U.S. patent application number 17/516530 was filed with the patent office on 2022-02-17 for electrospun material covered medical appliances and methods of manufacture.
The applicant listed for this patent is Merit Medical Systems, Inc.. Invention is credited to Bart Dolmatch, Zeke Eller, John William Hall, Robert S. Kellar, Wayne L. Mower, Rachel Lynn Simmons.
Application Number | 20220047783 17/516530 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-17 |
United States Patent
Application |
20220047783 |
Kind Code |
A1 |
Hall; John William ; et
al. |
February 17, 2022 |
ELECTROSPUN MATERIAL COVERED MEDICAL APPLIANCES AND METHODS OF
MANUFACTURE
Abstract
A medical appliance or prosthesis may comprise one or more
layers of electrospun nanofibers, including electrospun polymers.
The electrospun material may comprise layers including layers of
polytetrafluoroethylene (PTFE). Electrospun nanofiber mats of
certain porosities may permit tissue ingrowth into or attachment to
the prosthesis.
Inventors: |
Hall; John William; (North
Salt Lake, UT) ; Dolmatch; Bart; (Dallas, TX)
; Eller; Zeke; (Plano, TX) ; Kellar; Robert
S.; (Flagstaff, AZ) ; Simmons; Rachel Lynn;
(North Salt Lake, UT) ; Mower; Wayne L.;
(Bountiful, UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merit Medical Systems, Inc. |
South Jordan |
UT |
US |
|
|
Appl. No.: |
17/516530 |
Filed: |
November 1, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13827790 |
Mar 14, 2013 |
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17516530 |
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61703037 |
Sep 19, 2012 |
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International
Class: |
A61L 31/14 20060101
A61L031/14; A61L 31/04 20060101 A61L031/04; A61K 9/70 20060101
A61K009/70; D01D 5/00 20060101 D01D005/00; D01F 6/12 20060101
D01F006/12; A61L 27/16 20060101 A61L027/16; A61L 27/34 20060101
A61L027/34; A61L 27/56 20060101 A61L027/56; A61L 31/10 20060101
A61L031/10; D04H 1/728 20060101 D04H001/728; D04H 3/073 20060101
D04H003/073; A61F 2/82 20060101 A61F002/82; B05D 1/00 20060101
B05D001/00 |
Claims
1. A covered stent, comprising: a frame comprising a midbody and a
flare zone; and a cover coupled to the frame, wherein the cover
comprises an electrospun polytetrafluoroethylene (PTFE) material,
and wherein the frame and the cover are configured to promote
biocompatibility of the stent.
2. The stent of claim 1, wherein the midbody comprises a first apex
to apex length, wherein the flare zone comprises a second apex to
apex length, wherein the first apex to apex length is less than the
second apex to apex length, and wherein a resistance to radial
compression of the midbody is greater than a resistance to radial
compression of the flare zone.
3. The stent of claim 2, wherein the flare zone is configured to
engage with healthy tissue of a blood vessel and minimize trauma to
the healthy tissue.
4. The stent of claim 2, wherein the first apex to apex length
ranges from 2.0 mm to 30.0 mm, and wherein the second apex to apex
length ranges from 2.1 mm to 30.1 mm.
5. The stent of claim 1, wherein an end of the flare zone comprises
an alternating pattern of long apexes and short apexes about a
perimeter of the frame, wherein the alternating pattern is
configured to distribute an outwardly directed force along a length
of a vessel wall, and wherein the end of the flare zone is
configured to be a-traumatic to healthy tissue of the vessel
wall.
6. The stent of claim 1, wherein the cover includes a scallop
shaped end, wherein the scallop shaped end is configured to reduce
infolding of tissue of a vessel wall when an outside diameter of
the stent is greater than an inside diameter of a vessel.
7. A covered stent, comprising: a frame; and a cover coupled to the
frame, wherein the cover comprises an electrospun PTFE material,
and wherein an inner layer and an outer layer of the cover are each
configured to be cell permeable.
8. The covered stent of claim 7, wherein the inner layer is
configured to promote attachment of a coating of epithelial cells,
wherein the coating is configured to prevent thrombosis within a
lumen of the stent, and wherein the outer layer is configured to
permit healing of tissue adjacent the stent.
9. The covered stent of claim 7, wherein a porosity of the inner
layer and a porosity of the outer layer each range from 30% to
80%.
10. The covered stent of claim 7, wherein an average pore size of
the inner layer and an average pore size of the outer layer each
range from 1 micron to 12 microns.
11. The covered stent of claim 7, wherein a thickness of the inner
layer and a thickness of the outer layer each range from 20
micrometers to 100 micrometers.
12. The covered stent of claim 7, wherein the inner layer and the
outer layer comprise a plurality of fibers, and wherein an average
diameter of the plurality of fibers ranges from 50 nanometers to 3
micrometers.
13. The covered stent of claim 7, wherein the inner layer and the
outer layer are each configured to allow an average cell
penetration depth of greater than 98% of a thickness of the
layer.
14. The covered stent of claim 7, wherein the inner layer and the
outer layer are configured to produce an average fibrous capsule
thickness of less than 35 micrometers.
15. The covered stent of claim 7, wherein the cover is configured
to filter blood, wherein the inner layer and the outer layer are
configured to permit transmural migration of blood plasma and to
prevent transmural migration of red blood cells.
16. The covered stent of claim 15, wherein a middle layer is
configured to prevent transmural migration of cells, and wherein
the middle layer is configured to prevent restenosis of a
vessel.
17. The stent of claim 16, wherein the middle layer is configured
to prevent transmural fluid migration, and wherein the middle layer
is configured to contain a fluid within the stent.
18. A method of promoting biocompatibility of a stent, comprising:
promoting endothelial cell growth on a luminal surface of the
stent; reducing a tissue inflammatory response to the stent; or
resisting fibrous capsule formation adjacent the stent; wherein the
stent comprises a cover comprising an electrospun PTFE material,
the cover comprising: a porosity ranging from 30% to 80%; an
average pore size ranging from 1 micron to 12 microns; a thickness
ranging from 20 micrometers to 100 micrometers; and a plurality of
fibers having an average diameter ranging from 50 nanometers to 3
micrometers.
19. The method of claim 18, wherein promoting endothelial cell
growth comprises reducing turbulent flow within the stent.
20. The method of claim 18, wherein reducing an inflammatory
response comprises reducing macrophage and foreign body giant cell
counts adjacent the stent.
21. The method of claim 20, wherein reducing macrophage and foreign
body giant cell counts is configured to comprises an H-score of
less than 100.
22. The method of claim 18, wherein resisting fibrous capsule
formation comprises a fibrous capsule having a thickness of any one
of less than 35 micrometers, less than 30 micrometers, less than 25
micrometers, less than 20 micrometers, and less than 15
micrometers.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/827,790, filed on Mar. 14, 2013 and titled,
"Electrospun Material Covered Medical Appliances and Methods of
Manufacture," which claims priority to U.S. Provisional Application
No. 61/703,037 filed on Sep. 19, 2012 titled "Electrospun Material
Covered Medical Appliances and Methods of Manufacture," both of
which are hereby incorporated by reference in their entireties.
TECHNICAL FIELD
[0002] The present disclosure relates generally to medical devices.
More specifically, the present disclosure relates to medical
appliances or other prostheses, particularly those made of,
constructed from, or covered or coated with electrospun materials
including polymers such as polytetrafluoroethylene (PTFE).
BRIEF DESCRIPTION OF THE DRAWINGS
[0003] The embodiments disclosed herein will become more fully
apparent from the following description and appended claims, taken
in conjunction with the accompanying drawings. These drawings
depict only typical embodiments, which will be described with
additional specificity and detail through use of the accompanying
drawings in which:
[0004] FIG. 1 is a schematic illustration of one embodiment of an
electrospinning apparatus.
[0005] FIG. 2 is a schematic illustration of another embodiment of
an electrospinning apparatus.
[0006] FIG. 3A is a perspective view of a covered stent.
[0007] FIG. 3B is a cross-sectional view of the covered stent of
FIG. 3A taken through line 3B-3B.
[0008] FIG. 4A is a perspective view of an electrospun covering on
a mandrel.
[0009] FIG. 4B is a perspective view of the covering of FIG. 4A
partially removed from the mandrel.
[0010] FIG. 4C is a perspective view of the covering of FIG. 4A
repositioned on the mandrel.
[0011] FIG. 4D is a perspective view of a scaffolding structure
wound around the covering and mandrel of FIG. 4C.
[0012] FIG. 4E is a perspective view of the scaffolding structure
of FIG. 4D with a second electrospun covering.
[0013] FIG. 5 is a perspective view of a covered stent including
cuffs.
[0014] FIG. 6 is a front view of a medical appliance frame
structure.
[0015] FIG. 7A is a detail view of a portion of the frame of FIG.
6.
[0016] FIG. 7B is a detail view of an end of the frame of FIG.
6.
[0017] FIG. 7C is an alternative configuration of a portion of the
frame of FIG. 6.
[0018] FIG. 8 is an end view of a frame having flared ends.
[0019] FIG. 9 is a front view of a frame having flared ends.
[0020] FIG. 10 is a front view of a wire being shaped to form a
frame.
[0021] FIG. 11A is a cross-sectional view of two body lumens with a
stent disposed therein.
[0022] FIG. 11B is a side view of a portion of a stent comprising a
tapered segment.
[0023] FIG. 11C is a side view of another embodiment of a stent
comprising a tapered segment.
[0024] FIG. 12A is an SEM (scanning electron micrograph)
(950.times.) of a mat electrospun from a first polymer
dispersion.
[0025] FIG. 12B is an SEM (950.times.) of a mat electrospun from a
second polymer dispersion.
[0026] FIG. 12C is an SEM (950.times.) of a mat electrospun from a
third polymer dispersion.
[0027] FIG. 12D is an SEM (950.times.) of a mat electrospun from a
fourth polymer dispersion.
[0028] FIG. 12E is an SEM (950.times.) of a mat electrospun from a
fifth polymer dispersion.
[0029] FIG. 13A is an SEM (950.times.) of a mat electrospun from a
first polymer dispersion-water mixture.
[0030] FIG. 13B is an SEM (950.times.) of a mat electrospun from a
second polymer dispersion-water mixture.
[0031] FIG. 13C is an SEM (950.times.) of a mat electrospun from a
third polymer dispersion-water mixture.
[0032] FIG. 13D is an SEM (950.times.) of a mat electrospun from a
fourth polymer dispersion-water mixture.
[0033] FIG. 13E is an SEM (950.times.) of a mat electrospun from a
fifth polymer dispersion-water mixture.
[0034] FIG. 13F is an SEM (950.times.) of a mat electrospun from a
sixth polymer dispersion-water mixture.
[0035] FIG. 13G is an SEM (950.times.) of a mat electrospun from a
seventh polymer dispersion-water mixture.
[0036] FIG. 13H is an SEM (950.times.) of a mat electrospun from an
eighth polymer dispersion-water mixture.
[0037] FIG. 14A is an SEM (180.times.) of a cooked, electrospun
fluorinated ethylene propylene (FEP) coating over an electrospun
PTFE layer.
[0038] FIG. 14B is an SEM (950.times.) of the construct of FIG.
13A.
[0039] FIG. 15 is a graph showing average inflammatory score
(H-Score=0-300) of various PTFE materials following 2 weeks of
subcutaneous implantation in a mouse model.
[0040] FIG. 16 is a graphical representation of the differences in
cellular penetration between electrospun PTFE and expanded PTFE
(ePTFE) materials. Percent of cellular penetration is shown on the
y-axis.
[0041] FIG. 17 is a representative trichrome-stained histology
light microscopy image of electrospun PTFE material (MM1 E-OD).
Relative distance of cell penetration is marked by the double black
arrow. The dashed lines circumscribe the middle layer of the
electrospun PTFE material. (Scale bar=100 um.)
DETAILED DESCRIPTION
[0042] Medical appliances may be deployed in various body lumens
for a variety of purposes. Stents may be deployed, for example, in
the central venous system for a variety of therapeutic purposes
including the treatment of occlusions within the lumens of that
system. The current disclosure may be applicable to stents or other
medical appliances designed for the central venous (CV) system,
peripheral vascular (PV) stents, abdominal aortic aneurism (AAA)
stents, bronchial stents, esophageal stents, biliary stents,
coronary stents, gastrointestinal stents, neuro stents, thoracic
aortic endographs, or any other stent or stent graft. Further, the
present disclosure may be equally applicable to other prostheses
such as grafts. Any medical appliance comprised of materials herein
described may be configured for use or implantation within various
areas of the body, including vascular, cranial, thoracic,
pulmonary, esophageal, abdominal, or ocular application. Examples
of medical appliances within the scope of this disclosure include,
but are not limited to, stents, vascular grafts, stent grafts,
cardiovascular patches, reconstructive tissue patches, hernia
patches, general surgical patches, heart valves, sutures, dental
reconstructive tissues, medical device coverings and coatings,
gastrointestinal devices, blood filters, artificial organs, ocular
implants, and pulmonary devices, including pulmonary stents. For
convenience, many of the specific examples included below reference
stents. Notwithstanding any of the particular medical appliances
referenced in the examples or disclosure below, the disclosure and
examples may apply analogously to any prosthesis or other medical
appliance.
[0043] As used herein, the term "stent" refers to a medical
appliance configured for use within a bodily structure, such as
within a body lumen. A stent may comprise a scaffolding or support
structure, such as a frame, and/or a covering. Thus, as used
herein, "stent" refers to both covered and uncovered scaffolding
structures.
[0044] It will be readily understood that the components of the
embodiments as generally described and illustrated in the Figures
herein could be arranged and designed in a wide variety of
different configurations. Thus, the following more detailed
description of various embodiments, as represented in the Figures,
is not intended to limit the scope of the disclosure, but is merely
representative of various embodiments. While the various aspects of
the embodiments are presented in drawings, the drawings are not
necessarily drawn to scale unless specifically indicated.
[0045] The phrases "connected to," "coupled to," and "in
communication with" refer to any form of interaction between two or
more entities, including mechanical, electrical, magnetic,
electromagnetic, fluid, and thermal interaction. Two components may
be coupled to each other even though they are not in direct contact
with each other. For example, two components may be coupled to each
other through an intermediate component.
[0046] The directional terms "proximal" and "distal" are used
herein to refer to opposite locations on a stent or another medical
appliance. The proximal end of an appliance is defined as the end
closest to the practitioner when the appliance is disposed within a
deployment device that is being used by the practitioner. The
distal end is the end opposite the proximal end, along the
longitudinal direction of the appliance, or the end furthest from
the practitioner. It is understood that, as used in the art, these
terms may have different meanings once the appliance is deployed
(i.e., the "proximal" end may refer to the end closest to the head
or heart of the patient depending on application). For consistency,
as used herein, the ends labeled "proximal" and "distal" prior to
deployment remain the same regardless of whether the appliance is
deployed. The longitudinal direction of a stent is the direction
along the axis of a generally tubular stent. In embodiments where a
stent or another appliance is composed of a metal wire structure
coupled to one or more layers of a film or sheet-like components,
such as a polymer layer, the metal structure is referred to as the
"scaffolding" or "frame" and the polymer layer as the "covering" or
"coating." The terms "covering" or "coating" may refer to a single
layer of polymer, multiple layers of the same polymer, or layers
comprising distinct polymers used in combination. Furthermore, as
used herein, the terms "covering" and "coating" refer only to a
layer or layers that are coupled to a portion of the scaffold;
neither term requires that the entire scaffold be "covered" or
"coated." In other words, medical appliances wherein a portion of
the scaffold may be covered and a portion remain bare are within
the scope of this disclosure. Finally, any disclosure recited in
connection with coverings or coatings may analogously be applied to
medical devices comprising one or more "covering" layers with no
associated frame or other structure. For example, a hernia patch
comprising any of the materials described herein as "coatings" or
"coverings" is within the scope of this disclosure regardless of
whether the patch further comprises a frame or other structure.
[0047] Medical device coverings may comprise multilayered
constructs, comprised of two or more layers which may be serially
applied. Further, multilayered constructs may comprise
nonhomogeneous layers, meaning adjacent layers have differing
properties. Thus, as used herein, each layer of a multilayered
construct may comprise a distinct layer, either due to the distinct
application of the layers or due to differing properties between
layers.
[0048] Additionally, as used herein, "tissue ingrowth" and
"cellular penetration" refer to any presence or penetration of a
biological or bodily material into a component of a medical
appliance. For example, the presence of body tissues (e.g.,
collagen, cells, and so on) within an opening or pore of a layer or
component of a medical appliance comprises tissue ingrowth into
that component. Further, as used herein, "attachment" of tissue to
a component of a medical appliance refers to any bonding or
adherence of a tissue to the appliance, including indirect bonds.
For example, tissue of some kind (e.g., collagen) may become
attached to a stent covering (including attachment via tissue
ingrowth) and another layer of biologic material (such as
endothelial cells) may, in turn, adhere to the first tissue. In
such instances, the second biologic material (endothelial cells in
the example) and the tissue (collagen in the example) are
"attached" to the stent covering.
[0049] Furthermore, through the present disclosure, certain fibrous
materials (such as electrospun materials) may be referred to as
inhibiting or promoting certain biological responses. These
relative terms are intended to reference the characteristics of the
fibrous materials with respect to non-fibrous materials or
coatings. Examples of non-fibrous coatings include non-fibrous
polytetrafluoroethylene (PTFE) sheets, other similarly formed
polymers, and the like. Mats or other structures comprised of
serially deposited fibers, such as microfibers and/or nanofibers
are also examples of fibrous materials within the scope of this
disclosure.
[0050] Serially deposited fiber mats or lattices refer to
structures composed at least partially of fibers successively
deposited on a collector, on a substrate, on a base material,
and/or on previously deposited fibers. In some instances the fibers
may be randomly disposed, while in other embodiments the alignment
or orientation of the fibers may be somewhat controlled or follow a
general trend or pattern. Regardless of any pattern or degree of
fiber alignment, because the fibers are deposited on the collector,
substrate, base material, and/or previously deposited fibers, the
fibers are not woven, but rather serially deposited. Because such
fibers are configured to create a variety of structures, as used
herein, the terms "mat" and "lattice" are intended to be broadly
construed as referring to any such structure, including tubes,
spheres, sheets, and so on. Furthermore, the term "membrane" as
used herein refers to any structure comprising serially deposited
fibers having a thickness which is smaller than at least one other
dimension of the membrane. Examples of membranes include, but are
not limited to, serially deposited fiber mats or lattices forming
sheets, strips, tubes, spheres, covers, layers, and so forth.
Examples of serially deposited fibers include electrospun fibers
and rotational spun fibers. Expanded PTFE does not comprise
serially deposited fibers as used herein.
[0051] Lumens within the circulatory system are generally lined
with a single layer (monolayer) of endothelial cells. This lining
of endothelial cells makes up the endothelium. The endothelium acts
as an interface between blood flowing through the lumens of the
circulatory system and the inner walls of the lumens. The
endothelium, among other functions, reduces or prevents turbulent
blood flow within the lumen. The endothelium plays a role in many
aspects of vascular biology, including atherosclerosis, creating a
selective barrier around the lumen, blood clotting, inflammation,
angiogenesis, vasoconstriction, and vasodilation.
[0052] A therapeutic medical appliance that includes a covering of
porous or semi-porous material may permit the formation of an
endothelial layer onto the porous surface of the blood contact side
of the medical device. Formation of an endothelial layer on a
surface, or endothelialization, may increase the biocompatibility
of an implanted device. For example, a stent that permits the
formation of the endothelium on the inside diameter (blood
contacting surface) of the stent may further promote healing at the
therapeutic region and/or have longer term viability. For example,
a stent coated with endothelial cells may be more consistent with
the surrounding body lumens, thereby resulting in less turbulent
blood flow or a decreased risk of thrombosis, or the formation of
blood clots. A stent that permits the formation of an endothelial
layer on the inside surface of the stent may therefore be
particularly biocompatible, resulting in less trauma at the point
of application, fewer side effects, and/or longer term device
viability. Medical appliances including a covering of porous or
semi-porous material may be configured to inhibit or reduce
inflammatory responses by the body toward the tissue contacting
side of the medical appliance, for example. Mechanisms such as an
inflammatory response by the body toward the medical appliance may
stimulate, aggravate, or encourage negative outcomes, such as
neointimal hyperplasia. For example, a device configured to permit
tissue ingrowth and/or the growth or attachment of endothelial
cells onto the blood contacting side of the device may reduce the
likelihood of negative flow characteristics and blood clotting.
Similarly, a device so configured may mitigate the body's
inflammatory response toward the material on, for example, the
tissue or non-blood contacting side of the device. By modulating
the evoked inflammatory response, negative outcomes such as the
presence of bioactive inflammatory macrophages and foreign body
giant cells may be reduced. This may aid in minimizing the chemical
chain of responses that may encourage fibrous capsule formation
surrounding the device and events stimulating neointimal
hyperplasia.
[0053] Electrospun materials, such as those described herein, may
be used to comprise portions of medical appliances, such as stents,
patches, grafts, and so forth. The present disclosure is applicable
to any implantable medical appliance, notwithstanding any specific
examples included below. In other words, though particular medical
appliances, such as stents or patches, may be referenced in the
disclosure and examples below, the disclosure is also analogously
applicable to other medical appliances, such as those that comprise
a covering or layer of polymeric material.
[0054] In some embodiments, electrospun nanofibers (and/or
microfibers) may be configured to permit interaction with nanoscale
(and/or microscale) body structures, such as endothelial cells.
Electrospinning refers generally to processes involving the
expulsion of flowable material from one or more orifices, the
material forming fibers that are subsequently deposited on a
collector, and wherein there is an electrostatic charge between any
of the collector, the material, and the orifice. Examples of
flowable materials include dispersions, solutions, suspensions,
liquids, molten or semi-molten material, and other fluid or
semi-fluid materials.
[0055] For example, one embodiment of an electrospinning process
comprises loading a polymer solution or dispersion into a syringe
coupled to a syringe pump. The material is forced out of the
syringe by the pump in the presence of an electric field. The
material forced from the syringe may elongate into fibers that are
then deposited on a grounded collection apparatus. The system may
be configured such that the material forced from the syringe is
electrostatically charged, and thus attracted to the grounded
collector. Exemplary methods and systems for electrospinning
medical devices can be found in U.S. patent application Ser. No.
13/360,444, filed on Jan. 27, 2012 and titled "Electrospun PTFE
Coated Stent and Method of Use," which is hereby incorporated by
reference in its entirety.
[0056] Electrospinning may be configured to create mats, tubes, or
other structures comprised of elongate fibers, including nanofibers
(i.e., fibers that are smaller than 1 micron in diameter) or
microfibers (i.e., fibers that are between 1 micron and 1
millimeter in diameter). In some instances the fibers may be
randomly disposed, while in other embodiments the alignment or
orientation of the fibers may be somewhat controlled or follow a
general trend or pattern. Regardless of any pattern or degree of
fiber alignment, as the fibers are deposited on a collector or on
previously deposited fibers, the fibers are not woven, but rather
are serially deposited on the collector or other fibers. Because
electrospinning may be configured to create a variety of
structures, as used herein, the terms "mat" and "non-woven mat or
material" are intended to be broadly construed as referring to any
such electrospun structure, including tubes, spheres, and so
on.
[0057] The present disclosure relates to medical appliances that
may have, in certain embodiments, metal scaffolding covered with at
least one layer of electrospun material, such as electrospun PTFE.
Additionally, the present disclosure relates to medical appliances
formed of electrospun materials that may not have scaffolding
structures or have scaffolding structures that are not made of
metal. It will be appreciated that, though particular structures
and coverings are described below, any feature of the scaffolding
or covering described below may be combined with any other
disclosed feature without departing from the scope of the current
disclosure.
[0058] FIGS. 1 and 2 schematically illustrate certain embodiments
of electrospinning apparatuses. FIGS. 3A and 3B illustrate an
embodiment of a covered medical appliance. FIGS. 4A-4E illustrate
certain steps in a process of manufacturing a multi-layered
construct of electrospun materials. FIG. 5 illustrates an
embodiment of a medical appliance that includes cuffs at each end
of a stent. FIGS. 6-10 illustrate aspects of frames configured for
use in connection with medical appliances. Finally, FIGS. 11A-12H
are scanning electron micrographs (SEMs) of exemplary electrospun
materials. Again, regardless of whether a medical appliance
illustrated in any particular figure is illustrated with a
particular covering or coating, or without any covering or coating
at all, any embodiment of a medical appliance may be configured
with any of the combinations of coverings or coatings shown or
described herein.
[0059] Again, electrospinning generally references to processes
configured to deposit fibers (including microfibers and nanofibers)
on a collection apparatus in the presence of an electric field.
Variations in the material to be electrospun (including density,
viscosity, composition, and so forth) as well as variations in the
electric field or other parameters of the electrospinning apparatus
may be used to control or affect the deposition of fibers on the
collector.
[0060] Membranes composed of electrospun PTFE or other materials
may have a microstructure composed of numerous fibers crossing each
other at various and random points. The electrospinning process may
be configured to control the thickness of the mat, the density of
the fiber pattern, the thickness of the fibers, the permeability of
the mat, and so forth. In some instances, a thicker mat may tend to
be less permeable, due to successive layers of fibers occluding the
pores and openings of layers below.
[0061] FIG. 1 illustrates an electrospinning apparatus 100. This
Figure, as well as FIG. 2, discussed below, is intended to
schematically illustrate the operation of an electrospinning
apparatus, and is not meant to limit the particular structure,
shape, or arrangement of any electrospinning apparatus components
within the scope of this disclosure. The illustrated apparatus 100
comprises a syringe 110 coupled to a syringe pump 115. In other
embodiments, other pumps or devices may be configured to expel
material from an orifice. A high voltage source 120 may be in
communication with the syringe 110. Material to be electrospun may
be discharged from the syringe 110 through operation of the syringe
pump 115, and deposited on a collector 125. In the illustrated
embodiment, the collector is grounded, thus creating an
electrostatic potential between the high voltage source (and
components in communication therewith) and the collector 125.
Material discharged from the syringe 110 may form fibers 130 that
are subsequently deposited on the collector 125. In some
embodiments, the fibers 130 may be charged with respect to the
grounded collector 125, and thus attracted to the collector 125 by
electrostatic forces.
[0062] In one exemplary procedure, the syringe 110 may be loaded
with a polymer dispersion and the syringe pump 115 configured to
disburse the material at a constant rate. In one exemplary
procedure this rate was set at 0.1 ml of material per minute. The
syringe 110 was configured with a metal tip that was connected to
the positive lead of the high voltage source 120. The collector 125
was placed about 7 inches from the syringe tip, and grounded. The
voltage differential contributed in forcing the material from the
syringe 110 to the collector 125 in nanoscale fibers.
[0063] The apparatus 100 may be utilized to create a mat of
electrospun fibers deposited on the collector 125. In the
illustrated embodiment, the collector 125 comprises a flat plate.
In other embodiments, the collector may comprise other shapes, such
as rods, spheres, curved surfaces, and so forth. Thus, in some
embodiments, the collector 125 may be configured such that
structures such as rods, tubes, or spheres of electrospun fibers
are created.
[0064] In some embodiments, the apparatus 100 may be utilized to
create a mat of electrospun fibers by first filling the syringe 110
with a flowable material. In some instances polymer dispersions,
including aqueous dispersions or polymer solutions, may be used.
The syringe pump 115 may then be operated such that the dispersion,
or other flowable material, is forced out of the syringe 110.
Molecules, including polymer chains, may tend to disentangle and/or
align as the material is forced through an orifice of the syringe
110. In some embodiments the orifice of the syringe 110 may
comprise a cannula configured with a quick connection, such as a
luer connection, allowing for rapid exchange of various cannula
sizes.
[0065] As the dispersion is expelled from the syringe 110, the
stream or jet of material may elongate, forming a relatively small
diameter fiber of material. Further, in some embodiments, the
material may be electrically charged with respect to the collector
125. Thus, the material may be drawn to the collector 125 by
electrostatic forces. The electrostatic forces may tend to stretch
and/or elongate the material as the fibers 130 begin to form. The
electrostatic forces may further affect the deposition of the
fibers 130 on the collector 125. In some embodiments, the strength
of the electrostatic field may be varied in connection with
controlling the deposition of fibers 130 on the collector 125.
[0066] Additionally, certain components of the dispersion, such as
the dispersion medium or solvent, may partially or fully evaporate
as the material is drawn into the fibers 130. In embodiments
utilizing flowable materials that have no solvent, such as molten
material, there may be no evaporation as the material is drawn into
the fibers 130.
[0067] Thus, the fibers 130 eventually contact, and are deposited
on, the collector 125. The electrostatic forces, as well as the
inertia of the material discharged from the syringe 110 and/or
other forces such as drag on the fibers 130, may interact as the
fibers 130 are deposited, causing the fibers 130 to be disposed in
random patterns on the collector 125. In some embodiments, air
currents may be introduced (for example through the use of fans) to
partially control the deposition of the fibers 130 on the collector
125.
[0068] In embodiments utilizing certain flowable materials, the
fibers 130 may then be removed from the collector 125 and sintered,
or sintered and then removed. For example, sintering may be
applicable to PTFE fibers, including PTFE fibers electrospun from a
dispersion. The sintering process may set or bond the structure of
the mat and remove any remaining water or other dispersion medium
or solvent.
[0069] In some embodiments, the mat may be treated at a first
temperature to remove solvents and a second temperature to sinter
the mat. For example, a PTFE mat spun from an aqueous dispersion
may be first treated at a temperature below the sintering
temperature of PTFE in order to remove any remaining water. For
example, the mat may be heated to about 200 degrees C. to remove
any remaining water in the mat. Further, other materials such as
solvents or fiberizing agents may be evaporated or otherwise driven
off at this stage. In some embodiments--as further detailed
below--a PTFE dispersion may be mixed with polyethylene oxide (PEO)
prior to electrospinning the mat. Treating the spun mat at
temperatures such as 200 degrees C. may force off remaining PEO as
well as water. In some embodiments the PTFE mat may then be
sintered at about 385 degrees C. In other embodiments, PTFE
sintering may be completed at temperatures from about 360 degrees
C. to about 400 degrees C., and/or at temperatures in excess of the
crystalline melting point of the PTFE (about 342 degrees C.). In
other instances the mat may only be heated to the sintering
temperature, removing the remaining water and/or PEO while
simultaneously sintering the PTFE. Additionally or alternatively,
in some embodiments solvents or other materials may be removed by
rinsing the mat.
[0070] Sintering may set the structure of the mat even if the
temperature at which the material is sintered is not sufficient to
cause cross-linking of the polymer chains. PTFE sintering may
create solid, void-free, PTFE fibers.
[0071] The distance between the syringe 110 and the collector 125
may impact the diameter of the fibers 130 and/or the deposition of
the fibers 130 on the collector 125. In some embodiments,
variations to the degree of the electrostatic potential between
these components may also impact the fiber diameter in connection
with the distance between components.
[0072] Processes such as the exemplary process described above may
be utilized to create structures comprised of small diameter
fibers, including nanofibers. The fiber mat may then be
incorporated into a medical appliance configured for implantation
in the human body. Some such structures, including nanofiber
structures, may be configured to permit tissue ingrowth and/or
endothelial growth or attachment on the mat. For example, the mat
may be configured with openings within the fibers or similar
structures configured to permit interaction with tissue and/or
cells. As further detailed below, the percent porosity of a fiber
mat, the thickness of the mat, and the diameter of the fibers
comprising the mat may each be configured to create a fiber mat
with desired properties, including mats that tend to permit or
resist tissue ingrowth and/or endothelial growth or attachment.
[0073] A number of variables may be controlled to affect the
properties of an electrospun mat. Some of these variables include
the strength of the electrostatic charge; the viscosity of the
solution, dispersion, or other flowable material; the temperature
of the syringe 110; introduced air currents; the thickness of the
mat; and so on. In the case of fibers electrospun from molten
material, the melt flow index (MFI) of the material may also impact
the nature of the spun mat. In some embodiments, materials with an
MFI of from about 1 g/10 min to about 5000 g/10 min, including from
about 200 g/10 min to about 1500 g/10 min and from about 10 g/10
min to about 30 g/10 min, may tend to form fibers when spun.
[0074] In other embodiments an electrospun mat may be configured to
resist tissue ingrowth into or through the mat. In such
embodiments, the mat may be configured with very small pores, or
essentially no pores at all, thus preventing tissue ingrowth into
or through the mat. Certain medical appliances may be constructed
partially of electrospun materials configured to permit tissue
ingrowth and/or endothelial growth or attachment and partially of
electrospun materials configured to resist tissue ingrowth and/or
attachment. Characteristics of the electrospun fiber mat, such as
porosity and average pore size, may be controlled during the
electrospinning process to create certain mats that permit tissue
ingrowth and/or endothelial growth or attachment and other mats
that resist or are impermeable to tissue ingrowth and/or
attachment.
[0075] In some embodiments, a PTFE dispersion may be used to
electrospin a mat or another structure comprised of PTFE
nanofibers. Furthermore, in some exemplary embodiments PEO may be
added to the PTFE dispersion prior to electrospinning the material.
The PEO may be added as a fiberizing agent, to aid in the formation
of PTFE fibers within the dispersion or during the process of
electrospinning the material. In some instances the PEO may more
readily dissolve in the PTFE dispersion if the PEO is first mixed
with water. In some examples this increased solubility may reduce
the time needed to dissolve PEO in a PTFE dispersion from as long
as multiple days to as little as 30 minutes. After the material is
electrospun onto a collector, the material may then be sintered as
further described below. In some instances the sintering process
will tend to set or harden the structure of the PTFE. Furthermore,
as described above, sintering may also eliminate the water and PEO,
resulting in a mat of substantially pure PTFE. Additionally, as
also described above, the mat may first be heat treated at a
temperature below the sintering temperature of the PTFE, in order
to remove water and/or PEO from the mat. In some embodiments this
step may be completed at about 200 degrees C.
[0076] The water, PEO, and PTFE amounts may be controlled to
optimize the viscosity, PEO/PTFE ratio, or other properties of the
mixture. In some instances adding water to the PEO before mixing
with the PTFE dispersion may aid in reducing the number of solid
chunks or gels in the mixture, lower the preparation time for the
mixtures, and reduce the time needed for the combined mixture to
solubilize.
[0077] In one exemplary process, a 60 wt % PTFE water dispersion
was mixed with PEO and water as follows. First, 5 ml of water was
added to 1.4 g of PEO. The water and PEO were mixed until the PEO
was fully dissolved and the solution created a thick gel. 30 ml of
60 wt % PTFE was then added to the PEO/water mixture. The combined
solution was then allowed to sit or mix in a non-agitating jar
roller until the solution achieved homogeneity. In other examples,
the water, PEO, and PTFE amounts may be controlled to optimize the
viscosity, PEO/PTFE ratio, or other properties of the mixture. In
some instances adding water to the PEO before mixing with the PTFE
dispersion may aid in reducing the number of large solid chunks in
the mixture, lower the preparation time for the mixtures, and
reduce the time needed for the combined mixture to solubilize. In
other embodiments each of these materials, or sub-combinations
thereof, may be placed in a jar roller for about three to about
five days, after which time the mixture may be filtered through a 5
micron filter. Filtration may remove and/or break up any chunks or
gels in the mixture. Other filters, for example 1 micron filters,
may likewise be used.
[0078] A variety of materials may be electrospun to form structures
for use in medical appliances. Exemplary materials that may be
electrospun for use in implantable appliances include PTFE,
fluorinated ethylene propylene (FEP), Dacron or polyethylene
terephthalate (PET), polyurethanes, polycarbonate polyurethanes,
polypropylene, Pebax, polyethylene, biological polymers (such as
collagen, fibrin, and elastin), and ceramics.
[0079] Furthermore, additives or active agents may be integrated
with the electrospun materials, including instances where the
additives are directly electrospun with other materials. Such
additives may include radiopaque materials such as bismuth oxide,
antimicrobial agents such as silver sulfadiazine, antiseptics such
as chlorhexidine or silver, and anticoagulants such as heparin.
Organic additives or components may include fibrin and/or collagen.
In some embodiments, a layer of drugs or other additives may be
added to an electrospun appliance during manufacture. Additionally,
some appliances may be constructed with a combination of synthetic
components, organic components, and/or active ingredients including
drugs, including embodiments wherein an appliance is comprised of
alternating layers of these materials. Moreover, in some
embodiments a medical appliance may consist of layers of
electrospun materials configured to control the release of a drug
or another active layer disposed between such layers. Active layers
or ingredients such as drugs or other active agents may be
configured to reduce or otherwise modify or influence the
biological response of the body to the implantation of the medical
appliance.
[0080] Additionally, in some embodiments the material supplied to
the syringe 110 may be continuously supplied (for example by a feed
line), including embodiments where the syringe 110 is pressurized
or supplied by a pressurized source. Additionally, other discharge
mechanisms (such as a pump) may be used to discharge material to be
electrospun. Further, in some embodiments the material may be
heated near or above its melting point prior to electrospinning,
including embodiments wherein the material is melted and not
dispersed in a solvent. Thus, in some embodiments, electrospinning
molten material does not include the use of solvents; therefore
there is no need to remove solvents from the mat at a later step in
the process. In some instances the material may be supplied to the
syringe or other reservoir as pellets that are heated and melted
within the reservoir.
[0081] Another schematic embodiment of an electrospinning apparatus
is shown in FIG. 2. It shows an apparatus 200, analogous to that
shown in FIG. 1. It will be appreciated by one of skill in the art
having the benefit of this disclosure that analogous components of
the two apparatuses may be interchangeable and that disclosure
provided in connection with each embodiment may be applicable to
the other and vice versa.
[0082] FIG. 2 is a schematic diagram of an electrospinning
apparatus 200 comprising a syringe 210 coupled to a syringe pump
215. A high voltage source 220 may be in communication with the
syringe 210. Material to be electrospun may be discharged from the
syringe 210 through operation of the syringe pump 215, and
deposited on a collector 225. As with the embodiment of FIG. 1, in
the embodiment of FIG. 2, the collector is grounded, thus creating
an electrostatic potential between the high voltage source 220 (and
components in communication therewith) and the collector 225.
Material discharged from the syringe 210 may form fibers 230 that
are subsequently deposited on the collector 225. Again, in some
embodiments, the fibers 230 may be charged with respect to the
grounded collector 225, and thus attracted to the collector 225 by
electrostatic forces.
[0083] As compared to the apparatus 100 of FIG. 1, in the
embodiment of FIG. 2 the collector 225 comprises a rotating mandrel
226 as opposed to a flat plate. In other embodiments, other shapes
or types of collectors may be used. Thus, any collection device or
apparatus is within the scope of this disclosure, regardless of the
particular size, shape, or orientation of the collector. In some
embodiments, a collector may comprise multiple elements, such as
multiple cylinders or plates. In still other embodiments, the
collector may comprise a rotating belt (not shown), configured to
facilitate electrospinning of a continuous sheet of material.
[0084] In the embodiment of FIG. 2, the collector 225 comprises a
mandrel 226 that may be configured to rotate about its longitudinal
axis. In embodiments wherein such a mandrel is configured to rotate
during the electrospinning process, the system may be configured to
produce a seamless tube of electrospun material on the mandrel 226.
Additionally, some embodiments may comprise more than one mandrel
for use in connection with the electrospinning system. In the
illustrated embodiment, the mandrel 226 is disposed horizontally.
In another exemplary embodiment, the mandrel 226 may be disposed
vertically. In some embodiments, the rotational speed of the
mandrel 226 may affect the degree to which fibers deposited thereon
tend to be aligned.
[0085] In addition to horizontal mandrels, further embodiments may
comprise mandrels disposed in any relative position. Mandrels
mounted in any disposition may be configured as stationary
collection devices or configured to rotate. Additionally,
combinations of mandrels in a variety of positions may be used
simultaneously. Furthermore, in some embodiments one or more
mandrels may be configured for use in connection with a vacuum
system. For example, openings in the surface of the mandrel, such a
micro-porous mandrel, may tend to draw fibers toward the mandrel in
instances where the interior of the mandrel has lower pressure than
the exterior of the mandrel. Additionally, in some embodiments fans
or other devices may be configured to create air currents to direct
or otherwise influence the deposition of fibers on the mandrel.
[0086] In embodiments wherein the mandrel 226 is configured to
rotate, the spinning motion of each mandrel 226 may tend to deposit
the fibers 230 around the entire surface of the mandrel 226. Thus,
as the fibers 230 are deposited on the mandrel 226, a seamless tube
of nanofiber material may form on the mandrel 226. The density of
the fibers 230, the thickness of the mat, and other characteristics
may be controlled by such variables as the distance from the
syringe 210 to the mandrel 226, the magnitude of the electrostatic
charge, the rotational speed of the mandrel 226, the orientation of
the mandrel 226, the characteristics of the solution being spun,
and so forth. In some instances, mats of electrospun material
formed on a spinning mandrel 226 may thus comprise a tubular
membrane having no seam and substantially isotropic properties. In
some instances the collection mandrel 226 may rotate at rates
between about 1 RPM and about 10,000 RPM during the electrospinning
process, including rates from about 1500 RPM to about 5000 RPM or
at about 5000 RPM for more aligned fibers and from about 50 RPM to
about 500 RPM or at about 250 RPM for more random fiber
orientation.
[0087] Furthermore, controlling the rotational speed of the mandrel
226 may influence both the density of the mat formed on the mandrel
226 and the general alignment of the fibers 230 in the mat. For
instance, in some embodiments utilizing vertical mandrels, the
faster the mandrel 226 is spinning the more the fibers 230 may tend
to be deposited in-line with other fibers 230. Further, the
relative density of the fibers 230, for example, as measured by
percent porosity, may be controlled in part by the rotational speed
of the mandrel 226.
[0088] As further detailed in connection with FIGS. 4A-4E, once the
fibers 230 are electrospun onto the mandrel 226 the fibers 230 may
be sintered. In some embodiments a scaffolding structure, such as a
stent wire, may also be on the mandrel 226, and the fibers 230
electrospun directly onto the mandrel 226 and scaffolding
structure.
[0089] In addition to mandrels, some systems may be configured to
form a continuous sheet of electrospun material, including mats
from about 1 meter to about 9 meters wide, such as mats of about 3
meters wide. Also mats from about 1 foot wide to about 1 meter wide
(as well as larger or smaller mats) may be formed. In some
instances, a sintering oven may be positioned such that as the mat
moves away from the electrospinning apparatus (for example, on the
belt) the mat enters the oven and is sintered. The sintered mat may
then be collected onto a spool. Further, in some embodiments, the
entire spool may then be cut into smaller widths, forming strips of
material. For example, strips from about 0.1 inch wide to about 2
inches wide may be formed. Additionally, smaller strips, for
example about 0.1 inch wide, or larger strips, for example about 12
inches wide, may be formed. Such strips may be utilized for the
construction of tubular appliances by wrapping the strips around a
mandrel. The strips may overlap and/or may be wound such that the
tube formed does not have a distinct seam along the length of the
tube. In some instances, the mat may be wound in multiple layers
around the mandrel. Further, the mat formed may be relatively thin,
or film-like. The thickness of the covering formed on the mandrel
(and other characteristics such as porosity) may be controlled by
the number of layers of film wound onto the mandrel. Film layers of
differing materials may also be added to create a covering with
particular properties. For example, Kapton and/or FEP may be added
to increase strength in some instances.
[0090] In some embodiments, electrospun tubular medical devices,
such as stents, may comprise one or multiple bifurcations or
branches. Thus, medical devices that comprise a single lumen that
splits or bifurcates into two or more lumens are within the scope
of this disclosure. Likewise, medical appliances comprising a main
lumen with one or multiple branch lumens extending from the wall of
the main lumen are within the scope of this disclosure. For
example, a thoracic stent--configured for deployment within the
aorta--may comprise a main lumen configured to be disposed in the
aorta and branch lumens configured to extend into side branch
vessels originating at the aorta. Similarly, in some embodiments
such stents may alternatively be configured with access holes in
the main lumen configured to allow access (possibly for additional
stent placement) and flow from the main vessel to any branch
vessels extending therefrom.
[0091] In some embodiments, a bifurcated medical appliance may be
manufactured by first creating a bifurcated mandrel in which the
bifurcated mandrel portions are removable from the portion of the
mandrel coinciding with the main lumen. The leg or branch portions
of the mandrel may be splayed 180 degrees apart with a common axis
of rotation. Thus, in some embodiments, the entire mandrel may form
a T-shape. The entire mandrel may then be rotated about the axis of
the leg portions and electrospun fibers collected on the leg
portions of the mandrel. The mandrel may then be oriented to rotate
about the axis of the main lumen portion of the mandrel, and any
unwanted fibers disposed while spinning on the bifurcated leg
portions may be wiped off. The mandrel may then be rotated about
the axis of the main lumen portion and fibers collected on the main
lumen portion of the mandrel. The entire mandrel may then be placed
in an oven and sintered. The mandrel portions associated with the
bifurcated legs may then be removed from the leg or branch portions
of the appliance, and the single lumen mandrel portion subsequently
removed from the spun appliance. The appliance may then be placed
on or within a frame structure, such as a stent frame. A dip,
spray, or film coating (such as of FEP or PTFE) may then be applied
over the construct to create an impervious layer and/or to further
bond the frame to the spun portion of the appliance.
[0092] In any of the exemplary embodiments or methods disclosed
herein, in instances where the nanofibers are formed of PTFE, the
sintering temperature may be from about 360 degrees C. to about 400
degrees C., including at temperatures of about 385 degrees C. or at
temperatures above the crystalline melting temperature of the PTFE,
or about 342 degrees C. Similarly, for other materials, sintering
may be done at or above the crystalline melting temperature of
other spun polymers. Again, either prior to or as part of the
sintering process, heat treating may be configured to remove PEO
and/or water, in instances where the PTFE or other polymer was
combined with such elements prior to spinning the mat.
[0093] FIGS. 3A and 3B illustrate an exemplary medical appliance: a
stent 302. The stent 302 comprises a scaffolding structure 320 and
a covering comprising an inner layer 325, an outer layer 330, and a
tie layer 335. In other embodiments, a stent covering may have more
or fewer layers than the illustrated embodiment, including
embodiments with only one covering layer. Again, disclosure recited
herein with respect to specific medical appliances, such as stents,
may also be applicable to other medical appliances.
[0094] The cover of the stent 302 of FIG. 3A comprises a flat end
321 and a scalloped end 322. At the flat end 321 of the illustrated
embodiment, the cover of the stent 302 is cut substantially
perpendicular to the longitudinal axis of the stent 302. At the
scalloped end 322, the cover of the stent 302 comprises cut away,
or scalloped, portions at the end of the stent 302. Scalloped ends
may be configured to reduce infolding of the stent cover at the
ends. For example, in some instances, a stent may have a larger
diameter than a vessel in which it is deployed. Thus, the vessel
may partially compress the stent radially. In some instances this
radial compression may create folds or wrinkles in flat cut stent
covers. These folds may then impede blood flow or lead to clotting
within the vessel. Scalloped ends may reduce the occurrence of
infolding at the end of a radially compressed stent. It is within
the scope of this disclosure to use either type of end on any end
of any stent.
[0095] Membranes composed of electrospun mats may have a
microstructure composed of many fibers crossing each other at
various and random points. The electrospinning process may control
the thickness of this structure and thereby the relative
permeability of the mat. As more and more fibers are electrospun
onto a mat, the mat may both increase in thickness and decrease in
permeability (due to successive layers of strands occluding the
pores and openings of layers below). Certain details of this
microstructure are shown in FIGS. 11A-12H, which are discussed in
more detail below.
[0096] Mats produced in connection with the present disclosure may
be described by three general parameters: percent porosity, mat
thickness, and fiber diameter. Each of these parameters may impact
the nature of the mat, including the tendency of the mat to permit
tissue ingrowth and/or endothelial attachment or the tendency of
the mat to resist tissue ingrowth or endothelial attachment. Each
of these parameters may be optimized with respect to each other to
create a mat having particular characteristics.
[0097] Percent porosity refers to the percent of open space to
closed space (or space filled by fibers) in a fiber mat. Thus, the
more open the mat is, the higher the percent porosity measurement.
In some instances, percent porosity may be determined by first
obtaining an image, such as an SEM, of an electrospun material. The
image may then be converted to a "binary image," or an image
showing only black and white portions, for example. The binary
image may then be analyzed and the percent porosity determined by
comparing the relative numbers of each type of binary pixel. For
example, an image may be converted to a black and white image
wherein black portions represent gaps or holes in the electrospun
mat while white portions represent the fibers of the mat. Percent
porosity may then be determined by dividing the number of black
pixels by the number of total pixels in the image. In some
instances, a code or script may be configured to make these
analyses and calculations.
[0098] In some embodiments, percent porosities from about 30% to
about 80% may be configured to permit tissue ingrowth into the
layer and/or permit endothelial growth or attachment on the layer,
including mats of about 40% to about 60%, mats of about 45% to
about 50%, or mats of about 50% porosity. Less open layers may be
configured to resist such ingrowth and/or attachment. Because the
fibers comprising the mat are deposited in successive layers, the
second parameter, mat thickness, may be related to porosity. In
other words, the thicker the mat, the more layers of fibers and the
less porous the mat may be. In some embodiments, mats from about 20
micrometers to about 100 micrometers may be configured for use in
connection with the present disclosure, including mats from about
40 micrometers to about 80 micrometers. Finally, the third
parameter, fiber diameter, may be a measurement of the average
fiber diameter of a sample in some instances. In some embodiments
fiber diameters from about 50 nanometers to about 3 micrometers may
be used in connection with the present disclosure. Notwithstanding
these or other specific ranges included herein, it is within the
scope of this disclosure to configure a mat with any combination of
values for the given parameters.
[0099] In some embodiments the "average pore size" of the mat may
be used as an alternative or additional measurement of the
properties of the mat. The complex and random microstructure of
electrospun mats presents a challenge to the direct measurement of
the average pore size of the mat. Average pore size can be
indirectly determined by measuring the permeability of the mat to
fluids using known testing techniques and instruments. Once the
permeability is determined, that measurement may be used to
determine an "effective" pore size of the electrospun mat. As used
herein, the "pore size" of an electrospun mat refers to the pore
size of a membrane that corresponds to the permeability of the
electrospun mat when measured using ASTM standard F316 for the
permeability measurement. This standard is described in ASTM
publication F316, "Standard Test Methods for Pore Size
Characteristics of Membrane Filters by Bubble Point and Mean Flow
Pore Test," which is incorporated herein by reference. In some
instances this test can be used as a quality control after
configuring a mat based on the three parameters (percent porosity,
thickness, and fiber diameter) discussed above.
[0100] In some applications it may be desirable to create a medical
appliance such as stent 302 with an outer layer 330 that is
substantially impermeable. Such an impermeable outer layer 330 may
decrease the incidence of lumen tissue surrounding the stent 302
growing into or attaching to the stent 302. This may be desirable
in applications where the stent 302 is used to treat stenosis or
other occlusions; an impermeable outer layer 330 may prevent tissue
from growing into or through the material toward or into the lumen
of the stent 302 and reblocking or restricting the body lumen. In
some embodiments a substantially impermeable outer layer 330 may be
produced by using electrospun mats with a percent porosity from
about 0% to about 50%, including about 25%; a thickness from about
20 micrometers to about 100 micrometers, including from about 40
micrometers to about 80 micrometers; and fiber diameters from about
50 nanometers to about 3 micrometers.
[0101] Additionally, or alternatively, a substantially impermeable
mat may have an average pore size of about 0 microns to about 1.5
microns. In other embodiments, an impermeable layer may have an
average pore size of less than about 0.5 micron. In yet other
embodiments, an impermeable layer may have an average pore size of
less than about 1 micron. In some embodiments, the impermeable
layer may be a layer other than the outer layer, such as a tie
layer, an intermediate layer, or an inner layer.
[0102] In one example, a medical appliance such as stent 302 may be
covered with an electrospun PTFE inner layer 325 and an electrospun
PTFE outer layer 330. The outer layer 330 may be configured to be
substantially impermeable to tissue ingrowth and/or attachment. In
other embodiments the impermeability of the stent 302 may be
provided by a tie layer 335 disposed between the outer layer 330
and the inner layer 325. For example, a substantially impermeable
layer may be formed of FEP that is applied, for example, as a film,
spray, or dip coating between electrospun layers of PTFE.
Furthermore, FEP may be electrospun with a small average pore size
to create a substantially impermeable layer. In some embodiments
both the outer layer 330 and the tie layer 335 may be configured to
be substantially impermeable.
[0103] Dip coatings may be applied by dipping a portion of a layer
or construct in a polymer dispersion. For example, a PTFE layer may
be dip coated on a construct by adding 20 ml of water to 50 ml of a
60 wt % PTFE dispersion to thin the dispersion. A fiber mat may
then be dipped in the solution to coat the mat. The dip coat may
then be sintered at 385 degrees C. for 15 minutes. Other
concentrations of PTFE dispersions for dip coatings are also within
the scope of this disclosure.
[0104] Further, an FEP layer may be dip coated on a construct by
adding 20 ml of water to 50 ml of a 55 wt % dispersion to thin the
dispersion. A fiber mat may then be dipped in the solution to coat
the mat. The dip coat may then be cooked, for example, at 325
degrees C. for 15 minutes. Other concentrations of FEP dispersions
for dip coatings are also within the scope of this disclosure.
Additionally, polymer dispersions may be sprayed or otherwise
applied onto a surface (such as a fiber mat) to coat the surface.
Such coatings may be heat treated after application.
[0105] In some embodiments, more or less water, for example from
about 10 ml to about 50 ml, may be added to similar amounts and
concentrations of the dip dispersions above to thin the
dispersions. Additionally, substances other than, or in addition
to, water may be used to thin a dispersion for dip coating. For
example, a surfactant or a solvent may be used. In some such cases
the surfactant or solvent may later be removed from the construct,
including embodiments where it is allowed to evaporate when the
coat is sintered or cooked. Alcohols, glycols, ethers, and so forth
may be so utilized.
[0106] In some embodiments it may be desirable to create a medical
appliance such as stent 302 with an outer layer 330 that is more
porous. A porous outer layer 330 may permit healing and the
integration of the prosthesis into the body. For instance, tissue
of the surrounding lumen may grow into the porous outer diameter or
attach to the outer diameter layer. This tissue ingrowth may
permit, modulate, and/or influence healing at the therapy site. In
some embodiments a porous outer layer 330 may be formed of
electrospun PTFE.
[0107] In certain embodiments a relatively porous inner layer 325
may be desirable. This layer may or may not be used in conjunction
with a substantially impermeable outer layer 330. A relatively
porous inner layer 325 may permit tissue ingrowth and/or
endothelial attachment or growth on the inside diameter of the
stent 302 that may be desirable for any combination of the
following: healing, biocompatibility, prevention of thrombosis,
and/or reducing turbulent blood flow within the stent. In some
embodiments the inner layer 325 may be comprised of a mat, such as
an electrospun PTFE mat, having a percent porosity of about 40% to
about 80%, including about 50%; a thickness of about 20 micrometers
to about 100 micrometers, including from about 40 micrometers to
about 80 micrometers; and fiber diameters from about 50 nanometers
to about 3 micrometers.
[0108] Additionally, or alternatively, the mat may be comprised of
an electrospun mat, such as PTFE, with an average pore size of
about 1 micron to about 12 microns, such as from about 2 microns to
about 8 microns, about 3 microns to about 5 microns, or about 3.5
microns to about 4.5 microns.
[0109] FIG. 3B illustrates a cross-sectional view of the stent 302
of FIG. 3A, again comprising a scaffolding structure 320 and
covering comprising an inner layer 325, an outer layer 330, and a
tie layer 335. Though in the illustration of FIG. 3B the tie layer
335 is shown at the same "level" as the scaffolding structure 320,
the tie layer 335 may be above or below the scaffolding structure
320 in some embodiments. Further, as shown in FIG. 3B, each layer
of the covering may be disposed so that there are no voids between
layers.
[0110] In some embodiments the tie layer 335 may be configured to
promote bonding between the outer layer 330 and the inner layer
325. In other embodiments the tie layer 335 may further be
configured to provide certain properties to the stent 302 as a
whole, such as stiffness or tensile strength. The tie layer 335 may
thus be configured as a reinforcing layer. In some embodiments,
expanded PTFE may be configured as a reinforcing layer. ePTFE may
be anisotropic, having differing properties in differing
directions. For example, ePTFE may tend to resist creep in the
direction the ePTFE membrane was expanded. A reinforcing layer of
ePTFE may be oriented to increase strength, resist creep, or impart
other properties in a particular direction. ePTFE may be oriented
such that the expanded direction is aligned with an axial direction
of a medical device, a transverse direction, a radial direction, at
any angle to any of these directions, and so forth. Similarly,
multiple layers of ePTFE may be disposed to increase strength,
resist creep, or impart other properties in multiple directions.
The reinforcing layer may or may not be impermeable.
[0111] Additionally, in embodiments where both the inner layer 325
and the outer layer 330 are porous in nature, the tie layer 335 may
be configured to create an impermeable layer between the two porous
layers. In such embodiments the stent 302 may permit tissue
ingrowth, tissue attachment, and/or healing on both the inner and
outer surfaces of the stent 302 while still preventing tissue
outside of the stent 302 from growing into the lumen and occluding
the lumen. Thus, the tie layer 335 may be configured to create a
mid-layer portion of a construct, the tie layer 335 configured to
inhibit tissue ingrowth into the layer or to be impervious to
tissue migration into or through the layer or to substantially
inhibit tissue migration.
[0112] Furthermore, the tie layer 335 may be configured to be
impervious or substantially impervious to fluid migration across
the tie layer 335. Specifically, constructions comprising one or
more porous layers may allow fluid to cross the porous layer. In
the case of a medical appliance configured to control blood flow,
such as a graft, a porous layer may allow blood to leak across the
layer or may allow certain smaller components of the blood to cross
the layer while containing larger components, effectively filtering
the blood. In some instances this filtration or ultrafiltration may
allow components such as plasma to cross the barrier while
containing red blood cells, leading to seroma. Thus, a fluid
impermeable tie layer may be configured to contain fluid within a
medical device also comprised of porous layers. In some devices, a
tie layer may be both fluid impermeable and impervious to tissue
ingrowth, or may be configured with either of these properties
independent of the other. Constructs wherein any layer (other than,
or in addition to, a tie layer) is configured to be fluid
impermeable and/or impervious to tissue ingrowth are also within
the scope of this disclosure. Thus, disclosure recited herein in
connection with fluid impermeable and/or tissue impervious tie
layers may be analogously applied to impermeable layers at various
locations within a construct.
[0113] The tie layer (or any impermeable/impervious layer) may
include any thermoplastic and may or may not be electrospun. In one
embodiment, the tie layer may be ePTFE. In another it may be
electrospun PTFE. In other embodiments it may be FEP, including
electrospun FEP and FEP applied as a film or dip coating.
Furthermore, the tie layer may include any of the following
polymers or any other thermoplastic: dextran, alginates, chitosan,
guar gum compounds, starch, polyvinylpyridine compounds, cellulosic
compounds, cellulose ether, hydrolyzed polyacrylamides,
polyacrylates, polycarboxylates, polyvinyl alcohol, polyethylene
oxide, polyethylene glycol, polyethylene imine,
polyvinylpyrrolidone, polyacrylic acid, poly(methacrylic acid),
poly(itaconic acid), poly(2-hydroxyethyl acrylate),
poly(2-(dimethylamino)ethyl methacrylate-co-acrylamide),
poly(N-isopropylacrylamide),
poly(2-acrylamido-2-methyl-1-propanesulfonic acid),
poly(methoxyethylene), poly(vinyl alcohol), poly(vinyl alcohol) 12%
acetyl, poly(2,4-dimethyl-6-triazinylethylene),
poly(3morpholinylethylene), poly(N-1,2,4-triazolyethylene), poly
(vinyl sulfoxide), poly(vinyl amine), poly(N-vinyl
pyrrolidone-co-vinyl acetate), poly(g-glutamic acid),
poly(Npropanoyliminoethylene), poly(4-amino-sulfo-aniline), poly
[N-(p
sulphophenyl)amino-3-hydroxymethyl-1,4phenyleneimino-1,4-phenylene],
isopropyl cellulose, hydroxyethyl, hydroxylpropyl cellulose,
cellulose acetate, cellulose nitrate, alginic ammonium salts,
i-carrageenan, N-[(3'-hydroxy-2',3'-dicarboxy)ethyl]chitosan,
konjac glocomannan, pullulan, xanthan gum, poly(allyammonium
chloride), poly(allyammonium phosphate),
poly(diallydimethylammonium chloride), poly(benzyltrimethylammonium
chloride), poly(dimethyldodecyl(2-acrylamidoethyly) ammonium
bromide), poly(4-N-butylpyridiniumethylene iodine),
poly(2-N-methylpridinium methylene iodine), poly(N
methylpryidinium-2,5-diylethenylene), polyethylene glycol polymers
and copolymers, cellulose ethyl ether, cellulose ethyl hydroxyethyl
ether, cellulose methyl hydroxyethyl ether, poly(I-glycerol
methacrylate), poly(2-ethyl-2-oxazoline), poly(2-hydroxyethyl
methacrylate/methacrylic acid) 90:10, poly(2-hydroxypropyl
methacrylate), poly(2-methacryloxyethyltrimethylammonium bromide),
poly(2-vinyl1-methylpyridinium bromide), poly(2-vinylpyridine
N-oxide), poly(2-vinylpyridine), poly(3-chloro-2-hydroxypropyl
2-methacryloxyethyldimethylammonium chloride), poly(4vinylpyridine
N-oxide), poly(4-vinylpyridine), poly
(acrylamide/2-methacryloxyethyltrimethylammonium bromide) 80:20,
poly(acrylamide/acrylic acid), poly(allylamine hydrochloride),
poly(butadiene/maleic acid), poly(diallyldimethylammonium
chloride), poly(ethyl acrylate/acrylic acid), poly(ethylene glycol)
bis(2-aminoethyl), poly (ethylene glycol) monomethyl ether,
poly(ethylene glycol)bisphenol A diglycidyl ether adduct,
poly(ethylene oxide-bpropylene oxide), poly(ethylene/acrylic acid)
92:8, poly(llysine hydrobromide), poly(l-lysine hydrobromide), poly
(maleic acid), poly(n-butyl
acrylate/2methacryloxyethyltrimethylammonium bromide),
poly(Niso-propylacrylamide),
poly(N-vinylpyrrolidone/2dimethylaminoethyl methacrylate), dimethyl
sulfatequaternary, poly(N-vinylpyrrolidone/vinyl acetate),
poly(oxyethylene) sorbitan monolaurate (Tween 20.RTM.), poly
(styrenesulfonic acid), poly(vinyl alcohol),
N-methyl-4(4'formylstyryl)pyridinium, methosulfate acetal,
poly(vinyl methyl ether), poly(vinylamine) hydrochloride,
poly(vinylphosphonic acid), poly(vinylsulfonic acid) sodium salt,
and polyaniline.
[0114] Regardless of the material, the tie layer 335 may or may not
be electrospun. Further, in certain embodiments the stent 302 may
include two or more tie layers 335. The tie layer 335 may be formed
in any manner known in the art and attached to the inner 325 and
outer 330 layers in any manner known in the art. For example, the
tie layer 335 may comprise a sheet of material that is wrapped
around the inner layer 325 or a tube of material that is slipped
over the inner layer 325 that is then heat shrunk or otherwise
bonded to the inner 325 and outer 330 layers. Further, in
embodiments where the tie layer is electrospun, it may be
electrospun directly onto the inner layer 325, the scaffolding
structure 320, or both. In some instances the tie layer 335 may be
melted after the stent 302 is constructed to bond the tie layer 335
to adjacent layers of the stent covering.
[0115] Furthermore, the tie layer may be configured to change the
overall properties of the medical appliance. For example, in some
instances a cover or construct comprised solely of electrospun PTFE
(of the desired pore size) may not have desired tensile or burst
strength. A tie layer comprised of a relatively stronger material
may be used to reinforce the PTFE inner layer, the PTFE outer
layer, or both. For example, in some instances FEP layers may be
used to increase the material strength of the cover. Again, as
discussed above, the tie layer may also be configured as a portion
of the construct configured to be impervious to tissue ingrowth or
migration.
[0116] Further, one or more layers of electrospun PTFE may be used
in connection with a scaffolding structure other than that shown
herein. In other words, the disclosure above relating to covers,
layers, tie layers, and related components is applicable to any
type of scaffolding structure as well as to stents or grafts with
no separate scaffolding structure at all.
[0117] FIGS. 4A-4E illustrate certain steps in a process of
manufacturing a multilayer construct for use in connection with a
medical appliance. More specifically, these Figures illustrate a
process of creating a stent covered with electrospun material.
Again, this disclosure is equally relevant to all medical
appliances that may comprise a cover or multilayered construct,
including grafts, patches, stents, and so on. Additionally, as
suggested in the additional examples disclosed below, the
illustrated steps may be optional in some instances or augmented by
additional steps in others.
[0118] FIG. 4A illustrates a covering inner layer 425 disposed
around a mandrel 416. As described above, the inner layer 425 may
be electrospun directly onto the mandrel 416, including instances
wherein the mandrel 416 was rotating during the process. In the
illustrated embodiment, the inner layer 425 was electrospun onto a
rotating mandrel 416 such that the resultant tube of material has
no seam. After the inner layer 425 is electrospun onto the mandrel
416, the inner layer 425 may then be sintered. In the case of PTFE,
the membrane may be sintered at temperatures of about 385 degrees
C., including temperatures from about 360 degrees C. to about 400
degrees C. Sintering may tend to set the structure of the PTFE,
meaning sintering reduces the softness or flowability of the PTFE.
Furthermore, as discussed above, sintering or otherwise heat
treating the mat may evaporate any water or PEO mixed with the
PTFE, resulting in a material comprised substantially of pure
PTFE.
[0119] Once the inner layer 425 is sintered, the tube of material
may be removed from the mandrel 416, as illustrated in FIG. 4B. As
shown in the illustrated embodiment, the inner layer 425 may be
"peeled" from the mandrel 416 to initially break any adherence of
the inner layer 425 to the mandrel 416. The inner layer 425 may
also be removed by pushing the covering with respect to the mandrel
416, causing the material to bunch as it is removed from the
mandrel 416. In some embodiments, low friction coatings may
alternatively or additionally be applied to the mandrel 416 before
the inner layer 425 is electrospun. The inner layer 425 may then be
reapplied to the mandrel 416 by slipping the inner layer 425 over
the mandrel 416, as illustrated in FIG. 4C.
[0120] Once the inner layer 425 is reapplied to the mandrel 416, a
wire scaffolding 420 can be formed over the mandrel 416 and the
inner layer 425, as shown in FIG. 4D. FIG. 4E illustrates an outer
layer 430 of material that may then be electrospun onto the
scaffolding 420 and the inner layer 425. The entire construct may
then be sintered. Additional layers may also be added through
similar processes.
[0121] Many variations to the above-described process are within
the scope of the present disclosure. For example, one or more
layers may be applied by wrapping strips or mats of material around
the mandrel 416 and/or the other layers. Further, some of the
layers may be applied by spray or dip coating the mandrel 416
and/or the other layers. It is within the scope of this disclosure
to vary the process above to apply to any of the layers, or any
additional layers, using any method disclosed herein.
[0122] In another example, a stent may be comprised of an inner
layer of electrospun PTFE, a tie layer of FEP, and an outer layer
of PTFE. The properties of each of these layers, including percent
porosity, mat thickness, fiber diameter, and/or average pore size,
may be controlled to form a covering layer that inhibits the growth
of tissue into or through a particular layer or that permits
endothelial growth or attachment on a particular layer.
[0123] In some such embodiments, the inner layer of PTFE may be
electrospun on a mandrel, sintered, removed from the mandrel, and
replaced on the mandrel and then a scaffolding structure applied
around the inner layer (analogous to the procedure illustrated in
FIGS. 4A-4D). The FEP tie layer may then be applied by dipping,
spraying, applying a film layer, electrospinning, rotational
spinning, extrusion, or other processing.
[0124] In some embodiments, the FEP layer may be heated such that
the FEP becomes soft, in some cases flowing into open spaces in
adjacent PTFE layers. This may tie the FEP layer to adjacent PTFE
layers. In some instances, heating the construct to about 325
degrees C. may allow the FEP to partially flow into openings in
adjacent PTFE layers, without the FEP completely flowing through
the PTFE mat.
[0125] In another particular example, an inner layer of PTFE may be
electrospun on a mandrel, sintered, removed, and replaced, and then
a scaffolding structure applied around the inner layer. An FEP tie
layer may then be applied as a film layer. In some instances this
tie layer may be "tacked" into place, for example, by a soldering
iron. A tube of PTFE (which may be formed separately by
electrospinning onto a mandrel and sintering) may then be disposed
over the FEP film layer. The entire construct may then be
pressured, for example, by applying a compression wrap. In some
embodiments this wrap may comprise any suitable material, including
a PTFE-based material. In other embodiments a Kapton film may be
wrapped around the construct before the compression wrap, to
prevent the construct from adhering to the compression wrap.
[0126] The compressed layers may then be heated above the melting
temperature of the FEP tie layer, but below the sintering
temperature of the PTFE. For example, the melt temperature of the
FEP may be from about 264 degrees C. to about 380 degrees C.,
including about 325 degrees C. PTFE may be sintered at temperatures
from about 360 degrees C. to about 400 degrees C. Thus, the entire
construct may be heated to an appropriate temperature such as about
325 degrees C. In some embodiments the construct may be held at
this temperature for about 15 to about 20 minutes. Heating the FEP
layer to about 325 degrees C. may allow the FEP layer to remain
substantially impervious to tissue ingrowth and/or attachment,
creating a "barrier" layer within the construct, while still
adhering the FEP to adjacent layers of PTFE. In other embodiments,
heating the construct to higher temperatures, such as about 350
degrees C. or more, may be configured to allow the FEP to flow
around the PTFE such that the entire construct has a higher degree
of porosity and the FEP layer is not as impervious to ingrowth.
[0127] The joining of the FEP tie layer to the PTFE outer and inner
cover layers may increase the strength of the finished covering.
The construct may then be cooled and the compression wrap and the
Kapton film discarded. The construct may then be removed from the
mandrel.
[0128] A stent formed by the exemplary process described above may
be configured with desired characteristics of porosity and
strength. In some instances the FEP material may coat the PTFE
nanofibers but still allow for sufficient porosity to permit tissue
ingrowth and/or endothelial attachment or growth. The degree to
which the FEP coats the PTFE may be controlled by the temperature
and time of processing. The lower the temperature and/or the
shorter the time the construct is held at a certain temperature,
the less the FEP may flow. In some instances a tie layer of FEP
that is impervious to tissue ingrowth into or through the layer may
be formed by heating the construction only to about 270 degrees
C.
[0129] FIG. 5 illustrates a stent 502 that comprises a scaffolding
structure 520 and a covering 524. The covering 524 may be comprised
of any combination of layers disclosed herein. Additionally, the
stent 502 of FIG. 5 includes a cuff 540 at both ends of the stent
502. In other embodiments a cuff 540 may be located at only one end
of the stent 502.
[0130] The cuff 540 may comprise an additional covering layer on
the outside diameter of the stent 502, disposed adjacent to one or
both ends of the stent 502. The cuff 540 may be configured to
promote tissue ingrowth, attachment, and/or incorporation into the
cuff 540; for example, the cuff 540 may be more porous than an
outer layer of the covering 524 of the stent 502. Factors such as
porosity, type of covering or coating, type of material, use of
organic material, and/or use of composite materials formed of
synthetic material and organic material may be used to create a
cuff 540 configured for tissue ingrowth. Again, the cuff 540 may be
configured to promote tissue ingrowth and/or the growth or
attachment of endothelial cells at one or both ends of the stent
502. When implanted in the body, the cuffs 540 may tend to "anchor"
the ends of the stent 502 with respect to the vessel walls,
reducing the relative movement of the stent ends with respect to
the vessel walls. Such a reduction in movement may lessen
irritation of the vessel by the stent ends, minimizing
complications such as edge stenosis. Cuffs 540 may be configured
for use in CV type applications in some instances. Furthermore, a
band of porous material analogous to the cuff 540 illustrated may
be coupled to any medical appliance to anchor a portion of such a
device.
[0131] In some embodiments, the outer layer of the covering 524 of
the stent 502 may be relatively non-porous to inhibit tissue
ingrowth into or through the outer layer, but the cuff 540,
disposed about the outer layer, may provide a section near each end
at which some tissue ingrowth, attachment, or incorporation may
occur.
[0132] The cuff 540 may be comprised of an electrospun material,
such as PTFE, and may be bonded to the outer covering layer through
any method, including methods of multilayer device construction
described herein. For example, a layer of FEP may be disposed
between the outer covering layer and the cuff 540, and heated to
bond the layers. In other embodiments the cuff 540 may comprise a
collagen layer that is coupled to the stent. Further, a
co-electrospun collagen and PTFE cuff 540 may be utilized.
[0133] The current disclosure relates to medical appliances,
including stents, which may comprise a frame structure provided in
connection with one or more coverings or coatings. It will be
appreciated that, though particular structures, coverings, and
coatings are described herein, any feature of the frames or
coverings and/or coatings described herein may be combined with any
other disclosed feature without departing from the scope of the
current disclosure. For example, certain Figures referenced below
show a metal frame without any covering or coating; the features
described and illustrated in those Figures may be combined with any
combination of coverings or coatings disclosed herein. Further, as
used herein, the term "frame" refers to a support structure for use
in connection with a medical appliance. For instance, a scaffolding
structure, such as that described in connection with FIGS. 4A-4E,
above, is an example of a frame used in connection with a medical
appliance. In some embodiments, a medical appliance--such as a
stent--may comprise a frame alone, with no covering, coating, or
other components.
[0134] Moreover, the current disclosure is applicable to a wide
variety of medical appliances that may utilize any of the
electrospun mats disclosed herein, including medical appliances
that comprise multiple layers. For example, a hernia patch may
comprise a two-layered construction, with one side of the patch
configured to allow tissue ingrowth and/or attachment (for bonding
and healing) and the other side configured to resist such ingrowth
and/or attachment (to make the second side "slippery" with respect
to surrounding tissue). Further, a patch as described above may
also comprise a tie layer disposed between the two exterior layers.
The tie layer may be configured to resist tissue ingrowth or
attachment into or through the patch and/or to provide mechanical
properties such as strength to the construct.
[0135] FIGS. 6, 7A, and 7B show views of a possible embodiment of a
frame for use in connection with a medical appliance such as a
stent or graft. FIG. 7C is an alternative configuration of a
portion of the frame structure. FIGS. 8 and 9 are views of one
embodiment of a frame that includes flared ends. FIG. 10
illustrates one embodiment of how a wire may be shaped to form a
frame.
[0136] Frames for use in connection with medical appliances may be
fabricated or formed into particular geometries through a variety
of means. For example, a frame may be cut from a single tube of
material, including embodiments wherein the frame is first laser
cut, then expanded. In other embodiments, the frame may be molded,
including embodiments wherein the frame is molded from a polymeric
material. In still other embodiments, powder metallurgical
processes, such as powdered compression molding or direct metal
laser sintering, may be used.
[0137] FIG. 6 illustrates a front elevation view of an embodiment
of a frame. The illustrated embodiment depicts one embodiment of a
configuration for a metal wire 650 forming a frame. As depicted in
FIG. 6, the frame may consist of a single continuous wire.
[0138] Referring generally to FIGS. 6, 7A, and 7B, particular
features of the illustrated frame structure are indicated. It will
be appreciated that the numerals and designations used in any
figure apply to analogous features in other illustrated
embodiments, whether or not the feature is so identified in each
figure. As generally shown in these Figures, the frame structure
may consist of a wire 650 shaped to form the frame. The wire 650
may be shaped in a wave-type configuration, the waves defining
apexes 652 and arms 654 of the frame structure. The frame may
further be coupled to a covering layer (not pictured).
Additionally, in some embodiments, any covering as disclosed herein
may be applied to any type of frame, for example, laser cut frames,
polymeric frames, wire frames, and so forth.
[0139] The frame may be designed such that the midsection is
"harder" than the ends. The "hardness" of the frame refers to the
relative strength of the structure (e.g., its compressibility). A
harder portion of the frame will have greater strength (i.e., exert
a greater radial outward force) than a softer portion. In one
embodiment, the midsection is harder than the proximal and distal
end sections, which are relatively softer. Further, a frame may be
configured to be flexible to facilitate the ability of the device
to conform to the native anatomy at which the device is configured
for use. Similarly, covered devices may be configured with covers
that conform to the native anatomy at a therapy site.
[0140] Additionally, the frame may be configured to allow the
entire device to be crimped into a relatively low-profile
configuration for delivery. For example, devices of a certain
diameter or constrained profile are more feasible for delivery at
certain vascular or other access points than others. For example,
in many instances a device configured for insertion via the radial
artery may be relatively smaller than devices configured for
insertion via the generally larger femoral artery. A frame may be
configured to be crimped into a particular profile to enable
potential access at various or desired access points. Similarly,
devices having no frame may be configured to be disposed in a
particular profile to facilitate access and delivery. Once a device
is positioned within the body it may be expanded or deployed in a
number of ways, including use of self-expanding materials and
configurations. Additionally, some configurations may be designed
for expansion by a secondary device, such as a balloon.
[0141] Four basic design parameters may be manipulated to influence
the properties (hardness, strength, crush force, hoop force,
flexibility, etc.) of the illustrated frame. These properties are
(1) apex to apex distance, designated as H.sub.x in FIGS. 6 and 7A;
(2) arm length, designated as A.sub.x in FIGS. 6 and 7A; (3) apex
radius, designated as R.sub.x in FIG. 7A; and (4) the diameter of
the wire 650. These values may or may not be constant at different
points on a frame. Thus, the subscript "x" is used generically;
that is, each distance identified as "H" refers to an apex to apex
distance with subscripts 1, 2, 3, etc., signifying the apex to apex
distance at a particular point. It will be appreciated that these
subscript designations do not necessarily refer to a specific
distance, but may be used relatively (i.e., H.sub.1 may be
designated as smaller than H.sub.2 without assigning any precise
value to either measurement). Further, as will be apparent to one
skilled in the art having the benefit of this disclosure, an
analogous pattern of measurements and subscripts is employed for
other parameters described herein, for example A.sub.x and
R.sub.x.
[0142] The overall frame design may be configured to optimize
desired radial force, crush profile, and strain profile. The frame
design parameters may each be configured and tuned to create
desired characteristics. For example, the strain profile may be
configured to be less than the failure point for the material being
used.
[0143] A first parameter, the apex to apex distance, is designated
as H. This measurement signifies the distance between a first apex
and a second apex where both apexes substantially lie along a line
on the outside diameter of the frame that is co-planar with, and
parallel to, the longitudinal axis of the frame. In some
embodiments, H.sub.x may be constant along the entire length of the
frame. In other embodiments the length of the frame may be divided
into one or more "zones" where H.sub.x is constant within a zone,
but each zone may have a different H. In still other embodiments
H.sub.x may vary along the entire length of the frame. H.sub.x may
be configured, in connection with the other design parameters, to
determine the properties of the frame. Generally, regions of the
frame with a smaller H.sub.x value will be harder than regions with
a larger H.sub.x value.
[0144] In the embodiment illustrated in FIG. 6, there are two
"flare zones" at either end of the frame and a midbody zone along
the remaining length of the frame. In the illustrated embodiment,
H.sub.1 designates the apex to apex distance in the midbody zone of
the frame and H.sub.2 designates the apex to apex distance in the
flare zones of the frame. In the illustrated embodiment, the apex
to apex distance, H.sub.2, is the same in both the flare zone near
the distal end of the frame and the flare zone near the proximal
end of the frame. In some embodiments H.sub.1 may be smaller than
H.sub.2, resulting in a frame that is relatively harder in the
midbody and relatively softer on the ends. A frame with such
properties may be utilized in applications where strength is
necessary along the midbody, for example to treat a tumor or other
occlusion, but the ends are configured to rest on healthy tissue
where softer ends will minimize trauma to the healthy tissue.
[0145] In embodiments where soft ends and a hard midbody are
desirable, H.sub.1 may be between about 2 mm and 30 mm, and H.sub.2
between about 2.1 mm and 30.1 mm. For example, in frames configured
for use in connection with stents for CV or PV applications,
H.sub.1 may be between about 3 mm and 10 mm, and H.sub.2 between
about 3.1 mm and 10.1 mm, such as 3 mm<H.sub.1<8 mm and 3.5
mm<H.sub.2<9 mm, 3 mm<H.sub.1<6.5 mm and 4
mm<H.sub.2<8 mm, or 3 mm<H.sub.1<5 mm and 5.5
mm<H.sub.2<6.5 mm.
[0146] In other embodiments where two or more apex to apex lengths
are present in one frame, the change in apex to apex length may be
correlated to the displacement of the apexes from the midpoint of
the frame. In other words, the apex to apex length may increase
incrementally as one moves away from the midpoint of the frame
toward the ends in a manner that gives the frame the same geometry,
and therefore the same properties, on either side of the midpoint
of the length of the frame. In other embodiments, different
geometries may be utilized at any point along the length of the
frame. It will be appreciated that the ranges of values for H.sub.x
disclosed above apply analogously to embodiments where the frame
has multiple apex to apex lengths. For example, in one embodiment a
frame may have an apex to apex length at midbody within one of the
ranges disclosed above for H.sub.1, and the value of H.sub.x may
vary incrementally, in steps, or some other pattern, along the
length of the frame, reaching an apex to apex length at the ends
within the complementary range for H.sub.2.
[0147] Moreover, in some embodiments, the value of H.sub.x may be
small enough that adjacent coils are "nested" within each other. In
other words, the apexes of a first helical coil may extend up into
the spaces just below the apexes of the next adjacent coil. In
other words, apexes of lower coils may extend a sufficient amount
so as to be disposed between the arms of higher coils. In other
embodiments the value of H.sub.x may be large enough that adjacent
coils are completely separated. In embodiments wherein adjacent
coils are "nested," the number of wires at any particular
cross-section of the stent may be higher than a non-nested stent.
In other words, cutting the frame along an imaginary plane disposed
orthogonally to the longitudinal axis of the frame will intersect
more wires if the frame is nested as compared to not nested. The
smaller the value of H.sub.x, the more the rows may be intersected
by such a plane (that is, more than just the next adjacent row may
extend into the spaces below the apexes of a particular row).
Nested frames may create relatively higher strains in the frame
when a stent comprised of the frame is loaded into a delivery
catheter. In some instances the delivery catheter for a nested
frame may therefore be relatively larger than a delivery catheter
configured for a non-nested frame. Further, nested frames may be
relatively stiff as compared to non-nested stents with similar
parameters.
[0148] As will be apparent to those skilled in the art having the
benefit of this disclosure, frames with a hard midbody and soft
ends may be desirable for a variety of applications. Further, in
some instances a basically "symmetric" frame may be desirable; in
other words, a frame with certain properties at the midbody section
and other properties at the ends, where the properties at both ends
are substantially identical. Of course, other embodiments may have
varied properties along the entire length of the frame. It will be
appreciated that while the effect of changing variables, for
instance the difference between H.sub.1 and H.sub.2, may be
described in connection with a substantially symmetric stent (as in
FIG. 6), the same principles may be utilized to control the
properties of a frame where the geometry varies along the entire
length of the frame. As will be appreciated by those skilled in the
art having the benefit of this disclosure, this applies to each of
the variable parameters described herein, for example H.sub.x,
A.sub.x, and R.sub.x.
[0149] A second parameter, arm length, is designated as A.sub.x in
FIGS. 6 and 7A. As with H.sub.x, A.sub.x may be constant along the
length of the frame, be constant within zones, or vary along the
length of the frame. Variations in the length of A.sub.x may be
configured in conjunction with variations in the other parameters
to create a frame with a particular set of properties. Generally,
regions of the frame where A.sub.x is relatively shorter will be
harder than regions where A.sub.x is longer.
[0150] In some embodiments, the arm length A.sub.1 near the
midsection of the frame will be shorter than the arm length A.sub.2
near the ends. This configuration may result in the frame being
relatively harder in the midsection. In embodiments where soft ends
and a hard midbody are desirable, A.sub.1 may be between about 2 mm
and 30 mm, and A.sub.2 between about 2.1 mm and 30.1 mm. For
example, in frames for CV or PV applications, A.sub.1 may be
between about 2 mm and 10 mm, and A.sub.2 between about 2.1 mm and
10.1 mm, such as 2.5 mm<A.sub.1<8 mm and 3 mm<A.sub.2<9
mm, 3 mm<<6 mm and 4 mm<A.sub.2<7.5 mm, or 4
mm<<5 mm and 5 mm<A.sub.2<6 mm.
[0151] In other embodiments where two or more arm lengths are
present in one frame, the change in arm length may be correlated to
the displacement of the arm from the midpoint along the frame. In
other words, the arm length may increase incrementally as one moves
away from the midpoint of the frame toward the ends in a manner
that gives the frame the same geometry, and therefore the same
properties, on either side of the midpoint of the length of the
frame. In other embodiments, different geometries may be utilized
at any point along the length of the frame. It will be appreciated
that the ranges of values for A.sub.x disclosed above apply
analogously to embodiments where the frame has multiple arm
lengths. For example, in one embodiment a frame may have an arm
length at midbody within one of the ranges disclosed above for
A.sub.1, and the value of A.sub.x may vary incrementally, in steps
or some other pattern, along the length of the frame reaching an
arm length at the ends within the complementary range for
A.sub.2.
[0152] A third parameter, the apex radius, is designated as R.sub.1
in FIG. 7A. As with H.sub.x, and A.sub.x, R.sub.x may be configured
in order to create desired properties in a frame. In some
embodiments, the inside radius of each apex may form an arc that
has a substantially constant radius. As shown by a dashed line in
FIG. 7A, this arc can be extended to form a circle within the apex.
The measurement R.sub.x refers to the radius of the arc and circle
so described. Further, in some embodiments the arms and apexes of
the frame are formed by molding a wire around pins protruding from
a mandrel. The radius of the pin used gives the apex its shape and
therefore has substantially the same radius as the apex. In some
embodiments R.sub.x will be constant along the entire length of the
frame, be constant within zones along the length of the frame, or
vary along the entire length of the frame. Variations in the
magnitude of R.sub.x may be configured in conjunction with
variations in the other parameters to create a frame with a
particular set of properties. Generally, regions of the frame where
R.sub.x is relatively smaller will be harder than regions where
R.sub.x is larger.
[0153] Furthermore, in some instances, smaller values of R.sub.x
may result in relatively lower strain in the wire frame when the
frame is compressed, for example when the frame is disposed within
a delivery catheter. Moreover, wires of relatively larger diameters
may result in relatively lower strain at or adjacent to the radius
measured by R.sub.x when compressed, as compared to wires of
smaller diameters. Thus, in some instances, the strain may be
optimized for a particular design by varying the value of R.sub.x
and the diameter of the wire forming the frame.
[0154] Like the other variables, R.sub.x may take on a range of
values depending on the application and the desired properties of
the frame. In some embodiments R.sub.x may be between about 0.12 mm
and 1.5 mm, including from about 0.12 to about 0.64 mm. For
example, in frames configured for use with stents for CV or PV
applications, R.sub.x may be between about 0.35 mm and 0.70 mm,
such as 0.35 mm<R.sub.x<0.65 mm, 0.35 mm<R.sub.x<0.6
mm, or 0.4 mm<R.sub.x<0.5 mm.
[0155] It will be appreciated that the disclosed ranges for R.sub.x
apply whether the value of R.sub.x is constant along the length of
the frame, whether the frame is divided into zones with different
R.sub.x values, or whether R.sub.x varies along the entire length
of the frame.
[0156] The fourth parameter, wire diameter, is discussed in detail
in connection with FIG. 10 below.
[0157] FIG. 7A illustrates a cutaway view of the front portions of
two adjacent coils of a frame. The portions of the coils depicted
are meant to be illustrative, providing a clear view of the three
parameters H.sub.x, A.sub.x, and R.sub.x. It will be appreciated
that all three of these parameters may be configured in order to
create a frame with particular properties. Any combination of the
values, ranges, or relative magnitudes of these parameters
disclosed herein may be used within the scope of this disclosure.
As an example of these values taken together, in one embodiment of
a CV or PV frame with a relatively hard midbody and softer ends,
H.sub.1 may be about 4 mm and H.sub.2 about 5.9 mm, A.sub.1 may be
about 4.5 mm and A.sub.2 about 5.6 mm, and R.sub.1 about 0.5
mm.
[0158] FIG. 7B is a close-up view of one end of a frame. In
embodiments where the frame is formed by a single continuous wire,
FIG. 7B illustrates one way in which the end 656 of the wire may be
coupled to the frame. As illustrated, the wire may be disposed such
that the final coil approaches and runs substantially parallel to
the previous coil. This configuration results in the apex to apex
distance between the two coils decreasing near the end 656 of the
wire. In some embodiments this transition will occur along the
distance of about 4 to 8 apexes along the length of the wire. For
example, if a frame is configured with an apex to apex spacing of
H.sub.2' along the region of the frame nearest to the ends, the
apex to apex distance will decrease from H.sub.2' to a smaller
distance that allows the end 656 of the wire to meet the prior coil
(as illustrated in FIG. 7B) over the course of about 4 to 8
apexes.
[0159] FIG. 7C illustrates an alternative configuration of a
portion of a frame. In the embodiment of FIG. 7C, apexes 652'
alternate in relative height along the length of the wire. In
particular, in the embodiment shown, the apexes form a pattern
comprising a higher apex, a shorter apex, a higher apex, a shorter
apex, and so on, around the helical coil. In some instances, a
frame may be configured with alternating apexes at one or both ends
of the frame. For example, a frame as shown in FIG. 6 may be
configured with the pattern of apexes 652' and arms 654' shown in
FIG. 7C at one or both ends of the frame. Such an alternating
pattern of apexes may distribute the force along the vessel wall at
the ends of the frame, thus creating relatively a-traumatic
ends.
[0160] The end 656 may be attached to the frame in a variety of
ways known in the art. The end 656 may be laser welded to the frame
or mechanically crimped to the frame. In embodiments where the
frame is an element of a medical appliance further comprising a
polymer cover, the end 656 may be secured by simply being bound to
the cover. In other instances, a string may be used to bind or tie
the end 656 to adjacent portions of the frame. Similarly, in some
instances, a radiopaque marker may be crimped around the end 656 in
such a manner as to couple the end 656 to the frame. Additionally,
other methods known in the art may be utilized.
[0161] Furthermore, in some embodiments the frame may be configured
with radiopaque markers at one or more points along the frame. Such
markers may be crimped to the frame. In other embodiments a
radiopaque ribbon, for example a gold ribbon, may be threaded or
applied to the frame. In some embodiments these markers may be
located at or adjacent to one or both ends of the frame. Any
radiopaque material may be used, for example gold, bismuth, or
tantalum. Radiopaque elements may be configured to facilitate the
delivery and placement of a device and/or to facilitate viewing of
the device under fluoroscopy.
[0162] Referring again to FIG. 6 as well as to FIGS. 8 and 9, the
frame may be configured with flared ends. It will be appreciated
that in certain embodiments a frame may have a flare at both the
proximal and distal ends, only at the proximal end, only at the
distal end, or at neither end. In certain of these embodiments the
frame may have a substantially constant diameter in the midbody
zone of the frame, with the ends flaring outward to a larger
diameter. It will be appreciated that the geometry of the flares at
the proximal and distal ends may or may not be the same.
[0163] In the embodiment illustrated in FIG. 6, the frame has a
diameter, D.sub.1, at the midbody of the frame. This diameter may
be constant along the entire midbody of the frame. The illustrated
embodiment has a second diameter, D.sub.2, at the ends. This change
in diameter creates a "flare zone" at the end of the frame, or an
area in which the diameter is increasing and the frame therefore
may be described as including a "flared" portion. In some
embodiments the flare zone will be from about 1 mm to 60 mm in
length. For example, in certain frames configured for use with
stents designed for CV or PV applications, the flare zone may be
from about 3 mm to about 25 mm in length, such as from about 4 mm
to about 15 mm or from about 5 mm to about 10 mm in length.
[0164] The diameter of the stent at the midbody, the diameter at
one or both flares, or all of these dimensions may be configured to
be slightly larger than the body lumen in which the device is
configured for use. Thus, the size of the device may cause
interference with the lumen and reduce the likelihood the device
will migrate within the lumen. Further, active anti-migration or
fixation elements such as barbs or anchors may also be used.
[0165] FIGS. 8 and 9 also illustrate how a frame may be flared at
the ends. Diameters D.sub.1' and D.sub.1'' refer to midbody
diameters, analogous to D.sub.1, while D.sub.2' and D.sub.2'' refer
to end diameters analogous to D.sub.2. Further, as illustrated in
FIG. 9, the flared end may create an angle, alpha, between the
surface of the frame at the midbody and the surface of the flare.
In some instances the flare section will uniformly flare out at a
constant angle, as illustrated in FIG. 9. In some embodiments angle
alpha will be from about 1 degree to about 30 degrees. For example,
in some frames configured for use with stents designed for CV or PV
applications, alpha will be from about 2 degrees to about 8
degrees, such as from about 2.5 degrees to about 7 degrees or from
about 3 degrees to about 5 degrees. In one exemplary embodiment,
alpha may be about 3.6 degrees.
[0166] The frame of FIG. 6 also has a length L. It will be
appreciated that this length can vary depending on the desired
application of the frame. In embodiments where the frame has flare
zones at the ends, longer frames may or may not have proportionally
longer flare zones. In some embodiments, this flare zone may be any
length described above, regardless of the overall length of the
frame.
[0167] The disclosed frame may be formed in a variety of sizes. In
some embodiments, L may be from about 10 mm to about 200 mm. For
example, in CV applications the frame may have a length, L, of from
about 40 mm to 100 mm or any value between, for example, at least
about 50 mm, 60 mm, 70 mm, 80 mm, or 90 mm. In PV applications the
frame may have a length, L, of from about 25 mm to 150 mm or any
value between, for example, at least about 50 mm, 75 mm, 100 mm, or
125 mm. The frame may also be longer or shorter than these
exemplary values in other applications.
[0168] Likewise the frame may be formed with a variety of
diameters. In some embodiments the midbody diameter of the frame
may be from about 1 mm to about 45 mm, including from about 4 mm to
about 40 mm. For example, in CV or PV applications the frame may
have a midbody inside diameter of about 3 mm to 16 mm, or any
distance within this range such as between about 5 mm and about 14
mm or between about 7 mm and about 10 mm. Moreover, in some
instances, the diameter, or a diameter-like measurement of the
frame, may be described as a function of other components. For
example, the frame may be configured with a particular number of
apexes around a circumference of the frame. For example, some
frames may be configured with between about 2 and about 30 apexes
around a circumference of the frame.
[0169] The frame may or may not be configured with flared ends
regardless of the midbody diameter employed. In some CV embodiments
the maximum diameter at the flared end will be between about 0.5 mm
and about 2.5 mm greater than the midbody diameter. For example,
the maximum diameter at the flared end may be between about 1 mm
and about 2 mm, or alternatively between about 1.25 mm and about
1.5 mm, such as about 1.25 mm or about 1.5 mm greater than the
midbody diameter.
[0170] Referring now to FIG. 10, the frame may be formed from a
single continuous wire. In some embodiments the wire may be
comprised of Nitinol (ASTM F2063) or other suitable materials. In
some embodiments the wire will have a diameter between about 0.001
inch and about 0.05 inch, including from about 0.005 inch and about
0.025 inch. For example, in some frames designed for CV or PV
applications, the wire diameter may be from about 0.008 inch to
about 0.012 inch in diameter including certain embodiments where
the wire is from about 0.009 inch to about 0.011 inch in diameter
or embodiments where the wire is about 0.010 inch in diameter.
Furthermore, frames configured for the thoracic aorta may be formed
of wires up to 0.020 inch in diameter, including wires between
about 0.010 inch and 0.018 inch in diameter.
[0171] FIG. 10 illustrates how, in some embodiments, the wire 650
may be wound in a helical pattern creating coils that incline along
the length of the stent. The waves of the wire that form the arms
and apexes may be centered around this helix, represented by the
dashed line 660.
[0172] In some embodiments, a stent, graft, or other tubular device
may comprise a tapered segment along the length of the device. A
taper may be configured to reduce the velocity of fluid flow within
the device as the fluid transitions from a smaller diameter portion
of the device to a larger diameter portion of the device. Reducing
the fluid velocity may be configured to promote laminar flow,
including instances wherein a tubular member is tapered to promote
laminar flow at the downstream end of the device.
[0173] Further, in some embodiments, a stent or other tubular
member may be positioned at a junction between two or more body
lumens. For example, FIG. 11A illustrates a stent 702a disposed at
an intersection between two body lumens. In some embodiments, stent
702a may be configured to promote laminar flow at the intersection
of the lumens.
[0174] FIG. 11B illustrates a portion of a stent 702b having a
tapered segment 705b which may be configured to reduce flow
velocity within the stent 702b. In some embodiments, such as that
of FIG. 11B, the tapered segment 705b may be positioned upstream of
the downstream end of the stent 702b. FIG. 11C illustrates another
exemplary embodiment of a portion of a stent 702c having a tapered
segment 705c adjacent the downstream end of the stent 702c. Either
tapered segment (705b, 705c) may be used in connection with any
stent, including embodiments wherein the tapered segment is
configured to promote laminar flow in and around the stent. For
example, the stent 702a of FIG. 11A may be configured with either
tapered portion (705b, 705c) to promote laminar flow out of the
stent 702a and at the junction between the body lumens of FIG.
11A.
[0175] Use of electrospun coatings may facilitate application of a
covering of uniform thickness along a tapered stent. For example,
in some embodiments, electrospun coatings may be configured to
evenly coat devices comprised of various geometries. An electrospun
coating may deposit a substantially even coating along various
geometries such as tapers, shoulders, and so forth.
[0176] Additionally, various additional processing steps, methods,
procedures, and systems for serially deposited fiber mats, such as
electrospun or rotational spun mats, are within the scope of this
disclosure. Materials comprising serially deposited fiber mats
which have been processed by any of the methods or systems
described below are likewise within the scope of this disclosure.
These processes and materials may be used to create multilayered
constructs having one or more layers of serially deposited fiber
material which has been post processed as described below and/or
having one or more layers of serially deposited fiber material
which has not been post processed. The post processing methods and
related materials described below describe various methods of
modifying the material properties of serially deposited fiber
layers to, for example, change the strength of the material, change
the surface characteristics of the material, change the porosity of
the material, set the material in a particular geometry or shape,
and so forth.
[0177] Serially deposited fiber mats may comprise a membrane in the
form of a sheet, a sphere, a strip, or any other geometry. As used
herein, the term "membrane" refers to any structure comprising
serially deposited fibers having a thickness which is smaller than
at least one other dimension of the membrane. Examples of membranes
include, but are not limited to, serially deposited fiber mats or
lattices forming sheets, strips, tubes, spheres, covers, layers,
and so forth. Additionally, any material which can be serially
deposited as fibers may be processed as described below.
[0178] Further, as used herein, references to heating a material
"at" a particular temperature indicate that the material has been
disposed within an environment which is at the target temperature.
For example, placement of a material sample in an oven, the
interior of the oven being set at a particular temperature, would
constitute heating the material at that particular temperature.
While disposed in a heated environment, the material may, but does
not necessarily, reach the temperature of the environment. The term
"about," as used herein in connection with temperature, is meant to
indicate a range of .+-.5 degrees C. around the given value. The
term "about" used in connection with quantities or values indicates
a range of .+-.5% around the value.
[0179] Serially deposited membranes may be processed to alter the
strength or other characteristics of the material by stretching the
membrane in one or more directions. In some embodiments the
membrane may initially be sintered after it is serially deposited.
The membrane may then be heated at a particular temperature prior
to further processing of the membrane. As further outlined below,
heating and stretching a membrane of serially deposited fibers may
tend to cause increased strength in the direction the membrane is
stretched. In some embodiments, the material may also exhibit
increased fiber alignment in the direction of stretching.
[0180] Temperatures at which materials may be heated prior to
processing may vary depending on the material and depending on the
desired characteristics of the material after processing. For
example, a polymeric membrane may show more or less fiber alignment
after processing depending on various factors, such as the
temperature at which the materials are heated. In some instances a
membrane may be heated at a temperature at or above the crystalline
melt point of the material comprising the membrane, though it is
not necessary to heat the material as high as the crystalline melt
temperature to stretch process the material.
[0181] In the case of polymeric materials which are sintered, the
step of heating the membrane may be performed as a separate and
distinct step from sintering the membrane, or may be done as the
same step. For example, it is within the scope of this disclosure
to process a membrane directly after sintering the membrane, while
the membrane is at an elevated temperature due to the sintering
process. It is likewise within the scope of this disclosure to
obtain a previously sintered membrane which may have been
previously cooled to ambient or room temperature, then heat the
membrane as part of a heating and stretching process.
[0182] Membranes or any other mat or lattice of serially deposited
fibers may be stretched in any direction as part of a heating and
stretching process. For example, a tubular membrane may be
stretched in the axial/longitudinal direction, the radial
direction, or any other direction. Further, it is within the scope
of this disclosure to stretch a membrane in multiple directions,
either simultaneously or as part of separate steps. For example, a
tubular membrane may be stretched both axially and radially after
the membrane is initially heated, or the membrane may be stretched
in these or other directions as part of distinct and separate
steps. Additionally, the membrane may be heated multiple times
during such a process.
[0183] Various methods, modes, mechanisms, and processes may be
utilized to apply forces to stretch materials. For example, force
may be applied through mechanical, fluidic, electro-magnetic,
gravitational, and/or other mechanism or modes. In embodiments
wherein force is applied through fluidic interaction, a pressurized
gas or liquid could be used to generate the force while the
material is at an elevated temperature. The fluid may be stagnant
or recirculating. Further, the fluid may be used to heat and/or
cool the material. For example, the liquid may be used to rapidly
cool the material, locking the microstructure and geometry.
[0184] A heated and stretched membrane may be held in a stretched
position while the membrane cools. For example, a membrane may be
heated at an elevated temperature prior to stretching, stretched
while the membrane is at an elevated temperature, then held in the
stretched position while the membrane cools to an ambient
temperature, such as room temperature. Depending on the process,
when the membrane is stretched, it may be at a temperature lower
than the temperature at which it was heated, and it may or may not
cool completely to the ambient temperature while the position is
held.
[0185] Processing a mat or lattice of serially deposited fibers as
by heating and stretching may alter various material properties of
the mat or lattice. For example, and as further outlined below,
heating and stretching a fiber mat may increase the durability of
the material, increase the smoothness of the material, increase
handling characteristics, increase the tensile strength of the
material, increase resistance to creep, or otherwise alter the
material. Further, in some embodiments, heating and stretching the
material tends to align a portion of the fibers which comprise the
mat in the direction the material is stretched. This alignment of
the microstructure and/or nanostructure of the material may impact
microscale and/or nanoscale interactions between the mat and other
structures, such as body cells. Fiber alignment may likewise alter
the flow characteristics of a fluid flowing in contact with the
mat. For example, a tubular membrane configured to accommodate
blood flow may exhibit different flow conditions through the tube
if the fibers are aligned by heating and stretching as compared to
randomly disposed fibers.
[0186] Additionally, heating and stretching a mat may or may not
tend to align the fibers in the direction the material is
stretched. In some embodiments, the degree of fiber alignment may
be related to the temperature at which the mat was heated prior to
stretching. Further, stretching a mat in multiple directions may
tend to maintain random fiber disposition of a mat in embodiments
wherein the original mat exhibited generally random fiber
disposition.
[0187] Regardless of whether heating and stretching tend to align
the fibers in the direction the mat was stretched, the mat may
exhibit different properties in a stretched direction as compared
to a non-stretched direction. For example, the mat may exhibit
increased tensile strength and/or increased resistance to creep in
the stretched direction while these properties may be generally
unchanged or decreased in a non-stretched direction. Further,
stretching may increase the porosity of a mat of serially deposited
fibers. In some embodiments, stretching may increase the porosity
of a mat by up to 10 times the original porosity, including up to
eight times, up to six times, up to four times, and up to two times
the original porosity. In some embodiments, a mat may be stretched
while at room temperature to increase porosity, to increase
strength, or to modify other properties of the mat.
[0188] Additionally, in some embodiments, a tubular membrane heated
and stretched in the axial direction may exhibit greater tensile
strength in the axial direction as compared to the properties of
the membrane prior to heating and stretching. In this example, the
tensile strength in the radial direction, however, may be similar
to the tensile strength of the membrane in that direction prior to
heating and stretching. Thus, the membrane may have similar
properties in both these directions prior to heating and
stretching, but may exhibit greater tensile strength in the axial
direction after heating and stretching. In some embodiments, the
tensile strength of the membrane is 150%-300% that of the membrane
prior to heating and stretching in the direction of stretching. For
example, the tensile strength of the membrane is at least 150%, at
least 200%, at least 250% or at least 300% that of the membrane
prior to heating and stretching in the direction of stretching. In
some embodiments, a mat may exhibit decreased tensile strength or
other changes in properties in a non-stretched direction disposed
perpendicular to the direction of stretching, as compared to those
properties prior to stretching.
[0189] In some embodiments, a material is stretched in multiple
directions to increase strength or otherwise alter the properties
in those directions. In other embodiments, heating and stretching
change the properties in only one direction. For example, a tube
may be configured to be bolstered against creep in the radial
direction, without substantially affecting the material properties
in the axial direction. Again, in some instances an increase in
particular properties in a first direction is correlated with a
decrease in one or more of the same properties in a second
direction.
[0190] Additionally, materials having different properties in
different directions may be combined to create a composite
construct. For example, a composite construct comprising at least
one layer of axially stretched material and at least one layer of
radially stretched material may exhibit increased strength in both
directions. Various layers having various properties may be
combined to tailor the properties of the resultant construct. It is
within the scope of this disclosure to bond adjacent layers through
various processes, including use of tie layers disposed between
layers and bonded to each layer, heating adjacent layers to create
fiber entanglement, use of adhesives, and so forth. FEP may be used
as a tie layer in some embodiments. Further, ePTFE may be used as a
tie layer in some embodiments. One embodiment of a composite tube
can be created by helically or cigar wrapping a tube of serially
deposited fibers (un-stretched) with a film of heat and stretch
processed material, creating a porous luminal layer and a strong
creep resistant reinforcement layer. Additionally, layers (such as
an impervious layer and/or a porous abluminal layer) may be added
to the construct as well. Each layer may be configured to optimize
a physiologic interaction, for example.
[0191] Multilayered constructs may further comprise reinforcing
structures, such as metal scaffolds or frames. In some embodiments,
a reinforcing structure may comprise one of: Nitinol, stainless
steel, or titanium. Any layer of a construct may be configured to
be a blood contacting layer. Blood contacting layers may be
configured to interact with the blood or other biological elements
and may be configured with certain flow characteristics at the
blood interface. Further, any layer of a multilayered construct may
be configured to be impermeable to tissue or fluid migration. For
example an impermeable tie layer may be disposed between porous
inner and outer layers of a construct.
[0192] Single layer devices or multilayered constructs within the
scope of this disclosure may comprise tubes, grafts, stents, stent
grafts, vascular grafts, patches, prosthetics, or any other medical
appliance. Medical appliances configured for oral surgery and/or
plastic surgery are also within the scope of this disclosure.
[0193] Again, heat and stretch processing may increase strength in
the stretched direction while decreasing strength in a direction
perpendicular to the stretched direction. For example, a tubular
membrane stretched in the axial direction may exhibit greater
strength in the axial as opposed to the radial direction. Further,
a membrane so processed may exhibit greater elasticity or "spring"
in the non-stretched direction oriented perpendicular to the
stretched direction.
[0194] Heating and stretching a mat or lattice of serially
deposited fibers may tend to decrease the thickness of the mat or
lattice. For example, a tubular mat stretched in the range from
200% to 450% may exhibit a decrease in material thickness of
between 10% and 90%, including from 20% to 80% and from 40% to 60%.
Embodiments within these ranges may not exhibit holes or defects
from the stretching process, and the overall surface quality of the
material may be maintained after stretching. Further, these ranges
are intended to correlate the degree of stretching and the decrease
in material thickness, not to constitute upper or lower bounds.
Materials may be stretched further than the given range to further
decrease the material thickness, for instance.
[0195] As stated above, it is within the scope of this disclosure
to heat and stretch various serially deposited fiber mats
comprising various materials. Many of the examples discussed below
refer particularly to PTFE fiber mats which have been processed in
a variety of ways. These examples, or any other example referencing
PTFE, may analogously apply to other materials as well. Specific
temperatures for heating or otherwise processing a material may be
analogously applied to other materials by considering the material
properties (such as melting point) of such materials and
analogizing to the examples below.
[0196] Generally, serially deposited PTFE fiber mats may be heated
at temperatures between about 65 degrees C. and about 400 degrees
C. while heating and stretching the mats. For example, serially
deposited PTFE fiber mats may be heated at temperatures above about
65 degrees C., above about 100 degrees C., above about 150 degrees
C., above about 200 degrees C., above about 250 degrees C., above
about 300 degrees C., above about 350 degrees C., above about 370
degrees C., and above about 385 degrees C. Additionally, serially
deposited PTFE fiber mats may be stretched at room temperature (22
degrees C.) without heating.
[0197] Serially deposited PTFE mats may be stretched from 150% to
500% of the initial length of the mat in the direction of
stretching, including stretching mats to between 200% and 350%,
between 250% and 300%, and between 300% and 500% of the original
length of the mats in the direction of stretching. The amount of
length change may be related to the temperature at which the mat is
heated, the force applied when the mat is stretched, the original
thickness of the mat, and the rate at which the mat is
stretched.
[0198] Processing serially deposited fiber mats or lattices through
heating and stretching may impact various properties of the mats.
Tensile strength, resistance to creep, elasticity, and so forth may
all be impacted. In some embodiments, processed mats are used as
layers of multilayered constructs to provide particular properties
in a particular direction.
[0199] The temperature at which mats of serially deposited PTFE
fibers are heated may affect the tendency of the fibers of the mats
to align after the mats are stretched. Higher temperatures
generally correlate with increased fiber alignment. Generally, PTFE
mats heated at or above 370 degrees C. exhibit more fiber alignment
than mats heated at temperatures lower than 370 degrees C.
Additionally, an increase in tensile strength is correlated with
heating and stretching PTFE, whether or not the mat was heated at
370 degrees C. or more. The amount of the increase in tensile
strength may be affected by the temperature at which the mat was
heated and the amount the material was stretched.
[0200] Serially deposited fibers may be set in various geometries
by constraining the fibers in a particular geometry and heating the
fibers. For example, in some embodiments, constraining a previously
sintered (or otherwise structurally set) mat or lattice of serially
deposited fibers in a particular configuration, softening the
material of the mat or lattice (for example by heating), and
allowing the material to reset may result in a "memory" effect
wherein the material retains at least a portion of the constrained
geometry. Materials may be shape-set as described herein whether or
not the materials have been heated and stretched as described
above.
[0201] In embodiments comprising serially deposited polymeric
fibers, heating the material at about the crystalline melt point of
the material may facilitate setting of the geometry.
[0202] In one exemplary embodiment, a tubular membrane may be
serially deposited on a mandrel, sintered, and removed from the
mandrel. Though this specific example includes a tubular membrane,
the present disclosure also applies to sheets, spheres, and other
geometries of serially deposited fiber mats. The tubular membrane
of sintered serially disposed polymeric fibers may then be
constrained in a variety of configurations. For example, the
membrane may be compressed onto a mandrel such that the tubular
membrane is compressed along a shorter length, tending to create
annular ridges or corrugations along the length of the
membrane.
[0203] Once the membrane is constrained into the desired shape, the
membrane may be heated while constrained. After heating and
cooling, the membrane may tend to retain the constrained shape. A
tubular membrane set in a corrugated shape may exhibit elasticity
between the ends of the membrane due to the corrugation. When
pulled in the axial direction (opposite the direction the membrane
was compressed prior to heat-setting) then released, the membrane
will tend to return to the heat-set corrugated configuration.
[0204] Furthermore, in the case of a corrugated tubular membrane,
corrugations may facilitate bending of the membrane. Specifically,
the annular corrugations may both reinforce the membrane and
provide elasticity such that the membrane can bend in a variety of
configurations without kinking.
[0205] Multilayered constructs comprising corrugated or otherwise
heat-set components are within the scope of this disclosure. For
example, a tubular graft may comprise a corrugated tube coupled to
a second tube having a relatively smooth wall (with respect to the
corrugated tube). The tubes may overlap and be coaxial. In some
embodiments a construct will be configured with a smooth wall tube
defining an inside diameter (which may be a blood contacting
surface) and a corrugated tube defining an outside diameter (to
provide support to the construct). As used herein, a smooth wall
component refers to a component without visually apparent surface
defects or irregularities.
EXAMPLES
[0206] A number of exemplary PTFE mats were produced according to
the electrospinning disclosure above. FIGS. 12A-14B are SEMs of the
PTFE mats produced in each exemplary process. FIGS. 15-16 are
graphs comparing materials electrospun according to the present
disclosure with other materials. Finally, FIG. 17 is a
trichrome-stained histology light microscopy image of an
electrospun PTFE material. The following examples are intended to
further illustrate exemplary embodiments and are not intended to
limit the scope of the disclosure.
Example 1
[0207] An experimental apparatus was assembled inside a ventilated
hood. The experimental apparatus comprised a KD Scientific
motorized syringe pump, a 10 ml syringe fitted with a 25 gauge
metal syringe tip, and a Spellman CZE 1000R high voltage source.
The positive lead of the high voltage source was connected to the
metal syringe tip. The negative lead of the high voltage source was
connected to a metal collector mounted about 7 inches from the
syringe tip.
[0208] Polymer solution was prepared by obtaining a 60 wt % PTFE
aqueous dispersion. Crystalline PEO with an average chain molecular
weight of approximately 300,000 was used. The PEO was mixed with
water in an approximately 30 wt % concentration and mixed until
substantially homogeneous. The 60 wt % PTFE dispersion was added to
the PEO/water mixture to create five concentrations: a 0.016 g/ml
mixture of PEO to PTFE dispersion, a 0.02 g/ml mixture of PEO to
PTFE dispersion, a 0.032 g/ml mixture of PEO to PTFE dispersion, a
0.04 g/ml mixture of PEO to PTFE dispersion, and a 0.048 g/ml
mixture of PEO to PTFE dispersion. (Additionally, 35 ml of a 0.05
g/ml mixture of PEO to PTFE dispersion was obtained by adding 5 ml
of water to 1.4 grams of PEO which was then mixed with 30 ml of
PTFE dispersion. This concentration was not directly tested.) The
PTFE/PEO/water combination was then mixed until substantially
homogeneous. The resulting mixture was strained through a 70
micrometer nylon cell strainer to remove any remaining clumps in
the mixture.
[0209] Each polymer solution was separately loaded into the
syringe, and the syringe pump configured to dispense 0.01 ml of
solution per minute. The syringe pump was activated and the high
voltage power source turned on at 15,000 kV. The solution was
forced through the syringe tip, where it was electrically charged
and pulled in a small diameter fiber toward the collector. The
process was run for approximately 15 minutes for each polymer
solution, and the collector removed and sintered after running each
solution. The collector and thin mat of fibers was sintered in an
oven at 385 degrees C. for about 10 minutes. The resulting mat was
removed and the collector used for the next solution. Each sintered
mat was analyzed using a JEOL JSM-6510LV Scanning Electron
Micrograph.
[0210] FIGS. 12A-12E are SEMs of the five fiber mats corresponding
to the five polymer solutions spun in this example. Each SEM is at
950.times. magnification. FIG. 12A corresponds to the 0.016 g/ml
mixture, FIG. 12B to the 0.02 g/ml mixture, FIG. 12C to the 0.032
g/ml mixture, FIG. 12D to the 0.04 g/ml mixture, and FIG. 12E to
the 0.048 g/ml mixture.
[0211] It was observed that, in this example, the concentration of
PEO to PTFE dispersion appeared to affect fiber formation on the
mat. Both fiber diameter and the presence of "beads" within the
fibers appeared affected by the concentration. Solutions with low
concentrations (less than about 0.02 g/ml) produced beading that
may have been due to "sputtering" as the solution left the syringe.
Again, the resultant fiber mats are shown in FIGS. 12A-12E.
Additionally, it was observed that solutions with less than about
0.015 g of PEO per ml of PTFE dispersion did not tend to form
fibers, and solutions with greater than 0.06 g/ml concentrations
tended to dry in the syringe prior to electrospinning, creating
macroscopic defects in the mats.
[0212] In some embodiments, a construction comprised at least
partially of beaded fibers may be incorporated into a stent
covering or graft. For example, beaded fibers may increase
endothelial attachment in some instances. Thus, electrospun PTFE
beaded fibers, such as those shown in FIGS. 12A and 12B, may be
utilized in some constructions. As discussed above, beading may
occur with mixtures from about 0.010 g/ml to about 0.018 g/ml of
PEO per ml of PTFE.
Example 2
[0213] The apparatus described in Example 1 was again utilized to
electrospin eight additional solutions in connection with this
Example. Substantially the same procedures described above were
followed. However, additional water was added to the PEO-water
mixture prior to mixing with the PTFE dispersions. The additional
water appeared to facilitate electrospinning of a greater range of
PEO to PTFE dispersion concentrations, while minimizing beading and
sputtering. FIGS. 13A-13H are SEMs corresponding to eight different
concentrations with additional water added. Each SEM is at
950.times. magnification. FIG. 13A corresponds to a concentration
of 0.0256 g/ml of PEO to PTFE dispersion, FIG. 13B to a
concentration of 0.030 g/ml, FIG. 13C to a concentration of 0.035
g/ml, FIG. 13D to a concentration of 0.040 g/ml, FIG. 13E to a
concentration of 0.045 g/ml, FIG. 13F to a concentration of 0.050
g/ml, FIG. 13G to a concentration of 0.060 g/ml, and FIG. 13H to a
concentration of 0.070 g/ml.
[0214] It was observed that the additional water enabled bead-free
electrospinning of a wider range of concentrations than was seen in
Example 1. In the solution of FIG. 13C, it was observed that the
PEO did not fully evolve during the sintering process. This effect
was not seen in connection with the solutions of Example 1;
however, it was rare in connection with the solutions of Example
2.
Example 3
[0215] The apparatus described in Example 1 was again utilized to
electrospin an FEP/PEO dispersion. The polymer solution was
prepared by obtaining a 55 wt % FEP aqueous dispersion. Crystalline
PEO with an average chain molecular weight of approximately 300,000
was used. The PEO was mixed with water in an approximately 30 wt %
concentration and mixed until substantially homogenous. The 55 wt %
FEP dispersion was added to the PEO/water mixture to create a 0.06
g/ml mixture of PEO to FEP dispersion. The FEP/PEO/water
combination was then mixed until substantially homogeneous. The
resulting mixture was strained through a 70 micrometer nylon cell
strainer to remove any remaining clumps in the mixture.
[0216] The polymer solution was loaded into the syringe and the
syringe pump was configured to dispense 0.01 ml of solution per
minute. A sintered tube of electrospun 0.048 g/ml PTFE to PEO from
Example 1 was placed over the collector. The syringe pump was
activated and the high voltage power source turned on at 15,000 kV.
The solution was forced through the syringe tip, where it was
electrically charged and pulled in a small diameter fiber toward
the collector. The electrospun FEP fibers were collected on top of
the sintered PTFE tube. The process was run for approximately 15
minutes and the collector was removed and heated to 325 degrees C.
for 10 minutes. The collection and the heating processes were
repeated one time to increase the thickness of the covering. The
resulting mat was removed from the collector. The cooked FEP mat
was analyzed using a JEOL JSM-6510LV Scanning Electron
Micrograph.
[0217] FIGS. 14A and 14B are SEMs of the cooked electrospun FEP
over the electrospun PTFE. FIG. 14A is at 180.times. magnification
and FIG. 14B is at 950.times. magnification.
[0218] It was observed in this example that upon heating, the
electrospun FEP fibers would melt, creating a semi-porous coating
over the electrospun PTFE fibers. In other examples, the porosity
could be increased or decreased by increasing or decreasing,
respectively, the amount of time the FEP is electrospun onto the
PTFE fibers. Additionally, changing the heating temperature may
also affect the porosity of the cooked FEP layer. For example, the
higher the temperature, the more the FEP may tend to flow and fill
in voids. In some embodiments, an impervious layer may be created
by repeated electrospinning of an FEP layer. This type of coating
could additionally be used to create a secondary porosity for
hydrophobic or hydrophilic properties as well as a porous coating
configured to screen for ingrowth cells based on cell size.
Furthermore, the construct of this example exhibited an increase in
tensile strength as well as elasticity over the electrospun PTFE
alone.
Example 4: Dip Coating
[0219] Multilayered constructs may be formed in some embodiments by
dip coating an electrospun or other material. In some embodiments,
cracking of the dip coating may be reduced by reducing the
thickness of the dip solution.
[0220] For example, a PTFE layer was dip coated on a construct by
adding 20 ml of water to 50 ml of a 60 wt % PTFE dispersion to thin
the dispersion. A fiber mat was then dipped in the solution to coat
the mat. The dip coat was then sintered at 385 degrees C. for 15
minutes.
[0221] An FEP layer was dip coated on a construct by adding 20 ml
of water to 50 ml of a 55 wt % dispersion to thin the dispersion. A
fiber mat was then dipped in the solution to coat the mat. The dip
coat was then cooked at 325 degrees C. for 15 minutes.
[0222] In other embodiments, more or less water, for example from
about 10 ml to about 50 ml, may be added to similar amounts and
concentrations of dispersion to thin the dispersion. Additionally,
substances other than, or in addition to, water may be used to thin
a dispersion for dip coating. For example, a surfactant or a
solvent may be used. In some such cases the surfactant or solvent
may later be removed from the construct, including embodiments
where it is allowed to evaporate when the coat is sintered or
cooked. Alcohols, glycols, ethers, and so forth may be so
utilized.
Example 5: Endothelial Cell Attachment Assay
[0223] In some embodiments, the degree of endothelial cell
attachment to a material may be determined according to the
following assay. As used herein, values for "in vitro endothelial
cell attachment" are determined by following the procedure
disclosed below.
[0224] In this assay, the capacity of PTFE sample materials were
tested to determine their ability to support the growth and/or
attachment of porcine aortic endothelial cells. The PTFE materials
comprised electrospun PTFE fiber mats spun from a 0.032 g/ml
solution similar to that described in connection with FIG. 12C and
Example 1. A standard curve with a range of endothelial cell
seeding densities was generated to correlate cell attachment with
PTFE materials.
[0225] First, the PTFE materials and Beem capsules were ethylene
oxide (ETO) sterilized. The Beem capsules were assembled with PTFE
materials in an aseptic field.
[0226] An endothelial cell standard curve was prepared in a 96 well
plate with duplicate wells for 0, 2.5K, 5K, 10K, 20K, 40K, 60K, and
80K endothelial cells per well in 200 .mu.l total volume of media.
The endothelial cells were allowed to attach 90 minutes at
37.degree. C. in 5% CO.sub.2. At 90 minutes, 20 .mu.l of 5 mg/ml
MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide)
was added to each well and incubated at 37.degree. C. in 5%
CO.sub.2 for 3 hours. The assembly was inverted and the 96 well was
gently rapped on an absorbent bench coat to remove media and
unattached cells.
[0227] Actively respiring cells convert the MTT to an intracellular
purple formazan product. Thus, after the incubation period,
intracellular formazan must be solubilized by isopropanol. 200
.mu.l of 100% isopropanol was added to wells in the 96 well plate,
which was incubated at room temperature for 30 minutes. The
solution in each well was then mixed by pipeting. 100 .mu.l of
supernatant from the endothelial cell standard wells were
transferred to clean wells in 96-well clear-bottomed plate. The
optical density (OD) was read at 560 nm and 650 nm. The background
absorbance at 650 nm was subtracted from the 560 nm absorbance and
the results, minus control, were graphed.
[0228] As used herein, "optical density" (OD) measures the
absorbance of light in the solution. In this example, the greater
the number of cells which attach to the material, and are available
to react with the MTT, the greater the amount of formazan generated
within the cell, the darker the color of purple formazan extracted
into the supernatant, and, therefore, the higher the OD (or
absorbance of light). Assuming that all the cells in the experiment
convert MTT to its formazan derivative at the same rate, the OD
measurement is directly proportional to the number of attached
cells.
[0229] The PTFE materials in Beem capsules were pre-wet with 200
.mu.l of D-PBS (Dulbecco's phosphate buffered saline) and incubated
at 37.degree. C. in 5% CO2 for 50 minutes. The D-PBS was removed
from the Beem capsules. The Beem capsules were then seeded with 50K
endothelial cells in 200 .mu.l of complete media, with the
exception of a Beem control capsule for each test material, which
contained complete media only (no cells). The media-only Beem
capsule controls were processed identically as the Beem capsules
seeded with endothelial cells. The endothelial cells were allowed
to attach 90 minutes at 37.degree. C. in 5% CO.sub.2. At 90
minutes, 20 .mu.l of 5 mg/ml MTT
((3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was
added to each Beem capsule, including controls, and incubated at
37.degree. C. in 5% CO.sub.2 for 3 hours. The Beem capsules were
inverted and gently rapped on an absorbent bench coat to remove
media and unattached cells.
[0230] The PTFE materials were carefully removed from Beem
assemblies and placed in a microcentrifuge tube containing 200
.mu.l of 100% isopropanol for 30 minutes. The microcentrifuge tubes
were then vortexed with the PTFE materials and isopropanol for 3-5
minutes to release formazan into the supernatant. 100 .mu.l of
supernatant from the microcentrifuge tubes were transferred to
clean wells in 96-well clear-bottomed plate (the same plate with
the standards, described above). The OD was read at 560 nm and 650
nm. The background absorbance at 650 nm was subtracted from the 560
nm absorbance and the results, minus control were analyzed. The
number of cells attached to each sample was interpolated from the
standard curve results. As described in the standard curve wells
outlined above, the MTT formazan was produced in proportion to the
number of attached live cells within each capsule.
[0231] A standard curve of porcine endothelial cells was prepared
for each unique assay of test materials and run in parallel with
the materials in Beem capsules. In addition to electrospun samples,
commercial expanded PTFE (ePTFE) material samples were also tested
to provide a reference or comparison for the electrospun materials.
The control ePTFE material used was the commercially available Bard
Impra Straight Thinwall Vascular Graft (Cat #80S06TW), which is
often used as a control material in relevant literature as it is
known to have a favorable biologic response and favorable
endothelial cell attachment.
[0232] To quantify the measurements obtained for the test
materials, a standard curve was generated by measuring the optical
density using the wells known to contain 0, 2.5K, 5K, 10K, 20K,
40K, 60K, and 80K endothelial cells per well. Using the generated
standard curve, the number of attached cells in the experimental
wells was then calculated.
[0233] The materials disclosed herein may be configured to achieve
various amounts of in vitro endothelial cell attachment as defined
by this assay. As described above, changes to the percent porosity
of a mat, the thickness of the mat, and/or the diameter of fibers
comprising the mat may influence the characteristics of the mat,
including the response of the material to this assay. Thus, the
number of cells attached to the electrospun materials were compared
by normalizing the results to the number of cells attached the
ePTFE control material. The endothelial cell attachment for the
electrospun material assayed was greater that 170% of the
endothelial cell attachment of the ePTFE control material.
Materials within the scope of this disclosure may have in vitro
endothelial cell attachments of 170%, more than 170%, or less than
170% of an ePTFE control material. For example, from 30% to more
than 170% of the endothelial cell attachment of an ePTFE control
material, including more than 30%, more than 40%, more than 50%,
more than 75%, more than 100%, more than 125%, more than 150%, more
than 160%, more than 165%, and more than 170% of the endothelial
cell attachment of an ePTFE control material.
Example 6: Rodent Study
[0234] In this example, the biocompatibility response of an
electrospun polymer fiber-coated material was compared against
commercially-available ePTFE grafts and similar constructs. Eleven
rodents were each subcutaneously implanted with a pledget of
polymer material, the pledget obtained using a 2-4 mm biopsy punch.
Two rodents were implanted with an electrospun fiber coated PTFE
labeled MM1 E. This material was obtained by electrospinning a
0.032 g/ml solution, similar to that discussed in Example 5. The
implanted material comprised a layered construct, with an FEP film
disposed between two layers of electrospun PTFE coating. Two
rodents were implanted with portions of a commercially available
ePTFE stent graft material labeled ePTFE Sample 1, one rodent with
the inside diameter (ID) material and one with the outside diameter
(OD) material. Likewise, two rodents were implanted with inside and
outside diameter materials from a commercially available ePTFE
stent graft material labeled ePTFE Sample 2. Two rodents were
implanted with inside and outside diameter materials from a
commercially available heparin surface-coated ePTFE stent graft
material labeled ePTFE Sample 3. Two rodents were implanted with
inside and outside diameter materials from an ePTFE vascular graft
material labeled ePTFE Sample 4. ePTFE samples 1 to 4 are a
representative sampling of commercially available ePTFE stents and
vascular grafts. Finally, one rodent was implanted with a portion
of an ePTFE stent graft material labeled Control ePTFE. This sample
is a commercially available ePTFE material produced by Bard which
is often used as a control material in relevant literature.
[0235] After two weeks of implantation the implanted samples were
analyzed for inflammation and cellular penetration. Specifically,
pledgets of each of the above materials were cut or punched prior
to surgery. Materials were ETO sterilized. On the day of surgery,
subjects were prepped for sterile surgical procedures. Each subject
was ear tagged for unique study identification and for the ability
to evaluate subjects based on subject number to maintain an
investigator-blinded analysis of the data, prior to de-coding the
data.
[0236] At the end of the two-week implantation period, all subjects
were euthanized and implanted materials and surrounding tissue were
explanted. The explants were immediately placed into 2%
paraformaldehyde fixative for up to 48 hours and then changed into
a 70% ethanol solution for subsequent processing for paraffin
embedding. Tissue blocks were processed for histology and
immunohistochemistry then stained with hematoxylin and eosin or
trichrome stain or reacted with antibodies for vWF (an endothelial
cell marker) and CD-68 (a marker for activated macrophages). All
slides that were subjectively evaluated were digitally scanned
using the Aperio ScanScope CS system. Inflammatory response and
cellular penetration into the material were quantified as described
below.
A. Inflammatory Response
[0237] The inflammatory responses towards the various implanted
PTFE materials were compared. The outer diameter (OD) and the inner
diameter (ID) of the material were separately characterized. To
quantify the inflammatory response, an established equation was
used to provide weight to staining intensities and provide a
quantitative value to the macrophage counts. The equation was based
on equations currently used by pathologists in cancer research
called the H-score (Nakopoulou et al., Human Pathology vol. 30, no.
4, April 1999). The H-score was obtained by the formula:
(3.times.percentage of strongly staining
nuclei)+(2.times.percentage of moderately staining
nuclei)+(percentage of weakly staining nuclei)=a range of 0 to
300
[0238] Strongly staining nuclei were represented by red in a false
color mark-up in a digital algorithm, moderately stained nuclei
were represented by orange in the false color mark-up, and weakly
stained nuclei were represented by yellow. By inserting these
counts into the formula above, a quantitative inflammatory response
is obtained. A one-way ANOVA analysis with a Tukey post-hoc test
(p<0.05) was used to assess statistical differences.
[0239] FIG. 15 illustrates the inflammatory response caused by the
various materials as quantified by H-Score. Qualitatively, most
materials were found to be moderately reactive with an average
inflammatory score between 101 to 200, with scores over 250
considered inflammatory. The present electrospun PTFE material (MM1
E), both OD and ID and the ePTFE Sample 1 OD material had
inflammatory H-scores measuring below 150. Materials found to be
strongly reactive with inflammatory scores well above 150, such as
201 to 300 were the ePTFE Sample 1 ID and ePTFE Sample 3 ID
materials. The difference between the lower H-Scores and the higher
H-scores was statistically significant. The relatively low response
of ePTFE Sample 1 OD was counteracted by the high response seen on
the ID of the same sample.
[0240] Lower inflammation in response to the MM1 E material
indicates that it is less hostile to surrounding biological tissue.
MM1 E is the only material that showed significantly lower
inflammatory response on both the OD and ID, both of which would be
exposed to biological cells and tissue during use as a stent
coating. More specifically, the OD is adjacent the endothelial
layer of a blood vessel and the ID is in contact with blood cells.
These results indicate that MM1 E is more biocompatible than other
available materials.
B. Cellular Penetration
[0241] The ability of cells to penetrate the material from both the
inner to outer surfaces and the outer to inner surfaces was
measured and defined as cellular penetration. More specifically,
cellular penetration as a percentage of PTFE material thickness was
determined by performing measurements of the material thickness at
100 .mu.m intervals and measuring the depth of cellular penetration
from the superficial surface towards the midline. The percent of
cellular penetration was measured from the superficial sides (from
inner surface and from outer surface) of the material. A one-way
ANOVA analysis with a Tukey post-hoc test (p<0.05) was used to
assess statistical differences between groups.
[0242] This analysis demonstrated that all materials tested had
some degree of cellular penetration meaning that cells were able to
migrate into the architecture of the PTFE construct. As shown in
FIG. 16, the MM1 E-ID and VT-ID materials were found to be
statistically different from each other. However, relevant trends
were observed from the remainder. This graph demonstrates that
various PTFE materials/devices may have different cellular
ingrowth. For example, both the MM1 E and Fluency PTFE materials
(both OD and ID) demonstrated a tendency towards promoting a
greater amount of cellular penetration.
[0243] Of particular relevance, the MM1 E material was unique in
that it appeared to encourage the greatest cellular penetration
when characterized from the edge of the material (superficial side)
across to the middle layer. Both the MM1 E-OD and MM1 E-ID
constructs had greater than 80% migration of cells to the
relatively impermeable middle layer. FIG. 17 shows how cells
migrate through the outer (OD) and inner (ID) layers, but most
cannot penetrate the middle layer. Specifically, the dotted lines
in FIG. 17 indicate the middle layer of the construct. The lack of
dark spots (stained cells) in this zone reflects a lack of cellular
migration or cellular penetration into this zone. The areas
immediately adjacent the middle zone are the outer and inner
layers, one of which is indicated by the double headed arrow. The
dark spots in these zones reflect cellular penetration into these
more porous portions of the construct.
EXEMPLARY EMBODIMENTS
[0244] The following embodiments are illustrative and exemplary and
not meant as a limitation of the scope of the present disclosure in
any way.
[0245] I. Medical Appliance
[0246] In one embodiment a medical appliance comprises a first
layer of electrospun polytetrafluoroethylene (PTFE), having an
average percent porosity between about 30% and about 80%.
[0247] The electrospun PTFE may comprise a mat of PTFE
nanofibers.
[0248] The electrospun PTFE may comprise a mat of PTFE
microfibers.
[0249] The medical appliance may further comprise a second layer of
electrospun PTFE nanofibers, wherein the first layer of electrospun
PTFE is disposed such that it defines a first surface of the
medical appliance, and the second layer of electrospun PTFE is
disposed such that it defines a second surface of the medical
appliance.
[0250] In some embodiments, the first layer of electrospun PTFE has
an average percent porosity between about 35% and about 70%.
[0251] In other embodiments, the first layer of electrospun PTFE
has an average percent porosity of between about 40% and about
60%.
[0252] The first layer of electrospun PTFE may have an average pore
size configured to permit tissue ingrowth on the first surface of
the medical appliance.
[0253] The first layer of electrospun PTFE may permit tissue
ingrowth.
[0254] The second layer of electrospun PTFE may have an average
percent porosity of about 50% or less.
[0255] The second layer of electrospun PTFE may have an average
pore size configured to resist tissue ingrowth into or through the
second surface of the medical appliance.
[0256] The medical appliance may also further comprise a cuff
adjacent to an end of the medical appliance, the cuff configured to
permit tissue ingrowth into or tissue attachment to the cuff.
[0257] The medical appliance may further include a tie layer
disposed between the first layer of electrospun PTFE and the second
layer of electrospun PTFE.
[0258] The tie layer may be configured to inhibit tissue ingrowth
into or through the tie layer.
[0259] The first and second layers of electrospun PTFE and the tie
layer may be configured to inhibit an unfavorable inflammatory
response.
[0260] The first and second layers of electrospun PTFE material may
have inflammatory H-scores measuring below about 150.
[0261] The first and second layers of electrospun PTFE material may
be configured to allow an average cellular penetration of over
20%.
[0262] The first and second layers of electrospun PTFE and the tie
layer may be configured to inhibit hyperplastic tissue growth
including neointimal or pseudointimal hyperplasia.
[0263] The tie layer may comprise PTFE.
[0264] The tie layer may comprise a thermoplastic polymer.
[0265] The tie layer may comprise fluorinated ethylene propylene
(FEP).
[0266] The tie layer may comprise electrospun FEP.
[0267] The electrospun FEP layer may be cooked.
[0268] The electrospun FEP layer may be configured to resist
cellular ingrowth.
[0269] The electrospun FEP layer may be substantially impervious to
cellular ingrowth.
[0270] The electrospun FEP layer may be substantially
non-porous.
[0271] The electrospun FEP layer may be substantially porous.
[0272] The FEP may partially bond to the nanofibers of the first
and second layers of electrospun PTFE.
[0273] The FEP may flow into and coat the nanofibers of the first
and second layers of electrospun PTFE.
[0274] The FEP may coat the nanofibers of the first and second
layers while maintaining the porosity of the layers.
[0275] The electrospun PTFE may be formed from a mixture comprising
PTFE, polyethylene oxide (PEO), and water.
[0276] The mixture may be formed by combining a PTFE dispersion
with PEO dissolved in water.
[0277] The mixture may comprise between about 0.02 and about 0.070
grams of PEO per ml of 60 wt % PTFE aqueous dispersion.
[0278] The medical appliance may further comprise a main lumen
extending to a bifurcation and two branch lumens extending from the
bifurcation.
[0279] The medical appliance may further comprise a main lumen and
one or more branch lumens extending from a wall of the main
lumen.
[0280] The electrospun PTFE may comprise a mat of beaded PTFE
fibers.
[0281] At least one of the first and second layers of electrospun
PTFE may have been heated and stretched after sintering.
[0282] The medical appliance may further comprise a reinforcing
layer.
[0283] The reinforcing layer may comprise electrospun PTFE.
[0284] The reinforcing layer may have greater tensile strength in a
first direction of the layer than in a second direction
perpendicular to the first direction.
[0285] The medical appliance may comprise a tubular construct.
[0286] The reinforcing layer may comprise a tube disposed such that
the first direction is in the axial direction of the tubular
construct.
[0287] The reinforcing layer may comprise a strip wrapped helically
around a portion of the tubular construct.
[0288] The medical appliance may have increased resistance to creep
in the radial direction as compared to the axial direction.
[0289] II. Stents
[0290] In one embodiment, a stent comprises a frame configured to
resist radial compression when disposed in a lumen of a patient,
and a covering disposed on at least a portion of the scaffolding
structure, the covering comprising a first layer of electrospun
polytetrafluoroethylene (PTFE), the first layer having a percent
porosity between about 30% and about 80%.
[0291] The electrospun PTFE may comprise a mat of PTFE nanofibers
and/or PTFE microfibers.
[0292] The stent may further comprise a second layer of electrospun
PTFE nanofibers, wherein the stent is generally tubular in shape
and the first layer of electrospun PTFE is disposed such that it
defines an inside surface of the stent and the second layer of
electrospun PTFE is disposed such that it defines an outside
surface of the stent.
[0293] In such an embodiment, the first layer of electrospun PTFE
may have an average percent porosity between about 35% and about
70%.
[0294] The first layer of electrospun PTFE may have an average
percent porosity of between about 40% and about 60%.
[0295] The first layer of electrospun PTFE may have an average pore
size configured to permit tissue ingrowth on the inside surface of
the stent.
[0296] The first layer of electrospun PTFE may permit tissue
ingrowth.
[0297] The second layer of electrospun PTFE may have an average
percent porosity of about 50% or less.
[0298] The second layer of electrospun PTFE may have an average
pore size configured to resist tissue ingrowth into or through the
second layer of electrospun PTFE.
[0299] The stent may further comprise a cuff adjacent to an end of
the stent, the cuff configured to permit tissue ingrowth into the
cuff.
[0300] A tie layer may be disposed between the first layer of
electrospun PTFE and the second layer of electrospun PTFE.
[0301] The tie layer may be configured to inhibit tissue ingrowth
into the tie layer.
[0302] The tie layer may comprise PTFE.
[0303] The tie layer may be a thermoplastic polymer.
[0304] The tie layer may be fluorinated ethylene propylene
(FEP).
[0305] The tie layer may be electrospun FEP.
[0306] The electrospun FEP layer may be cooked.
[0307] The electrospun FEP layer may be configured to resist
cellular ingrowth.
[0308] The electrospun FEP layer may be substantially impervious to
cellular ingrowth.
[0309] The electrospun FEP layer may be substantially
non-porous.
[0310] The electrospun FEP layer may be porous.
[0311] The FEP may partially bond to the nanofibers of the first
and second layers of electrospun PTFE.
[0312] The second layer of electrospun PTFE material may be
configured to permit tissue ingrowth into the second layer to
reduce device migration.
[0313] The first and second layers of electrospun PTFE and the tie
layer may be configured to inhibit hyperplastic tissue growth such
as neointimal or psuedointimal hyperplasia.
[0314] The first and second layers of electrospun PTFE and the tie
layer may be configured to inhibit an unfavorable inflammatory
response.
[0315] The first and second layers of electrospun PTFE material
have inflammatory H-scores measuring below about 150.
[0316] The first and second layers of electrospun PTFE material may
be configured to allow an average cellular penetration of over
20%.
[0317] The FEP may flow into and coat the nanofibers of the first
and second layers of electrospun PTFE.
[0318] The FEP may coat the nanofibers of the first and second
layers while maintaining the porosity of the layers.
[0319] The electrospun PTFE may be formed from a mixture comprising
PTFE, polyethylene oxide (PEO), and water.
[0320] The mixture may be formed by combining a PTFE dispersion
with PEO dissolved in water.
[0321] The electrospun PTFE may be electrospun onto a rotating
mandrel.
[0322] The mixture may comprise between about 0.02 and about 0.070
grams of PEO per ml of 60 wt % PTFE aqueous dispersion.
[0323] The frame of the stent may be comprised of a single
wire.
[0324] The wire may be helically wound around a central axis of the
stent.
[0325] The wire may have a wave-like pattern defining apexes and
arms.
[0326] Alternating apexes adjacent an end of the stent may have
different relative heights.
[0327] Each apex may have a radius of between about 0.12 mm and
0.64 mm.
[0328] The stent may have a first portion disposed near the midbody
of the stent and second and third portions disposed near the ends
of the stent, and wherein the arms disposed within the second and
third portions are relatively longer than the arms disposed within
the first portion.
[0329] Moreover, a distance, apex to apex length, may be defined as
the distance between a first apex and a second apex wherein the
first apex lies on a first coil of wire and the second apex lies on
a second coil of wire adjacent to the first coil, and wherein the
first apex and the second apex lies substantially on a line on the
outer surface of the stent, the line being co-planar with and
parallel to a central axis of the stent, wherein the apex to apex
distance is smaller at the midbody of the stent, relative to the
apex to apex distance near the ends of the stent.
[0330] The stent may be structured such that a midbody portion of
the stent is relatively less compressible than a first and a second
end of the stent.
[0331] The stent may further comprise a main lumen extending to a
bifurcation and two branch lumens extending from the
bifurcation.
[0332] The stent may further comprise a main lumen and one or more
branch lumens extending from a wall of the main lumen.
[0333] The electrospun PTFE may comprise a mat of beaded PTFE
fibers.
[0334] III. Tubular Vascular Prosthesis
[0335] In one embodiment, a tubular vascular prosthesis comprises a
porous inner layer, a porous outer layer, and a substantially
non-porous tie layer disposed between the inner layer and the outer
layer.
[0336] At least one of the inner layer and the outer layer may
comprise an electrospun material.
[0337] The tie layer may be substantially impervious to cellular
ingrowth.
[0338] The inner and outer layers may be configured to permit
cellular ingrowth.
[0339] IV. Method of Constructing a Medical Appliance
[0340] In one embodiment, a method of constructing a medical
appliance comprises electrospinning a first tube of
polytetrafluoroethylene (PTFE) onto a mandrel, the first tube
having a percent porosity between about 30% and about 80%, and
sintering the first tube.
[0341] The first tube of PTFE may be electrospun onto a rotating
mandrel.
[0342] The method may further comprise applying a second tube of
electrospun PTFE around the first layer.
[0343] The method may further comprise applying a scaffolding
structure around the first tube, and applying a fluorinated
ethylene propylene (FEP) layer around the first tube and the
scaffolding structure, prior to applying the second tube of
electrospun PTFE.
[0344] The FEP layer may be configured to inhibit tissue ingrowth
into or through the FEP layer.
[0345] The method may further comprise heating the medical
appliance such that the FEP layer bonds to the first and second
tubes.
[0346] The FEP may partially bond to the fibers of the first and
second tubes.
[0347] The FEP may flow into and coat the fibers of the first and
second tubes.
[0348] The FEP may coat the fibers of the first and second tubes
while maintaining the porosity of the tubes.
[0349] The second tube of electrospun PTFE may be formed by a
method comprising electrospinning the second tube of PTFE onto a
rotating mandrel and sintering the second tube.
[0350] A compressive wrap may be applied around the second tube
before the medical appliance is heat treated.
[0351] Electrospinning the first tube of PTFE may comprise mixing a
PTFE dispersion with polyethylene oxide (PEO), wherein the PEO is
dissolved in water to form a mixture; and discharging the mixture
from an orifice onto the rotating mandrel.
[0352] The mixture may comprise between about 0.02 and about 0.07
grams of PEO per ml of 60 wt % PTFE aqueous dispersion.
[0353] The mixture comprises between about 0.03 and about 0.04
grams of PEO per ml of 60 wt % PTFE aqueous dispersion.
[0354] The method may further comprise coupling a cuff to an end of
the medical appliance, the cuff configured to permit tissue
ingrowth into the cuff.
[0355] V. Method for Promoting Endothelial Cell Growth
[0356] In one embodiment, a method for promoting endothelial cell
growth on an implantable medical appliance comprises implanting the
medical appliance into a patient, the medical appliance coated with
at least one electrospun polymer layer having a percent porosity of
between about 35% and about 70%, such that endothelial cells grow
on or attach to the surface of the at least one electrospun polymer
layer.
[0357] The implantable medical appliance may comprise a stent.
[0358] The implantable medical appliance may comprise a graft.
[0359] The at least one electrospun polymer layer may comprise an
electrospun PTFE layer.
[0360] The medical appliance may be coated with a second polymer
layer that inhibits tissue or fluid migration through the second
polymer layer.
[0361] The second polymer layer may comprise an FEP layer.
[0362] The electrospun fibrous PTFE may comprise randomized
microfibers or nanofibers.
[0363] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 30% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0364] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 40% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0365] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 50% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0366] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 75% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0367] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 100% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0368] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 125% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0369] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 150% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0370] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 160% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0371] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 165% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0372] The at least one polymer layer of the implanted medical
appliance may be configured to permit at least 170% in vitro
endothelial cell attachment, compared to an expanded PTFE control
material.
[0373] The percent porosity of the electrospun polymer layer may be
between about 40% and about 60%.
[0374] The mandrel may comprise a main portion and two leg
portions, the main portion configured to coincide with a main lumen
of a bifurcated medical appliance and the two leg portions
configured to coincide with the leg portions of the bifurcated
medical appliance.
[0375] The two leg portions of the mandrel may be removable from
the main portion of the mandrel.
[0376] The first tube may be electrospun by rotating the mandrel
about an axis of the leg portions of the mandrel while
electrospinning fibers and rotating the mandrel about an axis of
the main portion of the mandrel while electrospinning fibers.
[0377] VI. Method for Promoting Cellular Growth into an Implantable
Medical Appliance
[0378] In one embodiment, a method for promoting cellular growth
into an implantable medical appliance comprises: obtaining a
medical appliance coated with at least one electrospun polymer
layer having a percent porosity of between about 30% and about 80%
and at least one layer that is substantially impervious to cellular
growth; and implanting the medical appliance into a patient such
that the electrospun polymer layer of the medical appliance is in
direct contact with body fluid or body tissue.
[0379] The at least one electrospun polymer layer may comprise
electrospun PTFE.
[0380] The electrospun PTFE material may be configured to permit at
least 20% cellular penetration, in vivo two weeks after murine
implantation.
[0381] V. Method for Inhibiting a Neointimal Hyperplasia
Response
[0382] In one embodiment, a method for inhibiting a neointimal
hyperplasia response to an implantable medical appliance comprises
implanting the medical appliance into a patient, the medical
appliance coated with a first electospun PTFE layer comprising a
porous mat and a second polymer layer that inhibits tissue ingrowth
into or through the second polymer layer.
[0383] The first electrospun polymer layer may permit endothelial
cell growth or attachment on the surface of the first electrospun
polymer layer.
[0384] The first electrospun polymer layer may comprise a fibrous
PTFE layer and the second polymer layer may comprise an FEP
layer.
[0385] The medical appliance may also be coated with a third
polymer layer comprising an electrospun PTFE layer, such that the
FEP layer is disposed between the first and third polymer
layers.
[0386] The first and third polymer layers may comprise an
electrospun microfiber or nanofiber PTFE mat.
[0387] The second polymer layer may comprise an electrospun FEP
mat.
[0388] VIII. Method for Inhibiting an Inflammatory Response
[0389] In one embodiment, a method for inhibiting an inflammatory
response to an implantable medical appliance comprises implanting
the medical appliance into a patient, the medical appliance coated
with a first electrospun polymer layer comprising a porous PTFE mat
and a second polymer layer comprising FEP that inhibits tissue
ingrowth into or through the second polymer layer.
[0390] The first electrospun polymer layer, when placed in vivo,
may have an H-score of less than 150 two weeks after murine
implantation.
[0391] While specific embodiments of stents and other medical
appliances have been illustrated and described, it is to be
understood that the disclosure provided is not limited to the
precise configuration and components disclosed. Various
modifications, changes, and variations apparent to those of skill
in the art having the benefit of this disclosure may be made in the
arrangement, operation, and details of the methods and systems
disclosed, with the aid of the present disclosure.
[0392] Without further elaboration, it is believed that one skilled
in the art can use the preceding description to utilize the present
disclosure to its fullest extent. The examples and embodiments
disclosed herein are to be construed as merely illustrative and
exemplary and not as a limitation of the scope of the present
disclosure in any way. It will be apparent to those having skill in
the art, and having the benefit of this disclosure, that changes
may be made to the details of the above-described embodiments
without departing from the underlying principles of the disclosure
herein.
* * * * *