U.S. patent application number 16/017752 was filed with the patent office on 2019-01-31 for tissue-integrating electronic apparatus.
This patent application is currently assigned to Profusa, Inc.. The applicant listed for this patent is Profusa, Inc.. Invention is credited to Kristen HELTON, William A. MCMILLAN, Kurt E. PETERSEN, Natalie A. WISNIEWSKI.
Application Number | 20190029572 16/017752 |
Document ID | / |
Family ID | 51985877 |
Filed Date | 2019-01-31 |
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United States Patent
Application |
20190029572 |
Kind Code |
A1 |
WISNIEWSKI; Natalie A. ; et
al. |
January 31, 2019 |
TISSUE-INTEGRATING ELECTRONIC APPARATUS
Abstract
Tissue-integrating electronic apparatuses, systems comprising
such apparatuses and methods of using these apparatuses and systems
for the detection of one or more signals are provided.
Inventors: |
WISNIEWSKI; Natalie A.; (San
Francisco, CA) ; PETERSEN; Kurt E.; (Milpitas,
CA) ; HELTON; Kristen; (Seattle, WA) ;
MCMILLAN; William A.; (La Honda, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Profusa, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Profusa, Inc.
South San Francisco
CA
|
Family ID: |
51985877 |
Appl. No.: |
16/017752 |
Filed: |
June 25, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14461144 |
Aug 15, 2014 |
10010272 |
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16017752 |
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12789048 |
May 27, 2010 |
9517023 |
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14461144 |
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13267741 |
Oct 6, 2011 |
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12789048 |
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61390252 |
Oct 6, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/0031 20130101;
A61B 5/14865 20130101; A61B 5/01 20130101; A61B 5/742 20130101;
A61B 5/1451 20130101; A61B 5/11 20130101; A61B 5/0084 20130101;
A61B 5/0215 20130101 |
International
Class: |
A61B 5/145 20060101
A61B005/145; A61B 5/1486 20060101 A61B005/1486; A61B 5/00 20060101
A61B005/00 |
Claims
1. (canceled)
2. An apparatus, comprising: a tissue-integrating scaffold; a
flexible wire woven through the tissue-integrating scaffold; and a
light source disposed within the tissue-integrating scaffold and
electrically coupled to the flexible wire.
3. The apparatus of claim 2, wherein the flexible wire is a first
flexible wire, the apparatus further comprising: a second flexible
wire woven through the tissue-integrating scaffold; and an optical
detector disposed within the tissue-integrating scaffold and
electrically coupled to the second flexible wire.
4. The apparatus of claim 2, the apparatus further comprising: a
sensing moiety disposed within the tissue-integrating scaffold, the
light source configured to excite the sensing moiety, the sensing
moiety configured to emit an optical signal associated with a
quantity or concentration of an analyte in response to being
excited by the light source.
5. The apparatus of claim 2, wherein the flexible wire is a first
flexible wire, the apparatus further comprising: a sensing moiety
disposed within the tissue-integrating scaffold, the light source
configured to excite the sensing moiety, the sensing moiety
configured to emit an optical signal associated with a quantity or
concentration of an analyte in response to being excited by the
light source; a second flexible wire woven through the
tissue-integrating scaffold; and an optical detector disposed
within the tissue-integrating scaffold and electrically coupled to
the second flexible wire, the optical detector configured to detect
the optical signal emitted from the sensing moiety.
6. The apparatus of claim 2, wherein the flexible wire is a first
flexible wire, the apparatus further comprising: a sensing moiety
disposed within the tissue-integrating scaffold, the light source
configured to excite the sensing moiety, the sensing moiety
configured to emit an optical signal associated with a quantity or
concentration of an analyte in response to being excited by the
light source; a second flexible wire woven through the
tissue-integrating scaffold; and an optical detector disposed
within the tissue-integrating scaffold and electrically coupled to
the second flexible wire, the optical detector configured to detect
the optical signal emitted from the sensing moiety, the optical
detector configured to transmit an electrical signal associated
with the quantity or concentration of the analyte via the second
flexible wire.
7. The apparatus of claim 2, wherein the tissue-integrating
scaffold is constructed of a polymeric material.
8. The apparatus of claim 2, wherein the tissue-integrating
scaffold is a fabric.
9. The apparatus of claim 2, wherein the tissue-integrating
scaffold is porous and at least two pores of the tissue-integrating
scaffold are interconnected.
10. The apparatus of claim 2, further comprising a sensing moiety
disposed within the tissue-integrating scaffold, the
tissue-integrating scaffold being porous such that the
tissue-integrating scaffold is configured to have capillaries grow
into the tissue-integrating scaffold such that the sensing moiety
is in close proximity to capillaries when the tissue-integrating
scaffold is implanted into a tissue.
11. An apparatus, comprising: a tissue-integrating scaffold; a
flexible wire woven through the tissue-integrating scaffold; and an
optical detector disposed within the tissue-integrating scaffold
and electrically coupled to the flexible wire.
12. The apparatus of claim 11, wherein the flexible wire is a first
flexible wire, the apparatus further comprising: a second flexible
wire woven through the tissue-integrating scaffold; and a light
source disposed within the tissue-integrating scaffold and
electrically coupled to the first flexible wire.
13. The apparatus of claim 11, the apparatus further comprising: a
sensing moiety disposed within the tissue-integrating scaffold and
configured to emit an optical signal associated with a quantity or
concentration of an analyte, the optical detector configured to
receive the optical signal and transmit, via the flexible wire, an
electrical signal associated with the quantity or concentration of
the analyte.
14. The apparatus of claim 11, wherein the flexible wire is a first
flexible wire, the apparatus further comprising: a second flexible
wire woven through the tissue-integrating scaffold; a light source
disposed within the tissue-integrating scaffold and electrically
coupled to the second flexible wire; and a sensing moiety disposed
within the tissue-integrating scaffold, the light source configured
to excite the sensing moiety, the sensing moiety configured to emit
an optical signal associated with a quantity or concentration of an
analyte in response to being excited by the light source, the
optical detector configured to detect the optical signal emitted
from the sensing moiety and transmit an electrical signal
associated with the quantity or concentration of the analyte via
the first flexible wire.
15. A system including the apparatus of claim 11, the system
further comprising a light source disposed 1 millimeter or less
away from the tissue-integrating scaffold, the light source
configured to emit an optical signal to excite a sensing moiety
disposed within the tissue-integrating scaffold.
16. The apparatus of claim 11, wherein the optical detector is at
least one of tissue-integrating or tissue-anchoring.
17. The apparatus of claim 11, wherein the optical detector is an
organic photodiode.
18. An apparatus, comprising: a fabric, tissue-integrating
scaffold; and an electrode disposed within the tissue-integrating
scaffold and configured to generate an electrical signal associated
with a quantity or concentration of an analyte, the electrode
including an enzyme layer and a diffusion limiting membrane
layer.
19. The apparatus of claim 18, wherein the fabric,
tissue-integrating scaffold is an e-textile.
20. The apparatus of claim 18, wherein the fabric,
tissue-integrating scaffold is constructed of at least one
polymer.
21. The apparatus of claim 18, further comprising a flexible wire
woven through the tissue-integrating scaffold, at least one of a
light source or an optical detector electrically coupled to the
flexible wire.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/461,144, entitled "Tissue-Integrating
Electronic Apparatus," filed Aug. 15, 2014, which is a
continuation-in-part of U.S. patent application Ser. No.
12/789,048, entitled "Method and System for Directing a Localized
Biological Response to an Implant," filed May 27, 2010, the
disclosure of which is hereby incorporated by reference in its
entirety. U.S. patent application Ser. No. 14/461,144 is a
continuation of U.S. patent application Ser. No. 13/267,741,
entitled "Tissue-Integrating Sensors," filed Oct. 6, 2011, which
claims priority to U.S. Provisional Application No. 61/390,252,
filed on Oct. 6, 2010, the disclosures of each of which is hereby
incorporated by reference in its entirety.
TECHNICAL FIELD
[0002] This invention relates generally to implants. More
specifically, the invention relates to methods for directing a
localized biological response of a mammalian body to an implant
disposed within the body and to an implant system for long-term
use. This invention also relates to implantable tissue-integrating
electronic apparatuses capable of detecting one or more signals
(e.g., analyte, electrical, optical, mechanical, magnetic and/or
thermal signals) in an in vivo sample.
BACKGROUND
[0003] Methods have long been sought for extending the useful life
of an implant that is inserted into the body. Not only is it
important for an implant to last long enough to justify the cost,
potential complications, and pain of implantation, but many
situations exist in which there are strong medical reasons for
maintaining the same implant within the body for an extended period
of time. For example, when the implant is a sensor, having
reliable, consistent, and continuous data from the same sensor can
improve patient care.
[0004] Studies have shown that continuous measurement of
biochemical analytes or drugs in the body significantly improves
management and treatment of acute or chronic illnesses. For
example, continuous monitoring may provide better control of
diabetes, reducing the incidence of sequelae that lead to vision
loss and impaired circulation. In trauma and congestive heart
failure patients, the levels of lactate and glucose should be
monitored simultaneously and continuously to facilitate detection
of occult bleeding and changes in shock status. Real-time
monitoring over the course of systemic administration of drugs or
chemotherapeutic agents that have narrow ranges of effective
concentration can provide the clinician with feedback upon which to
make adjustments to dosing to assure proper concentrations are
achieved and maintained.
[0005] Over a period of more than 20 years, many attempts have been
made to develop an implanted sensor that provides frequent or
continuous monitoring. For example, U.S. Pat. No. 4,703,756 to
Gough et al., filed May 6, 1986, describes a sensor module for
implantation in the body to monitor glucose and oxygen levels. When
an apparatus having a sensor (or any other foreign body) is
implanted, inflammatory and immune responses are initiated. Within
minutes, protein (primarily fibrinogen) and platelets begin to
adhere to the implant, followed over hours to days by recruitment
of inflammatory and immune cells, which then surround the sensor.
These initial tissue responses result in protein fouling of the
sensor interface and potential degradation of the sensor chemistry
by enzymes. Over the subsequent days and weeks, granulation tissue
forms as the body attempts to repair the tissue damaged by the
implantation procedure. Eventually, continued collagen production
over the following weeks to months leads to formation of an
avascular capsule surrounding the sensor and causes loss of analyte
availability to the sensor. The avascular capsule is believed to be
ultimately responsible for the majority of the drift of signal,
loss of sensor sensitivity, and the need for frequent recalibration
or even sensor replacement.
[0006] Various technologies have attempted to overcome this
problem. For example, sensors have been developed that are placed
intravascularly to avoid the problems of a capsule by allowing the
tip of the sensor to be in continuous contact with the blood.
However, placing a sensor directly into the vasculature puts the
recipient at risk for thrombophlebosis, thromboembolism, and
thrombophlebitis.
[0007] Sensors have also been developed that have physical features
designed to address the problem of the foreign body response. For
example, U.S. Pat. No. 6,212,416 to Ward et al. and U.S. Pat. No.
7,134,999 to Brauker et al. both offer architectural solutions.
Ward et al. describe a movable outer membrane that can be renewed
when it becomes fouled. Brauker et al. describe a sensor having a
geometric design intended to minimize chronic inflammatory response
at the sensing region of the sensor. However, these solutions do
not permit the device to remain fully functional for long-term use,
i.e., over a period of months or even years.
[0008] Attempts have been made to control the foreign body response
by implanting therapeutic agents, e.g., tissue response modifiers,
at the same time as the sensor. Such tissue response modifiers
attempt to mask the presence of the implant within the body and
reduce or eliminate the foreign body response. Vachon, in U.S. Pat.
No. 6,212,416 describes a biosensor comprising an accessory
material that includes a coating containing a hydrophilic material
and/or a fiber modified to deliver a therapeutic agent. In U.S.
Pat. No. 6,497,729, Moussey et al. describe a tissue/implant
interface comprising a polymer layer that contains at least one
tissue response modifier covalently attached to the polymer layer
or entrapped within the polymer layer.
[0009] Such devices are successful in directing the foreign body
response for a period of time that is limited by the amount of
therapeutic agent that can be delivered along with the sensor. The
mass of a drug or other compound necessary to consistently control
the foreign body response over a period of 2-5 years is on the
scale of hundreds to thousands of milligrams. This quantity is too
large for a one-time administration or for incorporation into a
drug reservoir feature of the sensor. Because the foreign body
response increases when the size of the implant increases,
delivering a sensor made larger by its accompanying therapeutic
agent would be counterproductive. Furthermore, even if means were
conceived to achieve a one-time delivery of a large quantity of a
therapeutic agent, no known drugs or compounds for controlling a
foreign body response are capable of remaining stable at body
temperatures of 35.degree. C. to 37.degree. C. over a period of 2-5
years.
[0010] Therefore, it would be desirable to have an improved method
for directing a localized biological response of a mammalian body
to an implant and an implant system for long-term use that
overcomes the aforementioned and other disadvantages. It would also
be desirable to have a self-contained implant with electrical
components that may be used to generate and/or measure one or more
signals (e.g., analyte, electrical, optical, mechanical, magnetic
and/or thermal signals).
[0011] Because the foreign body response increases when the size of
the implant increases, having large electrical components in an
implant can be counterproductive. A self-contained implant with,
for example, a power source may be desirable to lessen the risk of
infection from a percutaneous wire. Attempts to miniaturize
apparatuses with sensors (e.g. analyte, electrical, optical,
mechanical, magnetic and/or thermal sensors) may result in
apparatuses for which a signal is not strong enough to be
detected.
[0012] Implanted apparatuses that are larger than the cellular
phagocytic size threshold become surrounded by immune cells and/or
encapsulated and they lose their ability to accurately and rapidly
sense blood-borne analytes in an unpredictable fashion. For
implanted apparatuses that are below the phagocytic size threshold,
they become engulfed by phagocytic cells and measure intracellular
analyte levels instead of measuring analyte levels in the
interstitial fluid as intended. Intracellular analyte levels are
often irrelevant for systemic analyte monitoring, as is the case
for continuous glucose monitors. The loss of contact between
sensors and the interstitial fluid containing the analyte of
interest, or the transport barriers imposed by the foreign body
response are the primary reasons current sensing technologies
typically fail after only a short time in the body (e.g., 2-7 days
for commercially available sensors).
[0013] Thus, there remains a clear need for sensing technologies
(e.g. analyte, electrical, optical, mechanical, magnetic and/or
thermal sensing technologies) that are tissue integrating to
provide long-term (e.g., weeks, months or years) and accurate
readings by remaining in contact with interstitial fluid (not the
internal cellular environment) and remaining in close proximity to
the vasculature so that the interstitial fluid surrounding the
sensor is in constant rapid equilibrium with nearby
capillaries.
SUMMARY
[0014] Disclosed herein are tissue-integrating electronic
apparatuses, systems comprising these apparatuses and methods of
using these apparatuses and systems to generate and measure various
signals.
[0015] In an embodiment, a tissue-integrating apparatus includes a
tissue-integrating scaffold including a flexible wire and a sensor
operatively coupled to the flexible wire and integrated with the
scaffold, the sensor configured to produce a detectable signal. The
tissue-integrating apparatus as described herein may provide
long-term detection of analyte(s). The tissue-integrating apparatus
may include at least one of a light source, a detector, a
temperature sensor, an accelerometer, a pressure sensor, a magnetic
sensor, or a piezoelectronic sensor. The tissue-integrating
scaffold may include one or more polymeric materials, for example
one or more hydrogels. The apparatus may further include sensing
moieties embedded and/or attached to the exterior of the scaffold
or that form a polymeric material coated on the scaffold. In
certain embodiments, the scaffold is porous and at least two of the
pores are interconnected. In certain embodiments, the sensor
includes a plurality of perforations. Any of the apparatuses
described herein may include one or more layers (with or without
sensing moieties in one or more of the layers) and/or one or more
fibers.
[0016] In some embodiments, a tissue-integrating apparatus includes
a tissue-integrating scaffold including a flexible wire or wires
and a tissue-integrating electrode or electrodes coupled to the
flexible wire, the flexible wire being configured to conduct at
least one electrical signal (e.g., an amperometric or a
potentiometric signal) flowing through the tissue-integrating
electrode, with at least one electrical signal being associated
with an amount of an analyte. In some embodiments, the
tissue-integrating electrode is at least one of a
tissue-integrating working electrode, a tissue-integrating counter
electrode or a tissue-integrating reference electrode. In some
embodiments, the tissue-integrating electrode is one of a plurality
of tissue-integrating electrodes connected in series. In certain
embodiments, the tissue-integrating electrode is one of a plurality
of tissue-integrating electrodes connected in parallel. The
apparatus may further include at least one of a temperature sensor,
an accelerometer, a pressure sensor, a magnetic sensor and/or a
piezoelectronic sensor.
[0017] In some embodiments, a system for detecting an analyte
includes one or more tissue-integrating apparatuses as described
herein; and an implantable module that measures the signal produced
by the tissue-integrating apparatus. In some embodiments, the
system further includes one or more of the following: a power
source, electrical control circuitry, a detector, a signal
receiver, a signal transmitter, a signal processor, a data storage
component, a data transmitter, a data processor and/or a display
and/or combinations thereof. In some embodiments, the system
further includes an external device having one or more of the
following: a power source, a signal receiver, a signal processor, a
data processor, memory for storing data and/or a display.
[0018] In other embodiments, methods of making and using the
apparatuses and systems as described herein are disclosed. A method
for detecting an analyte includes integrating one or more
apparatuses as described herein into the tissue of a subject and
detecting the presence of the analyte.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a flow diagram of one embodiment of a method for
directing a localized biological response of a mammalian body to an
implant disposed within the body, in accordance with the invention,
in which the method is used to prolong the useful life of the
implant.
[0020] FIG. 2 is a flow diagram of an embodiment of a method for
directing a localized biological response of a mammalian body to an
implant disposed within the body, in accordance with the invention,
in which the method is used to facilitate removal of the
implant.
[0021] FIG. 3 is a flow diagram of a method for directing a
localized biological response of a mammalian body, in accordance
with the invention, in which the method is used to aid in preparing
the body for an implant.
[0022] FIG. 4 is an illustration of an embodiment of an implant
system for long-term use, in accordance with the invention, the
implant shown as a sensor, and the nonsurgical means for delivering
a tissue response modifier shown as a patch.
[0023] FIG. 5 is a top view of the patch of FIG. 4.
[0024] FIG. 6A illustrates a perspective view of an example of a
tissue-integrating electronic apparatus including a scaffold having
flexible wires coated with a polymeric material, according to an
embodiment.
[0025] FIG. 6B illustrates a perspective view of an example of a
tissue-integrating electronic apparatus including a scaffold having
flexible wires in a fabric or mesh, according to an embodiment.
[0026] FIG. 7A is a simplified cross-sectional view of the scaffold
of the tissue-integrating electronic apparatus shown in FIG. 6A in
which the scaffold includes flexible wires coated with a polymeric
material, according to an embodiment.
[0027] FIG. 7B is a simplified cross-sectional view of the scaffold
of the tissue-integrating electronic apparatus shown in FIG. 6B in
which the scaffold includes flexible wires in a fabric mesh coated
with a polymeric material, according to an embodiment.
[0028] FIG. 8A is a simplified cross-sectional view of an example
of a tissue-integrating electronic apparatus as shown in FIG. 6A in
which the apparatus is a tissue-integrating opto-electronic
apparatus having a scaffold coated with a polymeric material,
according to an embodiment.
[0029] FIG. 8B is a simplified cross-sectional view of an example
of a tissue-integrating electronic apparatus as shown in FIG. 6B in
which the apparatus is a tissue-integrating opto-electronic
apparatus having a scaffold coated with a polymeric material,
according to an embodiment.
[0030] FIG. 9 is a perspective view of an example of a
tissue-integrating opto-electronic apparatus in which one or more
light sources are integrated with the scaffold, according to an
embodiment.
[0031] FIGS. 10A-10D are schematics of examples of a
tissue-integrating opto-electronic apparatus, according to
embodiments. FIG. 10A illustrates a tissue-integrating
opto-electronic apparatus in which one or more light sources are
integrated with the scaffold. FIGS. 10B and 10C illustrate
tissue-integrating opto-electronic apparatuses in which one or more
light sources are proximate the scaffold. FIG. 10D illustrates a
tissue-integrating opto-electronic apparatus in which one or more
light sources are sandwiched between layers of the scaffold.
[0032] FIG. 11 is a simplified cross-sectional view (boxed area of
FIG. 6A) of an example of a tissue-integrating opto-electronic
apparatus having sensing moieties embedded within a polymeric
material of the scaffold, according to an embodiment.
[0033] FIG. 12A is a simplified cross-sectional view of an example
of a tissue-integrating electronic apparatus as shown in FIG. 6A in
which the apparatus is a tissue-integrating electrochemical sensor
having a scaffold coated with a polymeric material, according to an
embodiment.
[0034] FIG. 12B is a simplified cross-sectional view of an example
of a tissue-integrating electronic apparatus as shown in FIG. 6B in
which the apparatus is a tissue-integrating electrochemical
apparatus having a scaffold coated with a polymeric material,
according to an embodiment.
[0035] FIG. 13A is an expanded view of FIG. 12B showing an example
of a tissue-integrating electrodes formed directly on the flexible
wires of a scaffold. For clarity, the polymeric coating is omitted
from the scaffold, according to an embodiment.
[0036] FIG. 13B is a cross-sectional view of an example of an
electrode illustrated in FIG. 13A, according to an embodiment.
[0037] FIG. 14A is an expanded view of FIG. 12B showing examples of
tissue-integrating electrodes formed on a substrate, which is
mounted on a flexible wire of a scaffold, according to an
embodiment. For clarity, the polymeric coating is omitted from the
scaffold.
[0038] FIG. 14B is a cross-sectional view of an example of the
electrode illustrated in FIG. 14A.
[0039] FIG. 15 is a flow chart of a process for manufacturing a
tissue-integrating electronic apparatus in which a templating mold
is used, according to an embodiment.
[0040] FIG. 16 is a flow chart of a process for manufacturing a
tissue-integrating electronic apparatus in which dip coating is
used, according to an embodiment.
[0041] FIG. 17 is a schematic of an example of a system including
one or more tissue-integrating electronic apparatuses, an
implantable module and a non-implantable external device, according
to an embodiment.
[0042] FIGS. 18A-18B are top and cross sectional schematic views of
an example of a system having a tissue integrating opto-electronic
apparatus in which a light source is integrated with a scaffold,
according to an embodiment. The system also includes an implantable
tissue anchoring module operatively coupled to the opto-electronic
apparatus.
[0043] FIG. 19 is a schematic top view of an example of a system
having a tissue integrating opto-electronic apparatus in which a
light source is integrated with a scaffold, according to an
embodiment. The system also includes an implantable tissue
anchoring module and an external module. The implantable module is
proximate (e.g., located at a distance of about 1 millimeter or
less away from) the opto-electronic apparatus and is operatively
coupled to a flexible wire in the opto-electronic apparatus.
[0044] FIGS. 20A-20B are top and side schematic view of an example
of an opto-electronic system having a tissue integrating scaffold
sandwiched between one or more light sources and one or more
detectors, according to an embodiment. The system also includes an
implantable tissue anchoring module operatively coupled to the one
or more light sources and the one or more detectors.
[0045] The figures depict embodiments of the present invention for
purposes of illustration only. One skilled in the art will readily
recognize from the following discussion that alternative
embodiments of the structures and methods illustrated herein may be
employed without departing from the principles of the invention
described herein.
DETAILED DESCRIPTION
[0046] Described herein are tissue-integrating electronic
apparatuses and systems useful for accurate and optionally long
term measurements of analytes in vivo. The implantable apparatuses,
systems and methods described herein provide for continuous or
semi-continuous collection of data of various signals (e.g.,
analyte, electrical, optical, mechanical, magnetic and/or thermal
signals) with the use of tissue-integrating electrical
components.
[0047] In particular, the tissue-integrating electronic apparatuses
that are the subject of this invention remain in good contact
(e.g., close proximity) to blood vessels and/or collagen. The
apparatuses also have direct access to measurements of interstitial
fluid. The apparatuses include tissue-integrating components (e.g.,
a tissue-integrating scaffold) and tissue anchoring components
(e.g., electrical, optical, mechanical, magnetic and/or thermal
components). The tissue-integrating and tissue anchoring components
encourage cellular integration and increase the contact surface
area between the tissue and apparatus. The tissue-integrating
scaffold may encourage capillary growth into and/or nearby the
sensing media. The tissue anchoring components of the apparatuses
may encourage capillary and/or collagen ingrowth. Additionally the
tissue-integrating electronic apparatus may have a modulus closer
to the texture of tissue, thus enhancing the integration in the
tissue. Furthermore, the tissue anchoring components may reduce the
interfacial stresses between the tissue and apparatus and as a
result, decrease the impact of the foreign body response to the
apparatus, improving its performance.
[0048] Thus, unlike other devices, the apparatuses described herein
allow cells and/or capillaries to grow in close proximity to
regions of the apparatus (e.g., on the surface and inside), which
results in accurate analyte measurements, including over the long
term. Tissue-integrating electronic apparatuses minimize the
foreign body response and/or promote vascularization. Capillary
growth directly into and throughout regions of the apparatus allows
unencumbered access to analytes of interest in the blood (e.g.,
glucose, lactate, pyruvate, cortisol, ions, proteins, nucleic
acids, alcohols, urea, etc.). The level of tissue integration and
proximity of capillaries to regions of the apparatus provide a
close, stable relationship between the analyte concentration in the
blood and in the tissue surrounding and integrated with the
apparatus.
[0049] Advantages of the device and methods described herein
include, but are not limited to: (1) providing devices that
integrate into the subject (e.g., through tissue and/or capillary
in-growth; (2) providing devices having at least one component that
anchors or holds the systems in place to or within the tissue of
the subject; (3) providing devices that can be implanted through
syringe injection, meaning that no surgery is required to put the
sensing media in place in the body; (4) providing devices having
material(s) having properties more similar to actual tissue (e.g.,
modulus that is more similar to tissue's modulus and water content)
to allow a better integration into the tissue; (5) providing
devices that accurately assess analyte(s) for long periods of time
(e.g., greater than a week, typically weeks, months or years)
and/or (6) providing devices of small dimensions that will result
in increased patient comfort and better acceptance by the body.
[0050] As used in this specification and the appended claims, the
singular forms "a", "an", and "the" include plural referents unless
the content clearly dictates otherwise. Thus, for example,
reference to a sensor comprising "a sensing moiety" includes
devices comprising two or more sensing moieties. Likewise,
reference to "an analyte" includes two or more analytes.
Definitions
[0051] As used in the specification and claims of this application,
the following definitions should be applied:
[0052] The term "tissue-integrating" refers to material (e.g.,
scaffold) that promotes cellular ingrowth (e.g., vascularization)
that, when integrated into living tissue, remains in close
proximity with the blood vessels of the tissue (e.g., capillaries).
By "close proximity," is meant that the average distance from any
point within the material (scaffold) implanted into the tissue to
the nearest blood vessel is no greater than 100 microns more than
the average distance from any point in the native (original) tissue
to the nearest blood vessel.
[0053] The term "tissue anchoring" refers to material or feature
(e.g., sensor, perforated substrate, textured surface) that, when
integrated into living tissue, holds one or more objects in place
and restricts movement of the one or more objects relative to the
native tissue as a result of the high contact surface area and
ability of cells to infiltrate and interact with the apparatus.
Tissue anchoring may also refer to material or features that reduce
the interfacial stresses between apparatus and tissue, minimizing
the impact of the foreign body response on the performance of the
apparatus. Tissue anchoring also refers to material or features
that, when integrated into living tissue, remains in close
proximity with vasculature of the tissue. The average distance from
any point in the tissue anchoring material to vasculature ranges
from about 1 micron to about 1000 microns.
[0054] The term "conductive" refers to material that conducts or
transmits electricity or electrical signals.
[0055] The term "flexible" refers to material that is capable of
bending, stretching, compressing or twisting without breaking.
[0056] Methods for Directing a Localized Biological Response to an
Implant
[0057] One aspect of the invention is a method for directing a
localized biological response of a mammalian body to an implant
disposed within the body. FIG. 1 shows a flow diagram of one
embodiment of the method in accordance with the invention.
[0058] In some embodiments, the implant is disposed within the
mammalian body adjacent to an outside surface of the body. For
example, the implant may be disposed in one or more of the
hypodermis, the subcutis, the subcutaneous adipose fat, the dermis,
an intradermal location, a subdermal location and a muscle
location. In some embodiments, the implant is positioned such that
it is fully enclosed within the mammalian body.
[0059] The implant may be any device or material disposed in or
under the skin. For example, the implant may be a sensor (e.g.,
analyte, electrical, mechanical, and/or thermal sensor), a drug
delivery device, a pump, a chip, combinations thereof, and the
like. The implant may also be a tissue integrating apparatus having
a sensor (e.g., optical, electrical, mechanical, magnetic, and/or
thermal sensor) as will be described, for example, with reference
to FIGS. 6A-20B. Typically the mammalian body is allowed to
stabilize for an appropriate period of time following insertion of
the implant before carrying out the method. The time may be minimal
where the implant is delivered via a syringe or catheter, or as
long as several days where the implant is delivered surgically.
[0060] In some embodiments, a tissue response modifier (comprising
one or more individual modifiers) is delivered into the body in a
quantity effective to direct a localized biological response of the
body to the implant, thereby prolonging the useful life of the
implant. As used herein, the terms "direct" and "directing" denote
both reducing and increasing various aspects of the localized
biological response as well as eliminating various aspects
altogether.
[0061] In the method shown at 100, a first delivery system is
positioned outside the mammalian body adjacent to the implant
(Block 110). The first delivery system may comprise one or more of
a cream, a gel, an ointment, a sprayer, a patch, a bandage insert,
an array of microneedles, a syringe, and the like. The delivery
system may also comprise one or more of a radiation source (e.g., a
source of light, ultrasound, electricity, magnetism, heat, and/or
cooling) and a pressure source (used, for example, for
laser-induced pressure delivery).
[0062] Where the delivery system is a patch or a bandage insert,
positioning the delivery system outside the body and adjacent to
the implant involves applying the patch or bandage insert to an
outside surface of the body adjacent to the implant (e.g., to the
epidermis in the area of the body within which the implant
resides). Positioning a cream, a gel, an ointment, or another
similar preparation that delivers a tissue response modifier
transdermally (i.e., through unbroken skin) involves applying the
preparation to an outside surface of the body. Where the delivery
system is, for example, a sprayer or a syringe, positioning the
delivery system outside the body adjacent to the implant involves
placing the system in position to spray material onto the skin or
inject material into or through the skin. A radiation source or
pressure source would be placed in position to allow delivery of
the radiation or pressure to skin tissue adjacent to the
implant.
[0063] The delivery system comprises a tissue response modifier
effective for directing a localized biological response of the body
to the implant. As defined herein, the term "tissue response
modifier" denotes a substance or physical phenomenon that
increases, decreases, or eliminates one or more aspects of the
tissue response. In some embodiments, the tissue response modifier
is selected to prevent or minimize a biological response that would
impede availability of analyte to the implant or otherwise limit
the useful life of the implant, or to increase a biological
response that would prolong the useful life of the implant.
[0064] The tissue response modifier may comprise, for example, one
or more of a collagen inhibitor, an anti-fibrotic agent, an
angiogenic agent, a vasculogenic agent, a pro-vascular dilation
agent, an immunosuppressive agent, an anti-proliferative agent, an
anti-migratory agent, an anti-inflammatory agent, a vasodilator, an
anti-histamine, an anti-protein-fouling agent, a synthetic
molecule, a biologically produced molecule, a permeation enhancer,
a gene therapy agent, a stem cell, a mammalian cell, a drug, and
the like. The tissue response modifier may also comprise visible
light, other wavelengths of light, ultrasound, heat, an electrical
pulse, a magnetic field, a magnetic pulse, and combinations
thereof.
[0065] Specific examples of tissue response modifiers include
aspirin, imatinib, celecoxib, rofecoxib, etoricoxib, transforming
growth factor .beta.3, interleukin 10, mannose-6-phosphate,
cortisone, prednisone, dexamethasone, ibuprofen, cromolyn sodium,
halofuginone hydrobromide, tranilast, perfenidone, D-penicillamine,
1-butyryl-glycerol, adenosine, methrotrexate, mycophenolate
mofetil, tacrolimus, paclitaxel, rapamycin, doxorubicin,
azathioprene, losartan potassium, mitomycin C, diclofenac,
dexamethasone, ketoprofane, prostscylin, nifedipine, loratadine,
nedocromil, detergents, tissue necrosis factors and/or their
inhibitors, platelet derived growth factor, portions of these
molecules, sense or anti-sense molecules, and combinations thereof.
The above lists are not intended to be exhaustive; additional,
unnamed tissue response modifiers are anticipated to be effective
in the claimed methods.
[0066] The tissue response modifier is delivered from the delivery
system into the body in a quantity effective to direct the
localized biological response of the body to the implant (Block
120). The tissue response modifier may be delivered transdermally
(through unbroken skin) and/or may be injected into the body
through skin tissue adjacent to the implant.
[0067] For example, the delivery system may be a patch that
includes a tissue response modifier that diffuses into the body
through the epidermis and onto and/or around the implant.
Alternatively or additionally, the patch may include an array of
microneedles, with the tissue response modifier injected by the
microneedles into skin tissue adjacent to the implant. The tissue
response modifier may also be delivered transdermally via a cream,
gel, ointment or sprayer or may be injected into the area of the
implant using a hypodermic needle, a catheter, or another injection
device, taking care to avoid the implant.
[0068] The tissue response modifier is not delivered from the
delivery system surgically, i.e., it is not delivered via an
incision, nor is the material contained in the delivery system
delivered along with the implant at the same time the implant is
inserted into the body. In the present method, the tissue response
modifier is delivered separately from and later than the
implant.
[0069] The tissue response modifier is delivered at a low level
(e.g., at a low dosage) because the tissue response modifier is not
intended to reach systemic levels but is intended to reach adequate
local levels to direct the biological response of the localized
tissue of the body to the implant. The tissue response modifier is
supplied in a quantity effective to direct the tissue architecture,
vascularity, collagen content, protein deposition, cellular
activity, and/or other tissue characteristics at the tissue-implant
interface and up to several centimeters away from the implant. This
quantity is low compared to the typically delivered system doses.
For example, aspirin, an anti-inflammatory and anti-platelet
molecule working by means of cycloxygenase inhibition, is typically
delivered systemically at a therapeutic level of 325 mg aspirin/80
kg body weight. Local delivery doses of aspirin to the region of a
typically sized electrochemical sensor implant would be
approximately 1,000 to 10,000 times less in dosage than
systemically delivered doses administered to achieve the same local
concentrations.
[0070] Delivery of the tissue response modifier may be aided by
processes such as electroporation, iontophoresis, sonophoresis,
laser-induced pressure, delivery of permeation enhancers, and the
like. The delivery system may include, in addition to the tissue
response modifier, a material effective to target delivery of the
tissue response modifier to a specific location within the body
and/or to modulate uptake of the tissue response modifier by the
body. For example, cell-specific adhesion molecules or other
specific adhesion molecules (e.g., to target adhesion to collagen
or proteoglycans in the interstitial space) may be included along
with the tissue response modifier to achieve targeted delivery of
the tissue response modifier to a specific location such as the
dermis or subcutis. The material may modulate uptake into the
bloodstream, into specific cell types, into specific structures
(e.g., collagen bundles) and/or into or through the epidermis,
dermis, and or subcutaneous.
[0071] In addition to materials or functions related to delivery of
the tissue response modifier, the delivery system may also include
components related to activities of the implant. For example, where
the implant is a device (e.g., a sensor or a pump), the delivery
system may include one or more components such as an actuator,
illuminator, a detector, a signal receiver, a signal transmitter,
an energy storage component, a data storage component, and the
like.
[0072] In some embodiments, in which the localized biological
response of the body to the implant is being directed to prolong
the useful life of the implant, typically a second (third, fourth,
etc.) delivery system is utilized. Before the tissue response
modifier provided by the first delivery system loses its
effectiveness, the second delivery system is positioned outside the
body and adjacent to the implant (Block 140), and the second tissue
response modifier is delivered from the second delivery system into
the body (Block 150). The second delivery system may include the
same or a different tissue response modifier (comprising one or
more individual modifiers) effective for directing the localized
biological response of the body to the implant. The second tissue
response modifier, like the first, is delivered nonsurgically.
[0073] The first delivery system may be removed (Block 130) prior
to positioning the second delivery system. For example, where the
delivery system comprises a patch, the first patch would be removed
prior to positioning a second patch. Where the first delivery
system is a topical preparation such as a cream, the cream need not
be washed off before a second tissue response modifier is
delivered. Typically a second delivery system will comprise the
same tissue response modifier as the first system, but an advantage
of delivering the tissue response modifier from outside the body is
that the tissue response modifier and/or its mode of delivery can
be changed or combined with another tissue response modifier and/or
mode of delivery to optimally direct the body's response to the
implant.
[0074] FIG. 2 shows a flow diagram of an embodiment of a method for
directing a localized biological response of a mammalian body to an
implant disposed within the body, in accordance with the invention.
In some embodiments, a tissue response modifier is delivered into
the body in a quantity effective to direct a localized biological
response of the body to the implant to aid in preparing the body
and/or the implant for removal of the implant.
[0075] In the method shown at 200, a first delivery system,
comprising a first tissue response modifier effective for directing
a localized biological response of the body to the implant, is
positioned outside the mammalian body adjacent to the implant
(Block 210). The first delivery system may be as described above
for method 100, with the tissue response modifier selected for
facilitating removal of the implant.
[0076] The tissue response modifier is delivered from the first
delivery system into the body in a quantity effective to direct the
localized biological response of the body to the implant (Block
220). Delivery of the tissue response modifier may be carried out
as described above for method 100. Some embodiments will find
particular utility where the localized biological response of the
body to the implant has not been directed during the tenure of the
implant within the body as described above and illustrated at 100.
For example, the tissue response modifier in some embodiments may
be a drug or other treatment intended to reduce vascularization in
the area of the implant to reduce bleeding during its removal. It
may also be a drug or other treatment effective to reduce collagen
buildup surrounding the implant to limit the amount of tissue that
will be removed along with the implant.
[0077] At some time after the tissue response modifier has been
delivered from the first delivery system into the body, the implant
is removed from the body (Block 230), typically by surgical means
(i.e., an incision is made in the body, and the implant is removed
through the incision). It is anticipated that a second (third,
fourth, etc.) delivery system may be used as needed prior to
removal of the implant.
[0078] FIG. 3 shows a flow diagram of one embodiment of a method
for directing a localized biological response of a mammalian body
to an implant, in accordance with the invention, in which the
method is used to aid in preparing the mammalian body for insertion
of an implant.
[0079] In the method shown at 300, a first delivery system,
comprising a first tissue response modifier effective for directing
a localized biological response of the body to the implant, is
positioned outside the mammalian body adjacent to a location within
the body identified for receiving the implant (Block 310). The
first delivery system may be as described above for method 100.
[0080] The tissue response modifier is delivered from the delivery
system into the body in a quantity effective to direct the
localized biological response of the body to the implant (Block
320). Delivery of the tissue response modifier is nonsurgical and
may be carried out as described above for method 100.
[0081] The delivery system is removed (Block 330) as needed, and
the implant is positioned at the location within the body
identified for receiving the implant (Block 340). By delivering a
tissue response modifier into the body in advance of the implant, a
localized biological response of the body to the implant may be
directed to minimize or avoid an undesirable response of the body
to the implant or to initiate or enhance a desired response.
[0082] A material that attracts and/or contains the tissue response
modifier may be implanted within the body adjacent to the implant,
and the tissue response modifier may then be delivered into the
implanted material. In the case of a tissue response modifier
delivered transdermally or using microneedles, the tissue response
modifier would diffuse into and pool within the implanted material.
In the case of a tissue response modifier injected using a
hypodermic needle or a catheter, the tissue response modifier could
be injected directly into the implanted material. The implanted
material serves as a reservoir for the tissue response modifier,
allowing it to be released into the area of the implant over
time.
[0083] Implant Systems Having a Tissue Response Modifier
[0084] An embodiment of an implant system, in accordance with the
invention, is illustrated in FIG. 4, which shows a cross-section
view of an implant 410 disposed within the body and nonsurgical
delivery means 420 disposed outside the body for delivering a
tissue response modifier 422 through the epidermis 432 of the body.
Tissue response modifier 422 is effective for directing a localized
biological response of the body to the implant.
[0085] Implant 410 may be any device or material suitable for
insertion within a mammalian body. It is desirable that implant 410
be small enough so that tissue displacement and acute inflammation
resulting from its implantation is minimized. Implant 410 may be
designed to be left in the body after its operational life is over
and may include a feature or features designed to maintain location
and directionality of the implant. Implant 410 is shown in FIG. 4
disposed in the dermis 434, but one of ordinary skill in the art
will appreciate that alternative locations within the body are
possible, (e.g., the implant may be disposed in one or more of the
hypodermis, the subcutis, the subcutaneous adipose fat, the dermis,
an intradermal location, and a subdermal location.)
[0086] Implant 410 may be, for example, a sensor (e.g., analyte,
electrical, mechanical, and/or thermal sensor), a drug delivery
device, a pump, a chip, and combinations thereof. Implant 410 may
also be, for example, a tissue-integrating electronic apparatus
having a sensor as will be described with reference to FIGS.
6A-20B.
[0087] Some embodiments, implant 410 is a glucose sensor comprising
a glucose-binding substance. The sensing material is suspended in,
contained within, attached to, or otherwise mixed with a hydrogel
containing anti-inflammatory drugs or other tissue response
modifying drugs. An appropriate amount of this mixture is implanted
in the body by hypodermic needle or by microneedle patches that
deliver the mixture into the dermis. During the healing process
(e.g., over the next 3-7 days), the biosorbable hydrogel dissolves
and is absorbed by the body, leaving the sensing material in place
in the dermis or subcutis.
[0088] Nonsurgical delivery device 420 for delivering a tissue
response modifier through the epidermis of the mammalian body may
be, for example a cream, a gel, an ointment, a sprayer, a patch, a
bandage insert, an array of microneedles, a syringe, combinations
thereof, and the like. The nonsurgical delivery means may also
comprise one or more of a radiation source (e.g., a source of
light, electricity, magnetism, heat, cooling) and a pressure source
(used, for example, for laser-induced pressure delivery).
[0089] Some embodiments, the nonsurgical delivery device is a patch
420, illustrated in side view in FIG. 4 and in top view in FIG. 5.
Like reference numbers are used in the drawings to refer to like
elements. Patch 420 includes tissue response modifier 422 disposed
in a treatment portion 424 of the patch. Patch 420 also includes a
backing portion 426 that provides support for treatment portion
424.
[0090] Tissue response modifier 422 may be a single modifier or a
combination of modifiers. Tissue response modifier 422 may
comprise, for example, a collagen inhibitor, an anti-fibrotic
agent, an angiogenic agent, a vasculogenic agent, a pro-vascular
dilation agent, an immunosuppressive agent, an anti-proliferative
agent, an anti-migratory agent, an anti-inflammatory agent, a
vasodilator, an anti-histamine, an anti-protein-fouling agent, a
metabolic depressor, a synthetic molecule, a biologically produced
molecule, a permeation enhancer, a gene therapy agent, a stem cell,
a mammalian cell, a drug, and combinations thereof. The tissue
response modifier may also comprise light, heat, an electrical
pulse, a magnetic field, a magnetic pulse, and combinations
thereof.
[0091] Specific examples of tissue response modifiers include
aspirin, imatinib, celecoxib, rofecoxib, etoricoxib, transforming
growth factor .beta.3, interleukin 10, mannose-6-phosphate,
cortisone, prednisone, dexamethasone, ibuprofen, cromolyn sodium,
halofuginone hydrobromide, tranilast, perfenidone, D-penicillamine,
1-butyryl-glycerol, adenosine, methrotrexate, mycophenolate
mofetil, tacrolimus, paclitaxel, rapamycin, doxorubicin,
azathioprene, losartan potassium, mitomycin C, diclofenac,
dexamethasone, ketoprofane, prostscylin, nifedipine, loratadine,
nedocromil, detergents, tissue necrosis factors and/or their
inhibitors, platelet derived growth factor, portions of these
molecules, sense or anti-sense molecules, and combinations thereof.
The above lists are not intended to be exhaustive; additional,
unnamed tissue response modifiers are anticipated to be effective
in the system.
[0092] The delivery device may also include a material effective to
target delivery of the agent to a specific location within the body
or to modulate uptake of the therapeutic agent by the body. The
delivery device may further include a component that is related to
or interacts with the implant. For example, the delivery device may
include an actuator, an illuminator, a detector, a signal receiver,
a signal transmitter, an energy storage component, a data storage
component, and combinations thereof.
[0093] Some embodiments, patch 420 includes six illuminators 425
and two detectors 427, which together make up an interrogator that
is capable of transmitting an interrogating signal to sensor 410
and receiving a sensor signal response. One skilled in the art will
appreciate that the precise number of illuminators and detectors is
not material to the practice of the invention.
[0094] Where interrogation of sensor 410 is optical, for example,
illuminators 425 may include an LED (light emitting diode) or laser
diode or other light source, and detectors 427 may include filtered
p/n diodes that detect the transmitted or reflected light
(absorbance spectroscopy) or emissions (fluorescence). The LED may
be a filtered micro-LED in the NIR (near-infrared) region. Such
LEDs efficiently illuminate through the skin. In the glucose sensor
described above, the glucose-binding chemistry fluoresces at a
different wavelength or absorbs a specific NIR region proportional
to the amount of glucose bound to the sensing media. The
fluorescent light or absorbed NIR light transmits back through the
skin and is detected by the filtered p/n diodes arrayed in the
patch.
[0095] In some embodiments, the interrogator may comprise a voltage
source (as the illuminator) for providing a source signal; an
antenna operable with the sensor for transmitting a source signal
to the sensor and receiving a signal therefrom; first and second
frequency filters (as the detector) operable with the voltage
source for receiving the source signal therefrom and providing
first and second reference signals; first and second multipliers
receiving the interrogation signal and the first and second
reference signals, respectively, for providing first and second
product signals therefrom; and first and second integrators for
receiving the first and second product signals and providing
signals indicative of pressure at the sensor. The interrogator may
further comprise third and fourth multipliers that receive a
delayed interrogation signal and the first and second reference
signals and provide third and fourth product signals therefrom, and
third and fourth integrators for receiving the third and fourth
product signals, respectively, and providing signals indicative of
temperature at the sensor.
[0096] In some embodiments, (e.g., as illustrated in FIGS. 4 and
5), illuminators 425 and detectors 427 are integral elements of
patch 420. In some embodiment, one portion of the interrogator may
be included in the delivery device, while the other portion is
implanted separately from but adjacent to the sensor. For example,
the detector may be associated with the patch, and the illuminator
portion may be implanted adjacent to the sensor; however, the
positions may be reversed, with the detector adjacent to the sensor
and the illuminator associated with the patch. Alternatively,
neither the illuminator nor the detector may be associated with the
patch. The invention admits variation in the configuration of the
components.
[0097] A controller, not shown, may also be associated with patch
420. The controller receives signals from the interrogator,
performs signal analysis, and calculates the analyte
concentration.
[0098] Patch 420 may include an array of microneedles or tissue
response modifier-eluting channels. Alternatively, patch 420 may
comprise a transdermal delivery preparation such as a cream, a gel,
or an ointment that includes tissue response modifier 422. As noted
above, microneedles and transdermal delivery preparations may also
serve as stand-alone delivery means.
[0099] Patch 420 is intended to be disposable. It includes
sufficient tissue response modifier to last for a specified
application period. Once the tissue response modifier is depleted,
the user is alerted via instructions or an included signal to
change the patch. Multiple patches may be required to achieve
long-term use of the implant.
[0100] Implants Having Tissue-Integrating Electronic
Apparatuses
[0101] Referring to FIG. 6A-14B, tissue-integrating electronic
apparatuses (e.g., tissue-integrating opto-electronic apparatuses
500 and 600 and tissue-integrating electrochemical apparatuses 800
and 900) for detecting one or more analytes are illustrated
according to embodiments of the invention. In the embodiments, the
apparatuses are implanted in a mammalian body and are used to
detect at least one analyte concentration from an in vivo sample
(e.g., tissue).
[0102] The tissue-integrating electronic apparatuses include a
tissue-integrating scaffold 502. In some embodiments, illustrated,
for example, in FIG. 7A, the tissue-integrating scaffold 502
includes one or more flexible wires 504 embedded in or surrounded
by a polymeric material 506. In another exemplary embodiment shown
in FIG. 7B, the tissue-integrating scaffold 502 includes one or
more layers of a conductive fabric or mesh material having one or
more flexible wires 504 (or conductive threads) woven throughout
the fabric. The conductive fabric (or e-textile) may be coated with
the polymeric material 506. E-textiles, also known as electronic
textiles, smart textiles, or smart fabrics, are fabrics that enable
digital components (including small computers), and electronics to
be embedded in them. Many intelligent clothing, smart clothing,
wearable technology, and wearable computing projects involve the
use of e-textiles.
[0103] The flexible wires 504 (see e.g., FIGS. 7A-9, 12A and 12B)
are conductive and operatively couple or connect a sensor embedded
in the scaffold 502 to a power source and/or control circuitry. The
flexible wires 504 include coils, bends or angles such that the
wires may stretch and twist with movement of the implanted
apparatuses within the tissue of a subject. The flexible wires 504
also prevent breakage of the connection between the sensor and the
power supply as well as the electrical control circuit. The
diameter of each of the flexible wires 504 is typically about 1
nanometer to about 1 micrometer
[0104] The flexible wires 504 may be formed of one or more
conductive materials including, but not limited to, Au, Pd, Pt, Ag,
Cu, Al, aluminum alloys, Ni, Zn, carbon, titanium, Cr, W, doped
amorphous or polycrystalline silicon, Mo, Ta, carbon, conductive
polymers, aligned tissue, and combinations thereof. Exemplary
conductive polymers include polyacetylene, polypyrrole, polyaniline
and copolymers thereof. Other examples of conductive polymers
include poly(p-phenylene vinylene) and its soluble derivatives.
Examples of aligned tissue (e.g., "biowires") include neurons or
heart cells that conduct electricity and that are grown on suture
material. Exemplary suture materials on which to grow cells include
plain catgut, chromic catgut, polyglycolide and/or
polydioxanone.
[0105] In embodiments in which the scaffold 502 is a conductive
fabric, the conductive fabric may include a non-conductive or less
conductive material such as, but not limited to, cotton, polyester,
nylon, stainless steel, aramids,
poly(p-phenylene-2,6-benzobisoxazole) and combinations thereof.
[0106] The tissue-integrating scaffold 502 may be constructed with
materials and/or micro-architecture such that the scaffold 502
promotes tissue-integration and/or vascularization, as described in
U.S. patent application Ser. No. 13/267,741 which is incorporated
herein by reference in its entirety. For example, scaffolds 502
with one or more pores 505 (e.g., shown as voids in FIGS. 7A- 9,
12A and 12B) provide tissue biomaterial anchoring and promote
in-growth throughout the pores 505. The resulting "hallway" or
"channel" pattern of tissue growth are healthy, space-filling
masses that persist over time and promote host cell integration. In
certain embodiments, the pore diameter may be from about 1 micron
to about 1000 microns. Most or all of the pores 505 of the
biomaterials described herein are preferably interconnected
(co-continuous). The co-continuous pore structure of the
biomaterials promotes space-filling in-growth of cells in the
implant, which in turn limits the foreign body response and leads
to long-term (greater than one week and up to years) persistence of
the implant's ability to act as a sensor. The pores 505 may be
uniform and/or irregular in shape. The pores 505 may be any shape,
including spherical, cubic, polyhedral, ellipsoidal and/or
cylindrical.
[0107] Alternative structures that provide tissue-integrating
scaffolds include fibers (e.g., 1 to 10 or more microns in
diameter, such as 5, 6, 7, 8, 9, 10 or more microns), which may be
arranged in non-random or random configuration. The polymeric
material 506 of the tissue-integrating scaffolds (in any
configuration) can also be formed by multiphoton polymerization
techniques. Kaehr et al. (2008) Proc. Nat'l. Acad. Sci. USA
105(26): 8850-8854; Nielson et al. (2009) Small 1:120-125;
Kasprzak, Doctoral Dissertation, Georgia Institute of Technology,
May 2009.
[0108] The polymeric material 506 may be composed of multiple
materials, such as an insulating polymer coating the wires and/or a
biocompatible polymer coating that forms the body contacting
surface of all the wires. In some embodiments, the polymeric
material 506 of the tissue-integrating scaffold 502 may include any
material, including but not limited to conductive polymers,
synthetic polymers, naturally occurring substances, or mixtures
thereof. Examples of conductive polymers include, but are not
limited to, polyacetylene, polypyrrole, polyaniline and copolymers
thereof. Other examples of conductive polymers include
poly(p-phenylene vinylene) and its soluble derivatives. Examples of
synthetic polymers include, but are not limited to, polyethylene
glycol (PEG), 2-hydroxyethyl methacrylate (HEMA), silicone rubber,
poly([epsilon]-caprolactone) dimethylacrylate, polysulfone,
(poly)methy methacrylate (PMMA), soluble Teflon-AF, (poly)
ethylenetetrapthalate (PET, Dacron), Nylon, polyvinyl alcohol,
polyacrylamide, polyurethane, and mixtures thereof. Examples of
naturally-occurring materials include, but are not limited to,
fibrous or globular proteins, complex carbohydrates,
glycosaminoglycans, extracellular matrix, or mixtures thereof.
Thus, the polymer material of the scaffold 502 may include
collagens of all types, elastin, hyaluronic acid, alginic acid,
desmin, versican, matricelluar proteins such as SPARC
(osteonectin), osteopontin, thrombospondin 1 and 2, fibrin,
fibronectin, vitronectin, albumin, chitosan etc. Natural polymers
may be used as the scaffold or as an additive.
[0109] In some embodiments, the polymeric material 506 of the
tissue-integrating scaffold 502 comprises a hydrogel. For example,
the polymeric material 506 may comprise a hydrogel, for example by
reacting hydroxyethyl methacrylate (HEMA), poly (hydroxyethyl
methacrylate), pHEMA. Furthermore, various comonomers can be used
in combination to alter the hydrophilicity, mechanical and swelling
properties of the hydrogel (e.g. PEG, NVP, MAA). Non-limiting
examples of polymers include 2-Hydroxyethyl methacrylate,
polyacrylamide, N-vinylpyrrolidone, N,N-Dimethylacrylamide,
poly(ethylene glycol) monomethacrylate (of varying molecular
weights), diethylene glycol methacrylate,
N-(2-hydroxypropyl)methacrylamide, glycerol monomethacrylate,
2,3-dihydroxypropyl methacrylate and combinations thereof.
Non-limiting examples of cross-linkers include tetraethylene glycol
dimethacrylate, poly(ethylene glycol) (n) diacrylate (of varying
molecular weights), ethoxylated trimethylolpropane triacrylate,
bisacrylamide and combinations thereof. Non-limiting examples of
initiators include irgacure Series (UV), Azobisisobutyronitrile
(AIBN) (thermal), Ammonium Persulfate (APS) (thermal).
[0110] The polymeric material 506 may be a sphere-templated
hydrogel, for instance an inverse colloid crystal, for example as
described in U.S. Pat. No. 7,972,628 to Ratner, et al. or other
tissue-integrating materials.
[0111] The polymeric material 506 may be degradable, either by the
body (biodegradable) or by the application of an external initiator
to start or speed up the degradation process (e.g. UV, ultrasonics,
radio frequency, or other exogenous sources to initiate
degradation.). For example, the polymeric material 506 may include
any biodegradable or bioresorbable polymers, including but not
limited to degradable forms of alginates, poly(lactic acid),
poly(vinyl alcohol), polyanhydrides, poly(glycolic acid),
microporous polyesters, microporous polyethers and cross-linked
collagen. One specific example is UV-photopolymerization of
poly(ethylene glycol)-diacrylate and acrylated protease-degradable
peptides and VEGF as described by Phelps, et al (2010) Proc. Nat'l.
Acad. Sci. USA 107(8):3323-3328.
[0112] Other specific examples are polymers described by Kloxin et
al. (2009) Science 324:59-63 and U.S. Pat. No. 6,013,122 whose
degradation is controlled through exposure to exogenous energy
forms as well as Alexeev et al. (2003) Anal. Chem. 75:2316-2323;
Badylak et al. (2008) Seminars in Immunology 20:109-116; Bridges et
al. (2010) 94(1):252-258; Isenhath et al. (2007) Research
83A:915-922; Marshall et al. (2004) Polymer Preprints, American
Chemical Society, Division of Polymer Chemistry 45:100-101; Phelps
et al. (2010) Proc Nat'l Acad Sci USA. 107(8):3323-8; Ostendorf and
Chichkov (2006) Two Photon Polymerization: A New Approach to
MicroMachining, Photonics Spectra; Ozdemir et al. (2005)
Experimental and Clinical Research, Plast. Reconstr. Surg. 115:183;
U.S. Patent Publication No. 20080075752; Sanders et al. (2003)
Journal of Biomedical Materials Research Part A 67A(4):1181-1187;
Sanders et al. (2002) Journal of Biomedical Materials Research
62(2):222-227; Sanders et al. (2003) Journal of Biomedical
Materials Research 65(4):462-467; Sanders et al. (2005)
Biomaterials 26:813-818; Sanders et al. (2005) Journal of
Biomedical Materials Research Part A 72(3):335-342; Sanders (2003)
Journal of Biomedical Materials Research 67(4):1412-1416; Sanders
et al. (2000) Journal of Biomedical Materials Research
52(1):231-237; and Young Min Ju et al. (2008) J Biomed Mater Res
87A:136-146.
[0113] In certain embodiments, the tissue-integrating scaffold 502
of the invention is constructed such that tissue response modifiers
are released from the polymeric material 506 to promote or enhance
tissue-integration and vascularization.
[0114] In addition, the tissue-integrating scaffold 502 of the
invention may be constructed such that it has conduits, pores or
pockets that are hollow or filled with degradable, angiogenic, or
other substances (e.g. stem cells). As noted above, once in the
body, the biodegradation of the material filling the conduits,
pores or pockets, creates space for tissue, including capillaries
to integrate with the material. The degradable material that
initially fills the conduits, pores or pockets may enhance vessel
growth or tissue growth within the scaffold. This architecture
promotes new vessel formation and maintains healthy viable tissue
within and around the implant.
[0115] The tissue-integrating scaffold 502 of the invention may be
constructed such that it is permeable to analytes of interest
(e.g., glucose can diffuse into a tissue-integrating conductive
hydrogel scaffold and reach the sensing moieties that are embedded
within the hydrogel matrix).
[0116] In some embodiments, the tissue integrating apparatuses
include one or more sensors such as, but not limited to, a light
source 508, a detector 510, a temperature sensor 511, a pressure
sensor 512, an accelerometer 513, a piezoelectric sensor, an
electrochemical sensor (i.e., an electrode) and combinations
thereof. The sensors may be sized such that they are tissue
integrating or tissue anchoring. In some embodiments, the tissue
integrating sensors are about 10 to 100 microns in at least one
dimension. In other embodiments, the tissue anchoring sensors are
about 100 microns or more in at least one dimension.
[0117] In some embodiments, the tissue anchoring sensors include a
plurality of holes or perforations to promote collagen and tissue
in-growth. The plurality of holes or perforations typically are at
least 1 micron in one dimension. In certain embodiments, the tissue
anchoring sensors include a porous coating of polymeric material
506 as described previously. In some embodiments, the tissue
anchoring sensors include a textured coating with one or more
projections that promote collagen and tissue in-growth. Textured
coatings may be formed with biocompatible polymeric materials 506
as described previously. In some embodiments, the tissue anchoring
sensors include pillars formed from silicon rubber. In some
embodiments, Velcro-like or velour-like coatings formed from PET
(Dacron). In some embodiments, the tissue anchoring sensors include
a textured or roughened surface formed by laser and/or chemical
etching of the sensor surfaces that are in contact with tissue. In
some embodiments, a mold with texturizing features is used during a
molding process of the sensor housing or substrate to introduce one
or more textured surfaces to the sensor.
[0118] The sensor may be of such a size that the sensor partially
or totally fills one or more pores 505 within the
tissue-integrating scaffold 502. In some embodiments, the sensor is
the same size as or at least 1.5 times larger than the diameter of
a pore within the tissue-integrating scaffold 502.
[0119] Examples of temperature sensors include, but are not limited
to, one or more CMOS-based microchip temperature sensors,
thermocouples, thermistors or combinations thereof. Temperature
sensors may be used to correct an analyte concentration measured
from an in vivo sample.
[0120] A. Tissue-Integrating Opto-Electronic Apparatuses
[0121] Referring to FIGS. 8A-12B, various views of embodiments of
tissue-integrating opto-electronic apparatuses 500 and 600 are
illustrated. FIG. 8A illustrates a tissue-integrating
opto-electronic apparatus 500 in which the scaffold 502 includes
one or more conductive flexible wires 504 embedded in a polymeric
material 506 as described. FIG. 8B illustrates a tissue-integrating
opto-electronic apparatus 600 in which the scaffold 502 includes
one or more conductive flexible wires 504 woven throughout a fabric
or mesh material, all of which is coated with a polymeric material
506 as described. In addition to the tissue-integrating scaffold
502, the tissue-integrating opto-electronic apparatuses 500 and 600
include a plurality of tissue-integrating sensors (i.e., at least
one light source 508 and at least one detector 510) and one or more
sensing moieties 514 (shown in FIG. 10). The light source 508 emits
light and the one or more sensing moieties 514 produce a detectable
signal in the presence of the analyte.
[0122] The light source 508 emits light in the near infrared
wavelength range of 600 nanometers to 900 nanometers. In some
embodiments, e.g., as illustrated in FIGS. 8A, 8B and 3, the
tissue-integrating light source 508 is integrated with the
tissue-integrating scaffold 502 such that the light emitted from
the light source 508 is efficiently transferred to the one or more
sensing moieties 514. In some embodiments, e.g., as illustrated in
FIGS. 10A, 18A and 18B, the tissue-integrating light source 508 may
be embedded in or surrounded by the tissue-integrating scaffold 502
having one or more sensing moieties 514. In some embodiments, e.g.,
as illustrated in FIGS. 10B and 19, the light source 508 is
adjacent to (e.g., located at a distance of about 100 microns or
less away from) the tissue-integrating scaffold 502 having one or
more sensing moieties 514. In some embodiments, e.g., as
illustrated in 10C, 20A and 20B, the light source 508 is proximate
(e.g., located at a distance of about 1 millimeter or less away
from) the tissue-integrating scaffold 502 having one or more
sensing moieties 514. In some embodiments, e.g., as shown in FIG.
10D, the light source 508 is sandwiched between layers of the
tissue-integrating scaffold 502.
[0123] In some embodiments, the light source 508 is one or more
light emitting diodes (LEDs), e.g., a multi-wavelength LED array.
In some embodiments, the light sources 508 are one or more micro
LEDs. In an embodiment in which the light sources 508 are one or
more micro LEDs, each micro LED is about 0.1 micrometers to about 6
micrometers in size. Typical materials from which the micro LEDs
are formed may include, but are not limited to, indium
arsenide-based nanocrystals, gallium nitride, indium gallium
arsenide, gallium arsenide, aluminum gallium arsenide, gallium
arsenide phosphide, aluminum gallium indium phosphide, gallium(III)
phosphide, organic polymers such as poly (9-vinylcarbazole) (PVK)
doped with an electron-transport material (e.g.,
2-(4-biphenylyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole) and a
near-IR-emitting molecule (e.g.,
2-(6-(p-dimethylaminophenyl)-2,4-neopentylene-1,3,5-hexatrienyl)-3-ethylb-
enzothiazolium perchlorate), and combinations thereof.
[0124] The light source 508 may be connected in series or in
parallel by the one or more conductive flexible wires 504 to a
power source and/or a control circuit.
[0125] Referring to FIG. 11, a cross sectional view the polymeric
material 506 of the tissue-integrating scaffolds 502 is illustrated
(e.g., boxed area of FIG. 8A). The polymeric material 506 described
herein can be combined with (or made up of) one or more sensing
moieties 514 that produce a detectable signal in the presence of
one or more analytes, as described in the aforementioned U.S.
patent application Ser. No. 13/267,741 which is incorporated herein
by reference in its entirety.
[0126] Non-limiting examples of analytes that may be detected by an
apparatus having the sensing moieties 514 include oxygen, reactive
oxygen species, glucose, lactate, pyruvate, cortisol, creatinine,
urea, sodium, magnesium, calcium, potassium, vasopressin, hormones
(e.g., Luteinizing hormone), pH, cytokines, chemokines,
eicosanoids, insulin, leptins, small molecule drugs, ethanol,
myoglobin, nucleic acids (RNAs, DNAs), fragments, polypeptides,
single amino acids and the like.
[0127] Any suitable moiety can be used to sense the analyte of
interest, including but not limited to analyte binding molecules
(e.g. glucose binding proteins), competitive binding molecules
(e.g. phenylboronic acid based chemistries), analyte specific
enzymes (e.g. glucose oxidase), ion sensitive materials, or other
analyte sensitive molecules (e.g. oxygen sensitive dyes such as
porphyrins). The sensing moieties 514 may be in any form, for
example, microspheres, nanospheres, fibers, etc. A single implant
(tissue-integrating scaffold) typically includes a plurality of
sensing moieties 514. In certain embodiments, the sensing moieties
514 are all the same while in other embodiments, a mixture of two
or more sensing moieties is used.
[0128] To enhance or create a detectable signal, sensing molecules
may be labeled with a reporter (e.g., one or more fluorophores, one
or more gold particles, one or more quantum dots and/or one or more
single-walled carbon nanotubes). Sensing molecules may also create
a signal through swelling, optical diffraction, change in
absorbance FRET, quenching.
[0129] Non-limiting examples of suitable sensing molecules include
but are not limited to dye labeled Concanavalin A with
glycodendrimer or dextran (see, e.g., Ballerstedt et al. (1997)
Anal. Chim. Acta 345:203-212) and alcohol sensitive
oxo-bacteriochlorin derivative fluorescent binding protein
developed by Takano, et al (2010) The Analyst 135:2334-2339 as well
as Vladimir et al. (2004) Clinical Chemistry 50:2353-2360; Aslan et
al. (2005) Chem. 1; 77(7):2007-14; Ballerstadt et al. (1997) Anal.
Chim. Acta 345:203-212 (1997); Billingsley et al. (2010) Anal. Chem
82(9):3707-3713; Brasuel et al. (2001) Anal. Chem 73(10):2221-2228;
Brasuel, et al. (2003) The Analyst 128(10):1262-1267; Horgan et al.
(2006) Biosensors and Bioelectronics 211838-1845; Ibey et al.
(2005) Anal Chem 77:7039-7046; Nielsen et al. (2009) Journal of
Diabetes Science and Technology 3(1):98-109; McShane et al. (2000)
IEEE Engineering in Medicine and Biology Magazine 19:36-45;
Mansouri & Schultz (1984) Bio/Technology 23:885-890; Rounds, et
al. (2007) Journal of Fluorescence 17(1):57-63; Russell et al.
(1999) Analytical Chemistry 71(15):3126-3132; Schultz et al. (1982)
Diabetes Care 5:245-253; Srivastava, & McShane (2005) Journal
of Microencapsulation 22(4):397-411; Srivastava et al. (2005)
Biotechnology and Bioengineering 91(1):124-131; Takano et al.
(2010) The Analyst 135:2334-2339.
[0130] The sensing moiety 514 may comprise other molecules besides
sensing molecules, such as carrier molecules/polymers (e.g. the
sensing moiety element may comprise PEG nanospheres, alginate
particles or other carrier materials that contain sensing
molecules). The sensing moiety 514 may also contain one or more
reference molecules 516 or stabilizing molecules that do not sense
any analytes, but that serves as calibrators or stabilizers.
Examples of calibrators include, but are not limited to, a
reference dye or any substance that provides a stable reference
signal (e.g., optical, magnetic, electrochemical, electrical,
temperature, pressure, ultrasound, acoustic, radiation) to which
the signal modulated by the analyte of interest may be compared for
calibration. Examples of stabilizers include, but are not limited
to, catalayse and/or any free-radical scavenger, which helps
preserve the sensing moieties or other stabilizer.
[0131] The sensing moiety 514 may be thermally responsive material,
pressure-responsive material or materials that swell, shrink,
change optical properties, or change other measurable properties in
response to a stimulus.
[0132] The analyte sensing moieties 514 may be combined with the
polymeric material 506 of the tissue-integrating scaffolds 502 in a
variety of ways to produce tissue-integrating opto-electronic
apparatuses 500 and 600. In some embodiments, the sensing moieties
514 are physically entrapped or chemically bound within the
scaffold 502. In other embodiments, the sensing moieties 514 are
attached directly (e.g., via covalent or noncovalent linkages) to
the surface of the tissue-integrating scaffold 502 and may
optionally be covered by an exterior coating. The purpose of the
exterior coating is, for example, to hold the sensing moieties in
place, to protect the sensing moieties from external forces, to
limit/impede diffusion of various molecules and/or to provide a
desired exterior surface, and to transduce the sensing signal from
the chemistry to the scaffold and/or external detector.
[0133] In some embodiments the tissue-integrating scaffold 502
itself is composed of sensing moieties where the sensing moieties
are in the form of particles (spherical or other shapes) that are
bonded together (e.g. chemically, thermally, pressure, etc.) or
where the polymer itself provides the sensing capability (e.g.
stimuli-sensitive polymers).
[0134] In some embodiments, the tissue-integrating scaffold 502 is
composed of distinct layers where sensing moieties 514 are
physically entrapped or chemically bound to or within specific
layers of the scaffold 502, and other layers provide other features
such as mechanical strength, elasticity, conductivity or other
properties.
[0135] In some embodiments, the tissue-integrating scaffold 502 is
composed of a polymer that swells or shrinks in response to a
stimulus (e.g. concentration of an analyte of interest,
temperature, or other stimuli). The shrinking or swelling may cause
optical change (e.g. due to light diffraction, change in distances
between gold nanoparticles contained within the matrix, or other
interaction (Aleexev et al and Aslan, et al)).
[0136] Table 1 below provides a matrix showing how sensing moieties
can be combined with tissue-integrating scaffolds in a variety of
ways to tissue-integrating sensing media.
TABLE-US-00001 TABLE 1 Sensing Media/Scaffold Matrix Sensing
Moieties Sensing particles (e.g. PEG microspheres Sensing chemistry
containing ConA (e.g. boronic acid with based chemistry, Any other
glycodendrimer, sensing chemistry fluorescent sensing Stimuli
responsive Tissue- alginate nanospheres attached to quantum assay
(e.g. glucose moieties integrating containing ApoGox dots or gold
nano- oxidase with (temperature, Scaffolds with reported dye.)
rods) porphyrin dye) pressure, other) Permeable Polymerization (SM
Polymerization (SM Polymerization (SM Polymerization (SM
Biomaterial contained within mesh of contained within mesh of
contained within mesh of contained within mesh of Scaffold (e.g.
scaffold polymer) scaffold polymer) scaffold polymer) scaffold
polymer) hydrogel ICC) Immobilization Immobilization Immobilization
Immobilization (Kotov, (conjugation or physical (conjugation or
physical (conjugation or physical (conjugation or physical
Marshall) entrapment) of SM on entrapment) of SM on entrapment) of
SM on entrapment) of SM on Non-Permeable surface surface surface
surface Scaffold (ICC) Making scaffold of sensing Making scaffold
of sensing Making scaffold of sensing Making scaffold of (e.g.
Porex, moiety moiety moiety sensing moiety MedPor) Immobilization
of SM on Immobilization of SM on Immobilization of SM on
Immobilization of SM on Naturally surface surface Surface surface
derived Physical entrapment of SM Physical entrapment of SM
Physical entrapment of SM Physical entrapment of SM scaffolds (e.g.
on surface on surface on surface on surface fibrin, BSA, SM
contained within mesh SM contained within mesh SM contained within
mesh SM contained within mesh collagen of naturally derived matrix
naturally derived matrix) of naturally derived matrix) of naturally
derived matrix synthetic or Immobilization of SM on Immobilization
of SM on Immobilization of SM on Immobilization of SM on
decellularized surface surface surface surface ECM (sECM), Physical
entrapment of SM Physical entrapment of Physical entrapment of SM
Physical entrapment of SM Prestwich, on surface SM on surface on
surface on surface Badylak, Polymerization (SM Polymerization (SM
Polymerization (SM Polymerization (SM Taylor, Small trapped IN
fiber matrix) trapped IN fiber matrix) trapped IN fiber matrix)
trapped IN fiber matrix) fibers (Sanders) Immobilization
Immobilization Immobilization Immobilization (conjugation or
physical (conjugation or physical (conjugation or physical
(conjugation or physical entrapment) of SM on entrapment) of SM on
entrapment) of SM on entrapment) of SM on surface surface surface
surface Making scaffold of sensing Making scaffold of sensing
Making scaffold of sensing Making scaffold of moiety moiety moiety
sensing moiety Multi-layer fibers (e.g. Multi-layer fibers (e.g.
Multi-layer fibers (e.g. Multi-layer fibers (e.g. sensing layer,
sensing layer, sensing layer, sensing layer, biocompatibility
layer, biocompatibility layer, biocompatibility layer,
biocompatibility layer, stabilizing or structural stabilizing or
structural stabilizing or structural stabilizing or structural
layer, voids or cellular layer, voids or cellular layer, voids or
cellular layer, voids or cellular conduits conduits conduits
conduits
[0137] In some embodiments, the apparatuses 500 and 600 further
comprise additional moieties (e.g., non-sensing or additional
sensing moieties different from the sensing moieties), for example
reference (or calibration) moieties 516 (see FIG. 11). Reference or
calibration moieties 516 include, but are not limited to, dyes,
fluorescent particles, lanthanides, nanoparticles, microspheres,
quantum dots or other additives or elements of the implant whose
signal does not change due to the presences of the analyte (e.g.,
glucose). See, e.g., Chaudhary et al. (2009) Biotechnology and
Bioengineering 104(6):1075-1085. Fluctuations in the reference
(calibration) signal(s) can be used to correct or calibrate the
sensing signal(s). Reference signals might fluctuate due to changes
in the amount of light reaching the implant (ambient light changes,
fluctuating LED or laser source). Sensing signals would also be
subject to fluctuations in the amount of light reaching the
implant; however it is desirable that the signal of interest only
fluctuates based on analyte (e.g., glucose) fluctuations. Therefore
the reference signal is used to correct or calibrate the sensing
signal when it fluctuates due to influences other than changes in
glucose concentration. Reference signals might also fluctuate due
to changes in the reference moiety itself (e.g. photodegradation,
chemical degradation). The sensing signal(s) would have the same
degradation or a rate of degradation that is relatable to the
reference to allow for correction or calibration by the reference.
Reference signals might also fluctuate due to physiological
fluctuations that alter the light propagation through tissue (e.g.
dehydration, oxygenation, blood flow). Sensing signals would be
affected in the same way or in a way that is relatable to the
reference fluctuations thereby permitting correction or calibration
of the sensing signal by the one or more references. Thus, the
sensing signal can be calibrated by reference to the signal(s)
obtained from the calibration (reference) moieties.
[0138] In some embodiments, the sensing moieties 514 produce a
detectable signal in the presence of glucose and the reference
moiety comprises a molecule that measures (produces a detectable
signal in the presence of) oxygen (O.sub.2). As noted above, the
sensing moieties can include an enzyme, for example glucose
oxidase, which is specific for the substrate glucose. The reaction
of glucose oxidase causes the substrate glucose to be converted to
D-glucono-1,5-lactone, which then hydrolyzes to gluconic acid.
Oxygen is consumed and converted to H.sub.2O.sub.2. The reduction
of O.sub.2 in the vicinity of the enzyme can be measured by using
an O.sub.2-sensitive fluorescent dye, such as a porphyrin dye.
These dye molecules are quenched in the presence of O.sub.2, so the
reduction of O.sub.2 by the action of GOx, causes an increase in
fluorescence. The amount of fluorescence emitted from the O.sub.2
calibration moieties is thus proportional to the concentration of
glucose in the sensor.
[0139] The concentration of O.sub.2 in the tissue can also vary
physiologically, thereby changing or limiting the reaction of the
enzyme in the sensing moieties. Therefore, the O.sub.2
concentration in the sensor can be measured independent of the
glucose concentration. Such a reference measurement of O.sub.2
would allow corrections to be made to the glucose-specific signal
from the sensing moieties.
[0140] In some embodiments, an analyte-specific enzyme that causes
a change in pH would require the use of a separate pH-sensitive
fluorescent dye with an emission spectral peak different and
distinguishable from the analyte-specific dye reporting on the
activity of the analyte-specific enzyme, for example when the
sensing moieties comprise, urease used for measuring urea.
[0141] In other embodiments, the sensing moieties 514 comprise a
first fluorescent dye and the reference molecule 516 comprises a
second (different) fluorescent dye. As noted above, the sensing
moieties may utilize an analyte-specific chemistry that includes a
ligand receptor moiety and an analyte analogue moiety. One of the
binding members is labeled with a fluorescent dye and the other
binding member is labeled with a dye that quenches the fluorescent
dye when the analyte analogue moiety binds to the ligand receptor
moiety. Non-limiting examples include glycodendrimer, which binds
to Concanavalin A, wherein the Concanavalin A is labeled with
Alexafluor 647 and the glycodendrimer is labeled with QDY21 dark
quencher. Concanavalin A binds to glucose and the glycodendrimer
competes with glucose for the binding to Concanavalin A. The
chemistry is immobilized as described in this invention within the
tissue-integrating scaffold 502 and implanted into the dermis or
subcutaneous tissue. To measure glucose in the tissue, the
tissue-integrating scaffold 502 is illuminated from a patch reader
on top of the skin above the implant with 650 nm light at desired
intervals over the long-term life of the implant (e.g., every 5-60
minutes over a period of 90 days or more). The amount of
fluorescent signal (e.g., from a molecule such as Alexafluor 647)
detected is proportional to the concentration of glucose in the
tissue. However, over the long-term life of the implants described
herein, the dye can photobleach, i.e., the amount of fluorescent
signal emitted back through the skin at a given glucose
concentration is diminished. Thus, a reduction of fluorescence due
to photobleaching can make it appear that analyte is at a lower
concentration than it really is.
[0142] To correct for this effect, a separate internal
photobleaching control is employed. In certain embodiments, the
separate internal control is a second fluorescent dye, different
from the fluorescent molecule included in the sensing moieties
(e.g., Alexafluor 750 in the reference moieties when the sensing
moieties comprise Alexafluor 647), which included immobilized in
the scaffold 502. The fluorescence of reference moieties is not
affected by the concentration of glucose, and both the first (e.g.,
Alexafluor 647) and second (e.g., Alexafluor 750) fluorescent dyes
have predictable and well-characterized photobleaching rates. To
control for the photobleaching of the dye of the sensing moieties,
the fluorescence is measured for both dyes. The fluorescence value
of the dye in the reference moieties can then be used to correct
for any photobleaching of the dye in the sensing moieties.
[0143] In some embodiments, internal reference control materials
can be employed that facilitate correcting for tissue optical
variation. The electronic tissue-integrating implanted biosensor
typically resides 3-4 mm under the surface of the scan. It is well
known that in skin excitation light and emitted fluorescent light
in the near infrared range are highly scattered as the light
traverses the tissue between the reader patch and the implant. The
extent of absorption and scattering is affected by physical
properties such as temperature or by tissue composition, including
but not limited to variations in blood perfusion, hydration, and
melanin concentration. Skin variations can occur between users or
between different time points for a single patient, and these
variations can affect the fluorescence excitation and emissions
signals causing in accurate signals for the analyte-specific
signal. Accordingly, a separate fluorescence molecule with emission
spectra distinguishable from the analyte-specific fluorescence can
be immobilized into the scaffold 502. The fluorescence from the
molecule can be measured separately from the analyte-specific
fluorescence to measure a signal that informs about variations in
tissue composition. The dye selected is based on having a similar
response to tissue variations as the analyte-specific dye. Dyes
such as Alexafluor 750, various quantum dots (QD's), or lanthanide
dye nanocrystals all can provide this capability.
[0144] Referring again to FIGS. 8A, 8B, 19, 20A and 20B, the
detector 510 of the tissue-integrating opto-electronic apparatuses
500-600 and 1100-1300 is configured to receive at least one
detectable signal from the sensing moieties 514 and to output an
electrical signal in response to the received signal.
[0145] In the embodiments illustrated in FIGS. 8A and 8B, the
detector 510 is tissue integrating (i.e., is about 500 nanometers
to about 100 microns in size) and is embedded within (or surrounded
by) the tissue-integrating scaffold 502. In an embodiment, the
detector 510 is one or more organic photodiodes. In an embodiment,
the one or more organic photodiodes includes a near-IR absorbing
layer formed from octabutoxy tin naphthalocyanine dichloride
(OSnNcCl2).
[0146] Unlike the embodiments shown in FIGS. 8A and 8B in which the
implantable apparatus 500/600 includes a detector 510,
opto-electronic apparatuses 700 and 1100 shown in FIGS. 9, 18A and
18B include a detector 510 located in an external device 520 (shown
in FIG. 17).
[0147] In other embodiments of an opto-electronic apparatus 1200
illustrated in FIG. 19, one or more detectors 510 are proximate
(e.g., located at a distance of about 1 millimeter or less away
from) the tissue-integrating scaffold 502 and are associated with
an implantable module 518. The detectors 510 are located such that
they do not promote the foreign body response at a surface of the
tissue-integrating scaffold 502. The location at which the detector
510 is placed can be chosen such that detection of one or more
signals from the sensing moieties 514 is optimized and such that
detection of light from the tissue-integrating light source 508 is
minimized. In an opto-electronic apparatus 1300 illustrated in
FIGS. 20A and 20B, the tissue-integrating scaffold 502 with sensing
moieties 514 is sandwiched between one or more light sources 508
and one or more detectors 510. In this embodiment, the light
sources 508 and the detectors 510 are proximate the
tissue-integrating scaffold 502.
[0148] The detectors 510 illustrated in FIGS. 19-20B are sized such
that one dimension is at least 500 nanometers (i.e., they may be
tissue integrating or tissue anchoring, depending on the size). In
some embodiments, the one or more detectors 510 are organic
photodiodes. In some embodiments, the detector 510 is a
multi-wavelength photodiode array having about a 50 micrometer to 2
millimeter square photosensitive area. Typical materials from which
the photodiodes are formed include but are not limited to Si,
InGaAS and combinations thereof. In some embodiments, the one or
more detectors 510 are a CCD image sensor.
[0149] The detector 510 may include one or more filters to filter
out stray light and/or light from the light source 508. The
detectors 510 may be connected in series or in parallel by flexible
wires 504 to a power source and/or electrical component control
circuitry, as will be described.
[0150] B. Tissue-Integrating Electrochemical Apparatuses
[0151] Referring to FIGS. 12A and 12B, cross sectional views of
embodiments of tissue-integrating electrochemical apparatuses 800
and 900 are illustrated. FIG. 12A illustrates a tissue-integrating
electrochemical apparatus 800 in which the scaffold 502 includes
one or more flexible wires 504 embedded in a polymeric material 506
as described. FIG. 12B illustrates a tissue-integrating
electrochemical apparatus 900 in which the scaffold 502 includes
one or more flexible wires 504 woven throughout a fabric (e.g.,
e-textile) or mesh material all of which is coated with a polymeric
material 506 as described. In addition to the tissue-integrating
scaffold 502, the tissue-integrating electrochemical apparatuses
800 and 900 include one or more tissue-integrating electrodes
(e.g., one or more working electrodes 830 and one or more
reference/counter electrodes 832).
[0152] An expanded view of a portion of the electrochemical
apparatus shown in FIG. 12B is illustrated in FIG. 13A. As
illustrated in FIG. 13A, at least one tissue-integrating electrode
(e.g. at least one working electrode 830 and at least one
reference/counter electrode 832) is formed as a discrete patch on
one or more flexible wires 504. The flexible wire 504 serves as a
conductive layer 806 onto which one or more other layers are
coated. In an embodiment, each tissue-integrating electrode may
also include one or more of an inner selective membrane layer 808,
an enzyme layer 810 and an outer diffusion limiting membrane layer
812, as illustrated in FIG. 13B (cross-sectional view of a working
electrode 830 shown in FIG. 13A).
[0153] Another expanded view of a portion of the electrochemical
apparatus shown in FIG. 12B is illustrated in FIG. 14A. As
illustrated in FIG. 14A, the flexible wire 504 is used as a support
for multiple electrodes and to connect the electrodes to a voltage
source (e.g., a potentiostat). The electrodes can be formed in a
separate process and are then mounted onto the scaffold. Each
electrode may include a substrate 805 onto which the conductive
layer 806, the inner selective membrane layer 808, the enzyme layer
810 and the outer diffusion limiting membrane layer 812 are
disposed, as illustrated in FIG. 14B (cross-sectional view a
working electrode 830 shown in FIG. 14A).
[0154] Processes used to form the layers directly on the flexible
wire 504 include dip coating, spray-coating, vapor deposition,
electro-deposition, etching and/or ink printing. Exemplary
processes used to form the layers on the substrate 805 include
spray-coating, vapor deposition, electro-deposition, etching and/or
ink printing. In embodiments of the electrochemical sensor having a
substrate 805, the substrate 805 may be formed from a planar sheet
of material such as, but not limited to, polyimide and/or
polyethylene tetraphthalate (PET).
[0155] The conductive layer 806 for forming electrodes may be used
for the electrochemical measurement of an analyte (e.g., glucose).
In an embodiment, one electrode is formed in the conductive layer
806. In another embodiment, more than one electrode (e.g., one or
more working, reference and/or counter electrodes) may be formed in
the conductive layer 806. The conductive layer 806 may also include
one or more conductive tracks electrically coupled to one or more
contact pads that connect each electrode to a voltage source by,
for example, spot welding each contact pad to a flexible wire 504.
Examples of materials from which the conductive layer 806 may be
formed include Au, Pd, Pt, Ag, Cu, Al, Ni, Zn, carbon, iridium
and/or titanium. In embodiments, the conductive layer 806 may be
100 nanometers or less in thickness.
[0156] The inner selective membrane layer 808 substantially
restricts, resists, or blocks one or more interferents from
reaching the electrochemically reactive surface of the
electrochemical sensor. The interferents may be reduced or
oxidized, resulting in a false positive analyte signal. Thus, the
inner selective membrane layer 808 allows the analyte of interest
to reach the electrode surface while being less permeable to the
one or more interferents. In an embodiment in which the sensor
detects glucose, typical interferents include acetaminophen,
ascorbic acid, bilirubin, cholesterol, creatinine, dopamine,
ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,
tetracycline, tolazamide, tolbutamide, triglycerides, and uric
acid. Examples of materials from which the inner selective membrane
layer 808 may be formed include cellulose acetate, cellulose
acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetate
phthalate, cellulose acetate proprionate and/or cellulose acetate
trimellitate. In embodiments, the inner selective membrane layer
may have a thickness of about 0.05 microns to about 20 microns.
[0157] The enzyme layer 810 includes at least one enzyme to
catalyze the reaction of the analyte and the enzyme cofactor. In an
embodiment in which glucose is the analyte of interest, glucose
oxidase is included in the enzyme layer 810. In other embodiments,
pyruvate oxidase, alcohol dehydrogenase, lactate dehydrogenase,
lactate oxidase, ethanol oxidase, pyruvate oxidase, bilirubin
oxidase, histamine oxidase, glucose dehydrogenase or any
combination of oxidases and/or dehydrogenases may be included in
the enzyme layer. Other additives necessary to functional operation
of the sensor may also be included in the enzyme layer including,
but not limited to, buffer for maintaining a pH, cofactors and
oxygen enhancing substances such as silicone or fluorocarbon. In
embodiments, the enzyme layer may have a thickness of about 0.05
microns to about 20 microns.
[0158] The outer diffusion limiting membrane layer 812 controls the
flux of oxygen and analyte to the enzyme layer such that oxygen is
in non-rate-limiting excess. Inclusion of the outer diffusion
limiting membrane layer 812 extends the upper limit of the linear
range of the analyte measurement. In embodiments, the outer
diffusion limiting membrane layer 812 may be formed from silicone
polymer and/or hydrophobic-hydrophilic polymer blends including,
but not limited to, components such as polyvinylpyrrolidone (PVP),
polyhydroxyethyl methacrylate, polyvinyl alcohol, polyacrylic acid,
polyethers such as polyethylene glycol or polypropylene oxide, and
copolymers thereof, including, for example, di-block, tri-block,
alternating, random, comb, star, dendritic, and graft copolymers.
In embodiments, the outer diffusion limiting membrane layer 812 may
have a thickness of about 0.05 microns to about 20 microns.
[0159] The one or more tissue-integrating electrodes may be
electrically connected in series or in parallel to a voltage source
in an implantable module 518 by one or more flexible wires 504, as
will be described with reference to FIG. 17.
[0160] It will be apparent that the overall dimensions of the
implantable electronic apparatuses 500-800 will vary according to
the subject and/or the analyte(s) or properties to be measured.
Typically, the implant will be between about 0.001 mm to 2 mm in
thickness (or any value there between) and between 1 mm and 1 cm in
diameter (or an equivalent cross sectional area of a non-circular
shape, for example length/width) and 15 mm in length or less, for
example a disk shaped sensor that is 2 mm or less thick and 10 mm
or less in diameter. In certain embodiments, the approximate sensor
size in injectable form is approximately 100-1000 microns in
diameter and the length is between 0.25 mm and 10 mm. The size of
the tissue-integrating sensing media in disk form is typically 2 mm
or less thick and 10 mm or less in diameter.
[0161] The electronic apparatuses 500-900 may be any suitable form
including, but not limited to block-like (or any thickness),
cube-like, disk-shaped, cylindrical, oval, round, random or
non-random configurations of fibers and the like.
[0162] The injected apparatus may be a single piece of
tissue-integrating material, or it may be several pieces or
particles of tissue-integrating sensing material. The apparatus may
be injected with a carrier substance (e.g. saline, PBS with
anti-inflammatory drugs or other tissue-response modifiers).
Furthermore, the apparatus may be implanted into any part of the
subject, including, for example, shoulder, arm, leg, abdomen, etc.
The apparatus may be implanted into the skin, for example, the
epidermis, the dermis and/or the subcutaneous layer of skin. The
apparatus may also be implanted into muscle and/or organs.
[0163] Methods of Making Tissue Integrating Apparatuses
[0164] Some embodiments include a method for making
tissue-integrating electronic apparatuses. The method for forming
tissue-integrating electronic apparatuses comprises a process for
combining the scaffold 502 and the other elements of the sensor in
a manner that preserves the integrity of the signal (e.g., optical
or electrochemical) measured in response to the analyte of
interest.
[0165] In some embodiments, the methods of the invention involve a
tissue-integrating electronic apparatus that has a scaffold formed
by combining flexible wires having integrated electronic components
(e.g., one or more LEDs, detectors, electrodes, temperature
sensors, accelerometers and/or pressure sensors) with polymeric
material. For tissue-integrating opto-electronic apparatuses,
sensing moieties are embedded or contained within the polymeric
material of the tissue-integrating scaffold 502. For
tissue-integrating electrochemical apparatuses, sensing moieties
are typically not included in the polymeric material of the
scaffold.
[0166] Referring to FIG. 15, the process of manufacturing a
tissue-integrating electronic apparatus may begin with combining
strings or meshes of flexible wires having integrated electronic
components with a polymer precursor (e.g. monomer, polymer beads,
etc.), followed by the formation of the scaffold (e.g.
polymerization around template beads, multiphoton polymerization,
electro spinning, micro- and nano-printing fabrication techniques,
polymer foaming, salt leaching, etc.) and the removal of any
residuals (e.g. dissolution of template beads, removal of
unpolymerized monomers, etc.). In an embodiment in which a
tissue-integrating opto-electronic apparatus is formed, sensing
moieties may be included in the step at which the flexible wires
are combined with the polymer precursor. In an embodiment in which
a tissue-integrating electrochemical sensor is formed, sensing
moieties may be omitted in the step at which the flexible wires are
combined with the polymer precursor.
[0167] Referring to FIG. 16, in other embodiments, the process of
manufacturing a tissue-integrating electronic apparatus may begin
with dipping or coating e-fabric or meshes of flexible wires having
integrated electronic components in a polymer precursor (e.g.
monomer) with or without sensing moieties, followed by crosslinking
of the polymeric material and removal of any unpolymerized
monomers.
[0168] In embodiments having sensing moieties, it will be apparent
that the relative amounts of polymeric material, sensing moieties
and/or reference moieties in the apparatuses will depend on the
polymers and sensing moieties used. For example, in certain
embodiments, the sensor will be made with between about 2-95%
vol/vol of a monomer or polymer (e.g., 2-85% vol/vol HEMA).
Likewise, when present, the amount of cross-linker used will depend
on the polymer, for example typically about 0.1 and 10% vol/vol of
TEGDMA may be used. Water and or other solvents may be present in
any amount (e.g., 5-95% vol/vol water or polyethylene glycol).
Initiators may also present in any amount, for example 0.35 to 5%
vol/vol of Irgacure. Sensing moieties may be present in any
suitable amount, for example, oxygen sensing porphyrins (PdP) may
be included at a concentration of about 200 nM to 1 nM.
[0169] In embodiments having sensing moieties, non-limiting
exemplary methods for embedding or containing the sensing moieties
within the polymeric material of the tissue-integrating scaffold
include (but are not limited to): polymerization around template
beads with or without subsequent dissolution, matrix or other
structure, polymerization of a three-dimensional structure using
multiphoton polymerization or 3D printing, electrospinning of small
fibers, sintering or melting scaffold precursor structures, or
swelling the polymeric material to permit entry of sensing moieties
followed by shrinking of scaffold. In certain embodiments, the
method comprises polymerizing glucose sensing moieties
(nanospheres) into an inverted crystal colloid (ICC) polymeric
material.
[0170] In other embodiments having sensing moieties, the sensing
moieties are immobilized (conjugated or physically entrapped) on
(or to) the surface of the tissue-integrating scaffold. The process
begins with an existing scaffold or the forming of a scaffold,
followed by the attachment of the sensing moieties to the scaffold.
The method may also include a coating step that protects or holds
in place (e.g. physical entrapment) the sensing moieties to the
scaffold. The coating may have the added benefit(s) of (1)
protecting the surface chemistry from degradation (e.g. proteases);
(2) a diffusion barrier (surface fouling); (3) improving the
biocompatibility (e.g. PEG, chitosan, pHEMA, etc.); (4) altering or
improving the surface characteristics (e.g. smoothness, pore size,
hydrophilicity, etc.). Exemplary methods for immobilizing the
sensing moieties on the tissue-integrating scaffold include, but
are not limited to: conjugation chemistry, adsorption,
electrostatics and covering with a continuous coating. Exemplary
coatings include PEG, pHEMA and chitosan.
[0171] In some embodiments, the apparatus is formed by constructing
simple or multi-layer fiber(s) implants. The polymeric material
(with or without sensing moieties) is part of one or more of the
base materials from which the fiber scaffold is created or the
polymeric material is contained in or comprises one of the layers
of sequential building up of layers. Some example processes for
producing such multi-layer fibers and/or for creating the layers of
polymeric material on top of already formed fibers are extrusion,
electrospinning, dip coating, spray forming, printing, stamping,
rolling, multiphoton polymerization and plasma deposition.
[0172] In some embodiments, the apparatus is formed by 3D printing
of conductive or non-conductive polymer in sequential layers along
with flexible wires to form an electronic apparatus of the desired
shape and size. In these embodiments, one or more sensors may be
placed in one or more layers of the apparatus manually or
automatically by a pick-and-place (or robotic) machine.
[0173] In forming any of the apparatuses as described herein, the
methods may also include step(s) for the sterilization of the
apparatus prior to implantation (e.g. ethylene oxide gas) or in
vitro use.
[0174] Tissue Integrating Electronic Systems
[0175] Referring to FIGS. 17-20B, systems for detecting one or more
analytes are illustrated according to exemplary embodiments of the
invention. In an embodiment, the system is used to continuously or
semi-continuously detect at least one analyte concentration from an
in vivo sample (e.g., tissue). The system may, for example, be
implanted subcutaneously at a depth of about 1 to 5 mm below the
surface of the skin.
[0176] The systems 1000-1300 include one or more tissue-integrating
apparatuses operably connected to the implantable (tissue
integrating or tissue anchoring) module 518 by the one or more
flexible wires 504. The wires may be bonded to the implantable
module 518 by, for example, a wire bonding process using heat,
pressure, ultrasonic energy, metal deposition in a vacuum, ink-jet
type printing, and/or micro-plasma printing. As shown in FIG. 17,
the flexible wires 504 may be coated with polymeric material 506.
The systems 1000-1300 may further include an external device
520.
[0177] The implantable module 518 includes a power source 522 that
powers the sensor and control circuitry 524 (e.g., an
application-specific integrated circuit or ASIC) that controls the
electronic components of the one or more sensors. In embodiments,
the power source 522 includes a battery, inductor, a photovoltaic
cell, or the like, as is appreciated by one skilled in the art. In
embodiments having tissue-integrating electrochemical apparatuses
700 and/or 800, in addition to the power source 522, the
implantable module 518 includes a potentiostat that is operably
connected to and applies one or more test voltages to the one or
more tissue-integrating electrodes such that one or more electrical
signals (e.g., test current or voltage) may be measured from the
sensor.
[0178] The implantable module 518 may also include a power storage
component, a signal processor, a signal transmitter, a data
transmitter and/or a data processor.
[0179] The implantable module 518 may include one or more
components or features that are tissue integrating and/or tissue
anchoring. In embodiments, the power source 522 and control
circuitry 524 are formed on a substrate 526 (e.g., a printed
circuit board). The substrate 526 may be tissue anchoring and may
include a plurality of perforations 528 or holes to promote
collagen and/or tissue in-growth. The substrate 526 or may be
partially (see FIG. 18A) or completely covered in the plurality of
perforations. The plurality of perforations 528 typically are at
least 1 micron in one dimension. The plurality of perforations may
be formed in the substrate 526 during manufacture of the substrate
(e.g., through photolithography) or may be added to the substrate
after manufacture by using a laser to punch holes in the substrate.
In certain embodiments, the tissue anchoring substrate 526 includes
a porous coating of polymeric material 506 as described previously.
In other embodiments, the tissue anchoring substrate 526 includes a
textured coating or surface as described previously.
[0180] Exemplary substrate materials include polyester (e.g.,
Mylar), plastic, fiberglass, polyimide, PEEK, transparent
conductive polyester, or combinations thereof. Exemplary processes
for forming the substrate include photolithography, silk screening,
milling, ink-jet printing and/or various 3-D printing
technologies.
[0181] The external device 520 may include a signal receiver, a
signal transmitter, a signal processor, a power source, a data
processor, a memory for storing data and/or an optional display for
displaying data. In an embodiment in which a tissue-integrating
opto-electronic apparatus includes one or more light sources and no
detector, the external device 520 may also include one or more
detectors. The external device 520 may be a wearable patch that
resides over the sensor to detect the signal or may be a hand held
or other device that is periodically held over the implanted sensor
to take the measurement.
[0182] Referring to FIGS. 17-20B, in operation of a system having a
tissue-integrating opto-electronic apparatus, the one or more light
sources 508 are activated to transmit light to the sensing moieties
514 within the apparatus. The sensing moieties 514 absorb light
from the light sources 508 and emit light (e.g., fluorescent light)
in a manner dependent on the concentration of the analyte of
interest. The emitted light is detected by the one or more
detectors 510 located in the apparatus or in the external device
520. The light detected by the one or more detectors 510 is then
converted into a digitized signal that is processed by a
microprocessor located in the implantable module 518 or in the
external device 520. The digitized signal may be stored in memory
and/or be used to calculate an analyte concentration, which may
then be displayed on a display in the external device 520. The
analyte concentration may optionally be wirelessly transmitted to
and displayed on a remote device such as a cell phone, a smart
phone, a smart watch, a personal data assistant and/or a
computer.
[0183] Referring to FIG. 17, in operation of a system having a
tissue-integrating electrochemical sensor 800 or 900, one or more
test voltages are applied to the one or more electrodes in the
sensor 800/900. Current is generated at the one or more electrodes
in a manner dependent on the concentration of the analyte of
interest. The generated current is converted into a digitized
signal that is processed by a microprocessor located in the
implantable module 518 or in the external device 520. The digitized
signal may be stored in memory and/or be used to calculate an
analyte concentration, which may then be displayed on a display in
the external device 520. The analyte concentration may optionally
be wirelessly transmitted to and displayed on a remote device such
as a cell phone, a smart phone, a smart watch, a personal data
assistant and/or a computer.
EXAMPLES
[0184] The following examples serve to illustrate, but not to
limit, the present invention.
Example 1
[0185] Skin Preparation
[0186] Sensing Media Insertion
[0187] Post-Healing Patch
[0188] Sensor Maintenance Patch Assembly
[0189] Explant Patch
[0190] A 0.75 cm.times.2 cm rectangular skin preparation patch
containing 300-750 .mu.m of betamethasone, 3.5 mg/gm neomycin base,
10,000 polymyxin B units/gm, and 0.5% hydrocortisone acetate 5 mg
(0.5%) is placed on the skin over the site of implantation, where
it adheres to the skin by an adhesive covering the bottom surface
of the patch. The drugs are contained in a section of the adhesive,
and drug diffuses during the next 12-24 hours through the skin. The
skin preparation patch also has a 1- to 2-mm hole near one edge
that is used to guide the implantation process. The analyte sensing
media, such as a 0.5 mm.times.10 mm rod-shaped pHEMA hydrogel
implant containing analyte sensing chemicals, such as concanavalin
A and dextran, or a phenylboronic-derivatized hydrogel backbone, or
other reversible ligand-binding analyte pair, is inserted by
syringe using the guide hole into the dermis or subcutis 0.5-5.0 mm
below the surface. The skin preparation patch is removed, and the
skin is cleansed. A 1.5- to 3-cm circular topical drug
post-insertion healing patch containing 25 mg of 1% wt/vol of
sildenafil or other nitric oxide synthase inhibitor, 10 mg of
2.5%-25% of L-arginine, and/or 2.5 mg of estradiol, is placed on
the skin over the site of implantation, where it adheres to the
skin by an adhesive covering the bottom surface of the patch. These
drugs or agents may be contained in the entire surface adhesive, in
a section of the adhesive, or in a mechanical depot within the
patch with manifold orifices over the prescribed surface above the
implant, and the drugs diffuse through the skin to achieve an
effective local concentration to encourage controlled
neovascularization, vascular permeability, and control of
overactivity of macrophages during implant tissue ingrowth and
healing. The patch remains in place for 24-48 hours, and is then
removed. A sensor maintenance patch assembly, comprising a drug
delivery interface and an electronic signal interrogation component
(e.g., light-emitting diodes and filtered photodiodes for
fluorescence), is placed over the site of the implant. The drug
delivery component provides, for example, an adhesive for adhering
the patch to the skin. The drug delivery component contains 125 mg
of 65- to 100-mM mannose-6-phosphate or 5% wt/wt halofuginone, and
100 mg of 2.5%-25% L-arginine, to inhibit collagen capsule
formation and to maintain adequate blood vessel dilation,
respectively. This patch is left on the skin for 5-15 days, and
during this time the interrogator collects data from the implant.
After 5-15 days, the patch is removed and the two components are
separated. The drug delivery component is discarded, and a new drug
delivery component is assembled to the electronic signal
interrogation component, and the assembly is then placed over the
implant site. Analyte sensing media interrogation then resumes.
These steps may be repeated as long as necessary. At the end of the
operational life of the implanted analyte sensing media, an
explantation preparation patch containing 50-150 mg of 0.1%
dexamethasone is placed over the analyte sensing media implant site
and allowed to stay in place for 3 days. The patch is then removed,
and the analyte sensing media is safely explanted.
Example 2
[0191] Skin Preparation
[0192] Sensing Media Insertion
[0193] Sensor Maintenance Patch
[0194] A skin preparation patch is placed on the skin at the future
implant site 6-24 hours before implantation of an implantable
analyte sensor (e.g., glucose, lactate, pyruvate, glycerol, urea).
The skin preparatory patch contains 50-150 mg of 0.1%
dexamethasone, which is released at a rate sufficient to achieve
localized concentrations of 0.05-20.0 mg/kg in an area ranging from
0.5 cm to 4.0 cm in diameter and 0.05 cm to 1.0 cm in depth. The
patch also contains a temporary skin colorant, e.g.,
2-hydroxy-1,4-naphthoquinone (also called Henna), which will
diffuse into the skin to demarcate the area that has been directly
exposed to the dexamethasone. Alternatively, a wide selection of
temporary transfer tattoo inks may be utilized as the temporary
colorant in the skin preparatory patch. Yet another alternative for
use as the temporary skin colorant is providone iodine
(Betadine.RTM.), which can also sterilize the skin in preparation
for injection, incision or other planned perforations of the skin
barrier. Yet another alternative skin colorant to denote the
implant area is a substance that will be visible only under UV
light, such as sodium fluorescein, which is widely used and
considered safe for epi-cutaneous labeling. After 2-24 hours, the
skin preparation patch is removed, and the analyte sensor is
implanted. Alternatively, implantation may take place prior to
removing the pre-implant patch, thus avoiding the need for
colorant, or the individual applying the patch may mark the skin
with a marking pen or other implement before placing the patch.
[0195] The analyte sensing media is implanted via a syringe-like
injection system at a depth under the outer surface of the skin
ranging from 0.05 to 1.0 cm. The skin colorant, which was delivered
by the skin preparatory patch and which remains visible on the skin
under normal or UV light, is used as a visual guide to placement of
the implant. The area of sensing media implantation coincides with
the colorant demarcating the area of the skin that received the
dexamethasone, which was delivered from the skin preparation
patch.
[0196] Immediately after sensing media insertion, a second patch,
called a post-insertion healing patch, is applied above the implant
that delivers 0.01-3% diclofenac sodium, 3.5 mg/gm neomycin base,
10,000 polymyxin B units/gm, and 0.5% hydrocortisone acetate 5 mg
(0.5%). The post-insertion healing patch releases contents in an
area ranging from 0.5 cm to 4.0 cm in diameter and to a depth
ranging from 0.05 cm to 1.0 cm. The post-insertion healing patch is
left in place for 3 to 7 days, after which time it is removed.
[0197] After the removal of the post-insertion healing patch, the
surface of the skin in the area of the analyte sensing media is
washed with mild detergent to remove surface oils and rinsed
thoroughly with water. The area is swabbed with rubbing alcohol and
allowed to air-dry. A third patch type, the sensor maintenance
patch, is then applied to the surface of the skin over the analyte
sensing media site. The sensor maintenance patch contains 5% wt/wt
halofuginone or 125 mg of 65- to 100-mM mannose-6-phosphate to
inhibit collagen synthesis and prevent collagen capsule formation
within or around the analyte sensing media. The sensor maintenance
patch also contains electronics for optical interrogation of the
sensor and radio frequency communication. Upon placement of the
sensor maintenance patch, the patient conducts a 2 point capillary
blood glucose calibration, and begins taking readings. Every 7
days, a patch replacement procedure is conducted. The old sensor
maintenance patch is removed; the area is washed with a mild
detergent, rinsed thoroughly with water, dried, swabbed with
rubbing alcohol, and allowed to air-dry. A fresh replacement sensor
maintenance patch is then applied over the implant, and a capillary
blood glucose calibration is conducted. Collection of analyte
measurements then resumes. The sensor maintenance patch replacement
procedure is conducted every 7 days throughout the lifetime of the
inserted sensor.
[0198] After the useful life of the analyte sensing media, the
sensor maintenance patch is removed, and the area is washed,
rinsed, and swabbed with disinfectant. The analyte sensing media is
then removed via a minimal incision. To continue analyte
measurements, a fresh analyte sensing media may be implanted in a
different location following the above procedure (including
application of a skin preparation patch). The new analyte sensing
media may be implanted greater than 2 cm away from the first
sensor. This entire procedure may be repeated as many times as
needed to replace a sensor whose useful life has expired. Also,
this entire procedure may be repeated as many times as needed for
insertion of multiple analyte sensors.
Example 3
[0199] Analyte Sensing Media Insertion
[0200] Post-Implant Healing Patch
[0201] Sensor Maintenance Patch
[0202] Analyte sensing media, such as a 0.5 mm.times.10 mm
rod-shaped pHEMA hydrogel implant containing analyte sensing
chemicals, such as concanavalin A and dextran, or a
phenylboronic-derivatized hydrogel backbone, or other reversible
ligand-binding analyte pair, is implanted into the dermis 0.5 mm to
5 mm below the surface of the skin by syringe or catheter. A 1.5-
to 3-cm circular topical drug post-insertion healing patch
containing 25 mg of 1% wt/vol of sildenafil or other nitric oxide
synthase inhibitor, 10 mg of 2.5%-25% of L-arginine, and/or 2.5 mg
of estradiol, is placed on the skin over the site of implantation,
where it adheres to the skin by an adhesive covering the bottom
surface of the patch. These drugs or agents may be contained in the
entire surface adhesive, in a section of the adhesive, or in a
mechanical depot within the patch with manifold orifices over the
prescribed surface above the implant, and the drugs diffuse through
the skin to achieve an effective local concentration to encourage
controlled neovascularization, vascular permeability, and control
of overactivity of macrophages during implant tissue ingrowth and
healing. The patch remains in place for 24-48 hours, and is then
removed.
[0203] After this period, a sensor maintenance patch comprising a
drug delivery interface (e.g., cream, ointment, microneedles,
iontophoretic electrode and drug reservoir) and an electronic
signal interrogation interface (e.g., light-emitting diodes and
filtered photodiodes for fluorescence) is placed over the site of
the implant. The drug delivery component contains 100 mg of
L-arginine, and 125 mg of 65- to 100-mM mannose-6-phosphate or 100
mg of 5% wt/wt halofuginone. The L-arginine maintains blood flow
through the newly generated microvessels within the implant, and
low-dose mannose-6-phosphate or halofuginone inhibit overabundant
Type 1 collagen capsule formation, which would otherwise reduce
diffusion of analyte to the sensor. This patch is left on the skin
for 3-14 days, and during this time the interrogator collects data
from the implant. After 3-15 days, the sensor maintenance patch is
removed and discarded, and another sensor maintenance patch is
placed over the implant site, and interrogation of the sensor
implant continues. These latter steps may be repeated as long as
necessary.
Example 4
[0204] Analyte Sensing Media Insertion
[0205] Post-Implant Healing
[0206] Interrogation Only
[0207] Explant Patch
[0208] A 0.5 mm.times.10 mm rod-shaped hydrogel implant containing
analyte sensing chemicals, such as concanavalin A and dextran, or
phenylboronic derivatized hydrogel backbone, or other reversible
ligand-binding analyte pair, is implanted into the dermis 2-3 mm
below the surface by syringe or catheter. A post-insertion healing
patch is applied above the implant that delivers 25 mg of 17B
estradiol, 0.01-3% diclofenac sodium, an NSAID (non-steroidal
anti-inflammatory drug), 3.5 mg/gm neomycin base, 10,000 polymyxin
B units/gm, and 0.5% hydrocortisone acetate 5 mg (0.5%). The
post-implant healing patch releases contents in an area ranging
from 0.5 cm to 4.0 cm in diameter and a depth ranging from 0.05 cm
to 1.0 cm. The post-implant healing patch is left in place for 3 to
7 days, after which time it is removed. After the removal of the
post-insertion healing patch, the surface of the skin in the area
of the implant is washed with mild detergent to remove surface oils
and rinsed thoroughly with water.
[0209] After this healing period, an interrogation
patch--comprising light-emitting diodes and filtered detector
photodiodes, microprocessor, power source, and RF communication
module, for fluorescence detection--is placed on the skin over the
implant site and allowed to stay in place for 30-180 days. The
interrogation patch may be held in place by an adhesive that is
replenished every 5-15 days or by a strap or other means to hold
the patch against the surface of the skin. During this time, data
are continuously collected from the implant.
[0210] If an adhesive is used, after a period of 5-15 days, the
interrogation patch is removed and the adhesive component is
replaced with a fresh adhesive component, and the interrogation
patch is placed back on the skin over the implant. This procedure
may be repeated as often as necessary over the life of the
implant.
[0211] When the implant reaches the end of its operational life, a
cream or ointment containing 0.05% clobetasol 17-propionate is
applied to the skin above the implant 2-3 times per day for 24-72
hours to prepare the tissue for explantation. This encourages
devascularization of the implant. The implant is then removed.
Example 5
[0212] Skin Preparation
[0213] Analyte Sensing Media Insertion
[0214] Interrogation
[0215] Explant Patch
[0216] A skin preparation cream or ointment containing a mild to
moderately potent steroid, e.g., 0.25% fluocinolone acetonide or 1%
hydrocortisone acetate, is applied to a 1- to 4-cm diameter area of
skin where an analyte sensing media will later be implanted.
Application of the cream or ointment is repeated every 4-6 hours
for at least 24 hours. The cream or ointment is removed and the
analyte sensing media is placed into the dermis 0.5 mm to 10 mm
below the surface of the skin. For the next 7-10 days the implant
is allowed to heal in place. After this healing period, an
interrogation patch--comprising light-emitting diodes and filtered
detector photodiodes, microprocessor, power source, and RF
communication module, for fluorescence detection--is placed on the
skin over the implant site and allowed to stay in place for 30-180
days. The interrogation patch may be held in place by an adhesive
that is replenished every 5-15 days or by a strap or other means to
hold the patch against the surface of the skin. During this time,
data are continuously collected from the implant. If an adhesive is
used, after a period of 5-15 days, the interrogation patch is
removed and the adhesive component is replaced with a fresh
adhesive component, and the interrogation patch is placed back on
the skin over the implant. This procedure may be repeated as often
as necessary over the life of the implant.
[0217] When the implant reaches the end of its operational life, a
cream or ointment containing 0.05% clobetasol 17-propionate is
applied to the skin above the implant 2-3 times per day for 24-72
hours to prepare the tissue for explantation. This encourages
devascularization of the implant. The implant is then removed.
Example 6
[0218] Skin Preparation
[0219] Analyte Sensing Media Insertion
[0220] Post-Insertion Healing
[0221] Sensor Maintenance Patch
[0222] Explant Patch
[0223] A 0.75 cm.times.2 cm rectangular skin preparation patch
containing 300-750 .mu.g of betamethasone is placed on the skin
over the site of implantation, where it adheres to the skin by an
adhesive covering the bottom surface of the patch. The drug is
contained in a section of the adhesive, and drug diffuses during
the next 12-24 hours through the skin and achieves a dermal
concentration of in the range of 0.1-1.0 m/mL wt/vol in the tissue
below. The formulation may contain a carrier and penetrant
additive(s) to facilitate penetration. Betamethasone blocks certain
aspects of the acute inflammation response in preparation for the
implant to be placed into the tissue. The skin preparation patch
also has a 1- to 2-mm hole near one edge that is used to guide the
implantation process. The analyte sensing media is then placed via
a syringe or catheter through the guide hole into the dermis or
subcutis 0.5-5.0 mm below the surface. The skin preparation patch
is then removed. A second patch, a post-insertion healing patch,
containing 25 mg of 17B estradiol to facilitate healing as well as
a small amount of non-steroidal anti-inflammatory compound to
dampen other aspects of the acute inflammatory response, is applied
over the site of implantation. This skin preparation patch is left
in place for 24 hours, and then it is removed. The implant is then
allowed to heal in place for the next 7-10 days. During this time,
tissue in-growth, neovascularization, and tissue modification
occurs.
[0224] After the healing phase, a sensor maintenance patch,
comprising a drug delivery interface (e.g., cream, ointment,
microneedles, iontophoretic electrode and drug reservoir) and an
electronic signal interrogation component (e.g., light-emitting
diodes and filtered photodiodes for fluorescence), is placed over
the site of the implant. The drug delivery component provides an
adhesive for adhering the patch to the skin. The drug delivery
component contains 125 mg of 65- to 100-mM mannose-6-phosphate or
5% wt/wt halofuginone, and 100 mg of 2.5%-25% L-arginine, to
inhibit collagen capsule formation and to maintain adequate blood
vessel dilation, respectively. This patch is left on the skin for
5-15 days, and during this time the interrogator collects data from
the implant.
[0225] After 5-15 days, the patch is removed and the two components
are separated. The drug delivery component is discarded, and a new
drug delivery component is assembled to the electronic signal
interrogation component, and the assembly is then placed over the
implant site. Analyte sensing media interrogation then resumes.
These steps may be repeated as long as necessary.
[0226] At the end of the operational life of the implanted analyte
sensing media, an explantation preparation patch containing 50-150
mg of 0.1% dexamethasone is placed over the analyte sensing media
implant site and allowed to stay in place for 3 days. The patch is
then removed and the analyte sensing media is safely explanted.
Example 7
[0227] Skin Preparation
[0228] Insertion
[0229] Light Treatment
[0230] Interrogation/Maintenance
[0231] Explant Patch
[0232] A skin preparation cream or ointment containing 0.05%
betamethasone or 1% hydrocortisone acetate is applied to a 1- to
4-cm diameter area of skin where an analyte sensor will later be
implanted. The application is repeated every 6 hours for 24-48
hours. Then the analyte sensing media, such as described in other
examples above, is then implanted into the dermis 0.5-5 mm below
the surface by syringe or catheter. An adhesive band containing
light emitting diodes or lasers to provide localized phototherapy
is then applied to the skin after implantation over the area of
implantation. The patch containing a cluster of 6 to 48 LED photons
at 510-543, 594-599, 626-639, 640-670 842-872, and 1049-1082 nm
wavelengths with 50-500 mW output power, is placed over the
implantation area. 2-15 J/cm.sup.2 treatments are administered 1-3
times daily to reduce inflammation and reduce damaging reactive
oxygen species in the wound healing environment. Alternatively, a
non-coherent light at 890 nm may be applied, which directs
macrophages to send inhibitory signals to quiet fibroblast
activity. Alternatively, or additionally, a light source at 625-635
nm may be used that inhibits cyclooxygenase (COX) and prostaglandin
E(2) (PGE(2)), to reduce reactive oxidative species, and promote
diabetic wound healing. Inhibition of COX and (PGE(2)) protects
cells against cell injury in specific pathophysiological
situations: inflammation and oxidative stress. Alternatively or
additionally, a light source at 1072 nm light may be used, which
has been shown to upregulate production of cytoprotective species
(e.g., indicible nitric oxide synthase). Specified phototherapy
depends on the stage of wound healing and foreign body response
(e.g., initially anti-inflammatory 625-635 nm light may be used,
and later, as the foreign body reaction ensues, 890 nm light to
calm fibroblast activity and 1072 nm light to enhance NO production
may be utilized). This treatment facilitates healing of the implant
in the implant site and proceeds for 48-72 hours.
[0233] After treatment, a sensor maintenance patch containing 5%
wt/wt halofuginone or 125 mg of 65- to 100-mM mannose-6-phosphate
is placed to inhibit collagen synthesis and prevent collagen
capsule formation within or around the analyte sensing media. The
sensor maintenance patch also contains electronics for optical
interrogation of the sensor and radio frequency communication.
After this period, a second patch, comprising a drug delivery
interface (e.g., cream, ointment, microneedles, iontophoretic
electrode and drug reservoir) and an electronic signal
interrogation interface (e.g., light-emitting diodes and filtered
photodiodes for fluorescence), is placed over the site of the
implant. The drug delivery component contains 100 mg of L-arginine,
and 125 mg of 65- to 100-mM mannose-6-phosphate or halofuginone.
The L-arginine maintains blood flow through the newly generated
microvessels within the implant, and low-dose mannose-6-phosphate
or halofuginone inhibit overabundant collagen capsule formation for
optimal analyte diffusion. This patch is left on the skin for 3-14
days, and during this time the interrogator collects data from the
implant.
[0234] After 5-15 days, the patch is removed and discarded, and
another interrogation/drug patch is placed over the implant site,
and interrogation of the sensor implant continues. These latter
steps may be repeated as long as necessary.
[0235] The same patch described above with multiple wavelength LED
clusters may be controlled via an external device (cell phone,
hand-held, wristwatch, computer or other device) to activate
certain LEDs and turn off others in order to change delivery
wavelengths and/or intensity of phototherapy.
Example 8
[0236] Insertion
[0237] Healing Phototherapy
[0238] Interrogation Plus Maintenance Therapy
[0239] An electrochemical glucose sensor is implanted
subcutaneously. For 1-3 weeks following implantation, tissue
response modifiers in the form of specific wavelengths and
intensity of light are delivered 1-3 times daily for 0.5-3.0
minutes from a portable hand-held device. This device is similar to
a miniaturized version of the Biolux Research light emitting diode
phototherapy device. Treatment is administered by the patient, who
holds the light emitting portion of the device against the skin in
the area of the implant for 0.5-3.0 minutes a day at an energy
density of 1-50 mW/cm.sup.2. The total dosage to the surface of the
skin overlying the implant is 6-20 J/cm.sup.2. This phototherapy
regimen accelerates healing and improves angiogenesis. Optionally,
silver oxide cream is applied twice daily to the implant area to
enhance wound healing. After 1-3 weeks of localized phototherapy
and application of silver oxide cream, the sensor has sufficiently
healed into the tissue, and analyte measurements are ready to be
taken. A hand-held RFID (radio frequency identification) and
wireless battery charging device is placed in contact with the skin
over the implant (may be the same device from which phototherapy
was delivered above). The implant sends a signal to the hand-held
and its internal battery is recharged wirelessly.
[0240] Upon initial use and once a week thereafter, a calibration
procedure is performed that requires patients to measure capillary
blood glucose using traditional fingerprick methods and enter that
data into the hand-held device. The hand-held then converts the
sensor signal to a glucose reading that is displayed to the
patient. Any time the patient wishes to take a glucose reading, the
hand-held device is held next to the skin.
[0241] Maintenance phototherapy may be delivered to the implant
area 1-7 times a week for 0.5-10 minutes to insure the integrity of
the tissue-sensor interface is maintained in a condition
appropriate to generate sensor signals that reflect blood glucose
readings. If continuous glucose monitoring is required rather than
frequent checks that can be performed with the hand held (e.g., at
night time for insulin dependent children), the patient may
attached an RFID patch to the implant area, which will wirelessly
transmit the signal coming from the electrochemical sensor to the
hand-held device.
Example 9
[0242] Implant Drug Pump
[0243] Healing Patch
[0244] A fully implantable drug pump is implanted subcutaneously.
Optionally, NSAID and utercalin microspheres are implanted adjacent
to the pump outlet. A post-implantation healing patch, containing
25 mg of 17B estradiol, 0.01-3% diclofenac sodium, an NSAID, 3.5
mg/gm neomycin base, 10,000 polymyxin B units/gm, and 0.5%
hydrocortisone acetate 5 mg (0.5%), is applied. This patch is left
in place for 24 hours, and then it is removed. The patch-delivered
drugs and the implanted microsphere-delivered drugs heal and
condition the tissue around the pump outlet to prevent foreign body
response occlusion of the outlet. The condition of the tissue
around the pump outlet is maintained by replacing the patch with a
maintenance patch containing 125 mg of 65- to 100-mM
mannose-6-phosphate or 5% wt/wt halofuginone, and 100 mg of
2.5%-25% L-arginine. The maintenance patch may be replaced
periodically.
Example 10
[0245] Production of a Tissue Integrating Opto-Electronic
Apparatus
[0246] Electronic components (LEDs, photodiodes, a temperature
sensor and a pressure sensor) are wire bonded to a flexible wire
mesh using a conventional ultrasonic wire bonding process. The mesh
containing electrical components is placed in a templating mold
(two glass slides with Teflon spacers) into which sieved PMMA
microspheres (36 microns with a CV less than 5%) are added. The
template is sonicated for 10 minutes to closely pack the
microspheres and then the template is heated to 177.degree. C. for
24 hours to fuse the microspheres.
[0247] Polymer pre-cursor that will form part of the scaffold is
then prepared. The general preparation of poly(2-hydroxyethyl
methacrylate) (pHEMA) scaffold is as follows: In separate vials,
two solutions are prepared: 0.89 ml of a 20% solution of APS
(ammonium persulfate) in water and 0.3 ml of a 15% solution TEMED
(tetramethylethylenediamine) in water. To a third vial 9.26 ml of
HEMA (2-hydroxyethyl methacrylate), 4.6 ml of
TEGDMA(triethyleneglycol-dimethacrylate), 2.6 ml of ethylene glycol
and 2.68 ml of water are added by volume measurement and mixed.
[0248] The TEMED solution (vial 2) is added to the main pre-polymer
(vial 3). Sensing nanospheres ranging from 2-95% volume of the
total reactant volume (e.g. 5 ml of 100-200 nm alginate nanospheres
containing fluorescent glucose sensing chemistry) are mixed with
the pre-polymer solution (vial 3). The pre-polymer solution is
filled into the mold and then the APS solution (vial 1) is added to
the mold. The mold is placed under vacuum to remove any bubbles and
completely infiltrate the PMMA-mold and then polymerized at room
temperature for one hour. Next, the PMMA microspheres are dissolved
by frequent exchange of dichloromethane or other solvent system for
24-48 hrs using a Soxhlet extractor or frequent volume changes. The
resulting tissue integrating opto-electronic apparatus is connected
to an implantable (tissue anchoring) electrical control circuit and
power supply.
Example 11
[0249] Production of a Tissue Integrating Electrochemical
Apparatus
[0250] A layer of gold is sputter coated onto a PET substrate at a
thickness of about 20 nanometers to about 80 nanometers. Using
photolithography, a plurality of electrodes, conductive traces and
electrode contact pads are created by insulatively etching the
gold. The electrodes will become the working and reference/counter
electrodes of the apparatus. Using standard thin film techniques,
the following layers are applied to the working and/or
reference/counter electrodes: (1) an inner selective membrane layer
of cellulose acetate at a thickness of about 20 microns or less;
(2) an enzyme layer of glucose oxidase at an enzyme limiting amount
and at a thickness of about 20 microns or less. The enzyme layer
also includes a buffer for maintaining a pH and oxygen enhancing
substances such as silicone or fluorocarbon; and (3) an outer
diffusion limiting membrane layer of polyhydroxyethyl methacrylate
and at a thickness of about 20 microns or less.
[0251] The resulting electrodes are singulated and the electrode
contacts are wire bonded to wires in a flexible wire mesh.
Electronic components (a temperature sensor and a pressure sensor)
are also wire bonded to the flexible wire mesh. The wire mesh with
electrodes and electronic components is placed in a templating mold
into which sieved PMMA microspheres (36 microns with a CV less than
5%) are added. The template is sonicated for 10 minutes to closely
pack the microspheres and then the template is heated to
177.degree. C. for 24 hours to fuse the microspheres.
[0252] Polymer pre-cursor that will form part of the scaffold is
then prepared. In separate vials, two solutions are prepared: 0.89
ml of a 20% solution of APS (ammonium persulfate) in water and 0.3
ml of a 15% solution TEMED (tetramethylethylenediamine) in water.
To a third vial 9.26 ml of HEMA (2-hydroxyethyl methacrylate), 4.6
ml of TEGDMA(triethyleneglycol-dimethacrylate), 2.6 ml of ethylene
glycol and 2.68 ml of water are added by volume measurement and
mixed.
[0253] The TEMED solution (vial 2) is added to the main pre-polymer
(vial 3). The pre-polymer solution is filled into the mold and then
the APS solution (vial 1) is added to the mold. The mold is placed
under vacuum to remove any bubbles and completely infiltrate the
PMMA-mold and then polymerized at room temperature for one hour.
Next, the PMMA microspheres are dissolved by frequent exchange of
dichloromethane or other solvent system for 24-48 hrs using a
Soxhlet extractor or frequent volume changes. The resulting
tissue-integrating electrochemical apparatus may be connected to an
implantable electrical control circuit having a potentiostat and a
power supply.
Example 12
[0254] Production of an Implantable Electrical Control Circuit and
Power Supply
[0255] An implantable electrical control circuit and power supply
is fabricated on a tissue anchoring substrate. To create the tissue
anchoring substrate, a plurality of holes ranging in size from 1
micron to 1000 microns are punched into a substrate such that the
holes cover the entire substrate. The implantable electrical
control circuit (/- a potentiostat) and power supply are fabricated
onto the tissue anchoring substrate using standard photolithography
techniques. One or more wires from electrical components of a
tissue integrating opto-electronic apparatus or a tissue
integrating electrochemical apparatus are bonded to wires from the
implantable electrical control circuit and the power supply.
Example 13
[0256] Implantation
[0257] A system including a tissue integrating apparatus connected
to an implantable electrical control circuit and power supply is
placed in a 19-23 Gauge insertion needle, trocar, modified biopsy
device or other devices engineered for injection under the
skin.
[0258] Upon insertion, skin is pinched up so that the insertion
needle is placed parallel to the surface of the skin 1-4 mm beneath
the surface. Fluid or a reverse displacement plunger (or trocar) is
used to leave the sensor in the tissue as the syringe is withdrawn.
Insertion site may include any subcutaneous area, typically the
abdomen, arm and thigh.
Example 14
[0259] Measurement
[0260] Data from a system having a tissue integrating electronic
apparatus is collected, processed and displayed on a smart phone,
other hand-held device, computer screen or other visualization
format, for example using commercially available data display
devices available for example from Medtronic. Raw data is converted
to an analyte concentration or some non-quantitative representation
of the analyte concentration (e.g. high, low, within range). Values
at any given point in time or trends (graphs over time) or summary
statistics over a period of time are provided. An indication of the
quality of the data is optionally provided.
[0261] All patents, patent applications and publications mentioned
herein are hereby incorporated by reference in their entirety.
[0262] Where methods and steps described above indicate certain
events occurring in certain order, those of ordinary skill in the
art will recognize that the ordering of certain steps may be
modified and that such modifications are in accordance with the
variations of the invention. Additionally, certain of the steps may
be performed concurrently in a parallel process when possible, may
be performed in reverse order when possible and may be performed
sequentially as described above.
[0263] Although the detailed description contains many specifics,
these should not be construed as limiting the scope of the
invention but merely as illustrating different examples and aspects
of the invention. It should be appreciated that the scope of the
invention includes other embodiments not discussed in detail above.
Various other modifications, changes and variations which will be
apparent to those skilled in the art may be made in the
arrangement, operation and details of the method and apparatus of
the present invention disclosed herein without departing from the
spirit and scope of the invention as defined in the appended
claims. Therefore, the scope of the invention should be determined
by the appended claims and their legal equivalents.
* * * * *