U.S. patent application number 12/895394 was filed with the patent office on 2011-03-31 for sensors with thromboresistant coating.
This patent application is currently assigned to Glumetrics, Inc.. Invention is credited to Soya Gamsey, David R. Markle, Matthew A. Romey.
Application Number | 20110077477 12/895394 |
Document ID | / |
Family ID | 43781089 |
Filed Date | 2011-03-31 |
United States Patent
Application |
20110077477 |
Kind Code |
A1 |
Romey; Matthew A. ; et
al. |
March 31, 2011 |
SENSORS WITH THROMBORESISTANT COATING
Abstract
Embodiments of the present invention relate to analyte sensors
comprising a heparin benzalkonium antithrombogenic coating, and
methods of coating analyte sensors.
Inventors: |
Romey; Matthew A.; (Newport
Beach, CA) ; Gamsey; Soya; (Huntington Beach, CA)
; Markle; David R.; (Berwyn, PA) |
Assignee: |
Glumetrics, Inc.
Irvine
CA
|
Family ID: |
43781089 |
Appl. No.: |
12/895394 |
Filed: |
September 30, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61247500 |
Sep 30, 2009 |
|
|
|
Current U.S.
Class: |
600/309 ;
422/82.05; 427/2.12 |
Current CPC
Class: |
A61B 5/14532 20130101;
G01N 2021/7786 20130101; A61B 5/14542 20130101; A61B 5/1459
20130101; G01N 21/80 20130101; G01N 21/7703 20130101; A61B 5/14539
20130101; G01N 2021/773 20130101 |
Class at
Publication: |
600/309 ;
427/2.12; 422/82.05 |
International
Class: |
A61B 5/1473 20060101
A61B005/1473; A61L 33/00 20060101 A61L033/00; G01N 21/00 20060101
G01N021/00 |
Claims
1. An analyte sensor, comprising: an elongate member; an
analyte-responsive indicator disposed along a distal portion of the
elongate member, wherein said indicator is capable of generating a
signal related to a concentration of analyte in the blood vessel; a
porous membrane covering at least the indicator along the distal
portion of the elongate member; and a coating comprising heparin
and benzalkonium stably associated with at least a portion of the
porous membrane.
2. The analyte sensor of claim 1, wherein the elongate member
comprises an optical fiber comprising a light path.
3. The analyte sensor of claim 2, wherein the analyte-responsive
indicator comprises a fluorophore operably coupled to an analyte
binding moiety, wherein analyte binding causes a change in the
emission intensity of the fluorophore, and wherein the analyte
responsive indictor is disposed within the light path of the
optical fiber.
4. The analyte sensor of claim 3, wherein the fluorophore is
HPTS-triCysMA and the binding moiety is 3,3'-oBBV.
5. The analyte sensor of claim 1, wherein the porous membrane is a
microporous membrane.
6. The analyte sensor of claim 5, wherein the microporous membrane
comprises one or more polymers selected from a group consisting of
the polyolefins, the fluoropolymers, the polycarbonates, and the
polysulfones.
7. The analyte sensor of claim 6, wherein the microporous membrane
comprises at least one fluoropolymer.
8. The analyte sensor of claim 7, wherein the at least one
fluoropolymer is selected from the group consisting of
polytetrafluoroethylene, perfluoroalkoxy polymer, fluorinated
ethylene-propylene, polyethylenetetrafluoroethylene,
polyvinylfluoride, polyethylenechlorotrifluoroethylene,
polyvinylidene fluoride, polychlorotrifluoroethylene,
perfluoropolyether, perfluoroelastomer, and fluoroelastomer.
9. The analyte sensor of claim 5, wherein the microporous membrane
comprises at least one polyolefin.
10. The analyte sensor of claim 9, wherein the at least one
polyolefin is polyethylene.
11. The analyte sensor of claim 3, wherein the analyte-responsive
indicator is immobilized within a hydrogel that comprises
heparin.
12. An equilibrium intravascular analyte sensor, comprising: an
optical fiber configured for positioning within a blood vessel and
comprising a light path and an outer surface; a chemical indicator
system comprising a fluorophore operably coupled to an analyte
binding moiety, wherein the fluorophore and analyte binding moiety
are immobilized within a water-insoluble organic polymer, and
wherein the chemical indicator system is disposed within the light
path along a distal portion of the optical fiber; and an
antithrombogenic, analyte-permeable coating on at least a portion
of the outer surface of the optical fiber and overlying the
chemical indicator system disposed therein, wherein the coating
comprises heparin covalently cross-linked to the outer surface.
13. The analyte sensor of claim 12, wherein the fluorophore is
HPTS-triCysMA and the binding moiety is 3,3'-oBBV.
14. The analyte sensor of claim 12, further comprising a porous,
analyte-permeable membrane disposed between the chemical indicator
system and the antithrombogenic coating.
15. A method for reducing the thrombogenicity of an analyte sensor,
comprising: providing the analyte sensor comprising an elongate
optical fiber defining a light path, an equilibrium fluorescent
chemical indicator system immobilized within a hydrogel and
disposed along a distal region of the optical fiber within the
light path, and an analyte-permeable porous membrane, which forms
an outer layer of at least a portion of the distal region, wherein
the indicator system is covered by the porous membrane; contacting
the analyte sensor with a single solution comprising a mixture of
heparin and benzalkonium, or with separate first and second
solutions, wherein the first solution comprises heparin and the
second solution comprises benzalkonium; and drying the analyte
sensor.
16. The method of claim 15, wherein the contacting and drying steps
are repeated between 2 and 10 times.
17. The method of claim 15, further comprising a step of soaking
the analyte sensor in a solution comprising heparin for a time
sufficient to allow the heparin to saturate the hydrogel.
18. The method of claim 15, wherein the equilibrium fluorescent
chemical indicator system comprises a fluorophore and an analyte
binding moiety.
19. The method of claim 18, wherein the fluorophore is
HPTS-triCysMA, the binding moiety is 3,3'-oBBV, and the hydrogel is
a DMAA (N,N-dimethylacrylamide) hydrogel matrix.
20. The method of claim 15, wherein the porous membrane comprises
microporous polyethylene.
21. A method for reducing the thrombogenicity of an analyte sensor,
comprising: providing the analyte sensor comprising an elongate
optical fiber defining a light path, an equilibrium fluorescent
chemical indicator system disposed along a distal region of the
optical fiber within the light path, and an analyte-permeable
porous membrane, which forms an outer surface over at least a
portion of the distal region, wherein the indicator system is
covered by the porous membrane; providing a photoactivatable
chemical linking agent and an antithrombogenic molecule, wherein
the linking agent is capable, upon activation, of covalent
attachment to the outer surface and the antithrombogenic molecule,
wherein the linking agent comprises a charged, nonpolymeric di- or
higher functional photoactivatable compound comprising two or more
photoreactive groups and one or more charged groups; and activating
the two or more photoreactive groups, thereby cross-linking the
antithrombogenic molecule to the outer surface.
22. The method of claim 21, wherein the equilibrium fluorescent
chemical indicator system comprises a fluorophore and an analyte
binding moiety, immobilized within a water-insoluble organic
polymer.
23. The method of claim 22, wherein the fluorophore is
HPTS-triCysMA, the binding moiety is 3,3'-oBBV, and the
water-insoluble organic polymer is a DMAA (N,N-dimethylacrylamide)
hydrogel matrix.
24. The method of claim 21, wherein the porous membrane comprises
microporous polyethylene.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 61/247,500, filed Sep. 30, 2009 the disclosure of
which is hereby expressly incorporated by reference and hereby
expressly made a portion of this application.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] Embodiments of the present invention generally relate to
thromboresistant coatings for medical devices, such as
intravascular glucose sensors, having a blood-contacting surface,
as well as to methods for forming such coatings, and to the medical
devices thus formed.
[0004] 2. Description of the Related Art
[0005] Achieving glycemic control is facilitated by continuous or
nearly continuous monitoring of patient blood glucose levels. One
method for accomplishing such monitoring is through the use of an
implanted glucose sensor. For example, an optical glucose sensor,
such as those disclosed in U.S. Pat. Nos. 5,137,033, 5,512,246,
5,503,770, 6,627,177, 7,417,164 and 7,470,420, and U.S. Patent
Publ. Nos. 2006/0083688, 2008/0188722, 2008/0188725, 2008/0187655,
2008/0305009, 2009/0018426, 2009/0018418, and co-pending U.S.
patent application Ser. Nos. 11/296,898, 12/187,248, 12/172,059,
12/274,617 and 61/045,887 (each of which is incorporated herein in
its entirety by reference thereto), can be deployed in the vascular
system of the patient, with glucose readings taken continuously, or
as needed. Of course, any indwelling intravascular glucose sensor
can potentially be used in monitoring glucose for the purpose of
achieving glycemic control.
[0006] The presence of foreign bodies in the vascular system of
patients, such as intravascular glucose sensors, can lead to the
formation of a blood clot or thrombus around the sensor. In some
cases, the thrombus can result in the restriction of blood flow
through the blood vessel, impairing functionality of the sensor
and/or health of the patient. In some cases, the thrombus can break
off and travel through the bloodstream to other parts of the body,
such as the heart or brain, leading to severe health problems. As
result, it is desirable to minimize the formation of a thrombus on
or near the sensor.
[0007] Heparin has been used clinically for decades as an
intravenous anticoagulant to treat clotting disorders and to
prevent thrombus formation during surgery and interventional
procedures. Coating the outer surface of a medical device, e.g.,
stents, prostheses, catheters, tubing, and blood storage vessels,
with heparin or a heparin containing complex (See, e.g., U.S.
Reissued Patent No. RE39,438 to Shah, et al.) may reduce the
thrombogenecity of the device when it comes into contact with blood
by: (1) inhibiting enzymes critical to the formation of fibrin
(which holds thrombi together); (2) reducing the adsorption of
blood proteins, which may lead to undesirable reactions on the
device surface; and (3) reducing the adhesion and activation of
platelets, which play an important role in thrombogenesis. Ideally,
the heparin coating substantially shields the blood from the
underlying surface of the medical device, such that the blood
components contact the heparin coating rather than the device
surface, thus reducing the formation of thrombi or emboli (blood
clots that release and travel downstream).
[0008] Unfortunately, depending on the surface material of the
device, heparin may not provide a lasting and/or contiguous
thromboresistant coating. Various strategies have been implemented
to enhance the integrity of the heparin coating. For example,
photo-activated coupling methods can be used to covalently bind
heparin to a device surface thereby extending the useful life of
the coating (See e.g., Surmodics' PHOTOLINK.RTM. process at
www.surmodics.com/technologies-surface-biocompatibility-heparin.html).
Alternatively, for certain materials, e.g., PVC, linkers such as
tridodecylmethyl ammonium chloride (TDMAC) and PEO-polyethylene
oxide, among others, have been used to space the heparin molecule
away from the PVC surfaces (See e.g., U.S. Pat. No. 5,441,759 to
Crouther et al.). Heparin may be cross-linked to polypeptides to
create a thromboresistant hydrogel with peptide-specific
functionality (See e.g., U.S. Pat. No. 7,303,814 to Lamberti, et
al. disclosing a wound-healing functionality). Heparin derivatives
or complexes, such as heparin benzalkonium chloride (hereinafter
"HBAC"), have also been applied as a thromboresistant coating for
medical devices. However, HBAC has not been used with success for
devices, such as intravascular analyte sensors, that require
passage of the analyte in the blood through the coating. Moreover,
Hsu (U.S. Pat. No. 5,047,020) disclosed use of various heparin
complexes for coating blood gas sensors and noted that the
benzalkonium heparin complex was unsuitable for such an
intravascular sensor.
[0009] Accordingly, there is an important unmet need for a
thromboresistant coating and methods for applying such a coating to
an intravascular analyte sensor, and in particular, a glucose
sensor.
SUMMARY OF THE INVENTION
[0010] Embodiments of the invention relate to an analyte sensor,
comprising: an elongate member; an analyte-responsive indicator
disposed along a distal portion of the elongate member, wherein the
indicator is capable of generating a signal related to a
concentration of analyte in the blood vessel; a porous membrane
covering at least the indicator along the distal portion of the
elongate member; and a coating comprising heparin and benzalkonium
stably associated with at least a portion of the porous
membrane.
[0011] In preferred embodiments of the analyte sensor, the elongate
member comprises an optical fiber comprising a light path. The
analyte-responsive indicator preferably comprises a fluorophore
operably coupled to an analyte binding moiety, wherein analyte
binding causes a change in the emission intensity of the
fluorophore, and wherein the analyte responsive indictor is
disposed within the light path of the optical fiber. More
preferably, the fluorophore is HPTS-triCysMA and the binding moiety
is 3,3'-oBBV.
[0012] In certain embodiments, the porous membrane is a microporous
membrane. The microporous membrane may comprise one or more
polymers selected from a group consisting of the polyolefins, the
fluoropolymers, the polycarbonates, and the polysulfones. More
preferably, the microporous membrane comprises at least one
fluoropolymer. The at least one fluoropolymer may be selected from
the group consisting of polytetrafluoroethylene, perfluoroalkoxy
polymer, fluorinated ethylene-propylene,
polyethylenetetrafluoroethylene, polyvinylfluoride,
polyethylenechlorotrifluoroethylene, polyvinylidene fluoride,
polychlorotrifluoroethylene, perfluoropolyether,
perfluoroelastomer, and fluoroelastomer.
[0013] In other embodiments of the analyte sensor, the microporous
membrane comprises at least one polyolefin. The polyolefin is
preferably polyethylene.
[0014] An equilibrium intravascular analyte sensor is disclosed in
accordance with other embodiments of the invention. The equilibrium
intravascular analyte sensor comprises: an optical fiber configured
for positioning within a blood vessel and comprising a light path
and an outer surface; a chemical indicator system comprising a
fluorophore operably coupled to an analyte binding moiety, wherein
the fluorophore and analyte binding moiety are immobilized within a
water-insoluble organic polymer, and wherein the chemical indicator
system is disposed within the light path along a distal portion of
the optical fiber; and an antithrombogenic, analyte-permeable
coating on at least a portion of the outer surface of the optical
fiber and overlying the chemical indicator system disposed therein,
wherein the coating comprises heparin covalently cross-linked to
the outer surface.
[0015] The fluorophore is preferably HPTS-triCysMA and the binding
moiety is preferably 3,3'-oBBV.
[0016] The equilibrium intravascular analyte sensor may further
comprise a porous, analyte-permeable membrane disposed between the
chemical indicator system and the antithrombogenic coating.
[0017] A method for reducing the thrombogenicity of an analyte
sensor is disclosed in accordance with other embodiments of the
invention. The method comprises: providing the analyte sensor
comprising an elongate optical fiber defining a light path, an
equilibrium fluorescent chemical indicator system disposed along a
distal region of the optical fiber within the light path, and an
analyte-permeable porous membrane, which forms an outer layer of at
least a portion of the distal region, wherein the indicator system
is covered by the porous membrane; contacting the analyte sensor
with a single solution comprising a mixture of heparin and
benzalkonium, or with separate first and second solutions, wherein
the first solution comprises heparin and the second solution
comprises benzalkonium; drying the analyte sensor; and repeating
the contacting and drying steps between 2 and 10 times.
[0018] In preferred embodiments of the method, the equilibrium
fluorescent chemical indicator system comprises a fluorophore and
an analyte binding moiety, immobilized within a water-insoluble
organic polymer. The fluorophore may be HPTS-triCysMA, the binding
moiety may be 3,3'-oBBV, and the water-insoluble organic polymer
may be a DMAA (N,N-dimethylacrylamide) hydrogel matrix.
[0019] In another embodiment of the invention, a method is
disclosed for reducing the thrombogenicity of an analyte sensor.
The method comprises: providing the analyte sensor comprising an
elongate optical fiber defining a light path, an equilibrium
fluorescent chemical indicator system disposed along a distal
region of the optical fiber within the light path, and an
analyte-permeable porous membrane, which forms an outer surface
over at least a portion of the distal region, wherein the indicator
system is covered by the porous membrane; providing a
photoactivatable chemical linking agent and an antithrombogenic
molecule, wherein the linking agent is capable, upon activation, of
covalent attachment to the outer surface and the antithrombogenic
molecule, wherein the linking agent comprises a charged,
nonpolymeric di- or higher functional photoactivatable compound
comprising two or more photoreactive groups and one or more charged
groups; and activating the two or more photoreactive groups,
thereby cross-linking the antithrombogenic molecule to the outer
surface.
[0020] The equilibrium fluorescent chemical indicator system
preferably comprises a fluorophore and an analyte binding moiety,
immobilized within a water-insoluble organic polymer. In certain
preferred embodiments of the method, the fluorophore is
HPTS-triCysMA, the binding moiety is 3,3'-oBBV, and the
water-insoluble organic polymer is a DMAA (N,N-dimethylacrylamide)
hydrogel matrix.
[0021] In certain preferred embodiments of the method, the porous
membrane comprises microporous polyethylene.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a cut-away view of a sensor where a portion of the
porous membrane sheath is cut away to expose the optical fiber and
hydrogel beneath the membrane.
[0023] FIG. 2 is a cross-sectional view along a longitudinal axis
of a sensor with a hydrogel disposed distal the optical fiber.
[0024] FIG. 3A shows a glucose sensor having a series of holes that
form a helical configuration.
[0025] FIG. 3B shows a glucose sensor having a series of holes
drilled or formed at an angle.
[0026] FIG. 3C shows a glucose sensor having at least one spiral
groove.
[0027] FIG. 3D shows a glucose sensor having a series of triangular
wedge cut-outs.
[0028] FIG. 4 shows a cross-sectional view of one embodiment of a
glucose sensor having a cavity in the distal portion of the
sensor.
[0029] FIG. 5 shows a glucose measurement system comprising two
excitation light sources and a microspectrometer and/or
spectrometer.
[0030] FIGS. 6A and 6B show alternative embodiments of an optical
glucose sensor, wherein the optical sensor is surrounded by a
tubular mesh (FIG. 6A) or coil (FIG. 6B), which is further
surrounded by a polymeric material with an open window.
[0031] FIG. 7A illustrates the adhesion of a coating of heparin
benzalkonium to a microporous membrane section of a sensor.
[0032] FIG. 7B illustrates the adhesion of a coating of heparin
benzalkonium to a nonporous precursor section of a sensor.
[0033] FIG. 8 shows the heparin activity of a glucose sensor that
has undergone heparin soaking.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0034] The following description and examples illustrate a
preferred embodiment of the present invention in detail. Those of
skill in the art will recognize that there are numerous variations
and modifications of this invention that are encompassed within its
scope. Accordingly, the description of a preferred embodiment
should not be deemed to limit the scope of the present
invention.
[0035] Various embodiments disclosed herein are generally directed
towards analyte sensors configured for in vivo deployment (e.g.,
intravascular, interstitial, etc.), preferably glucose sensors,
wherein the sensors further comprise a thromboresistant outer
surface, preferably a coating. Methods of coating sensors to create
a thromoboresistant outer surface are also disclosed. Of course,
intravascular sensors for detecting other analytes besides glucose
may also benefit from aspects of the invention, e.g., reducing,
inhibiting, and/or preventing blood clot or thrombus formation
around the sensor.
DEFINITIONS
[0036] Unless defined otherwise, technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. For
purposes of the present invention, the following terms are defined
below.
[0037] "Porous" is used herein to refer to material that has pores
in it to allow permeation of chemical species through the material.
The material can be "nanoporous" meaning the material has a mean
pore diameter of less than about 2 nm. The material can be
"microporous" meaning the material has a mean pore diameter between
about 2 nm and about 50 nm. The material can be "mesoporous"
meaning that the material has a mean pore diameter of greater than
about 50 nm. The material can also be semipermeable, allowing only
some chemical species to pass through while preventing or
inhibiting other materials from passing through.
[0038] "Polyolefin" is used herein to refer to polymers produced
from olefins, including copolymers. Two primary examples are
polyethylene and polypropylene. Many different grades of these are
available, with the grades frequently described in terms of
molecular weight or density. Polymers from longer chain monomers
than two or three carbons are also included.
[0039] "Fluoropolymer" is used herein to refer to polymers that
contain chlorine and/or fluorine atoms. Examples include
polytetrafluoroethylene, perfluoroalkoxy polymer, fluorinated
ethylene-propylene, polyethylenetetrafluoroethylene,
polyvinylfluoride, polyethylenechlorotrifluoroethylene,
polyvinylidene fluoride, polychlorotrifluoroethylene,
perfluoropolyether, perfluoroelastomer, and fluoroelastomer. These
materials may be rigid or elastomeric. Trade names include TEFLON,
TEFZEL, FLUON, TEDLAR, HALAR, KYNAR, KEL-F, CTFE, KALREZ,
TECNOFLON, FFKM, VITON, FOMBLIN, and GALDEN.
[0040] "Polycarbonate" is used herein to refer to polymers having
functional groups linked by carbonate groups. Trade names include
LEXAN, CALIBRE, MAKROLON, PANLITE, and MAKROLIFE.
[0041] "Polysulfone" is used herein to refer to polymers containing
the sulfone or sulfonyl group, and are most commonly made up of the
subunit (aryl 1)-SO.sub.2-(aryl 2).
[0042] "Heparin" as used herein includes polysaccharide materials
having anticoagulant and/or antithrombotic properties, and is
frequently referred to as containing alternating derivatives of
D-glycocyamine (N-sulfated or N-acetylated) and uranic acid
(L-iduronic acid with varying sulfate or D-glucuronic acid) joined
by glycosidic linkages, or as including heterogeneous mixtures of
variably sulfated polysaccharide chains composed of repeating units
of D-glucosamine and either L-iduronic or D-glucuronic acids.
Heparin can be derived from natural sources, such as bovine or
porcine mucosal tissue, such as from the lung or intestine, and can
have varying molecular weight.
[0043] "Benzalkonium chloride" is used herein to refer to halogen
salts of quaternary ammonium compounds and mixtures of quaternary
ammonium compounds primarily having a benzyl and three R-groups
attached to the nitrogen, as depicted in the following
structure:
##STR00001##
where R1 is in alkyl group having from about one to about five
carbons, R2 is an alkyl group having about one to about five
carbons, R3 is an alkyl group having about six to about 22 carbons,
and X.sup.- is a halogen counterion. While the use of the word
"chloride" refers to a specific halogen counter ion having atomic
number 17, any halogen counter ion, such as fluoride, chloride,
bromide, iodide, etc., with the most commonly used counter ion
being chloride may be used in aspects of the present invention.
Furthermore, "benzalkonium" is used herein to refer to the
quaternary ammonium compound itself. Thus, the halogen salt
"benzalkonium chloride" comprises "benzalkonium" and a chloride
counter ion. "HBAC" is used herein to refer to complexes of heparin
and benzalkonium chloride. Varying grades and molecular weights of
heparin can be used. Varying grades of benzalkonium chloride, as
well as other salts of benzalkonium ion having various chain
lengths for the R-groups, whether in purified or mixed forms, or
combined with other related or unrelated compounds can also be
used.
Analyte Sensors
[0044] Analyte sensors suitable for coating with a thromboresistant
surface include those analyte sensors having a polymeric external
surface on at least a portion of the sensor. Preferably, that
portion of the sensor is configured for in vivo deployment, and
more preferably for intravascular deployment. Polymeric materials
that can be utilized as a portion of the external surface include
hydrophobic polymers such as polyolefins (for example polyethylene
and polypropylene), polycarbonate, polysulfone, and fluorocarbons.
In some embodiments, the polymeric material can be nanoporous. In
some embodiments, the polymeric material can be microporous. In
certain such embodiments, the mean pore diameter may be between
about 2 nm and about 10 nm, or between about 10 nm and about 20 nm,
or between about 20 nm and 30 nm, or between about 30 nm and about
40 nm, or between about 40 nm and about 50 nm, including
combinations of the aforementioned ranges. Thus, for example, in
certain embodiments, the mean pore diameter may be between about 10
nm and about 30 nm, or between about 20 nm and about 40 nm. In
other embodiments, the polymeric material can be mesoporous.
[0045] In some embodiments, the porous polymeric surface can be a
covering or sheath for at least a portion of the body of the
sensor. When the polymeric surface is a covering or sheath, it can
be made and/or applied by any suitable method. Sensors can be
constructed in various ways, appropriate to the sensing
chemistry/technique that is utilized by the sensor. In one
embodiment, an optical sensor, such as a sensor producing a
fluorescent response in relation to the analyte concentration can
have a porous polymeric outer surface for at least a portion of the
sensor assembly.
[0046] In some embodiments, a sensor can include an insoluble
polymeric matrix, which immobilizes the analyte sensitive chemical
indicator systems and is sufficiently permeable to the analyte of
interest. Suitable polymeric matrix materials include those related
to acrylic polymers. In some embodiments, fluorophores and/or
binders/quenchers can be incorporated into the polymeric matrix
(See e.g., U.S. Pat. Nos. 6,627,177, 7,470,420 and 7,417,164; each
of which is incorporated herein in its entirety by reference).
[0047] Any other intravascular glucose sensor may be used in
accordance with embodiments of the invention, including for example
the electrochemical sensors disclosed in U.S. Publication Nos.
2008/0119704, 2008/0197024, 2008/0200788, 2008/0200789 and
2008/0200791.
[0048] Preferred embodiments of the glucose sensor are configured
for implantation into a patient. For example, implantation of the
sensor may be made in the arterial or venous systems for direct
testing of glucose levels in blood. The site of implantation may
affect the particular shape, components, and configuration of the
sensor. In some embodiments, the sensor may be configured for
interstitial deployment.
[0049] Examples of glucose-sensing chemical indicator systems and
glucose sensor configurations for intravascular glucose monitoring
include the optical sensors disclosed in U.S. Pat. Nos. 5,137,033,
5,512,246, 5,503,770, 6,627,177, 7,417,164 and 7,470,420, and U.S.
Patent Publ. Nos. 2008/0188722, 2008/0188725, 2008/0187655,
2008/0305009, 2009/0018426, 2009/0018418, and co-pending U.S.
patent application Ser. Nos. 11/296,898, 12/187,248, 12/172,059,
12/274,617 and 12/424,902; each of which is incorporated herein in
its entirety by reference thereto.
[0050] Other glucose sensors configured for intravascular
deployment include electrochemical sensors, such as those disclosed
in U.S. Patent Publ. Nos. 2008/0119704, 2008/0197024, 2008/0200788,
2008/0200789 and 2008/0200791; each of which is incorporated herein
in its entirety by reference thereto.
[0051] An optical glucose sensor in accordance with preferred
embodiments of the present invention comprises a chemical indicator
system. Some useful indicator systems comprise a fluorophore
operably coupled to an analyte binding moiety, wherein analyte
binding causes an apparent optical change in the fluorophore
concentration (e.g., emission intensity). For example, a glucose
binding moiety such as 3,3'-oBBV that is operably coupled to a
fluorescent dye such as HPTS-triCysMA will quench the emission
intensity of the fluorescent dye, wherein the extent of quenching
is reduced upon glucose binding resulting in an increase in
emission intensity related to glucose concentration. In further
preferred embodiments, the indicator systems also comprise a means
for immobilizing the sensing moieties (e.g., dye-quencher) such
that they remain physically close enough to one another to react
(quenching). Such immobilizing means are preferably insoluble in an
aqueous environment (e.g., intravascular), permeable to the target
analytes, and impermeable to the sensing moieties. Typically, the
immobilizing means comprises a water-insoluble organic polymer
matrix. For example, the HPTS-triCysMA dye and 3,3'-oBBV quencher
may be effectively immobilized within a DMAA
(N,N-dimethylacrylamide) hydrogel matrix.
[0052] Some preferred fluorophores (e.g., HPTS-triCysMA),
quenchers/analyte binding moieties (e.g., 3,3'-oBBV) and
immobilizing means (e.g., N,N-dimethylacrylamide), as well as
methods for synthesizing and assembling such indicator systems are
set forth in greater detail in U.S. Pat. Nos. 6,627,177, 7,417,164
and 7,470,420, and U.S. Patent Publ. Nos. 2008/0188722,
2008/0188725, 2008/0187655, 2008/0305009, 2009/0018426,
2009/0018418, and co-pending U.S. patent application Ser. Nos.
12/187,248, 12/172,059, 12/274,617 and 12/424,902.
[0053] Other indicator chemistries, such as those disclosed in U.S.
Pat. Nos. 5,176,882 to Gray et al. and 5,137,833 to Russell, can
also be used in accordance with embodiments of the present
invention; both of which are incorporated herein in their
entireties by reference thereto. In some embodiments, an indicator
system may comprise an analyte binding protein operably coupled to
a fluorophore, such as the indicator systems and glucose binding
proteins disclosed in U.S. Pat. Nos. 6,197,534, 6,227,627,
6,521,447, 6,855,556, 7,064,103, 7,316,909, 7,326,538, 7,345,160,
and 7,496,392, U.S. Patent Application Publication Nos.
2003/0232383, 2005/0059097, 2005/0282225, 2009/0104714,
2008/0311675, 2008/0261255, 2007/0136825, 2007/0207498, and
2009/0048430, and PCT International Publication Nos. WO
2009/021052, WO 2009/036070, WO 2009/021026, WO 2009/021039, WO
2003/060464, and WO 2008/072338 which are hereby incorporated by
reference herein in their entireties.
[0054] FIG. 1 shows a sensor 2 in accordance with an embodiment of
the present invention. The sensor comprises an optical fiber 10
with a distal end 12 disposed in a porous membrane sheath 14. The
optical fiber 10 has cavities, such as holes 6A, in the fiber optic
wall that can be formed by, for example, mechanical means such as
drilling or cutting. The holes 6A in the optical fiber 10 can be
filled with a suitable compound, such as a polymer. In some
embodiments, the polymer is a hydrogel 8. In other embodiments of
the sensor 2 as shown in FIG. 2, the optical fiber 10 does not have
holes 6A, and instead, the hydrogel 8 is disposed in a space distal
to the distal end 12 of the optical fiber 10 and proximal to the
mirror 23. In some embodiments, the sensor 2 is a glucose sensor.
In some embodiments, the glucose sensor is an intravascular glucose
sensor.
[0055] In some embodiments, the porous membrane sheath 14 can be
made from a polymeric material such as polyethylene, polycarbonate,
polysulfone or polypropylene. Other materials can also be used to
make the porous membrane sheath 14 such as zeolites, ceramics,
metals, or combinations of these materials. In some embodiments,
the porous membrane sheath 14 may be nanoporous. In other
embodiments, the porous membrane sheath 14 may be microporous. In
still other embodiments, the porous membrane sheath 14 may be
mesoporous.
[0056] In some embodiments as shown in FIG. 2, the porous membrane
sheath 14 is attached to the optical fiber 10 by a connector 16.
For example, the connector 16 can be an elastic collar that holds
the porous membrane sheath 14 in place by exerting a compressive
force on the optical fiber 10, as shown in FIG. 2. In other
embodiments, the connector 16 is an adhesive or a thermal weld.
[0057] In some embodiments as shown in FIG. 1, a mirror 23 and
thermistor 25 can be placed within the porous membrane sheath 14
distal the distal end 12 of the optical fiber 10. Thermistor leads
27 can be made to run in a space between the optical fiber 10 and
porous membrane sheath 14. Although a thermistor 25 is shown, other
devices such as a thermocouple, pressure transducer, an oxygen
sensor, a carbon dioxide sensor or a pH sensor for example can be
used instead.
[0058] In some embodiments as shown in FIG. 2, the distal end 18 of
the porous membrane sheath 14 is open and can be sealed with, for
example, an adhesive 20. In some embodiments, the adhesive 20 can
comprise a polymerizable material that can fill the distal end 18
and then be polymerized into a plug. Alternatively, in other
embodiments the distal end 18 can be thermally welded by melting a
portion of the polymeric material on the distal end 18, closing the
opening and allowing the melted polymeric material to resolidify.
In other embodiments as shown in FIG. 1, a polymeric plug 21 can be
inserted into the distal end 18 and thermally heated to weld the
plug to the porous membrane sheath 14. Themoplastic polymeric
materials such as polyethylene, polypropylene, polycarbonate and
polysulfone are particularly suited for thermal welding. In other
embodiments, the distal end 18 of the porous membrane sheath 14 can
be sealed against the optical fiber 10.
[0059] After the porous membrane sheath 14 is attached to the
optical fiber 10 and the distal end 18 of the porous membrane
sheath 14 is sealed, the sensor 2 can be vacuum filled with a first
solution comprising a monomer, a crosslinker and a first initiator.
Vacuum filling of a polymerizable solution through a porous
membrane and into a cavity in a sensor is described in detail in
U.S. Pat. No. 5,618,587 to Markle et al.; incorporated herein in
its entirety by reference thereto. The first solution is allowed to
fill the cavity 6 within the optical fiber 10.
[0060] In some embodiments, the first solution is aqueous and the
monomer, the crosslinker and the first initiator are soluble in
water. For example, in some embodiments, the monomer is acrylamide,
the crosslinker is bisacrylamide and the first initiator is
ammonium persulfate. In other embodiments, the monomer is
dimethylacrylamide or N-hydroxymethylacrylamide. By increasing the
concentrations of the monomer and/or crosslinker, the porosity of
the resulting gel can be decreased. Conversely, by decreasing the
concentrations of the monomer and/or crosslinker, the porosity of
the resulting gel can be increased. Other types of monomers and
crosslinkers are also contemplated. In other embodiments, the first
solution further comprises an analyte indicator system comprising a
fluorophore and an analyte binding moiety that functions to quench
the fluorescent emission of the fluorophore by an amount related to
the concentration of the analyte. In some embodiments, the
fluorophore and analyte binding moiety are immobilized during
polymerization, such that the fluorophore and analyte binding
moiety are operably coupled. In other embodiments, the fluorophore
and analyte binding moiety are covalently linked. The indicator
system chemistry may also be covalently linked to the polymeric
matrix.
[0061] In some embodiments, after the sensor 2 is filled with the
first solution, the optical fiber 10 and the first solution filled
porous membrane sheath 14 and cavity 6 are transferred to and
immersed into a second solution comprising a second initiator. In
some embodiments, the second solution is aqueous and the second
initiator is tetramethylethylenediamine (TEMED). In some
embodiments, the second solution further comprises the same
fluorescent dye and/or quencher found in the first solution and in
substantially the same concentrations. By having the fluorescent
dye and quencher in both the first solution and the second
solution, diffusion of fluorescent dye and quencher out of the
first solution and into the second solution can be reduced. In some
embodiments where a second solution is used, the second solution
further comprises monomer in substantially the same concentration
as in the first solution. This reduces diffusion of monomer out of
the first solution by reducing the monomer gradient between the
first solution and the second solution.
[0062] In some embodiments, at or approximately at the interface
between the first and second solutions, the first initiator and the
second initiator can react together to generate a radical. In some
embodiments, the first initiator and the second initiator react
together in a redox reaction. In other embodiments, the radical can
be generated by thermal decomposition, photolytic initiation or
initiation by ionizing radiation. In these other embodiments, the
radical may be generated anywhere in the first solution. Once the
radical is generated, the radical can then initiate polymerization
of the monomer and crosslinker in the first solution.
[0063] When the radical is generated via a redox reaction as
described herein, the polymerization proceeds generally from the
interface between the first and second solutions to the interior of
the porous membrane sheath 14 and towards the cavity in the optical
fiber 10. Rapid initiation of polymerization can help reduce the
amount of first initiator that can diffuse from the first solution
and into the second solution. Reducing the amount of first
initiator that diffuses out of the first solution helps reduce
polymerization of monomer outside the porous membrane sheath 14
which helps in forming a smooth external surface. Polymerization of
the monomer and crosslinker results in a hydrogel 8 that in some
embodiments substantially immobilizes the indicator system, forming
the sensor 2. Further variations on polymerization methodologies
are disclosed in U.S. Patent Publ. No. 2008/0187655; incorporated
herein in its entirety by reference thereto.
[0064] With reference to FIG. 3A, in certain embodiments, the
glucose sensor 2 is a solid optical fiber with a series holes 6A
drilled straight through the sides of the optical fiber. In certain
embodiments, the holes 6A are filled with the hydrogels 8. In
certain embodiments, the series of holes 6A that are drilled
through the glucose sensor 2 are evenly spaced horizontally and
evenly rotated around the sides of the glucose sensor 2 to form a
spiral or helical configuration. In certain embodiments, the series
of holes 6A are drilled through the diameter of the glucose sensor
2. With reference to FIG. 3B, in certain embodiments, the glucose
sensor 2 is a solid optical fiber with a series of holes 6A drilled
through the sides of the fiber at an angle. In certain embodiments,
the series of holes 6A drilled at an angle, which are filled with
hydrogel 8, are evenly spaced horizontally and evenly rotated
around the sides the glucose sensor 2. With reference to FIG. 3C,
in certain embodiments, the optical fiber comprises a groove 6B
along the length of the optical fiber, wherein the groove 6B is
filled with hydrogel 8. In certain embodiments, the depth of the
groove 6B extends to the center of the optical fiber. In certain
embodiments, the groove 6B spirals around the optical fiber. In
certain embodiments, the groove 6B spirals around the optical fiber
to complete at least one rotation. In certain embodiments, the
groove spirals 6B around the optical fiber to complete multiple
rotations around the optical fiber.
[0065] With reference to FIG. 3D, in certain embodiments, the
glucose sensor 2 is a solid optical fiber with triangular wedges 6C
cut from the fiber. In certain embodiments, the triangular wedge
areas 6C are filled with hydrogel 8. In certain embodiments, the
triangular wedges cut-outs 6C are evenly spaced horizontally and
around the sides of the glucose sensor 2. In certain embodiments,
all light traveling in the glucose sensor 2 is transmitted through
at least one hole 6A or groove 6B filled with hydrogel 8.
[0066] In certain embodiments, as illustrated in FIG. 4, the
glucose sensor 2 comprises an optical fiber 10 having a distal end
12, an atraumatic tip portion 134 having a proximal end 136 and a
distal end 138, a cavity 6 between the distal end 12 of the optical
fiber 10 and the proximal end 136 of the atraumatic tip portion
134, and a rod 140 connecting the distal end 12 of the optical
fiber 10 to the proximal end 136 of the atraumatic tip portion 134.
A hydrogel 8 containing glucose sensing chemistry, for example a
fluorophore and quencher, fills the cavity 6. Covering the hydrogel
filled cavity 6 is a selectively permeable membrane 14 that allows
passage of glucose into and out of the hydrogel 8. Although these
embodiments are described using a glucose sensor 2, it should be
understood by a person of ordinary skill in the art that the sensor
2 can be modified to measure other analytes by changing, for
example, the sensing chemistry, and if necessary, the selectively
permeable membrane 14. The proximal portion of the sensor 2
comprises the proximal portion of the optical fiber 10. In some
embodiments, the diameter, D1, of the distal portion of the sensor
2 is greater than the diameter, D2, of the proximal portion of the
sensor 2. For example, the diameter D1 of the distal portion of the
sensor 2 can be between about 0.0080 inches and 0.020 inches, while
the diameter D2 of the proximal portion of the sensor 2 can be
between about 0.005 inches to 0.015 inches. In some embodiments,
the diameter D1 of the distal portion of the sensor 2 is about
0.012 inches, while the diameter D2 of the proximal portion of the
sensor 2 is about 0.010 inches.
[0067] In some embodiments, the glucose sensor 2 includes a
temperature sensor 25, such as thermocouple or thermistor. The
temperature sensor 25 can measure the temperature of the hydrogel 8
and glucose sensing chemistry system. The temperature sensor 25 is
particularly important when the glucose sensing chemistry, such as
a fluorophore system, is affected by temperature change. For
example, in some embodiments, the fluorescence intensity emitted by
the fluorophore system is dependent on the temperature of the
fluorophore system. By measuring the temperature of the fluorophore
system, temperature induced variations in fluorophore fluorescence
intensity can be accounted for, allowing for more accurate
determination of glucose concentration, as more fully described
below.
[0068] In certain embodiments, the hydrogels are associated with a
plurality of fluorophore systems. In certain embodiments, the
fluorophore systems comprise a quencher with a glucose receptor
site. In certain embodiments, when there is no glucose present to
bind with the glucose receptor, the quencher prevents the
fluorophore system from emitting light when the dye is excited by
an excitation light. In certain embodiments, when there is glucose
present to bind with the glucose receptor, the quencher allows the
fluorophore system to emit light when the dye is excited by an
excitation light.
[0069] In certain embodiments, the emission produced by the
fluorophore system varies with the pH of the solution (for example,
blood), such that different excitation wavelengths (one exciting
the acid form of the fluorophore and the other the base form of the
fluorophore) produce different emissions signals. In preferred
embodiments, the ratio of the emission signal from the acid form of
the fluorophore over the emission signal from the base form of the
fluorophore is related to the pH level of the blood; the
simultaneous measurement of glucose and pH is described in detail
in U.S. Patent Publication No. 2008/0188722 (incorporated herein in
its entirety by reference thereto). In certain embodiments, an
interference filter is employed to ensure that the two excitation
lights are exciting only one form (the acid form or the base form)
of the fluorophore.
[0070] Variations optical sensing systems, light sources, hardware,
filters, and detection systems are described in detail in U.S.
Publication No. 2008/0188725; incorporated herein in its entirety
by reference thereto. See e.g., FIG. 5, wherein certain embodiments
comprise at least two light sources. In certain embodiments, the
light sources 301A, 301B generate excitation light that is
transmitted through a collimator lens 302A, 302B. In certain
embodiments, the resulting light from collimator lens 302A, 302B is
transmitted to interference filters 303A, 303B. In certain
embodiments, the resulting light from interference filters 303A,
303B is focused by focusing lens 304A, 304B into fiber optic lines
305A, 305B. In certain embodiments, fiber optic lines may be a
single fiber or a bundle of fibers. In certain embodiments, the
fiber optic line 309 may be a single fiber or a bundle of fibers.
In certain embodiments, fiber optic lines 305A, 305B, 309 are
bundled together at junction 306 and are connected at glucose
sensor 307. The glucose sensor 307 comprises hydrogels 8.
[0071] In certain embodiments, the emission light and the
excitation light are reflected off the mirror 13 and into the fiber
optic line 309. In certain embodiments, the fiber optic line 309 is
connected to microspectrometer 310 that measures the entire
spectrum of light in the glucose measurement system 300. The
microspectrometer 310 may be coupled to a data processing module
311, e.g., the sensor control unit and/or receiver/display unit. In
certain embodiments, the ratio of emission light over the
corresponding excitation light is related to the concentration of
glucose. In certain embodiments, the ratio of the emissions light
(for example, the acid form) produced by the first excitation light
over the emission light (for example, the base form) produced by
the second excitation light is related to pH levels in the test
solution, for example blood.
[0072] In certain preferred embodiments, the microspectrometer is
the UV/VIS Microspectrometer Module manufactured by Boehringer
Ingelheim. Any microspectrometer can be used. Alternatively, the
microspectrometer could be substituted with other spectrometer,
such as those manufactured by Ocean Optic Inc.
[0073] In certain embodiments described above, the ratiometric
calculations require measurements of various light intensities. In
certain embodiments, these measurements are determined by measuring
the peak amplitudes at a particular wavelength or wavelength band.
In certain embodiments, these measurements are determined by
calculating the area under the curve between two particular
wavelengths as for example with the output from a
microspectrometer.
[0074] With reference to FIGS. 6A and 6B, another embodiment of an
intravascular optical glucose sensor is illustrated; this sensor
configuration is disclosed in greater detail in WO2009/019470
(incorporated herein in its entirety by reference thereto). To
provide a stronger and more robust sensor, which can withstand the
pressures of being introduced into the body, yet retain some
flexibility, sensors have been developed with internal reinforced
walls, such as those depicted in FIGS. 6A and 6B. FIG. 6A shows a
tube having a densely packed mesh 501A made of a first material and
coated with an outer wall 502 of a second material. Three square
cutouts 503 in the outer wall 502 of the tube arranged in a line
can be seen in FIG. 6A, but cutouts of other shapes, positioned in
other arrangements, are clearly feasible, depending on the
embodiments. In the illustrated embodiment, the mesh 501A shows a
high density of filament crossovers. This embodiment therefore has
an increased strength and a reduced porosity. The braid is able to
provide strength to the sensor, while allowing the tubular
structure to flex and be maneuvered to the correct sensing
position.
[0075] FIG. 6B depicts an embodiment in which the first material is
in the form of a coil 501B which is coated with an outer wall 502
of the second material. Similar to FIG. 6A, three square cutouts
503 in the outer wall 502 of the tube arranged in a line can be
seen in FIG. 6B, but cutouts of other shapes, positioned in other
arrangements, are clearly feasible, depending on the embodiments.
In this embodiment, the coil 501B is densely packed, providing
increased strength and reduced porosity in a similar manner to the
embodiment depicted in FIG. 6A. The reinforced walls can be
provided in a number of ways, for example by providing a braided
tubular structure which contains the sensing apparatus, as
described in International patent publication WO2004/054438;
incorporated herein in its entirety by reference thereto.
[0076] The first material is in the form of a mesh 501A, the
density of filament crossovers may be varied in order to control
the properties of the resulting tube. For example, a high density
mesh may have greater strength and a low density mesh a greater
flexibility. Variation in mesh density will also vary the porosity
of the mesh. This is significant at the location of the opening in
the outer wall since the porosity of the mesh will control the
speed of diffusion of the material to be tested into the tube.
Variation in the tightness of a coil can provide a similar
effect.
[0077] The second material is used to coat the first material in
order to form a continuous substantially impermeable outer wall 502
of the hollow tube. As used herein, the phrase substantially
impermeable means that the second material forms an effectively
closed tube, which is impermeable to the ingress of material from
outside the tube to inside the tube. Accordingly, until a portion
of the second material is removed, the tube is effectively sealed
along its length, except, in some embodiments, at its ends.
[0078] Suitable materials for use as the second material generally
include polymeric materials, more particularly polyesters,
polyolefins such as polyethylene (PE), e.g. low density
polyethylene (LDPE), fluoropolymers such as fluorinated ethylene
propylene (FEP), polytetrafluoroethylene (PTFE) and perfluoroalkoxy
polymer (PFA), polyvinylchloride (PVC), polyamides such as
polyether block amide (PEBA), Pebax.RTM., nylon and polyurethane.
Polyesters and polyolefins are preferred due to their suitability
for extrusion over the coil 501B or tubular mesh 501A. The
selective removal of a portion of a polyester or polyolefin
coating, e.g. by laser ablation, is also straightforward.
Polyolefins are particularly preferred due to the ease of laser
ablating these materials.
[0079] In order to form a continuous substantially impermeable tube
prior to selective removal of a portion of the second material, the
second material is first used to coat the coil or tubular mesh
formed by the first material. The second material can either coat
the outer surfaces of the first material, and in effect form a
continuous substantially impermeable tube around the coil or
tubular mesh formed by the first material, or the second material
can entirely encapsulate the first material, effectively forming a
tube of the second material in which is embedded the coil or
tubular mesh formed by the first material. In one embodiment the
second material can be applied to the first material by dip coating
the coil or tubular mesh formed by the first material. In this
embodiment, the second material is probably a polyamide, which
results in a very stiff tube. In another embodiment, a tube of the
second material can be provided, around which is formed the coil or
tubular mesh of the first material. A further layer of the second
material is then applied over the first material, resulting in the
first material being sandwiched between two layers of the second
material.
[0080] In a preferred embodiment, the first material is metallic
and the second material is polymeric. In addition to the first and
second materials, it is possible to include further materials in
the tubes of the invention. For example, for some applications it
may be useful to include a radiopaque additive to enable the sensor
incorporating the tube to be visible in vivo. For example,
radiopaque additives such as barium sulfate, bismuth subcarbonate,
bismuth trioxide and tungsten can be added. Where present, these
are preferably doped within the second material.
[0081] In certain processes, a portion of the second material is
selectively removed in order to generate at least one opening in a
region of the outer wall, while retaining the first material in
that region. As the first material is present in the form of a coil
or a tubular mesh, the first material does not form a completely
closed tube. Accordingly, when the second material is removed in
said region, this effectively forms a break in the continuous
substantially impermeable wall of the tube. Where the second
material simply coats the first material, it is necessary simply to
remove the coating provided by this second material in the region
where the opening is to be formed. Where the second material
effectively encapsulates the first material, it is necessary to
remove all of the second material which surrounds and encapsulates
the first material in the region where the opening is to be
formed.
[0082] Preferably, the chemical indicator system of the sensor is
located adjacent to the opening formed by selective removal of the
second material. This allows sensing of the environment in the
region of the opening on the tube wall. For example, where the
sensor is a glucose sensor, glucose is able to pass from the blood
vessel or other cavity where the sensor is introduced through the
opening and into the tube where its presence can be detected and
measured by the probe.
[0083] The size of the opening in the outer wall will generally be
between 1 and 400 mm.sup.2, for example between 25 and 225
mm.sup.2. The size of the opening must not be too small otherwise
the blood or other substance into which the sensor is introduced
will not be able to pass through the opening or will pass through
in insufficient quantities for an accurate measurement to be made.
The opening must also be large enough to allow positioning of the
probe such that it is adjacent to the opening, even if it moves
slightly when the sensor is introduced into the body.
[0084] In one embodiment, only one opening is generated in the tube
wall, i.e. only one region of the second material is selectively
removed. Preferably the opening extends only a portion of the way
around the circumference of the tube. In one embodiment, it is
preferred to retain some continuity of the second material along
the entire length of the tube, and is hence preferred that the
opening does not extend fully around the circumference of the tube.
For example, it may be preferred that the opening extends around up
to a maximum 75%, more preferably up to 50%, of the circumference
of the tube. In another embodiment of the invention, a plurality of
openings can be generated in the tube wall, i.e. more than one
region of the second material can be selectively removed. This
embodiment allows for probes to be located at a number of points
along the length of the tube, and for multiple measurements to be
taken. Thus, it is possible for a number of probes to be located
within the tube, each tube being adjacent to a different opening
within the tube wall. Alternatively, a single probe could be
located within the tube and be provided with means for moving it
from one opening to another opening, hence allowing measurements to
be taken at a number of points along the length of the tube.
Thromboresistant Coatings
[0085] Molecules of a biocompatible agent are attached to the
surfaces of the medical device to improve biocompatibility, such as
antithrombogenic agents like heparin, albumin, streptokinase,
tissue plasminogin activator (TPA) or urokinase. For example, the
biocompatible agent may comprise molecules of both albumin and
heparin. In one embodiment the molecules of a biocompatible
material are joined to one another to form a film that is attached
to a solid surface by a linking moiety. In other examples, various
surface treatments of the optical glucose sensor can be used, such
as those disclosed in U.S. Pat. Nos. 4,722,906, 4,973,493,
4,979,959, 5,002,582, 5,049,403, 5,213,898, 5,217,492, 5,258,041,
5,512,329, 5,563,056, 5,637,460, 5,714,360, 5,840,190, 5,858,653,
5,894,070, 5,942,555, 6,007,833, 6,090,995, 6,121,027, 6,254,634,
6,254,921, 6,278,018, 6,410,044, 6,444,318, 6,461,665, 6,465,178,
6,465,525, 6,506,895, 6,559,132, 6,669,994, 6,767,405, 7,300,756,
7,550,443, 7,550,444, and U.S. Patent Publ. Nos. 20010014448,
20030148360, and 20090042742 (each of which is incorporated herein
in its entirety by reference thereto).
[0086] In one embodiment, the chemical linking moiety has the
formula A-X--B in which A represents a photochemically reactive
group capable of bonding covalently to a solid surface; B
represents a different reactive group capable desirably in response
to specific activation to which group A is unresponsive, of forming
a covalent bond to a biocompatible agent and X represents a
relatively inert, noninterfering skeletal moiety joining groups
"A", and "B", that is resistant to cleavage in aqueous
physiological fluid. The physiological fluid referred to is such
fluid with which X will come in contact (e.g., blood, interstitial
fluid, etc.). In a method of the invention group "A" of the linking
moiety is covalently bound to the solid surface, with a sufficient
population density to enable the molecules of the biocompatible
agent to effectively shield the solid surface when the molecules
are covalently bound to group "B" to provide a biocompatible
effective surface. A biocompatible device of this invention
includes a solid surface to which molecules of a biocompatible
agent have been bound via the chemical-linking moiety as follows:
solid surface-A residue-X--B residue-molecules of a biocompatible
agent.
[0087] In one embodiment, the molecules of the biocompatible agent
are selectively bound to the solid surface with a sufficient
population density to provide a biocompatible effective surface
using a chemically linking moiety that has the formula:
##STR00002##
in which R represents a selector group that is a member of a
specific bonding pair and that is reactive to form a bond with a
receptor forming the other member of the specific binding pair and
carried by a selected biocompatible agent and A, and B represent
the groups described above as A and B. X represents a relatively
inert, non-interfering skeletal radical joining groups "A", "B" and
"R" and sterically enabling group "B" to separate from group "R" by
at least about 10 .ANG..
[0088] Groups "B" and "R" are preferably sterically distinct
groups; that is, they may, during the course of thermal vibration
and rotation separate by a distance of at least about 10 .ANG..
Group R, a "selector" group, representing a member of a specific
binding pair, commonly forms a bond, usually noncovalent, with the
biocompatible agent at an epitopic or other binding site of the
latter (which site typifies a "receptor" herein). The group "B",
which upon activation can covalently bond to the biocompatible
agent, may be sterically spaced from the group "R", thereby
enabling the covalent bond to be formed at a site spaced from the
receptor site. In turn, the selector receptor bond may be
disassociated from the receptor site through breakage of a fragile
bond between the selector group and the chemical linking moiety
followed by removal of the selector by, e.g., dialysis,
environmental changes (pH, ionic strength, temperature, solvent
polarity, etc.) or through spontaneous catalytic modification of
the selector group (as when the biocompatible agent is an enzyme),
etc. The receptor thus is reactivated to permit subsequent reaction
with members of the specific binding pair.
[0089] As referred to herein, "specific binding pair" refers to
pairs of substances having a specific binding affinity for one
another. Such substances include antigens and their antibodies,
haptens and their antibodies, enzymes and their binding partners
(including cofactors, inhibitors and chemical moieties whose
reaction the enzymes promote), hormones and their receptors,
specific carbohydrate groups and lectins, vitamins and their
receptors, antibiotics and their antibodies and naturally occurring
binding proteins, etc. The concept of employing specific binding
pairs in analytical chemistry is well known and requires little
further explanation. Reference is made to Adams, U.S. Pat. No.
4,039,652, Maggio, et al, U.S. Pat. No. 4,233,402 and Murray, et
al, U.S. Pat. No. 4,307,071, the teachings of which are
incorporated herein by reference.
[0090] In certain embodiments, X is preferably a C.sub.1-C.sub.10
alkyl group such as polymethylene, a carbohydrate such as
polymethylol, a polyoxyethylene, such as polyethylene glycol or a
polypeptide such as polylysine.
[0091] The reactive group B is preferably a group that upon
suitable activation covalently bonds to proteinaceous or other
biocompatible agents. Such groups are typified by thermochemical
groups and photochemical groups, as described and exemplified in
Guire, U.S. Pat. No. 3,959,078, the teachings of which are
incorporated herein by reference.
[0092] The photochemically reactive groups (A) (the covalent
bonding of which is activated by actinic radiation) may be typified
by aryl, alkyl and acyl azides, oxazidines, isocyanates (nitrene
generators), alkyl and 2 ketodiazo derivatives and diazirines
(carbene generators), aromatic ketones (triplet oxygen generators),
aromatic diazonium derivatives and numerous classes of carbonium
ion and radical generators. Reference is made to Frederick J.
Darfler and Andrew M. Tometsko, chapter 2 of Chemistry and
Biochemistry of Amino Acids, Peptides and Proteins (Boris
Weinstein, ed) vol. 5, Marcel Dekker, Inc. New York, 1978, for
further description of photochemically reactive groups.
Azidonitrophenyls, fluoroazido nitrobenzenes, and aromatic ketones
form a preferred group due to their stability to chemical reaction
conditions in the dark and their susceptibility to activation by
light of wave lengths harmless to most biomaterials, to form
short-lived reactive intermediates capable of forming covalent
bonds in useful yield with most sites on the biomaterial.
[0093] Nitrophenylazide derivatives (shown as including the X
group) appropriate for use as photochemically reactive groups for
the most part can be derived from fluoro-2-nitro-4-azidobenzene,
and include 4-azido-2-nitrophenyl(ANP)-4-aminobutyryl,
ANP-6-aminocaproyl, ANP-11-aminoundecanoyl, ANP-glycyl,
ANP-aminopropyl, ANP-mercaptoethylamino, ANP-diaminohexyl,
ANP-diaminopropyl, and ANP-polyethylene glycol. ANP-6-aminocaproyl,
ANP-11-aminoundecanoyl, and ANP-polyethylene glycol are preferred.
Aromatic ketones preferred for use as photochemically reactive
groups include benzylbenzoyl and nitrobenzylbenzoyl.
[0094] Thermochemical reactive groups (that are activated by heat
energy) are typified by and include nitrophenylhalides, alkylamino,
alkylcarboxyl, alkylthiol, alkylaldehyde, alkylmethylimidate,
alkylisocyanate, alkylisothiocyanate and alkylhalide groups.
[0095] Groups appropriate for use as thermochemically reactive
groups include carboxyl groups, hydroxyl groups, primary amino
groups, thiol groups, maleimides and halide groups.
N-oxysuccinimide carboxylic esters of such groups as 6-amino
hexanoic acid and amino undecanoic acid, alkylthiol groups such as
mercaptosuccinic anhydride and beta-mercaptopropionic acid,
homocysteinethiolactones, and polyetheylene glycol derivatives are
preferred.
[0096] Other linking agents can also be used in the embodiments of
the present disclosure, such as those disclosed in U.S. Pat. No.
6,077,698, which is incorporated herein by reference. For example,
a chemical linking agent comprising a di- or higher functional
photoactivatable charged compound can be used. The linking agent
preferably provides at least one group that is charged under the
conditions of use in order to provide improved water solubility.
The linking agent may further provide two or more photoactivatable
groups in order to allow the agent to be used as a cross-linking
agent in aqueous systems. In preferred embodiments, the charge is
provided by the inclusion of one or more quaternary ammonium
radicals, and the photoreactive groups are provided by two or more
radicals of an aryl ketone such as benzophenone.
[0097] The thromboresistant agent may carry one or more latent
reactive groups covalently bonded to them. The latent reactive
groups are groups which respond to specific applied external
stimuli to undergo active specie generation with resultant covalent
bonding to an adjacent support surface. Latent reactive groups are
those groups of atoms in a molecule which retain their covalent
bonds unchanged under conditions of storage but which, upon
activation, form covalent bonds with other molecules. The latent
reactive groups generate active species such as free radicals,
nitrenes, carbenes, and excited states of ketones upon absorption
of external electromagnetic or kinetic (thermal) energy. Latent
reactive groups may be chosen to be responsive to various portions
of the electromagnetic spectrum, and latent reactive groups that
are responsive to ultraviolet, visible or infrared portions of the
spectrum are preferred. Latent reactive groups as described are
generally well known.
[0098] The azides constitute a preferred class of latent reactive
groups and include arylazides, such as those disclosed in U.S. Pat.
No. 5,002,582, which is incorporated by reference herein, for
example phenyl azide and particularly 4-fluoro-3-nitrophenyl azide,
acyl azides such as benzoyl azide and p-methylbenzoyl azide, azido
formates such as ethyl azidoformate, phenyl azidoformate, sulfonyl
azides such as benzenesulfonyl azide, and phosphoryl azides such as
diphenyl phosphoryl azide and diethyl phosphoryl azide. Diazo
compounds constitute another class of latent reactive groups and
include diazoalkanes (--CHN.sub.2) such as diazomethane and
diphenyldiazomethane, diazoketones such as diazoacetophenone and
1-trifluoromethyl-1-diazo-2-pentanone, such as t-butyl diazoacetate
and phenyl diazoacetates, and beta-ketone-alpha-diazoacetates such
as t butyl alpha diazoacetoacetate. Other latent reactive groups
include the aliphatic azo compounds such as azobisisobutyronitrile,
the diazirines such as 3-trifluoromethyl-3-phenyldiazirine, the
ketenes (--CH.dbd.C.dbd.O) such as ketene and diphenylketene and
photoactivatable ketones such as benzophenone and acetophenone.
Peroxy compounds are contemplated as another class of latent
reactive groups and include dialkyl peroxides such as di-t-butyl
peroxide and dicyclohexyl peroxide and diacyl peroxides such as
dibenzoyl peroxide and diacetyl peroxide and peroxyesters such as
ethyl peroxybenzoate. Upon activation of the latent reactive groups
to cause covalent bond formation to the surfaces to which polymer
molecules are to be attached, the polymer molecules are covalently
attached to the surfaces by means of residues of the latent
reactive groups. Exemplary latent reactive groups are recited in
U.S. Pat. No. 5,002,582 incorporated herein by reference.
[0099] The polymers and oligomers used may have one or more latent
reactive groups. In certain embodiments, the polymers have at least
one latent reactive group per molecule with the ratio of reactive
groups extended polymer length, in Angstroms, ranging from about
1/10 to about 1/700 and preferably from about 1/50 to 1/400. As
will be noted from the foregoing description, photoreactive latent
reactive groups are for the most part aromatic and hence generally
are hydrophobic rather than hydrophilic in nature.
[0100] The latent reactive groups and the polymer molecules to
which they are bonded may have substantially different solvophilic
properties. For example, the latent reactive groups may be
relatively hydrophobic, whereas the polymer molecules may be
relatively hydrophilic; when solution of the molecules is contacted
with a relatively hydrophobic surface, it is believed that the
latent reactive groups, being hydrophobic, tend to orient nearer
the surface so as to improve bonding efficiency when the latent
reactive groups are activated. The preferred latent reactive groups
are benzophenones, acetophenones, and aryl azides.
[0101] The loading density of polymers upon a surface may be
improved by a process in which a latent reactive molecule (a
molecule having a latent reactive group) is first brought into
close association (as by means of a solvent solution) to a surface,
and thereafter the polymer to be bonded to the surface is brought
into contact with and is covalently bonded to the latent reactive
molecule, as to a reactive group different from the latent reactive
group. Thereafter, the latent reactive groups may be activated to
cause them to covalently bond to the surface to thereby link the
polymers to the surface.
[0102] In other embodiments, polymer chains may be provided upon a
surface or other substrate by first covalently bonding to the
substrate through a latent reactive group a monomer, oligomer or
other reactive chemical unit. To the thus bonded reactive units are
covalently bonded monomers or oligomers in a polymerization
reaction or polymers via covalent bonding (grafting) of the
reactive units onto the polymer chains.
[0103] The reactive chemical units of the invention carry
covalently bonded thereto latent reactive groups as described
herein for covalent attachment to a non pretreated surface or other
substrate. These molecules are characterized as having reactive
groups capable of covalent bonding to polymer molecules of a
polymer having the desired characteristics, or of entering into a
polymerization reaction with added monomers or oligomers to produce
polymer chains having the desired characteristics. Reactive
chemical molecules capable of covalently bonding to polymer
molecules include not only monomers and oligomers of various types
but also molecules having such functional groups as carboxyl,
hydroxyl, amino, and N-oxysuccinimide, such groups being reactive
with reactive groups carried by the polymer chain to bond to the
chain. The reactive chemical molecules are preferably monomers or
oligomers and most preferably are ethylenically unsaturated
monomers capable of entering into an addition polymerization
reaction with other ethylenically unsaturated monomers.
Particularly preferred are the acrylate and methacrylate monomers
which are the esterification products of acrylic or methacrylic
acid and hydroxy-functional latent reactive groups. Examples of
such molecules include 4-benzoylbenzoyl-lysyl-acrylate.
[0104] Utilizing reactive chemical units bearing latent reactive
groups, one may first coat a surface or other substrate with a
solvent solution of such molecules. Upon removal of solvent, the
application of an appropriate external stimulus such as U.V. light
will cause the molecules to covalently bond, through the latent
reactive groups, to the substrate. The substrate may then be
appropriately contacted with a solution containing the desired
polymer, monomer or oligomer molecules to cause bonding to these
molecules. For example, if the reactive chemical unit molecule is
carboxyl functional, it may be reactive with, and covalently bonded
to, an appropriate hydroxyl-functional polymer such as dihydroxy
polyethylene glycol. If the reactive chemical molecule is a monomer
or oligomer, e.g., a methacrylate monomer, the substrate to which
the molecule is covalently bonded may be contacted with a solution
of addition-polymerizable monomers such as hydroxyethyl
methacrylate and a free-radical addition polymerization initiator
such as dibenzoyl peroxide under addition polymerization conditions
to result in the growth of polymer chains from the monomer
molecules bound covalently to the substrate. Once the desired
polymerization has occurred, the substrate may be washed to remove
residual monomer, solvent and non bound polymer that was
formed.
[0105] In other embodiments the thromboresistant coating can adhere
better by surface modification of the medical device by adsorbing a
layer of a polyamine having a high average molecular weight on to
the surface. The polyamine is stabilised by cross-linking with
crotonaldehyde, which is a mono-aldehyde having a C--C double bond
in conjugation with the aldehyde function. Thereafter one or more
alternating layers of an anionic polysaccharide and the
cross-linked polyamine, followed by a final layer of the said
polyamine, not cross-linked, may be adsorbed onto the first layer
of cross-linked polyamine, whereby a surface modification carrying
free primary amino groups is achieved.
[0106] In certain embodiments, the thromboresistant coating is made
by bringing the substrate into contact with an aqueous solution of
the polyamine at pH 8-10, for example pH 9. The concentration of
the initial polyamine solution will range from 1-10% by weight,
especially 5% by weight, 1 ml of which may be diluted to a final
volume of 500-2000 ml, especially 1000 ml. This final solution may
also comprise from 100-1000 especially 340 .mu.l crotonaldehyde.
Alternatively the substrate will be treated first with a solution
of polyamine of said concentration and pH, and then with a solution
of the crotonaldehyde of the said concentration and pH. The
temperature is not critical, so it is preferred for the treatment
to be at room temperature.
[0107] After rinsing with water, the substrate is treated with a
solution of an anionic polysaccharide, containing from about 10 to
about 500 mg, preferably about 100 mg of the polysaccharide in a
volume of 1000 ml. This step is executed at a temperature in the
range of 40.degree.-70.degree. C., preferably about 55.degree. C.
and pH 1-5, preferably about pH 3.
[0108] After another rinsing with water, these first steps may be
repeated one or several times and finally, after having adsorbed a
layer of polysaccharide, the substrate may be treated with a
polyamine solution having a concentration 1-20 times, preferably 10
times, that mentioned above, at the said temperature and pH. The
polyamine will preferably be a polymeric aliphatic amine,
especially polyethylene imine having a high average molecular
weight, but any polyamine having a high average molecular weight
and carrying free primary amino groups may be used. The anionic
polysaccharide will preferably be a sulfated polysaccharide. The
aminated surface may optionally be further stabilized by reduction
with a suitable reducing agent such as sodium cyanoborohydride. The
modified surface according to present invention has free primary
amino groups by which chemical entities may be bound either
ionically or covalently. Also aldehyde containing chemical entities
may be bound by formation of Schiffs bases, eventually followed by
a stabilization reaction such as a reduction to convert the Schiffs
bases to secondary amines. Further examples are disclosed in U.S.
Pat. No. 5,049,403 which is hereby incorporated by reference in its
entirety.
[0109] In certain embodiments, to provide a thromboresistant
coating to the medical device, a composition is prepared to include
a solvent, a combination of complementary polymers dissolved in the
solvent, and the bioactive agent or agents dispersed in the
polymer/solvent mixture. The solvent is preferably one in which the
polymers form a true solution. The pharmaceutical agent itself may
either be soluble in the solvent or form a dispersion throughout
the solvent.
[0110] Due to the properties of materials frequently used on the
outer surface of sensors, sensors can be difficult to coat with
conventional anticoagulants, or anti-thrombogenics, e.g., heparin,
to obtain a suitable anticoagulant coating, which is sufficiently
stable, long-lasting, and active for preferred intravascular
applications, and yet is sufficiently invisible to analytes of
interest and non-interfering with the sensor chemistry to allow
reliable and sufficiently long-lasting operation. Various issues
can arise relating to the suitability of a particular coating
including, for example, stability of the coating during
manufacturing and handling of the sensor, resistance of the coating
to removals during use, such as by solubilization, reaction, etc.,
resistance to diffusion through the coating of analytes of
interest, and interaction between species in the coating and the
sensor technology, whether by hydrolysis of detectable species from
the coating or by other means.
[0111] Coating materials comprising heparin are preferred, but
other polysaccharide and biologically derived materials and analogs
can be utilized as well, either with heparin or in place of
heparin. Preferred methods of applying the coating include
application of a heparin-quaternary ammonium complex in isopropanol
to a sensor wetted with water or water/surfactant under vacuum, but
other suitable methods of applying a coating can also be
successfully employed, such as application of a heparin-quaternary
ammonium complex from combinations of solvents, such as non-polar
solvents and polar solvents; sequential application of quaternary
ammonium compound and heparin, such as to form a heparin-quaternary
ammonium complex in-situ; covalently bonding heparin molecules to
the surface of the sensor, including methods for attaching
individual ends of heparin molecules to the surface such as
described by Carmeda AB (Upplands Vasby, Sweden); and application
of cross-linked forms of heparin or heparin with other
compounds.
[0112] In certain embodiments, a coating of heparin or a heparin
containing material can be applied to at least a portion of the
sensor surface to limit or prevent thrombus formation. However, in
some cases, application of such a coating can be difficult due to
problems of adhesion where the coating will not properly adhere to
the surface initially or will tend to detach or dissolve from the
surface upon use. Instances where the coating detaches upon use can
be particularly problematic due to the possibility of particulate
impurities being released into the bloodstream and the possibility
that these can result in plugging of small blood vessels. In
addition, detachment or dissolution of heparin coating material can
result in therapeutic or sub-therapeutic dosing of the patient with
an anticoagulant material. Such adhesion problems can be
particularly pronounced when applied to certain types of materials,
especially plastics such as polyolefins, fluoropolymers,
polycarbonate, and polysulfone. For example, polyolefins and
fluoropolymers in particular are especially difficult to adhere
materials to, as evidenced by the difficulty and limited strength
that is typically achieved when these plastics are glued.
[0113] The present inventors have found that surprisingly a coating
comprising heparin and benzalkonium can be effectively applied and
will maintain an acceptably stable and active coating over
polymeric surfaces of analyte sensors disclosed herein, including
polymeric surfaces such as polyolefins, fluoropolymers,
polycarbonate and polysulfone, porous polymeric surfaces, and
porous polymeric surfaces on sensors incorporating immobilizing
polymeric matrices, while still maintaining acceptable
functionality of the analyte sensor. In certain embodiments, the
porous surfaces capable of maintaining an acceptably stable and
active coating comprising heparin and benzalkonium are more
specifically described as microporous, nanoporous, or
mesoporous.
[0114] In preferred embodiments, the coating comprising heparin and
benzalkonium may include pharmaceutical grade heparin, such as
heparin sodium or heparin calcium as described in the U.S.
Pharmacopeia, revised Jun. 18, 2008, however, other grades and
forms of heparin can be utilized in various applications, including
instances where pharmaceutical regulations do not apply. Preferred
grades of heparin can have an average molecular weight of about 12
to about 15 kDa, however, individual strands can have molecular
weights as high as about 40 kDa or 50 kDA or even higher, and as
low as about 5 kDa or 3 kDa or even lower. In other embodiments,
heparin with average molecular weights higher or lower than about
12 to about 15 kDa can be successfully utilized, such as those as
high as about 20 or 30 kDa or as low as about 7 or 10 kDa.
[0115] In some preferred embodiments, the coating comprising
heparin and benzalkonium may include molecules of benzalkonium
chloride having alkyl groups of about 1 to about 5 carbons for two
of the R-groups and an alkyl group of about six to about 22 carbons
for the third R-group, either as a single pure compound or as a
combination of compounds with differing R-groups. In some
embodiments, grades of benzalkonium chloride include those having
compounds and mixtures of compounds having primarily two methyl
groups and an alkyl group of about six to about 22 carbons, or more
preferably two methyl groups and an alkyl group of about 10 to
about 18 carbons as the R-groups.
[0116] In certain embodiments, other ammonium complexes can be
used, e.g., particular alkylbenzyl dimethyl ammonium cationic
salts, which can be used in high loading concentrations with
heparin to form coatings, as disclosed in U.S. Pat. No. 5,047,020
to Hsu; incorporated herein in its entirety by reference. Hsu found
that commercially available benzalkonium chloride may comprise a
mixture of alkylbenzyldimethylammonium chloride of the general
formula, [C.sub.6H.sub.5CH.sub.2N(CH.sub.3).sub.2R]Cl, in which R
represents a mixture of alkyls, including all or some of the groups
comprising C8 and greater, with C12, C14 and C16 comprising the
major portion. Generally, the composition breaks down to more than
20% C14, more than 40%, C12 and a less than 30% mixture of C8, C10
and C16. In contrast, Hsu found that preferred heparin/quaternary
ammonium complexes have at least about 50 weight percent of the
organic cationic salt, and preferably from 60 to 70 weight percent.
Hsu found that optimum results were achieved with complexes
consisting of cetalkonium heparin and/or stearylkonium heparin and
mixtures thereof. Indeed, Hsu teaches that coatings for medical
devices consisting of complexes of cetalkonium heparin and/or
stearylkonium heparin and mixtures thereof, exhibit "vastly
superior hydrophobicity and surface adhesion over the presently and
most commonly used complexes of heparin and benzalkonium chloride."
Accordingly, in another aspect of the invention, other
heparin/quaternary ammonium complexes besides those comprising
benzalkonium, like those disclosed by Hsu, may be used to coat and
render thromboresistant the glucose sensors disclosed herein.
Surface Coating Agents
[0117] Various compounds can be useful as coating agents for the
thromboresistant coating of the medical device, for example those
disclosed in U.S. Pat. Nos. 6,278,018, 6,603,040, 6,924,390,
7,138,541, which are all incorporated herein by reference. In one
aspect, the present invention provides a compound comprising a
nonpolymeric core molecule comprising an aromatic group, the core
molecule having attached thereto, either directly or indirectly,
one or more substituents comprising negatively charged groups, and
two or more photoreactive species, wherein the photoreactive
species are provided as independent photoreactive groups. The first
and second photoreactive species of the present coating agent can,
independently, be identical or different.
[0118] In certain embodiments the core is provided as the residue
of a polyhydroxy benzene starting material (e.g., formed as a
derivative of hydroquinone, catechol, or resorcinol), in which the
hydroxy groups have been reacted to form an ether (or ether
carbonyl) linkage to a corresponding plurality of photogroups. In
one embodiment, a coating agent of this invention further comprises
one or more optional spacers that serve to attach a core molecule
to corresponding photoreactive species, the spacer being selected
from radicals with the general formula: wherein n is a number
greater or equal to 1 and less than about 5, and m is a number
greater or equal to 1 and less than about 4.
[0119] In another embodiment, such coating agents are selected from
the group
4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid
di(potassium and/or sodium) salt,
2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid
di(potassium and/or sodium) salt,
2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-sulfonic acid
monopotassium and/or monosodium salt.
[0120] Suitable core molecules of the present invention include
nonpolymeric radicals having a low molecular weight (e.g., 100-1000
MW). Suitable core molecules provide an improved combination of
such properties as coating density, structural stability, ease of
manufacture, and cost. Further, core molecules can be provided with
water soluble regions, biodegradable regions, hydrophobic regions,
as well as polymerizable regions. Examples of suitable core
molecules include cyclic hydrocarbons, such as benzene and
derivatives thereof.
[0121] The type and number of charged groups in a preferred coating
agent are sufficient to provide the agent with a water solubility
(at room temperature and optimal pH) of at least about 0.1 mg/ml,
and preferably at least about 0.5 mg/ml, and more preferably at
least about 1 mg/ml. Given the nature of the surface coating
process, coating agent solubility levels of at least about 0.1
mg/ml are generally adequate for providing useful coatings of
target molecules (e.g., polymer layers) on surfaces.
[0122] The coating agent can thus be contrasted with many coating
agents in the art, which are typically considered to be insoluble
in water (e.g., having a comparable water solubility in the range
of about 0.1 mg/ml or less, and more often about 0.01 mg/ml or
less). For this reason, conventional coating agents are typically
provided and used in solvent systems in which water is either
absent or is provided as a minor (e.g., less than about 50% by
volume) component.
[0123] Examples of suitable charged groups include salts of organic
acids (e.g., sulfonate, phosphonate, and carboxylate groups), as
well as combinations thereof. A preferred charged group for use in
preparing coating agents of the present invention is a sulfonic
acid salt, e.g., derivatives of SO.sub.3.sup.- in which the
counterion is provided by the salts of Group I alkaline metals (Na,
K, Li ions) to provide a suitable positively charged species.
[0124] The use of photoreactive species in the form of
photoreactive aryl ketones are preferred, such as acetophenone,
benzophenone, anthraquinone, anthrone, and anthrone-like
heterocycles (i.e., heterocyclic analogs of anthrone such as those
having N, O, or S in the 10-position), or their substituted (e.g.,
ring substituted) derivatives. Examples of preferred aryl ketones
include heterocyclic derivatives of anthrone, including acridone,
xanthone, and thioxanthone, and their ring substituted derivatives.
Particularly preferred are thioxanthone, and its derivatives,
having excitation energies greater than about 360 nm.
[0125] The functional groups of such ketones are preferred since
they are readily capable of undergoing the
activation/inactivation/reactivation cycle described herein.
Benzophenone is a particularly preferred photoreactive moiety,
since it is capable of photochemical excitation with the initial
formation of an excited singlet state that undergoes intersystem
crossing to the triplet state. The excited triplet state can insert
into carbon-hydrogen bonds by abstraction of a hydrogen atom (from
a support surface, for example), thus creating a radical pair.
Subsequent collapse of the radical pair leads to formation of a new
carbon-carbon bond. If a reactive bond (e.g., carbon-hydrogen) is
not available for bonding, the ultravieolet light-induced exitation
of the benzophenome group is reversible and the molecule returns to
ground state energy level upon removal of the energy source.
Photoactivatible aryl ketones such as benzophenone and acetophenone
are of particular importance inasmuch as these groups are subject
to multiple reactivation in water and hence provide increased
coating efficiency.
Coating Methodology
[0126] The coating processes disclosed herein include: 1) direct
coating of the heparin complex by straight application, as in the
case of dip coating, as well as 2) indirect coating, as in the case
of sequential applications of a quarternary ammonium salt plus
surfactant and the ionic heparin. Suitable methods for applying a
coating comprising heparin and benzalkonium may include multistep
layering techniques as well as single step application of heparin
complexes. In other embodiments, pretreatment methods are used,
such as soaking the sensors in sodium heparin solutions.
[0127] In the event that it is desired to apply the
thromboresistant coating to surfaces that are inert to certain
polymeric materials, adhesion can be facilitated by chemically
treating the surfaces in order to provide hydroxyl groups on or
near the surface thereof. Exemplary chemical surface treatments in
this regard include such known procedures as chemical etching,
surfactant adsorption, coextrusion, plasma discharge, surface
oxidation or reduction, radiation activation and oxidation, and
surface grafting with materials such as polyvinyl alcohol,
poly(2-hydroxyethyl methacrylate) and the like. Bulk modifications
of the substrate surface can also be accomplished in order to
provide active hydrogens. Examples of conventional modifications of
this type include blending with polymers having active hydrogens,
partial degradation of polymers, end group modification, monomer
functionalization, oxidation, reduction, copolymerization, and the
like.
[0128] In certain embodiments, a three-dimensional highly
crosslinked matrix containing aminosilanes is formed on the medical
device surface. The aminosilane is cured, crosslinked or
polymerized in place on the surface to be rendered
thromboresistant. This is carried out in a manner such that a
three-dimensional matrix is formed. The matrix can be either an
aminosilane homopolymer or a copolymer, including a graft
copolymer, of an aminosilane with another silane that is not an
aminosilane. Representative aminosilanes include
3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane,
2-aminoundecyltrimethoxysilane, aminophenyltrimethoxysilane,
N-(2-aminoethyl-3-aminopropyl)trimethoxysilane, and
trimethoxysilylpropyldiethylenetriamine.
[0129] Aminosilanes of this type can be used alone in order to form
a homopolymer matrix. For example, certain aminosilanes are
trifunctional and provide a highly crosslinked matrix. The
hydrophilicity can be reduced, when desired, by combining the
hydrophilic aminosilane with a less hydrophilic silane that is not
an aminosilane. In one embodiment, a matrix that is a copolymer of
one of these aminosilanes with another silane molecule that is not
an aminosilane and that is less hydrophilic than an aminosilane in
order to thereby adjust the hydrophilicity of the matrix. Other
methods and coating agents are also known in the art, including
U.S. Pat. Nos. 5,053,048, 4,973,493, 5,049,403, all of which are
incorporated by reference herein.
[0130] In preferred embodiments, a coating comprising heparin and
benzalkonium is applied by first wetting the sensor surface with
water or a combination of water and surfactant. Preferred
surfactants include anionic surfactants, however other surfactants
such as cationic surfactants or non-ionic surfactants may also be
successfully employed in some embodiments. In particular, suitable
surfactants include sodium laurel sulfate, sodium dodecyl sulfate,
ammonium lauryl sulfate, sodium laureth sulfate. The wetted sensor
is then treated with an alcoholic solution of heparin-quaternary
ammonium complex. In certain embodiments, the alcoholic solution
comprises isopropanol, however other alcohol based solutions may be
used as well, depending on the embodiment. Preferred solutions of
isopropanol may include about 1 to about 99% (wt.) of
heparin-benzalkonium complex in isopropanol, including 5%, 10%,
25%, 50%, 75%, 90%, and 95% (and also including ranges of weight
percentages bordered on each end by these recited weight
percentages). One preferred solution of heparin-benzalkonium in
isopropanol is manufactured by Celsus Laboratories, Inc. 12150 Best
Place, Cincinnati Ohio 45241, under product number BY-3189
(described as Benzalkonium heparin solution in isopropyl alcohol,
887 U/mL). The wetted sensor can be dipped in the
heparin-benzalkonium solution, or it can be sprayed onto the
surface of the sensor or applied by another suitable technique. The
sensor with coating solution applied is then dried. Additional
coating material, such as to improve consistency of a coating or to
thicken a coating, can be applied by dipping, spraying or other
suitable means. When material is applied, preferred methods include
those where the sensor is exposed to the heparin-benzalkonium
solution for only a limited time, such as less than one minute, or
less than about 30 seconds or about 10 seconds or even about 1 or 2
seconds, such as by dipping the sensor into the solution for only
about a second (and also including time intervals bordered on the
high end and the low end by the recited durations such as dipping
the sensor into the solution for between 10 and 30 seconds). In
some embodiments, short time intervals can prevent undesirable
results, such as excessive solubilization of material from the
sensor surface or excessive dehydration of the sensor. However, in
some embodiments, longer time periods can successfully be utilized
by, for example, increasing the concentration of
heparin-benzalkonium concentration of the solution or by
supplementing the solution with additional benzalkonium material or
heparin material, or by adjusting the pH, or ionic strength of the
solution. In some embodiments, during the coating process, the
sensor can be rehydrated as needed or desired by application of
water or a combination of water and surfactant and/or solvent.
[0131] However, other methods of applying a coating comprising
heparin and benzalkonium can also be successfully employed.
Suitable multistep layering techniques include those techniques
where an heparin and benzalkonium are applied by a process
comprising application of a suitable form and grade of benzalkonium
chloride followed by application of a suitable form and grade of
heparin. Any suitable solvent or combinations of solvents can be
used for heparin, such as water or aqueous alcohol, and for
benzalkonium chloride, such as nonpolar organic solvents (for
example, toluene, petroleum ether, etc.). Preferred heparin
solutions include those comprising heparin in a weight percentage
of about 0.05%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, and 95% (and also
including ranges of weight percentages bordered on each end by
these recited weight percentages). In certain such embodiments, a
preferred heparin solution comprises a weight percent of heparin
between about 0.05% to about 1%. Preferred benzalkonium chloride
solutions include those comprising benzalkonium in a weight
percentage of about 0.05%, 1%, 5%, 10%, 20%, 25%, 50%, 75%, 90%,
and 95% (and also including ranges of weight percentages bordered
on each end by these recited weight percentages). In certain such
embodiments, a preferred benzalkonium chloride solution comprises a
weight percent of benzalkonium chloride between about 1.0% to about
20%.
[0132] Other suitable coating techniques are described, for
example, in U.S. Pat. Nos. 3,846,353, to Grotta, and 5,047,020, to
Hsu, incorporated by reference herein in their entireties.
[0133] Single step application of heparin complexes can comprise
applying a solution comprising heparin and benzalkonium of a
suitable grade and form to the sensor, such as is described in U.S.
Pat. No. 5,047,020, to Hsu. In certain embodiments, the solution
may include benzalkonium chloride. Suitable solvents for the
heparin and benzalkonium include those comprising polar organic
solvents, alone or as mixtures, such as alcohols (e.g.
isopropanol), halogenated solvents (e.g. trifluoro-trichloro
ethane), etc. In some embodiments, the solution to be applied to
the polymeric surface may include heparin and benzalkonium in a
combined weight percentage of 0.1%, 1%, 5%, 10%, 25%, 50%, 75%, or
about 90% of the total weight of the solution (also including
ranges of weight percentages bordered on each end by these recited
weight percentages). In certain such embodiments, a solution may
contain between about 0.1% to about 75% heparin/benzalkonium by
weight. In some embodiments, successive layers of
heparin/benzalkonium complex can be applied to the surface of the
sensor, for example, to build up a coating having a desired
thickness and/or durability.
[0134] In certain embodiments, the distal portion of a pre-wetted
sensor is dipped in a solution comprising heparin and benzalkonium
in isopropanol, preferably for about 0.1 to about 30 seconds, and
more preferably for about 1 to about 10 seconds, and even more
preferably for about 1 second. In certain embodiments, the dipped
sensor is subsequently air dried, preferably for at least about 10
seconds, and more preferably for about 0.5 minutes to about 10
minutes, and even more preferably for about 1 minute. The
heparin/benzalkonium coating and drying steps are repeated in
accordance with various embodiments, preferably from about 1 to
about 20 times, or more preferably from about 2 to about 10 times,
or even more preferably from about 3 to about 8 times, and even
more preferably still from about 4 to about 6 times.
[0135] In certain embodiments, a sustained release of heparin from
the sensor surface into the surrounding vessel is achieved by
soaking the sensor. In one embodiment, the sensor, which optionally
contains a hydrogel underneath the optional microporous membrane,
is soaked in a solution of heparin for infusion of heparin into the
swollen hydrogel. In one embodiment, an aqueous solution of at
least about 10% sodium heparin is used. In a more preferred
embodiment, an aqueous solution of at least about 20% sodium
heparin is used. In a most preferred embodiment, an aqueous
solution of at least about 30% sodium heparin is used. In other
embodiments, other organic solvents and other forms of heparin may
be used. In one embodiment, the sodium heparin solution is in
phosphate buffered saline of about pH 5. After soaking for enough
time to saturate the hydrogel, the sensor is removed from the
solution and allowed to dry. In one embodiment, the sensor is
soaked for at least about 1 hour. In a preferred embodiment, the
sensor is soaked for about 2 hours. In one embodiment, the sensor
is soaked for at least about 3 hour. When the sensor is then
deployed in-vivo, the hydrogel re-swells in the bloodstream thus
releasing the heparin gradually over time.
[0136] Additional steps can be utilized as necessary, such as, for
example, cleaning the surface of the sensor with suitable agents
such as solvents, surfactants, etc. and/or drying the coating, such
as with a gas stream, or with heat, or with a heated gas stream, or
with one or more dehydrating agents. In some embodiments, it is
desirable to package the sensor as soon as possible after coating,
since in some embodiments, after coating, the surface of the sensor
may be somewhat tacky, and it may tend to pick up particulate
matter.
[0137] Other methods of applying a heparin-based coating to the
sensor includes covalently bonding heparin, or a heparin
derivative, to the surface of the sensor or to an intermediate
material applied to the surface of the sensor. Suitable techniques
include those that covalently bond the end of a heparin molecule to
the surface of the sensor or an intermediate, such as the
techniques utilized by Carmeda AB (Upplands Vasby, Sweden). Other
suitable methods also include those utilizing photoimmobilization
to attach heparin, or a heparin derivative to the surface of a
sensor or an intermediate material applied to the surface of the
sensor, such as are described herein and by Surmodics (Eden
Prairie, Minn.), as well as those depositing heparin complexes with
polar and nonpolar solvents, such as are described in U.S. Pat. No.
6,833,253 to Roorda, et al.
WORKING EXAMPLES
Example 1
Application of Thromboresistant Coating
[0138] An optical glucose sensor as described above (see e.g.,
FIGS. 1-4) was prepared for coating with benzalkonium/heparin by
immersing the portion of the sensor to be coated in a pH 3
phosphate buffered saline solution (although it is feasible to use
many types of aqueous buffer solutions or even just water).
[0139] A coating solution of 1.5% (by weight) benzalkonium heparin
in isopropanol (distributed by Celsus Laboratories, Inc. 12150 Best
Place, Cincinnati Ohio 45241 as Benzalkonium heparin solution in
isopropyl alcohol, 887 U/mL, Product Number BY-3189) was added to a
test tube. After equilibrating in the buffered saline solution, the
distal end portion of the sensing end of the sensor was immersed in
the benzalkonium heparin solution and immediately removed (with the
time of immersion in the benzalkonium heparin solution being
approximately one second). The wet sensor was allowed to air dry
for approximately 1 minute, resulting in a coating of benzalkonium
heparin on the sensor surface.
[0140] Immersion of the sensor in the benzalkonium/heparin solution
followed by air drying was repeated 4 times to build up additional
coating material on the surface of the sensor.
Example 2
Preparation of Sensor Blank
[0141] A sensor blank was prepared from a polyethylene microporous
membrane (of 0.017 inch outside diameter) surrounding a poly(methyl
methacrylate) optical fiber (of 0.010 inch diameter). The
polyethylene microporous membrane was obtained from Biogeneral 9925
Mesa Rim Road, San Diego Calif. 92121-2911). The distal end of the
sensor blank (the end to be coated) is heat welded to a rounded
polyethylene plug. The other end is sealed with a silicone
backfill. The distal end was then immersed in the buffered saline
solution of Example 1 for about 18 hours (although a shorter time
interval would also have been suitable). Finally, the distal end of
the sensor blank was immersed in the coating solution of Example 1
and subsequently air dried as in Example 1. The steps of immersing
in the coating solution and air drying were repeated four
times.
Example 3
Comparison of Coated Sensor and Coated Sensor Blank
[0142] Coated sensors and coated sensor blanks, prepared as
described in Examples 1 and 2, each having five dip coats of
heparin/benzalkonium applied, were subjected to handling tests as
follows.
[0143] Sensors consisted of a 1.3-inch long hollow, microporous
HDPE membrane (0.017 inches O.D., Biogeneral 9925 Mesa Rim Road,
San Diego Calif. 92121-2911, this is a custom part) butt-welded to
a 1.0-inch long, smooth (nonporous) HDPE tube. The microporous end
was heat-welded to a rounded polyethylene plug. Inside of the
hollow assembly was threaded a 0.010 inch PMMA optical fiber The
smooth HDPE end was filled with silicone backfill up to, but not
including, the microporous membrane. The area between the PMMA
optical fiber and the hollow microporous membrane was filled with a
dimethyl acrylamide gel which also contained covalently-bound
fluorescent dye and quencher. The sensor was prepared for
application of the coating comprising heparin and benzalkonium by
immersing the distal ("sensor") end in an aqueous solution of
phosphate buffered saline as described in Example 1 for about 18
hours (although this amount of time may not be necessary). The
sensor was then immersed in the heparin/benzalkonium solution and
air dried as described in Example 1. The immersion and drying steps
were repeated 4 times.
[0144] After repeated immersions in the coating solution and
drying, the sensors and sensor blanks were prepared for the
handling tests by staining with toluidine blue. Specifically, the
sensors and sensor blanks were pulled through the silicone rubber
seal, and then dipped in a 0.04% solution of toluidine blue in
water for 1 minute, rinsed with water and allowed to air dry for 30
minutes.
[0145] Toluidine blue stains heparin a purple color, and so a
darker purple color tends to indicate a higher concentration of
heparin than a lighter purple color or no purple color at all.
Thus, in order to assess the durability of the heparin coating, the
stained sensors and sensor blanks were subjected to the following
handling tests and subsequently visually examined under 20.times.
magnification to discern voids and thinness in the heparin coating
indicated by the lightening of the toluidine stain. The results are
described below as well.
Storage in Phosphate Buffered Saline Solution
[0146] Sensors were soaked in pH 7.4 phosphate buffered saline for
up to 48 hours at 37 C. Microporous membrane sections were observed
to retain an even purple color even after 48 hours. The stain on
nonporous polyethylene sections became lighter and less even after
as little as 2 hours.
Storage in Sensor Housing Assembly
[0147] A coated sensor was placed into a sensor housing assembly,
consisting of a polyurethane tubing and sealed with a
parylene-coated silicone rubber seal. The housing assembly was
filled with pH 7.4 phosphate buffered saline and the sensor was
soaked in the housing for 1 hour at room temperature. Afterwards,
the nonporous polyethylene section displayed (under magnification)
clear signs of damage to the heparin coating, with apparent scrapes
and voids in the purple stain. In contrast, the microporous
membrane section looked unaffected, with a consistent and smooth
purple stain. Abrasion: A sensor was soaked in pH 7.4 phosphate
buffered saline for 1 hour at room temperature, then rubbed
vigorously with a wet nitrile glove for one minute. It was then
stained with toluidine blue. Under magnification, the nonporous
polyethylene section was almost completely devoid of purple stain,
indicating a total loss of the heparin coating. The microporous
membrane section looked to be diminished and somewhat patchy,
although there was still a strong purple color along the entire
length. It should be noted that the handling in this portion of the
test was very extreme.
Sonication with Isopropanol
[0148] One sensor was sonicated three times in successive vials of
25 mLs isopropanol for 5 minutes each. It was then stained with
toluidine blue. Under magnification, the nonporous precursor
polyethylene section was almost completely devoid of purple stain,
indicating total loss of the heparin coating, as shown in FIG. 7A.
The microporous membrane section still maintained a strong, even
purple color, indicating that a consistent heparin coating
remained, as shown in FIG. 7B.
[0149] The results of subjecting the sensors and blanks to the
foregoing conditions are summarized in the following table:
TABLE-US-00001 Microporous membrane Nonporous polyethylene Test
condition stain stain Storage in phos- Dark, even purple stain
Lighter color, less even phate buffered saline solution Storage in
sensor Dark, even purple stain Clear signs of abrasion, housing
assembly large voids in purple stain Abrasion Lighter purple stain,
Purple stain completely still evenly coated removed Sonication with
Lighter purple stain, Purple stain completely isopropanol still
evenly coated removed Control (no Dark, even purple stain Dark,
even purple stain handling tests)
[0150] These results demonstrate the superior durability of the
benzalkonium heparin coating on the glucose sensor, having a porous
polymeric surface and hydrophilic polymer matrix, as compared in
benzalkonium heparin coating on a polymeric surface alone.
Example 4
Demonstration of Effectiveness of Antithrombotic Coating
[0151] 12 GLUCATH.RTM. sensors with a benzalkonium/heparin coating
and 12 BD L-Cath PICC lines (outside diameter 0.037 cm, 0.0145
inches; polyurethane) as controls without coating were prepared for
insertion into the cardiovascular system of four sheep. The coated
GluCath sensor was constructed of a fluorophore/quencher indicator
system embedded in a hydrophilic acrylic matrix, as described in
U.S. patent application Ser. No. 12/026,396. The benzalkonium
heparin coating was applied as described in Example 3.
[0152] Sensors and control catheters were inserted into the left
and right jugular veins and left and right cephalic veins, with the
sensor on one side and the control catheter on the other of the
same sheep. After 25 hours, two sheep were euthanized and the
sensors and controls were surgically exposed and examined by
incising and reflecting the skin and surrounding tissues overlying
the test article and vein, and then opening the vein longitudinally
taking care not to disturb the sensor or catheter or any cellular
accumulation or debris on the test articles or in the veins. After
22 additional hours (47 hours elapsed time), two additional sheep
were euthanized and the sensors surgically exposed and examined as
described above.
[0153] Digital photographs of each sensor or catheter were taken in
place. After examination, each sensor or catheter was removed from
the vein, stained with methylene blue, and examined microscopically
at 10-20.times. primary objective power to observe build up of
fibrin or cellular material or surface irregularities the low the
resolution of the photographs. Two of the test articles were found
to have been placed outside of the vein, in the surrounding tissue,
and were not included in the evaluations.
[0154] Tissue sections from the veins were also obtained and
characterized for the state of the vessel in proximity to the test
articles. The results of these evaluations are shown in the table
below:
TABLE-US-00002 Fibrin buildup on Fibrin buildup sensor on sensor
Sensor/ Time (gross (microscopic Article (Hr) Sheep Vessel
assessment) assessment) Vessel Wall Notes 4-GluCath 25 193/24 LJS 0
0 NGHL -- 5-GluCath 25 193/24 LJI NA* NA NGHL *Sensor not in
vessel, tip of sensor kinked. 6-GluCath 25 193/24 LC 0 0 Focal Tip
of sensor microscopic kinked. endothelial erosion, with minor
fibrin deposition 7-GluCath 25 196/25 RJS 0 0 NGHL -- 8-GluCath 25
196/25 RJI 0 1 (equivocal) NGHL -- 9-GluCath 25 196/25 RC 0 0 Focal
-- microscopic endothelial erosion, with minor fibrin deposition
1-BD-LC 25 193/24 RJS 1 1 NGHL -- 2-BD-LC 25 193/24 RJI 0** 0 NGHL
**Most of sensor inadvertently pulled from vessel during
dissection. This may have stripped some surface deposits off the
catheter surface. 3-BD-LC 25 193/24 RC 1 1 NGHL -- 10-BD-LC 25
196/25 LJS 1 1 NGHL -- 11-BD-LC 25 196/25 LC 1 1 NGHL -- 12-GluCath
47 194/27 RJS 0 0 NGHL -- 13-GluCath 47 194/27 RJI 0 0 NGHL Tip of
sensor is elongated and kinked. 14-GluCath 47 194/27 RC 0 0 Mass of
fibrin Tip of sensor on vessel wall kinked. at tip of sensor,
endothelium intact. 20-GluCath 47 195/26 LJS 0 0 NGHL -- 21-GluCath
47 195/26 LJI 0 0 NGHL -- 22-GluCath 47 195/26 LC 0 0 NGHL --
15-BD-LC 47 194/27 LJS 1 1 NGHL -- 16-BD-LC 47 194/27 LJI 0 1 NGHL
-- 17-BD-LC 47 194/27 LC 1 1 NGHL -- 18-BD-LC 47 195/26 RJS 1 1
NGHL -- 19-BD-LC 47 195/26 RC 0 0 NGHL --
[0155] Note that in the foregoing table "RC" means "Right
Cephalic," "LJS" means "Left Jugular Vein Superior," "LJI" means
"Left Jugular Vein Inferior," "RJS" means "Right Jugular Vein
Superior," "RJI" means "Right Jugular Vein Inferior," and "NGHL"
means "no gross or histologic legions." Furthermore, the numeric
descriptions contained in the foregoing table with respect to the
gross and microscopic fibrin buildup on the sensors is a shorthand
for the following:
[0156] "0" indicates none, or limited to hemostatic plug at
venipuncture site only;
[0157] "1" indicates scant discontinuous or microscopic deposition
only;
[0158] "2" indicates <1 mm in thickness;
[0159] "3" indicates >1 mm in thickness; and
[0160] "4" indicates complete vascular occlusion (thrombosis).
[0161] These evaluations demonstrate that the GluCath sensor with
heparin/benzalkonium coating was superior to the control catheters
in terms of fewer instances of macroscopic fibrin deposits and
fewer instances of microscopic fibrin deposition.
Example 5
Sustained Release Heparin
[0162] GluCath sensors were soaked in a 30% solution of sodium
heparin in pH 5 phosphate buffered saline for two hours to saturate
the hydrogel. After removal from the soak solution, the sensors
were dip-coated with heparin benzalkonium in isopropyl alcohol to
coat the outer surface. To serve as controls, other sensors which
had not undergone the sodium heparin soaking step were also heparin
benzalkonium dip-coated. After air drying overnight, the sensors
were subjected to flowing buffer (pH 7.4 phosphate buffered saline
at 37.degree. C.) for up to 48 hours. At 2.5, 24, and 48 hours, the
sensors were removed from the buffer and tested for heparin
activity using a chromogenic anti-FXa activity assay. The results,
shown in FIG. 8, showed that the heparin-soaked sensors retained
higher levels of activity than the control sensors at each time
point.
[0163] All references cited herein, including but not limited to
published and unpublished applications, patents, and literature
references, and also including but not limited to the references
listed in the Appendix, are incorporated herein by reference in
their entirety and are hereby made a part of this specification. To
the extent publications and patents or patent applications
incorporated by reference contradict the disclosure contained in
the specification, the specification is intended to supersede
and/or take precedence over any such contradictory material.
[0164] The term "comprising" as used herein is synonymous with
"including," "containing," or "characterized by," and is inclusive
or open-ended and does not exclude additional, unrecited elements
or method steps.
[0165] All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification are to be
understood as being modified in all instances by the term "about."
Accordingly, unless indicated to the contrary, the numerical
parameters set forth herein are approximations that may vary
depending upon the desired properties sought to be obtained. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of any claims in any
application claiming priority to the present application, each
numerical parameter should be construed in light of the number of
significant digits and ordinary rounding approaches.
[0166] The above description discloses several methods and
materials of the present invention. This invention is susceptible
to modifications in the methods and materials, as well as
alterations in the fabrication methods and equipment. Such
modifications will become apparent to those skilled in the art from
a consideration of this disclosure or practice of the invention
disclosed herein. Consequently, it is not intended that this
invention be limited to the specific embodiments disclosed herein,
but that it cover all modifications and alternatives coming within
the true scope and spirit of the invention.
* * * * *
References