U.S. patent application number 09/993907 was filed with the patent office on 2003-05-29 for implantable or insertable medical devices visible under magnetic resonance imaging.
Invention is credited to Ma, Enxin, Sahatjian, Ronald A., Zhong, Sheng-Ping.
Application Number | 20030100830 09/993907 |
Document ID | / |
Family ID | 25540056 |
Filed Date | 2003-05-29 |
United States Patent
Application |
20030100830 |
Kind Code |
A1 |
Zhong, Sheng-Ping ; et
al. |
May 29, 2003 |
Implantable or insertable medical devices visible under magnetic
resonance imaging
Abstract
Disclosed is an implantable or insertable medical device
comprising (a) a substrate and (b) a hydrogel polymer coating at a
least a portion of the surface of the substrate, wherein the
hydrogel polymer is adapted to render the medical device visible
under magnetic resonance imaging (MRI) upon insertion or
implantation of the medical device into a patient. Also disclosed
is the use of such a hydrogel coated implantable or insertable
medical device in a medical procedure, wherein during or after
insertion or implantation of the medical device in a patient, the
position of the medical device is viewed under MRI. The use of a
hydrogel polymer for coating a medical device wherein the hydrogel
polymer is adapted to render a medical device coated with the
hydrogel polymer visible under MRI and a hydrogel polymer adapted
to render a medical device coated therewith visible under MRI are
also disclosed.
Inventors: |
Zhong, Sheng-Ping;
(Northborough, MA) ; Sahatjian, Ronald A.;
(Lexington, MA) ; Ma, Enxin; (Natick, MA) |
Correspondence
Address: |
MAYER, FORTKORT & WILLIAMS, PC
251 NORTH AVENUE WEST
2ND FLOOR
WESTFIELD
NJ
07090
US
|
Family ID: |
25540056 |
Appl. No.: |
09/993907 |
Filed: |
November 27, 2001 |
Current U.S.
Class: |
600/431 ;
623/1.34 |
Current CPC
Class: |
A61L 31/145 20130101;
A61L 29/18 20130101; A61L 31/18 20130101; A61M 25/0108 20130101;
G01R 33/286 20130101; A61M 25/0045 20130101; A61L 29/145
20130101 |
Class at
Publication: |
600/431 ;
623/1.34 |
International
Class: |
A61F 002/02 |
Claims
What is claimed is:
1. An implantable or insertable medical device comprising: (a) a
substrate; (b) a hydrogel polymer coating at least a portion of the
surface of the substrate, wherein said hydrogel polymer is adapted
to render said medical device visible under magnetic resonance
imaging upon insertion or implantation of said medical device into
a patient.
2. The implantable or insertable medical device of claim 1, wherein
said hydrogel polymer is adapted such that detectable species
associated with said hydrogel polymer are differentiated from
detectable species in the environment surrounding the device.
3. The implantable or insertable medical device of claim 1, wherein
said hydrogel polymer is adapted by decreasing the relaxation time
of said detectable species associated with said hydrogel polymer
relative to the relaxation time of detectable species in the
environment surrounding the device.
4. The implantable or insertable medical device of claim 3, wherein
said detectable species associated with said hydrogel polymer
comprise detectable protons.
5. The implantable or insertable medical device of claim 4, wherein
water molecules associated with said hydrogel polymer comprise said
detectable protons.
6. The implantable or insertable medical device of claim 4, wherein
hydroxyl groups associated with said hydrogel polymer comprise said
detectable protons.
7. The implantable or insertable medical device of claim 6, wherein
a compound dispersed within said hydrogel polymer comprises said
hydroxyl groups.
8. The implantable or insertable medical device of claim 7, wherein
said compound dispersed with said hydrogel polymer comprises
glycerin.
9. The implantable or insertable medical device of claim 1, wherein
said hydrogel polymer is adapted by cross-linking said hydrogel
polymer to a degree sufficient to render said medical device
visible under magnetic resonance imaging upon insertion or
implantation of said medical device into a patient.
10. The implantable or insertable medical device of claim 1,
wherein said hydrogel polymer is adapted by incorporating
paramagnetic ions in said hydrogel polymer.
11. The implantable or insertable medical device of claim 1,
wherein hydrogel polymer is adapted by incorporating paramagnetic
particles in said hydrogel polymer.
12. The implantable or insertable medical device or claim 11,
wherein said paramagnetic particles comprise starch-coated iron
oxide particles.
13. The implantable or insertable medical device of claim 10,
wherein said hydrogel polymer is cross-linked.
14. The implantable or insertable medical device of claim 11,
wherein said hydrogel polymer is cross-linked.
15. The implantable or insertable medical device of claim 10
wherein said hydrogel polymer comprises paramagnetic ion chelating
groups.
16. The implantable or insertable medical device of claim 15,
wherein said paramagnetic ion chelating groups are covalently
bonded to the hydrogel polymer.
17. The implantable or insertable medical device of claim 10,
wherein said hydrogel polymer comprises a paramagnetic ion
chelation complex.
18. The implantable or insertable medical device of claim 17,
wherein said paramagnetic ion chelation complex is covalently
bonded to said hydrogel polymer.
19. The implantable or insertable medical device of claim 10,
wherein said paramagnetic ions are selected from the group of
chromium (III), manganese (II), iron (III), iron (II), cobalt (II),
copper (II), nickel (II), praesodymium (III), neodymium (III),
samarium (III), ytterbium (III), gadolinium (III), terbium (III),
dysprosium (III), holmium (III) and erbium (III).
20. The implantable or insertable medical device of claim 19
wherein said paramagnetic ions comprise gadolinium (III).
21. The implantable or insertable medical device of claim 15,
wherein said paramagnetic ion chelating groups comprise organic
acid functional groups.
22. The implantable or insertable medical device of claim 15,
wherein said paramagnetic ion chelating groups comprise carboxyl
groups.
23. The implantable or insertable medical device of claim 15,
wherein said paramagnetic ion chelating groups comprise
aminopolycarboxylic acid groups.
24. The implantable or insertable medical device of claim 22,
wherein said hydrogel polymer comprises substituted or
unsubstituted acrylic acid monomer units.
25. The implantable or insertable medical device of claim 24,
wherein said hydrogel polymer comprises polyacrylic acid.
26. The implantable or insertable medical device of claim 24,
wherein said hydrogel polymer further comprises substituted or
unsubstituted acrylamide monomer units.
27. The implantable or insertable medical device of claim 26,
wherein said hydrogel polymer is a copolymer of acrylic acid and
acrylamide.
28. The implantable or insertable medical device of claim 17,
wherein said paramagnetic ion chelation complex is selected from
the group consisting of diethylene triamine pentaacetic acid
(DTPA), tetraazacyclododecane tetraacetic acid (DOTA), and
tetraazacyclo tetradecane tetraacetic acid (TETA).
29. The implantable or insertable medical device of claim 28,
wherein said paramagnetic chelation complex comprises
diethylenetriamine pentaacetic acid (DTPA).
30. The implantable or insertable medical device of claim 1,
wherein said hydrogel polymer is selected from the group consisting
of polyacrylates; poly(acrylic acid); poly(methacrylic acid);
polyacrylamides; poly(N-alkylacrylamides); polyalkylene oxides;
poly(ethylene oxide); poly(propylene) oxide; poly(vinyl alcohol);
polyvinyl aromatics; poly(vinylpyrrolidone); poly(ethyleneimine);
polyethylene amine; polyacrylonitrile; polyvinyl sulfonic acid;
polyamides; poly(L-lysine); hydrophilic polyurethanes; maleic
anhydride polymers; proteins; collagen; cellulosic polymers; methyl
cellulose; carboxymethyl cellulose; dextran; carboxymethyl dextran;
modified dextran; alginates; alginic acid; pectinic acid;
hyaluronic acid; chitin; pullulan; gelatin; gellan; xanthan;
carboxymethyl starch; chondroitin sulfate; guar; starch; and
copolymers, mixtures and derivatives thereof.
31. The implantable or insertable medical device of claim 1,
wherein said hydrogel polymer is selected from the group consisting
of poly(acrylic acid); polyacrylamide; poly(N-alkylacrylamide);
copolymers of acrylic acid and acrylamide; poly(ethylene oxide);
poly(propylene oxide); copolymers of ethylene oxide and propylene
oxide; hyaluronic acid; and poly(L-lysine).
32. The implantable or insertable medical device of claim 31,
wherein said hydrogel polymer comprises poly(acrylic acid).
33. The implantable or insertable medical device of claim 31,
wherein said hydrogel polymer comprises a copolymer of acrylic acid
and acrylamide.
34. The implantable or insertable medical device of claim 1,
further comprising a lubricious coating layer disposed on said
hydrogel polymer.
35. The implantable or insertable medical device of claim 1,
wherein said medical device is selected from the group consisting
of catheters, guide wires, balloons and stents.
36. The implantable or insertable medical device of claim 35,
wherein said catheter is a neuro-interventional microcatheter.
37. The implantable or insertable medical device of claim 35,
wherein the stent is selected from the group consisting of
endovascular, biliary, tracheal, gastrointestinal, urethral,
ureteral and esophageal stents.
38. The implantable or insertable medical device of claim 37,
wherein the stent is a coronary stent.
39. The use of the implantable or insertable medical device of
claim 1 in a medical procedure, wherein during or after insertion
or implantation of said medical device in a patient, the position
of the medical device is viewed under magnetic resonance
imaging.
40. The use of the implantable or insertable medical device
according to claim 39, wherein said hydrogel polymer is adapted by
decreasing the relaxation time of detectable species associated
with said hydrogel polymer relative to the relaxation time of
detectable species in the environment surrounding the device.
41. The use of the implantable or insertable medical device
according to claim 40, wherein said detectable species comprise
protons in water molecules or hydroxyl groups associated with the
hydrogel polymer.
42. The use of the implantable or insertable medical device
according to claim 39, wherein said hydrogel polymer is adapted by
cross-linking said hydrogel polymer to a degree sufficient to
render said medical device visible under magnetic resonance imaging
upon insertion or implantation of said medical device into a
patient.
43. The use of the implantable or insertable medical device
according to claim 39, wherein said hydrogel polymer is adapted by
incorporating a member selected from the group consisting of
paramagnetic ions, paramagnetic particles and paramagnetic ion
chelation complexes in said hydrogel polymer.
44. The use of the implantable or insertable medical device
according to claim 43, wherein said paramagnetic ions comprise
gadolinium (III), said paramagnetic particles comprise
starch-coated iron oxide particles and said paramagnetic ion
chelation complex comprises Gd-DTPA.
45. The use of the implantable or insertable medical device
according to claim 43, wherein said hydrogel polymer is
cross-linked.
46. The use of the implantable or insertable medical device
according to claim 45, wherein said hydrogel polymer comprises
paramagnetic ion chelating groups.
47. The use of the implantable or insertable medical device
according to claim 46, wherein said paramagnetic ion chelating
groups are selected from the group consisting of carboxyl groups
and polyaminopolycarboxylic acid groups covalently bonded to the
hydrogel polymer.
48. The use of the implantable or insertable medical device
according to claim 45, wherein said hydrogel polymer comprises
polyacrylic acid or a copolymer of acrylic acid and acrylamide.
49. The use of a hydrogel polymer for coating at least a portion of
the surface of a medical device, wherein said hydrogel polymer is
adapted to render said medical device coated with said hydrogel
polymer visible under magnetic resonance imaging during or after
insertion or implantation of said medical device in a patient.
50. The use of a hydrogel polymer according to claim 49, wherein
said hydrogel polymer is adapted by decreasing the relaxation time
of detectable species associated with said hydrogel polymer
relative to the relaxation time of detectable species in the
environment surrounding the device.
51. The use of a hydrogel polymer according to claim 50, wherein
said detectable species comprise protons in water molecules or
hydroxyl groups associated with the hydrogel polymer.
52. The use of a hydrogel polymer according to claim 49, wherein
said hydrogel polymer is adapted by cross-linking said hydrogel
polymer to a degree sufficient to render said medical device
visible under magnetic resonance imaging upon insertion or
implantation of said medical device into a patient.
53. The use of a hydrogel polymer according to claim 49, wherein
said hydrogel polymer is adapted by incorporating a member selected
from the group consisting of paramagnetic ions, paramagnetic
particles and paramagnetic ion chelation complexes in said hydrogel
polymer.
54. The use of a hydrogel polymer according to claim 53, wherein
said paramagnetic ions comprise gadolinium (III), said paramagnetic
particles comprise starch-coated iron oxide particles and said
paramagnetic ion chelation complex comprises Gd-DTPA.
55. The use of a hydrogel polymer according to claim 53, wherein
said hydrogel polymer is cross-linked.
56. The use of a hydrogel polymer according to claim 55, wherein
said hydrogel polymer comprises paramagnetic ion chelating
groups.
57. The use of a hydrogel polymer according to claim 56, wherein
said paramagnetic ion chelating groups are selected from the group
consisting of carboxyl groups and polyaminopolycarboxylic acid
groups covalently bonded to the hydrogel polymer.
58. The use of a hydrogel polymer according to claim 55, wherein
said hydrogel polymer comprises polyacrylic acid or a copolymer of
acrylic acid and acrylamide.
59. A hydrogel polymer adapted to render a medical device coated
with said hydrogel polymer visible under magnetic resonance imaging
during or after insertion of said medical device in the
patient.
60. The hydrogel polymer of claim 59, wherein said hydrogel polymer
is adapted by decreasing the relaxation time of detectable species
associated with said hydrogel polymer relative to the relaxation
time of detectable species in the environment surrounding the
device.
61. The hydrogel polymer of claim 60, wherein said detectable
species comprise protons in water molecules or hydroxyl groups
associated with the hydrogel polymer.
62. The hydrogel polymer of claim 59, wherein said hydrogel polymer
is adapted by cross-linking said hydrogel polymer to a degree
sufficient to render said medical device visible under magnetic
resonance imaging upon insertion or implantation of said medical
device into a patient.
63. The hydrogel polymer of claim 59, wherein said hydrogel polymer
is adapted by incorporating a member selected from the group
consisting of paramagnetic ions, paramagnetic particles and
paramagnetic ion chelation complexes in said hydrogel polymer.
64. The hydrogel polymer of claim 63, wherein said paramagnetic
ions comprise gadolinium (III), said paramagnetic particles
comprise starch-coated iron oxide particles and said paramagnetic
ion chelation complex comprises Gd-DTPA.
65. The hydrogel polymer of claim 63, wherein said hydrogel polymer
is cross-linked.
66. The hydrogel polymer of claim 65, wherein said hydrogel polymer
comprises paramagnetic ion chelating groups.
67. The hydrogel polymer of claim 66, wherein said paramagnetic ion
chelating groups are selected from the group consisting of carboxyl
groups and polyaminopolycarboxylic acid groups covalently bonded to
the hydrogel polymer.
68. The hydrogel polymer of claim 65, wherein said hydrogel polymer
comprises polyacrylic acid or a copolymer of acrylic acid and
acrylamide.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to implantable or insertable
medical devices adapted to be visible under magnetic resonance
imaging (MRI). More particularly, the present invention relates to
medical devices provided with a coating adapted to render the
medical device visible under MRI; the use of such medical devices
in a medical procedure during or after which the position of the
medical device is viewed by MRI; and, the use of coatings adapted
to render medical devices coated therewith visible under MRI.
BACKGROUND OF THE INVENTION
[0002] The ability to non-invasively image internal body structures
and diseased tissues within a patient's body is an extremely
important diagnostic tool in the practice of modern medicine. Among
such non-invasive imaging techniques include magnetic resonance
imaging (MRI), x-ray imaging, ultrasonic imaging, x-ray computed
tomography, emission tomography, and others. Magnetic resonance
imaging can provide two-dimensional cross-sectional images through
a patient, providing color or gray scale contrast images of a
portion of the body. These two-dimensional images can then be
reconstructed to provide a 3-dimensional image of a portion of the
body. MRI is advantageous, inter alia, because it does not expose
the patient or medical practitioner to harmful radiation and can
provide detailed images of the observed area. These detailed images
are valuable diagnostic aids to medical practitioners and can be
used to devise, monitor or alter a treatment approach.
[0003] Magnetic resonance imaging (MRI) produces images by
differentiating detectable magnetic species in the portion of the
body being imaged. In the case of .sup.1H MRI, the detectable
species are protons (hydrogen nuclei) that possess an inherent spin
magnetic moment such that these protons behave like tiny magnets.
Images are obtained by placing the patient or area of interest
within a powerful, highly uniform, static magnetic field. The
protons in the area of interest align like tiny magnets in this
field. Radiofrequency pulses are then utilized to create an
oscillating magnetic field perpendicular to the main field, from
which the nuclei absorb energy and move out of alignment with the
static field, in a state of excitation. As the nuclei return from
excitation to the equilibrium or relaxed state, a signal induced in
the receiver coil of the instrument by the nuclear magnetization
can then be transformed by a series of algorithms into diagnostic
images. Images based on different tissue characteristics can be
obtained by varying the number and sequence of pulsed
radiofrequency fields in order to take advantage of magnetic
relaxation properties of the detectable protons in the area of
interest.
[0004] The environment of the detectable protons alters the
magnetic properties thereof such that different field strengths and
pulsation frequencies affect the ability of the MRI device to
detect such protons and differentiate them from other protons in
the surrounding environment. In order to obtain good images, MRI
relies upon the differentiation of such protons to provide contrast
between the area of interest and the surrounding environment. For
example, diseased or damaged tissue may result in a sufficiently
different environment for the detectable protons therein relative
to that of protons in the surrounding environment. Sufficient
contrast is thereby provided by the inherently different
environments to produce a good image of the area of interest.
[0005] However, in order to enhance the differentiation of
detectable species in the area of interest from those in the
surrounding environment, contrast agents are often employed. These
agents alter the magnetic environment of the detectable protons in
the area of interest relative to that of protons in the surrounding
environment and, thereby, allow for enhanced contrast and better
images of the area of interest.
[0006] Contrast agents thus function to alter the signal intensity
arising from detectable protons from that arising from detectable
protons in the surrounding environment, thereby differentiating the
area of interest from the surrounding environment. Nearly all of
the classes of contrast agents create their desired effect by
changing the spin-lattice relaxation time (T.sub.1) and/or the
spin-spin relaxation time (T.sub.2) of the detectable protons.
Those contrast agents that operate predominantly on spin-spin
relaxation times are the superparamagnets, such as particulate iron
oxides. Those contrast agents that operate predominantly on the
spin-lattice relaxation time are the paramagnets. These species
possess unpaired electrons and thus have a net magnetic moment. It
is the magnetic moment of the contrast agent that leads to an
increase in the spin-lattice relaxation rate of detectable protons,
thereby differentiating these protons from those in the surrounding
environment. For contrast-enhanced MRI it is desirable that the
contrast agent have a large magnetic moment, with a relatively long
electronic relaxation time. Based upon these criteria, contrast
agents such as Gd(III), Mn(II) and Fe(III) have been employed.
Gadolinium(III) has the largest magnetic moment among these three
and is, therefore, a widely-used paramagnetic species to enhance
contrast in MRI. Chelates of paramagnetic ions such as Gd-DTPA
(gadolinium ion chelated with the ligand
diethylenetriaminepentaacetic acid) have been employed as MRI
contrast agents. Chelation of the gadolinium or other paramagnetic
ion is believed to reduce the toxicity of the paramagnetic metal by
rendering it more biocompatible, and can assist in localizing the
distribution of the contrast agent to the area of interest.
[0007] Implantable or insertable medical devices such as catheters,
guidewires, balloons, stents, and a variety of other implantable or
insertable medical devices are conventionally used to both diagnose
and treat medical conditions. To maximize the effectiveness of such
medical devices, it is commonly desirable to both properly position
the device within a patient and thereafter ascertain the precise
location of such device upon implantation or insertion thereof.
[0008] In recent years, there has been a trend to use MRI as a
tracking/guiding tool for monitoring interventional procedures
using an implantable or insertable medical device or as a tool to
determine the position of the device upon implantation or insertion
thereof. The ability of MRI to produce extremely detailed images of
an area of interest, and the minimization of harmful radiation
exposure to the patient or medical practitioner of radiation
attendant to the use of X-ray imaging, are distinct advantages of
MRI over other imaging techniques. To this end, MRI has been used
with varying degrees of success to assist in the placement of a
medical device and/or to determine the position of a medical device
upon insertion or implantation. Unfortunately, most implantable or
insertable medical devices are composed of materials such as
organic polymers, metals, ceramics, or composites thereof, which do
not produce adequate signals for detection by MRI techniques.
Therefore, the effectiveness of MRI to monitor the insertion of
such devices and the position thereof after insertion or
implantation has been limited.
[0009] It would, therefore, be desirable to provide implantable or
insertable medical devices that are visible under MRI. For example,
it has been proposed in U.S. Pat. No. 5,154,179 to incorporate MRI
contrast enhancing agents such as ferromagnetic particles within
the polymeric material used to construct catheters. This patent
discloses incorporation of ferromagnetic particles such as iron and
iron oxides during the extrusion of the plastic to form the
catheter. The embedded ferromagnetic particles are disclosed to
make the catheter visible under MRI by providing contrast with
respect to the surrounding body tissues. The direct incorporation
of ferromagnetic or paramagnetic materials into the polymeric
material of catheters and other implantable or insertable medical
devices, however, suffers from numerous drawbacks. For example, in
order to provide enhanced contrast under MRI, paramagnetic
materials, such as paramagnetic ions, require the proximity of
water or another proton-bearing substance. It is difficult to
incorporate such substances during the shaping of the polymeric
materials used to construct the medical device. For example, water
associated with hydrated paramagnetic ions can be readily lost
during high temperature extrusion of the polymeric material used to
construct the medical device. Moreover, the incorporation of such
ferromagnetic or paramagnetic materials can detrimentally affect
the requisite mechanical properties, such as strength and
flexibility, of the polymeric materials used to construct the
implantable or insertable medical device.
[0010] U.S. Pat. No. 5,154,179 also discloses introduction of a
liquid or gel contrast agent containing a paramagnetic material
into a catheter lumen. The paramagnetic material is disclosed to
provide contrast with respect to surrounding body tissues to render
the catheter visible under MRI. The incorporation of a liquid or
gel in the catheter is difficult from a manufacturing view, limits
the flexibility of the catheter, and is generally inconvenient.
[0011] U.S. Pat. No. 5,817,017 discloses the incorporation of
paramagnetic ionic particles into non-metallic materials used to
construct catheters and other medical devices to provide such
devices with enhanced visibility under MRI. The paramagnetic ionic
particles comprise paramagnetic ions incorporated with water or
other proton-donating fluid into carrier particles such as
zeolites, molecular sieves, clays, synthetic ion exchange resins
and microcapsules. This patent discloses that the paramagnetic
ionic particles can be combined with suitable polymeric materials
and extruded into a desired shape, such as a flexible tube. This
patent further discloses that extrusion of polymeric materials
incorporating such paramagnetic ionic particles can be conducted
without substantial loss of the proton-donating fluid, which is
essential for image enhancement using the paramagnetic metals.
Among paramagnetic ions that can be incorporated into the carrier
particles are mentioned trivalent gadolinium. Among proton-donating
fluids that can be incorporated with the paramagnetic ions in the
carrier particles, are water, alcohols such as glycerols (e.g.,
propylene glycol, polyethylene glycol and ethylene glycol),
detergents such as sulfonated compounds, ethers such as glyme and
diglyme, amines, imidazoles, and Tris.
[0012] Despite these and other attempts to render implantable or
insertable medical devices visible under MRI, there remains a need
for a simplified, cost-effective approach that avoids the
disadvantages of the methods discussed above.
[0013] The present invention is, therefore, directed to implantable
or insertable medical devices adapted to be visible under magnetic
resonance imaging (MRI). More particularly, the present invention
is directed to medical devices provided with a coating adapted to
render the medical device visible under MRI; the use of such
medical devices in a medical procedure during or after which the
position of the medical device can be viewed by MRI; and, the use
of coatings adapted to render medical devices coated therewith
visible under MRI.
SUMMARY OF THE INVENTION
[0014] In one embodiment, the present invention is directed to an
implantable or insertable medical device comprising (a) a
substrate; and (b) a hydrogel polymer coating at least a portion of
the substrate surface, wherein the hydrogel polymer is adapted to
render the medical device visible under magnetic resonance imaging
upon insertion or implantation of the medical device into a
patient.
[0015] In another embodiment, the present invention is directed to
the use of an implantable or insertable medical device of the
present invention in a medical procedure, wherein during or after
insertion or implantation of the medical device in a patient, the
position of the medical device is viewed under magnetic resonance
imaging.
[0016] In still another embodiment, the present invention is
directed to the use of a hydrogel polymer for coating at least a
portion of the surface of a medical device, wherein the hydrogel
polymer is adapted to render the medical device coated with the
hydrogel polymer visible under magnetic resonance imaging during or
after insertion or implantation of the medical device in a
patient.
[0017] In a further embodiment, the present invention is directed
to a hydrogel polymer adapted to render a medical device coated
with the hydrogel polymer visible under magnetic resonance imaging
during or after insertion of the medical device in a patient.
[0018] The hydrogel polymer may be adapted to render a medical
device coated therewith visible under MRI by decreasing the
relaxation time of detectable species associated with said hydrogel
polymer relative to the relaxation time of detectable species in
the environment surrounding the device. The detectable species may
comprise, e.g., protons in water molecules or hydroxyl groups
associated with the hydrogel polymer.
[0019] The hydrogel polymer may also be adapted by cross-linking
the hydrogel polymer to a degree sufficient to render said medical
device visible under magnetic resonance imaging upon insertion or
implantation of said medical device into a patient.
[0020] The hydrogel polymer may also be adapted to render a medical
device coated therewith visible under MRI by incorporating a member
selected from the group consisting of paramagnetic ions,
paramagnetic particles or paramagnetic ion chelation complexes in
the hydrogel polymer. In some preferred embodiments, paramagnetic
ions include materials such as gadolinium(III); paramagnetic
particles include materials such as starch-coated iron oxide
particles; and paramagnetic ion chelation complexes include
materials such as gadolinium diethylenetriamine pentaacetic acid.
The hydrogel polymer itself may also comprise paramagnetic ion
chelating groups. In some preferred embodiments, the paramagnetic
ion chelating groups include carboxyl groups and
polyaminopolycarboxylic acid groups covalently bonded to the
hydrogel polymer.
[0021] Among some presently preferred hydrogel polymers are
included polyacrylic acids and copolymers of acrylic acid and
acrylamide, which may be cross-linked.
DETAILED DESCRIPTION OF THE INVENTION
[0022] It is known to provide implantable or insertable medical
devices with a coating on a surface of the device. Such coatings
may be provided for various purposes including, but not limited to,
carrying a therapeutic agent for localized delivery to a target
area within the body; providing a lubricious surface to facilitate
introduction of the medical device into the patient during an
interventional procedure; improving the biocompatibility of the
medical device with the surrounding environment; or, for a
combination of such or other purposes. Among coatings that have
been proposed for implantable or insertable medical devices are
polymeric materials such as hydrogels.
[0023] Hydrogels are typically hydrophilic polymeric materials that
have the ability to absorb large amounts, up to many times the
weight of the hydrogel itself, of water or other polar molecules.
Hydrogels have been disclosed as coatings for implantable or
insertable medical devices or as materials for constructing the
device itself in, for example, U.S. Pat. Nos. 6,316,522; 6,261,630;
6,184,266; 6,176,849; 6,096,108; 6,060,534; 5,702,754; 5,693,034;
and, 5,304,121, each of which is assigned to Boston Scientific
Corporation or SciMed Life Systems, Inc. and is incorporated herein
in its entirety by reference. Hydrogels, such as those described in
the foregoing exemplary U.S. patents, can be based on synthetic or
naturally occurring materials, or a composite thereof, can be
biodegradable or substantially non-biodegradable; and, can be
modified or derivatized in numerous ways to render the hydrogel
more suitable for a desired purpose. For example, the hydrogel can
be modified by chemically cross-linking with, for example, a
polyfunctional cross-linking agent that is reactive with functional
groups covalently bonded to the polymer structure. The hydrogel
polymer can also be ionically cross-linked with, for example,
polyvalent metal ions. Many hydrogel polymers mentioned herein can
be both chemically and ionically cross-linked. Therefore,
chemically and ionically cross-linkable hydrogel polymers are not
necessarily mutually exclusive groups of hydrogel polymers.
[0024] Cross-linking of a hydrogel polymer can be advantageous, for
example, to provide a more rigid material. Cross-linking may also
be conducted, for example, to render the hydrogel less soluble in a
particular environment or to modify the ability of the hydrogel
polymer to absorb water or to modify the manner in which water or
other molecules, compounds or groups are associated with the
hydrogel polymer
[0025] MRI based on detection of the spin relaxation of .sup.1H
nuclei (protons) relies on the differentiation of protons in the
area of interest relative to those in the surrounding environment.
For example, protons in water molecules in the area of interest,
while detectable using MRI, are often not sufficiently
differentiated from protons surrounding the area of interest to
provide the contrast necessary for producing a good image using
MRI. However, by changing the magnetic environment of the protons
in the water molecules in the area of interest relative to that of
protons in the surrounding environment, enhanced detection and
contrast can be achieved. Among methods generally known for
enhancing the contrast of protons in water molecules are included,
as discussed above, decreasing the spin relaxation time of the
protons by incorporating a paramagnetic species such as
gadolinium(III) in the environment of the water molecules in the
area of interest.
[0026] The present invention is based on the adaptation of hydrogel
polymers to render an implantable or insertable medical device
visible under MRI when the hydrogel polymer is provided as a
coating on at least a portion of the surface of the implantable or
insertable medical device. Hydrogel polymers are especially
suitable for differentiating MRI detectable species, such as
protons associated with the hydrogel polymer, from protons in the
environment surrounding the device. Contrast, which is essential
for detailed images using MRI, can thereby be achieved by adapting
the hydrogel polymers such that detectable species associated with
the hydrogel polymers are differentiated from detectable species in
the environment surrounding the medical device coated with the
hydrogel polymer.
[0027] Without being bound by theory, it is believed that hydrogel
polymers are particularly suitable for use in the present invention
because, inter alia, these polymers, provided as coatings on
implantable or insertable medical devices, can be adapted to
provide a magnetic environment for detectable species associated
with the hydrogel polymer that differs from the magnetic
environment of detectable species in the environment surrounding
the coated device. The magnetic environment experienced by
detectable species such as protons associated with the adapted
hydrogel polymer coating is, thus, sufficiently different from the
magnetic environment surrounding the medical device such that
protons associated with the hydrogel polymer coating have enhanced
detectability under MRI.
[0028] As used herein, the term "associated with" is meant to
include various means by which the detectable species, such as
protons, are incorporated within the hydrogel polymer, including
but not limited to, ionic bonding, hydrogen bonding, covalent
bonding, Van der Waals bonding, physical entrapment and
combinations of the same. Thus, for example, detectable protons may
be present in groups, such as pendant groups that are covalently or
ionically bonded to the hydrogel polymer; or they may be present in
molecules such as water or other molecules, compounds or groups
that are absorbed within or adsorbed on the hydrogel polymer, or
otherwise immobilized within the hydrogel polymer matrix.
Immobilization of such detectable species may be facilitated by
providing a cross-linked hydrogel polymer matrix. Such absorption,
adsorption and/or cross-linking immobilization may be further
facilitated by, for example, hydrogen bonding, ionic bonding or,
more generally, electrostatic interaction of molecules, compounds
or groups comprising the detectable species with the hydrogel
polymer or groups covalently or ionically bonded to the hydrogel
polymer.
[0029] Hydrogel polymers that can be adapted such that, when
provided as a coating on the surface of an implantable or
insertable medical device of the present invention, the medical
device is rendered visible under MRI include, without limitation,
any of the hydrogels disclosed in U.S. Pat. Nos. 6,316,522;
6,261,630; 6,184,266; 6,176,849; 6,096,108; 6,060,534; 5,702,754;
5,693,034; and, 5,304,121, mentioned above. Examples of hydrogel
polymers that can be adapted to render a medical device visible
under MRI include, without limitation, polyacrylates; poly(acrylic
acid); poly(methacrylic acid); polyacrylamides;
poly(N-alkylacrylamides); polyalkylene oxides; poly(ethylene
oxide); poly(propylene) oxide; poly(vinyl alcohol); polyvinyl
aromatics; poly(vinylpyrrolidone); poly(ethyleneimine);
polyethylene amine; polyacrylonitrile; polyvinyl sulfonic acid;
polyamides; poly(L-lysine); hydrophilic polyurethanes; maleic
anhydride polymers; proteins; collagen; cellulosic polymers; methyl
cellulose; carboxymethyl cellulose; dextran; carboxymethyl dextran;
modified dextran; alginates; alginic acid; pectinic acid;
hyaluronic acid; chitin; pullulan; gelatin; gellan; xanthan;
carboxymethyl starch; chondroitin sulfate; guar; starch; and
copolymers, mixtures and derivatives thereof.
[0030] Hydrogel polymers are hydrophilic and can absorb, relative
to their weight, relatively large amounts of water, typically from
about 30 wt % to about 50 wt % or more, or other polar molecules.
Thus, when provided as a coating on a substrate such as the surface
of a medical device, the hydrogel polymer can swell, upon
absorption of water, to several times its thickness in the absence
of the absorbed water. Water, as discussed above, comprises protons
that are detectable using MRI. It has been discovered that hydrogel
polymers can be adapted such that water molecules or other
detectable species associated with the hydrogel polymer experience
a substantially different magnetic environment relative to
detectable species in the surrounding environment. Therefore, when
such hydrogel polymer is provided as a coating on an implantable or
insertable medical device, enhanced detection of protons in water
molecules associated with the hydrogel coating is observed,
rendering the medical device visible under MRI.
[0031] While not wishing to be bound by theory, the enhanced
ability to detect protons in water or other molecules, compounds or
groups associated with the hydrogel polymer may result from
decreasing the spin relaxation time of the protons in the water,
other molecules, compounds or groups associated with the hydrogel
coating.
[0032] Molecules other than water, or in addition to water, may
also be associated with the hydrogel polymer to adapt the hydrogel
polymer to render the medical device coated therewith visible under
MRI. Such molecules are those that can be associated with the
hydrogel polymer and comprise species, such as protons, that are
detectable using MRI when incorporated within the hydrogel polymer.
Among such molecules are included, but not limited to,
hydroxyl-group containing compounds such as alkanols, e.g.,
ethanol, glycerine (glycerol), ethylene glycol, propylene glycol,
polyethylene glycol, polypropylene glycol and other hydroxylated
and polyhydroxylated compounds that are known in art and are
substantially non-toxic. When such hydroxyl-group containing
compounds are associated with the hydrogel polymer, the protons in
the hydroxyl groups may be sufficiently differentiated from protons
in the environment surrounding the implantable or insertable
medical device such that the device coated with the hydrogel
polymer incorporating such compounds is rendered visible under
MRI.
[0033] The detectable species associated with the hydrogel polymer
may be present in a compound, such as water or other hydroxylated
molecule, which is dispersed or absorbed within the hydrogel
polymer matrix and/or adsorbed on a surface thereof. For example,
such compounds may be associated with the hydrogel polymer by a
mechanism such as hydrogen bonding. However, it is understood that
the hydrogel polymer may also be adapted such that the detectable
species are present in groups that are chemically bonded, e.g., by
covalent or ionic bonding, to the polymer itself. Thus, the
compound comprising the detectable species may be covalently bonded
to a functional group that is itself covalently bonded to the
hydrogel polymer. Binding of the compound comprising the detectable
species may thus result from, e.g., reaction of a hydroxyl group
inherently found in the compound with a functional group in the
hydrogel polymer. The compound containing the detectable species
may also be modified from its inherent state to contain one or more
groups reactive with a functional group in the hydrogel polymer to
form, e.g., an amide, ester or other linkage of the compound to the
hydrogel polymer.
[0034] The hydrogel polymer of the present invention may be
cross-linked. Cross-linked hydrogel polymers, when coated on an
implantable or insertable medical device, are particularly
advantageous for use in rendering the medical device visible under
MRI upon insertion or implantation of the device. In accordance
with this embodiment of the present invention, hydrogel polymers
may be adapted by cross-linking to a degree sufficient to render
the medical device visible under magnetic resonance imaging upon
insertion or implantation of the medical device into a patient. It
is believed that by varying the degree of cross-linking, the
magnetic environment experienced by detectable species such as
protons in water or other molecules, compounds or groups associated
with the hydrogel polymer may be modified, relative to the magnetic
environment surrounding the medical device, thereby resulting in
enhanced visibility under MRI of such detectable species associated
with the hydrogel polymer coating. The enhanced visibility of the
detectable species in the cross-linked hydrogel polymer coating
renders the medical device visible under MRI upon insertion or
implantation of the coated medical device into a patient.
[0035] As discussed more fully below, cross-linked hydrogels are
also particularly advantageous to incorporate, within the
cross-linked hydrogel, paramagnetic materials such as paramagnetic
ions, paramagnetic ion chelation complexes, paramagnetic particles
and other materials that enhance the visibility under MRI of
detectable species such as protons in water or other molecules,
compounds or groups associated with the hydrogel polymer. Such
paramagnetic materials generally function by reducing the spin
relaxation time of such detectable species, thereby differentiating
such species from detectable species in the environment surrounding
the implantable or insertable medical device and, consequently,
providing the detectable species associated with the hydrogel
polymer with enhanced visibility under MRI.
[0036] Among cross-linked hydrogel polymers useful in the present
invention are those disclosed in U.S. Pat. No. 5,702,754 to Zhong
et al. Such polymers are characterized by the presence therein of
organic acid functional groups that are reactive with
polyfunctional cross-linking agents. By "organic acid functional
group" is meant any organic group containing an acidic hydrogen
atom such as a carboxylic, sulfonic or phosphoric acid group or a
metal salt of any such acid group, particularly alkali metal salts
such as lithium, sodium and potassium salts, and alkaline earth
metal salts such as calcium or magnesium salts, and quaternary
amine salts of such acid groups, particularly quaternary ammonium
salts.
[0037] Hydrogel polymers containing organic acid groups that can be
reacted with a polyfunctional cross-linking agent useful in the
present invention include homopolymers and copolymers of vinylic
monomer units, such as homopolymers or copolymers comprising
substituted or unsubstituted acrylic acid monomer units or
substituted or unsubstituted acrylamide units. Where the hydrogel
polymer is a copolymer, at least one of the co-monomer units will
contain a functional group, such as an organic acid functional
group, that is reactive with a polyfunctional cross-linking agent.
Thus, where the functional group in the polymer is an organic acid
functional group, any hydrogel polymer prepared, for example, from
an ethylenically unsaturated acid, or salt thereof as mentioned
above, may be cross-linked with a polyfunctional cross-linking
agent and utilized as a coating for a medical device in accordance
with the present invention. Thus, copolymers of, for example,
maleic acid, fumaric acid and isocrotonic may be employed, as well
as polymers containing substituted or unsubstituted acrylic acid
monomer units.
[0038] Substituted acrylic acid monomer units include, but are not
limited to, those substituted with lower (C1-C6) straight or
branched-chain alkyl groups, for example, methacrylic acid.
Substituted acrylamide monomer units include, but are not limited
to, those substituted with lower straight or branched chain alkyl
groups, for example, methacrylamide. Acrylamide monomer units may
also be N-substituted with groups including, but not limited to,
lower straight or branched chain alkyl substituents. Among
presently preferred polymers containing organic acid functional
groups are polyacrylic acid and copolymers of acrylic acid and
acrylamide monomer units. Other cross-linkable hydrogel polymers
include, without limitation, hydrophilic polyurethanes and
copolymers of urethane with acrylic monomers such as such as
acrylic acid, which may be substituted as described above. Such
polymers are disclosed in U.S. Pat. No. 5,702,754.
[0039] While the above-mentioned cross-linked hydrogel polymers may
be preferred in some embodiments of the invention, it is understood
that the present invention should not be construed as limited to
any particular type of hydrogel polymer, whether cross-linked or
not. Any hydrogel polymer adapted to render an implantable or
insertable medical device coated therewith visible under MRI is,
therefore, within the scope of the present invention.
[0040] When a cross-linked hydrogel polymer is employed, included
within the scope of the present invention are those cross-linked
hydrogel polymers suitable for coating an implantable or insertable
medical device and which can be adapted by varying the degree of
cross-linking thereof such that, when coated on an implantable or
insertable medical device, the cross-linked hydrogel polymer
renders the medical devisable visible under MRI upon insertion or
implantation thereof.
[0041] Hydrogel polymers that are cross-linked other than by means
of reaction of an organic acid functional group in the hydrogel
polymer with a polyfunctional cross-linking agent are, therefore,
included within the scope of the present invention.
[0042] As examples of other cross-linked hydrogel polymers that may
be used in accordance with the present invention, are included,
without limitation, hydrogel polymers that may be ionically
cross-linked. Tonically cross-linked hydrogel polymers for use with
implantable or insertable medical devices are disclosed, for
example, in U.S. Pat. Nos. 6,096,018 and 6,060,534 each of which is
incorporated herein in its entirety by reference. Tonically
cross-linked polymers can be either cationic or anionic in nature
and include, without limitation, carboxylic, sulfate, and amine
functionalized polymers such as polyacrylic acid, polymethacrylic
acid, polyhydroxy ethyl methacrylate, polyvinyl alcohol,
polyacrylamide, poly (N-vinyl pyrrolidone), polyethylene oxide,
hydrolyzed polyacrylonitrile, polyethylene amine, polysaccharides,
alginic acid, pectinic acid, carboxy methyl cellulose, hyaluronic
acid, heparin, heparin sulfate, chitosan, carboxymethyl chitosan,
chitin, carboxymethyl starch, dextran, carboxymethyl dextran,
chondroitin sulfate, cationic guar, cationic starch, alginic acid,
pectinic acid, pullulan, gellan, xanthan, collagen as well as
mixtures, derivatives (such as salts and esters) and copolymers
thereof. It is understood that many of these hydrogel polymers may
be cross-linked with chemical cross-linking agents and/or with
ionic cross-linking agents. Therefore, hydrogel polymers that may
be chemically cross-linked do not necessarily form a mutually
exclusive group from hydrogel polymers that may be ionically
cross-linked. In general, the hydrogel polymers useful in
accordance with the present invention can be ionically and/or
chemically cross-linked and may be cross-linked by other methods
known in the art as well.
[0043] The crosslinking ions used to tonically crosslink the
hydrogel polymers may be anions or cations depending on whether the
polymer is anionically or catonically crosslinkable. Appropriate
crosslinking ions include but are not limited to cations selected
from the group consisting of calcium, magnesium, barium, strontium,
boron, beryllium, aluminum, iron, copper, cobalt, lead and silver
ions. Anions may be selected from, but are not limited to, the
group consisting of phosphate, citrate, borate, succinate, maleate,
adipate and oxalate ions. More broadly, anions are commonly derived
from polybasic organic or inorganic acids. Crosslinking may be
carried out by methods known in the art, for example, by contacting
the polymers with an aqueous solution containing dissolved
ions.
[0044] As noted above, among various methods of cross-linking
hydrogel polymers are included, but not limited to, chemical
cross-linking with polyfunctional reagents that bridge hydrogel
polymer chains by reaction with functional groups in the hydrogel
polymer or cross-linking the hydrogel polymer with polyvalent metal
ions. Non-chemical cross-linking methods, such as by exposing the
hydrogel polymer to light of an appropriate frequency may also be
employed. Chemical cross-linking with polyfunctional reagents is
among preferred methods of cross-linking because the degree of
crosslinking can often be more readily controlled by, for example,
varying the amount and/or type of polyfunctional cross-linking
agent employed.
[0045] A polyfunctional cross-linking agent can be any compound
having at least two sites for reaction with functional groups, such
as amide or, in some preferred embodiments, organic acid functional
groups, in the hydrogel polymer. Any conventional polyfunctional
cross-linking agent known in the art may be employed. Preferably,
the crosslinking agent contains one or more of carboxyl, hydroxy,
epoxy, halogen or amino functional groups which are capable, via
well-known mechanisms such as nucleophilic or condensation
reactions, of reacting with functional groups present along the
polymer backbone or in the polymer structure. The polyfunctional
cross-linking agent may thus comprise, e.g., diazonium, azide
isocyanate, acid chloride, acid anhydride, imino carbonate, amino,
carboxyl, epoxy, hydroxyl, aldehyde, carbodimide and aziridine
groups. Examples of some preferred polyfunctional cross-linking
agents include, without limitation, polycarboxylic acids or
anhydrides; polyamines; epihalohydrins; diepoxides; dialdehydes
such as glutaraldehye; diols; carboxylic acid halides, ketenes and
like compounds. Examples of cross-linking agents are found in U.S.
Pat. Nos. 5,869,129, 5,702,754 and 6,060,534 each of which is
incorporated in its entirety herein by reference. Specific
cross-linking agents that may be used include, for example,
commercially available preparations sold by Zeneca Resins (e.g.,
NeoCryl CX 100), preparations sold by EIT Industries (e.g.,
XAMA-7), and preparations sold by Union Carbide (e.g., Ucarlink
XL-29SE). A combination of polyfunctional crosslinking agents may
be used to cross-link a hydrogel polymer useful in accordance with
the present invention.
[0046] The hydrogel polymer, whether cross-linked or not, may be
attached to a substrate, i.e., the surface of a medical device, by
any means known in the art. The mechanism by which the hydrogel
polymer is attached to the surface of the medical device is,
therefore, not critical to the practice of the invention disclosed
herein. Thus, the hydrogel polymer may be provided on the surface
of a substrate by, for example, dipping the medical device, or
portion thereof to be coated with the hydrogel polymer, into a
solution, dispersion or emulsion of the hydrogel polymer followed
by drying to remove the carrier fluid used to dissolve, disperse or
emulsify the hydrogel polymer. A solution, dispersion or emulsion
of the hydrogel polymer may also be sprayed onto the surface of the
medical device followed by drying.
[0047] Other methods known in the art for providing a hydrogel
polymer coating on the surface of a substrate may also adapted to
provide a hydrogel polymer coating on an implantable or insertable
medical device in accordance with the present invention. For
example, it is also possible to polymerize the hydrogel polymer on
the surface of the medical device by contacting the medical device,
or portion thereof to be coated with the hydrogel polymer, with a
solution, dispersion or emulsion containing a polymerizable monomer
or a mixture or polymerizable monomers and any other optional
reagents such as cross-linking reagents, initiators, etc., and
thereafter causing polymerization to occur in situ on the surface
of the medical device. The polymerizable monomer may also be
deposited on the surface of the medical device by, for example,
plasma enhanced chemical vapor deposition (PECVD) or other methods
known in the art. The polymerization reaction occurring on the
surface of the medical device may be triggered by, for example,
heating the coated medical device or exposing the coated medical
device to light of an appropriate frequency. Other methods known in
the art for causing polymerization to occur on a substrate may be
adapted to provide a hydrogel polymer on the surface of an
implantable or insertable medical device in accordance with the
present invention.
[0048] The surface of the medical device may also be pre-treated or
primed to enhance adherence of the hydrogel polymer or a
polymerizable monomer to the surface thereof. Such pre-treatment
can ultimately result in a hydrogel polymer coating that is more
tenaciously adhered to the medical device. In one embodiment, a
primer coating is applied to the device surface through
conventional methods, including dipping and spraying. The primer
solution may comprise, for example, an aqueous solution, dispersion
or emulsion of a polymer containing organic acid functional groups
and an excess of a polyfunctional cross-linking agent that is
reactive with the organic acid groups on the hydrogel polymer,
which is subsequently applied to the medical device having the
primer coating layer applied thereto. After the primer coat is
permitted to dry to form a substantially water-insoluble layer, the
dried primer coat is contacted with an aqueous solution, dispersion
or emulsion of a hydrogel polymer or hydrogel-forming monomers by
conventional methods. The hydrogel polymer may be provided as, for
example, an aqueous dispersion or emulsion of a hydrogel polymer or
hydrogel-forming monomers, a cross-linking agent and, optionally, a
paramagnetic material such as a paramagnetic ion, paramagnetic ion
chelation complex or a paramagnetic particle. Alternatively, a
paramagnetic material may be loaded into the hydrogel coating after
it is applied to the device surface. The hydrogel polymer is bonded
to the primer coating layer through excess unreacted polyfunctional
cross-linking agent.
[0049] One method for attaching the hydrogel polymer to the surface
of a medical device that may be advantageously employed in
accordance with the present invention is disclosed in U.S. Pat. No.
5,702,752. In this method, the substrate, i.e., the surface of a
medical device, is coated with a primer coating composition
comprising, for example, an aqueous dispersion or emulsion of a
polymer having organic acid functional groups and a polyfunctional
crosslinking agent having functional groups capable of reacting
with the organic acid functional groups in the subsequently applied
hydrogel polymer. The primer coating layer is dried to form a
substantially insoluble layer and then the substrate having the
primer coating layer disposed thereon is contacted with a solution,
dispersion or emulsion of a hydrogel polymer. The polyfunctional
crosslinking agent used in this method provides unreacted
functional groups for reaction with functional groups, such as
organic acid functional groups, in the hydrogel polymer. The
functional groups in the polyfunctional cross-linking agent thus
serve at least two purposes. The first purpose is to crosslink the
primer coating and thereby form a substantially water insoluble
primer coating layer. The second purpose is to covalently bond to
organic acid groups present in the hydrogel polymer, thereby
securing the hydrogel polymer to the primer coating layer.
Therefore, sufficient functionality must be present in the
crosslinking agent to accomplish both purposes. That is, the amount
or type of crosslinking agent used must be sufficient such that
enough functional groups are present to substantially crosslink the
primer coating and provide unreacted functional groups for
covalently bonding to the hydrogel polymer.
[0050] Unreacted functional groups in the polyfunctional
cross-linking agent may be present, for example, by supplying an
excess of the polyfunctional cross-linking agent during application
of the primer coating, or by utilizing a polyfunctional
cross-linking agent having more than two functional groups per
molecule. Among such polyfunctional cross-linking agents having
more than two functional groups per molecule are trifunctional
aziridines disclosed in U.S. Pat. No. 5,702,754.
[0051] The hydrogel polymer may be applied by contacting the first
dried cross-linked primer coating layer with an aqueous solution or
dispersion of a hydrogel polymer having organic acid functional
groups, and drying the combined coating. The hydrogel polymer is
thereby bonded to the primer coating by reaction of the organic
acid functional groups in the hydrogel polymer with unreacted
functional groups in the polyfunctional cross-linking agent. An
optional lubricious coating layer may be provided by a similar
method. This additional coating layer preferably comprises a
hydrogel polymer that provides lubricity that can facilitate
insertion of the implantable or medical device into the
patient.
[0052] The hydrogel polymer, when provided as a coating on a
surface of a medical device in accordance with the present
invention, will preferably have a thickness in the range of from
about 20 to about 3000 microns, more preferably from about 50 to
about 2000 microns. Hydrogel polymer thicknesses in the range of
from about 100 to about 1000 microns are particularly preferred.
The thickness of the hydrogel polymer may be adjusted to enhance
the visibility under MRI of the medical device, or a portion
thereof, coated with a hydrogel polymer in accordance with the
present invention. For example, the medical device may be provided
with a substantially uniform thickness of the hydrogel polymer, or
selected portions of the medical device may be provided with a
thicker or thinner hydrogel polymer coating as desired to enhance
contrast with respect to another portion of the medical device. It
is understood that the entire surface of the medical device need
not be provided with a hydrogel polymer coating in accordance with
the present invention. Thus, the coating maybe provided only on
selected portions of the medical device to enhance the visibility
thereof or to render such portions visible under MRI.
[0053] In some embodiments of the present invention, the hydrogel
polymer is adapted by incorporating a paramagnetic material within
the hydrogel polymer such that, when applied as a coating on an
implantable or insertable medical device, the medical device is
rendered visible under MRI. Paramagnetic materials for use as
contrast agents for MRI are known in the art and include, for
example, paramagnetic ions, paramagnetic ion chelation complexes,
paramagnetic particles and other materials that comprise
paramagnetic atoms and enhance the visibility under MRI of
detectable species, such as protons. Any paramagnetic material
known in the art as an MRI contrast agent may be incorporated
within a hydrogel polymer or provided as a coating on an
implantable or insertable medical device in accordance with the
present invention.
[0054] It is believed that the paramagnetic material, when
incorporated within a hydrogel polymer coating on a medical device
in accordance with the present invention, decreases the spin
relaxation time of detectable species such as protons in water or
other molecules, compounds or groups associated with the hydrogel
polymer. Consequently, the detectable species associated with the
hydrogel polymer have enhanced detectability under MRI relative to
detectable species in the environment surrounding the medical
device. Visibility of the medical device under MRI is, therefore,
enhanced.
[0055] Among paramagnetic materials that can be incorporated in a
hydrogel polymer provided as a coating on a medical device in
accordance with the invention include paramagnetic ions and
paramagnetic particles. Paramagnetic materials are typically those
that have a strong magnetic moment relative to detectable protons
in water or other molecules, compounds or groups in the vicinity of
the paramagnetic materials. Elements with atomic numbers 21-29, 42,
44, and 58-70, such as chromium (III), manganese (II), iron (III),
iron (II), cobalt (II), copper (II), nickel (II), praesodymium
(III), neodymium (III), samarium (III), ytterbium (III), gadolinium
(III), terbium (III), dysprosium (III), holmium (III) and erbium
(III) are examples of paramagnetic elements that can be used in
accordance with the present invention. A widely used element in
paramagnetic materials for MRI contrast agents is gadolinium (III),
a lanthanide having seven unpaired electrons in the 4f orbital,
which has a large magnetic moment. The large magnetic moment of the
gadolinium (III) causes a localized reduction of the relaxation
times in the protons in its environment, resulting in enhanced
visibility of the magnetic resonance images. Paramagnetic materials
based on gadolinium (III) are, therefore, among preferred
paramagnetic materials that can be incorporated within a hydrogel
polymer coating on an implantable or insertable medical device in
accordance with the present invention.
[0056] Paramagnetic material can be incorporated within the
hydrogel polymer by, for example, contacting the medical device
having the hydrogel polymer coated thereon with the paramagnetic
material, e.g., a solution of a soluble salt of the paramagnetic
ion, or a solution comprising a paramagnetic ion chelation complex.
Alternatively, the paramagnetic material can be incorporated within
the hydrogel polymer by, for example, contacting the hydrogel
polymer or a monomer precursor thereof with the paramagnetic ions
or a chelation complex thereof prior to formation of the hydrogel
polymer coating on the surface of the implantable or insertable
medical device. The paramagnetic ion or chelation complex thereof
then becomes incorporated within the hydrogel polymer matrix, for
example, by absorption/entrapment within the hydrogel polymer
matrix and/or adsorption on the surface of the hydrogel
polymer.
[0057] Where paramagnetic ions are incorporated, it is particularly
advantageous if the hydrogel polymer comprises groups that
facilitate securing the paramagnetic ions onto and/or within the
hydrogel polymer. Such groups may, for example, comprise organic
acid functional groups or other anionically ionizable groups in or
covalently bonded to the hydrogel polymer. It is believed that the
electrostatic attraction or ionic bonding of the cationic
paramagnetic ions to anionic groups such as carboxyl or other
groups in or covalently bonded to the hydrogel polymer (e.g.,
pendant from the hydrogel polymer backbone) can secure the
paramagnetic ions within and/or onto the hydrogel polymer. The
anionically ionizable groups may also be functionally referred to
herein as paramagnetic ion chelating groups. The paramagnetic ions
are, therefore, held by the hydrogel polymer such that excessive
leaching of such ions is prevented. Substantial immobilization of
the paramagnetic ions within the hydrogel polymer is, of course,
important to ensure that the hydrogel coating, and hence medical
device coated therewith, will have maximum visibility and
durability under MRI. Moreover, the paramagnetic ions are often
toxic and can, therefore, produce adverse reactions if excessively
leached from the coating and thereafter distributed systemically or
absorbed in specific areas of the patient.
[0058] Hence, hydrogel polymers that comprise paramagnetic ion
chelating groups are also useful in the present invention. Such
paramagnetic ion chelating groups can be covalently bonded to the
hydrogel polymer by, for example, reacting a polymerizable olefinic
monomer containing a paramagnetic ion chelating functionality with
a hydrophilic monomer such as substituted or unsubstituted acrylic
acid or acrylamide. The paramagnetic chelating functionality can be
provided, for example, by utilizing a polymerizable monomer
containing an aminopolycarboxylic acid group. Among
aminopolycarboxylic acid groups or other metal chelating groups
that may be incorporated within a polymerizable monomer used for
forming a hydrogel, or otherwise incorporated within a hydrogel
polymer in accordance with the present invention, are those known
in the art for chelating metal ions and include, without
limitation, diethylene triaminepentaacetic acid (DTPA);
1,4,7,10-tetraazacyclododecane-N,N,N',N'- "-tetraacetic acid
(DOTA); ethylenediaminetetraacetic acid (EDTA);
1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid (DO3A);
1,4,7-triazacyclononane-N,N',N"-triacetic acid (NOTA);
1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid
(TETA); and hydroxybenzylethylene-diamine diacetic acid (HBED). The
paramagnetic ions may be incorporated within the hydrogel polymer
for chelation with such metal chelating groups before or after the
hydrogel polymer is provided on the surface of the implantable or
insertable medical device.
[0059] The hydrogel polymer used to coat medical devices in
accordance with the present invention may also comprise a
paramagnetic ion chelation complex that is not necessarily
covalently bonded to the hydrogel polymer. Such paramagnetic
chelation complexes may, for example, be complexes of any
paramagnetic ion, such as those mentioned hereinabove, with any
conventional metal chelating compound including, without
limitation, DTPA, DOTA, EDTA, NOTA, TETA and HBED. Gadolinium
diethylene triaminepentaacetic acid (Gd-DTPA) is among presently
preferred paramagnetic ion chelation complexes that can be
incorporated in a hydrogel polymer for coating a medical device in
accordance with the present invention. A paramagnetic ion chelation
complex can be incorporated within the hydrogel polymer by
contacting the hydrogel polymer with, e.g., a solution of the
chelation complex, either before or after the hydrogel polymer is
formed on the surface of an implantable or insertable medical
device. For example, the chelating compound can be incorporated
within a hydrogel polymer by, for example, forming a suspension or
dispersion of the hydrogel and chelating compound and, thereafter
applying the suspension or dispersion to the surface of a medical
device, followed by drying. The chelating compound can also be
combined with the hydrogel-forming monomers, and any crosslinking
agents used to form the hydrogel polymer, prior to polymerizing the
same. It is also possible to apply the chelating compound to the
surface of a medical device previously coated with a hydrogel
polymer by, e.g., by spraying a solution of the chelating compound
on the polymer, or dipping the polymer into the same.
[0060] The hydrogel polymer used in an implantable or insertable
medical device in accordance with the present invention may also
have incorporated therein paramagnetic particles. Paramagnetic
particles are distinguished herein from paramagnetic ions or
chelation complexes of paramagnetic ions in that such particles, as
the name implies, are solids. Such solids are, preferably,
substantially insoluble in an aqueous environment, such as the
aqueous environment of a hydrogel having water associated therewith
or the aqueous environment provided by bodily fluids in contact
with the implantable or insertable medical device coated with a
hydrogel polymer.
[0061] Such paramagnetic particles can be incorporated within a
hydrogel polymer by, for example, forming a suspension or
dispersion of the hydrogel and paramagnetic particles and,
thereafter applying the suspension or dispersion to the surface of
a medical device, followed by drying. The paramagnetic particles
can also be combined with the hydrogel-forming monomers, and any
crosslinking agents used to form the hydrogel polymer, prior to
polymerizing the same. It is also possible to apply the
paramagnetic particles to the surface of a medical device
previously coated with a hydrogel polymer by, e.g. contacting the
coated medical device with the particles by spraying the particles
onto the coated medical device. Other methods known in the art for
coating polymeric surfaces with particulate substances may also be
adapted to provide a hydrogel coated medical device in accordance
with the present invention wherein a surface thereof comprises
paramagnetic particles.
[0062] Any paramagnetic particles known in the art for use as MRI
contrast agents may be utilized in this embodiment of the present
invention. Among such paramagnetic particles that are useful,
therefore, include solid compounds of any of the paramagnetic
elements mentioned above. Particularly preferred solid compounds of
such elements include the paramagnetic and superparamagnetic oxides
of such elements. Among presently preferred paramagnetic particles
are ultrasmall superparamagnetic iron oxide particles coated with
starch or other polysaccharides or cellulosic materials. Examples
of such coated ultrasmall iron oxide particles are found, for
example, in U.S. Pat. Nos. 6,207,134 and 6,123,920 (and the patents
cited therein) assigned to Nycomed Imaging AS, both of which are
incorporated in their entireties herein by reference.
[0063] In embodiments of the present invention wherein any of the
above-described or other paramagnetic materials are incorporated
within a hydrogel polymer, it may be preferred to utilize a
cross-linked hydrogel polymer. In addition to the previously
mentioned advantages of using cross-linked hydrogel polymers for
medical devices in accordance with the present invention, such
polymers can also facilitate immobilization of the paramagnetic
materials incorporated therein. Paramagnetic ions or other
paramagnetic materials are more effectively immobilized within the
matrix provided by a cross-linked hydrogel polymer and are,
thereby, less susceptible to leaching from the hydrogel polymer. In
addition, immobilization of the paramagnetic ions incorporated
within a cross-linked hydrogel may be further enhanced by ionic
bonding of the paramagnetic ions to, for example, organic acid
functionality or metal chelating functionality provided by the
hydrogel polymer as described above. Further, where the hydrogel
polymer is cross-linked, metal chelating functionality can also be
provided by utilizing a polyfunctional cross-linking agent that
comprises a metal chelating group covalently bonded to the
cross-linking agent. Any metal chelating group including, without
limitation, DTPA, DOTA, EDTA, NOTA, TETA and HBED, that can be
covalently bonded to a functional group in a cross-linking agent,
while retaining the ability of the cross-linking agent to
cross-link the hydrogel polymer is within the scope of the present
invention. Further, polyfunctional cross-linking agents having, for
example, groups such as carboxyl groups that facilitate
electrostatic attraction or ionic bonding thereto of paramagnetic
cations are within the scope of the present invention. Chelation of
paramagnetic ions to metal chelating groups covalently bonded to
the cross-linking agent or electrostatic attraction/ionic bonding
of paramagnetic ions to groups in the cross-linking agent may
further enhance the ability of the cross-linked hydrogel polymer to
immobilize the paramagnetic ions.
[0064] The present invention is also directed to the use of an
implantable or insertable medical device of the present invention
in a medical procedure, wherein during or after insertion or
implantation of the medical device in a patient, the position of
the medical device is viewed under magnetic resonance imaging. The
medical device, as described hereinabove, comprises (a) a substrate
and (b) a hydrogel polymer coating at a least a portion of the
surface of the substrate, wherein the hydrogel polymer is adapted
to render the medical device visible under magnetic resonance
imaging upon insertion or implantation of the medical device into a
patient.
[0065] In another embodiment, the present invention is directed to
the use of a hydrogel polymer for coating at least a portion of the
surface of a medical device, wherein the hydrogel polymer is
adapted to render the medical device coated with the hydrogel
polymer visible under magnetic resonance imaging during or after
insertion or implantation of the medical device in a patient. The
hydrogel polymer can be any hydrogel polymer described herein that
is adapted for rendering the medical device visible under magnetic
resonance imaging.
[0066] The present invention is also directed to a hydrogel polymer
adapted to render a medical device coated with the hydrogel polymer
visible under magnetic resonance imaging during or after insertion
of the medical device in a patient. The hydrogel polymer can be any
hydrogel polymer described herein that is adapted for rendering the
medical device visible under magnetic resonance imaging.
[0067] The present invention is not limited in scope to any
particular implantable or insertable medical device or any material
used to form such medical device. Therefore, the present invention
has wide applicability to all types of implantable or insertable
medical devices known in the art whether such medical devices are
used primarily in conjunction with observational, diagnostic or
therapeutic medical procedures. Most generally, the present
invention may be practiced with any implantable or insertable
medical device for which visualization thereof under MRI during or
after insertion of the device is desired.
[0068] Among such implantable or insertable medical devices are
included, without limitation, catheters such as
neuro-interventional microcatheters; guide wires; balloons such as
those used in angioplasty procedures; stents including
endovascular, biliary, tracheal, gastrointestinal, urethral,
ureteral and esophageal stents; stent grafts; prosthetic devices
such as artificial limbs; endoscopic devices; and, laparoscopic
devices. The medical device comprising the substrate onto which the
hydrogel polymer is coated in accordance with the present invention
can be constructed of any material conventionally used for such
devices including, without limitation, metals and metal alloys such
as superelastic shape memory alloys; ceramics; glasses; polymeric
materials which may be based on natural, semi-synthetic, and
synthetic polymeric materials; and composites of any of such
materials. The material is preferably a biocompatible material,
i.e., does not produce, either systemically or locally, an
unacceptable adverse reaction in the patient, and may be
biodegradable or substantially non-biodegradable in the environment
surrounding the medical device upon insertion or implantation
thereof. Biocompatibility of the material used to construct the
medical device may be enhanced by providing a biocompatible
hydrogel coating in accordance with the present invention.
[0069] The hydrogel polymer coating the medical device in
accordance with the present invention can also be adapted to
incorporate a diagnostic or a therapeutic agent such as a drug.
Incorporation of a therapeutic agent in a coating provided on the
surface of a medical device is generally known in the art and is
advantageous inter alia, because it enables localized
administration of the therapeutic agent. Localized administration
is, in many cases, beneficial to ensure that a therapeutically
effective amount of the agent is administered to the target
location and to minimize adverse reactions associated with systemic
administration of the agent. Any methods known in the art for
loading a therapeutic agent within or on the surface of a polymeric
material to be provided as a coating on a medical device can be
employed. In the context of the present invention, the therapeutic
agent can be included within a solution, dispersion or emulsion of
the hydrogel polymer or hydrogel-forming monomers to be provided as
a coating onto the medical device. Alternatively, the therapeutic
agent can be incorporated into a hydrogel coating previously
applied onto the medical device by, for example, dipping or soaking
the medical device in a solution or dispersion of the therapeutic
agent followed by drying, or by spraying a solution or dispersion
of the therapeutic agent onto the medical device coated with the
hydrogel polymer.
EXAMPLES
[0070] In order to characterize the ability of the hydrogel to
retain the paramagnetic ions, loading and release tests were
performed on a coated substrate. A portion of coated substrate was
soaked and shaken in a vial at 37.degree. C. Aliquots of the
soaking solution were removed at certain time points and the amount
of paramagnetic ion was measured by an appropriate technique, e.g.,
the amount of gadolinium (III) was measured using Inductively
Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES), monitoring
at 342.247 nm (nanometers).
[0071] The results demonstrate that the amount of gadolinium
released over time did not vary significantly, e.g., 7.4 micrograms
(.mu.g)/inch of catheter after 1 minute of soaking compared to 9.8
.mu.g/inch of catheter after 4 hours of soaking. In addition, by
weighing the coated substrates loaded with the paramagnetic ion
complex, and comparing the weights against controls where no
paramagnetic ion was added to the hydrogel solutions, the amount of
paramagnetic ion present on the substrate could be estimated.
Therefore, the percent of paramagnetic ion released was also
calculated. The data indicated that the majority of gadolinium is
retained in the hydrogel without leaching out during prolonged
soaking of the coated substrate. For example, 96.5% of the
gadolinium was retained after 1 minute of soaking and 95.4% of the
gadolinium was retained after 4 hours of soaking.
[0072] The durability of the hydrogel coating is also an important
consideration. Durability of the coating ensures prolonged
visibility of the device since its MR image will fade away or
completely disappear if the coating breaks down and the
paramagnetic ions cannot be retained near the surface of the
device. In order to test the durability of the coating, the coated
substrates were pre-soaked in saline for certain periods of time
before being placed in another medium and visualized by MRI.
Uncoated substrate was used as a control. In contrast to the
control samples, all of the coated substrates were visible by MRI
after 0, 5, 10, 20, 40, and 60 minutes of soaking in a saline
solution.
[0073] The following are example methods of preparing and testing
various primer solutions and hydrogels. These examples should not
be construed as limiting the scope of the invention in any
manner.
Example 1
Preparation of Primer Solutions
[0074] Primer 1
[0075] In a glass beaker, 980 grams of Bayhydrol PR240, available
through Bayer, and 20 grams of NeoCryl CX-100, available through
NeoResin, were stirred until thoroughly mixed. Bayhydrol PR240 is a
solvent-free anionic aliphatic polyurethane dispersion in water.
NeoCryl CX-100 is a polyfunctional aziridine crosslinking
agent.
[0076] Primer 2
[0077] In a glass beaker, 875 grams of Bayhydrol PR240, 25 grams of
NeoCryl CX-100, and 100 grams of D.I. water were stirred until
thoroughly mixed.
Example 2
Preparation of Hydrogel Containing Paramagnetic Ions
[0078] Hydrogel 1
[0079] 990 grams of deionized water was poured into a glass beaker
and the mixer was started. 10 grams of Glascol WN33, by Allied
Colloids, a copolymer of sodium acrylate and acrylamide, was slowly
added into the beaker. The beaker was covered with parafilm and the
solution was stirred continuously for 15 hours until the Glascol
WN33 had sufficiently dissolved to obtain a 1% (wt) Glascol
solution. 13.5 grams of Gd-DTPA, by Aldrich, was then added into
the Glascol WN33 solution very slowly, with stirring, in order to
avoid forming any precipitate. Gd-DTPA
(diethylenetriaminepentaacetic acid, gadolinium(III) dihydrogen
salt hydrate) is a stable Gd(III) chelate widely used as MRI
contrast agent. A proper amount of ammonium hydroxide was added to
adjust to pH 8-10. The beaker was then covered with parafilm and
the solution was continuously stirred for 6-15 hours until the
Glascol WN33 and Gd-DTPA were thoroughly mixed and dissolved. 3.8
grams of 23% (wt) sodium chloride solution was added with stirring.
Preparation was complete after 40 grams of Primer 1 fluid was added
and thoroughly mixed.
[0080] Hydrogel 2
[0081] 950 grams of de-ionized water was poured into a glass beaker
and the mixer was started. 40 grams of Glascol S19, by Allied
Colloids, polyacrylic acid, was slowly added into the beaker. The
beaker was covered with parafilm and the solution was stirred
continuously for 15 hours until the Glascol S19 had sufficiently
dissolved to obtain a 1% (wt) Glascol solution. 10 grams of
Gd-DTPA, by Aldrich, was then added into the Glascol S19 solution
very slowly with stirring in order to avoid forming any
precipitate. The beaker was then covered with parafilm and the
solution was continuously stirred for 6-15 hours until the Glascol
S19 and Gd-DTPA were thoroughly mixed and dissolved. 5.0 grams of
23% (wt) sodium chloride solution was added, followed by a proper
amount of ammonium hydroxide to adjust to pH 9-10. Preparation was
complete after 40 grams of Primer 1 fluid was added and thoroughly
mixed.
[0082] Hydrogel 3
[0083] 975 grams of deionized water was poured into a glass beaker
and the mixer was started. 15 grams of Glascol WN23, by Allied
Colloids, a copolymer of acrylic acid and acrylamide, was slowly
added into the beaker. The beaker was covered with parafilm and the
solution was stirred continuously for 15 hours until the Glascol
WN23 had sufficiently dissolved to obtain a 1% (wt) Glascol
solution. 10 grams of Gd-DTPA, by Aldrich, was then added into the
Glascol WN23 solution very slowly, with stirring, in order to avoid
forming any precipitate. The beaker was then covered with parafilm
and the solution was continuously stirred for 6-15 hours until the
Glascol WN23 and Gd-DTPA were thoroughly mixed and dissolved. 5.0
grams of 23% (wt) sodium chloride solution was added with stirring,
followed by a proper amount of ammonium hydroxide to adjust to pH
9-10. 20 grams of Primer 1 fluid was then added and the solution
was thoroughly mixed. Preparation was complete after 5 grams of
NeoCryl CX-100 was added drop-wise with agitation.
[0084] Hydrogel 4
[0085] 700 grams of de-ionized water was poured into a glass beaker
and the mixer was started. 300 grams of Glascol E15, by Allied
Colloids, an aqueous polyacrylic acid solution with 15% solid
content, was slowly added into the beaker. The beaker was covered
with parafilm and the solution was stirred continuously for 15
hours until the Glascol E15 had sufficiently dissolved to obtain a
1% (wt) Glascol solution. 10 grams of Gd-DTPA, by Aldrich, was then
added into the Glascol E15 solution very slowly, with stirring, in
order to avoid forming any precipitate. The beaker was then covered
with parafilm and the solution was continuously stirred for 6-15
hours until the Glascol E15 and Gd-DTPA were thoroughly mixed and
dissolved. 5.0 grams of 23% (wt) sodium chloride solution was added
with stirring, followed by a proper amount of ammonium hydroxide to
adjust to pH 9-10. Preparation was complete after 10 grams of
NeoCryl CX-100 was added drop-wise with agitation.
Example 3
Immobilization of Hydrogel Containing Paramagnetic Ions
[0086] Hydrogel 1
[0087] A 6 French (F) catheter made of polyether-amide was cleaned
with isopropanol. A Teflon coated stainless steel mandrel of proper
size was inserted into the lumen to keep the catheter straight. The
catheter was immersed in the Primer 1 solution and dried in the
open air for 10 minutes. The catheter was then immersed into the
Hydrogel 1 solution and dried in the open air for 15 minutes. The
catheter was then immersed again into the Hydrogel 1 solution,
air-dried for 15 minutes and then placed in an oven at 140.degree.
F. for post curing for 8-24 hours.
[0088] Hydrogel 2
[0089] A 3 French catheter made of polyethylene was cleaned with
isopropanol. A Teflon coated stainless steel mandrel of proper size
was inserted into the lumen to keep the catheter straight. The
catheter was immersed in the Primer 1 solution and dried in the
open air for 10 minutes. The catheter was then immersed in the
Hydrogel 2 solution and subsequently air-dried for 15 minutes. The
step of immersing the catheter in the Hydrogel 2 solution, followed
by air-drying, was repeated before it was placed in an oven at
140.degree. F. for post curing for 8-24 hours.
[0090] Hydrogel 3
[0091] A 3 French catheter made of nylon was cleaned with
isopropanol. A Teflon coated stainless steel mandrel with proper
size was inserted into the lumen to keep the catheter straight. The
catheter was immersed in the Primer 2 solution, and subsequently
dried in the open air for 10 minutes. The catheter was then
immersed in the Hydrogel 3 solution, followed by air-drying for 15
minutes. The step of immersing the catheter in the Hydrogel 3
solution, followed by air-drying, was repeated before the catheter
was placed in an oven at 140.degree. F. for post curing for 8-24
hours.
[0092] Hydrogel 4
[0093] A 6 French catheter made of polyurethane was cleaned with
isopropanol. A Teflon coated stainless steel mandrel of proper size
was inserted into the lumen to keep the catheter straight. The
catheter was immersed in the Primer 1 solution and then dried in
the open air for 10 minutes. The catheter was then dipped into the
Hydrogel 4 solution and subsequently air-dried for 15 minutes. The
step of immersing the catheter in the Hydrogel 4 solution, followed
by air-drying, was repeated before the catheter was placed in an
oven at 140.degree. F. for post curing for 8-24 hours.
Example 4
Loading and Release Tests of Paramagnetic Ions
[0094] A piece of a 6 French polyether-amide catheter coated with
Hydrogel 1, approximately an inch in length, was cut and placed in
a 5 ml polypropylene vial. After adding 5.0 ml of a phosphate
buffered solution ("PBS") in the vial to soak the catheter, the
vial was placed on a shaker in the oven at 37.degree. C. After
soaking for 1 minute, 5 minutes, 30 minutes, 1 hour, and 4 hours,
an aliquot of the soaking solution was taken to determine the
amount of gadolinium present by ICP-AES, monitored at 342.247 nm.
The amount of gadolinium released from the coated catheter, in
.mu.g/inch, was calculated and is shown in Table 1 below.
[0095] The percent of gadolinium released was also estimated and is
shown in Table 1. The substrates were weighed after immersing only
in the primer solution, immersing once in the hydrogel solution,
and immersing twice in the hydrogel solution. The differences in
weight of the coated substrates were calculated, yielding the
amount of Glascol and Gd-DTPA coated on each substrate. A control
was run in which the hydrogel solutions did not contain any
Gd-DTPA. Therefore, the amount of gadolinium on the substrate could
be estimated by comparing the weights of the substrates with and
without the Gd-DTPA, and the percentage of gadolinium released from
the coat could be calculated.
1TABLE 1 Soaking test of the coated catheter in PBS solution Time
of soaking in PBS solution 1 min 5 min 30 min 1 hr 4 hrs Released
Gd 7.4 7.0 9.4 9.8 9.8 (.mu.g/inch coated catheter) % of Gd
Released 3.5 3.3 4.4 4.6 4.6
Example 5
MRI Images of the Hydrogel Containing Paramagnetic Ions
[0096] The hydrogel samples coated in Example 3 were tested in
phantom under MRI to determine their visibility over time. In order
to check the durability of the gadolinium visibility in the
hydrogel, the samples coated with the different hydrogels were
pre-soaked in saline for certain amounts of time before they were
placed in fat-free yogurt phantom, a tissue mimic, and viewed by
MRI. The soaking times were 0, 5, 10, 20, 40, and 60 minutes. An
uncoated 6 French nylon catheter was used as a control. All of the
coated samples were visible at every time point analyzed. The
control sample was not visible at any of the time points. This is
summarized in Table 2 below.
2TABLE 2 MRI Visibility Summary of Samples Samples 0 min 5 min 10
min 20 min 40 min 60 min Uncoated .largecircle. .largecircle.
.largecircle. .largecircle. .largecircle. .largecircle. Hydrogel 1
X X X X X X Hydrogel 2 X X X X X X Hydrogel 3 X X X X X X
.largecircle.: not visible; X: visible
[0097] The following MRI scan parameters were used with a Siemens
1.0T Harmony MRI scanner: the Pulse Sequence was set to
SE.sub.--14b89; TR=400 ms; TE=15 ms; coronal and axial images
FOV=200 mm; 90.degree. flip angle; 10 slices; number of
acquisitions=2 (total imaging time=3 min 28 seconds); distance
factor=0.3 (separation between slices is 1.3.times.slice
thickness); slice thickness=2.0 mm; in-plane resolution=0.78
mm.times.0.78mm; matrix=256.times.256.
Example 6
Effect of Degree of Hydrogel Polymer Cross-Linking on Proton
Relaxation Time
[0098] The effect of varying the degree of cross-linking on the
relaxation time of protons associated with a hydrogel polymer was
determined. Three aqueous solutions of Glascol WN33 (0.5 wt %) were
prepared in beakers. The first solution contained no cross-linking
agent; the second solution contained 0.1 wt % CX-100 as a
cross-linking agent; and, the third solution contained 0.25% wt %
CX-100. The beakers containing the solutions were subjected to MRI
wherein the time between successive excitation pulses was 150, 200,
300, 400, 600 and 1000 milliseconds (ms). The proton TI
(longitudinal spin) relaxation time was calculated, based on the
observed signal intensity, for each of the three solutions at the
successive excitation pulses as is known in the art. T1 for
solution 1 was 5356 ms; T1 for solution 2 was 5524 ms; and, T2 for
solution 3 was 4690 ms. These results demonstrate that a hydrogel
polymer can be adapted by cross-linking to varying degrees to the
modify relaxation time of detectable protons associated with the
hydrogel polymer.
* * * * *