Note: Descriptions are shown in the official language in which they were submitted.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
1
METHOD AND APPARATUS FOR COATING MEDICAL IMPLANTS
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a method and apparatus for coating an object
and, more particularly, to a method and apparatus for coating an object using
electrospinning. The present invention is particularly useful for coating
medical
implants.
Production of fibrous products is described in the literature inter alia using
the
technique of electrospinning of liquefied polymer, so that products comprising
l0 polymer fibers are obtained. Electrospinning is a method for the
manufacture of ultra
thin synthetic fibers, which reduces the number of technological operations
and
increases the stability of properties of the product being manufactured.
The process of electrospinning creates a fine stream or jet of liquid that
upon
proper evaporation of a solvent to solid transition state yields a nonwoven
structure.
The fine stream of liquid is produced by pulling a small amount of polymer
solution
through space by using electrical forces. More particularly, the
electrospinning
process involves the subjection of a liquefied substance, such as polymer,
into an
electric field, whereby the liquid is caused to produce fibers that are drawn
by electric
forces to an electrode, and are, in addition, subjected to a hardening
procedure. In the
case of liquid which is normally solid at room temperature, the hardening
procedure
may be mere cooling; other procedures such as chemical hardening
(polymerization)
or evaporation of solvent may also be employed. The produced fibers are
collected on
a suitably located precipitation device and subsequently stripped from it. The
sedimentation device is typically shaped in accordance with the desired
geometry of
the final product, which may be for example tubular, flat or even an
arbitrarily shaped
product.
Examples of tubular fibrous product which can be manufactured via
electrospinning are vascular prosthesis, particularly a synthetic blood
vessel, and tubes
through which a wire or other device or structure may pass or lie. Tubular
fibrous
products may also be used as various kinds of artificial ducts, such as, for
example,
urinary, air or bile duct.
Electrospinning can also be used for coating various objects, such as stems
and
other medical implants. Stems are widely used to provide coronaries with
radial
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
2
support so as to prevent constriction thereof. Nevertheless, clinical data
indicates that
stems are usually unable to prevent late restenosis beginning at about three
months
following an angioplasty procedure. Known in the art are stems having a
mechanical
barrier thereacross, designed to prevent biological material from the lesion
to move
through the stent and into the lumen during placement of the stmt.
The use of electrospinning for stent coating permits to obtain durable coating
with wide range of fiber thickness (from tens of nanometers to tens of
micrometers),
achieves exceptional homogeneity, smoothness and desired porosity distribution
along
the coating thickness. Stents themselves do not encourage normal cellular
invasion
1o and therefore caxi lead to an undisciplined development of cells in the
metal mesh of
the stmt, giving rise to cellular hyperplasia. When a stmt is coated by a
graft of a
porous structure, the pores of the graft component are invaded by cellular
tissues from
the region of the artery surrounding the stmt graft. Moreover, diversified
polymers
with various biochemical and physico-mechanical properties can be used in
coating.
is With respect to mechanical barriers, coated stems having a mechanical
barner
can prevent excessive tissue growth from occluding the vessel. U.S. Pat. No.
5,916,264, the contents of which are hereby incorporated by reference,
disclose a stmt
graft including a sheet of PTFE sandwiched between two metal stents. Although
this
device has been successful at sealing aneurysms and perforations, it is a
bulky device
2o with a significantly larger crossing profile and reduced flexibility
compared to a state-
of the-art stmt.
Examples of electrospinning methods in stmt graft manufacturing are found in
U.S. Patent Nos. 5,639,278, 5,723,004, 5,948,018, 5,632,772, 5,855,598,
International
Patent Application No. W0249535 and Australian Patent No. AU2249402.
25 It is known that the electrospinning technique is rather sensitive to the
changes
in the electrophysical and rheological parameters of the solution being used
in the
coating process. In addition, incorporation of drugs into the polymer in a
sufficient
concentration so as to achieve a therapeutic effect typically reduces the
efficiency of
the electrospinning process and causes different defects of the coating. Still
in
3o addition, drug introduction into a polymer reduces the mechanical
properties of the
resulting coating. Although this drawback is somewhat negligible in relatively
thick
films, for submicron fibers this effect may be adverse.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
3
It is desired that a stmt coat will have good adhesion to the stent metal
basis in
body liquids, so as not too detached after or during implantation. Further,
the
elasticity and strength of the stmt coat should be compatible with the
enormous
inflation of the stmt metal upon opening (about 300-500 %). Additionally, it
is
desired that the stmt coat will promote better grafting, reduce restenosis
risk and
optimize medication discharge into implantation-adjacent tissues.
With respect to the above requirements, the properties of prior art stent
coats
are far less than satisfactory. For example, in electrospinning systems having
elongated electrode system, the electric field becomes critically
asymmetrical, and the
l0 fibers obtain preferential longitudinal orientation. Such coat structure is
known to
have high anisotropy of mechanical properties in which axial strength (along
fiber
orientation) is favored over radial strength. It is recognized that radial
strength is a
crucial parameter, in particular in stmt coat which, as stated, has to comply
with
significant inflation of the stmt metal. In addition, in prior art
electrospinning systems
electrostatic repulsion between fibers results in increased opening angle of
the jet, an
expanded sedimentation area and low rupture strength.
In percutaneous coronary intervention (PCI), including balloon angioplasty and
stmt deployment, there is a risk of vessel damage during stmt implantation.
When the
stmt is expanded radially in the defective site, the plaques on the wall of
the artery
2o cracks and sharp edges thereof cut the surrounding tissue. This causes
internal
bleeding and a possible local infection, which, if not adequately treated, may
spread
and adversely affect other parts of the body.
Local infections in the region of the defective site in an artery do not lend
themselves to treatment by injecting an antibiotic into the blood stream of
the patient,
for such treatment is not usually effective against localized infections. A
more
common approach to this problem is to coat the wire mesh of the stmt with a
therapeutic agent which makes contact with the infected region. However, such
one
shot treatment is not sufficient to diminish infections, and it is often
necessary to
administer antibiotic andlor other therapeutic agents for several hours or
days, or even
months.
The risk of vessel damage during stent implantation may be lowered through
the use of a soft stmt serving to improve the biological interface between the
stent and
the artery and thereby reduce the risk that the stmt will inflict damage
during
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
4
implantation. Examples of polymeric stems or stmt coatings with biocompatible
fibers are found in, for example, U.S. Patent Nos. 6,001,125, 5,376,117 and
5,628,788,
all of which are hereby incorporated by reference.
U.S. Patent No. 5,948,018 discloses a graft composed of an expensible stmt
component covered by an elastomeric polymeric graft component which, because
of
its stretchability, does not inhibit expansion of the stmt. The graft
component is
fabricated by electrospinning to achieve porosity hence to facilitate normal
cellular
growth. However, U.S. Patent No. 5,948,018 fails to address injuries inflicted
by the
stent in the course of its implantation on the delicate tissues of the artery.
These
1o injuries may result in a local infection at the site of the implantation,
or lead to other
disorders which, unless treated effectively, can cancel out the benefits of
the implant.
Additional prior art of interest include: Murphy et al. "Percutaneous
Polymeric
Stents in Porcine Coronary Arteries", Circulation 86: 1596-1604, 1992; Jeong
et al.
"Does Heparin Release Coating of the Wallstent limit Thrombosis and Platelet
is Deposition?", Circulation 92: 173A, 1995; and Wiedermann S.C.
"Intercoronary
Irradiation Markedly Reduces Necintimal Proliferation after Balloon
Angioplasty in
Swine" Amer. Col. Cardiol. 25: 1451-1456, 1995.
Prior art technologies, however, suffer from poor radial strength or having
unsuitable porosity for being implanted in the body. Additionally, prior art
2o technologies fail to provide a method of coating a medical implant while
being
mounted on a delivery system, such as a catheter balloon.
There is thus a widely recognized need for, and it would be highly
advantageous to have a method and apparatus for coating medical implants,
devoid of
the above limitations.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a method of
coating a non-rotary object with an electrospun coat, the method comprising,
dispensing a charged liquefied polymer through at least one dispensing element
within
3o an electric field to thereby form a jet of polymer fibers, and moving the
dispensing
element relative to the object so as to coat the object with the electrospun
coat.
According to fiuther features in preferred embodiments of the invention
described below, the method further comprises translationally moving the
object
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
relative to the jet of the polymer fibers so as to uniformly distribute the
polymer fibers
onto the object.
According to still further features in the described preferred embodiments the
translational motion is a harmonic motion.
5 According to still further features in the described preferred embodiments
the
translational motion is a reciprocation motion.
According to still further features in the described preferred embodiments the
object is an expandable tubular supporting element.
According to still further features in the described preferred embodiments the
to expandable tubular supporting element comprises a deformable mesh of metal
wires.
According to still further features in the described preferred embodiments the
expandable tubular supporting element comprises a deformable mesh of stainless
steel
wires.
According to still further features in the described preferred embodiments the
object is a stmt.
According to still further features in the described preferred embodiments the
object is a stmt assembly having at least one coat.
According to still further features in the described preferred embodiments the
object is a stmt mounted on a stmt delivery system.
2o According to still further features in the described preferred embodiments
the
object is an implantable medical device.
According to still fiu-ther features in the described preferred embodiments
the
object is an implantable medical device mounted on a stent delivery system.
According to still further features in the described preferred embodiments the
method further comprises mounting the expandable tubular supporting element
onto a
mandrel, prior to the dispensation of the charged liquefied polymer.
According to still further features in the described preferred embodiments the
method further comprises dispensing the charged liquefied polymer through the
at
least one dispensing element within the electric field, and moving the
dispensing
3o element relative to the mandrel so as to coat the mandrel, hence providing
an inner
coat to the expandable tubular supporting element.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
6
According to still further features in the described preferred embodiments the
method further comprises providing at least one adhesion layer onto the
expandable
tubular supporting element.
According to still further features in the described preferred embodiments the
at least one adhesion layer is an impervious adhesion layer.
According to another aspect of the present invention there is provided an
apparatus for coating a non-rotary object with an electrospun coat, the
apparatus
comprising at least one dispensing element being at a potential difference
relative to
the object, the at least one dispensing element being capable of moving
relative to the
object while dispensing a charged liquefied polymer within an electric field
defined by
the potential difference, to thereby form a jet of polymer fibers coating the
object.
According to further features in preferred embodiments of the invention
described below, the at least one dispensing element is capable of moving
along a
circular path.
According to still further features in the described preferred embodiments the
at least one dispensing element is capable of moving along a helix path.
According to still further features in the described preferred embodiments the
at least one dispensing element is capable of moving along a zigzag path.
According to still further features in the described preferred embodiments the
2o at least one dispensing element is designed and constructed such that the
electric field
moves synchronically with the motion of the at least one dispensing element.
According to still further features in the described preferred embodiments the
motion of the at least one dispensing element is selected so as to establish a
spiral
motion of the jet of the polymer fibers about the object, the spiral motion
being
characterized by a gradually deceasing radius.
According to still further features in the described preferred embodiments the
at least one dispensing element comprises an arrangement of electrodes.
According to still further features in the described preferred embodiments the
at least one dispensing element comprises a rotatable ring having at least one
capillary.
3o According to still further features in the described preferred embodiments
the
rotatable ring is made of a dielectric material.
According to still further features in the described preferred embodiments the
rotatable ring is made of a conductive material.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
7
According to still further features in the described preferred embodiments the
apparatus further comprises a bath for holding a liquefied polymer, the bath
being in
fluid communication with the at least one dispensing element.
According to still further features in the described preferred embodiments the
apparatus further comprises a pump for transferring the liquefied polymer from
the
bath to the at least one dispensing element.
According to still further features in the described preferred embodiments the
apparatus further comprises a mechanism for translationally moving the object
relative
to the jet of the polymer fibers so as to uniformly distribute the polymer
fibers onto the
to object.
According to still further features in the described preferred embodiments the
apparatus further comprises the charged liquefied polymer and further wherein
a
medicament is mixed with the charged liquefied polymer and is co-dispensed
therewith through the at least one dispensing element, so as to coat the
object with an
electrospun medicated coat.
According to still further features in the described preferred embodiments the
apparatus further comprises a sprayer for distributing compact objects
constituting a
mendicant therein between the polymer fibers.
According to yet another aspect of the present invention there is provided a
2o method of treating a constricted blood vessel, the method comprising: (a)
providing a
stmt assembly; (b) dispensing a charged liquefied polymer through at least one
dispensing element within an electric field to thereby form a jet of polymer
fibers, and
moving the dispensing element relative to the stmt assembly so as to coat the
stmt
assembly with an electrospun coat; and (c) placing the stmt assembly in the
constricted blood vessel.
According to further features in preferred embodiments of the invention
described below, the method further comprises expanding the stent assembly so
as to
dilate tissues surrounding the stent assembly in a manner such that flow
constriction is
substantially eradicated.
3o According to still further features in the described preferred embodiments
the
motion of the at least one dispensing element is selected so as to establish a
spiral
motion of the jet of the polymer fibers about the stmt assembly, the spiral
motion
being characterized by a gradually deceasing radius.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
8
According to still further features in the described preferred embodiments the
method further comprises translationally moving the stmt assembly relative to
the jet
of the polymer fibers so as to uniformly distribute the polymer fibers onto
the stent
assembly.
According to still further features in the described preferred embodiments a
medicament is mixed with the charged liquefied polymer and is co-dispensed
therewith through the at least one dispensing element, so as to coat the
object with an
electrospun medicated coat.
According to still further features in the described preferred embodiments the
to medicament is dissolved in the charged liquefied polymer.
According to still further features in the described preferred embodiments the
medicament is suspended in the charged liquefied polymer.
According to still further features in the described preferred embodiments the
medicament is constituted by particles embedded in the polymer fibers.
is According to still further features in the described preferred embodiments
the
method further comprises constituting a mendicant into compact objects and
distributing the compact objects between the polymer fibers.
According to still further features in the described preferred embodiments the
medicament is heparin.
2o According to still further features in the described preferred embodiments
the
medicament is a radioactive compound.
According to still further features in the described preferred embodiments the
medicament is silver sulfadiazine.
According to still further features in the described preferred embodiments the
25 compact objects are capsules.
According to still further features in the described preferred embodiments the
compact objects are in a powder form.
According to still further features in the described preferred embodiments the
distributing of the compact objects is by spraying.
3o According to still further features in the described preferred embodiments
the
method further comprises providing at least one additional coat on the
electrospun
coat.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
9
The present invention successfully addresses the shortcomings of the presently
known configurations by providing a method and apparatus for coating a non-
rotary
object with an electrospun coat
Unless otherwise defined, all technical and scientific terms used herein have
the same meaning as commonly understood by one of ordinary skill in the art to
which
this invention belongs. Although methods and materials similar or equivalent
to those
described herein can be used in the practice or testing of the present
invention, suitable
methods and materials are described below. In case of conflict, the patent
specification, including definitions, will control. In addition, the
materials, methods,
to and examples are illustrative only and not intended to be limiting.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is herein described, by way of example only, with reference to
the accompanying drawings. With specific reference now to the drawings in
detail, it
is stressed that the particulars shown are by way of example and for purposes
of
illustrative discussion of the preferred embodiments of the present invention
only, and
are presented in the cause of providing what is believed to be the most useful
and
readily understood description of the principles and conceptual aspects of the
invention. In this regard, no attempt is made to show structural details of
the invention
2o in more detail than is necessary for a fundamental understanding of the
invention, the
description taken with the drawings making apparent to those skilled in the
art how the
several forms of the invention may be embodied in practice.
In the drawings:
FIG. 1 is a schematic illustration of a prior art electrospinning apparatus;
FIG. 2a is a flowchart diagram of a method of coating a non-rotary object with
an electrospun coat, according to a preferred embodiment of the present
invention;
FIGs. 2b-a are schematic illustrations of paths along which a dispensing
element can move, according to a preferred embodiment of the present
invention;
FIG. 2f is a schematic illustration of a spiral trajectory of a polymer fiber,
3o according to a preferred embodiment of the present invention;
FIG. 3 is a cross-sectional view of a stmt assembly according to a preferred
embodiment of the present invention;
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
FIG. 4a is an end view the stent assembly, according to a preferred
embodiment of the present invention;
FIG. 4b is an end view of a stent assembly which further comprises at least
one
adhesion layer, according to a preferred embodiment of the present invention;
5 FIG. 5 is a tubular supporting element which is designed and constructed for
dilating a constricted blood vessel in a body vasculature, according to a
preferred
embodiment of the present invention;
FIG. 6 is a portion of the tubular supporting element of Figure 5 comprising a
deformable mesh of metal wires, according to a preferred embodiment of the
present
10 invention;
FIG. 7 is a stmt assembly, manufactured according to the teachings of the
present invention, occupying a defective site in an artery;
FIG. 8 is a portion of a non-woven web of polymer fibers produced according
to a preferred embodiment of the present invention;
FIG. 9 is a portion of a non-woven web of polymer fibers which comprises a
pharmaceutical agent constituted by compact objects and distributed between
the
electrospun polymer fibers;
FIG. 10 is a schematic illustration of an apparatus for coating a non-rotary
object with an electrospun coat, according to a preferred embodiment of the
present
2o invention; and
FIG. 11 is a flowchart diagram of a method of treating a constricted blood
vessel, according to a preferred embodiment of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is of a method and apparatus for coating an object which
can be implantable medical device. Specifically, the present invention can be
used to
provide an electrospun coat to non-rotary objects, such as, but not limited
to, stems or
other implantable medical devices while being mounted on a delivery system
(e.g., a
stmt delivery system) or a portion thereof. The present invention is further
of a
3o method of treating a constricted blood vessel.
For purposes of better understanding the present invention, as illustrated in
Figures 2-11 of the drawings, reference is first made to the construction and
operation
of a conventional (i.e., prior art) electrospinning apparatus as illustrated
in Figure 1.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
11
Before explaining at least one embodiment of the invention in detail, it is to
be
understood that the invention is not limited in its application to the details
of
construction and the arrangement of the components set forth in the following
description or illustrated in the drawings. The invention is capable of other
embodiments or of being practiced or carried out in various ways. Also, it is
to be
understood that the phraseology and terminology employed herein is for the
purpose
of description arid should not be regarded as limiting.
Referring now to the drawings, Figure 1 illustrates a conventional
electrospinning apparatus for manufacturing a nonwoven material, generally
referred
to to herein as apparatus 1.
Apparatus 1 includes a dispenser 2 which can be, for example, a bath provided
with one or more capillary apertures 4. Dispenser 2 serves for storing the
polymer to
be spun in a liquid form (dissolved or melted). Dispenser 2 is positioned at a
predetermined distance from a precipitation electrode 6, defining a first axis
5
therebetween. Precipitation electrode 6 serves for forming a structure
thereupon.
Precipitation electrode 6 is typically manufactured in accordance with the
geometrical
properties of the final product which is to be fabricated. For example,
precipitation
electrode 6 can be a mandrel having a longitudinal axis 3 which can be used
for
manufacturing tubular structures.
2o Dispenser 2 is typically grounded, while precipitation electrode 6 is
connected
to a source of high voltage (not shown in Figure 1), preferably of negative
polarity,
thus forming an electric field between dispenser Z and precipitation electrode
6.
Alternatively, precipitation electrode 6 can be grounded while dispenser 2 is
connected
to a source of high voltage with positive polarity.
To generate a nonwoven material, the liquefied polymer is extruded, for
example under the action of hydrostatic pressure, or using a pump (not shown
in
Figure 1), through capillary apertures 4 of dispenser 2. As soon as meniscus
of the
extruded liquefied polymer forms, a process of solvent evaporation or cooling
starts,
which is accompanied by the creation of capsules with a semi-rigid envelope or
crust.
3o An electric field, occasionally accompanied by a unipolar corona discharge
in the area
of dispenser 2, is generated by the potential difference between dispenser 2
and
precipitation electrode 6. Because the liquefied polymer possesses a certain
degree of
electrical conductivity, the above-described capsules become charged. Electric
forces
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
12
of repulsion within the capsules lead to a drastic increase in hydrostatic
pressure. The
semi-rigid envelopes are stretched, and a number of point micro-ruptures are
formed
on the surface of each envelope leading to spraying of ultra-thin jets of
liquefied
polymer from dispenser 2.
s Under the effect of a Coulomb force, the jets depart from dispenser 2 and
travel
towards the opposite polarity electrode, i.e., precipitation electrode 6.
Moving with
high velocity in the inter-electrode space, the jet cools or solvent therein
evaporates,
thus forming a jet of polymer fibers, collected on the surface of
precipitation electrode
6, thus forming a non-woven structure thereupon. Tubular non-woven structures
are
to conventionally produced by rotating precipitation electrode 6 about
longitudinal axis 3
during the electrospinning process, so as to circularly coat precipitation
electrode 6.
Typical electrospinning processes (e.g., as employed by apparatus 1) suffer
from several limitations.
First, as will be appreciated by a skilled artisan, when precipitation
electrode 6
15 has a small radius of curvature, the polymer fibers tend to align axially
along
longitudinal axis 3. In such cases the resulting structure has an axial
strength which is
favored over the radial strength. Thus, small diameter products, have limited
radial
strength when manufactured via conventional electrospinning processes.
Second, conventional electrospinning processes for non-woven tubular
2o structures are limited to the manufacturing of hollow tubes. This is done
either by
coating precipitation electrode 6 by the electrospun coat or by mounting a
tubular
member on precipitation electrode 6 prior to the initiation of the
electrospinning
process. In any event, the final product, once removed from precipitation
electrode 6,
is hollow. However, it is often desired to produce structures having
additional
25 members designed to engage the internal volume of the structure, it is
recognized that
with prior art electrospinning techniques, such additional internal members
can only
be inserted into the non-woven structure after the structure is removed from
precipitation electrode 6. For example, with conventional electrospinning
processes, it
is not possible to coat a stmt if it is already mounted on a stmt delivery
system.
3o Third, in a typical electrospinning process the electric field, generated
between
dispenser 2 and precipitation electrode 6, is static and the charged polymer
fibers,
which tend to align with the field lines, move along static trajectories. This
limits the
capability to control fiber orientation hence the strength of the final
product.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
13
While conceiving the present invention it has been hypothesized, and while
reducing the present invention to practice it has been realized, that objects
can be
coated by allowing the dispensing element of the electrospinning apparatus to
move
along a predetermined path while keeping the objects in a non-rotary or static
state.
The advantage of the present embodiment in which the objects are non-rotary is
that
there is no need to mount the objects on a rotating electrode prior to the
electrospinning process, thus allowing the coating of non-hollow as well as
hollow
objects. For example, the present embodiment can be used for providing an
electrospun coat on stents or other medical implantable devices, either alone
or while
1o being mounted on a suitable delivery system, e.g., a stmt delivery system,
such as, but
not limited to, a catheter balloon. This embodiment is useful when it is
desired to
improve strength, form a mechanical barrier and/or incorporate medicaments
into
commercially available medical implantable devices which are typically
supplied by
the vendor as "one unit products" in which the medical implantable devices are
mounted on or integrated with additional members or devices.
Reference is now made to Figure 2a, which is a flowchart diagram of a method
of coating a non-rotary object, according to a preferred embodiment of the
present
invention. In a first step on the method, designated in Figure 2 by Block 7, a
charged
liquefied polymer is dispensed through at least one dispensing element within
an
2o electric field, to thereby form a jet of polymer fibers. In a second step
of the method,
designated by Block 8, the dispensing element is moved relative to the object
so as to
coat the object with the electrospun coat. While moving along the
predetermined path,
the dispensing elements) can change the direction and/or magnitude of the
electric
field. These changes can be tailored in accordance with the desired
orientation of the
polymer fibers on the object. As further detailed hereinabove.
As stated, the dispensing element can be moved along a predetermined path.
The path is preferably selected so as to coat the entire object or selected
portions
thereof, as desired. For example, referring, to Figures 2b-d, when the object
has a
tubular shape (e.g., a cylinder) the dispenser can be moved along a helix path
(Figure
2b), a circular path (Figure 2c), a zigzag path (Figure 2d-e) and the like.
The path and
the parameters characterizing the path are preferably selected according to
the desired
orientation of fibers on the object. Several sweeps of the dispensing element
along the
objects can be employed so as to improve the homogeneity of the electrospun
coat.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
14
The number of seeps is preferably selected according to the desired porosity
of the
coat, where larger number of sweeps corresponds to lower average pore size.
Additionally, the density of the fibers and/or the type of liquefied polymer
can be
changes from one sweep to the other thereby to provide a multilayer coat, as
further
detailed hereinunder.
The motion of the dispensing element can be supplemented by a translational
motion (e.g., reciprocation motion, harmonic motion, etc.) of the object
relative to the
jet of polymer fibers. This embodiment is particularly useful when the motion
path of
the dispensing element is planar (e.g., a circular path), such that upon
reciprocal travel
to of the object relative to the motion plane of the dispensing element the
fibers are re-
distributed along the object and the homogeneity of the coat is improved.
According to the electrospinning principles, the electrical field is generated
by
a potential difference between the dispensing element and the object. Typical
potential difference is from about 20 kV to about 50 kV. Such potential
difference can
be established, e.g., by grounding the dispensing element and placing the
object in a
negative potential or in any other electrostatic configuration which ensures
the motion
of the charged liquefied polymer from the dispensing element to the object.
When the
object comprises conductive parts (e.g., a metal mesh of a stmt) the
conductive parts
can be connected to a voltage source, preferably of negative polarity. When
the object
2o is non conductive, or if desired, the object can be mounted on a
precipitation electrode
(e.g., a mandrel), connected to a voltage source.
When the fibers moves in space they are subjected to friction forces which
result from collisions between molecules of the medium surrounding the object
(typically air) and molecules of the fibers. The higher the density of the
surrounding
medium the larger are the friction forces. According to a preferred embodiment
of the
present invention the velocity of the dispensing element is selected such that
the the
polymer fibers acquire a sufficient transverse velocity relative to the axis
defined by
the dispensing element and the object (see, e.g., axis S in Figure 1). A
typical linear
velocity of the dispensing element is from about 100 cm/sec to about 3000
cmlsec.
3o For a rotary motion of the dispensing element (e.g., helical, circular), a
typical rotation
frequency is from about 100 rpm to about 1200 rpm.
As used herein the term "about" refers to ~ 10 %.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
The trajectory of the polymer fibers in the medium surrounding the objects
thus depends on (i) the electrical force applied by the electric field; (ii)
the friction
force applied by molecules of the surrounding medium; and (iii) the transverse
velocity of the fibers. As will be appreciated by one of ordinary skill in the
art, when
5 the electrospinning process is performed in a vacuum, there is no friction
force and the
trajectory of the polymer fibers depends only on the electric force and the
transverse
velocity. Thus, when the electrospinning process is performed in gaseous
medium the
trajectory of the polymer fiber is curvilinear, while for a process performed
in a
vacuum, due to the lack of friction, the trajectory is substantially
rectilinear.
to Beside the transverse velocity of the fibers, they also accelerate under
the
influence of the electric field in the direction of the electric field lines.
Thus, the
direction of motion of the fibers at a given instant is the (vector) sum of
the transverse
velocity and the velocity acquired in the direction of the electric field. For
example,
when the dispensing element moves along a circular path, the jet of fibers
moves along
15 a spiral motion, characterized by a gradually deceasing radius. A
representative
example of a spiral trajectory is shown in Figure 2f.
It was found by the present inventors that although the polymer fibers have
relatively low mass per unit length, the momentum acquired by the fibers due
to
tangent movement becomes sufficient to oppose the electrical field perturbing
forces
and to stabilize the movement of the fibers in space. For a tubular object and
a
circular motion of the dispensing element, it was found that at the
aforementioned
circular frequencies, the acquired momentum of the fibers is sufficient to
provide a
coat in which the fibers have a predominant azimuthal spatial orientation. In
this
respect, higher frequencies result in higher is azimuthal orientation extent.
According
to a preferred embodiment of the present invention the motion characteristics
(e.g.,
path, linear velocity, frequency) of the dispensing element are selected such
that at
least 60 % of the polymer fibers, more preferably at least 80 %, most
preferably at
least 90 % has an azimuthal orientation with respected to the longitudinal
axis of the
object. Additionally or alternatively, the motion characteristics (e.g., path,
linear
3o velocity, frequency) of the dispensing element are selected such that the
electrospun
coat is capable of bearing a radial expansion of at least 300 %, more
preferably at least
400 %, most preferably at least 500 % without being ruptured.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
16
It was further found by the present inventors that the motion of the
dispensing
element substantially narrows the jet spraying angle, thereby producing more
concentrated jet resulting in a low average pore size of the final coat. The
jet angle
can further be narrowed by a judicious selection of the geometrical shape of
the
s dispensing element thereby the magnitude and direction of the electric field
near the
object and along the trajectory of the fibers. According to a preferred
embodiment of
the present invention the motion and/or shape of the dispensing element is
selected
such that the spraying angle is narrowed by at least 10 %, more preferably at
least
30 % and most preferably at least 60 %. Thus, the combination of the electric
force,
to friction force, transverse velocity and preferably the translational motion
of the objects
allows controlling the orientation, porosity as well as the density of the
final coat.
For example, in applications in which the electrospun coat is applied on a
stmt,
or other medical tubular implant, it is desired that the properties of the
coat are suitable
for implantation. Specifically, for high radial strength, a predominant
azimuthal
15 orientation of the fibers is preferred, which azimuthal orientation can be
obtained, as
stated, by selecting a circular motion for the dispensing element.
Additionally, for
blood vessel implants, such as stents and vascular prostheses, the porosity is
selected
so as to accommodate cells migrating from the surrounding tissues and to
facilitate the
proliferation of these cells while, at the same time, preventing undesired
chemical
2o materials and plaque debris from entering the blood vessel lumen during
placement of
the stent or prosthesis.
Furthermore, the controllable porosity of the present embodiment allows to
design local drug delivery elements, whereby the coat may be incorporated with
a
mendicant or another pharmaceutical agent. In such devices, the porosity of
the coat is
25 preferably designed both to bear the independent drug load and to serve as
a barrier
controlling the drug release rate.
The embodiments of the present invention can be used for coating expandable
tubular supporting elements of stems, as well as stmt assemblies which already
have a
preliminary coat. In any event, the above method can be used for providing
single as
3o well as multilayer coats, such as the coats disclosed in International
Patent Application
No. PCT/IL01/01171, the contents of which are hereby incorporated by
reference.
Reference is now to Figure 3 which is a schematic illustration of a cross-
sectional view of a scent assembly, coated using selected steps of the method
of the
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
17
present invention. The stmt assembly comprises an expendable tubular
supporting
element 10 and at least one coat 12, having a predetermined porosity. Coat 12
comprises an inner coat 14, lining an inner surface of element 10 and an outer
coat 16,
covering an outer surface of element 10. Figure 4a illustrates an end view of
the stmt
assembly, showing element 10, internally covered by inner coat 14 and
externally
covered by outer coat 16. With reference to Figure 4b, coat 12 may further
comprise
at least one adhesion layer 15, for adhering the components of the stmt
assembly as
further detailed hereinafter.
Each of inner 14 and outer 16 coats can be provided using the above method
to by moving the dispensing element relative to expandable supporting element
10.
Preferably, inner 14 and outer 16 coats are made of different liquefied
polymers and
have predetermined porosities, which may be different or similar as desired.
According to a preferred embodiment of the present invention, the liquefied
polymer
of inner 14 and/or outer 16 coats can be mixed with a mendicant or a
pharmaceutical
agent prior to the electrospinning process. The mendicant can be either
dissolved or
suspended in the liquefied polymer.
There is more than one way to provide outer coat 16. In one embodiment,
element 10 is mounted on a precipitation electrode (e.g., a mandrel), prior to
the
electrospinning process. In this embodiment, the precipitation electrode
function both
2o as a carrier for element 10 and as a conductive element to which a high
voltage is
applied to establish the electric field. As a consequence, the polymer fibers
emerging
from the dispensing element are projected toward the precipitation electrode
and form
outer coat 16 on tubular supporting element 10. This coating covers both the
metal
wires of element 10 and gaps between the wires.
In another embodiment, element 10 serves as a precipitation electrode. In this
embodiment, polymer fibers are exclusively attracted to the wires of tubulax
supporting element 10 exposing the gaps therebetween. The resultant coated
stmt
therefore has pores which serve for facilitating pharmaceutical agent delivery
from the
stmt assembly into body vasculature.
3o According to a preferred embodiment of the present invention inner coat 14
is
provided as follows. First, the electrospinning process is employed so as to
directly
coat the mandrel, so as to form inner coat 14 thereon. Once the mandrel is
coated, the
electrospinning process is temporarily ceased and element 10 is slipped onto
the
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
18
mandrel and drawn over inner coat 14. Outer coat 16 is then provided by
resuming the
electrospinning process onto element 10.
Since the operation for providing inner coat 14 demands a process cessation
for
a certain period, a majority of solvent contained in inner coat 14 may be
evaporated.
This may lead to a poor adhesion between the components of the stmt assembly,
once
the process is resumed, and might result in the coating stratification
following stmt
graft opening.
The present invention successfully addresses the above-indicated limitation by
two optimized techniques. According to one technique, the outer sub-layer of
inner
to coat 14 and the inner sub-layer of outer coat 16 are each made by
electrospinning with
upgraded capacity. A typical upgrading can may range from about 50 % to about
100 %. This procedure produce a dense adhesion layer made of thicker fibers
with
markedly increased solvent content. A typical thickness of the adhesion layer
ranges
between about 20 pm and about 30 ~tm, which is small compared to the overall
diameter of the stmt assembly hence does not produce considerable effect on
the coats
general parameters. According to an alternative technique, the adhesion layer
comprises an alternative polymer with lower molecular weight than the major
polymer, possessing high elastic properties and reactivity.
Other techniques for improving adhesion between the layers and tubular
2o supporting element 10 may also be employed. For example, implementation of
various adhesives, primers, welding, chemical binding in the solvent fumes can
be
used. Examples for suitable materials are silanes such as aminoethyaminopropyl
triacytoxysilane and the like.
The advantage of using the electrospinning method for fabricating inner coat
14 and outer coat 16 the is flexibility of choosing the polymer types and
fibers
thickness, thereby providing a final product having the required combination
of
strength, elastic .and other properties as delineated herein. In addition, an
alternating
sequence of the sub-layers forming at coat 12, each made of differently
oriented fibers,
determines the porosity distribution nature along the stmt assembly wall
thickness.
3o Still in addition, the electrospinning method has the advantage of allowing
the
incorporation of various chemical components, such as pharmaceutical agents,
to be
incorporated in the fibers by mixing the pharmaceutical agents in the
liquefied
polymers prior to electrospinning.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
19
Reference is now made to Figure 5 which is a schematic illustration of tubular
supporting element 10 designed and constructed for dilating a constricted
blood vessel
in the body vasculature. Element 10 expands radially thereby dilates a
constricted
blood vessel. According to a preferred embodiment of the present invention,
the
expansibility of the stmt assembly may be optimized by a suitable construction
of
element 10 and coat 12. The construction of element 10 will be described
first, with
reference to Figure 6, and the construction of coat 12 will be described
thereafter.
Hence, Figure 6 illustrates a portion of element 10 comprising a deformable
mesh of metal wires 18, which can be, for example, a deformable mesh of
stainless
l0 steel wires. When the stmt assembly is placed in the desired location in an
artery,
element 10 rnay be expanded radially, to substantially dilate the arterial
tissues
surrounding the stent assembly to eradicate a flow constriction in the artery.
The
expansion may be performed by any method known in the art, for example by
using a
balloon catheter or by forming element 10 from a material exhibiting
temperature-
activated shape, memory properties, such as Nitinol. According to a presently
preferred embodiment of the invention, the polymer fibers forming coat 12 are
elastomeric polymer fibers which stretch as element IO is radially expanded.
According to a preferred embodiment of the present invention inner coat 14 and
outer
coat 16 are coextensive with element 10, i.e., tubular supporting element 10
is
2o substantially coated. Alternatively, inner coat 14 and/or outer coat 16 may
be shorter
in length than element 10, in which case at least one end of element 10 is
exposed.
Reference is now made to Figure 7, which illustrates the stmt assembly
occupying a defective site 20 in an artery. The outer diameter of the stmt
assembly in
its unexpanded state, including outer coat 16, is such that it ensures
transporting of the
stmt assembly through the artery to defective site 20, for example by a
catheter. The
expending range of the stmt assembly is such that when in place at defective
site 20,
the expanded assembly then has a maximum diameter causing the arterial tissues
surrounding the stent assembly to be dilated to a degree eradicating the flow
constriction at the site.
3o Implantation of the stmt assembly in a blood vessel may result in disorders
in
the blood vessel, for example an injury inflicted on tissues of the blood
vessel upon the
implantation, restenosis, in-scent stenosis and hyper cell proliferation. To
treat such
injury or other disorders, coat 12 may comprise a medicament for delivery of
the
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
medicament into a body vasculature. Hence, coat 12 not only serves to graft
the
assembly to the artery but also functions as a reservoir for storing the
medicament to
be delivered over a prolonged time period. Within the above diameter
limitation, the
larger the aggregate volume of coat 12, the larger its capacity to store the
medicament.
5 Reference is now made to Figure 8 which illustrates a portion of a non-woven
web of polymer fibers produced according to a preferred embodiment of the
present
invention. Fibers 22, 24 and 26 intersect and are joined together at the
intersections,
the resultant interstices rendering the web highly porous. Since electrospun
fibers are
ultra-thin, they have an exceptionally large surface area, which allows a high
quantity
10 of pharmaceutical agents and medicaments to be incorporated thereon. The
surface
area of the electrospun polymer fibers approaches that of activated carbon,
thereby
making the non-woven web of polymer fibers an efficient local drug delivery
system.
The preferred mechanism of medicament release from the coat is by diffusion,
regardless of the technique employed to embed the medicament therein. The
duration
15 of therapeutic drug release in a predetermined concentration depends on
several
variants, which may be controlled during the manufacturing process. One
variant is
the chemical nature of the carrier polymer and the chemical means binding the
medicament to it. This variant may be controlled by a suitable choice of the
polymers) used in the electrospinning process. Another variant is the area of
contact
2o between the body and the medicament, which can be controlled by varying the
free
surface of the electrospun polymer fibers. Also affecting the duration of
medicament
release is the method used to incorporate the medicament within at least one
coat 12,
as is further described herein.
According to a preferred embodiment of the present invention, the coat
comprises a number of sub-layers. Depending on their destination, the sub-
layers can
be differentiated by fiber orientation, polymer type, medicament incorporated
therein
and desired release rate thereof. Thus, medicament release during the first
hours and
days following implantation may be achieved by incorporating a solid solution,
containing a medicament such as anticoagulants and antithrombogenic agents, in
a
3o sub-layer of readily soluble biodegradable polymer fibers. During the first
period
following implantation the medicament that releases includes anticoagulants
and
antithrombogenic agents.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
21
Referring now again to Figure 8, the medicament may be constituted by
particles 28 embedded in the electrospun polymer fibers forming a sub-layer of
at least
one coat 12. This method is useful for medicament release during the first
post-
operative days and weeks. To this end, the medicament can include
antimicrobials or
antibiotics, thrombolytics, vasodilators, and the like. The duration of the
delivery
process is effected by the type of polymer used for fabricating the
corresponding sub-
layer. Specifically, optimal release rate is ensured by using moderately
stable
biodegradable polymers.
Reference is now made to Figure 9 illustrating an alternative method for
to incorporating the medicament in the coat, ensuring medicament release
during the first
post-operative days and weeks. Thus, according to a preferred embodiment of
the
present invention, the medicament is constituted by compact objects 30
distributed
between the electrospun polymer fibers of the coat. Compact objects 30 may be
in any
known form, such as, but not limited to, moderately stable biodegradable
polymer
capsules.
The present invention is also provides a method of releasing medicament,
which may last, from several months to several years. According to a preferred
embodiment of the present invention the medicament is dissolved or
encapsulated in a
sub-layer made of biosatable fibers. The rate diffusion from within a
biostable sub-
layer is substantially slower, thereby ensuring a prolonged effect of
medicament
release. Medicaments suitable for such prolonged release include, without
limitation,
antiplatelets, growth-factor antagonists and free radical scavengers.
Thus, the sequence of medicament release and impact longevity of a certain
specific medicaments is determined by the type of drug-incorporated polymer,
the
method in which the medicament is introduced into the electrospun polymer
fibers, the
sequence of layers forming the coat, the matrix morphological peculiarities of
each
layer and the concentration of the medicament.
Reference is now made to Figure 10, which is a schematic illustration of an
apparatus 50 for coating a non-rotary object 52 with an electrospun coat,
according to
a preferred embodiment of the present invention. Apparatus 50 comprises at
least one
dispensing element 37 being at a potential difference relative to object 52,
dispensing
element 53 is capable of moving relative to object 52 while dispensing the
charged
liquefied polymer as further detailed hereinabove. Dispensing element 37 may
be for
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
22
example, an arrangement of electrodes or a rotatable ring 45 having at least
one
capillary 46, preferably radially oriented. Ring 45 can be made of a
dielectric or
conductive material as desired. Capillaries 46 are made of conductive material
and in
electrical communication thereamongst. Preferably, the number of capillaries
is from
1 capillary to more than 10 capillaries, more preferably 2-4 capillaries, most
preferably
3 capillaries. The diameter of ring 45 and the length of capillaries 46 are
preferably
selected such that the distance between object 52 and tip 51 of capillary 46
is from
about 100 mm to about 250 mm, more preferably from about 120 mm to about
180 mm, most preferably about 150 mm.
According to a preferred embodiment of the present invention dispensing
element 37 is connected to a shaft 47 having at least one arm 48. Arms 48 and
shaft
47 are preferably hollow elements to allow flow of the liquefied polymer
therethrough.
Alternatively a system of flexible tubes can be used to establish fluid
communication
between dispensing element 37 and a bath 41 which holds the liquefied polymer.
Shaft 47 is preferably positioned between one or more bearings 58 and serves
for
mechanically connecting dispensing element 37 with an electric drive 54.
Apparatus 50 may further comprise a mandrel 42 which may be connected to a
power supply 43 in embodiments in which mandrel 42 serves as conductive
electrodes. Mandrel 42 or object 52 (in embodiments in which mandrel 42 is not
used)
2o is preferably operatively associated with a mechanism 56 for
translationally moving
object 52 as further detailed hereinabove.
According to a preferred embodiment of the present invention apparatus 50
further comprises a pump 40, connected to bath 41 for drawing the liquid
polymer
stored in bath 41 into dispensing element 37. Apparatus 50 may further
comprise one
or more filters 49, through which the liquefied is transferred via shaft 47
and arm 48
into element 37.
Optionally and preferably, apparatus 50 comprises a sprayer 57 for
distributing
compact objects (e.g., objects 30) constituting a mendicant therein between
the
polymer fibers, as further detailed hereinabove.
Reference is now made to Figure 1 l, which is a flowchart diagram of a method
of treating a constricted blood vessel, according to a preferred embodiment of
the
present invention. In a first step a first step on the method, designated in
Figure 11 by
Block 60, a stmt assembly is provided. In a second step, designated by Block
62, a
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
23
charged liquefied polymer is dispensed through a moving dispensing element as
further detailed hereinabove. In a third step of the method, designated by
Block 64,
the stent assembly is placed in the constricted blood vessel, for example,
using a
catheter balloon or other stmt delivery system. In a forth step of the method,
designated by Block 66, the stmt assembly is preferably expanded so as to
dilate the
arterial tissues .surrounding the stmt assembly to a degree eradicating the
flow
constriction of the blood vessel.
It should be understood, that although the invention has been described in
conjunction with medical implants, other medical implants, not necessarily of
tubular
l0 structure, may be coated using the techniques of the present invention. For
example,
grafts and patches, which may be coated prior to procedure of implantation or
application can be drug-loaded and enjoy the advantages as described herein.
The coat may be made from any known biocompatible polymer. In the layers
which incorporate medicament, the polymer fibers are preferably a combination
of a
biodegradable polymer and a biostable polymer.
Representative examples of biostable polymers with a relatively low chronic
tissue response include, without limitation, polycarbonate based aliphatic
polyurethanes, siloxane based aromatic polyurethanes, polydimethylsiloxane and
other
silicone rubbers, polyester, polyoleflns, polymethyl- methacrylate, vinyl
halide
2o polymer and copolymers, polyvinyl aromatics, polyvinyl esters, polyamides,
polyimides, polyethers and many others that can be dissolved in appropriate
solvents
and electrically spun on the stmt.
Biodegradable fiber-forming polymers that can be used include poly (L-lactic
acid), poly (lactide-co-glycolide), polycaprolactone, polyphosphate ester,
poly
(hydroxy- butyrate), poly (glycolic acid), poly (DL-lactic acid), poly (amino
acid),
cyanocrylate, some copolymers and biomolecules such as DNA, silk, chitozan and
cellulose.
These hydrophilic and hydrophobic polymers which are readily degraded by
microorganisms and enzymes are suitable for encapsulating material for drugs.
In
3o particular, Polycaprolacton has a slower degradation rate than most other
polymers
and is therefore especially suitable for controlled-release of medicament over
long
periods of time scale ranging from about 2 years to about 3 years.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
24
Suitable pharmaceutical agents that can be incorporated in at least one coat
12
include heparin, tridodecylmethylammonium-heparin, epothilone A, epothilone B,
rotomycine, ticlopidine, dexamethasone, caumadin, and other pharmaceuticals
falling
generally into the categories of antithrombotic drugs, estrogens,
corticosteroids,
cytostatics, anticoagulant drugs, vasodilators, and antiplatelet drugs,
trombolytics,
antimicrobials or antibiotics, antimitotics, antiproliferatives, antisecretory
agents, non-
sterodial antiflammentory drugs, grow factor antagonists, free radical
scavengers,
antioxidants, radiopaque agents, immunosuppressive agents and radio-labeled
agents.
to It is expected that during the life of this patent many relevant
implantable
medical devices will be developed and the scope of the term implantable
medical
device is intended to include all such new technologies a priori.
Additional objects, advantages and novel features of the present invention
will
become apparent to one ordinarily skilled in the art upon examination of the
following
examples, which are not intended to be limiting. Additionally, each of the
various
embodiments and aspects of the present invention as delineated hereinabove and
as
claimed in the claims section below finds experimental support in the
following
examples.
EXAMPLES
Reference is now made to the following examples, which together with the
above descriptions illustrate the invention in a non limiting fashion.
Materials, Devices a~zd Methods
A Carbothane PC-3575A was purchased from Thermedics Polymer Products,
and was used for coating. This polymer has satisfactory fiber-forming
abilities, it is
biocompatible and is capable of lipophilic drug incorporation. A mixture of
dimethylformamide and toluene of ratio ranging from 1:1 to 1:2 was used as a
solvent
3o in all experiments.
A PHD 2000 syringe pump was purchased from Harvard Apparatus and was
used for feeding the polymer solutions into the in the electrospinning
apparatus. The
dispensing element included a hollow ring, 400 mm in diameter, made of
stainless
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
tube. Three capillaries, 25 mm in length and 0.5 mm in internal diameter, were
symmetrically disposed the internal surface of a ring. The flow-rate at each
capillary
was between 1 ml/min and 5 ml/min. The dispensing element was connected to the
pump with flexible polytetrafluorethylene tubes and was grounded. A rod of
polished
5 stainless steel, 1.05 mm in diameter and 60 mm in length, was used as a
mandrel and
was kept at a potential of 30 kV. The mandrel was positioned in the
geometrical
center of the ring, about 175 mm from the capillaries ends.
The ring was rotated at a frequency of 60-1000 rpm and the mandrel was
actuated to a longitudinal reciprocation motion, 30 - 40 mm in amplitude and
12-15
to motions/min in frequency.
EXAMPLE 1
A stent assembly, 16 mm in length was manufactured using a stainless-steel
stmt, 3.4 mm in diameter in its expanded state and 1.1 mm in diameter in its
non-
is expanded state, as the tubular supporting element. The used stainless-steel
stmt is
typically intended for catheter and balloon angioplasty. For adhesion
upgrading in
polymer coating, the stmt was exposed to 160-180 kJ/m2 corona discharge,
rinsed by
ethyl alcohol and deionized water, and dried in a nitrogen flow. The solution
parameters were: concentration of 8 %, viscosity of 560 cP and conductivity of
20 0.8 mS. For the pharmaceutical agent, heparin in tetrahydrofurane solution
was used,
at a concentration of 250 Ulml. The polymer to heparin-solution ratio was
100:1. The
dispensing element rotating frequency was 60 rpm.
A two step coating process was employed. First, the mandrel was coated by
electrospinning with polymer fiber layer the thickness of which was about 20
~,m.
25 Once the first step was accomplished, the tubular supporting element was
put over the
first coat hence an inner coating for the tubular supporting element was
obtained.
Second, an outer coating was applied to the outer surface of the tubular
supporting
element. The thickness of the outer coat was about 40~,m.
The stent assembly was removed from the mandrel, and was placed for about
30 seconds into the saturated dimethylformamide (DNTF) vapor atmosphere at 45
°C,
so as to ensure upgrading the adhesion strength between the inner coat and the
outer
coat. To remove solvent remnants, the stmt was exposed to partial vacuum
processing
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
26
for about 24 hours. Once the coating process was completed, the coated stent
was
subjected to elasticity tests by radial inflation.
The fibers of the resultant coat had a random orientation. The coat was
capable
of bearing a 320 % radial expansion without being ruptured.
EXAMPLE 2
A stmt assembly was manufactured as described in Example 1, with an
increased rotation frequency of 600 rpm. About 80 % of the fibers of the
resultant
coat had an azimuthal orientation. The coat was capable of bearing a 410 %
radial
expansion without being ruptured.
EXAMPLE 3
A stmt assembly was manufactured as described in Example 1, with an
increased rotation frequency of 1000 rpm. The resultant coat was more uniform
and
the fibers were mostly azimuthally oriented: about 95 % of the fibers had an
azimuthal
orientation, and the coat was capable of bearing a 550 % radial expansion
without
being ruptured.
EXAMPLE 4
2o A stmt assembly was manufactured as described in Example 2, with a heparin
solution at a concentration of 380 U/ml mixed with 15 % poly (DL-Lactide-CD-
Glycolide) solution in chloroform. The change in the pharmaceutical agent did
not
affect the quality of the coat.
EXAMPLE 5
A stmt assembly was manufactured from the materials described in Example
1, with 60 wm inner coat of biodegradable heparin-loaded polymer, and an outer
coat
of polyurethane fibers completing an overall coat thickness of 100 ~,m. The
rotation
frequencies of 60 rpm and 1000 rpm were used for providing the inner and outer
coats,
3o respectively. The resulting inner coat had a predominant axial
(longitudinal)
orientation, whereas the outer coat had a predominant azimuthal orientation,
thus
verifying that fiber orientation can be controlled by the dispensing element
rotation
frequency.
CA 02541520 2006-04-04
WO 2005/032400 PCT/IL2004/000917
27
It is appreciated that certain features of the invention, which are, for
clarity,
described in the context of separate embodiments, may also be provided in
combination in a single embodiment. Conversely, various features of the
invention,
which are, for brevity, described in the context of a single embodiment, may
also be
s provided separately or in any suitable subcombination.
Although the invention has been described in conjunction with specific
embodiments thereof, it is evident that many alternatives, modifications and
variations
will be apparent to those skilled in the art. Accordingly, it is intended to
embrace all
such alternatives, modifications and variations that fall within the spirit
and broad
scope of the appended claims. All publications, patents and patent
applications
mentioned in this specification are herein incorporated in their entirety by
reference
into the specification, to the same extent as if each individual publication,
patent or
patent application was specifically and individually indicated to be
incorporated herein
by reference. In addition, citation or identification of any reference in this
application
shall not be construed as an admission that such reference is available as
prior art to
the present invention.
