U.S. patent application number 13/418733 was filed with the patent office on 2012-11-01 for compressed high density fibrous polymers suitable for implant.
Invention is credited to Timothy A. Ringeisen, W. Christian Wattengel.
Application Number | 20120277152 13/418733 |
Document ID | / |
Family ID | 34633868 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277152 |
Kind Code |
A1 |
Ringeisen; Timothy A. ; et
al. |
November 1, 2012 |
COMPRESSED HIGH DENSITY FIBROUS POLYMERS SUITABLE FOR IMPLANT
Abstract
An embodiment of the present invention may be made by the
following steps: providing a mixture comprising a plurality of
fibers, a lubricant, and a suspension fluid, with the suspension
fluid filling a void space between said fibers and subjecting said
mixture to at least one compressive force. The compressive force
causes the migration and alignment of said fibers; and may remove
substantially all of the suspension fluid from said mixture. The
mixture may further comprise a biologically active agent, or a
reinforcing agent.
Inventors: |
Ringeisen; Timothy A.;
(Exton, PA) ; Wattengel; W. Christian; (West
Chester, PA) |
Family ID: |
34633868 |
Appl. No.: |
13/418733 |
Filed: |
March 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10729146 |
Dec 4, 2003 |
8133500 |
|
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13418733 |
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Current U.S.
Class: |
514/8.8 ;
162/116; 162/151; 514/7.6; 514/772; 514/773 |
Current CPC
Class: |
A61L 31/141 20130101;
A61L 31/10 20130101; A61L 27/502 20130101; A61P 19/00 20180101 |
Class at
Publication: |
514/8.8 ;
162/151; 162/116; 514/772; 514/773; 514/7.6 |
International
Class: |
A61K 47/42 20060101
A61K047/42; A61P 19/00 20060101 A61P019/00; A61K 38/18 20060101
A61K038/18; D21F 11/00 20060101 D21F011/00; A61K 47/30 20060101
A61K047/30 |
Claims
1) The method of fabricating a fibrous member comprising the steps
of: a) providing a mixture, said mixture comprising a plurality of
fibers, a lubricant, and a suspension fluid, said suspension fluid
filling a void space between said fibers; b) subjecting said
mixture to at least one compressive force, said compressive force
causing the migration and at least partial alignment of said
fibers; and c) removing substantially all of said suspension fluid
from said mixture.
2) The method of claim 1, wherein said mixture further comprises a
biologically active agent.
3) The method of claim 1, wherein said mixture further comprises a
reinforcing agent.
4) The method of claim 2, wherein said mixture further comprises a
reinforcing agent.
5) The method of claim 1, wherein said removing of said suspension
fluid comprises wicking away suspension fluid that is on an
exterior surface of said fibrous member.
6) The method of claim 2, wherein said wicking away of suspension
fluid involves compressing said mixtures against at least one
wicking element
7) The method of claim 1, wherein said compressive forces reduce
said void space between said fibers.
8) The method of claim 1, wherein said lubricant is in the form of
a liquid.
9) The method of claim 1, wherein said lubricant is in the form of
a solid.
10) The method of claim 9, wherein said solid lubricant is further
provided in a carrier fluid.
11) The method of claim 1, wherein said compressive force induces
flow of the suspension fluid.
12) The method of claim 11, wherein said suspension fluid flow
causes plates of oriented fibers to be formed.
13) The method of claim 1, wherein said compressive force is
applied by a molding surface, thereby creating a shaped fibrous
member in said mold.
14) The method of claim 13, wherein said shaped fibrous member is
in the shape selected from the group comprising a sheet, cylinder,
block, sphere, tube, and a valve.
15) The method of claim 1, further comprising the step of: d)
machining said compressed mixture.
16) The method of claim 1, further comprising the step of: d)
cross-linking at least a portion of said compressed mixture by
exposure to a cross-linking agent.
17) The method of claim 16, further comprising the step of: e)
machining said compressed mixture.
18) The method of claim 1, further comprising the step of: d)
drying said compressed mixture.
19) The method of claim 18 further comprising the step of: e)
cross-linking at least a portion of said dried, compressed mixture
by exposure to a cross-linking agent.
20) The method of claim 19 further comprising the step of: f)
machining said compressed mixture.
21) The method of fabricating a fibrous member comprising the steps
of: a) providing a mixture, said mixture comprising a plurality of
fibers, a lubricant and a suspension fluid, said suspension fluid
filling a void space between said fibers; b) subjecting said
mixture to at least one compressive force, said compressive force
causing the migration and at least partial alignment of said
fibers; c) cross-linking at least a portion of said mixture; d)
subjecting said at least partially cross-linked mixture to a second
compressive force; and e) removing substantially all of said
suspension fluid from said mixture.
Description
RELATED APPLICATION
[0001] This application is a Divisional of U.S. patent application
Ser. No. 10/729,146, filed on Dec. 4, 2003, entitled COMPRESSED
HIGH DENSITY FIBROUS POLYMERS SUITABLE FOR IMPLANT, which issued on
Mar. 13, 2012 as U.S. Pat. No. 8,133,500, which is assigned to the
same assignee as this invention, and whose disclosure is
incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] Despite the growing sophistication of medical technology,
repairing and replacing damaged tissues remains a costly, and
serious problem in health care. Currently, implantable prostheses
for repairing tissues are made from a wide number of synthetic and
natural materials. Ideally, these prosthetic material should be
chemically inert, biocompatible, noncarcinogenic, capable of being
secured at the desired site, suitably strong to resist mechanical
stress, capable of being fabricated in large quantities in the form
required, sterilizable, and free of viruses or other contaminating
agents. Examples of tissue that can be treated with implantable
prostheses include dura mater, tendon (e.g., rotator cuff, anterior
cruciate, etc.) and rectic abdominus muscle due to herniation.
[0003] A wide variety of prosthetic materials have been used,
including tantalum, stainless steel, Dacron, nylon, polypropylene
(e.g., Marlex), microporous expanded-polytetrafluoroethylene (e.g.,
Gore-Tex), dacron reinforced silicone rubber (e.g., Silastic),
polyglactin 910 (e.g., Vicryl), polyester (e.g., Mersilene),
polyglycolic add (e.g., Dexon), and cross-linked bovine pericardium
(e.g., Peri-Guard). To date, no single prosthetic material has
gained universal acceptance.
[0004] Metallic meshes, for example, are generally inert and
resistant to infection, but they are permanent, do not generally
adapt in shape as a skeletal structure grows, and they shield the
healing tissues from the stresses that may be necessary to generate
fully functioning tissue. Non-resorbable synthetic meshes have the
advantage of being easily molded and, except for nylon, retain
their tensile strength in the body. Their major disadvantages are
their lack of inertness to infection, the occasional interference
with wound healing, and that they are often long-term implants.
Absorbable meshes have the advantage of facilitating tissue
in-growth and remodeling at the site of implantation, but often do
not have the short-term or long-term mechanical strength necessary
for the application.
[0005] Both U.S. Pat. No. 4,948,540, granted to Nigam and U.S. Pat.
No. 5,206,028 granted to Li, disclose a collagen membrane suitable
for medical uses. In the case of Li, the membrane is constructed in
a fashion to make it easier for implantation, by ensuring the
membrane is not transparent, and not slippery. Both patents begin
by providing a solution of collagen, which is freeze-dried,
cross-linked, and then compressed. Li then utilizes a second
cross-linking, freeze-drying and compression step. The initial
cross-linking step locks the fibers into a specific orientation.
The compression step merely reduces the porosity within the sheet
without inducing fiber migration that would substantially improve
the strength of the composition. A second cross-linking step is
necessary to hold the sheet in its compressed conformation. What is
needed is a sheet with improved strength, capable of maintaining
its structural competence without the need of multiple
freeze-drying and cross-linking steps.
[0006] In U.S. Pat. No. 6,599,524 granted to Li, there is disclosed
a membrane sheet having oriented biopolymeric fibers. The membrane
is manufactured with oriented parallel fibers formed around a
rotating mandrel. The rotations of the mandrel as the fibers are
added results in the orientation of the fibers. The membrane is
then compressed to drive out excess liquid, and cross-linked,
resulting in a membrane with directionally oriented fibers. This
material is only aligned in a single direction and must be
laminated with binding agents in order to create a functional
device. Additionally, such a device does not provide gradients such
as those seen in natural tissues. What is needed is a method that
allows for layering that occurs at the microscopic as well as the
macroscopic level as part of a one step process and more closely
represents the layered structure of natural connective tissues.
[0007] Prosthetic devices are used in the repair, augmentation, or
replacement of articulating organs. For example, the rotator cuff
(i.e., shoulder joint) is made up by a combination of the distal
tendinous portion of four muscles: the supraspinatus, subspinatus,
subscapularis and the teres minor. Proper functioning of this
tendonous cuff, depends on the fundamental centering and
stabilizing role of the humeral head with respect to sliding action
during lifting and rotation movements of the arm. A tear in the
rotator cuff tendons is a common injury that can be caused by
constant friction from repetitive overhead motion, trauma, or
age-related degeneration that can narrow the space between the
clavicle and the top of the scapula.
[0008] To repair large tears of the rotator cuff, it is desirable
to use a scaffold or graft material to help support the damaged
tissue and guide its repair. Several types of materials have been
used for such procedures. Wright Medical (Memphis, Tenn.) markets a
product known as GraftJacket, which is manufactured by Lifecell
Corporation (Branchburg, N.J.) from human cadaver skin. Human
cadaverous tissue products can be difficult to obtain and have the
potential for disease transmission. Tissue Sciences (Covington,
Ga.) markets a product known as Permacol, which is comprised of
cross-linked porcine dermis. DePuy (Warsaw, Ind.) markets the
Restore Patch which is fabricated from porcine small intestine
submucosa. Biomet (Warsaw, Ind.) markets a product known as
CuffPatch another porcine small intestine product. The CuffPatch
and the Restore Patch products provide biocompatible scaffolds for
wound repair but they are complicated to manufacture, as they
require the lamination of multiple layers of submucosal tissues to
gain the strength needed for these applications. Fabrication of
such patches from porcine small intestine submucosa are described
in U.S. Pat. Nos. 4,902,508 Badylak et al. and 5,573,784 Badylak et
al.
[0009] Additional applications for prosthetic devices exist in the
form of membrane patches. The spinal cord and brain are covered
with a protective membrane that is known as the dura mater. The
integrity of the dura mater is critical to the normal operation of
the central nervous system. When this integrity is intentionally or
accidentally compromised (e.g., ruptured, severed, damaged, etc.),
serious consequences may ensue, unless the membrane can be
repaired. Typically, dura tissue is slow to heal. To enhance the
healing process, graft materials can be utilized to guide the
regeneration of the tissue. Repairing damaged membranes has largely
focused on implantable materials known as dural substitutes, which
are grafted over the damaged dura mater and are designed to replace
and/or regenerate the damaged tissue.
[0010] Thus, there is a need for an effective dura substitute that
would be biocompatible, sufficiently noninfectious (e.g., purified,
etc.) to prevent the transmission of disease, conformable,
available in a variety of sizes, high in tensile strength, inert,
suturable, and optionally capable of forming a water-tight
seal.
[0011] Researchers have experimented with a wide variety of
substances to act as dura substitutes. Autologous grafts of tissue,
such as pericardium, can be effective as a dura substitutes;
however, autologous tissue is not always available and it posses
additional costs and risks for the patient. Cadaverous dura mater
has also been used but like autologous tissues, cadaverous tissues
can be difficult to obtain. Tutogen Medical Inc. (West Paterson,
N.J.) markets a product known as Tutoplast dura mater, which is
obtained from human cadavers. Processed human cadaveric dura mater
has been implicated in the transmission of cases of the fatal
Creutzfeldt-Jakob disease. Other products overcome this shortcoming
by using alternate materials. The Preclude Dura substitute,
manufactured by W. L. Gore (Newark, Del.), is an inert elastomeric
fluoropolymer material. The material is biocompatible but is a
permanent implant and does not resorb over time. Dural substitutes
comprising collagen have been also been explored as described in
U.S. Pat. No. 5,997,895 (Narotam et al.). Integra Lifesciences
Corporations (Plainsboro, N.J.) distributes a product known as
DuraGen. The product is manufactured from bovine achilles tendon
and is a pliable porous sheet. Although the material is resorbable
and biocompatible, the integrity of the material is not sufficient
enough to withstand suturing to the wound site.
[0012] The present invention overcomes these suturing and other
difficulties of the materials currently available and provides a
structure capable of being adapted to a wide variety of surgical
applications.
[0013] Other applications for the implantable prosthesis of this
invention, in the form of a surgical mesh, include pelvic floor
disorders such uterine and vaginal vault prolapse. These disorders
typically result from weakness or damage to normal pelvic support
systems. The most common etiologies include childbearing, removal
of the uterus, connective tissue defects, prolonged heavy physical
labor and postmenopausal atrophy. Many patients suffering from
vaginal vault prolapse also require a surgical procedure to correct
stress urinary incontinence that is either symptomatic or
latent.
[0014] Another embodiment of the present invention is directed to
devices useful as prosthetic menisci, and in vivo or ex vivo
scaffolds for regeneration of meniscal tissue.
[0015] The medial and lateral menisci are a pair of cartilaginous
structures in the knee joint which together act as a stabilizer, a
force distributor, and a lubricant in the area of contact between
the tibia and femur. Damaged or degraded menisci can cause stress
concentrations in the knee thereby creating abnormal joint
mechanics and leading to premature development of arthritic
changes.
[0016] In the prior art, treatment of injured or diseased menisci
has generally been both by surgical repair and by tissue removal
(i.e., excision). With excision, regeneration of meniscal tissue
may not always occur. Allografting or meniscal transplantation is
another method of replacement, which has been previously tried.
[0017] This approach has been only partially successful over the
long term due to the host's immunologic response to the graft and
to failures in cryopreservation and other processes. Alternately,
menisci have been replaced with permanent artificial prostheses
such as Teflon and polyurethane. Such prostheses have been selected
to be inert, biocompatible, and structurally sound to withstand the
high loads which are encountered in the knee joint. Typically,
these permanent implants do little to encourage the regeneration of
the damaged host tissue. Therefore, what is needed is an improved
prosthetic meniscus composed of biocompatible materials, which are
biocompatible, compliant, durable, and suitable to acts as a
temporary scaffold for meniscal fibrocartilage infiltration and
regeneration of the host tissue.
[0018] In U.S. Pat. No. 5,184,574 granted to Stone and U.S. Pat.
No. 6,042,610 granted to Li, there is disclosed a meniscus
replacement material, manufactured by shape molding collagen fibers
within a mold via application of low pressure by a piston prior to
or after drying. Stone requires the step of applying freezing
cycles to the material. The fibrous materials achieve densities of
0.07-0.5 g/cc. Hydrated fibers at these density range from a free
flowing liquid slurry to a loose dough-like material unable to
maintain a shape. Freezing and possibly lyophilizing of the
material is necessary to remove it from the mold and cross-linking
solutions are applied to it while still in the frozen or
lyophilized state so that it does not warp. Fiber orientation may
be obtained by applying a rotating force to the piston in order to
form a circumferential orientation. However, this orientation
occurs only in areas directly in contact with the rotating piston.
What is necessary is a fibrous construct with sufficient integrity
to be handled without the necessity of freezing and/or lyophilizing
and that can be implanted without the requirement of cross-linking,
if desired. Additionally, this construct lacks any consistency
throughout the thickness of its structure, being able to create
oriented fibers only at the periphery.
[0019] Another embodiment of the present invention is directed to
devices useful as prosthetic ligament, and in vivo or ex vivo
scaffold for regeneration of ligament tissue and to methods for
their fabrication.
[0020] The anterior cruciate ligament (ACL) of the knee functions
to resist anterior displacement of the tibia from the femur during
flexure. The ACL also resists hyperextension and serves to
stabilize the fully extended knee during internal and external
tibial rotation. Partial or complete tears of the ACL are common.
The preferred treatment of the torn ACL is ligament reconstruction,
using a bone-ligament-bone autograft (e.g., from the patient's
patellar tendon or hamstring tendon). Cruciate ligament
reconstruction generally provides immediate stability and a
potential for immediate vigorous rehabilitation. However, ACL
reconstruction is not ideal; the placement of intraarticular
hardware is required for ligament fixation; anterior knee pain
frequently occurs, and there is an increased risk of degenerative
arthritis with intraarticular ACL reconstruction. Another method of
treating ACL injuries involves suturing the torn structure back
into place. This repair method has the potential advantages of a
limited arthroscopic approach and minimal disruption of normal
anatomy. A disadvantage of this type of repair is that there is
generally not a high success rate for regeneration of the damaged
tissues due to the lack of a scaffold or other cellular inductive
implant.
[0021] Another embodiment of the present invention relates to
devices useful as a prosthetic intervertebral disc. The
intervertebral disc plays an important role in stabilizing the
spine and distributing the forces between the vertebral bodies. In
the case of a damaged, degenerated, or removed disc, the
intervertebral space collapses over time and leads to abnormal
joint mechanics and premature development of arthritis.
[0022] In the prior art, discs have been replaced with prostheses
composed of artificial materials. The use of purely artificial
materials in the spine minimizes the possibility of an
immunological response. Such materials must withstand high and
repeated loads seen by the spinal vertebral joints, early attempts
focused upon metallic disc implants. These efforts met with failure
due to continued collapse of the disc space and or erosion of the
metal prosthesis into the adjacent bone.
SUMMARY OF THE INVENTION
[0023] The current invention is directed to a general prosthesis,
which, when implanted into a mammalian host, undergoes controlled
biodegradation accompanied by adequate living cell replacement,
such that the original implanted prosthesis is remodeled by the
host's cells before it is degraded by the host's enzymes and/or by
hydrolosis. The device of the subject invention is structurally
stable, pliable, semi-permeable, and suturable.
[0024] Embodiments of this invention can be utilized to repair,
augment, or replace diseased or damaged organs, such as rotator
cuff injuries, dura defects, abdominal wall defects, pericardium,
hernias, and various other organs and structures including, but not
limited to, bone, periosteum, perichondrium, intervertebral disc,
articular cartilage, dermis, epidermis, bowel, ligaments, tendon,
vascular or intra-cardiac patch, or as a replacement heart
valve.
[0025] The device if this invention could be used for sling
procedures (e.g., surgical methods that place a sling to stabilize
or support the bladder neck or urethra). Slings are typically used
to treat incontinence. Additionally, in the form of a surgical
mesh, the device can be used for such applications as hernia and
dura repair.
[0026] In another embodiment, this invention provides a ligament
repair or replacement prosthesis that is biocompatible, is able to
withstand ACL forces, and promotes healing of the injured tissues
by acting as a scaffold for cellular infiltration. Another
embodiment of this invention is to provide an improved disc
replacement or prosthesis that is biocompatible, does not interfere
with normal vertebral segment motion, is able to withstand normal
spinal column forces, does not wear into the surrounding bone,
promotes regrowth of intervertebral disc material and acts as a
scaffold for fibrocartilage infiltration.
[0027] The tissue repair implant of this invention, functioning as
a substitute body part, may be flat, tubular, hollow, solid, or of
complex geometry depending upon the intended use. Thus, when
forming the structure of the prosthesis of this invention, a mold
or plate can be fashioned to accommodate the desired shape.
[0028] Flat sheets may be used, for example, to support prolapsed
or hypermobile organs by using the sheet as a sling for those
organs or tissues (e.g., bladder or uterus). Tubular grafts may be
used, for example, to replace cross sections of tubular organs such
as esophagus, trachea, intestine, and fallopian tubes. These organs
have a basic tubular shape with an outer surface and a luminal
surface. In addition, flat sheets and tubular structures can be
formed together to form a complex structure to replace or augment
cardiac or venous valves and other biological tissue
structures.
[0029] The tissue repair implant of the present invention may be
rendered porous to permit the in-growth of host cells for
remodeling or for deposition of the collagenous layer. The device
can be rendered "non-porous" to prevent the passage of fluids if
necessary or the porosity can be adjusted to create a membrane
capable of selective permeability. The degree of porosity will
affect mechanical properties of the implant, and these properties
are also affected by processing (as will be discussed).
[0030] The mechanical properties include mechanical integrity such
that the tissue repair implant resists creep for the necessary
period of time, and additionally is pliable (e.g., has good
handling properties) and suturable. The term "suturable" means that
the mechanical properties of the layer include suture retention,
which permits needles and suture materials to pass through the
prosthesis material at the time of suturing of the prosthesis to
sections of native tissue. During suturing, such prostheses must
not tear as a result of the tensile forces applied to them by the
suture, nor should they tear when the suture is knotted.
Suturability of tissue repair implant, i.e., the ability of
prostheses to resist tearing while being sutured, is related to the
intrinsic mechanical strength of the prosthesis material, the
thickness of the prosthesis, and the tension applied to the suture.
The mechanical integrity of the prosthesis of this invention is
also in its ability to be draped or folded, as well as the ability
to cut or trim or otherwise shape the prosthesis.
[0031] In another embodiment of the invention, reinforcing elements
(e.g., threads, fibers, whiskers, textiles, etc.) are incorporated
into the tissue repair implant for reinforcement or for different
rates of remodeling. Thus, the properties of the tissue repair
device can be varied by the geometry of the thread used for the
reinforcement. Additionally thread constructs such as a felt, a
flat knitted or woven fabric, or a three-dimensional knitted, woven
or braided fabric may be incorporated between layers or on the
surface of the construct. Porous, non-fibrous sheets of polymer
foam may also be incorporated between layers or on the surface of
the construct. Such polymer foams can be made by methods known in
the art such as particulate leaching or solvent freeze-drying
methods.
[0032] An embodiment of the present invention may be made by the
following steps: providing a mixture comprising a plurality of
fibers, a lubricant, and a suspension fluid, with the suspension
fluid filling a void space between said fibers and subjecting said
mixture to at least one compressive force. The compressive force
causes the migration and alignment of said fibers; and may remove
substantially all of the suspension fluid from said mixture. The
mixture may further comprise a biologically active agent, or a
reinforcing agent.
[0033] Additionally, the compressive forces may reduce the void
space between the fibers, and the lubricant may assist fiber
movement during compression, and be in the form of a liquid or a
solid, and may be provided in a carrier fluid. The suspension fluid
flow may also cause plates of oriented fibers to be formed.
[0034] The compressive force may be applied by a molding surface,
thereby creating a shaped fibrous member in said mold.
Additionally, or alternatively, the material may be machined,
allowing the fabrication of complicated shapes.
[0035] In a preferred embodiment, at least a portion of said
compressed mixture may be cross-linked by exposure to a
cross-linking agent. This process will affect the strength and
resorption rate of the implant. Additionally, the strength may be
tailored by a reinforcing element, such as particulates, threads,
fibers, whiskers, textiles, rods, meshes, or combinations thereof.
The function or properties of the implant may also be affected by
additives, such as ceramics, polymers, cells, biologically active
agents, liquids, surfactants, plasticizers, and combinations
thereof.
DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 depicts fibrous dough prior to and after
compression.
[0037] FIG. 2 depicts a change in fiber orientation and inter-fiber
void space as the fibrous dough is compressed.
[0038] FIG. 3 depicts fibrous dough prior to and after
compression.
[0039] FIG. 4 depicts compression of fibrous dough as it passes
through rollers.
[0040] FIG. 5 depicts three-dimensional compression of fibrous
dough.
[0041] FIG. 6 depicts compression of a cylindrical mass of fibrous
dough.
[0042] FIG. 7 depicts incorporation if reinforcing materials within
compressed fibers.
[0043] FIG. 8 depicts incorporation of particulates, biologics
within the compressed fibrous matrix.
[0044] FIG. 9 depicts incorporation of microstructures within the
compressed fibrous matrix.
[0045] FIG. 10 depicts a hemostatic tract plug of compressed
fibrous matrix.
[0046] FIG. 11 depicts hemispherical cups of compressed fibrous
matrix.
[0047] FIG. 12 depicts a selectively compressed ring of fibrous
matrix surrounding a non-compressed fibrous matrix.
[0048] FIG. 13 depicts selective compression of a fibrous
matrix.
[0049] FIG. 14 depicts compressed fibrous constructs useful
surgical applications.
[0050] FIG. 15 depicts the surgical application of a compressed
fibrous construct.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0051] Embodiments of this invention include compressed,
biodegradable, fibrous compositions for application to a tissue
site in order to support, promote or facilitate new tissue growth.
One aspect of this invention is a fibrous component (e.g.,
collagen, elastin, chitosan, alginate, hyaluronic acid,
polyglycolic acid, polyurethane, silk, etc.; see table 1) that
provides unique mechanical and physical properties, as will be
discussed. Such fibrous components in slurry form may be
pre-processed into a fibrous dough or paste by removal of a portion
of suspension fluid, as known in the art, prior to formation into a
compressed conformation, as will be disclosed. An example is in the
form of an interlaced matrix described in U.S. patent application
Ser. No. 10/601,216 filed on Jun. 20, 2003 and assigned to the same
assignee of the present invention, which is incorporated by
reference herein. The material is a natively cross-linked collagen
such as Semed F produced by Kensey Nash Corporation (Exton,
Pa.).
[0052] The fibrous dough is dehydrated/desolvated by applying a
compressive force in such a manner as to reduce the inter fiber
space by removing at least a portion of the suspension fluid. In a
preferred embodiment substantially all of the suspension fluid is
removed. Unlike unaltered or natural matrices (e.g., dermis, small
intestine submucosa, etc.), the thickness, porosity, fiber-density,
fiber-orientation, fiber-length, fiber composition and
component-ratio (e.g., Collagen to Elastin ratio), as a
non-limiting example, can be controlled with the current
invention.
[0053] To improve the migration of fibers and prevent clumping
during the compressive process it is preferred to incorporate a
percentage (e.g., 0%-50% by mass of fibers) of one or more
lubricants (e.g., biocompatible oils, hydrogels, liquid polymers,
low-molecular weight polymers, glycosaminoglycans, surfactants,
waxes, fatty acids, fatty acid amines and metallic stearates such
as zinc, calcium, magnesium, lead and lithium stearate, etc.) into
the fibrous dough suspension. A lubricant is defined as a
substance, which is capable of making surfaces smooth or slippery.
These characteristics are due to a reduction in friction between
the polymers to improve flow characteristics and enhance the
knitting and wetting properties of compounds. Said lubricant may be
liquid or solid and may be suspended or dissolved in a carrier
solvent (e.g., water, alcohol, acetone, etc.). Additionally the
lubricant may only become lubricious under compressive force or
change in temperature. The lubricant may remain in its entirety in
the final invention; may be partially removed in the
dehydration/desolvation process; or, may be washed out or removed
by methods known in the art during further processing. Lubricants
that remain in the final invention may be biologically active
agents or may form microstructures. Preferred lubricants include
Tween-80, hyaluronic acid, alginate, glycerin or soluble collagen
with the most preferred being acid soluble collagen such as Semed S
produced by Kensey Nash Corporation (Exton, Pa.).
[0054] Additional ways in which to add lubricity include physically
or chemically altering the surface of the fibers making up the
composition. Such alterations can be achieved through chemical or
physical attachment of a lubricious substance to the fibers,
temperature induced phase changes to the surfaces of the fibers or
partial solubilization of the fibers through alteration of the pH
and/or conductivity of the free fluid or use of a percentage of
solvent for the fibers within the free fluid. Other methods of
creating lubricity are known to those skilled in the art, and are
embraced by this disclosure.
[0055] During the compression step of the fibrous dough, the fibers
align themselves into layered or plate-like structures. As the
inter fiber void space is collapsed, the displaced fluid is forced
outward and begins to flow out of the device. The flow may play a
role in aligning the fibers in that direction. The rate of flow is
directly affected by rate and duration at which compression occurs.
This phenomenon occurs throughout the structure and results in
aligned fibrous layers or plates separated by fluid planes. These
planes facilitate migration within the structure, allowing the
fibers within a single layer to move without interference from
fibers in a different layer.
[0056] The compression induced fluid migration may occur
three-dimensionally, thereby dissecting planes in the structure as
it runs into resistance. Additionally the fluid may be forced
through narrow passageways in the fibrous mats and begin creation
of a new plane at a different level within the construct. Thus it
is possible to create a structure wherein the planes do not
traverse the entire length of the device, but instead exist as
multiple fissures located randomly within the construct and each
fissure can be defined by fibrous plates having an aligned fiber
orientation unique from that of neighboring fissures. The plates
themselves may be organized in a random, oriented, or aligned
fashion. As compression continues, the lubricant reduces the
friction, allowing the aligned fibers within the plates or planes
to slide across each other and nest in the most compact
orientation. Additional compression brings the plates of fibers in
closer contact, allowing them to become locked into a compact
anisotropic structure, although the material may be isotropic in
two dimensions.
[0057] Unlike existing state of the art sheets, this layering
occurs at the microscopic as well as the macroscopic level as part
of a one step process and more closely represents the layered
structure of natural connective tissues. Additionally, the amount
of fiber compaction within a plate or layer and the spacing between
the plates or layers can be controlled by the force applied and the
amount of time allowed for equilibration at a specific force. The
preferred force applied is from 0.01 tons/square inch to 100
tons/square inch with the most preferred force being in the range
of 0.2 tons/square inch to 2.0 tons/square inch. This amount of
force is in excess of state of the art methods used merely to
extract fluid and concentrate the fibers into workable dough-like
material. Existing methods do not induce fiber migration or layer
formation. Devices created under such conditions as described above
do not require additional steps such as freezing and/or
cross-linking within molds to be handled. The preferred amount of
equilibration time is in the range of about less than one minute to
more than 500 minutes with a more preferred range of about 1 minute
to 60 minutes.
[0058] The use of wicking materials such as paper towels/sponges or
fluid removal systems such as screens or vacuum systems prevent
excessive pooling of fluid in any single area of the structure
during compression. If fluid is allowed to accumulate, it can
create craters or voids within the structure. If the fibers
surround these pools of fluid succumb to the compressive forces, a
rip or discontinuity in the structure will form as the fluid is
forcibly expelled. Strategic location of fluid exit pores within a
mold can be used to create unique directional flows that in turn
align the fibers within a layer or plate. In this way the fibers
forming plates at each level can be oriented in the same direction
or turned at any conceivable angle to each other. Although
orientation of fibers from plate to plate may be organized or
random, fiber orientation within a plate is organized with the
fibers running predominantly parallel to each other. Molds with
fluid vacuum assist further improve control of fiber orientation.
Additionally, materials such as threads and screens provide avenues
for fluid escape. As the fluid flows along the length of the
threads and screens, the fibers adjacent to them are aligned
parallel to them. Use of porous rods or porous hollow tubes that
can be extracted or left in place as reinforcement can also be used
to facilitate uniform fluid removal. If the fluid extraction tubes
are removed, long channels will be left that can be utilized for
purposes such as suture line conduits.
[0059] As the inter fiber space is reduced and the free fluid
within the dough is expelled, the overall porosity of the
compressed composition is reduced towards a theoretical zero point.
The amount of porosity as well as the size of the pores dictates
whether the device functions as a tissue matrix or barrier.
Additionally, the physical/mechanical properties are highly
influenced by the amount of inter fiber space. Another factor
affecting the mechanical and physical properties of the composition
is the use of additives (e.g., surfactants, plasticizers,
particulates, porosifiers, meshes, etc.).
[0060] In a preferred embodiment, the method of preparing the
high-density fibrous matrix involves: providing a fibrous material;
contacting said fibrous material with a suspension fluid and a
lubricant; applying a compressive force within one or more
dimensions that partially dehydrates/desolvates the fibrous
material. Subsequently, the fibrous material may be cross-linked.
It may be further desirable to provide a directed means of egress
for the suspension fluid during compression, as previously
discussed. Additionally use of a fibrous suspension having
interlaced, interlocked fibers may be desirable.
[0061] In another embodiment, the partially dehydrated fibrous
matrix is fully dried (e.g. vacuum dried, freeze-dried, air-dried.)
after which it may be cross-linked. It may be further desirable to
rehydrate/resolvate the fibrous matrix to facilitate incorporation
of cross-linking agents, plasitisizers, surfactants, biologically
active agents, microstructures, cells or other materials. If
desired the sheet may again be dried.
[0062] Any method of compression known by those skilled in the art
is conceivable for this invention, including, but not limited to,
using hydraulically or pneumatically powered platens or pistons to
compress the fibrous matrix material. Other methods include but are
not limited to using a screw or an arbor press to compress the
material, using centrifugation to extract fluid and compress the
fibers, or forcing the material between rollers.
[0063] The structure of the fibrous matrix material is also
influenced by the amount of compressive force applied to the
material. The amount of compression may change the porosity of the
fibrous matrix material. The pore size distribution will also be
affected by the amount of compression as the fibrous matrix
material may be compressed so that only certain areas have
collapsed, or so that all areas collapse. The direction of
compression in relationship to the original structure of the
fibrous matrix material will also affect the structure of the
compressed fibrous matrix material. For example, if the initial
fibrous matrix material has long parallel fibers, a force applied
could be used to force the fibers together in a parallel fashion or
bunch up the fibers as the force attempts to shorten the length of
the fibrous composition.
[0064] Compression of the fibrous matrix material can be controlled
to create various structural patterns within the material;
likewise, the mechanical properties of the material may be altered
to meet specific requirements. The amount of compression is
directly related to the tear strength of the material. If a medical
device fabricated from the compressed material is not in the form
of a sheet, the compressed material can be compressed
three-dimensionally to form the desired shape. If the medical
device is axially loaded, the compressed material may be compressed
in one direction to optimize the mechanical properties of the
material in that direction.
[0065] If not compressed initially into the final shape, after
being compressed and removed from the compression device, the
fibrous matrix material may be machined into a new shape or design
with various features. Machining processes are well known to those
skilled in the art. (e.g., punching, coring, milling, sawing,
lathing, etc.) Additionally, the compressed fibrous matrix may
function as a component of a larger device and if not attached
during the compression step, may be attached to components by
methods known to those in the art (e.g., gluing, stapling, sewing,
etc.).
[0066] The inventors have discovered that after the compressive
dehydration/desolvation process the resultant material has
mechanical properties, including tear strength, superior to those
of non-compressed materials that have been cross-linked. Not being
confined to a single theory, it is believed that the high
compressive forces will create weak chemical linkages aside from
the physical interaction of the fibers. This permits the current
invention to be utilized in applications that initially require
specific tear strength but where it is desirable for the device to
be quickly degraded away after fulfilling its initial function such
as dura repair. The current invention can be cross-linked, either
chemically (e.g., EDC) or by non-chemical methods (e.g.,
dehydrothermal (DHT)) know to those skilled in the art, for
applications requiring strength for an extended period of time,
such as hernia repair.
[0067] The inventors have further discovered that a non-compressed
or mildly compressed sheet can be cross-linked, completely or only
at the surface, by a first method after which it is fully
compressed and cross-linked by a second method. The first
cross-linking restricts motion of the fibers during the compression
step, retarding an increase in the footprint of the sheet. Even
thought the sheet is cross-linked in the non-compressed state, the
addition of a lubricant facilitates migration and shifting of the
partitions making up the sheet. This allows thick sheets to achieve
the same fiber density per unit volume as thin sheets.
[0068] Highly compressed sheets of collagen fibers placed into
cross-linking solutions have formed a tough cross-linked skin
around a minimally non-cross-linked center. The center of such
sheets are easily separated forming a shell, pocket or bladder. The
permeability of the bladders varied depending upon the initial
compression. Low compression produced bladders that slowly allowed
dyed fluid to exude. Moderate compression allowed water to pass
through but filtered out the larger dye molecules. High compression
created a barrier to fluid water but slowly allowed the escape of
water vapor. Such a phenomenon was not evident in DHT cross-linked
sheets.
[0069] Such devices would be useful for tissue engineering
applications associated with bladder, intestine, tendons, ligaments
and vessels, as well as the creation of rotator cuff patches,
hernia repair sheets, orbital implant coverings, graft wraps and
the formation of anti-adhesion devices. The shell of material could
be filled with ceramics or polymers useful in bone repair or used
as containment devices for injection of settable polymers or
ceramics. Additionally, the center could be filled with fluids
prior to or after implantation for applications such as controlled
drug delivery or the creation of shock absorbing vessels useful for
breast implants, fat pad replacement or meniscus and disc repair or
replacement.
[0070] Restricted contact of cross-linking solutions with the
surfaces of collagen devices control the degree of cross-linking in
fibrous, non-fibrous, compressed and non-compressed materials. For
example, restricted contact can be achieved by placing shaped,
fully hydrated, collagen dough into a cross-linking solution. The
cross-linking solution slowly displaces hydration fluid at the
periphery but does not immediately come into contact with the
hydrated material in the center. As the material continues to sit
in the cross-linking solution a gradient begins to form with a
greater amount of cross-linking occurring at the surface and lesser
amounts of cross-linking occurring toward the center.
[0071] Additionally, a second type of cross-linking could be
introduced after drying to create a bi-phasic cross-linking (e.g.,
DHT, chemical vapors, radiation). Devices having such unique
cross-linkings would be useful in tissue-engineering applications
involving multi-phasic tissues such as cartilage and skin or could
function as in-vivo cell culture vessels capable of protecting
foreign cells, such as islet cells from a different person or
animal, from attack by the recipients' immune system.
[0072] The central portion of units cut from compressed collagen
sheets having only the surface cross-linked swell when in contact
with excess aqueous fluids. A small amount of fluid hydrates the
sheet and creates thin flexible units. Only after being placed in
contact with excess fluid does the sheet begin to swell. The
swelling can be delayed by minutes to hours depending upon the
initial thickness, magnitude of compression, and the amount of
cross-linking at the surface. This creates a large central porosity
suitable for cell migration and/or delayed drug or biologics
delivery, centered between two low-porosity protective sheets. Such
a device would also be suitable in applications requiring
implantation through a small opening that will swell to full size
after becoming fully hydrated by body fluids.
[0073] The fibrous matrix material may be compression molded into
an initial or final design of a medical device. If the device has
complicated geometry, various features may be machined after
compression molding. The material and mechanical properties of the
final device can be altered by the temperature of the molds, the
amount of overall compression, the design of the mold, etc. The
fibrous matrix material may be compressed before molding, or all
the compression may occur during the molding process. The direction
of compression before or during compression molding will also
affect the mechanical properties of the device. For example, a
cylinder of fibrous dough material may be three-dimensionally
compressed to improve the mechanical properties and then
compression molded into a threaded bone screw. Additionally, the
cylinder of fibrous material could be compressed into a cone shape
providing a gradient of compression. Such gradients would be useful
for multi-phasic tissue or multi-phasic drug delivery.
[0074] The implantable prosthesis of the present invention may be
sterilized by any method known in the art. (e.g., exposure to
ethylene oxide, hydrogen peroxide gas plasma, e-beam irradiation,
gamma irradiation, etc.) The sterilization minimizes the
opportunity of infection to occur as a result of the implant.
[0075] In the preferred embodiment of the invention, the fibrous
prosthesis is manufactured from a resorbable material, although
this is not meant to exclude the use of non-resorbable polymers,
minerals and metals within the final structure.
[0076] Different polymers, molecular weights, additives, processing
methods, cross-linking methods and sterilization methods can be
used to control the resorption rates of resorbable polymers and is
well know by those skilled in the art. For example, reconstituted
collagen fibers degrade faster than natively cross-linked collagen
fibers and collagen that has not been cross-linked degrades faster
than cross-linked collagen. Additives such as ceramics capable of
increasing the localized pH also increase the rate of degradation,
as do chemotactic ground substances that attract cells to the
localized area. Resorption rates can be adjusted to be shorter for
applications that require mechanical strength for only a short
period of time or longer for applications that require mechanical
strength to be present for a longer duration. Examples of
resorbable polymers that can be formed into fibers and used to form
the prosthesis are shown in Table 1. These materials are only
representative of the materials and combinations of materials that
can be used as prosthetic material and this table is not meant to
be limiting in any way.
[0077] For the purposes of promoting an understanding of the
principles of this invention, reference will now be made to the
embodiments illustrated in the drawings and specific language will
be used to describe the embodiments and elements of the
embodiments. It must be understood that no limitation of the scope
or applications of the invention is thereby intended. For ease of
understanding, fibers are represented in the drawings by simple
crossed lines, by no way does this indicate that they may not be
interconnected, interwoven, interlaced or entangled, or that the
final structure is porous or non-porous, organized or random,
and/or reticulated, except as otherwise noted. In theory, the
compressed fibrous structure could in fact be produced through the
compression of a single continuous fiber.
[0078] Referring now to the drawings, FIG. 1 shows the fibrous
matrix material before and after compression. Before compression,
shown in FIG. 1A, the fibrous matrix material 100 comprises a large
percentage of void space surrounding the fibers 110. The fibers 110
form a structure composed mostly of inter fiber void space 120.
After being compressed, shown in FIG. 1B the compressed porous
matrix material 130 contains the same amount of fibrous material
140; however, the sacrificed, inter fiber void space 150 has
resulted in a reduced porosity in the material. It should be noted
that the inter fiber void space in this figure and all other
figures may contain a lubricant as has been discussed.
[0079] In another embodiment depicted in FIG. 2A, the fibrous
matrix material 200 is placed between two compressive devices 210
(e.g., platens, pistons, etc.), which may or may not be heated or
cooled. Heating can be used for such purposes as to modify the
fibers (e.g.,--denature, soften, melt), increase the rate of fluid
evaporation, fuse the fibers once compressed, or improve the
activity of any lubricant. Cooling can be used for such purposes as
protecting the fibers from excessive heat during compression or to
induce phase change or thickening of the suspension fluid and/or
lubricant. The fibers 220 and the inter fiber void space 230 define
the structure of the fibrous matrix material. In FIG. 2B, the top
compressive device 215 is lowered to compress the fibrous matrix
material 240 while the compressive device 210 remains stationary. A
gradient is formed starting at the top of the material where fibers
250 are forced together, reducing the interfiber void space 230,
while the fibers 220 in the lower part of the material retain their
conformation. This can be employed to create an implant for
biphasic tissues such as bone or cartilage. Two gradients can be
formed by compressing the fibrous matrix material 260 with both
compressive devices 215 at the same time, as shown in FIG. 2C. The
top and bottom surfaces have a majority of compressed fibers 250.
The next top and bottom layer of fibers 280 will be mildly
compressed and have a reduced inter fiber void space 270. The
middle of the material 260 will have fibers 220 that maintain their
original inter fiber void space 230. This can be employed to create
an implant for a triphasic tissue such as the skull that
transitions from cortical bone to cancellous bone and back to
cortical bone. As shown in FIG. 2D, if compressive devices 215
continue to exert force the material 290 could be evenly compressed
with no gradients. The compressed fibers 250 and inter fiber void
space 295 will be evenly distributed, or nearly so, through the
material 290. Continued compression by compressive devices 215, as
shown in FIG. 2E initiates migration of fully compressed fibers 296
in the material 297. This further reduces the inter fiber void
space 298. This is useful in the creation of sheet implants having
superior strength and finely controlled porosity to replace those
currently manufactured for such applications as dura, tendon and
hernia repair.
[0080] It is envisioned that desired percentages of porosity or
desired pore distribution can be controlled based on the amount and
method of compression. Specific pore volumes or densities may
promote different types of tissue ingrowth (e.g., bone or vascular
tissue ingrowth). Based on desired porosity or density, the fibrous
matrix material may act as a cellular scaffold for various uses in
tissue engineering.
[0081] In another embodiment as illustrated in FIG. 3A, an
amorphous mass of fibrous dough 300 containing fibers 310 and inter
fiber void space 320 is compressed to form an anisotropic sheet
material 330 shown in FIG. 3B. The fibers 340 begin to align in the
radial direction as force 350 induces migration of the fibers 340
collapsing the inter fiber void space 360.
[0082] Another form of compression is illustrated in FIG. 4. An
amorphous mass 400 containing fibers 410 and inter fiber void space
420 is drawn through rollers 430. This drawing motion compresses
and aligns fibers 440 while simultaneously reducing the inter fiber
void space 450. The rollers could also be aligned circumferentially
around the mass and used to draw the material into an elongated
cylinder (not shown).
[0083] Another form of compression utilizes centrifugal force to
compress fibers in an outward direction onto a porous structure.
For example, the fibers could be forced out against a spinning
porous drum creating a cylinder of compressed fibrous material (not
shown). The drum could contain any number of contours or structures
that would form corresponding negatives and positives in the
fibrous material. Such a method could be used to create detailed
anatomical structures such as the cheek, nose or ear. Additionally,
this process could be used to create multi-layered constructs or
embed materials such as sutures, particulates or meshes into the
fibrous constructs. In another preferred embodiment, the above
formed multi-layer construct is placed over a mandrel and further
compressed creating a structure useful for tissue engineering
applications such as vascular grafts, where each layer corresponds
to the individual layers within an artery. In another embodiment,
the above mandrel is replaced by a series of fibers or threads,
which may or may not be woven or spun together, wherein the
compressed fibrous material interpenetrates/interdigitates the
series of fibers or threads, locking them into a conformation
suitable for tendon, ligament or muscle repair.
[0084] In another embodiment as illustrated in FIG. 5, a sphere 500
of fibrous matrix material is three-dimensionally compressed by
force 510. Fibers 520 separated by inter fiber void space 530
create the sphere's 500 structure. After being compressed, the
porosity, inter fiber void space and size of the sphere 540 are
decreased. Unlike two-dimensional compression, the fibers 550 have
not collapsed into thin layers. The three-dimensional compression
caused each fiber 550 to fold or coil as the inter void space 560
was reduced. This embodiment could be used as a device to promote
staged delivery of biologically active agents or it could be split
in half to create a chin or cheek implant, for example. A polymeric
material could be placed in the center to release a biologically
active agent (not shown). This embodiment may also be used to
create a cell based implant wherein the cells supported in the
non-compressed center of the device are protected from the body's
immune system by the collapsed porous exterior. The center could
also be hollowed out by using a central core material (e.g., ice,
polymer, salt, etc) that could function similar to a porosifying
agent and be removed after compression and replaced with cells (not
shown). This would be particularly useful in supporting and
protecting transplanted tissue (autograft or xenograft) such as
islet cells capable of producing insulin. While the compressed
fibers 550 would prevent immune cells from entering the sphere 540
and destroying the islet cells, oxygen and nutrients would readily
pass through the compressed inter fiber space 560. In turn, waste
product and insulin would pass out of the sphere.
[0085] A modified three-dimensional compression is illustrated on a
cylinder 600 of fibrous matrix material in FIG. 6. Like the sphere
500, the cylinder 600 is composed of fibers 610 separated by inter
fiber void space 620. Compression can be applied to the cylinder
600 by applying force around the circumference of the cylinder 600
while restricting elongation (or increasing) of its height. This
type of three-dimensional compression would cause the compressed
cylinder's 630 fibers 640 to pack together as the inter fiber space
650 is reduced. If elongation is encouraged, the fibers would draw
out as the inter fiber space is reduced (not shown). Depending on
the amount of compression, and direction of fiber migraton, the
fibers 640 could define thin channels running parallel to each
other throughout the height or width of the cylinder 630. Devices
like this would be useful as orthopedic rods or nerve guides.
Placement of one or more removable solid rods in the center of the
mass would allow for the formation of one or more lumen within the
cylinder. Uses would include tissue engineering of vessel and
nerves as well as any other tubular tissue.
[0086] In another embodiment, the compressed fibrous material
contains reinforcing materials such as long threads, meshes, rods,
and other fibers. The migration of the fibers under the compressive
force may confine, and lock the reinforcing material within a
spatial conformation. This could retard the reinforcing material
from migrating within, or dissecting from, the compressed fibrous
material. This phenomenon can be used to alter mechanical
properties (e.g., tear strength) of the construct. Additionally,
the compressed fibrous material may improve the biocompatibility of
the reinforcing material (e.g., improved cellular migration within
or adhesion to a mesh). FIG. 7A shows a construct 700 comprised of
an embedded mesh/screen 710 embedded/entangled within the fibers
720.
[0087] The reinforcing material may be centered within the
construct, located on or just below one or more surfaces or
interspersed throughout the entire construct. As an example shown
in FIG. 7B, the fibrous material 730 may be compressed over a bone
screw 740 creating a coating 750 approximating the shape of the
screw that is used to temporarily or permanently hide the material
of the screw from the body's immune system. The coated implant 760
is useful as an improved interference screw. Additionally, the
reinforcing material may be porous and permit interdigitation of
the fibers. This porosity also assists in the removal of
fluid/lubricant during compression. If desired, vacuum can be used
to facilitate drawing of fluid and fibers into the porosity. The
lubricant may itself function as a bridging agent locking the
fibrous coating to the porous reinforcing material.
[0088] In another embodiment, as seen in FIG. 8, a device 800
containing compressed fibers 810 are used to control the location
and delivery of biologically active agents 820 (e.g., growth
factors, cytokines, genes, hormones, BMP, drugs, cells, viruses,
etc., see Table 2). The unique compressive forces used to create
the device can be used to control flow of fluid (e.g., blood,
interstitial fluid, etc.) within the device during processing,
allowing for tailored release properties. The biologically active
agents 820 could be located within or supported between the
compressed fibers 810 making up the device 800. Additionally, the
biologically active agents 820 could be physically or chemically
attached or bonded to the fibers 810 or suspended within a
hydration fluid that is supported within the inter fiber void space
830. This hydration fluid may contain a soluble polymer that
suspends or binds the biologically active agent. Additionally, the
hydration fluid containing the soluble polymer may be removed
leaving the soluble polymer as a coating on the compressed fibers
or microstructure suspended within the inter fiber void space
between the compressed fibers.
[0089] In another embodiment, also shown in FIG. 8, the compressed
fibers 810 are used to control the location and orientation of
reinforcing and/or biologically active particulate components 840
compounded into the fiberous material (e.g., tricalcium phosphate,
hydroxyapatite, calcium sulfate, autologous bone graft, allograft
bone matrix, DBM, polymers, microspheres, etc; additionally, see
Table 3). The compressed fibers 810 may confine, and lock the
particulate components 840 within the inter fiber void space 830.
This retards the particulate from migrating within or
disassociating from the compressed fibrous device/construct 800.
When adding particulate, the addition of a lubricant facilitates
movement of the particulate within the construct during the
compression step preventing stratification or clumping of the
particulate in the final product. Additionally, the lubricant can
be left within the polymer as a velour or coating entrapping the
particulate.
[0090] It should also be noted that the use of reinforcing
materials (e.g., polymer mesh, titanium screens, TCP, etc.) or
addition of biologically active agents (e,g, growth factors, DBM,
cells, drugs, etc.) may be employed as or in a fiber, rod, thread,
wire, particulate, microsphere, fragment, suspension, emulsion or
other addition. These materials can be uniformly distributed
throughout the compressed fibrous construct, or if desired,
stratified or concentrated to specific areas of the construct. This
can be easily achieved by placing depots of materials between two
or more layers of fibrous material prior to compression, as well as
by the methods previously discussed.
[0091] It is also conceived that in one embodiment of this
invention the material can contain an additive that can be used to
help deliver or retain the previously described biologically active
agents. As an example shown in FIG. 9, the inter fiber void space
910 of the gross compressed fibrous structure 900 could be invested
with a chemotactic ground substance 920, such as the velour of
hyaluronic acid suspended between the compressed fibers 930. A
velour could accomplish several biochemical and biomechanical
functions essential for wound repair. For example, since hyaluronic
acid is extremely hydrophilic, it may be valuable for drawing body
fluid (e.g., blood, bone marrow) or other fluid-based biologically
active agents into the fibrous device. Upon hydration, the
hyaluronic acid can become an ideal carrier for pharmacological or
biologically active agents (e.g., osteoinductive or osteogenic
agents such as the bone morphogenetic protein (BMP) and other
bone-derived growth factors (BDGF)) by providing for chemical
binding sites, as well as by providing for mechanical entrapment of
the agent as the velour forms a hydrogel. It is further conceived
and shown in FIG. 9B that the velour 940 extend beyond the
boundaries of the compressed fibers 950, creating a layer of
microstructure attached to the compressed fibrous structure. This
bi-phasic device 960 is useful as an adhesive bandage when the
microstructure is a tissue adhesive agent.
[0092] In another embodiment, the material may be cross-linked to
impart improved characteristics such as: mechanical strength (e.g.,
suturablity, compression, tension, etc.), and biodurability (e.g.,
resistant to enzymatic and hydrolytic degradation). This may be
accomplished using several different cross-linking agents, or
techniques known to those skilled in the art (e.g., thermal
dehydration, radiation, EDC, aldehydes (e.g., formaldehyde,
glutaraldehyde, etc.), natural agents such as genipin or
proanthocyanidin, and combinations thereof).
[0093] In another embodiment, a sheet produced by methods previous
described may be rolled, contoured or shaped prior to cross-linking
to lock the sheet into a unique spatial configuration, for example,
a spiral configuration may be created having a plane separating
each successive revolution of the sheet. The plane provides unique
compressive qualities, that when combined with the compressive
qualities of the cross-linked compressed fibers, is ideal for
applications receiving directional compressive loads. These
applications include but are not limited to joint meniscus,
intervertebral disk and articular cartilage. In another embodiment,
the plane formed by the spiral configuration can be filled with
materials to enhance its mechanical or biologic characteristics
(e.g., reinforcing materials, particulates, biologically active
agents, natural and synthetic polymers).
[0094] In another embodiment, fibers can be compressed directly
into a mold that approximates the gross anatomy of a tissue or
organ (e.g., blood vessel, heart valve, ear, nose, breast,
finger-bones, etc.) after which the construct may be cross-linked.
The reduced inter fiber void space of the compressed fiber provides
superior shape holding characteristics due to the unique resistance
to fiber disassociation. A star-shaped structure 1000 shown in FIG.
10 illustrates a possible design for a hemostatic tract plug made
possible by the superior shape-holding characteristics of the
present invention. Preferably such a device is not cross-linked to
provide the shortest resorption time post implantation. Upon
exposure to body fluids the construct swells, creating a tampanode
effect. Due to the compressive forces used during fabrication, the
fibers do not readily disassociate from the unit. If cross-linking
is desired, it is preferable to cross-link the outer surface only
so that the interior fibers are able to swell. As the center of the
device swells, the star's concave portions are pushed out creating
a cylinder that seals the wound site.
[0095] Such a swellable device has applications which include the
occluding of other openings, ducts or lumens in the body (both
natural and artificial) and that it can be utilized to deliver
biologically active agents and drugs. Additionally, those skilled
in the art will recognize other useful shapes (e.g., threaded,
oval, square, circle, etc.) for specific applications (e.g., bone
plug, plastic or cosmetic surgery, oviducts, etc.). Such constructs
can be delivered through cannulas or by syringe-like devices.
[0096] In another embodiment, shown in FIG. 11A, a hollow
hemi-spherical device 1100 depicts circumferentially aligned and
compressed fibers 1110 and corresponding inter fiber void space
1120. Methods of producing said construct include compressing
masses of fibrous dough-like material around spherical and
hemi-spherical molds with and without rotation of the compression
device and formation of bladders as previously described. FIG. 11B
illustrates a cross section of a hollow device 1130 that contains a
material 1140. This material 1140 (e.g., cells, particulate, gel or
fluid-like material, settable materials, etc.) may have been placed
in the hollow device prior to or after implantation. Hollow
structures as described above are useful for tissue engineering
applications such as in-vivo cell reservoirs, drug delivery
systems, plastic and reconstructive surgery implants, and shock
absorbing indications as previously described. For example,
bladders could be formed to receive autologous fat cells, which
could be relocated within the body for cosmetic augmentation.
[0097] In another embodiment, a bladder manufactured by above
methods may be used to reduce and repair a fractured vertebral body
by inserting the bladder into the injury site and inflating (e.g.,
gel or fluid, settable fluid, etc.) to realign the spinal column by
returning the vertebra superior and inferior of the injury site to
their appropriate location.
[0098] In another embodiment, shown in FIG. 12A (top view) and FIG.
12 B (side view), a ring of material 1200 is selectively compressed
surrounding a minimally-compressed to non-compressed fibrous region
1210. The device 1230 is useful in such applications such as a
hernia patch or where a sponge-like material is needed with the
additional requirement of suturability around the periphery of the
device. Similar to FIGS. 12A and 12B, FIG. 13 depicts a device 1300
that contains a preferentially compressed region 1310 adjacent to a
minimally-compressed to non-compressed region 1320. Such a device
may be useful in the repair of transitional zones between tissues
such as tendon to muscle or ligament to bone.
[0099] It is believed that the high compressive forces will create
chemical linkages aside from the physical interaction of the
fibers. In the case of collagen, it is believed that the
compressive force re-establishes non-covalent forces such as
hydrogen bonding, hydrophobic/hydrophilic interactions, and
electrostatic interactions, that the individual fibers and fibrils
previously embodied in the native, pre-extracted tissues. These
additional chemical linkages may act to create a pseudo-molecular
weight increase to the matrix, providing improved mechanical
properties prior to cross-linking, thereby providing for highly
detailed crisp margins within the compressed fibrous construct that
are locked in place with cross-linking Constructs made using
fibrous materials defined in the prior art do not hold crisp
margins. Therefore, material in this embodiment would be useful as,
but not limited to, devices for cosmetic and reconstructive
surgery, intervertebral disks, joint meniscus and hollow tissues
and organs (e.g., intestine, esophagus, ureter, etc.).
[0100] In another embodiment, a fibrous material can be compressed
into a mold containing a structure or component (e.g., ring, mesh,
particulate, screw, rod, etc.) to which the fibers attach, after
which cross-linking may occur. The compressed fibers support,
confine, and lock the structure or component within a spatial
conformation. Additionally, the structure or construct may be
porous and permit interdigitation of the fibers. This porosity also
assists in the removal of fluid/lubricant during compression. If
desired, vacuum can be used to facilitate drawing of fluid and
fibers into the porosity. The lubricant may itself function as a
bridging agent locking the fibrous coating to the porous
reinforcing material.
[0101] Additionally, the compressed fibrous material may contain
reinforcing materials such as long polymer threads or mesh(es) or
may include particulates or biologically active agents. (e.g.,
growth factors, hormones, bmp, drugs, cells, viruses, etc.)
Additionally, the biologically active agents could be located
within fibers making up the compressed fibrous material,
mechanically or chemically attached to the fibers making up the
compressed material, between the fibers in the inter fiber void
space, or suspended within a hydration fluid or second soluble
polymer suspended in the inter fiber void space. The biologically
active agents and/or soluble polymer may be added prior to or after
fiber compression and prior to or after cross-linking.
[0102] In various embodiments, the fibrous matrix material may be
composed of layers of the same or different types of polymers. It
is envisioned that this invention may be useful for medical devices
that require specific abilities, material or mechanical properties,
or biological conditions to function optimally in the body. For
example, devices may undergo changes in loading over time, require
specific degradation rates, may be loaded differently across the
surface of the implant, etc. To accommodate the special
requirements of some devices, layers of different compressed
fibrous matrix material may be layered with two or more different
polymers comprising one device. The layers of compressed fibrous
material may increase or decrease degradation, provide controlled
drug delivery to specific locations, etc. The layers may be stacked
on one another or side-by-side. The layers may be fused together
and may be separated by layers of biologics, particulates, or
reinforcing materials. The layers will provide the device the
ability to be multi-functional. For example, one or more layers
will perform one function (e.g., provide structurally integrity,
maintain shape, etc.) for the device while one or more other layers
perform another function (e.g., drug delivery, allow tissue
ingrowth). Another way to modify the device is by compressing the
layers by different methods or by different amounts of
compression.
[0103] In another embodiment, two or more pre-compressed fibrous
masses of dough-like material may be layered and compressed to
create a laminated structure. The fibrous mass may or may not
consist of different polymers. Depending on the starting material
composition and compressive forces used, resultant constructs range
in composition from a single homogeneous structure to a
multi-layered laminate. Gradients and/or laminates may also be
created in a similar fashion by layering multiple sheets of varying
compressions and composition before applying a final compression to
laminate them into a single unit. In another embodiment,
reinforcing materials, foamed polymer sheets, biologically active
agents, sheets of microstructure, particulates, etc. may be placed
between the layers before compression. In another embodiment, a
pre-compressed sheet is roll-compressed, radially creating a spiral
laminate suitable for controlled drug delivery and creation of
nerve guides when wrapped around a removable central core
material.
[0104] In another embodiment, compressed porous matrix material can
be machined or molded into distinctive geometric shapes useful as
internal fixation devices used for surgical repair, replacement, or
reconstruction of damaged bone or soft tissue in any area of the
body. Internal repair devices may be successfully employed for many
conditions, such as orthopedic, spinal, maxiofacial, craniofacial,
etc. Compressed fibrous matrix material can be machined or molded
into any configuration. In various embodiments illustrated in FIGS.
14A and 14B, internal fixation, trauma, or sport medicine devices
may be fabricated into any configuration from the compressed
fibrous matrix material. For example, the device 1400 shown in FIG.
14A is a T-shaped compressed fibrous construct intended for
implantation into an osteoarthritic joint. Tab 1410 separates the
damaged joint surfaces and functions as a cushion while wings 1420
provide anchorage points to prevent migration of the device. Device
1430 shown in FIG. 14B is a Y-shaped compressed fibrous construct
intended for repair and reinforcement of damaged ligaments and
tendons. In a ligament application/procedure the damaged tissue is
placed in between tabs 1440 and secured in place with tacks,
staples or sutures. Extension 1450 is then approximated to the
original insertion point on the long bone and secured by methods
such as interference screws, tacks or staples. Additional
applications, such as an augmentation device for the anterior
cruciate ligament (ACL), for constructs illustrated in FIGS. 14A
and 14B or similar constructs will be obvious to those skilled in
the art.
[0105] One embodiment of the device can be used to aid in the
repair of muscle and tendon surrounding a joint. In FIG. 15, a
glenohumeral joint 1500 in which damaged tissue 1510 encompassing
the rotator cuff is shown along with the device 1520. The rotator
cuff is made up of the confluent tendons of four muscles (i.e.
supraspinatus, infraspinatus, subscapularis, teres minor)
originating on the scapula 1530, and is also associated with tendon
from the long end of the bicep. These muscles control the proximal
end of the humerus 1540, which is inserted into the glenoid cavity
of the scapula. The damage to the rotator cuff may be a tear in one
of the tendon insertions (for example a crescent or an acute
L-shaped tear of the supraspinatus). In this case, the invention
can be used as a reinforcement patch. The tear is repaired by
normal suturing, and is then protected and reinforced by overlaying
the repair with the invention. The muscle will be able to function,
but while it is healing, the reinforcement patch takes on some of
the load. Additionally, tissue will become integrated within the
pores of the overlay graft and the implant will add bulk mass and
strength to the repaired muscle tissue. In the situation where the
torn muscle and tendon cannot be fixed by suture alone, an
alternate use for the invention is to act as an artificial tendon.
In the example of a torn infraspinatus tendon, the invention is
sutured to a secure area of the torn infraspinatus. The implant
material can then bridge the necessary distance and be sutured to
the posterior aspect of the greater tuberosity of the humerus.
TABLE-US-00001 TABLE 1 Examples of Biodegradable Polymers for
Construction of the Fibrous Device Aliphatic polyesters Cellulose
Chitin Collagen Copolymers of glycolide Copolymers of lactide
Elastin Fibrin Glycolide/l-lactide copolymers (PGA/PLLA)
Glycolide/trimethylene carbonate copolymers (PGA/TMC) Hydrogel
Lactide/tetramethylglycolide copolymers Lactide/trimethylene
carbonate copolymers Lactide/.epsilon.-caprolactone copolymers
Lactide/.sigma.-valerolactone copolymers L-lactide/dl-lactide
copolymers Methyl methacrylate-N-vinyl pyrrolidone copolymers
Modified proteins Nylon-2 PHBA/.gamma.-hydroxyvalerate copolymers
(PHBA/HVA) PLA/polyethylene oxide copolymers PLA-polyethylene oxide
(PELA) Poly (amino acids) Poly (trimethylene carbonates) Poly
hydroxyalkanoate polymers (PHA) Poly(alklyene oxalates)
Poly(butylene diglycolate) Poly(hydroxy butyrate) (PHB)
Poly(n-vinyl pyrrolidone) Poly(ortho esters)
Polyalkyl-2-cyanoacrylates Polyanhydrides Polycyanoacrylates
Polydepsipeptides Polydihydropyrans Poly-dl-lactide (PDLLA)
Polyesteramides Polyesters of oxalic acid Polyglycolide (PGA)
Polyiminocarbonates Polylactides (PLA) Poly-l-lactide (PLLA)
Polyorthoesters Poly-p-dioxanone (PDO) Polypeptides
Polyphosphazenes Polysaccharides Polyurethanes (PU) Polyvinyl
alcohol (PVA) Poly-.beta.- hydroxypropionate (PHPA)
Poly-.beta.-hydroxybutyrate (PBA) Poly-.sigma.-valerolactone
Poly-.beta.-alkanoic acids Poly-.beta.-malic acid (PMLA)
Poly-.epsilon.-caprolactone (PCL) Pseudo-Poly(Amino Acids) Starch
Trimethylene carbonate (TMC) Tyrosine based polymers
TABLE-US-00002 TABLE 2 Examples of Biologically Active Agents
Deliverable via the Present Invention Adenovirus with or without
genetic material Alcohol Amino Acids L-Arginine Angiogenic agents
Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)
Angiotensin II antagonists Anti-angiogenic agents Antiarrhythmics
Anti-bacterial agents Antibiotics Erythromycin Penicillin
Anti-coagulants Heparin Anti-growth factors Anti-inflammatory
agents Dexamethasone Aspirin Hydrocortisone Antioxidants
Anti-platelet agents Forskolin GP IIb-IIIa inhibitors eptifibatide
Anti-proliferation agents Rho Kinase Inhibitors
(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl) cyclohexane
Anti-rejection agents Rapamycin Anti-restenosis agents Adenosine
A.sub.2A receptor agonists Antisense Antispasm agents Lidocaine
Nitroglycerin Nicarpidine Anti-thrombogenic agents Argatroban
Fondaparinux Hirudin GP IIb/IIIa inhibitors Anti-viral drugs
Arteriogenesis agents acidic fibroblast growth factor (aFGF)
angiogenin angiotropin basic fibroblast growth factor (bFGF) Bone
morphogenic proteins (BMP) epidermal growth factor (EGF) fibrin
granulocyte-macrophage colony stimulating factor (GM-CSF)
hepatocyte growth factor (HGF) HIF-1 insulin growth factor-1
(IGF-1) interleukin-8 (IL-8) MAC-1 nicotinamide platelet-derived
endothelial cell growth factor (PD-ECGF) platelet-derived growth
factor (PDGF) transforming growth factors alpha & beta
(TGF-.alpha., TGF-beta.) tumor necrosis factor alpha (TNF-.alpha.)
vascular endothelial growth factor (VEGF) vascular permeability
factor (VPF) Bacteria Beta blocker Blood clotting factor Bone
morphogenic proteins (BMP) Calcium channel blockers Carcinogens
Cells and cellular material Adipose cells Blood cells Bone marrow
Cells with altered receptors or binding sites Endothelial Cells
Epithelial cells Fibroblasts Genetically altered cells
Glycoproteins Growth factors Lipids Liposomes Macrophages
Mesenchymal stem cells Progenitor cells Reticulocytes Skeletal
muscle cells Smooth muscle cells Stem cells Vesicles
Chemotherapeutic agents Ceramide Taxol Cisplatin Cholesterol
reducers Chondroitin Collagen Inhibitors Colony stimulating factors
Coumadin Cytokines prostaglandins Dentin Etretinate Genetic
material Glucosamine Glycosaminoglycans GP IIb/IIIa inhibitors
L-703, 081 Granulocyte-macrophage colony stimulating factor
(GM-CSF) Growth factor antagonists or inhibitors Growth factors
Bone morphogenic proteins (BMPs) Core binding factor A Endothelial
Cell Growth Factor (ECGF) Epidermal growth factor (EGF) Fibroblast
Growth Factors (FGF) Hepatocyte growth factor (HGF) Insulin-like
Growth Factors (e.g. IGF-I) Nerve growth factor (NGF) Platelet
Derived Growth Factor (PDGF) Recombinant NGF (rhNGF) Tissue
necrosis factor (TNF) Transforming growth factors alpha (TGF-alpha)
Transforming growth factors beta (TGF-beta) Vascular Endothelial
Growth Factor (VEGF) Vascular permeability factor (UPF) Acidic
fibroblast growth factor (aFGF) Basic fibroblast growth factor
(bFGF) Epidermal growth factor (EGF) Hepatocyte growth factor (HGF)
Insulin growth factor-1 (IGF-1) Platelet-derived endothelial cell
growth factor (PD-ECGF) Tumor necrosis factor alpha (TNF-.alpha.)
Growth hormones Heparin sulfate proteoglycan HMC-CoA reductase
inhibitors (statins) Hormones Erythropoietin Immoxidal
Immunosuppressant agents Inflammatory mediator Insulin Interleukins
Interlukin-8 (IL-8) Interlukins Lipid lowering agents Lipo-proteins
Low-molecular weight heparin Lymphocites Lysine MAC-1 Methylation
inhibitors Morphogens Nitric oxide (NO) Nucleotides Peptides
Polyphenol PR39 Proteins Prostaglandins Proteoglycans Perlecan
Radioactive materials Iodine - 125 Iodine - 131 Iridium - 192
Palladium 103 Radio-pharmaceuticals Secondary Messengers Ceramide
Somatomedins Statins Stem Cells Steroids Thrombin Thrombin
inhibitor Thrombolytics Ticlid Tyrosine kinase Inhibitors ST638
AG-17 Vasodilators Histamine Forskolin Nitroglycerin Vitamins E C
Yeast Ziyphi fructus
[0106] The inclusion of groups and subgroups in Table 2 is
exemplary and for convenience only. The grouping does not indicate
a preferred use or limitation on use of any drug therein. That is,
the groupings are for reference only and not meant to be limiting
in any way (e.g., it is recognized that the Taxol formulations are
used for chemotherapeutic applications as well as for
anti-restenotic coatings). Additionally, the table is not
exhaustive, as many other drugs and drug groups are contemplated
for use in the current embodiments. There are naturally occurring
and synthesized forms of many therapies, both existing and under
development, and the table is meant to include both forms.
TABLE-US-00003 TABLE 3 Examples of Reinforcing and/or Biologically
Active Particulates Alginate Bioglass Calcium Compounds Calcium
Phosphate Ceramics Chitosan Cyanoacrylate Collagen Dacron
Demineralized bone Elastin Fibrin Gelatin Glass Gold Hyaluronic
acid Hydrogels Hydroxy apatite Hydroxyethyl methacrylate Hyaluronic
Acid Liposomes Mesenchymal cells Nitinol Osteoblasts Oxidized
regenerated cellulose Phosphate glasses Polyethylene glycol
Polyester Polysaccharides Polyvinyl alcohol Platelets, blood cells
Radiopacifiers Salts Silicone Silk Steel (e.g. Stainless Steel)
Synthetic polymers Thrombin Titanium
[0107] The following examples are given for purposes of
illustration to aid in understanding the invention and it is to be
understood that the invention is not restricted to the particular
conditions, proportion, and methods set forth therein.
Example 1
[0108] Starting with a dough-like material (90:10 ratio of fibrous
collagen (Semed F, supplied by Kensey Nash Corporation) to soluble
collagen (Semed S, supplied by Kensey Nash Corporation))
(approximately 20% solids), the composition was rolled into a flat
sheet approximately 5 mm thick. This was then sandwiched between
two sheets of wicking material, such as a paper towel. This entire
arrangement was placed in a 30 ton hydraulic press at 60,000 lbf.
The product was left until equilibrium was achieved and no
additional water was being expelled from the product at the given
pressure. The press was opened and the product was removed as an
approximately 1 mm sheet. An expansion of approximately 30-40% was
noted in a radial direction. The sheet was cross-linked using 50 mM
EDC (pH 5.4) in water. The sheet was soaked overnight in the
solution and then serially rinsed 3.times. for 2 hours with
agitation in water. Tear strengths in excess of 120 N were
achieved.
Example 2
[0109] Starting with a fibrous dough-like material (90:10 ratio of
fibrous collagen (Semed F, supplied by Kensey Nash Corporation) to
soluble collagen (Semed S, supplied by Kensey Nash Corporation))
(approximately 20% solids), the composition was rolled into a flat
sheet approximately 5 mm thick. This was then sandwiched between
two sheets of wicking material, such as a paper towel. The product
was then wrung through a set of high compression rollers allowing
the wicking material to remove a large portion of the available
water. It was noted the material expanded in both the lengthwise
and widthwise directions unless constrained in one direction. The
sheet was then freeze dried to preserve the small amount of
porosity that was still remaining within the sample.
Example 3
[0110] Starting with a fibrous dough-like material (85:15 ratio of
fibrous collagen (Semed F, supplied by Kensey Nash Corporation) to
soluble collagen (Semed S, supplied by Kensey Nash Corporation))
(approximately 12% solids), the composition was spread into a flat
sheet approximately 3 mm thick. This was then sandwiched between
two sheets of wicking material, such as a paper towel. The entire
composition was then placed in a 30 ton hydraulic press and
subjected to 60,000 lbf for 15 minutes. The sheet was removed and a
thickness of approximately 0.2 mm was noted. Additionally, the
material had expanded radially 200-300%. The material was
crosslinked using 50 mM EDC (pH 5.4) in water. The sheet was soaked
overnight in the solution and then serially rinsed 3.times. for 2
hours with agitation in water. This was then allowed to air
dry.
[0111] Thus since the invention disclosed herein may be embodied in
other specific forms without departing from the spirit or general
characteristics thereof, some of which forms have been indicated,
the embodiments described herein are to be considered in all
respects illustrative and not restrictive, by applying current or
future knowledge. The scope of the invention is to be indicated by
the appended claims, rather than by the foregoing description, and
all changes which come within the meaning and range of equivalency
of the claims are intended to be embraced therein.
* * * * *