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Medical Patent Abstract
A medical device comprising a substrate having a plasma polymerized
functionality bonded to at least a portion of the substrate. A superoxide
dismutase mimic agent having a complimentary functional group to
the plasma polymerized functionality is bonded to the portion of
the substrate by bonding to the plasma polymerized functionality.
Medical Patent Claims
We claim:
1. A medical device comprising: a substrate having a plasma polymerized
functionality layer bonded to at least a portion of the substrate,
the plasma polymerized functionality layer comprising a first plurality
of functional groups; and a superoxide dismutase mimic agent having
a second plurality of functional groups complementary to the first
plurality of functional groups; wherein the first plurality of functional
groups comprise acid chloride derivatives of carboxylate functional
groups, the second plurality of functional groups comprise amine
functional groups, and wherein the acid chloride derivatives bond
to the amine functional groups.
2. The medical device of claim 1 wherein the concentration of superoxide
dismutase mimic agent is between 10 .mu.g/cm.sup.2 to 50 .mu.g/cm.sup.2.
3. The medical device of claim 1 wherein the medical device comprises
one of an electrical signal generator, a pacemaker lead or an electrically
conductive electrophysiology lead.
4. The medical device of claim 1, further comprising, one of an
electrically conductive electrophysiology lead, a pacemaker lead,
or a combination of an electrical signal generator and an electrically
conductive electrophysiology lead having a component formed at least
in part of the substrate.
5. A medical device comprising: a substrate having a plasma polymerized
functionality layer bonded to at least a portion of the substrate,
the plasma polymerized functionality layer comprising a first plurality
of functional groups; a superoxide dismutase mimic agent having
a second plurality of functional groups complementary to the first
plurality of functional groups; and a plurality of polyethylene
glycol functional groups wherein the first plurality of functional
groups comprise one of carboxylate or acid chloride derivatives
of carboxylate functional groups, the second plurality of functional
groups comprise amine functional groups, and the amine functional
groups and the plurality of polyethylene glycol functional groups
bond to one of the carboxylate or acid chloride derivatives of carboxylate
functional groups.
6. The medical device of claim 5 wherein the concentration of superoxide
dismutase mimic agent is between 10 .mu.g/cm.sup.2 to 50 .mu.g/cm.sup.2.
7. The medical device of claim 5 wherein the medical device comprises
one of an electrical signal generator, a pacemaker lead or an electrically
conductive electrophysiology lead.
8. The medical device of claim 5, further comprising, one of an
electrically conductive electrophysiology lead, a pacemaker lead,
or a combination of an electrical signal generator and an electrically
conductive electrophysiology lead having a component formed at least
in part of the substrate.
9. A medical device comprising: a substrate; a plasma polymerized
functionality layer on at least a portion of the substrate, the
plasma polymerized functionality layer having a first plurality
of functional groups wherein the first plurality of functional groups
is present in an amount to facilitate a density of a superoxide
dismutase mimic agent between of 10 .mu.g/cm.sup.2 to 50 .mu.g/cm.sup.2
bonded thereto; and the superoxide dismutase mimic agent on the
functionality layer, the superoxide dismutase mimic agent having
a second plurality of functional groups complementary to the first
plurality of functional groups, wherein the plurality of first functional
groups comprise acid chloride derivatives of carboxylate functional
groups and the plurality of second functional groups comprise amine
functional groups.
10. The medical device of claim 9, further comprising, one of an
electrically conductive electrophysiology lead, a pacemaker lead,
or a combination of an electrical signal generator and an electrically
conductive electrophysiology lead having a component formed at least
in part of the substrate.
11. A medical device comprising: a substrate; a plasma polymerized
functionality layer on at least a portion of the substrate, the
plasma polymerized functionality layer having a first plurality
of functional groups wherein the first plurality of functional groups
is present in an amount to facilitate a density of a superoxide
dismutase mimic agent of between 10 .mu.g/cm.sup.2 to 50 .mu.g/cm.sup.2
bonded thereto; and the superoxide dismutase mimic agent on the
functionality layer, the superoxide dismutase mimic agent having
a second plurality of functional groups complementary to the first
plurality of functional groups, wherein the first plurality of functional
groups comprise one of carboxylate or acid chloride derivatives
of carboxylate functional groups, the second plurality of functional
groups comprise amine functional groups and polyethylene glycol
functional groups, and the amine functional groups and the polyethylene
glycol functional groups bond to one of the carboxylate or acid
chloride derivatives of carboxylate functional groups.
12. The medical device of claim 11, further comprising, one of
an electrically conductive electrophysiology lead, a pacemaker lead,
or a combination of an electrical signal generator and an electrically
conductive electrophysiology lead having a component formed at least
in part of the substrate.
Medical Patent Description
BACKGROUND OF THE INVENTION
This invention relates to implantable medical devices for therapeutic
or diagnostic uses such as endocardial cardiac pacemaker leads and/or
cardioverter/defibrillator leads. There are various types of transvenous
pacing and cardioversion or defibrillation leads developed for introduction
into different chambers of a patient's heart. These implantable
leads are usually constructed with an outer biocompatible insulating
sheath encasing one or more conductors, one of which is typically
attached at its distal end to an exposed tip electrode.
The tip electrode is usually placed in contact with endocardial
tissue at the chosen site of the heart chamber by percutaneous introduction
and passage through a venous access, often the sub-clavian vein
or one of its tributaries, which leads to the heart chamber. As
the lead is implanted into the patient, one typical response to
this implantation is the fibrotic encapsulation (e.g., protein encapsulations)
of the lead. The presence of fibrotic encapsulation can compromise
the performance of the lead, especially in more permanent implantation
situations. Furthermore, during the removal of the lead, it is typical
to require a surgical procedure to remove a portion of the lead.
For example, after a portion of a lead is excised from its position,
a suspended weight (approximately 5 lbs) is attached to the exposed
portion of the lead to allow for an application of a constant force
over a period of several hours to extract the lead from the fibrotic
encapsulation. Such removal procedure creates discomfort and pain
to the patient.
It has been shown in the literature that modification of a plastic
(e.g., polyethylene and polyetherurethane) with superoxide dismutase
mimic (SODm) results in a significant reduction in fibrotic encapsulation
in an implanted foreign device. See "Modification of Inflammatory
Response to Implanted Biomedical Materials In Vivo by Surface Bound
Superoxide Dismutase Mimics" authored by Kishore Udipi, et.
al, Journal of Biomedical Material Research 2000, Sep. 15, 51(4):549-60.
The method contemplated by Udipi does not result in a high density
grafting of SODm on the surface of the plastic and is dependent
on the composition of the substrate.
It would be a significant advantage to provide endocardial cardiac
pacemaker leads and/or cardioverter/defibrillator leads or other
medical device component having SODm surface treatment with improved
bondability and densities, on a variety of substrates including
those difficult to modify such as fluoropolymers.
SUMMARY OF THE INVENTION
A medical device coated with superoxide dismutase mimic (SODm)
and methods to fabricate the same are described. In one example,
the medical device comprises a substrate having a plasma polymerized
functionality bonded to at least a portion of the substrate. A superoxide
dismutase mimic agent having a complimentary functional group to
the plasma polymerized functionality is bonded to the portion of
the substrate by bonding to the plasma polymerized functionality.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention is illustrated by way of example and not
limitation in the figures of the accompanying drawings, in which
like references indicate similar elements and in which:
FIG. 1 illustrates an exemplary pacemaker lead of the present invention
that can be coated with SODm;
FIG. 2 illustrates a cross-sectional view of the exemplary pacemaker
lead of FIG. 1 shown to include a polymeric insulation layer and
a conductive element;
FIG. 3 illustrates a cross-sectional view of the exemplary pacemaker
lead of FIG. 1 shown to include a polymeric insulation layer and
several conductors;
FIG. 4 illustrate a cross-sectional view of the exemplary pacemaker
lead of FIG. 1 shown to include a polymeric insulation layer which
is treated to include plasma polymerized functionality and coated
with a SODm coating;
FIG. 5 illustrates an exemplary method of coating a pacemaker lead
with SODm;
FIG. 6 illustrates another exemplary method of coating a pacemaker
lead with SODm;
FIG. 7 illustrates yet another exemplary method of coating a pacemaker
lead with SODm;
FIG. 8 illustrates further yet another exemplary method of coating
a pacemaker lead with SODm;
FIG. 9 illustrates another exemplary method of coating a pacemaker
lead with SODm; and
FIG. 10 illustrates an exemplary plasma chamber that can be used
to practice the present invention.
DETAILED DESCRIPTION OF THE INVENTION
In the following description, for purposes of explanation, numerous
specific details are set forth in order to provide a thorough understanding
of the present invention. It will be evident, however, to one skilled
in the art that the present invention may be practiced without these
specific details. In other instances, specific apparatus structures
and methods have not been described so as not to obscure the present
invention. The following description and drawings are illustrative
of the invention and are not to be construed as limiting the invention.
The present invention is directed to coating implantable medical
devices such as endocardial cardiac pacemaker leads and/or cardioverter/defibrillator
leads. Exemplary embodiments of the present invention are applicable
to the medical devices having components that are designed for being
implanted inside a patient's body. These components are often made
out of or coated with biocompatible materials such as polymeric
materials selected from the group consisting of a fluoropolymer,
polytetrafluoroethylene, expanded polytetrafluoroethylene, high
density polyethylene, polyimide, polyetherether ketone, polyimide,
polyolefin, polyurethane, polycarbonate urethane, siliconized urethane,
and silicone rubber. Furthermore, the medical device of the present
invention comprises an electrically conductive electrophysiology
lead that can be implanted in the patient's heart. Alternatively,
the medical device of the present invention comprises a pacemaker
lead that can be implanted in the patient's heart. And, the medical
device of the present invention comprises an electrical generator
and an electrically conductive electrophysiology lead that can be
implanted in the patient's heart.
One example of such medical device is a pacemaker lead and/or a
cardioverter/defibrillator lead. A pacemaker lead and/or a cardioverter
defibrillator lead that the present invention can be applied to
has electrical signals generating circuitry for pacing and defibrillating
functions. The lead conducts the signals to the appropriate treatment
sites in a patient's body. Such a pacemaker lead and/or a cardioverter
defibrillator lead are well known in the art. An exemplary pacemaker
lead and/or a cardioverter defibrillator lead of the present invention
has at least a portion being coated with a SODm coating having functional
groups such as amine binding sites or carboxylate binding sites.
The portion being coated with SODm is first treated such that it
includes a plasma polymerized functionality complimentary to the
functional group on the SODm. The exemplary pacemaker lead is coated
with a high density SODm layer.
FIG. 1 shows a side view of an exemplary pacemaker lead 100 that
the present invention can be applied to. The lead 100 includes an
elongated lead body which is covered with an insulation sheath 102.
The lead body may be coupled to a tip electrode 104 and a connector
assembly 106 having sealing rings 108 which engage connector element
or pin 120. Tip electrode 104 is the conductive point for the pacemaker
lead and is typically not insulated with insulation sheath 102.
Pin 120 may be coupled to an implantable pulse generator (not shown)
at the proximal end of the lead body. The connector assembly 106
may be constructed using techniques known in the art and may be
fabricated of silicone rubber, polyurethane or other suitable polymer.
The connector pin 120 may be fabricated of stainless steel or other
conductive material.
FIG. 2 illustrates, in a cross-sectional view, that the pacemaker
lead in this example also includes a conductive element 112 which
is encapsulated by insulation sheath 102 and which is coupled to
tip electrode 104. FIG. 3 illustrates that in another embodiment,
conductive element 112 may also includes several conductors, (e.g.,
conductor 114, 115, and 116) each of which may be insulated by a
silicone jacket 118. As illustrated, conductive element 112 is coated
with insulation sheath 102 which may be fabricated of silicone rubber,
polyurethane, fluoropolymers, polytetrafluoroethylene (PTFE), expanded
polytetrafluoroethylene (ePTFE), polyolefins such as high density
polyethylene (HDPE), and engineering thermoplastic, thermoset polymers
such as polyetherether ketone (PEEK), polyimide, urethane, polyurethane,
polycarbonate urethane, siliconized urethane, silicone rubber, or
any other suitable material. Insulation sheath 102 is generally
referred to as polymeric insulation layer 102 throughout this document.
FIG. 4 illustrates a cross-sectional view of a section 101 of pacemaker
lead 100 of the present invention. Section 101 is taken through
a portion of the pacemaker lead that will be coated with SODm coatings
103 of the present invention. In a preferred embodiment, section
101 includes portions of pacemaker lead 100 that are implanted inside
a patient's body. Section 101, however, does not show electrode
tip 104 since that portion is typically the conductive point of
pacemaker lead and includes no polymeric insulation layer 102. The
electrode tip 104 is electrically conductive and not covered by
insulation so that it makes proper electrical contact with the tissue
of the patient's body.
In a preferred embodiment, it is to be noted that the electrode
tip 104 should remain free of coating to maintain unimpeded electrical
conductivity. Thus, no SODm coating will be done to the electrode
tip 104.
FIG. 4 further illustrates that pacemaker lead 100 includes conductive
element 112 and polymeric insulation layer 102 coated around the
conductive element 112. In one example, polymeric insulation layer
102 is a substrate upon which a plasma polymerized functionality
layer 140 is formed. As plasma polymerized functionality layer 140
is formed around polymeric insulation layer 112 at least a portion
of pacemaker lead 100 is coated with plasma polymerized functionality
layer 140. In one example, the entire length of polymeric insulation
layer 102 of pacemaker lead 100 is coated with plasma polymerized
functionality layer 140. Plasma polymerized functionality layer
140 facilitates the bonding of SODm coating 103 to the surface of
the insulation layer with high densities of the SODm molecules on
the surface polymeric insulation layer of the lead. In one exemplary
embodiment, the SODm coating 103 has a density within the range
of 10 .mu.g/cm.sup.2 to 50 .mu.g/cm.sup.2. In another embodiment,
the SODm coating 103 has a density of 30 .mu.g/cm.sup.2. For comparison
purpose, conventional methods of coating SODm onto a substrate yield
an SODm layer having density in the range of 1 .mu.g/cm.sup.2 to
10 .mu.g/cm.sup.2. The SODm coating 103 of the present invention
thus has a much higher density as compared to conventional methods
of forming the SODm layer.
In one example, plasma polymerized functionality layer 140 comprises
of functional groups such as carboxylic acid, amine or sulfate.
SODm coating 103 includes functionality groups such as amine or
carboxylate which is complimentary to the plasma polymerized functionality
layer 140 to enhance the bonding of the plasma polymerized functionality
layer to the SODm coating 103. In one instance, plasma polymerized
functionality layer 140 comprises of carboxylic acid groups and
SODm coating 103 comprises of amino groups. These two functionality
groups are thus complimentary to each other. In another instance,
both the plasma polymerized functionality layer 140 and the SODm
coating 103 comprise amine functional groups. A crosslinker is used
to bond these two layers together (see FIG. 8).
In one example, only a portion of the lead is coated with plasma
polymerized functionality layer 140. The portion that is coated
with plasma polymerized functionality layer 140 is the portion that
will be coated with SODm coating 103. The remaining portions of
plasma polymerized functionality layer 140 of the pacemaker lead
thus, may not need to be treated with the plasma polymerized functionality
layer 140 and are left for other purposes (e.g., drug delivery)
in the use of the pacemaker lead.
In one exemplary embodiment, the surfaces of pacemaker lead 100
is chemically modified by modifying polymeric insulation layer 102.
The chemically modified surfaces of pacemaker lead 100 comprise
plasma polymerized functionality layer 140 deposited on the surfaces
of polymeric insulation layer 102 by plasma polymerization. In a
presently preferred embodiment, polymeric insulation layer 102 is
chemically modified to create a carboxylate-rich surface from a
plasma state derived from an organic carboxylate decomposed in a
radio frequency field, which will be denoted as an RF field within
the embodiments. However, a variety of suitable functionalities
can be plasma polymerized on the surfaces of the pacemaker lead
including amine, and sulfate functionalities. In a presently preferred
embodiment, the plasma polymerized carboxylate film comprises an
acrylate or acrylate-like polymer layer deposited onto the polymeric
insulation layer by exposing the polymeric insulation layer to a
plasma, which in a presently preferred embodiment is an acrylic
acid plasma. One of skill in the art will recognize that some fragmentation
of the acrylate typically occurs during plasma polymerization, resulting
in an acrylate-like polymer layer of fragmented acrylate. In a presently
preferred embodiment, the acrylate is acrylic acid. While discussed
below primarily in terms of applying a carboxylate film by plasma
polymerization of acrylic acid on the polymeric insulation layer,
it should be understood that a variety of functionalities (such
as amines) on a variety of substrates may be used.
It will be appreciated that not all portions of a pacemaker lead
100 needs to be chemically modified. The portions that need to be
coated with SODm coating 103 are portions to undergo chemical modification.
In one exemplary method, the whole pacemaker lead 100 is placed
in the reaction chamber for chemical modification. Masking is used
to block off the portions that do not need the chemical modification.
For instance, a masking agent such as polyvinyl alcohol is coated
over the portions (e.g., the distal end of the electrode tip 104
portion) that do not need the chemical modification. This masking
can be removed at the end of the process when SODm coating 103 is
successfully coated on polymeric insulation layer 102 of pacemaker
lead 100.
In a presently preferred embodiment, the polymeric insulation layer
is chemically modified to create a carboxylic acid rich surface
by exposure to an acrylic acid plasma. In one embodiment, the method
comprises introducing the polymeric insulation layer into an argon
plasma field to remove organic processing debris from the surface
of the polymeric insulation layer before deposition of the plasma
polymerized film. The method can be carried out in a plasma reaction
chamber 30 illustrated in FIG. 10 (see below). Preferably, polymeric
insulation layer 102 is pre-treated in the argon plasma field at
about 100 to 250 mTorr, preferably about 150 mTorr, with an applied
RF field of about 80 to 250 W, preferably about 100 W, for about
1 to 10 minutes, preferably about 3 minutes. During the pretreatment,
argon gas is introduced into the chamber with a flow rate of approximately
230 sccm. After the 3 minute plasma pretreatment, the pressure in
the plasma chamber is reduced to less than 1 mTorr.
An acrylic acid plasma is then applied to the polymeric insulation
layer to produce a carboxylate rich film on the polymeric insulation
layer. The plasma power is formed by an application of a RF field
between 20 KHz and 2.45 GHz. In this embodiment the RF field has
a frequency of 13.56 MHz. The plasma power together with a flow
of acrylic acid creates an acrylic acid plasma having power of about
80 to about 200 W, and preferably about 100 W. The acrylic acid
flow rate for the reaction ranges from 0.1 to 0.5 mL/min, and preferably
at 0.2 mL/min. The acrylic acid may be mixed with a carrier gas
such as carbon dioxide introducing into the chamber with a flow
rate of approximately 90 sccm. The pressure for the reaction is
maintained at about 150 mTorr. The concentration of the carboxylate
is dependent on the decomposition of the acrylic acid in the RF
field. The parameters which vary the decomposition of acrylic acid
include the plasma power, wherein the carboxylate concentration
decreases as the RF power increases. The acrylic acid plasma is
applied for about 3 to 10 minutes, preferably about 5 to 10 minutes,
depending on the desired thickness of the carboxylate rich film.
The thickness of the carboxylate rich film is about 25 to 150 nm,
preferably about 50 to about 125 nm. In one embodiment, following
exposure to the acrylic acid plasma, the plasma field is purged
with argon under no RF power to allow surface free-radicals to recombine
before exposure to atmospheric oxygen. For instance, after the reaction
time, the RF power is terminated and the pressure in the plasma
chamber is reduced to below 1 mTorr. And, upon achieving the low
pressure, the plasma chamber is purged with argon gas having a flow
rate of approximately 250 sccm while maintaining a pressure of about
230 mTorr with no RP power for 3 minutes. After the 3 minutes, the
plasma chamber is vented to atmospheric pressure.
In a presently preferred embodiment, carbon dioxide is included
in the acrylic acid plasma to limit the rate of decarboxylation
from the surface of the polymeric insulation layer. The composition
of polymerized material is dependent on the fragmentation of the
acrylic acid. The fragmentation process results in reactive species
that polymerize with the substrate surface and species that become
nonreactive gaseous products. One such nonreactive gaseous product
is a result of the decarboxylation of the acrylic acid with the
formation of carbon dioxide. Thus, by adding carbon dioxide to the
acrylic acid plasma, the decarboxylation of the organic reactive
species in the RF field can be decreased. In a preferred embodiment,
the carbon dioxide concentration in the acrylic acid plasma is about
8% to about 10%, preferably about 9%.
The plasma polymerization results in a thin carboxylate film deposited
onto the substrate (e.g., polymeric insulation layer 102 of pacemaker
lead 100), and will be described as the plasma polymerized functionality
within the embodiments. The surface of the substrate has the same
polymer composition as the bulk of the substrate, so that the surface
and the bulk of the substrate have similar carboxylate concentration
following deposition of the plasma polymerized film. The similar
carboxylate concentration minimizes the time dependent variation
of the surface energy. The structural integrity of the polymeric
insulation layer of the lead is minimally or not affected by the
plasma polymerization.
In another example, the polymeric insulation layer is chemically
modified to create an amine-rich surface by exposure to an allylamine
plasma. The same method discussed above can be use. The plasma chamber
is fed with allylamine having a flow rate of 0.225 mL/min. A CO.sub.2
carrier gas is not required in this example. The plasma power is
formed with an RF source of 13.56 MEZ as above. The power is supplied
at 30 W and the pressure is maintained at approximately 100 mTorr.
All other conditions can be the same as for the creating of the
carboxylic acid rich surface discussed above.
The methods to create the plasma polymerized functionality on the
pacemaker lead 100 above can be applied to a variety of medical
devices made out of a variety of materials. The parameters above
may be adjusted to suit different types of materials. For instance,
when HDPE, or PTFE is used the power used in the pretreatment step
may be lowered to 80-100 W.
FIG. 5 illustrates an exemplary method 500 to coat SODm on the
surfaces of polymeric insulation layer 102 of pacemaker lead 100
of the present invention. As set forth in steps 502, 504, 506, and
508, pacemaker lead 100 is treated so that it comprises a plasma
polymerized functionality including carboxylic functional groups
on the surface of polymeric insulation layer 102 of pacemaker lead
100. Steps 502, 504, 506 and 508 are illustrations of the plasma
polymerization methods described above. As set forth in step 510,
the pacemaker lead 100 comprising plasma polymerized functionality
is then placed in a reaction tube (e.g., a glass tube) that allows
full-linear covering of the carboxylated pacemaker lead 100 without
a 180-degree bend. The carboxylated pacemaker lead 100 is allowed
to react with an SODm-EDC solution 516, and in one example, for
4 hours with agitating or shaking at room temperature.
As mentioned, SODm stands for superoxide dismutase mimics, which
are low molecular weight molecules that catalyze the conversion
of superoxide into oxygen and hydrogen peroxide. In one example,
the SODm has a molecular weight ranging from 500 to 600 Da. Examples
of SODm include the macrocyclic ligands taught by Riley et al. in
U.S. Pat. No. 6,084,093 and U.S. Pat. No. 5,610,293. These patents
are hereby incorporated by reference. The SODm including the macrocyclic
ligands are related to manganese (II) or manganese (III) complexes
of nitrogen-containing fifteen-membered macrocyclic ligands. Alternatively,
the SODm can be obtained from chemical suppliers such as Metaphore
Pharmaceuticals Inc., (1910 Innerbelt Business Center Drive St.
Louis, Mo. 63114). For example, an SODm from Metaphore Pharmaceuticals
Inc. has a product code of M-40470 SODm which has the generic chemical
name of [Manganese(II)dichloro{24-[2-aminoethylthio-](4R,9R14R,19R)-3,10,13,20,26-
-pentaazatetracyclo[20.3.10.sup.4,9.0.sup.14,19]hexacosa-1(26),22(23),24-t-
riene with the formula C.sub.23H.sub.40N.sub.6Cl.sub.2SMn. Any variation
of the formula above as taught by the Riley patents and any variation
of the SODm from Metaphore Pharmaceuticals Inc. can also be used
in accordance with the present invention, provided some functional
ligand is available on the molecule for coupling to a surface containing
a functional reactive group. Examples of functional reactive groups
on a surface for coupling are primary amine, carboxyl, or sulfate.
It is to be understood that the above examples are not to be interpreted
as limiting.
EDC stands for (1-Ethyl-3-[3-Dimethylaminopropyl] carbodiimide
Hydrochloride) which can be obtained from Pierce, Rockford, Ill.
In one example, the SODm solution shown at step 514 is prepared
by mixing SODm (e.g., Metaphor M40470 SODm) having a primary amine
ligand in a buffer such as MES/KOH (pH 6-6.5). The SODm solution
514 has a concentration between 0.1 mg/mL to 1.0 mg/mL. The SODm-EDC
solution 516 is then created by dissolving EDC from step 512 into
SODm solution 514 at 4-12 mg of EDC per 1 mL of SODm solution.
The reaction yields a 0-length amide linkage between the carboxyl
surface (the plasma polymerized functionality) on polymerized insulation
layer 102 and the SODm amine creating a covalent bonding between
the polymeric insulation layer 102 of pacemaker lead 100 and the
SODm. The final product is pacemaker lead 100 comprising insulation
layer 102 that further comprises plasma polymerized functionality
which is covalently bonded to a SODm having amine functional groups
via amide linkages as illustrated in box 518. The SODm bonded to
the pacemaker lead 100 retains the function of converting superoxide
into oxygen and hydrogen peroxide. The presence of the SODm on the
pacemaker lead 100 thus significantly reduces fibrotic encapsulation
on the pacemaker lead 100.
FIG. 6 illustrates another exemplary method 600 to coat SODm on
the surfaces of polymeric insulation layer 102 of pacemaker lead
100 of the present invention. As set forth in steps 602, 604, 606,
and 608, pacemaker lead 100 is treated so that it comprises a plasma
polymerized functionality including carboxylic functional groups
on the surface of polymeric insulation layer 102 of pacemaker lead
100. Steps 602, 604, 606 and 608 are illustrations of the plasma
polymerization method described above. As set forth in step 610,
pacemaker lead 100 comprising plasma polymerized functionality is
then placed in a reaction tube (e.g., a glass tube) that allows
full-linear covering of the carboxylated pacemaker lead 100 without
a 180-degree bend. The plasma polymerized functionality on pacemaker
lead 100 is allowed to react with an SODm-EDC solution 616, and
in one example, for 4 hours with agitating or shaking at room temperature.
In one example, the SODm solution shown at step 614 is prepared
by mixing SODm (e.g., Metaphor M40470 SODm) having a primary amine
ligand in a buffer such as MES/KOH (pH 6-6.5). The SODm 614 solution
has a concentration between 0.1 mg/mL to 1.0 mg/mL. The SODm solution
at step 614 may further include an amine terminated agent such as
amine terminated polyethylene glycol (e.g., PEG, from Shearwater
2V3F0F01). The PEG concentration in the SODm solution ranges form
0.1 mg/mL to 5 mg/mL. The SODm-PEG-EDC solution 616 is then created
by dissolving EDC from step 612 into SODm solution 614 at a concentration
between 4-12 mg of EDC per 1 mL of SODm solution.
The reaction yields a 0-length amide linkage between the carboxyl
surface (the plasma polymerized functionality) on polymerized insulation
layer 102 and the SODm amine creating a covalent bonding between
the polymeric insulation layer 102 of pacemaker lead 100 and the
SODm. The final product is pacemaker lead 100 comprising insulation
layer 102 that further comprises plasma polymerized functionality
which is covalently bonded to a SODm via having amine functional
groups amide linkages as illustrated in box 618. The SODm bonded
to the pacemaker lead 100 retains the function of converting superoxide
into oxygen and hydrogen peroxide. The presence of the SODm on the
pacemaker lead 100 thus significantly reduces fibrotic encapsulation
on the pacemaker lead 100.
FIG. 7 illustrates yet another exemplary method 700 to coat SODm
on the surfaces of polymeric insulation layer 102 of pacemaker lead
100 of the present invention. As set forth in steps 702, 704, 706,
and 708, pacemaker lead 100 is treated so that it comprises a plasma
polymerized functionality including carboxylic functional groups
on the surface of polymeric insulation layer 102 of pacemaker lead
100. Steps 702, 704, 706 and 708 are illustrations of the plasma
polymerization method described above.
In this exemplary method, pacemaker lead 100 comprising plasma
polymerized functionality is further treated such that the carboxylate
functional group on insulation layer 102 is further derivatized
with an acid chloride such as thionyl chloride. In one example,
step 710 sets forth that pacemaker lead 100 comprising plasma polymerized
functionality is dipped in a dipolar aprotic or anhydrous solvent
such as N,N-Dimethyl acetamide (DMAC), dimethyl sulfoxide (DMSO),
or acetone which includes thionyl chloride at 1% to 10% (w/v) for
30 to 60 minutes. The pacemaker lead 100 is then removed and rinsed
with DMAC, DMSO, acetone, or methylene chloride. The pacemaker lead
100 comprising plasma polymerized functionality now includes derivatives
that are acid chlorides.
As set forth in step 711, pacemaker lead 100 comprising plasma
polymerized functionality and acid chloride derivatives is then
placed in a reaction tube (e.g., a glass tube) that allows full-linear
covering of the carboxylated pacemaker lead 100 without a 180-degree
bend. The pacemaker lead is allowed to react with SODm-PEG-EDC solution
716 for 30 to 60 minutes at room temperature with agitating or shaking.
SODm-PEG-EDC solution 716 is made by mixing EDC and SODm and polyethylene
glycol (PEG) together. In one example, the SODm solution shown at
step 714 is prepared by mixing SODm (e.g., Metaphor M40470 SODm)
having a primary amine ligand in a buffer such as MES/KOH (pH 6-6.5).
The SODm solution has a concentration between 0.1 mg/mL to 1.0 mg/mL.
The SODm solution at step 674 further includes PEG which is an amine
terminated agent that can be obtained from Shearwater (catalog #2V3F0F01).
The PEG concentration in the SODm solution ranges from 0.1 mg/mL
to 5 mg/mL. The SODm-PEG-EDC solution 716 is then finally created
by dissolving EDC from step 712 into SODm solution 714 at a concentration
between 4-12 mg of EDC per 1 mL of SODm solution.
Alternatively, PEG is not added to the SODm solution 714, this
SODm solution is thus similar to solution 514 described in FIG.
5. The SODm-EDC solution 716 is also made similar to the SODm-EDC
solution 516 above.
The reaction yields a 0-length amide linkage between the carboxyl
surface (the plasma polymerized functionality) on polymerized insulation
layer 102 and the SODm amine creating a covalent bonding between
the polymeric insulation layer 102 of pacemaker lead 100 and the
SODm. The final product is pacemaker lead 100 comprising polymeric
insulation layer 102 that further comprises plasma polymerized functionality
derivatives which is covalently bonded to SODm having amine functional
groups via amide linkages as illustrated in box 718. The SODm bonded
to the pacemaker lead 100 retains the function of converting superoxide
into oxygen and hydrogen peroxide. The presence of the SODm on the
pacemaker lead 100 thus significantly reduces fibrotic encapsulation
on the pacemaker lead 100.
FIG. 8 illustrates another exemplary method 800 to coat SODm on
the surfaces of polymeric insulation layer 102 of pacemaker lead
100 of the present invention. As set forth in steps 802, 804, 806,
and 808, pacemaker lead 100 is treated so that it comprises a plasma
polymerized functionality including amine functional groups on the
surface of polymeric insulation layer 102 of pacemaker lead 100.
Steps 802, 804, 806 and 808 are illustrations of the plasma polymerization
method described above. As set forth in step 810, pacemaker lead
100 comprising plasma polymerized amine functionality is then placed
in a reaction tube (e.g., a glass tube) that allows full-linear
covering of the aminated pacemaker lead 100 without a 180-degree
bend. The plasma polymerized amine functionality on pacemaker lead
100 is allowed to react with a SODm solution 816 having a crosslinker.
In one example, agitating or shaking at room temperature for 30
to 60 minutes is required.
In one example, the SODm solution 816 having the crosslinker is
prepared as followed. First, the SODm solution shown at step 814
is prepared by mixing SODm (e.g., Metaphor M40470 SODm) having a
primary amine ligand in a buffer such as MES/KOH (pH 5.5-6). The
SODm solution 814 has a concentration between 0.1 mg/mL to 1.0 mg/mL.
In another example, the MES/KOH buffer is replaced with bicarbonate
buffer at pH 7.0. Then, the SODm solution 816 having the crosslinker
is created by mixing a water soluble crosslinker such as homobifunctional
N-hydroxysuccinimide ester (di-NHS ester) from step 812 into SODm
solution 814 at a concentration between 1-15 mg di-NHS ester per
1 mL of SODm solution 814. An exemplary di-NHS ester crosslinker
includes disulfosuccinimidyl suberate, disuccinimidyl suberate,
and bis(sulfosuccinimidyl)suberate made by Pierce.
The reaction yields 2 amide linkages between the amine functional
groups (the plasma polymerized functionality) on polymerized insulation
layer 102 and the SODm amine creating a covalent bonding between
the polymeric insulation layer 102 of pacemaker lead 100 and the
SODm. The final product is pacemaker lead 100 comprising insulation
layer 102 that further comprises plasma polymerized functionality
which is covalently bonded to SODm having amine functionality via
amide linkages as illustrated in box 818. The SODm bonded to the
pacemaker lead 100 retains the function of converting superoxide
into oxygen and hydrogen peroxide. The presence of the SODm on the
pacemaker lead 100 thus significantly reduces fibrotic encapsulation
on the pacemaker lead 100.
FIG. 9 illustrates another exemplary method 900 to coat SODm on
the surfaces of polymeric insulation layer 102 of pacemaker lead
100 of the present invention. This method is similar to method 800
described above. As set forth in steps 902, 904, 906, and 908, pacemaker
lead 100 is treated so that it comprises a plasma polymerized functionality
including amine functional groups on the surface of polymeric insulation
layer 102 of pacemaker lead 100. Steps 902, 904, 906 and 908 are
illustrations of the plasma polymerization method described above.
As set forth in step 910, pacemaker lead 100 comprising plasma polymerized
amine functionality is then placed in a reaction tube (e.g., a glass
tube) that allows full-linear covering of the aminated pacemaker
lead 100 without a 180-degree bend. The plasma polymerized amine
functionality on pacemaker lead 100 is allowed to react with an
SODm solution 916 having a crosslinker. In one example, agitating
or shaking at room temperature for 30 to 60 minutes is required.
In one example, the SODm solution 916 having the crosslinker is
prepared as followed. First, the SODm solution shown at step 914
is prepared by mixing SODm (e.g., Metaphor M40470 SODm) having a
primary amine ligand in a high pH buffer such as sodium carbonate/HCl
buffer at pH 7.5 to 9.0 and 0.1 mM. The concentration of SODm in
the buffer is approximately 0.1 to 1 mg/mL. Then, the SODm solution
916 having the crosslinker is created by dissolving a bis imidoester
crosslinker from step 912 into SODm solution 914 at a concentration
between 1 to 10 mg of bis imidoester crosslinker per 1 mL of SODm
solution 914. An exemplary bis imidoester crosslinkers include dimethyl
pimelimidate, dimethyl suberimidate, dimethyl adipimidate, and dimethyl
3,3-dithiobispropionimid ate made by Pierce.
The reaction yields 2 imidoamide linkages with a C4 spacer (for
dimethyladipimidate) between the amine surface (the plasma polymerized
functionality) on the plasma polymerized insulation layer 102 and
the SODm amine creating covalent bonding between the polymeric insulation
layer 102 of pacemaker lead 100 and the SODm. The final product
is pacemaker lead 100 comprising insulation layer 102 that further
comprises plasma polymerized functionality which is covalently bonded
to SODm having amine functional groups via amide linkages as illustrated
in box 918. The SODm bonded to the pacemaker lead 100 retains the
function of converting superoxide into oxygen and hydrogen peroxide.
The presence of the SODm on the pacemaker lead 100 thus significantly
reduces fibrotic encapsulation on the pacemaker lead 100.
The above-described methods can be performed by any suitable apparatus
known to one of ordinary skill in the art. One example of such an
apparatus is a plasma reaction chamber 30 illustrated in FIG. 10.
Chamber 30 can be cylindrical in shape and can be fabricated from
any number of suitable materials, such as glass and aluminum. By
way of example, chamber 30 can be from about 4 inches (10.16 cm)
to about 15 inches (38.1 cm) in diameter and from about 5 inches
(12.7 cm) to about 18 inches (45.72 cm) in height.
A mandrel 32 holds a single medical device 34 (e.g., pacemaker
lead 100) or multiple medical devices 34 in position relative to
the interior wall of chamber 30. Medical device 34 can be oriented
at any position within chamber 30 as required to achieve a desired
implantations or deposition. One end of mandrel 32 can be coupled
to an electrode 36.
Electrode 36 can be made from any suitable electrically conductive
material including, but not limited to, steel, copper, chromium,
nickel, tungsten, iron, and similar materials. A first power source
38, electrically coupled to electrode 36 via electrical feedthrough
port 40, can apply a voltage to electrode 36. In one example, power
source 38 is an AC voltage source.
In one embodiment, an insulator 42, formed of a non-electrically
conductive material, including materials such as rubber, ceramic,
or plastic is provided. Insulator 42 can include a connector 44,
which can be either electrically coupled to first power source 38
or an independent second power source 48 for applying a voltage
to a cage 50. In one example, a second power source 48 is a DC voltage
source.
Cage 50 can be positioned within chamber 30 in symmetrical conformity
about medical device 34 so as to protect and reduce dielectric breakdown
to medical device 34 due to arcing in the plasma field from all
directions. Cage 50 can be manufactured from a conductive material
such as carbon, or alternatively, can be made of a base material
that is coated with carbon. Alternatively, cage 50 can be made out
of other conductive materials such as metals, stainless steel, or
titanium. Cage 50 can be cylindrically shaped. Cage 50 can be perforated.
By way of example, case 50 can be a perforated cylinder measuring
approximately 0.5 inches (1.27 cm) to 3.0 inches (7.62 cm) in diameter,
approximately 2 inches (5.08 cm) to 12 inches (30.48 cm) in height,
and approximately 1/32 of an inch (0.08 cm) thick. The diameter
of the perforations can be from about 0.125 inches (0.318 cm) to
about 0.25 inches (0.635 cm). The percentage of the grid occupied
by perforation, as opposed to conductive material, can be from about
40% to about 80% of the total surface area.
Gas ports 52 can be positioned on top of chamber 30, while aspiration
ports 54 can be positioned at or near the base of chamber 30. Gas
ports 52 are used to flux a gaseous medium in liquid or vapor form
into chamber 30, where it is converted into ionized plasma. Aspiration
ports 54 are used after processing is complete, or when a new gas
is desired, purge chamber 30.
Additionally, an apparatus for accomplishing the method of the
present invention includes a plasma-generating assembly. The plasma-generating
assembly can be, for example, a radio frequency source and antenna,
a microwave source, or any other suitable element known to one of
ordinary skill in the art. By way of example, FIG. 10 illustrates
a radio frequency source 56, such as that manufactured by Dressler
of Germany, and an antenna 58. In one such embodiment, antenna 58
can be a radio-frequency conducting filament that is wrapped about
chamber 30 in a helical or corkscrew-like fashion.
While particular embodiments of the present invention have been
shown and described, it will be obvious to those skilled in the
art that changes and modification can be made without departing
from this invention it its broader aspects and, therefore the appended
claims are to encompass within their scope all such changes and
modifications as fall within the true spirit and scope of this invention.
It is illustrated that the present invention enables coating of
the SODm onto the surface of a pacemaker lead. However, it should
be appreciated that the methods and the SODm coating described above
can be applied to many other medical devices without deviating from
the scope of the present invention. The method and the SODm coating
described above are especially useful for coating SODm onto hard
to coat materials (e.g., silicon rubber, fluoro polymer, polyethylene,
and polypropylene) that are used to make many medical devices.
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