U.S. patent application number 10/207285 was filed with the patent office on 2002-12-26 for system for repairing inter-vertebral discs.
Invention is credited to Haldimann, David.
Application Number | 20020198599 10/207285 |
Document ID | / |
Family ID | 22440777 |
Filed Date | 2002-12-26 |
United States Patent
Application |
20020198599 |
Kind Code |
A1 |
Haldimann, David |
December 26, 2002 |
System for repairing inter-vertebral discs
Abstract
An intervertibral disc made up of an annulus fibrosus having at
least one defect therein, a cross linked visco-elastic solid
polymer in said defect and adhering to remaining annulus fibrosus
and thereby closing said defect and a nucleus pulposus.
Inventors: |
Haldimann, David;
(Loretohohe, CH) |
Correspondence
Address: |
LOWE HAUPTMAN GILMAN AND BERNER, LLP
1700 DIAGONAL ROAD
SUITE 300 /310
ALEXANDRIA
VA
22314
US
|
Family ID: |
22440777 |
Appl. No.: |
10/207285 |
Filed: |
July 30, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10207285 |
Jul 30, 2002 |
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09549332 |
Apr 14, 2000 |
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6428576 |
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60129607 |
Apr 16, 1999 |
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Current U.S.
Class: |
623/17.16 |
Current CPC
Class: |
A61F 2/442 20130101;
A61L 27/16 20130101; A61L 27/16 20130101; A61L 27/24 20130101; A61F
2002/30583 20130101; A61F 2310/00365 20130101; A61F 2002/4435
20130101; A61L 27/227 20130101; A61F 2/4611 20130101; A61F
2310/00377 20130101; A61L 2430/38 20130101; A61F 2002/30677
20130101; C08L 33/06 20130101; A61F 2210/0085 20130101 |
Class at
Publication: |
623/17.16 |
International
Class: |
A61F 002/44 |
Claims
What is claimed is:
1. An intervertebral disc assembly comprising a nucleus pulposus;
an annulus fibrosus substantially surrounding a lateral edge of
said nucleus pulposus, wherein said annulus fibrosus has a defect
therein; and a cured bio-compatible, cross linked polymeric
visco-elastic sealant in said defect in a form sufficient to at
least impede exudation and extrusion of nucleus pulposus material
through said defect.
2. An intervertebral disc assembly as claimed in claim 20 wherein
said sealant has been disposed in said defect in an uncured
condition, and has been cured in situ.
3. An intervertebral disc assembly as claimed in claim 20 wherein
said sealant has been disposed in said defect in a cured condition.
Description
[0001] This application is a continuation of application Ser. No.
09/549,332, filed Apr. 14, 2000, which was a continuation in part
of provisional application serial No. 60/129,607, filed Apr. 16,
1999, and the entire contents of which are incorporated herein by
reference.
INTRODUCTION
[0002] The present invention is directed to a system for repairing
tissue defects in intervertebral discs. It more particularly is
concerned with repairing the portion of an intervertebral disc that
has been subject to damage, such as herniation, as well as to
repairing that portion of an intervertebral disc remaining after
the performance of a partial discectomy intervention. Such
discectomies are conventionally performed to treat a severe hernia
of an intervertebral disc.
REVIEW OF THE STATE OF THE ART
[0003] A disc hernia is a radial rupture of the annulus fibrosus of
the intervertebral disc that is accompanied by a protrusion
(sometimes a very large protrusion) of the annulus fibrosus and/or
by an extrusion of disc material through the rupture in the annulus
fibrosus. The rupture of the annulus fibrosus is often accompanied
by a compression of the spinal canal and pressure on the nerve
roots that pass through the disc protrusion or extrusion. This
usually leads to strong and progressive pain that emanates from the
compromised segment of the spine. This condition may require a
surgical intervention.
[0004] Patients with a symptomatic disc hernia, and indication for
a surgical intervention at the disc, normally undergo a partial or
total discectomy operation. In a partial discectomy, protruding
annulus disc material and a portion of the nucleus pulposus of the
disc are removed. The resulting reduction in the volume of disc
material within the epidural space leads to decreased pressure on
the compressed nerve roots and/or the spinal cord, respectively.
Without repair, the radial rupture defect in the annulus fibrosus
will remain and will not close, at least it will not close in a
relatively short time. Without repair, a considerable risk of
post-discectomy complications, such as a re-herniation of the disc,
will remain.
[0005] A successful discectomy intervention will result in lasting
pain relief for the patient. However, it has been shown that severe
post-discectomy complications may occur in about 6-16% of all
surgical interventions. These are often caused by events such as a
re-herniation of the disc, extensive epidural scar formation or
vascularization and nerve ingrowth into the defect in the annulus
fibrosus.
[0006] The cells of the nucleus pulposus produce cytokines and
inflammatory mediators, such as nitric oxide, that have been shown
to be responsible for nerve root irritation and sensitization that
can lead to severe radicular pain. In a post-discectomy situation,
without repair of the annulus fibrosus, nucleus pulposus material
may migrate into the epidural space and/or nucleus pulposus-derived
cytokines and inflammatory mediators may diffuse into the epidural
space through the annulotomy site. Both events may result in
post-discectomy complications such as persistent nerve root
pain.
[0007] As a side effect of the volume reduction that is attendant
upon a discectomy intervention, the intervertebral disc height, and
thus the vertical distance between adjacent vertebral bodies, will
be reduced. The decreased intervertebral disc height may be one of
the reasons for a re-herniation of the disc. Further, the reduction
in intervertebral disc height has been reported to lead to an
accelerated mono-segmental degeneration of the annulus fibrosus or
of the facet joints of the affected spinal segment.
[0008] Dr. Hansen YUAN (Professor of Medicine at Syracuse
University) has recently presented a review of the available
technology that is currently being exploited in connection with
disc repair and replacement (13.sup.th annual meeting of the North
American Spine Society, Oct. 30, 1998 in San Francisco, Calif.
USA). According to an abstract of this presentation, many different
people and groups are working on mechanical disc replacements,
hydrogel implant replacements and in situ curable polyurethane disc
replacements.
OBJECTS AND BRIEF DESCRIPTION OF THE INVENTION
[0009] It is an important object of this invention to provide means
for reducing the incidence of post-discectomy complications by
closing the annulus defect that remains after a discectomy surgical
intervention.
[0010] It is another object of this invention to provide an in-situ
curable sealant material that provides the surgeon with means for
reducing the risk of re-herniation whilst leaving as much
potentially regenerating nucleus pulposus tissue as possible within
the disc space.
[0011] It is another object of the invention to provide means for
closure of a ruptured or incised annulus fibrosus site after
discectomy sufficient to seal the compartment restraining and
surrounding the nucleus pulposus (portion) of the disc and to
prevent later extrusion of further disc material (recurrent disc
hernia).
[0012] It is another object of the invention to prevent, by sealing
the annulus fibrosus, hypertrophic scar formation, vascularization,
nerve ingrowth, or infection of the ruptured annulus fibrosus or in
the nucleus pulposus cavity.
[0013] It is another object of the invention to prevent, by sealing
the annulus, migration of nucleus pulposus cells into the epidural
space, and to prevent, by sealing the annulus, diffusion of nucleus
pulposus-derived cytokines and inflammatory mediators into the
epidural space through the annulotomy site. The thus resulting
prevention of contact between nucleus pulposus cells, and its
cytokines or inflammatory mediators, with nerve roots after
discectomy is another object of the invention and will assist to
minimize nucleus pulposus-induced nerve root injury and nerve root
pain.
[0014] It is another object of the invention to provide means to
repair a ruptured annulus fibrosus, where the means functions as a
sealant for the ruptured annulus fibrosus and, provided the nucleus
pulposus contains a sufficient number of viable cells, assists in
the restoration of the load-bearing and viscoelastic properties of
the defective intervertebral disc.
[0015] It is another objective of the invention to provide an
implant that minimizes removal of nucleus pulposus material during
a discectomy intervention without having an elevated risk of
recurrent disc hernia. Since the nucleus pulposus tissue in most
disc hernia patients is viable and has regenerative potential,
leaving as much nucleus pulposus tissue as possible in the disc
space may be conducive to the gradually regeneration of the disc
and restoration of its physiological functions.
[0016] Other and additional objects of this invention will become
apparent from a consideration of this entire specification,
drawings and claims.
[0017] In accord with and fulfilling these objects, one aspect of
this invention comprises the use of compositions comprising an
in-situ curable sealant(s), made of a bio-compatible material, to
repair defects in an annulus fibrosus of an intervertebral disc.
Such defects may be fissures and ruptures of the annulus fibrosus
due to disc degeneration or disc hernia, as well as injuries due to
incisions and punctures of the annulus fibrosus such as from
annulotomy or discectomy procedures.
[0018] In general, defects in the annulus fibrosus have the shape
of a complex radial cleft that extends from the innermost edge of
the annulus fibrosus, that is at the border of the nucleus
pulposus, to the outermost layers of the annulus fibrosus. The
defect may originate A) because of a burst canal or rupture of the
annulus fibrosus that permitted extrusion there through of material
from the nucleus pulposus, or, B) by reason of incisions that had
to be made during surgery in order e.g. to remove nucleus pulposus
material from within the intervertebral disc that has caused a
large bulge or protrusion of the disc.
[0019] Another type of defect of the annulus fibrosus is often
observed in the case of severely degenerated intervertebral discs.
In this condition, the disc tissue has become severely dehydrated
and has lost its elasticity. As a result, the annulus fibrosus
tissue has become brittle, friable and unstable to the extent that
tissue fragments may come loose and migrate out of the annulus
fibrosus, leaving space through which nucleus pulposus material can
exude. These fragments are separated from the main body of the
annulus fibrosus by numerous interconnecting fissures and are often
held in place only by a thin outer lamella of the annulus fibrosus
(see FIG. 3 for illustration). When this thin layer tears, the
fragments may migrate into the epidural space and cause pressure on
the spinal nerves, that in turn may cause severe pain.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a cross-sectional view, in the horizontal plane of
the lumbar vertebral column, showing a portion of a spinal column
and including surrounding soft tissues. The intervertebral disc
shown in the lower center has a large defect in its annulus
fibrosus that has been closed with a sealant, according to this
invention, for the annulus fibrosus.
[0021] FIG. 2 is a cross-sectional view in the sagittal plane of an
intervertebral disc. The annulus fibrosus is shown with a large
defect that is filled with a sealant, according to this invention,
for the annulus fibrosus.
[0022] FIG. 3 is a cross-sectional view of a severely degenerated
disc. On the right side, fragments from the outer annulus fibrosus
are shown to be held in place by a thin lamella. Portions of the
disc protrude to the right into the epidural space proximate to the
spinal cord (not shown).
[0023] In the practice of the present invention, for repairing
defects of the annulus fibrosus, the sealant composition of this
invention may be applied in several ways, depending on the clinical
situation with the disc degeneration. A particularly preferred
application mode for the present invention is to put up the sealant
composition as an injectable material. The composition is then
injected into the proximity to the defect, whereupon it fills and
closes incisions, clefts or fissures in the annulus fibrosus, such
as occur after a disc hernia has been surgically treated. The
sealant cures in-situ. In this particularly preferred application,
the intervertebral disc is sealed in order to prevent a later
extrusion of further disc material. This procedure is useful where
the remaining nucleus pulposus is comprised of a sufficient amount
of viable cells to perform its function. That is, this procedure is
most useful where the amount of nucleus pulposus remaining in the
disc after effecting repair is sufficient for the disc to continue
to perform its intended function.
[0024] In another preferred application, the present invention can
be used to patch up or consolidate brittle and friable tissue that
exists in the outer annulus fibrosus of a severely degenerated
intervertebral disc. In this application, the sealant composition
of the present invention serves as a putty or cement in order to
bind together the remaining tissue fragments of the outer annulus
fibrosus. This procedure is preferably used as an alternative to
the filling of a crevasse created by surgical intervention, as has
been previously mentioned. However, it is also within the scope of
the instant invention to both fill cracks or openings in the
annulus fibrosus and cement together degenerated, but remaining,
portions of the annulus fibrosus. This aspect of this invention
does not particularly envision using the composition of this
invention as a sealant for the entire disc, but such use can be
accomplished. This application of the practice of this invention
could also be described as annulus augmentation or partial
annuloplasty, where the brittle annulus fibrosus is reinforced and
stabilized through the in-situ curing of a sealant according to
this invention. This application of the invention is intended to
prevent tissue fragment migration and thus reduces the risk of
spinal nerve compression by sequestrated fragments of the
degenerated annulus fibrosus.
[0025] The bio-compatible compositions, comprising the in situ
curable sealant of this invention, are based on materials that
range in viscosity and physical state from an injectable liquid to
a visco-elastic solid. The materials are preferably prepared from
human or animal origin or may be made through conventional chemical
synthesis or by a recombinant DNA technique. In general, it is
important that the bio-compatible material compositions have the
property of forming, upon curing, a strongly bonding, visco-elastic
material that becomes sealed to the annulus fibrosus, or to
fragments thereof, within about 2 to 40 minutes, preferably 2 to 10
minutes, after application (by injection or otherwise). The in-situ
curing process must work well under wet conditions, at or near
physiological pH (e.g. a pH of about 5-10), at or near
physiological temperature (e.g. about 4-50.degree. C.) and in the
presence of interstitial body fluids (such as spinal fluid and/or
blood). The sealant must cure to create a non-toxic, bio-compatible
and strongly tissue adhesive seal of the annulus fibrosus or of
materials that make up this feature. It should be of sufficient
strength to stay in place without decomposition under permanent
cyclic physiological loads.
[0026] A bio-compatible material that can serve as sealant of the
annulus fibrosus has to meet exceptional characteristics with
regard to its strength, tissue adhesion properties and
bio-compatibility both when strategically placed and after curing.
In addition, only an in-situ curing process of the biomaterial will
form a sealant that perfectly conforms to the complex shape of a
defect or incision in the annulus fibrosus.
[0027] Various bio-compatible material compositions have been
described in the art. Some of these may be useful as in-situ
curable sealants for defects of, or incisions in, the annulus
fibrosus. None of the published disclosures of biomaterial
compositions describe the potential application of such materials
as in-situ curable sealants for use in connection with repair of
the annulus fibrosus. Furthermore, none of the applications for the
various bio-compatible materials that have been described in the
prior art are similar or comparable to the use of such a sealant in
connection with damaged annulus fibrosus. There are no disclosures
in the prior art that described applications in which an uncured
liquid bio-compatible material is caused to flow into a complex
three-dimensional tissue defect, and therein to become cured
whereby to seal or patch up the defect. There is no disclosure in
the prior art that shows using such sealants bio-compatible
materials to prevent re-herniation of the annulus fibrosus, or
prevent, or at least minimize, annulus fibrosus tissue migration.
Thus, this invention provides an annulus fibrosus sealing means,
formed from in-situ curable formulations comprising flowable
bio-compatible material, that can be caused to cure in situ.
DETAILED DESCRIPTION OF THE INVENTION
PREFERRED BIO-MATERIALS
[0028] Preferred bio-compatible materials for use in the practice
of the invention include all bio-compatible, hydrophilic synthetic
or naturally occurring polymers that are curable to a visco-elastic
end product under physiologic conditions. These polymers are
cross-linked by an internal mechanism. That is, in some cases, no
outside energy input or material is needed to cause the flowable
bio-compatible polymers of this invention to become cured into a
relatively permanently placed visco-elastic material. In other
situations, the flowable bio-compatible polymers of this invention
will need the input of outside influences, such as irradiation
and/or heat, to cause them to cross link and become the desired
visco-elastic materials. Such heat and/or irradiation can be very
localized so as to cause the cross linking and curing to occur
exactly where it is needed. In either case, the end product cross
linked visco-elastic polymer materials will maintain its location,
shape and structure, and lend stability and physical strength to a
damaged annulus fibrosus. This can be on a permanent basis, that is
the repairing sealant will become a permanent part of the annulus
fibrosus.
[0029] It is also within the scope of this invention that the
visco-elastic sealant used in this invention will be a temporary
material that will bind and repair the damaged annulus fibrosus for
a time sufficient to prevent re-injury of this member and to enable
scar formation with fibrocartilaginous tissue to occur. This type
of sealant will be composited such that it will degrade with time
so that by the time the annulus fibrosus has accomplished
sufficient self repair, the added sealant will have degraded and be
expelled from the body. This cross-linking can be accomplished by
making up a flowable mixture of two or more precursors molecules
that react with each other over a short time to form the desired in
situ cured visco elastic product that has physical and chemical
properties that resemble those of the annulus fibrosus sufficiently
to perform its function, at least substantially, while the natural
annulus fibrosus regenerates itself. This flowable, in situ curable
material may be made up of a single precursor that reacts with
itself, e.g. by heating, or by irradiation with electromagnetic
energy, such as visible or ultra violet light. It is also within
the scope of this invention to use a one or plural component
curable flowing material that is cured by the action of a catalyst
and/or initiator that is included in the composition.
[0030] Some or all of the chemical compounds, cross linkable
polymers, or pre-polymers, that form the precursor materials, or
are the building blocks from which the precursor components are
formed, can be bio-compatible, hydrophilic synthetic or naturally
occurring polymers. Even if some of the precursor components are
not especially bio-compatible, since they are intended for use
within an animal, especially human, body, it is essential that none
of these precursor materials themselves nor the polymers that
result from their curing be detrimental to the animal, especially
human, host. The cured polymer products are preferably completely
bio-compatible, e.g. they do not induce extensive chronic
inflammation, do not induce excessive complement activation, and do
not induce excessive local cytotoxicity, such as for Example as a
result of components that leach out of these cured or uncured
materials. It is important that the cured polymers be hydrophilic,
so as to form materials that are hydrogels, e.g. polymers with
absorbed water contents in excess of approximately 25% of their own
weight. The tissue specific compatibility of the resulting
hydrogels is generally better than is the case with less
hydrophilic materials. This is as a result of the water
permeability of the hydrogel being similar to that of the
surrounding tissue, and because of the better matching of the
mechanical properties of the instant sealing material with the
surrounding natural annulus fibrosus tissue.
[0031] The cured polymers that are useful in this invention may be
synthetic or naturally occurring. It may be more reliable to ensure
the long-term stability of a cured sealant that is based on
synthetic polymers.
[0032] Alternatively, a controlled degradation can be engineered
into a synthetic polymer by incorporation of slowly hydrolyzable
linkages, such as for Example ester, amide, carbonate or anhydride
linkages, into the cured polymer. Naturally occurring polymers
generally will form sealing members that become more easily
degraded in vivo, and there may be cases in which this is
desirable, e.g. when the sealant is intended to be replaced by
natural tissue that is being generated as a result of healing in
the annulus fibrosus. This may be particularly desirable when the
cured sealant member contains a bio-active agent to promote
healing.
[0033] Examples of the type of synthetic polymers that can be used
as building blocks in accord with this invention are polyethylene
glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylic acid,
polyethoxazoline, polyhydroxyethyl acrylate, and polyhydroxyethyl
methacrylate. These materials can be further functionalized in
order to increase their ability to form hydrogels gels in situ.
[0034] Polysaccharides that are useful in the present invention
include glycosaminoglycans such as hyaluronic acid, chondroitin
sulfate A, chondroitin sulfate C, dermatan sulfate, keratan
sulfate, chitin, chitosan, heparin, and derivatives or mixtures
thereof. Further, proteoglycans such as decorin, biglycan and
fibromodulin may also be used in the present invention.
Proteoglycans are components of the extracellular matrix of
cartilage cells and contain one or more glycosaminoglycan molecules
bound to a core protein. Furthermore, mixtures of various species
of glycosaminoglycans or proteoglycans with various proteins, or
mixtures of various species of glycosaminoglycans or proteoglycans
with proteins can be used in the practice of the present
invention.
[0035] Various synthetic polypeptides can also be used in the
practice of the present invention. The term "synthetic polypeptide"
is intended to encompass polypeptides that have been produced using
recombinant DNA techniques, as well as those produced by other
methods of chemical synthesis.
[0036] Various naturally occurring proteins such as albumin,
collagen, fibrin and elastin may also be used alone or in
combination with other materials in the practice of the present
invention.
[0037] The terms "albumin" "collagen" or "elastin" or "fibrin" as
used herein refer to any types of these naturally occurring
proteins, from any source, including, but not limited to, protein
extracted from tissue or fractionated from blood or recombinant
proteins. Further, these terms refer to all forms of these
naturally occurring proteins, including those that have been
processed, denatured or otherwise modified.
[0038] In general, collagen, elastin, fibrinogen or fibrin from any
source may be used in the practice of the present invention. The
preparation of purified, non-immunogenic proteins from human or
animal tissues as well as recovered by different methods of
producing recombinant human collagen or fibrin are thoroughly
described in the literature.
[0039] Collagen of any type, including, but not limited to, types
II, III, V, VI, IX or any combination thereof, are preferred to be
used in the practice of the present invention, although collagens
of type I and type II are generally the most preferred types.
Collagen for use in the present invention may be in a fibrillar or
non-fibrillar form. The preferred form of the preferred collagen
for the practice of the present invention is the fibrillar form of
collagen due to its higher persistence and mechanical strength.
[0040] Elastin of any type can be used for the practice of the
present invention. Elastin of type I is generally preferred.
PREFERRED BIO-MATERIAL COMPOSITIONS FOR THE SEALANT OF THIS
INVENTION
[0041] In a preferred embodiment of the present invention, the
sealant for the damaged annulus fibrosus is a bio-compatible
polymer composition of viscosity that is sufficiently low to permit
injection and which forms a visco-elastic material upon becoming
cured. The bio-compatible polymer precursor(s), when implanted in
the situs of the defect in the annulus fibrosus, are flowable
material(s), preferably a liquid of suitable viscosity such that
when the liquid conforms to the damaged area of the annulus
fibrosus, it tends to stay in place while it is curing in situ.
[0042] In general, the preferred material composition for use in
the practice of the invention is an in-situ curing, bio-compatible
polymer composition that has, when cured, the properties of an
elastic, or visco elastic, substantially solid hydrogel. The
preferred bio-compatible polymer material composition may include
two or more precursor components that are dissolved or dispersed in
two different solvents/carriers, A) and B). The
solutions/suspensions are suitably mixed immediately prior to the
application of the sealant into the situs of the damage.
Alternatively, a single solution containing the appropriate
bio-compatible material composition can be used in combination with
a separate initiator system to start the curing reaction, as for
Example the composition disclosed for a different purpose in U.S.
Pat. No. 5,626,863.
[0043] A preferred bio-compatible material composition that is
useful for sealing damage to the annulus fibrosus is made of two
precursor components, a bio-compatible material solution and an
activated crosslinking agent. In this preferred composition,
bio-compatible materials, such as collagen or glycosaminoglycans,
and cross linking agents, such as synthetic hydrophilic polymers as
disclosed for a different purpose in U.S. Pat. Nos. 5,324,775 or
5,328,955, can be used. Preferred synthetic hydrophilic polymers
for use in the invention include bifunctionally activated
polyethylene glycols, as disclosed for a different purpose in U.S.
Pat. Nos. 5,326,955 or 5,583,114.
[0044] Another preferred bio-compatible material composition for
the sealant of a damaged annulus fibrosus is made of two precursor
components, a buffered protein solution and a bifunctional cross
linking agent. More specifically, the protein is preferably be a
non-immunogenic, water soluble protein. Materials such as serum
albumin or derivatives of elastin, fibrinogen or collagen can be
used as protein, and polyethylene glycol, with activated terminal
groups may be used as the preferred cross linking agent in this
preferred composition. Such a composition is disclosed for other
purposes in U.S. Pat. No. 5,583,114.
[0045] Another preferred bio-compatible material composition that
is useful for the sealant of the annulus fibrosus according to this
invention is made of a polymerizable component that includes a
water soluble core region and polymerizable terminal group(s) or
functional group(s). In addition, the component may include a
biodegradable extension of the core region. A preferred embodiment
of this aspect of this invention includes polyethylene glycol as
the core region and one or more acrylate moieties as the
polymerizable end cap or terminal portion, as disclosed for other
purposes in U.S. Pat. No. 5,626,863. In the practice of using this
component as in-situ curable sealant for the damaged annulus
fibrosus, a free radical polymerization reaction of the component
must be initiated, either after the composition has been placed at
the situs, or immediately prior to introduction of the composition
into the damaged area(s) of the annulus fibrosus. For initiation of
the polymerization immediately prior to application, the
polymerizable component may be extruded from a syringe or a
piston-driven cartridge and passed through a light or temperature
conducting cannula before it reaches the situs of the annulus
fibrosus defect. The free radical polymerization reaction may be
initiated through photo-initiation by UV or visible light
irradiation of the cannula. In the case of a thermal polymerization
initiator system, as disclosed in U.S. Pat. No. 5,826,803, the
cannula may be heated to a controlled temperature that is not
higher than about 48.degree. C. For initiation of the free radical
polymerization reaction in situ, either a thermal polymerization
initiator system, that is sensitive to a temperature of about
37.degree. C. or, alternatively, chemical initiation systems may be
used in the practice of the present, invention. Such systems are
disclosed for other purposes in U.S. Pat No. 5,626,863.
[0046] A particularly preferred bio-compatible material composition
that is useful for sealing damage in an annulus fibrosus is made of
two precursor components that can co-polymerize in a self-selective
manner, such as by a nucleophilic addition reaction, as disclosed
in pending U.S. patent application Ser. No. 60/118,093 , filed on
or about Feb. 1, 1999 in the names of Jeffrey A. Hubbell, Donald L.
Elbert, and Alyssa Panitch, and carrying an attorney's docket
number ETH 103. The entire contents of this provisional patent
application, which was copending with the parent provisional
application of the instant application, is incorporated herein by
reference. In a preferred embodiment, a hydrophilic linear or
crosslinked polymer with two or more terminal unsaturated groups is
used as the first precursor component, and another hydrophilic
polymer with two or more terminal nucleophilic groups is used as
the second precursor component. In a particularly preferred
embodiment, polyethylene glycol constitutes the hydrophilic
polymer, acryloyl moieties are used as unsaturated end groups, and
compounds with thiol functional groups are used as the nucleophilic
groups. Such compositions are disclosed in this provisional patent
application.
[0047] When using this embodiment in the practice of the present
invention, the two precursor components should be quickly mixed
immediately prior to use and then applied to the annulus fibrosus
defect using a common applicator. As a preferred embodiment, the
two components may be filled into a dual syringe or a dual-chamber
piston-driven cartridge. Both chambers of the syringe, or the
cartridge, have openings that merge together into one outlet tube.
This tube, is fitted with a suitable mixing nozzle, such as a
spiral mixer nozzle, that serves as a static mixer for the two
components when they are pressed out of the syringe and passed
through the nozzle. As the mixed components are pressed out of the
tip of the nozzle, they can be directly applied into the operation
situs, i.e. the damage or defect site of the annulus fibrosus.
[0048] It is desirable for the mixed bio-compatible material
composition to have a low surface tension in relation to
physiological materials such as fluids and the annulus fibrosus,
and a good intrudability into such systems. These properties permit
the bio-compatible material to optimally penetrate into
micro-fissures that may be present at the application site of the
annulus fibrosus. The intrusion of the biomaterial into
micro-fissures and clefts of the damaged annulus fibrosus allows
for a strong mechanical interlocking with the natural tissue at the
application site and helps to mechanically secure the sealant
within the application site during the curing time.
[0049] The term "intrudability" relates to the ability of a liquid
material composition to penetrate into complex microstructures and
to fill small voids. This intrusion or penetration into said
microstructure may be caused by low injection pressures,
gravitation, capillary forces or non-covalent interactions between
the liquid and the microstructure. The intrudability of the mixed
biomaterial composition can be increased by including one or more
bio-compatible fluid lubricants or surfactants, for Example
dextrose, maltose, glycogen, dextran, dextran sulphate, hyaluronic
acid glycerol, phospholipids polyoxyethylene sorbitan esters or
polyethylene/polypropylene glycols.
[0050] Various particulate materials may also be incorporated into
the bio-compatible material compositions for use in the invention.
Suitable particulate materials include, without limitation;
particulate elastin fibers and crosslinked or non-crosslinked
fibrillar collagen.
[0051] Various biologically or pharmaceutically active agents may
also be incorporated into the bio-compatible material compositions
for use in the invention. Examples of active agents include,
without limitation, growth factors, differentiation factors,
enzymes, receptor agonists or antagonists, antibodies, hormones,
analgesics, local anesthetics, anti-inflammatory drugs, such as
Indomethacin and tiaprofenic acid, antibiotics or anti-microbial
agents. The term "active agent" as used herein refers to molecules,
usually organic, that exert biological effects in vivo. This term
also encompasses combinations or mixtures of two or more active
agents.
SUMMARY OF DISCLOSED MEDICAL APPLICATIONS OF BIO-COMPATIBLE
MATERIAL COMPOSITIONS THAT ARE SUITABLE AS SEALANT FOR THE ANNULUS
FIBROSUS
[0052] The patents listed above describe various methods of using
in-situ curable bio-compatible material compositions in the field
of soft and hard tissue surgery, such as to position tissue flaps,
to attach side grafts, to prevent air leaks in pulmonary surgery,
to inhibit bleeding, to avoid unwanted tissue adhesions, to fill
and augment any void spaces in the body, or more generally to close
undesired lesions and fissures such as fistular orifices or
cysts.
[0053] However, these prior art patents do not describe or mention
an application or method of using such materials as an in-situ
curing sealant to treat defects in the annulus fibrosus and thereby
to create an annulus sealing device. There is also no prior art
that describes applications that are similar or comparable to the
specifications and objectives of a sealant for the annulus
fibrosus, as described in the following two sections. Specifically,
none of the prior art describes applications in which a liquid or
semi-solid biomaterial is caused to flow into a complex three
dimensional annulus fibrosus tissue defect, to seal or patch up the
defect and prevent a re-herniation or annulus tissue migration, and
assists to restore, at least partially, the hydrodynamic function
of the intervertebral disc.
[0054] Thus, there is described an annulus sealing device,
comprising in-situ curable biomaterial formulations that cure to a
visco elastic member that at least partially simulates the
structure, physical properties and biomechanical functions of the
annulus fibrosus and maintains the integrity of this member
permanently or for a time sufficient to enable the regeneration of
the natural annulus fibrosus tissue.
DESCRIPTION OF IMPORTANT FEATURES OF THE SEALANT FOR THE ANNULUS
FIBROSUS ACCORDING TO THIS INVENTION
[0055] Because of the unique bio-mechanical and physiological
properties of the intervertebral disc in general and the annulus
fibrosus in particular, a functioning and efficient sealant for the
annulus fibrosus should meet numerous specifications, even if it
replaces just a small portion of the damaged natural tissue of the
annulus fibrosus.
[0056] The sealant of the annulus fibrosus is implanted in a
low-viscosity liquid form, thus allowing the implanting material to
penetrate into tears and micro-fissures with a width of at least
100 micrometers that are interconnected with a radial rupture or
principal defect of the annulus fibrosus.
[0057] The sealant of this invention for the annulus fibrosus has
the property of becoming strongly attached to the surrounding
tissue of the annulus fibrosus by close interlocking and
entanglement of its shape with the structure of the annulus
fibrosus surrounding the defectand by filling cavities in the
nucleus that were created during discectomy, thus forming an inner
portion of the implant that has a larger cross section than the
protrusion canal. The adhesion of the sealant to the surrounding
annulus fibrosus tissue is enhanced through polar group interaction
or chain inter penetration between the hydrophilic implant material
and the surrounding tissue. In addition, covalent bonds formed
between the preferred hydrogel bio-compatible material and the
surrounding annulus fibrosus tissue further increase and secure the
attachment of the sealant of this invention to the annulus fibrosus
tissue in proximity to the defect in the annulus fibrosus.
[0058] The annulus sealing material that seals the defects in the
annulus fibrosus may be the result of the interaction of at least
two bio-material precursor components that react with each other in
situ, preferably in a self selective reaction. Alternatively, a
single bio-compatible material precursor composition that is
activated for polymerization, such as for Example by activation
either in situ or application immediately prior to implanting, may
be used. Both systems result in a sealant that substantially
perfectly conforms to the complex and irregular shape of an annulus
fibrosus defect and bonds strongly to the tissue surrounding the
defect. In addition, the self-selectivity of the reaction is an
important feature to minimize toxic or denaturing effects of the
curing bio-compatible material composition.
[0059] The sealant of the annulus fibrosus is preferably formed
from previously pre-polymerized materials that are employed as
prepolymer or macromer precursor components. In this way, the risk
of exposing a patient to volatile and toxic residual monomers that
may remain after curing of the sealant can be avoided.
[0060] The sealant of the annulus fibrosus must have adequate
impact and tensile strength and must be adequately resistant to
fatigue from repetitive loading and unloading or repetitive torsion
moments that the annulus fibrosus is conventionally subjected to.
This allows the sealant to permanently stay in place and remain
intact after implantation. An even more important property of the
sealant of the annulus fibrosus is its ability to withstand
intradiscal pressures of the nucleus pulposus in the upper
physiological range and to efficiently seal the annulus fibrosus so
that the nucleus pulposus is contained within the intervertebral
disc.
[0061] The sealant of the annulus fibrosus closes the defect in the
annulus fibrosus so as to reduce the risk of a recurrent disc
hernia and to prevent the further extrusion of nucleus pulposus
material through the defect, , thus avoiding contact between
nucleus pulposus cells and its cytokines or mediators with nerve
roots after discectomy and preventing or minimizing nucleus
pulposus-induced nerve root injury and nerve root pain.
[0062] The sealant of the annulus fibrosus assists in the
restoration of the physiological function of the herniated
intervertebral disc. In particular, the sealant of the annulus
fibrosus assists the nucleus pulposus to restore its hydrodynamic
function after a discectomy intervention by being able to gradually
build up the physiological intradiscal pressure. This will also
allow the intervertebral disc to act as a cushion for physiological
cyclic loads and to gradually restore the normal disc height and
thus protect the facet joints in the damaged segment from excessive
and long term loads.
[0063] The sealant of the annulus fibrosus has adequate
visco-elastic properties due to its water content and strong three
dimensional network of interconnecting polymer molecules. This
minimizes the creep behavior of the sealant and enables it to
withstand cyclic loads under physiological conditions for long
periods without significant degradation and without losing
elasticity.
[0064] The material composition for the sealant of the annulus
fibrosus may be radio-opaque to a similar degree as a
polymethyl-methacrylate based bone cement that is commonly used for
the fixation of joint replacement prostheses. This feature is
intended to allow the surgeon to monitor the correct implantation
of the implanted sealant per-operatively and to identify the
implant post-operatively in an X-ray radiograph.
[0065] The preferred final water content of the cured implant is
about 30% to 90%. Generally, the final implant water content
increases as the concentration of PEG (polyethylene glycol) in the
precursor component solutions decreases.
[0066] According to this invention, the sealant of the annulus
fibrosus is highly bio-compatible and is well tolerated in the body
due to its following properties: A) it is preferably a hydrogel
material that is hydrophilic and water-permeable similar to the
surrounding tissues, B) the sealant material is non-toxic and C)
the sealant material has a stiffness coefficient, in relation to
the application of physiological loads and stresses, such as in
compression, tension, and axial rotation, that is the same as or
less than the stiffness coefficient of the natural annulus fibrosus
tissue.
[0067] By being as strong as, but softer than, the surrounding
tissue, friction, if any, between implant and surrounding tissue
remains low and stress-shielding of the tissue is avoided. By
avoiding friction with the implant and stress-shielding of the
surrounding tissue, the conditions for a normal long term
remodeling of the annulus tissue are optimized and the risk of
gradual implant rejection or hypertrophic tissue reactions is
minimized. The sealant for the annulus fibrosus is permeable to
water and water soluble substances, such as nutrients, metabolites,
drugs and the like.
[0068] The sealant for the damaged annulus fibrosus may also serve
as a carrier and controlled release drug delivery system for
topical applications of drugs for anti-inflammatory, antibiotic,
analgesic or other therapies. In the case of a non-biodegradable
sealant for the annulus fibrosus, the release mechanism is
primarily based on diffusion of the drug through the cross linked
sealant and into contact with other elements of the body where
therapy is required. In the case of a hydrolytically stable,
bioerodible material composition for the sealant, the drug release
rate will be steady and predictable and will be proportional to the
controlled bioerosion of the sealant material over an extended
period of time, while newly formed annulus fibers and nucleus
tissue gradually replace the sealant material put in place
according to this invention.
[0069] Preferably, the sealant for the annulus fibrosus may also
function as a carrier for the controlled release of various growth
and/or differentiation factors, such as basic fibroblast growth
factor (bFGF), insulin-like growth factor (IGF), transforming
growth factor beta (TGF), platelet derived growth factor (PDGF),
chondromodulin (ChM), bone morphogenic protein (BMP), etc. For the
successful administration of these auto- or paracrine growth
factors, a biologically relevant concentration must be maintained
in the disc tissue over an extended period of time. Due to its
proximity to the annular lesion, the sealant for the annulus
fibrosus, when used as a carrier for the controlled release of
growth factors, may allow for an excellent bioavailability of the
mentioned growth factors covering a therapeutic window of several
weeks or months.
GENERAL MODE OF USE AND ADMINISTRATION OF THE SEALANT
[0070] In the preferred form of the invention, the precursor
components are stored in a piston driven, one or two chamber
cartridge that serves as a transport and storage container. Each
chamber of the cartridge is closed by a sealing membrane within the
extrusion flange at the tip of the cartridge.
[0071] In preparation for using the sealant, the sealant
application system comprising the application instrument, precursor
filled cartridge, mixer nozzle (for two component systems) and
injection cannula has to be prepared. To do so, the precursor
filled cartridge is placed into an application instrument that
serves to press the pistons of the cartridge in a reproducible and
volume controlled manner. Immediately prior to the injection of the
sealant, the sealing membrane of the cartridge is broken and a
spiral or other mixer nozzle (for two component systems) is
attached onto the extrusion flange. An injection cannula with a
blunt ended tip is placed on top of the mixer nozzle that allows
for precise application of the sealant into even narrow defects of
the annulus. If necessary, electromagnetic radiation, such as UV or
visible light, or heat is supplied through a light or temperature
transparent/conducting cannula before the sealant reaches the
application site.
[0072] The sealant for the damaged annulus fibrosus; can be applied
post operatively at the end of a standard micro-discectomy surgery
with the patient in prone position. For application of the sealant,
the cannula of the prepared application system is placed deep into
the defect or incision of the annulus fibrosus in such a way that
the tip of the cannula is proximate to the inside edge (that is the
edge of the annulus fibrosus that boarders on the nucleus pulposus)
of the cavity created by removal of disc tissue during discectomy.
This placement is followed by injecting the precursor components of
the sealant of this invention into the defect until the defect is
completely filled, which typically requires 1/2 to up to about 2 ml
of precursor component volume. As the precursor components are
pressed out of the cartridge, they are mixed in the nozzle and,
dependent on the bio-compatible material composition used, the
polymerisation or nucleophilic addition reaction, that results in
the curing of bio-compatible material composition, is initiated.
Because of its low viscosity and low surface tension as compared
with physiological fluids, the mixed precursor components are able
to penetrate into micro-fissures in the degenerated or remaining
(after the discectomy) annulus fibrosus tissue that are
interconnected with the radial cleft.
[0073] In the preferred form of the invention, the two precursor
components of the sealant cure in situ within more than about 2
minutes but less than about 10 minutes to form a solid
visco-elastic polymer hydrogel implant that conforms to the shape
of the annulus fibrosus defect. The thus formed implant becomes
closely interlocked with the annulus fibrosus structure that
surrounds the defect and is inherently shaped to conform, when
cured, to the shape of the defect in the annulus fibrosus that it
has filled.
EXAMPLES
[0074] The following Examples are provided to describe and
illustrate the practice of the invention and not to limit or to
restrict the scope of the invention. It will be apparent to those
skilled in the art that certain changes and modifications may be
practiced within the scope of the present invention.
[0075] The following protocols, materials and procedures may be
partly modifications of procedures and adaptations of materials
reported in U.S. Patent Nos. 5,324,776, 5,328,956, 5,626,863,
5,324,775; 5,328,966; 5,583,114; 5,626,863 and the above referred
to co-pending provisional patent application. All of these
references are incorporated herein by reference, respectively.
Example 1
[0076] A 105 mg/ml (10.5% W/V) aqueous solution of fibrillar
collagen in 0.05 M sodium bicarbonate buffer and 0.15 M sodium
chloride is adjusted to pH 9.5. 2.5 ml of this biomaterial solution
(solution A) is aspirated into a dual chamber polypropylene
cartridge through one of the two extrusion flanges of the
cartridge. 2.5 ml of a solution of difunctionally activated
N-succinimidyl carbonate PEG (DSC-PEG, MW 3600) in 0.005 M sodium
carbonate/bicarbonate buffer and 0.15 M sodium chloride at pH 6.0
and in a 1 to 10 molar ratio of collagen (solution A) to DSG-PEG
(solution B) is filled into the second chamber of the
cartridge.
[0077] Both chambers of the cartridge are closed by attaching a
spiral mixer nozzle (3.2 mm inner diameter, 6.2 cm length, 0.38 ml
void volume) onto the dual extrusion flanges. The cartridge is
placed into a manual application instrument that allows for a
reproducible and volume controlled extrusion of the bio-material in
increments of 0.5 ml per step. A blunt tip aspiration needle (18
gauge, 90 mm length) is placed on the tip of the mixer nozzle.
Immediately prior to this application of the sealant, the handle of
the application instrument is pressed three times (3.times.0.5 ml)
in order to fill the void of the mixer and needle with the mixed
bio-material precursor solutions. About 1 ml of mixed precursor
solution flows out of the needle tip and is discarded. The cross
linking process is now activated and care must be taken to apply
the sealant without delay, i.e. within less than about 60 seconds
in this Example.
[0078] A bovine cadaveric lumbar trunc is placed in prone position
(spine axis horizontally with spinal processes facing up) and
prepared with a standard posterolateral microdiscectomy approach
using a 4 cm outer incision. The annulus fibrosus is incised
posterolaterally with a full thickness square incision
(fenestration with size: 3 mm.times.3 mm). The loose annulus tissue
is then removed from the fenestration site with a 2 mm rongeur,
followed by removal of at least one gram or one ml of nucleus
pulposus tissue--in order to create the typical operation situs at
the end of a lumbar discectomy. All of this is done prior to
activating the crosslinking process. The needle tip of the sealant
applicator is placed about 2 cm deep into the disc, near the bottom
of the nucleus cavity that has been created by the incision. About
1-2 ml of sealant is extruded by pressing the handle of the
application instrument (preferably at a rate of about 2 steps per
second), until the sealant fluid appears at the outside edge of the
incision and forms a convex bulge on the outer periphery of the
disc. The needle is then withdrawn from the incision and the
sealant allowed to cure for 5 minutes.
Example 2
[0079] A 380 mg/ml (38% w/v) aqueous solution of human serum
albumin (MW 68000) in 0.1 M sodium bicarbonate buffer and 0.15 M
sodium chloride is adjusted to pH 8.2 (solution A buffered protein
solution). A 200 mg/ml (25% w/v) aqueous solution of difunctionally
activated N-succinimidyl propionate PEG (DSP-PEG, MW 3400) in 0.01
M sodium carbonate/bicarbonate buffer at pH 6.0 is prepared as
solution B (cross linking agent). Solutions A and B are placed in
the dual chamber cartridge and applied in the animal annulotomy
model as described in Example 1. In this Example 2, the application
of the sealant without delays is particularly important because of
the short curing time of this type of sealant (2-3 minutes).
Example 3
[0080] 180 mg/ml (18% w/v) of PEG tetraacrylate (MW 8200) is
dissolved in a buffer of 0.02 M sodium phosphate at pH 7.4 and 0.15
M sodium chloride. Ammonium persulfate (0.01 M) and sodium
bisulfite (0.005 M) are added to the solution that now represents
the polymerizable bio-material with thermal polymerization
initiation system. 5 ml of this bio-material solution is aspirated
into a polypropylene syringe that is fitted with a Luer type
adapter tip. The syringe is closed by placing a
temperature-controlled, flow through heating cylinder, that is
connected to a control unit, onto the tip of the syringe. The
syringe is placed into a manual application instrument that allows
for a reproducible and volume-controlled extrusion of the
bio-material in increments of 0.25 ml per step. A blunt tip
aspiration needle (18 gauge, 90 mm) is placed on the tip of the
heating cylinder. The handle of the application instrument is
pressed four times (4.times.0.25 ml) in order to fill the void of
the heating cylinder and needle with the bio-material solution.
About 0.2 ml of bio-material solution flows out of the needle tip
and is discarded.
[0081] Immediately prior to the application of the sealant, the
heater is turned on and the heater control unit is set at
50.degree. C. As soon as the heater reaches a temperature of
45.degree. C., the polymerization process will start and care must
be taken to apply the sealant without delay, i.e. within less than
about 15 seconds and at a rate of approximately two steps per
minute (0.5 ml of volume/min).
[0082] The sealant is applied in the animal annulotomy model as
described in Example 1.
Example 4
[0083] ExampleEqual volumes of 10 mM phosphate buffered saline
(PBS), adjusted to pH 9.0 with triethanolamine ((EtOH).sub.3N), and
of 10 mM PBS, adjusted to pH 9.0 with 1N NaOH, were combined to
form a PBS pH 9.0 solution. In 1 ml of this solution, 893 mg of
pentaerythritol tetrakis (3-mercaptopropionate)(QT) were dissolved.
This solution represents solution A (solution of polymer with
terminal nucleophilic groups). Solution B was made up of 2.1 g of
polyethylene glycol diacrylate having a molecular weight of 570
(PEGDA 570). Both solutions were combined and mixed well by
vortexing. Air bubbles were removed by sonicating. The mixture was
cast in polypropylene molds to form cylindrical testing samples of
biomaterial, and allowed to cure for 60 minutes at room
temperature. The resulting cured biomaterial has a solid material
content of 75% (w/w) or 72% (v/v), respectively. This biomaterial,
when tested in displacement controlled compressive stress mode,
demonstrated an ultimate strength of more than 2 MPa and withstood
deformations of about 35% in compression.
Example 5
[0084] Solutions A and B were prepared as described in Example 4.
After mixing solutions A and B by vortexing, 100 microliters of the
mixture was placed between 20 mm plates of a CVO 120 rheometer with
a gap of 100 um. The mixture was maintained at 37.degree. C. while
the elastic modulus, complex modulus and viscosity were followed
with time using shear at 1 Hz with a strain amplitude of 0.3. With
progression of the reaction. the two combined precursors showed a
gel point, defined by the time when the elastic modulus becomes
greater than the complex modulus. Using these testing conditions,
the gel point occurred in about 11 minutes.
Example 6
[0085] Mechanical properties of cross-linked hydrogel systems can
be manipulated by using bi- or multimodal molecular weight
distributions in the material compositions. Including a low molar
content of a high molecular weight precursor in a low molecular
weight system can synergistically combine properties from either
molecular weight component and improve the mechanical properties of
the material as compared to gels formed from either molecular
weight component alone. For Example, a system composed of
cross-linked low molecular weight materials may be strong, but may
not elastically withstand large deformations (strain) in
compression or tension. Systems composed of cross-linked high
molecular weight materials with long polymer chains may withstand
tremendous strains, but at the cost of decreased strength. A
preferred bimodal hydrogel system combines predominately short
polymer chains with a small molar ratio of the longer chains and
results in biomechanically relevant stress and strain resistance
properties.
[0086] Solution A was prepared as described in Example 4. 1.37 g of
polyethylene glycol diacrylate with a molecular weight of 570
(PEGDA 570) and 440 ul of 1-methyl-2-pyrrolidone were mixed and
heated to 50.degree. C., while 0.73 g of polyethylene glycol
diacrylate with a molecular weight of approx. 20,000 was slowly
added and allowed to dissolve. This solution represents solution B.
Solutions A and B were mixed and tested as described in Example 4.
The resulting hydrogels showed an ultimate strength of more than 3
MPa and withstood deformations of about 60% in compression.
Example 7
[0087] Including inorganic particles as components of cross-linked
hydrogels is a way to render the sealant of the annulus fibrosus
radio-opaque. Furthermore, addition of sub-micrometer sized
particles to hydrogels can be used as a way to modulate the
mechanical properties of the cured biomaterial gels.
[0088] Solution A was prepared as described in Example 4. Solution
B was made of 2.1 g of polyethylene glycol diacrylate with a
molecular weight of 570 (PEGDA 570) that was loaded with 300 mg of
BaSO.sub.4 particles type blanc fixe (10% w/w), with an average
particle size of 800 nm. Solutions A and B were combined as
described in Example 4. The cured biomaterials resulting from
addition of the BaSO4 were highly radioopaque and showed a
stiffness of 55 N/mm, representing a 30% increase in stiffness over
the biomaterials described in Example 4. Further, a similar
material composition was prepared that contained 10% of fumed
silica particles with an average particle size of 14 nm instead of
the above BaSO.sub.4 particles. The cured material resulting from
this precursor composition showed significant increases in its
ultimate strength. After 100 cycles, with 4 MPa of maximum load in
compression stress testing, these materials had not failed.
Example 8
[0089] Including lubricants or surfactants into the material
composition for the sealant of the annulus fibrosus can be used
both to increase the tissue intrudability of the uncured sealant
material and to improve the mechanical properties of the cured
sealant material.
[0090] Solution A was prepared as described in EExample 4. Solution
B was made of 2.1 g of polyethylene glycol diacrylate with a
molecular weight of 570 (PEGDA 570) that was mixed with 30 mg of
sorbitan monooleate. Solutions A and B were combined as described
in the previous Example 5, resulting in a biomaterial with a final
concentration of 1% (w/w) of sorbitan monooleate. The resulting
gels exhibited a similar increase in ultimate strength compared to
the gels with inorganic particles added, as described in Example 8,
but without the associated increase in stiffness.
Example 9
[0091] Toxicity and biocompatibility of the low molecular weight
components of the material composition for the sealant of the
annulus fibrosus according to this invention can be improved by
pre-reacting these components, such as to obtain higher molecular
weight components with remaining functional groups.
[0092] 1.89 g of PEG hexathiol that was obtained through a reaction
of tetrakis (3-mercaptopropionate) pentaerythritol (QT) and PEG
diacrylate (MW=575), was suspended in 0.48 ml of PBS buffer at pH
9.0 by sonication. The mixture represents solution A. Solution B
was 2.1 g PEG tetraacrylate that was obtained through in a reaction
of a 10-fold excess of PEG diacrylate (MW=575) with QT. Both
solutions were combined, mixed and biomaterial gels were prepared
as described in Example 4. The resulting biomaterial gels
demonstrated mechanical properties similar to those already
described in Example 4; i.e. better than 2 MPa for ultimate
strength and a stiffness of 40 N/mm.
Example 10
[0093] Sterile solutions A and B from Example 4 were combined with
sterile sorbitan monooleate and BaSO.sub.4 particles and the
quantities described in Examples 7 and 8. Gel pins of 1 mm in
diameter and 10 mm length were prepared using the same procedure as
described above in Example 4, except that the mixture of solutions
A and B was placed in molds to form pins prior to gel
formation.
[0094] The pins were implanted into the right or left lumbar
posterior muscles of rabbits. Pins made of polyethylene were
implanted on the controlateral side of the animal as reference
implants. After 4 weeks, the animals were sacrificed and
histological sections of the implants and the surrounding tissue
were performed. With both gel types tested, no significant
differences were apparent compared to the reference materials. Rare
macrophages, fibroblasts and neovessels were associated with the
implanted gel pins. No necrosis, degeneration or any other local
intolerance signs were induced by these material compositions.
[0095] The same gel compositions were also injected into the lumbar
intervertebral discs of rabbits in situ. A small injury in the
lumbar intervertebral disc of the rabbit was created with a needle.
A sham injury was also created two segments cranial from the
segment of the first defect.
[0096] Not earlier than 5 minutes before implantation, the sterile
solutions A and B were each filled into 1 ml syringe cartridges and
mixed by simultaneously passing the contents of both cartridges
through a spiral mixer nozzle element, as described in Example 1.
Because of the small volumes of sealant needed in this animal
model, the mixture was transferred into a 1 ml syringe and injected
into the defect with a 22G needle.
[0097] After 4 weeks, the animals were sacrificed and the implant
and sham sites sectioned for the preparation of histological
slides. Histological work-up showed that the injected materials
gelled in situ, were in close contact with the surrounding tissue
and had no specific reaction associated with the tissue. No
activated immunologic cells were detected and no necrotic or
degenerative processes were seen and only rare active macrophages
and giant cells were observed.
[0098] In the accompanying drawings, the following reference
numbers indicate the identified elements for the drawing:
1 1 Sealant in annulus defect 2 Nucleus pulposus 3 Annulus fibrosus
4 Epidural space 5 Facet joint 6 Spinal cord and nerve root 7 Bone
of vertebral body
[0099] The following references are pertinent to the instant
invention:
ORAL PRESENTATION
[0100] YUAN, Hansen, Paper Presented at 13.sup.th Annual Meeting of
the North American Spine Society, Oct. 30, 1998
2 U.S. Pat. DOCUMENTS 5,324,776 June 1994 Rhee et al. Class
525/54.2 (Collagen Corp.) 5,328,956 June 1994 Rhee et al. Class
525/54.1 (Collagen Corp.) 5,583,114 July 1994 Class 514/21 (3M
Corp.) Barrows et al. 5,626,863 January 1995 Class 424/426
(University of Hubbell et al. Texas, Austin) 0/60/118,093 February
1999 (Univ. Zurich/ Hubbell et al. ETH) (pending)
* * * * *