuous information regarding, for example,
glucose levels of a host over extended periods of time. Because of
these abilities, the biointerface membranes of the present
invention can be extremely important in the management of
transplant patients, diabetic patients and patients requiring
frequent drug treatment.
Definitions
[0026] In order to facilitate an understanding of the present
invention, a number of terms are defined below.
[0027] The terms "biointerface membrane," and the like refer to a
permeable membrane that functions as a device-tissue interface
comprised of two or more domains. Preferably, the biointerface
membrane is composed of two domains. The first domain supports
tissue ingrowth, interferes with barrier cell layer formation and
includes an open cell configuration having cavities and a solid
portion. The second domain is resistant to cellular attachment and
impermeable to cells (e.g., macrophages). The biointerface membrane
is made of biostable materials and may be constructed in layers,
uniform or non-uniform gradients (i.e. anisotropic), or in a
uniform or non-uniform cavity size configuration.
[0028] The term "domain" refers to regions of the biointerface
membrane that may be layers, uniform or non-uniform gradients (e.g.
anisotropic) or provided as portions of the membrane.
[0029] The term "barrier cell layer" refers to a cohesive monolayer
of closely opposed cells (e.g. macrophages and foreign body giant
cells) that may adhere to implanted membranes and interfere with
the transport of molecules across the membrane.
[0030] The phrase "distal to" refers to the spatial relationship
between various elements in comparison to a particular point of
reference. For example, some embodiments of a device include a
biointerface membrane having an cell disruptive domain and a cell
impermeable domain. If the sensor is deemed to be the point of
reference and the cell disruptive domain is positioned farther from
the sensor, then that domain is distal to the sensor.
[0031] The term "proximal to" refers to the spatial relationship
between various elements in comparison to a particular point of
reference. For example, some embodiments of a device include a
biointerface membrane having a cell disruptive domain and a cell
impermeable domain. If the sensor is deemed to be the point of
reference and the cell impermeable domain is positioned nearer to
the sensor, then that domain is proximal to the sensor.
[0032] The term "cell processes" and the like refers to pseudopodia
of a cell.
[0033] The term "solid portions" and the like refer to a material
having a structure that may or may not have an open-cell
configuration, but in either case prohibits whole cells from
traveling through or residing within the material.
[0034] The term "substantial number" refers to the number of linear
dimensions within a domain (e.g. pores or solid portions) in which
greater than 50 percent of all dimensions are of the specified
size, preferably greater than 75 percent and, most preferably,
greater than 90 percent of the dimensions have the specified
size.
[0035] The term "co-continuous" and the like refers to a solid
portion wherein an unbroken curved line in three dimensions exists
between any two points of the solid portion.
[0036] The term "biostable" and the like refers to materials that
are relatively resistant to degradation by processes that are
encountered in vivo.
[0037] The term "sensor" refers to the component or region of a
device by which an analyte can be quantitated.
[0038] The term "analyte" refers to a substance or chemical
constituent in a biological fluid (e.g., blood or urine) that is
intended to be analyzed. A preferred analyte for measurement by
analyte detection devices including the biointerface membranes of
the present invention is glucose.
[0039] The terms "operably connected," "operably linked," and the
like refer to one or more components being linked to another
component(s) in a manner that allows transmission of signals
between the components. For example, one or more electrodes may be
used to detect the amount of analyte in a sample and convert that
information into a signal; the signal may then be transmitted to an
electronic circuit means. In this case, the electrode is "operably
linked" to the electronic circuitry.
[0040] The term "electronic circuitry" refers to the components of
a device required to process biological information obtained from a
host. In the case of an analyte measuring device, the biological
information is obtained by a sensor regarding a particular analyte
in a biological fluid, thereby providing data regarding the amount
of that analyte in the fluid. U.S. Pat. Nos. 4,757,022, 5,497,772
and 4,787,398 describe suitable electronic circuit means that may
be utilized with devices including the biointerface membrane of the
present invention.
[0041] The phrase "member for determining the amount of glucose in
a biological sample" refers broadly to any mechanism (e.g.,
enzymatic or non-enzymatic) by which glucose can be quantitated.
For example, some embodiments of the present invention utilize a
membrane that contains glucose oxidase that catalyzes the
conversion of oxygen and glucose to hydrogen peroxide and
gluconate: Glucose+O.sub.2=Gluconate+H.sub.2O.sub.2-. Because for
each glucose molecule metabolized, there is a proportional change
in the co-reactant O.sub.2 and the product H.sub.2O.sub.2, one can
monitor the current change in either the co-reactant or the product
to determine glucose concentration.
[0042] The term "host" refers generally to mammals, particularly
humans.
[0043] The term "accurately" means, for example, 90% of measured
glucose values are within the "A" and "B" region of a standard
Clarke error grid when the sensor measurements are compared to a
standard reference measurement. It is understood that like any
analytical device, calibration, calibration validation and
recalibration are required for the most accurate operation of the
device.
[0044] The phrase "continuous glucose sensing" refers to the period
in which monitoring of plasma glucose concentration is continuously
performed, for example, about every 10 minutes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] FIG. 1 is an illustration of classical three-layered foreign
body response to a synthetic membrane implanted under the skin.
[0046] FIG. 2 is an illustration of a device having increased
neovascularization within the intermediary layer of the foreign
body response.
[0047] FIG. 3 is an illustration of a membrane of the present
invention including a barrier-cell disruptive domain composed of
fibers and a cell impermeable domain.
[0048] FIG. 4 is an illustration of a three dimensional section of
the first domain showing the solid portions and cavities.
[0049] FIG. 5 is an illustration of a cross-section of the first
domain in FIG. 4 showing solid portions and cavities.
[0050] FIG. 6A depicts a cross-sectional drawing of one embodiment
of an implantable analyte measuring device for use in combination
with a membrane according to the present invention.
[0051] FIG. 6B depicts a cross-sectional exploded view of the
sensor head shown in FIG. 6A.
[0052] FIG. 6C depicts a cross-sectional exploded view of the
electrode-membrane region set forth in FIG. 6B.
[0053] FIG. 7 is a graphical representation of the number of
functional sensors versus time (i.e. weeks) comparing control
devices including only a cell-impermeable domain ("Control"), with
devices including a cell-impermeable domain and a barrier-cell
domain, in particular, wherein the barrier-cell disruptive domain
includes non-woven fiber ("Non-Woven Fibers") and wherein the
barrier-cell disruptive domain includes porous silicone ("Porous
Silicone").
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0054] The present invention relates generally to novel
biointerface membranes, their uses with implantable devices and
methods for determining analyte levels in a biological fluid. More
particularly, the invention provides biointerface membranes that
may be utilized with implantable devices and methods for monitoring
and determining glucose levels in a biological fluid, a
particularly important measurement for individuals having
diabetes.
[0055] Although the description that follows is primarily directed
at glucose monitoring devices including the biointerface membranes
of the present invention and methods for their use, these
biointerface membranes are not limited to use in devices that
measure or monitor glucose. Rather, these biointerface membranes
may 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 [see, e.g., U.S. Pat. No. 4,703,756 to Gough et al., hereby
incorporated by reference] cell transplantation devices (U.S. Pat.
Nos. 6,015,572, 5,964,745 and 6,083,523), drug delivery devices
(U.S. Pat. Nos. 5,458,631, 5,820,589 and 5,972,369) 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), electrocardiogram device (U.S. Pat. Nos.
4,625,730 and 5,987,352) and electrical nerve stimulating devices
(U.S. Pat. Nos. 6,175,767, 6,055,456 and 4,940,065).
[0056] Implantable devices for detecting analyte concentrations in
a biological system may utilize the biointerface membranes of the
present invention 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 may utilize the biointerface membranes of the
present invention 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
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 may utilize the
biointerface membranes of the present invention 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.
[0057] The materials contemplated for use in preparing the
biointerface membrane also eliminate or significantly delay
biodegradation. This is particularly important for devices that
continuously measure analyte concentrations. For example, in a
glucose-measuring device, the electrode surfaces of the glucose
sensor are in contact with (or operably connected with) a thin
electrolyte phase, which in turn is covered by a membrane that
contains an enzyme, e.g., glucose oxidase, and a polymer system.
The biointerface membrane covers this enzyme membrane and serves,
in part, to protect the sensor from external forces and factors
that may result in biodegradation. By significantly delaying
biodegradation at the sensor, accurate data may be collected over
long periods of time (e.g. months to years). Correspondingly,
biodegradation of the biointerface membrane of implantable cell
transplantation devices and drug delivery devices could allow host
inflammatory and immune cells to enter these devices, thereby
compromising long-term function.
[0058] Devices and probes that are implanted into subcutaneous
tissue will almost always elicit a foreign body capsule (FBC) as
part of the body's response to the introduction of a foreign
material. Therefore, implantation of a glucose sensor results in an
acute inflammatory reaction followed by building of fibrotic
tissue. Ultimately, a mature FBC including primarily a vascular
fibrous tissue forms around the device (Shanker and Greisler,
Inflammation and Biomaterials in Greco RS, ed. Implantation
Biology: The Host Response and Biomedical Devices, pp 68-80, CRC
Press (1994)).
[0059] In general, the formation of a FBC has precluded the
collection of reliable, continuous information because it was
previously believed to isolate the sensor of the implanted device
in a capsule containing fluid that did not mimic the levels of
analytes (e.g. glucose and oxygen) in the body's vasculature.
Similarly, the composition of a FBC has prevented stabilization of
the implanted device, contributing to motion artifact that also
renders unreliable results. Thus, conventionally, it has been the
practice of those skilled in the art to attempt to minimize FBC
formation by, for example, using a short-lived needle geometry or
sensor coatings to minimize the foreign body reaction.
[0060] In contrast to conventionally known practice, the teachings
of the present invention recognize that FBC formation is the
dominant event surrounding long-term implantation of any sensor and
must be managed to support rather than hinder or block sensor
performance. It has been observed that during the early periods
following implantation of an analyte-sensing device, particularly a
glucose sensing device, glucose sensors function well. However,
after a few days to two or more weeks of implantation, these device
lose their function. For example, U.S. Pat. No. 5,791,344 and Gross
et al. Performance Evaluation of the Minimed Continuous Monitoring
System During Patient home Use", Diabetes Technology and
Therapuetics, Vol 2 Number 1, pp 49-56, 2000 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. We have observed similar device behavior with our implantable
sensor. These results suggest that there is sufficient
vascularization and, therefore, perfusion of oxygen and glucose to
support the function of an implanted 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.
[0061] We have observed that this lack of sensor function after
several days 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. These cells consume glucose and
oxygen. If there is an overabundance of such cells, they may
deplete the glucose and/or oxygen before it is able to reach the
sensor enzyme layer, therefore reducing the sensitivity of the
device or rendering it non-functional. After the first few days,
further inhibition of device function may be due to cells that
associate with the membrane of the device and physically block the
transport of glucose into the device (i.e. barrier cells).
Increased vascularization would not be expected to overcome barrier
cell blockage. The present invention contemplates the use of
particular biointerface membrane architectures that interfere with
barrier cell layer formation on the membrane's surface. The present
invention also contemplates the use of these membranes with a
variety of implantable devices (e.g. analyte measuring devices,
particularly glucose measuring devices, cell transplantation
devices, drug delivery devices and electrical signal delivery and
measuring devices).
[0062] The sensor interface region refers to the region of a
monitoring device responsible for the detection of a particular
analyte. For example, in some embodiments of a glucose-monitoring
device, the sensor interface refers to that region where a
biological sample contacts (directly or after passage through one
or more membranes or layers) an enzyme (e.g., glucose oxidase). The
sensor interface region may include a biointerface membrane
according to the present invention having different domains and/or
layers that can cover and protect an underlying enzyme membrane and
the electrodes of an implantable analyte-measuring device. In
general, the biointerface membranes of the present invention
prevent direct contact of the biological fluid sample with the
sensor. The membranes only permit selected substances (e.g.,
analytes) of the fluid to pass therethrough for reaction in the
immobilized enzyme domain. The biointerface membranes of the
present invention are biostable and prevent barrier cell formation.
The characteristics of this biointerface membrane are now discussed
in more detail.
I. Biointerface Membrane
[0063] The biointerface membrane is constructed of two or more
domains. Referring now to FIG. 3, preferably, the membrane includes
a cell impermeable domain 50 proximal to an implantable device,
also referred to as the second domain; and a cell disruptive
domain, which in the embodiment illustrated includes non-woven
fibers 49 distal to an implantable device, also referred to as the
first domain.
[0064] A. Barrier-Cell Disruptive (First) Domain
[0065] As described above, the outermost domain of the inventive
membrane includes a material that supports tissue ingrowth. The
barrier-cell disruptive domain may be composed of an open-cell
configuration having cavities and solid portions. For example, FIG.
4 is an illustration of a three dimensional section 60 of a
barrier-cell disruptive domain having solid portions 62 and
cavities 64. Cells may enter into the cavities, however, they can
not travel through or wholly exist within the solid portions. The
cavities allow most substances to pass through, including, e.g.,
macrophages.
[0066] The open-cell configuration yields a co-continuous solid
domain that contains greater than one cavity in three dimensions
substantially throughout the entirety of the membrane. In addition,
the cavities and cavity interconnections may be formed in layers
having different cavity dimensions.
[0067] In order to better describe the dimensions of cavities and
solid portions, a two dimensional plane 66 cut through the
barrier-cell disruptive domain can be utilized (FIG. 5). A
dimension across a cavity 64 or solid portion 62 can be described
as a linear line. The length of the linear line is the distance
between two points lying at the interface of the cavity and solid
portion. In this way, a substantial number of the cavities are not
less than 20 microns in the shortest dimension and not more than
1000 microns in the longest dimension. Preferably, a substantial
number of the cavities are not less than 25 microns in the shortest
dimension and not more than 500 microns in the longest
dimension.
[0068] Furthermore, the solid portion has not less than 5 microns
in a substantial number of the shortest dimensions and not more
than 2000 microns in a substantial number of the longest
dimensions. Preferably, the solid portion is not less than 10
microns in a substantial number of the shortest dimensions and not
more than 1000 microns in a substantial number of the longest
dimensions and, most preferably, not less than 10 microns in a
substantial number of the shortest dimensions and not more than 400
microns in a substantial number of the longest dimensions.
[0069] The solid portion may be comprised of
polytetrafluoroethylene or polyethyleneco-tetrafluoroethylene.
Preferably, the solid portion includes polyurethanes or block
copolymers and, most preferably, is comprised of silicone.
[0070] In desired embodiments, the solid portion is composed of
porous silicone or non-woven fibers. Non-woven fibers are
preferably made from polyester or polypropylene. For example, FIG.
3 illustrates how the non-woven fibers 49 serve to disrupt the
continuity of cells, such that they are not able to form a
classical foreign body response. All the cell types that are
involved in the formation of a FBR may be present. However, they
are unable to form an ordered closely opposed cellular monolayer
parallel to the surface of the device as in a typical foreign body
response to a smooth surface. In this example, the 10-micron
dimension provides a suitable surface for foreign body giant cells,
but the fibers are in such proximity to allow and foster in growth
of blood vessels 45 and vascularize the biointerface region (FIG.
3). Devices with smaller fibers have been used in previous
inventions, but such membranes are prone to delamination due to the
forces applied by cells in the interstices of the membrane. After
delamination, cells are able to form barrier layers on the smooth
or microporous surface of the bioprotective layer if it is adhesive
to cells or has pores of sufficient size for physical penetration
of cell processes, but not of whole cells.
[0071] When non-woven fibers are utilized as the solid portion of
the present invention, the non-woven fibers may be greater than 5
microns in the shortest dimension. Preferably, the non-woven fibers
are about 10 microns in the shortest dimension and, most
preferably, the non-woven fibers are greater than or equal to 10
microns in the shortest dimension.
[0072] The non-woven fibers may be constructed of 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). Preferably, the
non-woven fibers are comprised of polyolefins or polyester or
polycarbonates or polytetrafluoroethylene. The thickness of the
cell disruptive domain is not less than about 20 microns and not
more than about 2000 microns.
[0073] B. Cell Impermeable (Second) Domain
[0074] The inflammatory response that initiates and sustains a FBC
is associated with disadvantages in the practice of sensing
analytes Inflammation is associated with invasion of inflammatory
response cells (e.g. macrophages) which have the ability to
overgrow at the interface forming barrier cell layers which may
block transport across the biointerface membrane. These
inflammatory cells may also biodegrade many artificial biomaterials
(some of which were, until recently, considered nonbiodegradable).
When activated by a foreign body, tissue macrophages degranulate,
releasing from their cytoplasmic myeloperoxidase system
hypochlorite (bleach) and other oxidative species. Hypochlorite and
other oxidative species are known to break down a variety of
polymers. However, polycarbonate based polyurethanes are believed
to be resistant to the effects of these oxidative species and have
been termed biodurable. In addition, because hypochlorite and other
oxidizing species are short-lived chemical species in vivo,
biodegradation will not occur if macrophages are kept a sufficient
distance from the enzyme active membrane.
[0075] The present invention contemplates the use of cell
impermeable biomaterials of a few microns thickness or more (i.e.,
a cell impermeable domain) in most of its membrane architectures.
Desirably, the thickness of the cell impermeable domain is not less
than about 10 microns and not more than about 100 microns. This
domain of the biointerface membrane is permeable to oxygen and may
or may not be permeable to glucose and is constructed of biodurable
materials (e.g. for period of several years in vivo) that are
impermeable by host cells (e.g. macrophages) such as, for example,
polymer blends of polycarbonate based polyurethane and PVP.
[0076] The innermost domain of the inventive membrane is
non-adhesive for cells (i.e. the cell impermeable domain), which is
in contrast to the inventions of Brauker et al. (supra), and Shults
et al. (supra). In both of these previous patents, examples are
provided in which the cellimpenetrable membrane (Brauker et al.) or
biointerface membrane (Shults et al.) are derived from a membrane
known as Biopore.TM. as a cell culture support sold by Millipore
(Bedford, Mass.). In the presence of certain extracellular matrix
molecules, and also in vivo, many cell types are able to strongly
adhere to this membrane making it incapable of serving as a
non-adhesive domain. Further, since they allow adherence of cells
to the innermost layer of the membrane they promote barrier cell
layer formation that decreases the membranes ability to transport
molecules across the device-tissue interface. Moreover, when these
cells multiply, they ultimately cause pressure between the membrane
layers resulting in delamination of the layers and catastrophic
failure of the membrane.
[0077] As described above, in one embodiment of the inventive
membrane, the second domain is resistant to cellular attachment and
is impermeable to cells and preferably composed of a biostable
material. The second domain may be formed from materials such as
those previously listed for the first domain and as copolymers or
blends with hydrophilic polymers such as polyvinylpyrrolidone
(PVP), polyhydroxyethyl methacrylate, polyvinylalcohol, polyacrylic
acid, polyethers, such as polyethylene glycol, 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).
[0078] Preferably, the second domain is comprised of a polyurethane
and a hydrophilic polymer. Desirably, the hydrophilic polymer is
polyvinylpyrrolidone. In one embodiment of this aspect of the
invention, the second domain is polyurethane comprising not less
than 5 weight percent polyvinylpyrrolidone and not more than 45
weight percent polyvinylpyrrolidone. Preferably, the second domain
comprises not less than 20 weight percent polyvinylpyrrolidone and
not more than 35 weight percent polyvinylpyrrolidone and, most
preferably, polyurethane comprising about 27 weight percent
polyvinylpyrrolidone.
[0079] As described above, in one desired embodiment the cell
impermeable domain is comprised of a polymer blend comprised of a
non-biodegradable polyurethane comprising polyvinylpyrrolidone.
This prevents adhesion of cells in vitro and in vivo and allows
many molecules to freely diffuse through the membrane. However,
this domain prevents cell entry or contact with device elements
underlying the membrane, and prevents the adherence of cells, and
thereby prevents the formation of a barrier cell layer.
II. Implantable Glucose Monitoring Devices Using the Biointerface
Membranes of the Present Invention
[0080] The present invention contemplates the use of unique
membrane architectures around the sensor interface of an
implantable device. However, it should be pointed out that the
present invention does not require a device including particular
electronic components (e.g., electrodes, circuitry, etc). Indeed,
the teachings of the present invention can be used with virtually
any monitoring device suitable for implantation (or subject to
modification allowing implantation); suitable devices include,
analyte measuring devices, cell transplantation devices, drug
delivery devices, electrical signal delivery and measurement
devices and other devices such as those described in U.S. Pat. Nos.
4,703,756 and 4,994,167 to Shults et al.; U.S. Pat. No. 4,703,756
to Gough et al., and U.S. Pat. No. 4,431,004 to Bessman et al.; the
contents of each being hereby incorporated by reference, and Bindra
et al., Anal. Chem. 63:1692-96 (1991).
[0081] We refer now to FIG. 6A, which shows a preferred embodiment
of an analyte measuring device for use in combination with a
membrane according to the present invention. In this embodiment, a
ceramic body 1 and ceramic head 10 houses the sensor electronics
that include a circuit board 2, a microprocessor 3, a battery 4,
and an antenna 5. Furthermore, the ceramic body 1 and head 10
possess a matching taper joint 6 that is sealed with epoxy. The
electrodes are subsequently connected to the circuit board via a
socket 8.
[0082] As indicated in detail in FIG. 6B, three electrodes protrude
through the ceramic head 10, a platinum working electrode 21, a
platinum counter electrode 22 and a silver/silver chloride
reference electrode 20. Each of these is hermetically brazed 26 to
the ceramic head 10 and further affixed with epoxy 28. The sensing
region 24 is covered with the sensing membrane described below and
the ceramic head 10 contains a groove 29 so that the membrane may
be affixed into place with an o-ring.
[0083] FIG. 6C depicts a cross-sectional exploded view of the
electrode-membrane region 24 set forth in FIG. 6B detailing the
sensor tip and the functional membrane layers. As depicted in FIG.
6C, the electrode-membrane region includes the inventive
biointerface membrane 33 and a sensing membrane 32. The top ends of
the electrodes are in contact with the electrolyte phase 30, a
free-flowing fluid phase. The electrolyte phase is covered by the
sensing membrane 32 that includes an enzyme, e.g., glucose oxidase.
In turn, the inventive interface membrane 33 covers the enzyme
membrane 32 and serves, in part, to protect the sensor from
external forces that may result in environmental stress cracking of
the sensing membrane 32.
III. Experimental
[0084] The following examples serve to illustrate certain preferred
embodiments and aspects of the present invention and are not to be
construed as limiting the scope thereof
[0085] In the preceding description and the experimental disclosure
which follows, the following abbreviations apply: Eq and Eqs
(equivalents); mEq (milliequivalents); M (molar); mM (millimolar)
.mu.M (micromolar); N (Normal); mol (moles); mmol (millimoles);
.mu.mol (micromoles); nmol (nanomoles); g (grams); mg (milligrams);
.mu.g (micrograms); Kg (kilograms); L (liters); mL (milliliters);
dL (deciliters); .mu.L (microliters); cm (centimeters); mm
(millimeters); .mu.m (micrometers); nm (nanometers); h and hr
(hours); min. (minutes); s and sec. (seconds); .degree. C. (degrees
Centigrade); Astor Wax (Titusville, Pa.); BASF Wyandotte
Corporation (Parsippany, N.J.); Data Sciences, Inc. (St. Paul,
Minn.); Douglas Hansen Co., Inc. (Minneapolis, Minn.); DuPont
(DuPont Co., Wilmington, Del.); Exxon Chemical (Houston, Tex.); GAF
Corporation (New York, N.Y.); Markwell Medical (Racine, Wis.);
Meadox Medical, Inc. (Oakland, N.J.); Mobay (Mobay Corporation,
Pittsburgh, Pa.); Sandoz (East Hanover, N.J.); and Union Carbide
(Union Carbide Corporation; Chicago, Ill.).
Example 1
[0086] Preparation of Biointerface Membrane with Non-Woven
Fibers
[0087] The barrier-cell disruptive domain may be prepared from a
non-woven polyester fiber filtration membrane. The cell-impermeable
domain may then be coated on this domain layer. The
cell-impermeable domain was prepared by placing approximately 706
gm of dimethylacetamide (DMAC) into a 3 L stainless steel bowl to
which a polycarbonateurethane solution (1325 g, Chronoflex AR 25%
solids in DMAC and a viscosity of 5100 cp) and polyvinylpyrrolidone
(125 g, Plasdone K-90D) were added. The bowl was then fitted to a
planetary mixer with a paddle type blade and the contents were
stirred for 1 hour at room temperature. This solution was then
coated on the barrier-cell disruptive domain by knife-edge drawn at
a gap of 0.006'' and dried at 60.degree. C. for 24 hours. The
membrane is then mechanically secured to the sensing device by an
O-ring.
Example 2
[0088] Preparation of Biointerface Membrane with Porous
Silicone
[0089] The barrier-cell disruptive domain can be comprised of a
porous silicone sheet. The porous silicone was purchased from Seare
Biomatrix Systems, Inc. The cell-impermeable domain was prepared by
placing approximately 706 gm of dimethylacetamide (DMAC) into a 3 L
stainless steel bowl to which a polycarbonateurethane solution
(1,325 gm, Chronoflex AR 25% solids in DMAC and a viscosity of 5100
cp) and polyvinylpyrrolidone (125 gm, Plasdone K-90D) were added.
The bowl was then fitted to a planetary mixer with a paddle type
blade and the contents were stirred for 1 hour at room temperature.
The cell-impermeable domain coating solution was then coated onto a
PET release liner (Douglas Hansen Co.) using a knife over roll set
at a 0.012'' gap. This film was then dried at 305.degree. F. The
final film was approximately 0.0015'' thick. The biointerface
membrane was prepared by pressing the porous silicone onto the cast
cell-impermeable domain. The membrane is then mechanically secured
to the sensing device by an O-ring.
Example 3
[0090] Test Method for Glucose Measuring Device Function
[0091] In vivo sensor function was determined by correlating the
sensor output to blood glucose values derived from an external
blood glucose meter. We have found that non-diabetic dogs do not
experience rapid blood glucose changes, even after ingestion of a
high sugar meal. Thus, a 10% dextrose solution was infused into the
sensor-implanted dog. A second catheter is placed in the opposite
leg for the purpose of blood collection. The implanted sensor was
programmed to transmit at 30-second intervals using a pulsed
electromagnet. A dextrose solution was infused at a rate of 9.3
ml/minute for the first 25 minutes, 3.5 ml/minute for the next 20
minutes, 1.5 ml/minute for the next 20 minutes, and then the
infusion pump was powered off Blood glucose values were measured in
duplicate every five minutes on a blood glucose meter (LXN Inc.,
San Diego, Calif.) for the duration of the study. A computer
collected the sensor output. The data was then compiled and graphed
in a spreadsheet, time aligned, and time shifted until an optimal
R-squared value was achieved. The R-squared value reflects how well
the sensor tracks with the blood glucose values.
Example 4
[0092] In Vivo Evaluation of Glucose Measuring Devices Including
the Biointerface Membranes of the Present Invention
[0093] To test the importance of a cell-disruptive membrane,
implantable glucose sensors comprising the biointerface membranes
of the present invention were implanted into dogs in the
subcutaneous tissues and monitored for glucose response on a weekly
basis. Control devices comprising only a cell-impermeable domain
("Control") were compared with devices comprising a
cell-impermeable domain and a barrier-cell disruptive domain, in
particular, wherein the barrier-cell disruptive domain was either a
non-woven fiber ("Non-Woven Fibers") or porous silicone ("Porous
Silicone").
[0094] Four devices from each condition were implanted
subcutaneously in the ventral abdomen of normal dogs. On a weekly
basis, the dogs were infused with glucose as described in Example 3
in order to increase their blood glucose levels from about 120
mg/dl to about 300 mg/dl. Blood glucose values were determined with
a LXN blood glucose meter at 5-minute intervals. Sensor values were
transmitted at 0.5-minute intervals. Regression analysis was done
between blood glucose values and the nearest sensor value within
one minute. Devices that yielded an R-squared value greater than
0.5 were considered functional. FIG. 7 shows, for each condition,
the number of functional devices over the 12-week period of the
study. Both test devices performed better than the control devices
over the first 9 weeks of the study. All of the porous silicone
devices were functional by week 9. Two of 4 polypropylene fiber
devices were functional by week 2, and 3 of 4 were functional on
week 12. In contrast, none of the control devices were functional
until week 10, after which 2 were functional for the remaining 3
weeks. These data clearly show that the use of a cell-disruptive
layer in combination with a cell-impermeable layer improves the
function of implantable glucose sensors.
[0095] The description and experimental materials presented above
are intended to be illustrative of the present invention while not
limiting the scope thereof It will be apparent to those skilled in
the art that variations and modifications can be made without
departing from the spirit and scope of the present invention.
* * * * *