U.S. patent application number 12/105502 was filed with the patent office on 2009-02-12 for composite expandable device with impervious polymeric covering and bioactive coating thereon, delivery apparatus and method.
This patent application is currently assigned to NFOCUS NEUROMEDICAL, INC.. Invention is credited to Phillip CHIU, Mai Huong DANG, Ara DAVIDIAN, Mir A. IMRAN, Kevin T. LARKIN, Leon V. RUDAKOV.
Application Number | 20090043375 12/105502 |
Document ID | / |
Family ID | 23522460 |
Filed Date | 2009-02-12 |
United States Patent
Application |
20090043375 |
Kind Code |
A1 |
RUDAKOV; Leon V. ; et
al. |
February 12, 2009 |
COMPOSITE EXPANDABLE DEVICE WITH IMPERVIOUS POLYMERIC COVERING AND
BIOACTIVE COATING THEREON, DELIVERY APPARATUS AND METHOD
Abstract
A composite expandable device for delivery into a vessel
carrying blood comprising an expandable support frame having first
and second end portions. An impervious polymer sleeve having inner
and outer surfaces extending over the support frame. A coating is
disposed on at least one of the inner and outer surfaces of the
polymer sleeve for enhancing endothelial cell growth on the device
and polymer sleeve.
Inventors: |
RUDAKOV; Leon V.; (Belmont,
CA) ; IMRAN; Mir A.; (Los Altos Hills, CA) ;
DAVIDIAN; Ara; (Foster City, CA) ; LARKIN; Kevin
T.; (Menlo Park, CA) ; DANG; Mai Huong; (Palo
Alto, CA) ; CHIU; Phillip; (San Francisco,
CA) |
Correspondence
Address: |
Nfocus Neuromedical Inc.,c/o Levine Bagade Han LLP
2483 East Bayshore Road, Suite 100
Palo Alto
CA
94303
US
|
Assignee: |
NFOCUS NEUROMEDICAL, INC.
Palo Alto
CA
|
Family ID: |
23522460 |
Appl. No.: |
12/105502 |
Filed: |
April 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09935417 |
Aug 22, 2001 |
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12105502 |
|
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09385691 |
Aug 30, 1999 |
6371980 |
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09935417 |
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Current U.S.
Class: |
623/1.15 ;
623/1.17; 623/1.42 |
Current CPC
Class: |
A61F 2230/0013 20130101;
A61F 2/91 20130101; A61F 2250/0067 20130101; A61F 2/915 20130101;
A61F 2002/91533 20130101; A61F 2002/91566 20130101; A61F 2/07
20130101; A61F 2002/91525 20130101; A61F 2002/91558 20130101 |
Class at
Publication: |
623/1.15 ;
623/1.17; 623/1.42 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Claims
1. An expandable device for delivery into a blood vessel carrying
blood comprising: an expandable support frame having first and
second end portions, a polymer sleeve having inner and outer
surfaces and where the polymer sleeve comprises a polymer that is
difficult to obtain endothelial cell growth thereon, and a coating
having a first layer capable of providing free amine groups
comprising a plasma activated stable functional group, a second
linker layer having a terminal COOH group, and a third cell
adhesion peptide layer, wherein the linker layer is positioned
between and covalently bonded to each of the first and third
layers, said coating carried on and attached to at least one of the
inner and outer surfaces of the polymer sleeve for enhancing
endothelial cell growth on the polymer sleeve, wherein second
linker layer coverage with linkers having a terminal COOH group
reduces a thrombogenic risk of unbound linkers on the layer.
2. The device of claim 1, wherein said coating is prepared by
treating said inner and outer surface with a gaseous plasma
cleaning process utilizing radiofrequency energy to ablate said
inner or outer surface and to functionalize said inner or outer
surface and to produce a plasma-deposited layer having functional
groups, and subjecting said plasma-deposited layer to
multifunctional linkers in a wet chemical treatment to form
covalent bonds between the linkers/spacers and the functional
groups of the plasma-deposited layer to covalently bind the
cell-adhesion peptides to said inner or outer surface of the
substrate.
3. The device of claim 1, wherein said cell-adhesion peptide has an
amino acid sequence presented as SEQ ID NO: 1.
4. The device of claim 2, wherein said cell-adhesion peptide has an
amino acid sequence presented as SEQ ID NO: 1.
5. The device of claim 1, wherein a linker having a terminal COOH
group binds one or more cell-adhesion peptides having an amino acid
sequence presented as SEQ ID NO: 1.
6. The device of claim 2, wherein a linker having a terminal COOH
group binds one or more cell-adhesion peptides having an amino acid
sequence presented as SEQ ID NO: 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. patent application Ser. No.
09/935,417 filed Aug. 22, 2001 which is a continuation of U.S.
patent application Ser. No. 09/385,691 filed Aug. 30, 1999, now
U.S. Pat. No. 6,371,980 issued Apr. 16, 2002, the contents of which
are incorporated herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] This invention relates to a composite expandable device with
a polymeric covering on the device and a bioactive coating on
device and the polymeric covering, a delivery apparatus and a
method.
[0003] Saphenous vein grafts have heretofore been utilized for
bypassing occluded arterial blood vessels in the heart. Because
they are vein tissue rather than arterial tissue, they have
different characteristics and generally do not function well long
term as arterial vessels. Saphenous bypass veins are less muscular
and are generally quite flimsy and compliant. When these saphenous
vein grafts become diseased with age, stenoses and obstructive
deposits which are cheesy or buttery in consistency and which are
very malleable are formed which cannot be treated effectively with
interventional catheter procedures even when followed with a stent
implant. The plaque material forming the stenosis tends to ooze
through the stent struts and reoccludes flow passage through the
stent and the saphenous vein graft. Other vascular obstructions,
such as in femoral and popliteal vessels and in carotids as well as
in native coronary arteries also suffer from occlusions. In many of
these cases, plaque proliferates through the stents when stents are
deployed in the vessels. Therefore a great need exits for a new and
improved device and method to provide a lasting therapeutic relief
in such situations.
SUMMARY OF THE INVENTION
[0004] In general, it is an object of the present invention to
provide a composite expandable device with a substantially
impervious polymeric covering thereon with a bioactive coating on
the device and covering and a method for using the same which can
be utilized for treating occlusions or partial occlusions in blood
vessels and particularly saphenous vein grafts.
[0005] Another object of the invention is to provide a device of
the above character which will provide a lasting therapeutic
solution to the occurrence of plaque in stents in saphenous vein
grafts.
[0006] Another object of the invention is to provide a device of
the above character which can be used for repaving with endothelial
cells the portion of the vessel being treated.
[0007] Another object of the invention is to provide a device of
the above character which has physical characteristics which
substantially match or mimic the physical characteristics of blood
vessels.
[0008] Another object of the invention is to provide a device of
the above character in which a uniformly distributed structural
support is provided for the polymeric covering.
[0009] Another object of the invention is to provide a device of
the above character which is very flexible and can bend axially to
accommodate the tortuosity of blood vessels.
[0010] Another object of the invention is to provide a device of
the above character which can be placed in tandem with another
similar device in a vessel to treat a long stenosis in a
vessel.
[0011] Additional objects and features of the invention will appear
from the following description in which the preferred embodiments
are set forth in detail in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a side elevational view of a composite expandable
device with a polymeric covering and a bioactive coating thereon,
with certain portions broken away, mounted on a balloon delivery
catheter.
[0013] FIG. 2 is a cross-sectional view taken along the line 2-2 of
FIG. 1.
[0014] FIG. 3 is a cross-sectional view taken along the line 3-3 of
FIG. 1.
[0015] FIG. 4 is an enlarged detail view of the balloon with the
composite expandable device mounted thereon shown in FIG. 1.
[0016] FIG. 5 is a plan view of the expandable device which has
been split apart longitudinally and spread out to show its
construction.
[0017] FIG. 6 is a side elevational view of another embodiment of a
composite expandable device with polymeric covering and bioactive
coating thereon which is tapered and is carried by a tapered
balloon for expansion and delivery.
[0018] FIG. 7 is a schematic illustration of a heart showing the
manner in which a saphenous vein graft is treated utilizing the
composite expandable device of the present invention.
[0019] FIG. 8 is an enlarged detail view showing the docking of a
tapered composite expandable device being docked with a cylindrical
composite expandable device.
[0020] FIG. 9 is a flow chart showing the method of the present
invention.
[0021] FIG. 10 is a cross-sectional view of a medical device having
a surface treated in accordance with the present invention.
DETAILED DESCRIPTION
[0022] In general, the composite expandable device incorporating
the present invention is for delivery into a vessel carrying blood
and comprises an expandable support frame having first and second
ends. An impervious polymer sleeve extends over the support frame
and may leave the first and second ends of the support frame
exposed. A bioactive coating is provided on one or both of the
inner and outer surfaces of the polymer sleeve and the frame for
enhancing endothelial cell growth on the blood contact surfaces of
the polymer sleeve and frame.
[0023] More in particular, the composite expandable device 11 as
shown is mounted on a delivery apparatus 12 which consists of an
expandable balloon 13 mounted on the distal extremity of a shaft or
catheter 14 and having a wye fitting 16 mounted on the proximal
extremity. The shaft or catheter 14 is provided with a central
lumen 17 which is adapted to receive a conventional guide wire 18
through a port 19 provided in the fitting 16. The catheter shaft 14
is provided with a concentric lumen 21 which is in communication
with a port 22 of the fitting 16. The lumen 21 extends through the
balloon 13 and an opening (not shown) is provided in the shaft 14
within the balloon for inflating and deflating the balloon.
[0024] The composite expandable device 11 consists of an expandable
frame 26 which has a polymeric sleeve 27 covering the same. The
sleeve has folds 28 therein when the frame is in an unexpanded
condition as shown in FIG. 4.
[0025] The expandable balloon 13 has a substantially continuous
diameter and is provided with distal and proximal portions 31 and
32 and an intermediate portion 33 which serves as a working portion
of the balloon, having a length which will accept the length of the
composite device 11. The balloon 13 is provided with folds 34 when
deflated as shown in FIGS. 1, 3 and 4. Radiopaque marker bands 36
and 37 are provided on the portion of the shaft 14 extending
through the balloon 13 and are mounted in the distal and proximal
portions 31 and 32 as shown adjacent to the intermediate portion
33. These marker bands 36 and 37 are within the distal and proximal
portions 31 and 32 of the balloon 13 but have a diameter which is
substantially greater than the inner diameter of the intermediate
portion 33 with the composite expandable device 11 mounted on the
intermediate portion 33 to serve as stops or abutments to prevent
the composite expandable device 11 from inadvertently slipping off
of the balloon 13 during positioning and deployment of the
composite expandable device 11.
[0026] The frame 26 which forms a part of the composite expandable
device 11 consists of a plurality of circumferentially spaced-apart
elongated struts 41 having first and second ends 42 and 43.
Foldable links 46 are secured to the first and second ends 42 and
43 and extend circumferentially of the frame 26 and serve in
conjunction with the elongate struts to form a circular belt 47. As
shown in FIG. 4, a plurality of serially-connected belts 47 are
provided which are axially aligned with each other.
[0027] Sinusoidal-shaped end portions 48 and 49 are provided on
opposite ends of the plurality of serially-connected belts 47.
Interconnecting means 50 is provided for interconnecting the
plurality of belts 47 and the end portions 48 and 49 so that the
belts 47 and end portions 48 and 49 extend along an axis while
permitting axial bending between the belts 47 and the end portions
48 and 49 while maintaining a constant length of the device 11. The
means 50 consists of at least one strut 51 which is relatively
short in length in comparison to the length of the elongate struts
41 and a plurality of S-shaped links 52. Thus, as shown in FIG. 5,
between each end portion and a belt and between adjacent belts
there is provided a single strut 51 and two S-shaped links 52 all
of which are spaced 120.degree. apart the interconnecting means
between adjacent belts and/or end portions are offset by 60.degree.
Thus, with the construction shown in FIG. 4 there are provided four
belts 47 and two end portions 48 and 49 with five sets of
interconnecting means 50.
[0028] It can be seen that the length of the frame 26 can be
readily increased or decreased by changing the number of belts 47
provided in the frame 26.
[0029] The frame 26 can be formed of a suitable material such as a
metal or plastic. Suitable metals are stainless steel, titanium,
and alloys thereof and other biocompatible metals. The plastic can
be a polymer. Since the frame to be utilized in the composite
expandable device is typically used in a saphenous vein graft, it
need not have the radial strength normally required for stents
placed in native arterial vessels. The frame 26 has been
specifically designed to support the polymer sleeve 27 for use in a
saphenous vein graft to closely approximate mechanical properties
of the saphenous vein graft. The same principles can be used for a
composite device for arterial vessels and other blood vessels. Thus
the frame 26 provides the necessary strength and consistency
throughout its length while giving good flexibility throughout its
length to accommodate movement of the saphenous vein graft.
[0030] As shown in FIG. 4, the polymer sleeve extends over
substantially the entire length of the frame 26 but leaving end
portions 48 and 49 substantially exposed for a purpose hereinafter
described. The sleeve 27 typically is formed of a suitable polymer.
One polymer found to be particularly satisfactory is PTFE which is
supplied as a tube having a wall thickness ranging from 0.002'' to
0.010'' and preferably 0.004'' to 0.008'' and having a suitable
original diameter as for example 2 to 4.5 mm. The expanded PTFE
material should have a pore size of approximately 10 to 50 .mu.m.m.
In addition in certain applications of this device, it may be
desirable that the material be expandable from two to six times its
original size yet retain elasticity properties to remain tightly
over and in close engagement with the frame 26 prior to and after
expansion. After placing the sleeve 27 over the working or
intermediate portion 33 of the balloon, the sleeve 27 may be
secured to the frame 26 so that it does not move axially of the
frame 26 during deployment as hereinafter described. To accomplish
this, the sleeve 27 can be wrapped into a fold or a wing 28 and
held in place along a line 61 (see FIG. 3) or tacked by
spaced-apart heat seals (not shown) that are easily rupturable upon
expansion of the frame 26. It has been found that such tacking by
the use of heat seals on a fold or wing of the polymer sleeve 27
makes it easy for the balloon 13 when expanding to open the sleeve
27 without any significant additional balloon pressure being
required.
[0031] With such a construction as shown in FIG. 3, the frame 26
which has been crimped onto the intermediate portion 33 of the
balloon 13 and the sleeve 27 wrapped over onto the same and seamed
into place will have an overall profile which has a diameter or
size which is not greater than or desirably less than the diameters
of the proximal and distal portions 31 and 32. Since the marker
bands 36 and 37 have larger diameters than the intermediate portion
33 of the balloon 13, they will ensure that the composite
expandable device consisting of the frame 26 and the sleeve 27
cannot inadvertently slip off of the balloon 13 during the
procedure.
[0032] Another embodiment of a composite expandable device
incorporating the invention is in the device 71 shown in FIG. 6. It
is tapered rather than cylindrical to more closely approximate
natural vessel geometry. In this device 71, a frame 72 is provided
which is constructed in substantially the same manner as frame 26
but with the belts 73 increasing successively in circumference in
one direction along the axis of the device 71 by providing foldable
links 46 of successively greater lengths to provide the tapered
construction shown in which one expandable end portion 76 has a
lesser diameter than the other end portion 77. The means connecting
the belts 73 and the end portions 76 and 77 are like the
interconnecting means 50 hereinbefore described.
[0033] A tapered polymer sleeve 81 is provided on the exterior of
the frame 72 while leaving the end portions 76 and 77 substantially
exposed. A tapered balloon 86 is disposed within the frame 72 and
is utilized for expanding the composite expandable device 71. The
tapered balloon 86 is mounted on the distal extremity of a balloon
shaft or catheter 87 and is constructed in the same manner as
balloon shaft 14 and provides a delivery apparatus 89.
[0034] In order to provide a cell-friendly surface or surfaces on
the sleeves 27 and 81, at least one surface of the outer and inner
surfaces and preferably both inner and outer surfaces are treated
in the manner described in co-pending application Ser. No.
09/385,692 filed Aug. 30, 1999.
[0035] In general the method of the present invention is for
treating a medical device having at least one surface exposed to
tissue and/or blood and comprises the steps of subjecting the one
surface to a low temperature plasma of an appropriate chemical
agent to provide a plasma deposited layer having functional groups
like amine, carboxylic, or hydroxyl groups covalently bound to the
surface of the device. The plasma deposited layer is then subjected
to a chemical treatment with multifunctional linkers/spacers which
then become covalently bound with the plasma deposit layer. A
bioactive coating is then covalently bound to spacers/linkers.
[0036] More in particular, the method of the present invention as
hereinafter described utilizes a plasma chamber (not shown) of the
type as described in U.S. Pat. No. 5,643,580 well known to those
skilled in the art and thus will not be described in detail.
Typically the plasma utilized in the method of the present
invention utilizes a "low temperature" or "cold" plasma produced by
glow discharge. A low temperature plasma is created in an evacuated
chamber refilled with a low pressure gas having a pressure on the
order of 0.05 to 5 Torr and with the gas being excited by
electrical energy usually in the radio frequency range. A glow
discharge is created typically in the range of 2-300 watts for low
power and 50-1000 watts for high power depending on the chamber
volume.
[0037] The steps for the method of the present invention are shown
in FIG. 9 for the treatment of a substrate 111 shown in FIG. 10 and
having first and second surfaces 112 and 113. The substrate 111 is
part of a medical implant or medical device that has at least one
surface which is to be treated, such as one of the surfaces 112 and
113, to achieve desirable biological activities on that surface.
The substrate 111 is formed of a suitable material such as a
fluorinated thermoplastic or elastomer or more specifically, by way
of example, PTFE. The latter material is particularly desirable
where the medical implant or medical device is in the form of
small-diameter vascular grafts. The substrate can also be formed of
any polymer and polymer composites, metals and metal-polymer
composites.
[0038] Let it be assumed that the surface 112 of the substrate 111
is to be treated in accordance with the method set forth in FIG. 9.
The surface 112 is cleaned in an oxygen or air plasma as shown by
step 116 in a relatively short period of time. The plasma cleaning
process is an ablation process in which radiofrequency power, as
for example 50-1000 watts, under a higher pressure e.g. 0.1 to 1.0
Torr at a high flow rate, as for example of at least 50 cc. per
minute gas passing through the plasma chamber. Such a cleaning
process can use oxygen, alone, a mixture of oxygen with argon or
nitrogen for a period of time of up to 5 minutes. Thus, a plasma of
oxygen air, or inert gases can be utilized for plasma cleaning.
[0039] Thereafter, the surface 112 after being cleaned as shown in
step 117, is functionalized by subjecting the surface 112 to a pure
gas or gas mixture plasma to assist in the deposition of functional
groups on the surface 112 to provide a deposited layer 118 which is
covalently bound to the surface 112. Other methods which can be
utilized in place of the plasma deposition step 117 include a
modification by irradiation with ultraviolet or laser light in the
presence of organic amine or hydrazine. The plasma deposition step
117 used to achieve activation of the surface utilizes precursor
gases which can include the following inorganic and organic
compounds: NH.sub.3 (ammonia), N.sub.2 H.sub.4 (hydrazine)
aliphatic amines, aliphatic alcohols, aliphatic carboxylic acids,
allylamine, water vapor, allyl alcohol, vinyl alcohols, acrylic
acid, methacrylic acid, vinyl acetate, saturated or unsaturated
hydrocarbons and derivatives thereof. Precursors can be saturated
(aliphatic amines, aliphatic alcohols, aliphatic acids) or
unsaturated (allyl, vinyl and acrylated compounds). Employing
unsaturated precursors or operating pulsed plasma (single mode or
gradient) tend to preserve functional groups rather than form
defragmentation products, having the potential of introducing a
significantly higher percentage of reactive groups.
[0040] The deposition step 117 can be performed in continuous or
pulsed plasma processes. The power to generate plasma can be
supplied in pulsed form or can be supplied in graduated or gradient
manner, with higher power being supplied initially, followed by the
power being reduced or tapered towards the end of the plasma
deposition process. For example, higher power or higher power
on/off ratios can be utilized at the beginning of the step 117 to
create more bonding sites on the surface 112 which results in
stronger adherence between the substrate surface 112 and the
deposited layer 118. Power is then tapered off or reduced as for
example by reducing the power-on period to obtain a high percentage
of functional groups on the surface 112.
[0041] The plasma deposition layer 118 created on the surface 112
has a thickness ranging from 5-1000 .ANG. By way of example this
can be a layer derived from allylamine plasma. This plasma-assisted
deposition typically is carried out at a lower power that ranges
from 2-400 watts and typically from 5-300 watts depending upon the
plasma chamber size, pressure and gas flow rate. This step 117 can
be carried out for a period of time ranging from 30 seconds to 30
minutes while being sure that the reactive group created is
preserved.
[0042] When it is desired to retain only those functional groups in
the layer 118 which have established stable bonds to the substrate
surface 112, as for example to a PTFE surface, an optional step 121
can be performed by rinsing or washing off loosely bound deposits
with solvents or buffers. Thus, deposits which are merely adsorbed
on the surface 112 are rinsed and washed off and the covalently
bound deposits remain on the surface. Such a step helps to ensure
that parts of the coating forming the layer 118 cannot thereafter
be washed off by shear forces or ionic exchanges with blood flow
passing over the surface.
[0043] Plasma-assisted deposition has been chosen because it is a
clean, solvent-free process which can activate the most inert
substrates like PTFE. Plasma produces high energy species, i.e.,
ions or radicals, from precursor gas molecules. These high energy
species activate the surface 112 enabling stable bondings between
the surface 112 and activated precursor gas. Allylamine has been
chosen as a precursor for the plasma-assisted deposition step
because it has a very low boiling point of 53.degree. C., making it
easy to introduce as a gas into the plasma chamber. By using
allylamine, the desire is to have radicals created by tile plasma
occurring preferentially at C.dbd.C double bonds so that the free
amine groups created are preserved for other reactions as
hereinafter described. Also, it is believed to give a high yield of
the desired primary amine group on the surface 112.
[0044] In the rinsing step 121, a solvent rinse such as
dimethylsulfoxide (DMSO) is used for removing all of the allylamine
deposit which has not been covalently bound to the surface 112,
i.e. to remove any allylamine which has only been adsorbed on the
surface. Another material such as dimethylformamide (DMF),
tetrahydrofuran (THF) or dioxane can be utilized as a solvent
rinse. In addition, for removing polar deposits, a buffer rinse can
be utilized. As soon as the rinsing step 121 has been completed and
the substrate 111 dried, wetting or surface tension measurement
showed very hydrophilic PTFE (layer 118) completely wet with water.
The presence of free amine groups can be visualized by tagging
fluorescent probes reactive with amine groups. ATR-FTIR (attenuated
total reflectance-fourier transform infrared) or ESCA (electron
spectroscopy for chemical analysis) may give information about the
presence of amine or nitrogen in layer 118, respectively.
[0045] Subsequently, in step 123, homo or hetero multifunctional
linkers/spacers react and form stable linkages with the functional
groups in layer 118 obtained by the plasma-assisted deposition
process. This treatment in step 123 serves to provide
linkers/spacers as represented by symbols 126 in FIG. 10 to improve
accessibility of coating agents, as for example peptides and
proteins, to functional groups on substrates. Vice versa, it is
believed that the linkers 126 enhance the exposure of peptides and
proteins to the environment. Also the linkers give peptides or
proteins in the final coating more space and freedom to assume
their natural conformations. As a result, the covalently bound
coating agents are more likely to maintain their natural
conformations and therefore their bioactivity.
[0046] By way of example, primary amine groups obtained after
allylamine plasma react with succinic anhydride leading to a
substrate covered by linkers 126 ended with COOH groups. Thus, the
coverage with linkers 126 is less thrombogenic and more
cell-friendly compared to the coverage with NH.sub.2 rich layer
118. The linker/spacer attachment step 123 can also be utilized to
introduce desirable functional groups which can readily react with
the final coating agents. For example, COOH groups at the end of
linker 126 can form stable amide linkage with NH.sub.2 groups in
cell-adhesion peptides and proteins, anti-inflammatory peptides,
anti-thrombogenic peptides and proteins, growth factors, etc. The
COOH groups can also form an ester linkage with OH groups in the
anti-coagulant agent heparin. Taking the nature of the substrate,
functional groups obtained after plasma, the availability of
functional groups and the size and nature of the final coating
agents into consideration, the chemistry and size of the linkers
may be selected. Multifunctional linkers usually have 2-20 carbon
atoms in the backbone. They can be anhydrides of dicarboxylic
acids, dicarboxylic acids, diamines, diols, or amino acids. Linkers
can be just one molecule, a string of several molecules, such as a
string of amino acids, a string of alternate dicarboxylic
acids-diamines, dicarboxylic acids-diols or anhydrides-diamines.
This chemical treatment step 123 hereinbefore described can also be
characterized as one that introduces other desirable functional or
activating groups.
[0047] Organic solvents which are miscible with water can be used
as solubility enhancers to facilitate coupling efficiency between
the plasma-treated substrate and the linkers (step 123) and/or
coating agents (step 128) in an aqueous medium. DMSO, DMF or
dioxane can be used as such solubility enhancers. They facilitate
the contact between functional groups present in molecules of
different hydrophilicity or hydrophobicity. After the corresponding
functional groups come close enough to each other, chemical
reactions between them can occur. So, solubility enhancers in an
aqueous solution can augment the binding reactions. The solubility
enhancers may also enhance the accessibility of the linker/coating
agents to the functional groups on porous surfaces.
[0048] After completion of the wet chemistry linker/spacer
attachment step 123, the wetting behavior/surface tension of the
resulting surface can be analyzed. Appropriate techniques, such as
ESCA, SIMS, ATR-FTIR can be used to characterize the hydrophilic
surface created in step 123. Fluorescent imaging of functional
groups can also be carried out.
[0049] The bioactive/biocompatible coating step 128 can be carried
out to provide the final layer of coating 131 on the surface 112 of
the substrate 111 (as shown in FIG. 10). In this step, the
available functional groups provided by the linkers 126, are used
to covalently bind molecules of a bioactive/biocompatible agent,
such as a cell-adhesion peptide P15 as hereinafter described,
possessing desirable properties to the substrate surface 112 to
provide the final resulting coating on the surface 112 as for
example a PTFE surface. Of interest are bioactive/biocompatible
coatings which, among others, can reduce foreign body reactions,
accelerate the functioning and integration, as well as increase the
long-term patency of implants. Such coatings can include cell
adhesion peptides, proteins or components of extra-cellular matrix
to promote cell migration and proliferation, leading to a rapid and
complete coverage of the blood-contacting surface by a natural
endothelial cell lining. Coatings with growth factors such as VEGF
may lead to similar results. Non-adhesive coatings with
polyethylene glycol derivatives are used for biocompatible
hydrophilic surfaces as separation membranes, immuno barriers or
surfaces free of platelet adhesion. Also, anti-thrombogenic
coatings with hirudin, hirudin analogs, reversible and irreversible
thrombin inhibitor peptides, or anti-coagulant coatings with
heparin are desirable to reduce or prevent thrombosis formation at
the implanting site. These local anti-thrombogenic or
anti-coagulant coatings are more preferable than a systemic
anti-coagulant treatment. Anti-inflammatory coatings can be used
because occlusions may originate at inflamed sites.
Anti-proliferative coatings are another way to reduce vessel
occlusions by preventing smooth muscle cell proliferation.
[0050] Chemical/biological testing such as AAA (amino acid
analysis), in vitro cell cultures followed by SEM (scanning
electron microscopy), and in vivo testing can be used for
evaluating the coatings of the present invention.
[0051] A specific example of a coating having biological activity
and medical implants having a surface carrying the same and the
method incorporating the present invention may now be described as
follows.
[0052] Let it be assumed that it is desired to coat long porous
PTFE tubes, as for example having a length of 11 cm., which are to
be utilized as medical implants and to be treated with a coating
using the method of the present invention. The tubes can be
prepared for treatment by mounting the same on an anodized aluminum
wire frame and then inserting them in a vertical position in the
upper portion of the plasma chamber being utilized. The tubes are
then cleaned in an air plasma by operating the plasma chamber at
0.3 torr at 50 watts for 3 minutes. After the plasma cleaning
operation has been performed, the chamber is flushed with
allylamine gas at 0.2 torr for 10 minutes. Allylamine plasma is
then created at 0.2 torr at 15 watts for 30 minutes. Radiofrequency
power is turned off and allylamine is permitted to flow at 0.2 torr
for 2 minutes. The allylamine flow after plasma treatment is
provided to react with any free radicals on the PTFE. The
allylamine flow is then terminated and a vacuum is maintained in
the chamber for 15 minutes. Thereafter, the pressure in the plasma
chamber is increased to atmospheric pressure. The tubes being
treated are then removed from the chamber and transferred to clean
glass rods. The tubes are then submerged and rinsed in an
appropriate volume of DMSO. The samples are then removed from the
DMSO rinse and washed with deionized (DI) water and optionally
ultrasonically at room temperature for 3 minutes.
[0053] In the covalent linker attachment step 123, a 1 M (one
molar) succinic anhydride solution is prepared using DMSO and
placed in a covered glass tray container. The plasma treated and
optionally rinsed tubes are then submerged in the succinic
anhydride solution in the glass tray container and subjected to an
ultrasonic mix at 50.degree. C. in order to bring the succinic
anhydride into close proximity to the free amine groups on the PTFE
surface. A one molar (1M) Na.sub.2 HPO.sub.4 solution in DI water
is used to adjust the pH between 6 to 9, preferentially pH 8. A
higher pH results in a faster reaction. This reaction between the
free amine groups and the succinic anhydride can be carried out
between room temperature and 80.degree. C. and preferentially
between 20-50.degree. C.
[0054] After this has been accomplished, the tubes are removed and
rinsed with DI water optionally utilizing ultrasound. The tubes are
then dried with nitrogen.
[0055] Let it be assumed that a peptide coating is desired to be
applied to the surface thus far created. Solubility enhancers such
as DMSO and DMF can be added between 0-50 volume/volume v/v %,
preferentially 10-30%. A 90 mL. DI water/DMSO solution is prepared
by taking 70 mL. of DI water and mixing the same in a glass
container with 20 mL. of DMSO. The dried tubes are then placed in
the DMSO solution and ultrasonically mixed for a period of 1
minute.
[0056] Freshly prepared EDC
[N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride]
(Fluka) solution in 5 ml DI water is poured over the tubes
submerged in water/DMSO to activate COOH groups on the PTFE
surface. After 0.5-3 min., P15
((H-Gly-Thr-Pro-Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln-Arg-Gly-Val-Val-OH)
acetate salt, GLP grade peptide) solution in 5 ml DI water is
added. For hydrophobic peptides, the peptides may be dissolved in
an organic solvent miscible with water (DMSO, DMF or dioxane). EDC
and P15 amounts are based on the following final concentrations:
0.02 M EDC to be used and 0.0002 M P15 in the final reaction
volume, i.e. 100.times. molar excess of EDC to P15. The reaction at
room temperature is carried out between 1-16 hours, preferentially
2-8 hours. The tubes are then rinsed several times with deionized
water with an optional one minute ultrasonic treatment. The tubes
are then dried with nitrogen gas. The tubes are then inverted to
bring the coated side to the inside. Amino acids analysis revealed
that up to 1.5 nmol P15/cm.sup.2 was bound to the PTFE surface.
[0057] From the foregoing it can be seen that there has been
provided a coating which has biological activities which can be
utilized on surfaces of medical implants and devices and a method
for accomplishing the same. The coating and method can be utilized
on many different types of devices which are intended to be
implanted in the human body or in other words to remain in the
human body for a period of time. Such devices include stents and
grafts placed in various vessels of the human body. Other medical
devices such as heart valves, defibrillators and the like have
surfaces which are candidates for the coating and method of the
present invention. The coating and method is particularly
advantageous for use on surfaces which heretofore have been
difficult to obtain cell growth on, as for example PTFE and ePTFE.
By utilizing the coating and method of the present invention, it
has been found that cell growth has been greatly enhanced, making
possible long term implantation of said devices in the human
body.
[0058] Thus the surface of the polymer can be characterized as
having applied thereto a bioactive coating which is cell friendly
and which enhances growth of cells thereon. As described therein, a
low temperature plasma-deposited layer is provided on the surface
of the polymer to functionalize the surface and provide free amine
groups thereon. A spacer/linker molecular layer is covalently
bonded to the plasma-deposited layer. A peptide coating such as P15
(Gly-Thr-Pro-Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln-Arg-Gly-Val-Val; SEQ
ID NO: 1) is deposited on the spacer/linker layer. By way of
example, the outer surface of the sleeve 27 can be treated first.
Thereafter, the sleeve 27 can be inverted by turning it inside out
and treating the inside surface which is now outside.
Alternatively, both the outside and inside surfaces can be treated
at the same time.
[0059] Operation and use of the composite expandable devices 11 and
71 with the delivery apparatus 12 and delivery apparatus 89 may now
be briefly described as follows. In this connection let it be
assumed that a human heart 101 as shown in FIG. 6 has previously
had a coronary artery 102 in which there had been formed therein a
substantially total occlusion 103. Also let it be assumed that it
was found necessary to perform a bypass operation and to insert a
saphenous vein graft utilizing a length of saphenous vein 106 which
has one end connected into the aorta 107 of the heart by a proximal
anastomosis 108 for a blood supply and bypassing the coronary
artery occlusion 103 and making a connection to the coronary artery
102 at a distal anastomosis 109. Now let it be assumed that after a
period of time there has been a build-up of plaque forming a
stenosis in the saphenous vein graft 106 in the region near the
distal anastomosis 109.
[0060] With such a condition, it is desirable to first use a
tapered composite expandable device 71, delivering the same by the
use of the tapered balloon 86 of the delivery apparatus 89 on a
guide wire in a conventional manner through the femoral artery into
the aorta, then through the proximal anastomosis 108 and then
advanced into a region adjacent the distal anastomosis 109. The
distal tapered balloon 86 is then expanded to expand the device 71
into engagement with the wall of the saphenous vein graft and to
thereby enlarge the opening through the saphenous vein graft to
enhance blood flow therethrough, through the flow passage formed by
the device 71. Thereafter, the tapered balloon 86 and the delivery
apparatus 89 is removed.
[0061] Let it be assumed that the tapered device 71 has an
inadequate length to treat the entire stenosis and it is desired to
place another composite expandable device as for example the device
11 (FIG. 1) in tandem or in series with the device 71. Assuming
that the guide wire is in place that was used for deploying the
first device 71, the shaft 14 of the delivery apparatus 12 can be
threaded over the guide wire 18 and a balloon with a composite
expandable device 11 mounted thereon advanced into the saphenous
vein graft 106 until the distal extremity of the device 11 meets
within the proximal larger end 77 of the device 71. The distal
extremity can be docked into the open proximal end of the device
71. Thereafter, the balloon 13 can be expanded to complete the
docking of the distal extremity of the device 11 in the proximal
extremity of the device 71 so that they are deployed in the
saphenous vein graft 106 in tandem. The balloon 13 then can be
deflated and removed with the delivery apparatus 12 along with the
guide wire 18. The positioning of the devices 71 and 11 can be
observed fluoroscopically by observing the locations of the
radiopaque markers 56 provided on the devices 11 and 71. If the
occlusion in the saphenous vein graft is sufficiently long, an
additional device 11 can be placed in tandem with the device 11
already in place. If this is desired, the guide wire can be left in
place and another balloon delivery apparatus 12 with a device 11
mounted thereon can be advanced into the saphenous vein graft 106
and the distal extremity docked into the expanded proximal
extremity of the already positioned device 11. The balloon 13 can
be deflated and then removed along with the guide wire 18 and the
femoral artery closed in an appropriate manner.
[0062] From the foregoing it can be seen that the balloon
expandable devices 11 and 71 form a vascular prosthesis which has
mechanical and biomedical properties which re-establish and mimic
the composition of the biological function and environment of a
healthy natural vessel as for example a recently transplanted
saphenous vein graft. The support frame for the polymer sleeve is
designed to provide adequate support for the polymer sleeve while
still providing appropriate compliance corresponding to that of the
vessel in which it is disposed. The device with its free outer ends
is capable of firmly engaging the wall of the vessel in which it is
disposed to ensure that the device remains in place in the desired
position within the vessel after deployment. By the use of
cylindrical and tapered devices, it is possible to construct a
vascular prosthesis which corresponds to the natural geometry of
the vessel. The delivery apparatus has a low profile which by
utilizing a balloon having an intermediate working portion of a
lesser diameter retains this low profile even when the composite
expandable device is mounted thereon to facilitate positioning and
deployment of the device to the site. Use of the polymer sleeve in
the device prevents plaque or deposits within the blood vessel as
for example a saphenous vein graft from oozing through the
interstices of the frame so that there is unimpeded blood flow
through the expanded frame. By covering the polymer sleeve with a
peptide such as P15, endothelial cell growth is stimulated. In this
way, it is possible to repave the vessel with endothelial cells,
nature's most blood compatible surface, and help prevent further
spread or degradation of the lumen in the vessel at that site. The
construction of the device permitting axial bending makes it
possible for the expanded device to readily flex with the vessel.
Sequence CWU 1
1
1115PRTArtificial Sequenceportion of a1 chain of collagen 1Gly Thr
Pro Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val Val1 5 10 15
* * * * *