U.S. patent application number 13/303319 was filed with the patent office on 2014-02-27 for electrospinning process for making a textile suitable for use as a medical article.
The applicant listed for this patent is Martin J. Bide, Philip J. Brown, Matthew D. Phaneuf. Invention is credited to Martin J. Bide, Philip J. Brown, Matthew D. Phaneuf.
Application Number | 20140054828 13/303319 |
Document ID | / |
Family ID | 45817040 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140054828 |
Kind Code |
A9 |
Phaneuf; Matthew D. ; et
al. |
February 27, 2014 |
ELECTROSPINNING PROCESS FOR MAKING A TEXTILE SUITABLE FOR USE AS A
MEDICAL ARTICLE
Abstract
The present invention is a bioactive, nanofibrous material
construct which is manufactured using a unique electrospinning
perfusion methodology. One embodiment provides a nanofibrous
biocomposite material formed as a discrete textile fabric from a
prepared liquid admixture of (i) a non-biodegradable durable
synthetic polymer; (ii) a biologically active agent; and (iii) a
liquid organic carrier. These biologically-active agents are
chemical compounds which retain their recognized biological
activity both before and after becoming non-permanently bound to
the formed textile material; and will become subsequently released
in-situ as discrete freely mobile agents from the fabric upon
uptake of water from the ambient environment.
Inventors: |
Phaneuf; Matthew D.;
(Ashland, MA) ; Brown; Philip J.; (Williamston,
SC) ; Bide; Martin J.; (Hope Valley, RI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Phaneuf; Matthew D.
Brown; Philip J.
Bide; Martin J. |
Ashland
Williamston
Hope Valley |
MA
SC
RI |
US
US
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20120068384 A1 |
March 22, 2012 |
|
|
Family ID: |
45817040 |
Appl. No.: |
13/303319 |
Filed: |
November 23, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11366165 |
Mar 2, 2006 |
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13303319 |
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11211935 |
Aug 25, 2005 |
7413575 |
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11366165 |
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12954829 |
Nov 26, 2010 |
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11211935 |
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60658438 |
Mar 4, 2005 |
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Current U.S.
Class: |
264/466 |
Current CPC
Class: |
D01F 6/62 20130101; A61K
9/0092 20130101; D01D 1/02 20130101; A61K 9/70 20130101; D04H 1/728
20130101; B29C 48/022 20190201; D04H 3/011 20130101; D04H 3/02
20130101; D04H 1/435 20130101; D01D 5/0038 20130101; B29C 48/05
20190201; D04H 3/16 20130101 |
Class at
Publication: |
264/466 |
International
Class: |
B29C 47/00 20060101
B29C047/00 |
Claims
1. An electrospinning perfusion method for forming a fabricated
textile suitable for use as a medical article, said method
comprising the steps of: dissolving a non-biodegradable polymer and
a pre-chosen biologically-active agent in an organic solvent to
provide an admixture, the dissolving step occurring at an ice-cold
temperature; permitting the admixture to warm to a temperature
between about 20.degree. C. and about 50.degree. C.; loading the
admixture into an electrospinning perfusion assembly comprised of
at least one perfusion instrument which can be set at a specified
flow rate; perfusing said admixture onto a target surface at the
specified flow rate, the step of perfusing occurring at a
temperature between about 20.degree. C. and about 50.degree. C. to
provide a perfused material; removing the perfused material from
the target surface to form a nanofibrous fabricated textile.
2. The method as recited in claim 1, wherein the nanofibrous
fabricated textile has a longitudinal axis, the method further
comprising the steps of: stretching the nanofibrous fabricated
textile along the longitudinal axis after it has been removed from
the target surface to apply a set strain; and removing residual
organic solvent from the stretched nanofibrous fabricated textile
while the set strain is applied.
3. The method as recited in claim 2, wherein the step of removing
the residual organic solvent is accomplished by treatment with
ethanol.
4. The method as recited in claim 2, wherein the nanofibers are
tubes and, after the stretching step, the nanofibers have an inner
diameter that remains uniform over their length, the inner diameter
being less than 1 mM.
5. The method as recited in claim 1, wherein the perfusion
instrument has a needle, the method including the step of
positioning the needle and the target surface a distance apart of
between 10 cm and 40 cm.
6. An electrospinning perfusion method for forming a fabricated
textile suitable for use as a medical article, said method
comprising the steps of: dissolving a non-biodegradable polyester
or polyurethane and a pre-chosen biologically-active agent in
hexafluoroisopropanol to provide an admixture, the dissolving step
occurring at an ice-cold temperature; loading the admixture into an
electrospinning perfusion assembly comprised of at least one
perfusion instrument which can be set at a specified flow rate, the
perfusion instrument having a spinneret sized to produce nanofibers
with a diameter of less than about 2 micrometers; perfusing said
admixture through the spinneret and onto a target surface at the
specified flow rate, the step of perfusing occurring at a
temperature between 15.degree. C. and 30.degree. C. to provide a
perfused admixture comprising polymeric fibers with a diameter of
less than about 2 micrometers; removing the perfused admixture from
the target surface to form a nanofibrous fabricated textile which
consists essentially of the non-degradable polyester or
polyurethane and the pre-chosen biologically-active agent, the
biologically active agent being releasably entrapped within the
non-degradable polyester or polyurethane.
7. The method as recited in claim 6, wherein the ice-cold
temperature is between 0.degree. C. and 5.degree. C.
8. The method as recited in claim 6, wherein the nanofibrous
fabricated textile has a longitudinal axis, the method further
comprising the steps of: stretching the nanofibrous fabricated
textile along the longitudinal axis after it has been removed from
the target surface to provide a set strain; and removing residual
hexafluoroisopropanol from the stretched nanofibrous fabricated
textile while the set strain is applied.
9. The method as recited in claim 6, wherein the biologically
active agent is maintained at a temperature below about 50.degree.
C. during the steps of dissolving, loading, perfusing and removing
such that the biologically active agent maintains the same
biological activity after the method as it had before the
method.
10. An electrospinning perfusion method for forming a fabricated
textile suitable for use as a medical article, said method
comprising the steps of: dissolving a non-biodegradable polymer and
a pre-chosen biologically-active agent in an organic solvent to
provide an admixture, the dissolving step occurring at temperature
of about 4.degree. C.; permitting the admixture to warm to a
temperature between about 20.degree. C. and about 25.degree. C.;
loading the admixture into an electrospinning perfusion assembly
comprised of at least one perfusion instrument which can be set at
a specified flow rate; perfusing said admixture onto a target
surface at the specified flow rate, the step of perfusing occurring
at a temperature between about 20.degree. C. and about 25.degree.
C. to provide a perfused material; removing the perfused material
from the target surface to form a nanofibrous fabricated textile.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. Ser. No.
11/366,165 (filed Mar. 2, 2006) which is a continuation-in-part of
U.S. Ser. No. 11/211,935 (filed Aug. 25, 2005) which claims
priority to U.S. Provisional Application 60/658,438 (filed Mar. 4,
2005), which applications are incorporated herein by reference in
their entirety.
FIELD OF THE INVENTION
[0002] The instant invention provides a variety of
non-biodegradable, formed fabric materials, articles, and devices
suitable for the in-situ delivery of many different
biologically-active agents. The disclosure also offers a wide range
of fabricated nanofibrous textiles having varying and diverse
individual biologic properties, or combinations thereof; and
provides medical products which are resistant to breakage and
tearing as well as demonstrate a specifically desired localized
effect such as resistance to infection--properties which will aid
in reducing both the morbidity and mortality of a person afflicted
with an injury or ailment.
BACKGROUND
[0003] There are over 13 million medical articles and devices
utilized annually in the United States for prophylactic and/or
therapeutic treatment. These items range in sophistication from
simple devices such as hernia repair mesh, wound dressings and
catheter cuffs--to more complex implantable devices such as the
total implantable heart, left ventricular assist devices and
prosthetic arterial grafts. Although utilization of these medical
articles and devices has improved the health and quality of life
for the patient population as a whole, the in-vivo application of
all such medical implements are prone to two major kinds of
complications: infection and incomplete/non-specific cellular
healing.
[0004] In general, regardless of the particular causative agent,
infection remains one of the major complications associated with
utilizing biomaterials, with the clinical infection occurring at
either acute or delayed time periods after in-vivo use or
implantation of the medical article or device. Today, surgical site
infections account for approximately 14-16% of the 2.4-million
nosocomial infections in the United States, and result in an
increased patient morbidity and mortality. The inherent bulk
properties of various biomaterials that comprise these articles and
devices typically provide a milieu for initial bacterial/fungus
adhesion with subsequent biofilm production and growth.
[0005] Similarly, unregulated cellular growth affects various
medical devices such as stents and vascular grafts. Occlusion rates
for diseased blood vessels after placement of a bare metallic stent
(restenosis) have been reported as high as 27%, a significant
problem based on the 1.1 million stents annually implanted.
Moreover, since the currently available biomaterials in these
medical articles and devices are typically comprised of foreign
polymeric compounds, these biomaterials do not emulate the
multitude of dynamic biologic and healing processes that occur in
normal tissue; and consequently, the cellular components normally
present within native living tissue are not available for
controlling and/or regulating the reparative process. Thus, the
search continues today for novel biomaterials (such as drug
releasing biomaterials) that would direct or enhance some of the
normal healing processes of native tissue, and would decrease
patient morbidity and mortality rates.
[0006] Currently, drug delivery from a majority of implantable
medical devices such as stents is achieved via the coating/sealing
of a device or scaffold with a biodegradable polymer composition
which serves as a drug reservoir. There are several potential
problems with utilizing this system in that: (1) polymer coating
onto the device can be inconsistent, resulting in areas with
minimum/no localized drug release; (2) polymer coating efficiency
can be limited based on the device design or composition of the
base material; (3) drug release is dependent on biodegradation of
the polymer reservoir, resulting in inconsistent drug release; and
(4) application of the exogenous polymer can have adverse effects
on tissue/organ healing or upon the biocompatibility (i.e.
increasing thrombogenecity) of the original implant.
[0007] Electrospinning provides a technique for making nanofibrous
material substrates. Electrospinning to produce nanoscale fibers,
fabrications and textiles, however, is still a manufacturing
technique in need of further development and refinement.
Utilization of electrospinning as a technique to synthesize various
nanofibrous materials from polymers such as polyurethane, polyvinyl
alcohol (or "PVA"), poly(lactic glycolic) acid (or "PLGA"), nylon,
and polyethylene oxide has been investigated for several decades
(see for example Subbiah et al., "Electrospinning Of Nanofibers",
J. Applied Polymer Sci. 96:557-569 (2005).
[0008] While inclusion of bioactive agents has been accomplished
for several other polymers (such as polyurethane, PLGA, alginate
and collagen), the electrospinning technique has not been realized
for polyethylene terephthalate ("PET"), or "polyester" as
understood generally in textile circles, until recently. Since
then, Ma et al. was able to electrospin polyethylene terephthalate
using a melt-spinning technology [see Ma Z, Kotaki M, Yong T, He W,
Ramakrishna S., "Surface engineering of electrospun polyethylene
terephthalate (PET) nanofibers towards development of a new
material for blood vessel engineering", Biomaterials 26:2527
(2005)]. However, the Ma et al. reported technique requires a
surface modification in which formaldehyde and several
cross-linkers were utilized post-spinning subsequently to
incorporate gelatin, owing to the high temperatures employed in
their manufacturing process. These modification procedures are and
remain a major issue because of their high temperature requirements
and the consequential failure of the protein (or other temperature
sensitive agent) to maintain its characteristic biological activity
throughout the material fabrication process.
[0009] Accordingly, despite all these developments to date, there
remains a recognized and continuing need for further improvements
in the making of medical devices and articles comprised of
nanofibrous materials which would demonstrate adequate physical
strength characteristics and durability as fabricated items, and
which would serve as biomedical constructs formed of fibrous
materials having demonstrable biologically active properties. All
such improvements in the making and/or preparation of such
nanofibrous materials and articles would be readily seen as a major
advantage and outstanding benefit in the medical field.
SUMMARY OF THE INVENTION
[0010] The present invention is a major advance in the development
of biomedical materials, devices and constructs. Accordingly, the
invention has multiple aspects, some of which may be defined as
follows.
[0011] A first aspect provides a method for forming a fabricated
textile suitable for use as a medical article. The method includes
the steps of dissolving a non-biodegradable polymer and a
pre-chosen biologically-active agent in an organic solvent at an
ice-cold temperature. Once dissolved, the admixture is permitted to
warm before electrospinning at room temperature to form the
fabricated textile.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The present invention is disclosed with reference to the
accompanying drawings, wherein:
[0013] The present invention may be more easily understood and more
readily appreciated when taken into conjunction with the
accompanying drawing, in which:
[0014] FIG. 1 is an illustration of the chemical structure of
Ciprofloxacin;
[0015] FIG. 2 is an illustration of the chemical structure of
Diflucan;
[0016] FIG. 3 is an illustration of the chemical structure of
Paclitaxel;
[0017] FIG. 4 is a an illustration of the apparatus for performing
the electrospinning methodology;
[0018] FIG. 5 is scanning electron microphotograph of a nPET
(electrospun polyethylene terephthalate) textile segment showing
the diameter size of the fibers within the nanofibrous
material;
[0019] FIG. 6 is an overhead view of the UV illumination
differences between nPET segments, nPET-Cipro segments, and
nPET-Diflucan segments;
[0020] FIG. 7 is a graph showing the release profile of Cipro from
nPET-Cipro segments over time;
[0021] FIG. 8 is a graph showing the release profile of Diflucan
from nPET-Diflucan segments over time;
[0022] FIG. 9 is a an overhead view of the inhibitions zone against
Staphylococcus aureus streaked onto agar plates;
[0023] FIG. 10 is a graph showing the antimicrobial activity of
nPET-Cipro segments over time;
[0024] FIG. 11 is a graph showing the anti-fungal activity of
nPET-Diflucan segments against varying concentrations of Candida
albicans; and
[0025] FIG. 12 illustrates an overhead view of a flat sheet of
electrospun textile fabric.
[0026] Corresponding reference characters indicate corresponding
parts throughout the several views. The examples set out herein
illustrate several embodiments of the invention but should not be
construed as limiting the scope of the invention in any manner.
DETAILED DESCRIPTION
[0027] Disclosed in this specification is a bioactive, nanofibrous
material construct which is manufactured either in tubular or flat
sheet form using an unique electrospinning perfusion methodology.
One particular embodiment provides a nanofibrous biocomposite
material formed as a discrete textile fabric from a prepared liquid
admixture of (i) a biodurable synthetic polymer; (ii) a
biologically active agent; and (iii) a liquid organic carrier. The
prepared liquid admixture of diverse compositions is employed in a
novel electrospinning perfusion process to form an agent-releasing
textile comprised of nanofibrous material, which in turn, can serve
as the antecedent precursor and tangible workpiece for subsequently
making the desired medical article or device suitable for use
in-vivo. Prior art medical devices generally includes an underlying
non-polymeric support (e.g. scaffold, stent, etc) and coat the
support with a biodegradable polymer and then soaks the resulting
coated support in a biologically-active agent to embed the agent in
the polymer. In contrast, the medical devices of the present
invention are discrete articles that omit the underlying scaffold
and the medical devices consist essentially of a non-biodegradable
polymer that has the biologically-active agent embedded therein.
The materials of the present invention have mechanical properties
which are sufficient to permit the manufacturer to omit the
scaffolds that were previously required by the prior art.
[0028] After the agent-releasing textile has been fabricated as a
discrete article, one or more pre-chosen biologically-active agents
will have become non-permanently immobilized and releaseably bound
to the tangible nanofibrous material of the fabricated textile.
These non-permanently immobilized biologically-active agents are
well established chemical compounds which retain their recognized
biological activity both before and after becoming impermanently
(i.e., temporarily or reversibly) bound to the textile fabric; and
will become subsequently released in-situ and directly delivered
into the ambient environment as discrete mobile entities when the
textile fabric takes up any fluid--i.e., any aqueous or organic
based liquid. Accordingly, via the transitory immobilization of one
or more biologically active molecules to the nanofibrous
biocomposite material, the agent-releasing textile is very suitable
for inclusion and use in-vivo as a clinical/therapeutic
construct.
[0029] The present electrospinning perfusion method of making
agent-releasing nanofibrous textiles provides several major
advantages and desirable benefits to the commercial manufacturer as
well as to the physician and surgeon. Among these are the
following:
[0030] First, the manufacturing methodology comprising the present
invention does not utilize any immersion techniques and does not
require submerging the fabricated textile in any immersion baths,
soaking tanks, or dipping pools for any purpose. Rather, the
methodology preferably utilizes the unique technique of
electrospinning perfusion as a manufacturing method in order to
blend a synthetic substance and a biologically active agent of
choice together as a fabricated textile.
[0031] Second, the electrospinning perfusion method of manufacture
yields a fabricated textile having particular characteristics. The
fabricated textile is initially fashioned either as an elongated
hollow tube having two discrete open tubular ends and fixed inner
and outer wall diameters; or as a flat or planar sheet of
nanofibrous fabric. In either format, the fabricated textile can be
folded, or twisted, and otherwise manipulated to meet specific
requirements of thickness, gauge, or deniers; and can also be cut,
split, tailored, and conformed to meet particular shapes,
configurations and patterns.
[0032] Third, the fabricated textile is a nanofibrous material
composite comprised of multiple fibers, has a determinable
individual fiber thickness in or near the nanometer size range
(typically less than 2 microns), and presents a discernible fiber
organization and distribution pattern. These fabricated textiles
provide and demonstrate excellent suture retention, burst strength,
break strength, tear strength and/or biodurability.
[0033] Fourth, the manufacturing method comprising the present
invention employs limited heat and compression force to alter the
exterior surface of the fabricated textile originally formed via
the electrospinning perfusion technique. This exterior surface
treatment portion of the manufacturing process is optional, but
when employed, will produce a highly desirable crimped exterior
surface over the entire linear length of the fabricated textile
article. A notable feature of this exterior surface treatment
procedure is that the inner diameter size (typically less than 1 mm
to not greater than about 30 mm, but can vary from these particular
parameters) of the fabricated textile remains constant and uniform,
despite the effects of the limited heating and compression
treatment of the textile exterior surface.
[0034] Fifth, the biologically active agent will retain its
characteristic biological activity both before and after being
temporarily bound to the nanofibrous material. The attributes and
properties associated with the biologically active agent of choice
will co-exist with and be an integrated feature of the resulting
textile article at the time it is utilized.
The Agent-Releasing Nanofibrous Textile and Its Role as an
Antecedent in the Making of a Prepared Medical Article or
Device
[0035] The method of the present invention is directed in part to
the making of an agent-releasing textile, an antecedent article of
manufacture, which is then employed as a tangible workpiece to
generate a subsequently prepared medical article or device suitable
for use in-vivo. An agent-releasing textile is a fabricated textile
comprising nanofibrous matter which has at least one biologically
active agent immobilized onto and/or within the material substance
of the textile; and which, upon wetting, is then able to release
the biologically active agent in-situ and deliver it in a
functionally operative form into the adjacent local area or
immediately surrounding environment. Such a prepared nanofibrous
textile must provide and release at least one active chemical
composition, compound, or molecule which is active, functional and
operative either to influence and/or to initiate or cause a
recognizable pharmacological effect or determinable physiological
change in the living cells, tissues and organs of the host patient.
A fabricated textile is an article of manufacture which is
comprised, in whole or in part, of fibers arranged as a fabric. The
fibers comprising the fabricated textile may be chosen from a
diverse range of organic synthetics, prepared polymer compounds, or
naturally-occurring matter. In general, the fabricated textile is
often prepared as a cloth or fabric; and may comprise a single
fiber film, or a single layer of fibrous matter; or exist as
multiple and different deniers of fibers which are present in a
range of varying thickness, dimensions, and configurations.
[0036] It will be appreciated that, after the agent-releasing
nanofibrous textile has been manufactured and is present as a
discrete entity, it can optionally serve as a tangible workpiece in
combination with other items and additional components and hardware
to yield the desired end product, a clinically or therapeutically
useful "medical article or device". Thus, regardless of its true
chemical composition/formulation or the particular mode of
construction, the initially formed "agent-releasing textile" and
the subsequently generated "medical article or device" are directly
and intimately related; and thus share a number of specific
qualities and characteristics in common. These mutually shared
attributes include: [0037] (i) Each agent-releasing textile is
formed as an elongated hollow tube having a determinable overall
tubular length and two open ends; has at least one internal lumen
of determinable volume which is co-incidental and coextensive with
the internal wall surface; and has at least one exterior wall
surface which is co-incidental and co-extensive with the outer wall
topography. [0038] (ii) Each agent-releasing textile has a
determinable length, girth and depth of non-perforated fibrous
material which can be prepared to meet specific shapes, sizes and
thicknesses of solid matter; [0039] (iii) Each agent-releasing
textile can be employed either as a configured tubular conduit
whose internal lumen is usefully employed for the conveyance of
fluids in-situ; or, alternatively, as a solid mass of nanofibrous
material which achieves its intended purpose without regard to or
actual use of the internal lumen then existing within the textile
fabric.
[0040] By definitional requirement, the agent-releasing nanofibrous
textile (optionally also the antecedent forerunner of each
subsequently generated medical article or device) is a non-woven
material comprised of discrete fibers. The nanofibrous composite
material forming the textile fabric has been electrospun from a
liquid admixture and blending in a liquid organic carrier of at
least two different materials: a synthetic substance and a
biologically active agent. This admixture of two diverse chemical
compositions can be prepared in a wide range of varying ratios
using a liquid organic carrier, followed by application of an
electric current to create the biocomposite material
[0041] To illustrate the range and variety of compositions deemed
suitable for use as a blended mixture, a listing of suitable
synthetic substances is presented by Table 1 below. It will be
noted that the listing of Table 1 presents some exemplary synthetic
substances long deemed suitable for use as synthetic fibers. To
complete the description, Table 2 lists some of the typical and
more commonly available organic liquids which can be usefully
employed alone and/or in blends as the liquid carriers.
TABLE-US-00001 TABLE 1 Illustrative Synthetic Substances Polymeric
Fibers polyethylene terephthalate; polybutylene terephthalate;
polytrimethylene terephthalate Polyurethane; polyglycolic acid;
polyamides, including nylons and aramids; Polytetrafluoroethylene;
and mixtures of these substances Other synthetic fiber compositions
(using TFPIA generic fiber names) Acetate; Triacetate; Acrylic;
Modacrylic; Olefin (Polypropylene, polyethylene, and other
polyolefins); saran
TABLE-US-00002 TABLE 2 Representative Organic Liquid Carriers
Hexafluoroisopropanol; Dimethylformamide; Dimethylsulfoxide;
Acetonitrile; Acetone; Hexamethylphosphoric triamide;
N,N-diethylacetamine; N-methylpyrrolidinone; Ethanol;
4-methylmorpholine-N-oxide monohydrate
[0042] At least some of the fibers comprising the textile fabric
will demonstrate a range of properties and characteristics, as
follows.
[0043] 1. The fibers constituting the agent-releasing textile (and
the subsequently generated medical article or device) will have a
demonstrable capacity to take up water and/or aqueous liquids
and/or organic liquids and/or organic based liquids (with or
without direct wetting of the fibrous material). The mode or
mechanism of action by which organic and aqueous fluids are taken
up by the fibers of the textile (and/or become wetted by the fluid)
is technically insignificant and functionally meaningless.
[0044] Thus, among the different possibilities of fluid (aqueous
and/or organic) uptake are the individual alternatives of:
absorption; adsorption; cohesion; adhesion; covalent bonding;
non-covalent bonding; hydrogen bonding; miscible envelopment;
molecule entrapment; solution-uptake between fibers; fiber wetting;
as well as others well documented in the scientific literature. Any
and/or all of these may contribute to organic and/or aqueous fluid
uptake in whole or in part. Which mechanism of action among these
is actively in effect in any instance or embodiment is
irrelevant.
[0045] 2. By choosing a particular chemical formulation and/or
desired stereoscopic (or three-dimensional) structure for the
synthetic substance of the fabrication, the resulting biologically
active textile can be prepared as a fabric having a markedly long
functional duration and lifespan for in-vivo use. Accordingly, by
choosing one or more durable and highly resilient chemical
compositions as the fibers of choice, textiles effective for many
years' duration and utility may be routinely made. All of these
choices and alternatives are conventionally known and commonly used
today by practitioners in this field.
[0046] It is also well recognized that some synthetic chemical
compositions, are available in a range of diverse formulations. As
one example of a highly resistant chemical composition having many
alternative formulations are the polyethylene terephthalates, of
which one particular formulation is sold under the trademark
DACRON.
[0047] As is commonly known in this field, a range of differently
formulated polyethylene terephthalates (or "PETs") are known to
exist and are commercially available, each of these alternatives
having a different intrinsic viscosity [or "IV", as measured in
o-chlorophenol or "OCP", at 25.degree. C.]. Typically, these
differently formulated polyethylene terephthalate compounds can
vary from less than 0.6 dl/g [IV] to greater than 1 dl/g [IV]; yet
each of these alternative polyethylene terephthalate formulations
can be dissolved in ice-cold 100% hexafluoroisopropanol. Thus, the
electrospinning of appropriately prepared HFIP solutions containing
any of such alternatively formulated polyethylene terephthalates
will result in the fabrication of nanofibrous textile fabrics which
are capable of independent or combined release of many diverse
drugs, proteins and genetic materials.
[0048] 3. The fibers comprising the agent-releasing textile (and
the subsequently generated medical article or device) can be
prepared in a variety of organizations as a tangible structure.
Thus, as conventionally recognized within the textile industry, the
textile fabric may vary in size or thickness; and may optionally
receive one or more interior and/or exterior surface treatments to
enhance particular attributes such as increased in-vivo
biocompatibility or a greater expected time for functional
operation and use in-vivo. All of these organizational variances
are deemed to be routine matters which will be optionally chosen
and desirably used to meet particular medical needs or individual
patient requirements.
[0049] 4. The fibers comprising the agent-releasing textile (and
the subsequently generated medical articles or devices) can be
prepared to meet the particulars of the intended in-vivo medical
use circumstances or the contingencies of the envisioned
clinical/therapeutic application. Thus, the textile fabric can
alternatively be prepared either as a relatively thin-walled
biocomposite, or alternatively as a thick-walled material; be
produced as an elongated object having a diverse range of different
outer diameter and inner diameter sizes; and be fashioned as a
relatively inflexible or unyielding item or as a very flexible and
easily contorted length of matter.
[0050] B. The Choosing of an Appropriate Biologically Active
Agent
[0051] A number of different biologically active agents can be
beneficially and advantageously utilized in tandem with the
nanofibrous textile fabric. However, there are several minimal
requirements and qualifications which the biologically active
molecule--whatever its particular composition and formulation as a
chemical compound, composition or molecule--must demonstrably
provide in order to be suitable for use in the present invention.
These are: [0052] (i) The chosen agent must be capable of
demonstrating its characteristic biological activity before
becoming temporarily bound to and immobilized by the material
substance of the fabricated textile. This characteristic biological
activity must be well recognized and will constitute its
ability/capacity to function as an active mediator in-situ. [0053]
(ii) The particular agent immobilized upon or within the material
substance of the textile fabric must be capable of demonstrating
its characteristic biological activity (its mediating capacity)
after becoming immobilized and bound; and [0054] (iii) The
immobilized agent bound into the material substance of the textile
fabric will be released in-situ from the non-biodegradable polymer
and be delivered into the surrounding local environment as a freely
mobile molecule which retains its characteristic biological
activity (its mediating capacity) over an extended period of time
after the agent-releasing textile has been utilized in-vivo and
allowed to take up water.
[0055] In addition, since the primary medical application for the
fabricated textile is expected to differ and vary extensively from
one embodiment to another, it is intended that the characteristic
biological properties of the chosen agent serve to aid, promote,
and/or protect the naturally occurring pathways and processes of
the body which occur in-vivo.
[0056] Accordingly, it is deemed likely that the primary function
and capabilities of the chosen biologically active molecule will
differ and vary in many instances; and thus there are multiple
purposes and a range of individual goals for the releasable
substance, among which are the following: (1) to serve as an
antimicrobial agent--i.e., as an anti-bacterial or anti-fungal
composition having a broad or narrow spectrum of activity; (2) to
function as an anti-neoplastic compound effective against specific
kinds of tumors; (3) to operate as a selective physiological
aid--i.e., as a mediator which serves to avoid vascular
complications such as blood coagulation or acts to prevent the
formation of blood clots; and (4) to act as a pharmacological
composition--i.e., as a drug or pharmaceutical which deactivates
specific types of cells and/or functions to suppress or inhibit a
variety of different humoral and cellular responses associated with
or related to inflammation and the inflammatory response in-vivo.
Examples of each are presented hereinafter.
The Unique Electrospinning Perfusion Method Of Manufacture
The Generation of Nanofibrous Tubular Structures
[0057] A preferred method for making the agent-releasing textile of
the present invention is via the unique technique of
electrospinning perfusion. For this purpose, an electrospinning
perfusion assembly is erected which comprises, at a minimum, a
rotating mandrel with a target surface which can be set at a
pre-selected rotation speed; a needle fronted perfusion instrument
with a spinerette, such as a syringe, which can be set to deliver a
liquid mixture at a pre-specified flow rate; an electrical coupling
for controlling and coordinating the electrical voltage applied
across the perfusion needle and which is grounded to the rotating
mandrel; and a controllable supply of electrical power.
[0058] An admixture is prepared comprising a chosen
non-biodegradable material and a biologically active agent of
choice. These components are blended together into an organic
liquid carrier. In one embodiment, the organic liquid carrier is
cooled to an ice-cold (e.g. about 4.degree. C.) temperature. For
reasons that are not clear, this cooling step facilities the proper
formation of the admixture and speeds the dissolution of the
non-biodegradable material. For example, one preferred liquid
admixture or blending is obtained by combining 20% w:v polyethylene
terephthalate (PET) with 1.5% w:v of an antimicrobial (e.g., Cipro
or Diflucan), or with 1.5% w:v of an anti-neoplastic compound
(e.g., Paclitaxel), in a sufficient quantity of ice-cold
hexafluoroisopropanol (hereinafter "HFIP"). The resulting admixture
is subsequently loaded into the electrospinning perfusion
assembly.
[0059] For example, a 10 ml syringe with a stainless steel 18-gauge
blunt spinneret (0.5 mm internal diameter) is then filled with the
liquid polymer blending and placed onto a Harvard Apparatus syringe
pump for subsequent perfusion. Perfusion is the action and the act
of causing a liquid or other fluid to pass across the external
surfaces of, or to permeate through, the substance of a tangible
entity or a configured physical construct. Perfusion of a liquid or
fluid thus includes the alternative actions of: a sprinkling,
pouring, or diffusing through or overlaying action; a covering,
spreading, penetrating or saturating action (termed "suffusion"); a
slow injection or other gradual introduction of fluid into a
configured space or sized internal volume (termed "infusion"); and
a passage across a surface or through a discrete surface or
tangible thickness of matter, regardless of the mechanism or manner
of transfer employed for such fluid passage.
[0060] Once the admixture has been properly loaded, the electrical
coupling and syringe pump are activated and the admixture is
electrospun onto the target surface. In one embodiment, the step of
electrospinning is carried out at a temperature which does not harm
the biological activity of the biologically-active agent in the
admixture. The reaction temperature is, in one embodiment, ambient
room temperature (20-25.degree. C.), but when necessary or desired
can be chosen to be within a temperature reaction range of about
0-50.degree. C.
[0061] Utilization of this assembly permits uniform coating of the
liquid admixture onto the surface of the mandrel; and the applied
electrical voltage can be varied as needed to control the formation
of the nanofibers upon the mandrel's surface.
[0062] It will be recognized in particular that electrospinning
over a broad range of conditions is possible for polyesters. Thus,
a range of differently formulated polyethylene terephthalates (or
"PETs") of intrinsic viscosity [or "IV" as measured in OCP at
25.degree. C.] that range from less than 0.6 dl/g [IV] to greater
than 1 dl/g [IV] can be dissolved in ice-cold 100%
hexafluoroisopropanol. Electrospinning appropriately prepared HFIP
solutions of such polyethylene terephthalates results in the
fabrication of nanofibrous textile fabrics capable of independent
or combined release of diverse drugs, proteins and genetic
materials.
A Small Batch System
[0063] For fabricating small batches of product using this unique
method, a chemically resistant syringe with a stainless steel blunt
spinneret can serve as a functional instrument for perfusion.
Alternatively, of course, any other tool, assembly or instrument
capable of performing perfusion at a pre-selected flow rate and low
reaction temperature can be usefully employed.
[0064] In this small batch system, the perfusion syringe of the
assembly is filled with the prepared liquid mixture described above
and placed onto a Harvard Apparatus syringe pump. The perfusion
rate is preferably set at 3 ml/hour at 25.degree. C. If desired,
however, the flow rate can be increased and/or decreased to meet
specific requirements. Similarly, the reaction temperature is
preferably ambient room temperature (20-25.degree. C.), but when
necessary or desired can be chosen to be within a temperature
reaction range of about 0-50.degree. C.
[0065] A PTFE-coated stainless steel mandrel (diameter=4 mm) is
preferably set at a jet gap distance of 15 cm from the tip of the
syringe needle. Gap distance can be varied at will to change the
fiber diameter size. The rotatable mandrel was then electrically
grounded to the power source, with the positive high potential
source connected to the syringe needle. The mandrel rotates or
spins at a pre-selected rate of rotation throughout the act of
liquid perfusion.
Perfusion
[0066] Perfusion of the polymer solution begins upon application of
the electric current to the tip of the syringe needle (typically 15
kV), which then moves at a preset constant speed and fixed distance
from the mandrel surface for a limited time period (typically about
40-90 minutes in duration). This process of manufacture is
therefore termed "electrospinning perfusion"; and yields a fully
fabricated, elongated nanofibrous textile conduit whose inner
diameter size corresponds to the overall diameter of the mandrel
(in this instance, 4 mm).
[0067] When using a single nozzle (or syringe needle), it was that
increasing electrospinning time significantly beyond about 40
minutes increased the rigidity of the resulting nPET material.
However, multiple nozzles (or syringe needles) can be used
concurrently to reduce the time required to fabricate tubular
structures of the appropriate rigidity. The use of multiple
injection streams to increase production rates is a familiar
concept to those skilled in the art; and, accordingly, the use of
multiple nozzles lies within the scope of the present
invention.
Optional Follow-Up Processing
[0068] When the process is used to make certain kinds of medical
articles such as synthetic vascular graft prostheses, a crimping
procedure is employed as an optional, but very desirable, follow-up
process. Accordingly, after being formed as a hollow tube by
electrospinning perfusion, the thickness and girth of the
originally formed fibrous composite wall and exterior surface
preferably is then intentionally altered into a crimped structural
form via a limited heat (low temperature) set technique, followed
by compression of the fibrous composite wall, in order to provide
kink-resistance for the elongated tube.
[0069] In brief, the end portions of the formed hollow tube
(appearing about 1 cm from each end of the mandrel) are cut off and
discarded. The remainder of the elongated hollow tube is then
stretched 25% of the starting segment size while on the mandrel in
order to provide a set strain across the fibers, a manipulation
that occurs in normal fiber extrusion. The stretched tubes are then
immediately exposed to 100% ethanol for 2 hours time at room
temperature (or in 100% ethanol for 30 minutes with sonication) in
order to remove the residual solvent, followed by air-drying
overnight at room temperature. This crimping technique permits a
user to form specific shapes (e.g. bends, etc) in the fabric
without using high-temperature melt techniques which would damage
the biologically-active agent.
The Generation of Flat Sheet Nanofibrous Textile Fabrics
[0070] Similar in its essentials to the technique described above,
DACRON chips were dissolved in ice-cold 100% hexafluoroisopropanol
(19% w:v) and mixed on an inversion mixer for 48 hours in order
completely solubilize the chips. The self-contained, semi-automated
electrospinning apparatus containing a Glassman power supply, a
Harvard Apparatus syringe pump, an elevated holding rack, a
modified polyethylene chamber, a spray head with power attachment
and a reciprocating system was again used.
[0071] The Wheaton stirrer was used to provide a holding chamber
for the new flat collecting plate employed to generate a sheet
format. The design of this surface is based upon the collecting
plate employed by Li et. al. [see Li W J, Laurencin C T, Caterson E
J, Tuan R S, Ko F K., "Electrospun nanofibrous structure: A novel
scaffold for tissue engineering", J Biomed Mater Res 60:613
(2002)]. In short, a flat 12 cm.times.10 cm copper plate,
containing a 6 cm stainless steel rod extending from the underside
of the plate was designed and grounded to the power source.
[0072] A 10 ml chemical-resistant syringe was filled with the
polymer liquid. A stainless steel 18-gauge blunt spinneret (0.5 mm
internal diameter) was then cut in half, with the syringe fitting
end connected to the polymer-filled syringe. Nalgene PVC tubing was
connected to the syringe filled with the polymer solution followed
by connection to the other half of the blunt spinneret within the
spray head. The line was then purged of air, with the syringe then
placed onto the syringe pump. The high potential source was
connected to the spray head tip, with the plate set at a jet gap
distance of 15 cm from the tip of the needle. The perfusion rate
was set at 3 ml/hour at 25.degree. C.
[0073] Perfusion of the polymer liquid was started upon application
of the current to the tip of the needle (15 kV) with
electrospinning proceeding for 1 hour and 40 minutes, with rotation
of the plate 20 degrees every 20 minutes. This resulted in a flat,
planar sheet of nanofibrous textile material being formed.
[0074] The agent releasable nanofibrous textile formed by the
electrospinning method described above has a number of unique
structural features which are the direct result and characteristic
of its unique mode and manner of manufacture.
[0075] 1. The agent-releasing textile fabricated via one of the two
different electrospinning perfusion techniques will yield a
discrete tubular article of fixed inner-wall and outer wall
diameters, and a solid wall girth and configuration formed of a
nanofibrous composite composition. The material substance of the
fabricated wall typically shows that the synthetic substance is
present as discrete fibers about 10.sup.-8 meters in diameter size.
The fiber size is clearly demonstrated by the empirical data
presented subsequently herein.
[0076] 2. The interior wall surface and the exterior wall surface
of the tubular structure comprising the agent-releasing textile are
markedly different owing to the crimping and heat setting
treatments following the initial electrospinning perfusion steps of
the methodology. Thus, the exterior wall surface can possess a
crimped and a somewhat irregular appearance. In comparison, the
interior wall surface and the internal lumen of the conduit as a
whole presents a smooth, regular, and even appearance which is
devoid of perceptible projections, lumps, indentations, and,
roughness.
[0077] 3. The nanofibrous composite material substance of the
textile fabric, whether existing in tubular structure form or in
planar sheet form, is resilient and can be prepared in advance to
provide varying degrees of flexibility, springiness, suppleness,
and elasticity. Moreover, the nanofibrous biocomposite wall is
durable and strong; is hard to tear, cut, or breakup; and is
hard-wearing and serviceable for many years' duration.
[0078] 4. The nanofibrous material substance of the agent
releasable textile, whether present in tubular structure form or in
planar sheet form, is biocompatible with the cells, tissues and
organs of a living subject; and can be implanted surgically in-vivo
without initiating or inducing a major immune response by the
living host recipient. While aseptic surgical technique and proper
care against casual infection during and after surgery must be
exercised, the agent releasable textile can be usefully employed
for a variety of applications in-vivo.
The Major Benefits And Advantages Of The Electrospinning Perfusion
Techniques
[0079] The electrospinning perfusion technique--whether employed to
fabricate tubular structures or flat sheets, has a number of
advantages over conventionally known manufacturing processes. These
include the following:
[0080] A first benefit is that no exogenous binders, cross-linking
compounds, or functional agents are required by the process either
to form the substance of the fabric or to maintain the integrity of
the fabricated textile. The synthetic substance prepared in liquid
organic solvent can be generated directly into nanofibrous fabric
form via the low reaction temperatures (typically ranging between
0-50.degree. C.) permitted and used by the electrospinning
perfusion process. In addition, the nanofibers of the fabric act to
seal the interstices of the composite material; therefore, no
sealants as such are required. This manufacturing technique also
benefits the manufacturer in that the technology is not a dipping
or immersion method of preparation, which can be awkward and
difficult to perform; or is a process which typically requires the
addition of heat, such as if a conventional melt spinning method of
fiber formation were employed.
[0081] A second benefit is that the electrospinning perfusion
technique yields a textile fabric formed as a nanofibrous composite
in which the fibers (e.g., PET) exist independently and are visibly
evident throughout the material of the textile. This structural
distribution of discrete fibers within the fabric adds strength and
flexibility to the textile as a whole. Also, the presence of these
fibers collectively provides sites into which diverse biological
agents (such as antimicrobials, anti-neoplastic agents, and the
like) can be temporarily incorporated and indefinitely, although
non-permanently, immobilized until such time as the textile takes
up fluid--i.e., any aqueous and/or organic liquid.
[0082] A third benefit is the capability for direct incorporation
of biologically-active agents onto the nanofibrous material,
whatever its final shape and structure. This process holds several
key advantages over other conventionally known methodologies in
that:
[0083] The active agent is incorporated into the fabricated
nanofibrous material without molecular modification, and is
non-permanently immobilized within each individual fiber surface as
the individual fibers are formed.
[0084] No one particular mechanism of incorporation is responsible
for the active agent becoming non-permanently immobilized within
each individual fiber of the fabricated nanofibrous material; and
thus any and all of the commonly known mechanisms--such as
absorption, adsorption, polarity, ion attraction, and the like--may
be involved.
[0085] The amount of active agent can be adjusted within the bulk
polymer depending on the specific or intended application.
[0086] No cross linking agents are needed, or used, or desired at
all, thereby avoiding concerns over drug carrier toxicity,
biocompatibility, and mutagenicity.
[0087] Low reaction temperatures are used during the fiber/fabric
formation procedure, thus maintaining the biologic activity of the
active agent.
[0088] Active agent elution from the textile fabric is controlled
and sustained over time, as shown in the experimental studies and
empirical data presented hereinafter.
The Releasable Anti-Neoplastic Agents
[0089] Paclitaxel, also known as Taxol, a diterpenoid-structured
molecule shown by FIG. 3, is a potent anti-neoplastic agent.
Paclitaxel has been shown to inhibit vascular smooth muscle cell (V
SMC) proliferation, migration and inflammation. Additionally,
Paclitaxel has been shown to inhibit the secretion of extracellular
matrix by VSMCs, a major component of neointima formation leading
to vessel restenosis. Paclitaxel stabilizes and enhances assembly
of polymerized microtubules, an important component of the
cytoskeleton involved in cell division, cell motility and cell
shape.
[0090] Additionally, microtubules are involved in signal
transduction, intracellular transport and gene activation.
Paclitaxel has shown promise as a treatment for various types of
cancers as well as for the prevention of restenosis following stent
placement.
[0091] Nevertheless, when Paclitaxel is incorporated into a
hydrophobic carrier polymer coated onto a metallic stent, it elutes
for only 10-14 days. Other research groups have attempted to
incorporate Paclitaxel into biodegradable polymers that would
comprise the stent. However, Paclitaxel activity was significantly
reduced due to the melt extrusion process for the fibers.
[0092] This issue would not be a problem with the present invention
due to the low temperature formation of the nanofibrous
polyethylene terephthalate (PET) fibers. Therefore, the fabrication
of a nanofibrous polyethylene terephthalate (PET) material with a
slow-releasing anti-neoplastic agent such as Paclitaxel would be
particularly effective and medically applicable to endovascular
stents and prosthetic vascular grafts, both of which currently
experience neointimal hyperplasia. Additional examples of other
active anti-neoplastic agents suitable for use in the present
invention include Rapamycin and Dexamethasone.
The Fluoroquinolone Antibiotics
[0093] Antibiotics vary in structural type, spectrum of activity,
and clinical usefulness. Fluoroquinolones such as Ciprofloxacin
(hereinafter "Cipro") are shown structurally by FIG. 1, and are of
particular use and value in this invention. Quinolone antibiotics
are chemically stable, and effective at low concentrations against
the common clinically encountered organisms, particularly those
bacteria responsible for biomaterial infection. These antibiotics
also have structural features (solubility, molecular mass, and
functional groups) that coincide with those of textile dyes known
to have interactions with polyethylene terephthalates.
[0094] This family of antibiotics now includes at least thirteen
members--Ciprofloxacin, Ofloxacin, Norfloxacin, Sparfloxacin,
Tomafloxacin, Enofloxacin, Lovafloxacin, Lomefloxacin, Pefloxacin,
Fleroxacin, Avefloxin, Moxifloxacin and DU6859a; and the
fluoroquinolone family as a whole has become the drug of choice for
many applications. These antibiotics are effective at low
concentrations; and hold an ideal antimicrobial spectrum against
microorganisms most commonly encountered clinically in wound
infection, with significant activity against many relevant
pathogens--such as S. aureus, methicillin-resistant S. aureus, S.
epidermidis, Pseudomonas species, and Escherichia coli. Moreover,
Fluoroquinolones are heat stable; are of 300-400 r.m.m.; and have
many structural features analogous to dyes. Accordingly, this
family of antibiotics possesses those characteristics which are
highly desired for use with the present invention.
[0095] A list of some representative antimicrobial/antiseptic
agents that can be used solely or in conjunction with the
fluoroquinolones is includes .beta.-lactams, biguanides
cephalosporins, chloamphenicol, macrolides, aminoglycosides,
quaternary ammonium salts, tetracyclines, sulfur-containing
antimicrobials, silver-containing compounds, bis-phenols
(triclosan), vancomycin, novobiocin and steriods (fusidic acid)
The Anti-Fungal Agents
[0096] Development of antifungal agents has been on the rise over
the past two decades due to a significant increase of superficial
(i.e. nail beds) and invasive (i.e. blood-borne and medical-device
related) infections. Fluconazole, known as Diflucan, a
triazole-structured antifungal agent introduced in early 1990 and
structurally shown by FIG. 2, has emerged as one of the primary
treatments for Candida infections. The mode of action of Diflucan
is the inhibition of 14.alpha.-lanosterol demethylase in the
ergosterol biosynthetic pathway, and results in the accumulation of
lanosterol and toxic 14.alpha.-methylated sterols in the fungal
membrane. Similar to the selection of Cipro, Diflucan has
structural features (solubility, molecular mass, and functional
groups) that coincide with those of textile dyes known to have
interactions with polyethylene terephthalate fibers. A
agent-releasing textile combining polyethylene terephthalate with a
slow-releasing antifungal agent such as Diflucan will have a marked
impact on topical and implantable biomaterials such as medicated
pads (useful for nail bed and skin infections), tampons (using
localized release for yeast infection) and catheter cuffs.
[0097] Other examples of anti-fungal agents typically will include
amphotericin B, Nystatin, Terbinafine, Voriconazole, Echinocandin B
and Itraconazole
The Antimicrobial Peptides
[0098] A novel class of antimicrobial agents known as antimicrobial
peptides (or "AMPs") has been discovered during the past two
decades. These "natural" antimicrobial agents, which consist of a
large number of low molecular weight compounds, have been
discovered in plants, insects, fish and mammals, including humans
[see for example, Marshall S H & Arenas G., "Antimicrobial
peptides: A natural alternative to chemical antibiotics and a
potential for applied biotechnology", J Biotech 6(2): 1 (2003)].
These peptides, whose composition can range from 6-50 amino acids,
have been shown to have an important role in innate immunity. There
are 5 general classifications for AMPs [see for example, Sarmafilk
A., "Antimicrobial peptides: A potential therapeutic alternative
for the treatment of fish diseases", Turk J Biol 26:201 (2002)],
which are based on the three-dimensional structure of the peptide
as well as the biochemical characteristics. These groups consist
of: (1) linear peptides without cysteine residues or hinge region;
(2) linear peptides without cysteine residues and a high proportion
of certain amino acids; (3) antimicrobial peptides with one
disulfite bonds that form a loop structure; (4) antimicrobial
peptides with two or more disulfite bonds; and (5) antimicrobial
peptides that have been derived from other larger proteins via
post-translational processing.
[0099] AMPs have shown broad spectrum antimicrobial activity
against both gram-positive (i.e., Staphylococcus aureus and
epidermidis) and negative (i.e., Pseudomonas aeruginosa, E. coli)
bacteria. Some AMPs have also been shown to be effective against
fungus [see for example, De Lucca A. J., "Antifungal peptides:
Potential candidates for the treatment of fungal infections",
Expert Op Invest Drugs 9(2):273 (2000); and Selitrennikoff CP,
"Antifungal proteins", Appl Environ Microbiol 67(7):2883 (2001) and
several antibiotic-resistant bacteria such as Mycobacterium
tuberculosis [see for example, Linde C M A, Honer S E, Refai E,
Andersson M., "In vitro activity of PR-39, a proline-arginine-rich
peptide, against susceptible and multi-drug resistant Mycobacterium
tuberculosis", J Antimicrob Chemother 47:575 (2001); Miyakawa Y,
Ratnakar P, Rao A G, Costello M L, Mathieu-Costello O, Lehrer R I,
Catanzaro, A., "In vitro activity of the antimicrobial peptides
human and rabbit defensins and porcine leukocyte protegrin against
Mycobacterium tuberculosis", Infect Immun 64(3):926 (1996); and
Sharma S, Verma I, Khuller G K, "Therapeutic potential of human
neutrophil peptide 1 against experimental tuberculosis", Antimicrob
Agents Chemother 45(2):639 (2001)].
[0100] Although the mode of action by these peptides has not been
fully elucidated, it is postulated that many of these peptides
interact directly with the bacteria wall, creating small channels
(pores) which causes membrane destabilization, thereby depleting
the bacteria of its cytoplasmic content [see for example, Matsuzaki
K., "Why and how peptide-lipid interaction utilized for self
defense? Magainins and tachyplesins as archetypes", Biochemica
Biophys Acta 1462(1-2):456 (1999)]. While effective against
bacteria walls, there appears to be limited affinity for eukaryotic
cells possibly due to the different composition and net charge of
the membranes. Several AMPs (i.e., Nisin and Daptomycin) have been
recently approved by the FDA for commercial and medical markets.
This acceptance paves the way for utilizing other AMPs such as
pleurocidin. Additionally, federal standard testing procedures,
which were used to provide safety and efficacy data for these AMPs,
have been established. Other representative types of AMPs include
Cationic peptides such that Cecropins, Defensins, Thionins, Amino
Acid-Enriched Histone-Derived Beta-Hairpin and other Natural and
Functional Proteins. Further examples of anionic peptides include
Asparitc Acid-Rich, Aromatic Dipeptides and Oxygen-Binding
Proteins.
The Analgesic Agents
[0101] Analgesic agents are widely used in human and veterinary
medicine in order to prevent inflammation, thereby reducing pain
and other symptoms such as itching and swelling. These agents have
structural properties that are comparable to standard textile dyes
such as molecular weight, functional groups and benzene-ring based
composition. Exemplifying such analgesic agents are Diphenhydramine
Hydrochloride, Hydrocortisone Acetate, Pramoxine Hydrochloride,
Lidocaine and Benzocaine.
The Anti-Viral Agents
[0102] Antiviral agents have been used to combat viral infections
ranging from the flu to HIV infection and organ transplant
rejection. Examples of some antiviral agents include Oseltamivir
(Flu), Zanamivir (Flu), Saquinavir (HIV), Ritonavir (HIV),
Interferon (HIV/Implant Rejection).
Other Classes Of Suitable Biologically Active Agents
[0103] A number of other classes of biologically active agents can
also be used in the agent releasable textile. All of these choices
are biochemical mediators which can be initially immobilized via
the electrospinning technique without serious deterioration, and
then subsequently released from the nanofibrous textile fabric upon
uptake of water. Representative examples of such classes comprising
additional suitable biologically active agents are presented by
Tables 9, 10, and 11 of U.S. Publication no. 2006/0200232A1, the
content of which is incorporated by reference.
The Medical Articles Fashioned From The Agent Releasable
Textile
[0104] It is expected and envisioned that each agent-releasing
textile can be employed in the alternative either (1) as a
configured tubular conduit whose internal lumen is usefully
employed for the conveyance of fluids in-situ; or (2) as a solid
mass of flat or planar nanofibrous sheet fabric which achieves its
intended purpose without regard to or actual use of any internal
lumen within the textile fabric. Some representative examples of
the tubular format include vascular articles such as arterial
vascular grafts; venous vascular grafts; prostheses for aneurysms;
liners and covers for stents (coronary or endovascular) as well as
non-vascular devices including catheter cuffs and coating for wires
for transdermal devices (pacemaker leads). Illustrative examples of
flat sheet formats include wound dressings such as treatment
dressings, films, and/or sheets; gauze pads; absorbent sponges;
bandages; and sewing cuffs. Further examples include trans-dermal
release patches such as infection treatment; skin tumor treatments;
and finger/toenail treatment. Further examples include personal
hygiene products such as tampons; and contraceptive delivery.
Some Intended Clinical/Therapeutic Applications For The
Invention
[0105] The kinds of clinical/therapeutic applications for the
prepared medical articles and devices are intended to include major
traumatic wounds caused by accident, negligence, or battlefield
conditions; planned surgical incisions and invasive body surgical
procedures performed under aseptic conditions; transcutaneous
incisions and vascular openings for catheter insertion and blood
vessel catheterization procedures; and other body penetrations and
openings made for therapeutic and/or prophylactic purposes.
[0106] The medical articles provided by the present invention thus
are intended and expected to be manufactured as pre-packaged and
pre-sterilized textile fabric articles; be an item which can be
prepared in advance, be stocked in multiples, and be stored
indefinitely in a dry state without meaningful loss of biological
function or efficacy; and serve effectively in the treatment of
disease, disorders, and pathological conditions under many
different clinical circumstances.
[0107] The medical articles should be manufactured and tailored in
advance to meet a wide range of intended use circumstances or
contingencies expected to be encountered in a particular situation.
For this reason, the constructed textile article can and should
alternatively be prepared as a thick cloth and as a thin gauze; as
a solid-walled configured tube; and as a delicate film. Equally
important, the resulting construct may take physical form either as
a stiff, inflexible and unyielding mass or as a very flexible and
supple layer; have a varied set of dimensions and girth; appear as
both a geometrically symmetrical or asymmetrical configured fabric;
and can exist even as a slender cord or string-like length of
material.
[0108] Medically, the agent releasable textile articles of the
present invention can be employed in-vivo in the following ways:
topically or subtopically; transcutaneously, percutaneously, or
subcutaneously; or internally within the body's interior;
vascularly or humorally; and applied to any kind of body cavity,
body tissue or body organ without regard to anatomic site or
location.
Experiments, Empirical Data, and Results
[0109] To demonstrate the merits and value of the present
invention, a series of planned experiments and empirical data are
presented below. It will be expressly understood, however, that the
experiments described herein and the results provided below are
merely the best evidence of the subject matter as a whole which is
the present invention; and that the empirical data, while limited
in content, is only illustrative of the scope of the present
invention as envisioned and claimed.
[0110] An illustrative recitation and representative example of the
present invention is the preferred manner and mode for practicing
the methodology is also presented below as part of the experimental
method. It will be expressly understood, however, that the recited
steps and manipulations presented below are subject to major
variances and marked changes in the procedural details; all of
which are deemed to be routine and conventional in this field and
may be altered at will to accommodate the needs or conveniences of
the practitioner.
Series A
Preparation and Characterization Of Nanofibrous (nPET) Textiles
Experiment 1
The Electrospinning Perfusion Technique
The Electrospinning Apparatus
[0111] For small batch purposes, a self-contained semi-automated
electrospinning perfusion apparatus was assembled which included a
Glassman power supply, a Harvard Apparatus syringe pump, an
elevated holding rack, a modified polyethylene chamber, a spray
head with power attachment, a reciprocating system, and a Wheaton
stirrer for controlled mandrel rotation. Such an assembly is shown
by FIG. 4.
[0112] Utilization of this assembly permits uniform coating of a
liquid polymer onto the PTFE-coated stainless steel mandrel
(diameter=4 mm). A 10 ml chemical-resistant syringe was filled with
the liquid polymer; and a stainless steel 18 gauge blunt spinneret
(0.5 mm internal diameter) was cut in half, with the syringe
fitting half connected to the chemical-resistant syringe.
[0113] Nalgene PVC tubing (1/32 ID.times. 3/32 OD; 66 cm length)
was then connected to the syringe, followed by connection to the
other half of the blunt spinneret within the spray head. The line
was purged of air, with the syringe then placed onto the syringe
pump. The high potential source was connected to the spray head
tip; and the mandrel was set at a jet gap distance of 15 cm from
the tip of the needle. The mandrel was then grounded to the power
source; and the perfusion rate was set at 3 ml/hour at 25.degree.
C.
The Polymer
[0114] A polyethylene terephthalate (20% w:v) polymer was prepared
in ice-cold 100% hexafluoroisopropanol. The 10 ml syringe with a
stainless steel 18-gauge blunt spinneret (0.5 mm internal diameter)
was filled with the solution and placed onto the Harvard Apparatus
syringe pump.
The Perfusion Technique
[0115] Perfusion of the polymer was then started upon application
of the current to the tip of the needle (15 kV) with
electrospinning proceeding for 40 minutes. After electro spinning,
the end portions of the resulting tubular structures comprised of
nanofibrous polyethylene terephthalate, now termed "nPET"
structures, were cut off and discarded (1 cm from each end of the
mandrel). The original nPET tubular structures were then stretched
25% of the starting segment size while on the mandrel in order to
provide a set stain across the fibers, a process that occurs in
normal fiber extrusion. This yielded sized tubular segments of nPET
fabric.
[0116] Some, but not all, of the stretched nPET segments were then
immediately exposed to 100% ethanol for 2 hours at room temperature
(or for 30 minutes in 100% ethanol with sonication) in order to
remove the residual solvent. Then, all of the nPET tubular
structures (ethanol exposed or not) were air-dried overnight at
room temperature.
Results
[0117] The nPET tubular segments, whether air-dried or exposed to
ethanol followed by air-drying, had a consistent 4 mm internal
diameter throughout the lumen (length=7.5 cm). A total of 4 nPET
structures were synthesized for each method using the
above-described process.
[0118] For this experimental study, the nPET segments air-dried at
60.degree. C. were employed for all of the subsequently conducted
in-vitro studies reported herein. This post-synthesis treatment was
performed owing to the possibility of Cipro eluting during the
ethanol incubation for the other methodology described later
herein.
[0119] Concerning the electrospinning technique itself for tubular
structures fabricated using the described parameters, it was found
that increasing electrospinning time significantly beyond 40
minutes increased the rigidity of the resulting nPET material.
Conversely, electrospinning the liquid polymer blending for shorter
periods of time (e.g., 1-15 minutes) provided a tubular structure
without significant (less than 1 pound break strength) wall
strength. Major differences in and variance of tubular wall
rigidity may be desired for the various medical articles and
devices to be employed clinically. However, the chosen parameters
employed for nPET material formation in these experimental studies
were uniformly and consistently maintained at 40 minutes of
electrospinning time, a polymer concentration of 20%, an applied
voltage (15 kV), and a gap distance of 15 cm.
Experiment 2
Characterization Of Physical Properties Of Electrospun nPET
Material Tensile Strength/Ultimate Elongation
[0120] Tensile strength (pounds force), strain at maximum load (%)
and strain at break (%) for knitted DACRON segments (formed of a
commercially obtained standard textile material) and for
electrospun nPET segments (formed of a polyethylene terephthalate
compound prepared as described above) were measured using
previously published techniques. Control and test segments (7 mm
width, 3 cm length; n=3/test condition) of both kinds of material
were measured and cut.
[0121] A Q-Test Tensile Strength Apparatus (MTS Systems, Cary,
N.C.) was calibrated according to manufacturer's specifications in
a climate-controlled environment (room temperature=70.degree. F.,
65% relative humidity). Each of the samples under test were also
conditioned in this environment for 24 hours. Segment stretching
(crosshead speed=50 mm/min, gauge length=2 cm, load cell=25 lb) was
then initiated and terminated upon segment breakage.
Results
[0122] There was a marked difference between the break load of
knitted DACRON segments (42.+-.9 pounds force) and electrospun nPET
segments (3.7.+-.0.9 pounds force). This difference in breaking
load was expected owing to the significantly greater wall thickness
of the knitted DACRON material. The other physical properties, such
as the percent strain at maximum load (60.+-.24 versus 55.+-.8) and
percent strain at break (60 versus 62.+-.3), were comparable
between the two test materials, indicating that the difference in
break strength was directly related to wall thickness. Thus, the
nPET material is shown to possess significant physical
characteristics that would permit its presence and application in
various medical devices.
Experiment 3
Evaluation Of Electrospun nPET Material Via Scanning Electron
Microscopy
Scanning Electron Microscopy (SEM)
[0123] Two electrospun nPET segments were randomly selected and
examined via a JEOL JSM 5900 LV electron microscope in order to
determine fiber size and distribution throughout the material
wall.
Results
[0124] Analysis of electrospun nPET tubular structures via SEM
revealed that the diameter of the polyethylene terephthalate fibers
comprising the nanofibrous material varied from about 100 nm to
3000 nm in size. This is shown by the microphotograph of FIG. 5. A
comparison SEM analysis of the knitted DACRON samples revealed that
the knitted DACRON fibers ranged from 15 to 30 micrometers in
diameter size (data not shown) and thus were significantly larger
than the nPET fiber diameter size range.
Series B
The Agent-Releasing Textiles Comprising The Present Invention
Experiment 4
Synthesis Of Novel nPET Materials With Biologically Active
Agents
[0125] Prior to forming the blended polymer solution, the
solubility of Cipro, Diflucan and Paclitaxel in the HFIP
(hexafluoroisopropanol) solvent was determined. Based on the
pre-chosen concentration of active agent to be employed in the
composite, 15 mg of each respective agent was placed into 1 ml of
the HFIP solvent, mixed and observed.
[0126] Following this initial assessment, polyethylene
terephthalate (19%) polymer solutions containing either Cipro, or
Diflucan, or Paclitaxel (1.5% w:v) respectively were prepared in
ice-cold 100% hexafluoroisopropanol. These individually prepared
polymer solutions of Cipro, or Diflucan, or Paclitaxel were mixed
on an inversion mixer for 48 hours in order to completely
solubilize both the polyethylene terephthalate polymer and each
active agent component in their respective individual solutions.
Then, the self-contained, semi-automated electrospinning apparatus
(described previously herein) was again employed for fabricating
each version of nanofibrous textile material.
[0127] Utilization of this system permits uniform coating of the
prepared polyethylene terephthalate polymer solution onto the
PTFE-coated stainless steel mandrel (diameter=4 mm). Using the
uniform set of parameters of the previously described experimental
series, the mandrel was set at a jet gap distance of 15 cm from the
tip of the needle. The mandrel was then grounded to the power
source. The perfusion rate was set at 3 ml/hour at 25.degree. C.
Perfusion of the polyethylene terephthalate/active agent mixture
was then started upon application of the current to the tip of the
needle (15 kV) with electrospinning proceeding for 40 minutes.
After electrospinning, the end portions of the original tubular
structure (1 cm from each end of the mandrel) were cut off and
discarded. This resulted in textile tubular segments of fixed
length.
[0128] The resulting tubular segments were then stretched 25% of
the starting segment size while on the mandrel in order to provide
a set strain across the fibers, a process that occurs in normal
fiber extrusion. These tubular segments were then either air-dried
at 60.degree. C. overnight; or exposed to 100% ethanol for 2 hours
at room temperature in order to remove the residual solvent. Due
the fluorescent properties of Cipro, nPET segments (those having no
active agent) and nPET-Cipro segments (those having Cipro as the
active agent)--having been already exposed to 60.degree. C.
temperature overnight or to 100% ethanol for 2 hours--were then
exposed to a hand-held UV light to qualitatively assess Cipro
presence within the textile structure.
Results
[0129] Cipro, Diflucan and Paclitaxel individually were each found
to have excellent solubility in the HFIP solvent. Once combined
with the polyethylene terephthalate polymer/HFIP liquid, the
solubility of each respective active agent remained unchanged.
Formation of nPET (as a substantive material) and of nPET tubular
structures containing either Cipro, or Diflucan, or Paclitaxel were
all successfully accomplished. All these structures showed a
consistent 4 mm internal diameter throughout the lumen for each
tubular structure (material length=7.5 cm). Based on the perfusion
rate in conjunction with electrospinning time, each tubular segment
incorporated approximately 30 mg of each respective active
agent.
[0130] In addition, similarly to our previous experimental series,
increasing electro spinning time significantly increased the
rigidity of the resulting nanofibrous material. Conversely, electro
spinning for shorter periods of time (1-15 minutes) provided a
tubular structure without significant wall strength.
[0131] Furthermore, gross observation of the various resulting
tubular segments via UV illumination revealed intense fluorescence
from the nPET-Cipro segments, whether air-dried or ethanol washed,
when compared to the nPET segments. This UV illumination data
demonstrated the presence of Cipro to be only within the nPET-Cipro
segments. This effect is illustrated by FIG. 6.
Experiment 5
Determination Of Cipro and Diflucan Release From nPET-Cipro And
nPET-Diflucan Segments Via UV/VIS Spectrophotometer
Methods
[0132] nPET segments, nPET-Cipro segments, and nPET-Diflucan
segments (0.5 cm segment length, n=3 segments/time interval/segment
treatment) were individually placed into 5 ml of phosphate buffered
saline (PBS) followed by continuous agitation using Rugged Rotator
inversion mixer (33 r.p.m.) at 37.degree. C. Wash solutions were
sampled at acute (0, 1, 4 and 24 hours) and chronic (2-21 days for
Cipro and 2-7 days for Diflucan) time periods, with replacement of
the wash solution with a fresh 5 ml PBS after sampling. The
absorbance of wash solutions were read at 322 nm (PBS blank) using
a Beckman DU640 UV/VIS spectrophotometer.
[0133] A standard curve using known Cipro concentrations ranging
from 0-100 micrograms per ml was prepared. This Cipro standard
curve was then used to extrapolate the antibiotic concentration
within the wash solutions.
Results
[0134] The release profiles for the nPET-Cipro segments are shown
by FIG. 7, and the release profiles for the nPET-Diflucan segments
are shown by FIG. 8. Notably, the release profiles for each type of
segment are markedly different.
[0135] As observed and recorded, Cipro release within the first 4
hours was consistent at 5.+-.2 micrograms per ml, and was followed
by a sharp increase in rate to 13.+-.4 micrograms per ml at 24
hours. Cipro release then decreased to 6.+-.4 micrograms per ml by
48 hours, but persisted (ranging from 1-2 micrograms per ml)
throughout the time duration of this study (504 hours). The amount
of Cipro released has significant biological activity, owing to the
low MIC.sub.50 for Cipro (0.26 micrograms per ml).
[0136] In comparison, Diflucan release followed typical first order
kinetics in that the greatest release occurred within the first 24
hours (17, 12 and 11 micrograms per ml, respectively). This was
followed by a slow sustained release over the remaining time
periods over the 168 hour study period, the time duration of this
study.
[0137] Overall therefore, nPET segments containing Cipro and
Diflucan demonstrated significant release of each active agent
throughout the time periods empirically evaluated.
Experiment 6
Antimicrobial Activity Of nPET Segments And nPET-Cipro Segments Via
A Zone Of inhibition Assay
Methods
[0138] nPET segments (n=3 segments/time interval) and nPET-Cipro
segments (n=9 segments/time interval), which were previously washed
as described above, were then evaluated for antimicrobial activity
using a zone of inhibition assay.
[0139] A stock solution of S. aureus was thawed at 37.degree. C.
for 1 hour. Upon thawing, 1 microlter of this stock was added to 5
ml of Trypticase Soy Broth (TSB) and incubated overnight at
37.degree. C. From this solution, 10 microliters was streaked onto
Trypticase Soy Agar (TSA) plates. nPET segments and nPET-Cipro
segments were individually embedded into the S. aureus streaked TSA
plates; and each prepared plate was then placed into a 37.degree.
C. incubator overnight. Standard 5 micrograms Cipro Sensi-Discs
(n=3) were also embedded into the S. aureus streaked TSA plates at
each time interval as a positive control. The zone of inhibition
each piece was determined, taking the average of 3 individual
diameter measurements. Zone size (mm) over time was determined for
each parameter. The prepared assay plates are illustrated by FIG.
9.
Results
[0140] The nPET-Cipro segments demonstrated significantly greater
antimicrobial activity than nPET segment controls at all of time
periods examined. This is graphically shown by the data of FIG.
10.
[0141] The zone of inhibition created by the 5 micrograms Cipro
Sensi-Discs was consistent at 23 mm. The nPET-Cipro segment
antimicrobial activity profile correlated with the Cipro release
determined in the spectrophotometric studies--in that the greatest
antimicrobial activity occurred within the first 48 hours. Cipro
antimicrobial activity, presumably caused by lower Cipro
concentrations being released over time as determined by the
spectrophotometry, decreased slowly over the remaining time
periods. Nevertheless, significant antimicrobial activity was still
evident even after 504 hours, with inhibition zones being
comparable to those of the Sensi-Disc results. Thus, this study
demonstrates that Cipro release from the nPET material persisted
for over 504 hours, with antimicrobial activity correlating to the
quantity of Cipro release.
Experiment 7
Anti-Fungal Activity Of nPET Segments And nPET-Diflucan Segments
Using A Turbidity Assay
Methods
[0142] Candida albicans was purchased from ATCC. The fungus was
re-hydrated in YM Broth with 0.5% dextrose and grown for 30 hours
at 30.degree. C. under humidified conditions. nPET segments and
nPET-Diflucan segments (1 square cm, n=2
segments/inoculum/treatment) were prepared as previously described
herein, and then tested against various Candida albicans
concentrations.
[0143] A broth macrodilution assay was performed based on the NCCLS
M27-A protocol. The stock fungal inoculum concentration was
determined via backplating a set volume of the diluted fungus broth
onto Trypticase Soy Agar plates. The number of colony forming units
(cfu) grown per plate was then counted and extrapolated to
determine the starting Candida concentration.
[0144] The stock fungus solution was then diluted to 10.sup.6,
10.sup.5 and 10.sup.4 cfu/ml. After incubating the individual test
segments in 2 ml of the fungus solutions for 24 hours at 30.degree.
C., the optical density of the broth solutions was measured at 492
nm. These values were compared to Candida solutions without any
nPET materials (serving as the positive control) as well as against
YM Broth only and Candida solutions with 40 micrograms Diflucan
solution (both serving as negative controls).
Results
[0145] The nPET-Diflucan segments had significantly greater
antifungal activity at all wash periods as compared to nPET
segments which had no antifungal activity (turbidity comparable to
Candida control). This is graphically shown by the data of FIG.
11.
[0146] Diflucan (40 micrograms) in solution demonstrated excellent
antifungal activity against this inoculum, with decreasing activity
as the inoculum increased. Antifungal activity by the nPET-Diflucan
segments was clearly evident at all Candida concentrations
evaluated with activity mimicking solution-based Diflucan (data not
shown). Thus, this experimental study demonstrated that Diflucan is
released from the electrospun nanofibrous material even after
extensive washing for 2 days, with Diflucan maintaining it
recognized and characteristic antifungal activity after synthesis
of the nPET-Diflucan tubular structure.
Experiment 8
Development Of Electrospinning Methodology For Flat Sheet
Nanofibrous (nPET) Material
Methods
[0147] As described in Series A above, prepared polyethylene
terephthalate chips were dissolved in ice-cold 100%
hexafluoroisopropanol (19% w:v) and mixed on an inversion mixer for
48 hours in order completely solubilize the chips. The
self-contained, semi-automated electrospinning apparatus containing
a Glassman power supply, a Harvard Apparatus syringe pump, an
elevated holding rack, a modified polyethylene chamber, a spray
head with power attachment and a reciprocating system was again
used.
[0148] The Wheaton stirrer was used to provide a holding chamber
for the new flat collecting plate employed to generate a sheet
format. The design of this surface is based upon the collecting
plate. In short, a flat 12 cm.times.10 cm copper plate, containing
a 6 cm stainless steel rod extending from the underside of the
plate was designed and grounded to the power source.
[0149] A 10 ml chemical-resistant syringe was filled with the
polymer liquid. A stainless steel 18-gauge blunt spinneret (0.5 mm
internal diameter) was then cut in half, with the syringe fitting
end connected to the polymer-filled syringe. Nalgene PVC tubing was
connected to the syringe filled with the polymer solution followed
by connection to the other half of the blunt spinneret within the
spray head. The line was then purged of air, with the syringe then
placed onto the syringe pump. The high potential source was
connected to the spray head tip, with the plate set at a jet gap
distance of 15 cm from the tip of the needle. The perfusion rate
was set at 3 ml/hour at 25.degree. C.
[0150] Perfusion of the polymer liquid was started upon application
of the current to the tip of the needle (15 kV) with
electrospinning proceeding for 1 hour and 40 minutes, with rotation
of the plate 20.degree. every 20 minutes. This resulted in a flat,
planar sheet of nPET nanofibrous material being formed. The
resulting nPET sheet is illustrated by FIG. 12.
[0151] After the electrospinning procedure was completed, a 1.0 cm
margin around the perimeter edge of the entire nPET planar sheet
was cut off in order to eliminate potential variability in the
fabric thickness along the edge. The flat nPET sheet construct was
then stretched 25% in the width and length of the material in order
to provide a uniform set strain across the fibers, followed by
air-drying at 60.degree. C. overnight.
Results
[0152] A flat sheet of electrospun nPET textile fabric (8
cm.times.10 cm) was formed using this alternative method and
technology. When viewed in gross, the nPET planar sheet had
excellent handling characteristics and possessed physical
properties comparable to the nPET tubular structures.
VII. Conclusions Drawn From And Supported By The Empirical Data
[0153] 1. The self-contained, semi-automated electrospinning
apparatus provided by the present invention can be employed to
generate two different formats of nanofibrous textile fabrics. One
format is a tubular structure having determinable inner wall and
outer wall diameter sizes, two open ends, and an internal lumen
typically less than about 6 millimeters in diameter. This tubular
structure format presents an interior wall surface and an exterior
wall surface, and is a conduit biocompatible with and suitable for
the conveyance of liquids and gases through its internal lumen.
[0154] A second format is a flat or planar sheet construction
having determinable, length, width, and depth dimensions. The flat
sheet fabric can be folded and refolded repeatedly; can be cut and
sized to meet specific configurations; is resilient and can be
prepared in advance to provide varying degrees of flexibility,
springiness, suppleness, and elasticity.
[0155] 2. A wide range and variety of agent-releasing textiles can
be prepared for use as medical articles and devices using the
present invention. The agents are biologically active and well
characterized; are incorporated in chosen concentrations as an
ingredient in the bulk polymer prior to making the textile fabric;
and become indefinitely attached to and non-permanently immobilized
upon the fabricated nanofibrous textile material as a concomitant
part of the process for manufacturing the textile.
[0156] 3. After being placed in a water containing environment, the
agent-releasing textile will begin to take up water; release its
incorporated biologically active agent in-situ over time; and
deliver the release active agent at measurable concentrations
directly into the adjacent and surrounding milieu. The in-situ
released agent is function, operative and potent; and
provides/performs its well recognized and characteristic
biologically activity whenever and wherever it is delivered.
[0157] While the invention has been described with reference to
preferred embodiments, it will be understood by those skilled in
the art that various changes may be made and equivalents may be
substituted for elements thereof to adapt to particular situations
without departing from the scope of the invention. Therefore, it is
intended that the invention not be limited to the particular
embodiments disclosed as the best mode contemplated for carrying
out this invention, but that the invention will include all
embodiments falling within the scope and spirit of the appended
claims.
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