Note: Descriptions are shown in the official language in which they were submitted.
CA 02461258 2004-03-18
\.,
- 1 -
METHOD OF PREPARATION OF BIOABSORBABLE POROUS REINFORCED
TISSUE IMPLANTS AND IMPLANTS THEREOF
FIELD OF THE INVENTION
The present invention relates to bioabsorbable, porous, reinforced
implantable devices for use in the repair of soft tissue injuries, and methods
of '
using and manufacturing such devices.
BACKGROUND OF THE INVENTION
Injuries to soft tissue, including, for example, musculoskeletal tissue, may
require repair by surgical intervention, depending upon factors such as the
severity
and type of injury. Such surgical repairs can be effected by using a number of
conventional surgical procedures, for example, by suturing the damaged tissue,
and/or by mounting an implant to the damaged tissue. It is known that an
implant
may provide structural support to the damaged tissue, and it may also serve as
a
substrate upon which cells can grow, thus facilitating more rapid healing.
One example of a fairly common tissue injury is damage to or prolapse of
the pelvic floor. This is a potentially serious medical condition that may
occur during
childbirth or from subsequent complications, which can lead to an injury of
the
vesicovaginal fascia. This type of injury may result in a cystocele, which is
a
hemiation of the bladder. Similar medical conditions include rectoceles (a
hemiation
of the rectum), enteroceles (a protrusion of the intestine through the
rectovaginal or
vesicovaginal pouch), and enterocystoceles (a double hernia in which both the
bladder and intestine protrude).
CA 02461258 2004-03-18
- 2 -
Another example of a fairly common soft tissue injury is damage to the
rotator cuff or rotator cuff tendons. The rotator cuff facilitates circular
motion of the
humerus relative to the scapula. Damage to the rotator cuff is a potentially
serious
medical condition that may occur during hypere)dension, from an acute
traumatic
tear or from overuse of the joint. The most common injury associated with the
rotator cuff region is a strain or tear involving the supraspinatus tendon. A
tear at
the insertion site of the tendon with the humerus, may result in the
detachment of
the tendon from the bone. This detachment may be partial or full, depending
upon
the severity of the injury. Additionally, the strain or tear can occur within
the tendon
itself. Treatment for a strained tendon usually involves physical cessation
from use '
of the tendon, i.e., rest. However, depending upon the severity of the injury,
a torn
tendon might require surgical intervention as in the case of a full tear or
detachment
of the supraspinatus tendon from the humerus. Damage to the rotator cuff may
also
include degeneration. This is a common situation that arises in elderly
patients. In
degenerative cases there is loss of the superior portion of the rotator cuff
with
complete loss of the supraspinatus tendon. Similar soft tissue pathologies
include
tears in the Achilles' tendon, the anterior cruciate ligament and other
tendons or
ligaments of the knee, wrist, hand, and hip, spine, etc.
An example of a common ligament injury is a torn anterior cruciate ligament
(ACL), which is one of four major ligaments of the knee. The primary function
of the
ACL is to constrain anterior translation, rotary laxity and hyperextension.
The lack
of an ACL causes instability of the knee joint and leads to degenerative
changes in
the knee such as osteoarthritis. The most common repair technique is to remove
and discard the ruptured ACL and reconstruct a new ACL using autologous bone-
patellar, tendon-bone or hamstring tendons. Although this technique has shown
long-term clinical efficacy, there is morbidity associated with the harvest
site of the
tissue graft. Synthetic prosthetic devices are known and have been clinically
evaluated in the past with little long-term success. The advantages of a
synthetic
implant are that the patient does not suffer from the donor site morbidity
that is
CA 02461258 2004-03-18
- 3 -
associated with autograft procedures, and that patients having a synthetic
implant
are able to undergo faster rehabilitation of the knee. These synthetic
prosthetic
devices were composed of non-resorbable materials and were designed to be
permanent prosthetic implants. A number of disadvantages may be associated
with
synthetic prosthetic implants, such as for example, synovitis, bone tunnel
enlargement, wear debris, and elongation and rupture of the devices. Overall,
autograft reconstruction is still the widely accepted solution for repairing a
ruptured
ACL.
Herniation and tears of soft tissue are typically treated by conventional
surgical procedures in which the protruding organs or tissue tears are
repositioned
or reconsolidated. The prevailing standard of care for some procedures, for
example, is to use a conventional mesh-like patch to repair the damaged site.
There is a constant need in this art for new surgical procedures for the
treatment
and repair of damaged soft tissue that facilitate more rapid healing and
improved
patient outcomes. In response to this need, a variety of implants, in addition
to
meshes, have been developed and used in surgical procedures to help achieve
these benefits. One type of conventional implant is made from biologically
derived
tissue (e.g. allografts and autografts). Biologically derived materials,
although
generally safe and effective, may have several disadvantages associated with
their
use. For example, if not properly aseptically processed in accordance with
prevailing and accepted standards and regulations, they may contribute to
disease
transmission. In addition, biologically derived products may be somewhat
difficult to
harvest and acquire, and, may be burdensome to process such that their
properties
are within required specifications and standards.
Another common soft tissue injury involves damage to cartilage, which is a
non-vascular, resilient, flexible connective tissue. Cartilage typically acts
as a
shock-absorber and/or sliding contact surface at articulating joints, but some
types
of cartilage provide support to tubular structures, such as for example, the
larynx,
_ _
CA 02461258 2004-03-18
- 4 -
air passages, and the ears. In general, cartilage tissue is comprised of
cartilage
cells, known as chondrocytes, located in an extracellular matrix composed of
collagen, a structural scaffold, and aggrecan, a space-filling proteoglycan.
Several
types of cartilage can be found in the body, including hyaline cartilage,
fibrocartilage
and elastic cartilage. Hyaline cartilage is generally found in the body as
articular
cartilage, costal cartilage, and temporary cartilage (i.e., cartilage that is
ultimately
converted to bone through the process of ossification). Fibrocartilage is a
transitional tissue that is typically located between tendon and bone, bone
and
= bone, and hyaline cartilage and hyaline cartilage. Elastic cartilage,
which contains
elastic fibers distributed throughout the extracellular matrix, is typically
found in the
=
epliglottis, the ears and the nose.
One common example of hyaline cartilage injury is a traumatic focal articular
cartilage defect to the knee. A strong impact to the joint can result in the
complete
or partial removal of a cartilage fragment of various size and shape. Damaged
articular cartilage can severely restrict joint function, cause debilitating
pain and
may result in long term chronic diseases such as osteoarthritis, which
gradually =
destroys the cartilage and underlying bone of the joint. Injuries to the
articular
cartilage tissue will typically not heal spontaneously and require surgical
intervention if symptomatic. The current modality of treatment. consists of
lavage,
removal of partially or completely unattached tissue fragments. In addition,
the
surgeon will often use a variety of methods such as abrasion, drilling or
microfractures, to induce bleeding into the cartilage defect and formation of
a dot.
It is believed that the cells coming from the marrow will form a scar-like
tissue called
fibrocartilage that can provide temporary relief to some symptoms.
Unfortunately,
the fibrocartilage tissue does not have the same mechanical properties as
hyaline
cartilage and degrades faster over time as a consequence of wear. Patients
typically have to undergo repeated surgical procedures which can lead to the
complete deterioration of the cartilage surface. More recently, experimental
approaches involving the implantation of autologous chondrocytes have been
used
CA 02461258 2004-03-18
- 5 --
with increasing frequency. The process involves the harvest of a small biopsy
of
articular cartilage in a first surgical procedure, which is then transported
to a
laboratory specialized in cell culture for amplification. The tissue biopsy is
treated
with enzymes that will release the chondrocyte cells from the matrix, and the
isolated cells will be grown for a period of 3 to 4 weeks using standard
tissue
culture techniques. Once the cell population has reached a target number, the
cells
are sent back to the surgeon for implantation during a second surgical
procedure.
This manual labor-intense process is extremely costly and time consuming.
Although, the clinical data suggest long term benefit for the patient, the
prohibitive
cost of the procedure combined with the traumatic impact of two surgical
procedures to the knee, has hampered adoption of this technique.
Another example of cartilage injury is damage to the menisci of a knee joint.
The meniscus is a C-shaped concave fibrocartilage tissue that is found between
two bone ends of the leg, the femur and tibia. There are two menisci of the
knee
joint, a medial and a lateral meniscus. In addition to the menisci of the knee
joint,
fibrocartilage tissue can also be found in the acromioclavicular joint, i.e.,
the joint
between the clavicle and the acromion of the scapula, in the stemoclavicular
joint,
i.e., the joint between the clavicle and the sternum, in the temporomandibular
joint,
i.e., the joint of the lower jaw, and in the intervertebral discs which lie
between the
vertebral bodies in the spine. The primary functions of meniscal cartilage are
to
bear loads, to absorb shock and to stabilize a joint. Meniscus tears of the
knee
often result from sudden traumatic injury, especially in association with
ligament
injuries, or due to the degeneration of the tissue. Meniscus tears often cause
joint
pain and catching or locking of the joint. If not treated properly, an injury
to the
meniscus, such as a "bucket-handle tear" in the knee joint, may lead to the
development of osteoarthritis. Current conventional treatments for damaged
meniscal cartilage include the removal and/or surgical repair of the damaged
cartilage. Other less established or unproven techniques include allografts
and
collagen-based implants.
CA 02461258 2012-07-30
- 6 -
Synthetically based, non-absorbable materials have been developed as an
alternative to biologically derived products. Although patches or implants
made
from such synthetically based non--absorbable materials are useful to re pair
some herniations, they are found to be inadequate in repairs made in regions
such
as the pelvic floor due to the fact that the patches or implants are made from
non-
bioabsorbable materials and may lead to undesirable tissue erosion and
abrasion.
Tissue erosion and abrasion may be counteracted by the use of patches,
substrates, and implants manufactured from bioaborbable materials.
There continues to be a need for bioabsorbable tissue repair implant devices
having sufficient structural integrity and sufficiently long residence time to
effectively
withstand the stresses associated with implantation into an affected area.
There it
also a continuing need for bioabsorbable tissue repair implant devices that
minimize or eliminate long-term erosion and abrasion (or other pathology) to
the
tissues in the surrounding area.
Bioabsorbable, porous foams may be used as implants to facititate tissue
growth. Bioabsorbable, foamed tissue engineered implant devices that have been
reinforced to increase mechanical properties are disclosed in U.S. Patent
Application Serial No. 09/747489 entitled "Reinforced Tissue Implants and
Methods
of Manufacture and Use" filed December 21, 2000, and also disclosed in U.S.
Patent Application No. 09/747488 entitled "Reinforced Foam Implants with
Enhanced Integrity for Soft Tissue Repair and Regeneration" filed December 21,
2000, now issued as US Patents Nos. 6,599,323 and 6,852,330, respectively.
Methods for manufacturing the foam component of the tissue implant include a
variety of methods known and used in this art. For example, they include
lyophilization, supercritical solvent foaming, extrusion or mold foaming (e.g.
external gas injection or in situ gas generation), casting with an extractable
material
(e.g., salts, sugar or similar suitable materials) and the like.
CA 02461258 2004-03-18
- 7 -
Of particular utility is foam formation by freeze drying or lyophilization.
The
advantages of lyophilization include the avoidance of elevated temperatures,
thus
minimizing the potential for temperature-associated degradation and enabling
the
inclusion of temperature sensitive bioactive agents. Additional advantages
include
the ability to control the pore size and porosity of the foamed material. Non-
aqueous lyophilization also eliminates the need for exposure of the processed
material to water as is required in salt leaching processes that may cause
premature hydrolysis. Lyophylization is a cost effective, simple, one-step
process
3.0 that facilitates manufacturing, and is widely known and used in the
food and
pharmaceutical industries.
Lyophilization is a process for removing a (frozen or crystallized) solvent,
frequently water, from various materials. Lyophilization of enzymes,
antibodies, and
sensitive biological materials is quite often the method of choice for
extending the
shelf life of these products and preserving their biological activity. As
practiced as a
means of foam formation, the lyophilization process usually requires that a
polymeric material be rendered soluble in a crystallizable solvent capable of
being
sublimed, usually at reduced pressure. Although the solvent may be water, 1,4-
dioxane is commonly used. This solvent has found great utility in foam
formation
because many medically important polymers are soluble in it. It is
crystallizable
(melting point approximately 12 C), and it can generate a significant vapor
pressure
at temperatures in which it is still a solid, i.e. it can be sublimed at
reduced
pressure.
It will be generally recognized by one with ordinary skill, however, that
lyophilization has certain limitations when applied to the manufacture of
reinforced
tissue engineered implant devices. For example, reinforcing elements must have
limited solubility in the solvent employed. The integrity of reinforcing
elements must
withstand exposure to a solvent for the duration of the lyophilization
process,
CA 02461258 2004-03-18
=
- 8
otherwise the reinforcing elements (e.g., fibers, mesh, etc.) quickly lose
their
strength, and thus the advantages that the reinforcement is meant to provide.
Selection of appropriate reinforcing materials may overcome at least one
aspect of
this problem. For example, absorbable polyglycolide (also known as
polyglycolic
acid) fibers, do not readily dissolve in many solvents and, in particular, do
not
dissolve in 1,4-dioxane. This property of polyglycolide fiber allows it to
function as a
suitable reinforcing element in many applications. Typically the fibers will
be used in
conjunction with a matrix polymer that is necessarily soluble in the same
lyophilization solvent in which the fibers are not soluble. The matrix
polymer, for
o example polylactide, is then capable of being foamed about these non-
dissolving
fibers during a lyophilization process.
However, bioabsorbable polyglycolide reinforcing elements are not
acceptable for all surgical repairs. In some surgical applications, for
example, they
lose their mechanical strength too quickly after implantation. There is a need
for
bioabsorbable surgical devices in the form of a mechanically reinforced foam
that
retain their mechanical strength for extended periods of time after
implantation to
=
facilitate slow-to-heal tissue repairs. Surgical procedures requiring extended
healing
time include various soft tissue injury repairs, for example, damage to the
pelvic
floor, ligament or tendon tears, cartilage tears, and rotator cuff tears.
Polylactide or
certain lactide-rich lactide/glycolide copolymers such as 95/5 poly(lactide-co-
glycolide), can be made into reinforcing elements that retain their strength
for
prolonged time periods. These polymers, however, readily dissolve in the
commonly-used lyophilization solvent, 1,4-dioxane. Methods for making such
mechanically reinforced foamed devices have not been discovered.
There continues to be a need in this art for bioabsorbable foam tissue repair
implants having sufficient structural integrity that is sufficient to
effectively withstand
the stresses associated with implantation into an affected body area, and that
can
CA 02461258 2011-10-07
- 9 -
retain their mechanical strength for a sufficient time for use in slow-to-heal
tissue repairs,
and that can be made, at least in part, by lyophilization.
SUMMARY OF THE INVENTION
A bioabsorbable, reinforced tissue implant is disclosed. The tissue implant
has a
biocompalible polymeric foam and a biocompatible polymeric reinforcement
member. The
foam and the reinforcement member are soluble in a common solvent
Yet another aspect of the present invention is a method for manufacturing a
bioabsorbable, reinforced tissue implant A solution of a foam-forming,
biocompatible polymer
in a solvent is provided. The solvent has a freezing point. A biocompatible
polymeric reinforcement member is additionally provided. The polymeric
reinforcement member is placed in a cavity of a suitable mold. The solution is
added to the cavity of the mold such that at least a part of the cavity is
filled with the solution
and at least part of the reinforcing member is in contact with the solution.
The reinforcement
member and solution are quenched to below the freezing point of the solvent,
and then are
lyophilized.
More particularly, there is disclosed a method of manufacturing a
biocompatible
tissue implant, comprising: providing a solution comprising a foam forming,
biocompatible
polymer in a solvent, said solvent having a freezing point providing a
biocompatible
polymeric reinforcement member, said reinforcement member being selected from
lactide-
rich polymers and copolymers and said reinforcement member being soluble in
said
solvent; annealing the reinforcement member; placing the polymeric
reinforcement member
in a cavity of a suitable mold; adding the solution to the cavity of the mold
such that at least
a part of the cavity is filled with the solution and at least part of the
reinforcing member is in
contact with the solution; quenching the reinforcement member and solution to
below the
freezing point of the solvent, and lyophilizing.
Still yet another aspect of the present invention is a method of repairing
damaged
tissue, particularly damaged soft tissue. A biocompatible tissue implant is
provided. The implant
has a biocompatible polymeric foam component and a biocompatible reinforcement
member.
The polymeric foam and the reinforcement member are soluble in the same
solvent. The
implant is then placed in a desired position at a site relative to a tissue
injury.
These and other aspects and advantages of the present invention will be more
apparent by the following description and accompanying drawings.
CA 02461258 2004-03-18
- 10 -
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a reinforced tissue implant of the present
invention.
FIG. 2 is a cross-sectional view of hte tissue implant device of FIG. 1.
FIG. 3 is a cross-sectional view of an alternative embodiment of a tissue
io implant of the present invention.
FIG. 4 is a cross-sectional view of yet another embodiment of a tissue
implant of the present invention.
FIG. 5 is a scanning electron micrograph of a section of an implant
according to the present invention.
FIG. 6 is an exploded perspective view of a stretcher and damp apparatus
used to keep the reinforcing mesh flat, level, and under tension during
manufacturing of a tissue implant of the present invention.
FIG. 7 is a view of the stretcher and clamp of FIG. 6 holding a mesh
reinforcement.
FIG. 8 is an illustration of a patient's shoulder with a tear in the rotator
cuff
tendon.
FIG. 9 is an illustration of an implant device of the present invention
implanted in a patient's shoulder for repairing a tear in the rotator cuff
tendon.
CA 02461258 2004-03-18
- 1 1
Detailed Description of the Invention
The present invention relates to a biocompatible tissue implant or "scaffold"
device which, preferably, is bioabsorbable, and to methods for making and
using
such a device. The implant includes one or more layers of a bioabsorbable
polymeric foam having pores with an open or closed cell pore structure. A
reinforcement component or components are also present within the implant to
contribute enhanced mechanical and handling properties. The reinforcement
component is preferably in the form of a mesh fabric that is biocompatible.
The
1.0 reinforcement component is preferably bioabsorbable as well.
In some surgical applications, such as for use as a reinforcement material
for repair of the pelvic floor or rotator cuff, the tissue implants of the
invention
should have sufficient mechanical integrity to be handled in the operating
room, and
they must be able to be sutured without tearing. Additionally, the implants
should
have sufficient burst strength to effectively reinforce the tissue, and the
structure of
the implant must be suitable to encourage tissue ingrowth. A preferred tissue
ingrowth-promoting structure is one where the cells of the foam component are
open and sufficiently sized to permit cell ingrowth. A suitable pore size is
one that is
sufficiently effective and in which the pores have an average diameter in the
range
of typically about 10 to 1000 microns and, more preferably, about 50 to 500
microns.
In general, the shape and size of the scaffold will preferably closely mimic
, the size and shape of the defect it is trying to repair. For a rotator cuff
repair, for
example, it may be preferable to use a sheet configuration such as a
rectangular
patch, or a circular patch that can be cut to size. Preferably, the strength
of the
reinforcement should be highest and stiffest in the direction parallel to the
collagen
fiber direction of the tendon. Referring to FIGS. 1 through 4, the implant 10
includes
a polymeric foam component 12 and a reinforcement member 14. The foam
___________________________________________________________ _
CA 02461258 2004-03-18
- 12 -
component preferably has pores 13 with an open cell pore structure. Although
illustrated as having the reinforcement component disposed substantially in
the
center of a cross section of the implant, it is understood that the
reinforcement
material can be disposed at any location within the implant. Further, as shown
in
FIG.3, more than one layer of each of the foam component 12a, 12b and
reinforcement component 14a, 14b may be present in the implant. It is
understood
that various layers of the foam component and/or the reinforcement material
may
be made from different materials.
FIG.4 illustrates an embodiment in which a barrier layer 16 is present in the
implant. Although illustrated as being only on one surface of the implant 10,
the
barrier layer 16 may be present on either or both of the top and bottom
surfaces 18,
of the implant.
15 The
implant 10 must have sufficient structural integrity and physical
properties to facilitate ease of handling in an operating room environment,
and to
permit it to accept and retain sutures without tearing. Adequate strength and
physical properties are developed in the implant through the selection of
materials
used to form the foam and reinforcement components, and the manufacturing
20 process.
As shown in FIG. 5, the foam component 12 is integrated with the
reinforcement component 14 such that the pores 13 of the foam component
penetrate the mesh of the reinforcement component 14 and interlock with the
reinforcement component. The walls in adjacent layers of the foam component
also
interlock with one another, regardless of whether the foam layers are
separated by
a layer or reinforcement material or whether they are made from the same or
different materials.
The bioabsorbable polymers that can be used to make porous, reinforced
tissue engineered implant or scaffold devices according to the present
invention
include conventional biocompatible, bioabsorbable polymers including polymers
CA 02461258 2004-03-18
- 13 -
selected from the group consisting of aliphatic polyesters, poly(amino acids),
copoly(ether-esters), polyalkylenes oxalates, polyamides, tyrosine derived
polycarbonates, poly(iminocarbonates),
polyorthoesters, polyoxaesters,
polyamidoesters, polyoxaesters containing amine groups, poly(anhydrides),
polyphosphazenes, poly(propylene fumarate), poly(ester urethane), biomolecules
(i.e., biopolymers such as collagen, elastin, bioabsorbable starches, etc.)
and
blends thereof.
As used herein, the term "polyglycolide" is understood to include polyglycolic
acid. Further, the term "polylactide" is understood to include polymers of L-
Iactide,
D-Iactide, meso-lactide, blends thereof, and lactic acid polymers and
copolymers in
which other moieties are present in amounts less than 50 mole percent.
Currently, aliphatic polyesters are among the preferred absorbable polymers
for use in making the foam portion of the foam implants according to the
present
invention. Aliphatic polyesters can be homopolymers, copolymers (random,
block,
segmented, tapered blocks, graft, triblock, etc.) having a linear, branched or
star
structure. Suitable monomers for making aliphatic homopolymers and copolymers
may be selected from the group consisting of, but are not limited, to lactic
acid (both
L- and D- isomers), lactide (including L-, D-, and meso-lactide), glycolic
acid,
glycolide, c-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylene
carbonate
(1,3-dioxan-2-one), and combinations thereof.
Elastomeric copolymers are also particularly useful in the present invention.
Suitable elastomeric polymers include those with an inherent viscosity of 1.2
dUg or
greater, more preferably about 1.2 dUg to 4 dUg and most preferably about 1.4
dUg to 2 dUg, as determined at 25 C in a 0.1 gram per deciliter (g/dL)
solution of
polymer in hexafluoroisopropanol (HFIP). Further, suitable elastomers exhibit
a high
percent elongation and a low modulus, while possessing good tensile strength
and
good recovery characteristics. In the preferred embodiments of this invention,
the
CA 02461258 2004-03-18
- 14 -
elastomer from which the foam component is formed exhibits a percent
elongation
(e.g., greater than about 200 percent and preferably greater than about 500
percent). In addition to these elongation and modulus properties, suitable
elastomers should also have a tensile strength greater than about 500 psi,
preferably greater than about 1,000 psi, and a tear strength of greater than
about
50 lbs/inch, preferably greater than about 80 lbs/inch.
Exemplary bioabsorbable, biocompatible elastomers include but are not
limited to elastomeric copolymers of 6-caprolactone and glycolide (including
polyglycolic acid) with a mole ratio of E-caprolactone to glycolide of from
about '
35/65 to about 65/35, more preferably from 45/55 to 35/65; elastomeric
copolymers
of E-caprolactone and lactide (including L-lactide, D-lactide, blends thereof,
and
lactic acid polymers and copolymers) where the mole ratio of E-caprolactone to
lactide is from about 30/70 to about 95/5 and more preferably from 30/70 to
45/55
or from about 85/15 to about 95/5; elastomeric copolymers of p-dioxanone (1,4-
dioxan-2-one) and lactide (including L-lactide, D-lactide, blends thereof, and
lactic
acid polymers and copolymers) where the mole ratio of p-dioxanone to lactide
is
from about 40/60 to about 60/40; elastomeric copolymers of E-caprolactone and
p-
dioxanone where the mole ratio of, E-caprolactone to p-dioxanone is from about
from 30/70 to about 70/30; elastomeric copolymers of p-dioxanone and
trimethylene
carbonate where the mole ratio of p-dioxanone to trimethylene carbonate is
from
about 30R0 to about 70/30; elastomeric copolymers of trimethylene carbonate
and
glycolide (including polyglycolic acid) where the mole ratio of trimethylene
carbonate to glycolide is from about 30/70 to about 70/30; elastomeric
copolymers
of trimethylene carbonate and lactide (including L-lactide, D-lactide, blends
thereof,
and lactic acid polymers and copolymers) where the mole ratio of trimethylene
carbonate to lactide is from about 30/70 to about 70/30); and blends thereof.
It is to
understood that the exemplary bioabsorbable, biocompatible elastomers may be
generally synthesized by a ring-opening polymerization of the corresponding
CA 02461258 2004-03-18
- 15 -
lactone monomers or by polycondensation of the corresponding hydroxy-acids, or
by combinations of these two polymerization methodologies.
One of ordinary skill in the art will appreciate that the selection of a
suitable
polymer or copolymer for forming the foam depends on several factors. The more
relevant factors in the selection of the appropriate polymer(s) that is used
to form
the foam component include bioabsorption (or bio-degradation) kinetics; in-
vivo
mechanical performance; cell response to the material in terms of cell
attachment,
proliferation, migration and differentiation; and biocompatibility. Other
relevant
factors, which to some extent dictate the in-vitro and in-vivo behavior of the
polymer, include the chemical composition, spatial distribution of the
constituents,
the molecular weight of the polymer, and the degree of crystallinity.
The ability of the material substrate to resorb in a timely fashion in the
body
environment is critical. But the differences in the absorption time under in-
vivo
conditions can also be the basis for combining two different copolymers. For
example, a copolymer of 35/65 c-caprolactone and glycolide (a relatively fast
absorbing polymer) is blended with 40/60 e-caprolactone and L-Iactide
copolymer (a
relatively slow absorbing polymer) to form a foam component. Depending upon
the
processing technique used, the two constituents can be either randomly inter-
connected bicontinuous phases, or the constituents could have a gradient-like
architecture in the form of a laminate type composite with a well integrated
interface
between the two constituent layers. The microstructure of these foams can be
optimized to regenerate or repair the desired anatomical features of the
tissue that
is being engineered.
In one embodiment it is desirable to use polymer blends to form structures
which transition from one composition to another composition in a gradient-
like
architecture. Foams having this gradient-like architecture are particularly
advantageous in tissue engineering applications to repair or regenerate the
CA 02461258 2004-03-18
=
- 16 -
structure of naturally occurring tissue such as cartilage (articular,
meniscal, septa!,
tracheal, etc.), esophagus, skin, bone, and vascular tissue. For example, by
blending an elastomer of E-caprolactone-co-glycolide with E-caprolactone-co-
lactide
(e.g., with a mole ratio of about 5/95) a foam may be formed that transitions
from a
softer spongy material to a stiffer more rigid material in a manner similar to
the
transition from cartilage to bone. Clearly, one of ordinary skill in the art
will
appreciate that other polymer blends may be used for similar gradient effects,
or to
provide different gradients (e.g., different absorption profiles, stress
response
profiles, or different degrees of elasticity). Additionally, these foam
constructs can
o be
used for organ repair replacement or regeneration strategies that may benefit
from these unique tissue implants. For example, these implants can be used for
spinal disc, cranial tissue, dura, nerve tissue, liver, pancreas, kidney,
bladder,
spleen, cardiac muscle, skeletal muscle, tendons, ligaments and breast
tissues.
The reinforcing component of the tissue implant of the present invention is
comprised of any absorbable polymer that is normally soluble in the
lyophilizing
solvent. Of particular utility are the lactide-rich polymers and copolymers.
This
reinforcing component can be in any form including particles, fibers, sheets,
nonwovens, and textiles with woven, knitted, warped knitted (i.e., lace-like),
non-
woven, and braided structures. In an exemplary embodiment of the reinforcing
component has a mesh-like structure. In any of the above structures,
mechanical
properties of the material can be altered by changing the density or texture
of the
material, or by embedding particles in the material. The fibers used to make
the
reinforcing component can be monofilaments, multifilament yarns, threads,
surgical
sutures, braids, or bundles of fibers. These fibers can be made of any
biocompatible materials such as polylactide (or polylactic acid),
polycaprolactone,
copolymers or blends thereof. In one embodiment, the fibers are formed from a
lactide, glycolide copolymer at a 95/5 mole ratio (95/5 poly(lactide-co-
glycolide)).
CA 02461258 2004-03-18
- 17 -
'
The reinforcing material may also be formed from a thin, perforation-
containing elastomeric sheet with perforations to allow tissue ingrowth. Such
a
sheet could be made of blends or copolymers of polylactic acid, and
polycaprolactone.
In one embodiment, filaments that form the reinforcing material may be co-
extruded to produce a filament with a sheath/core construction. Such filaments
are
comprised of a sheath of biodegradable polymer that surrounds one or more
cores
comprised of another biodegradable polymer. This may be desirable in instances
o where extended support is necessary for tissue ingrowth
One of ordinary skill in the art will appreciate that one or more layers of
the
reinforcing material may be used to reinforce the tissue implant of the
invention. In
addition, biodegradable reinforcing layers (e.g., meshes) of the same
structure and
chemistry or different structures and chemistries can be overlaid on- top of
one
another to fabricate reinforced tissue implants with superior mechanical
strength.
The steps involved in the preparation of these foams include choosing the
right solvents for the polymers to be lyophilized and preparing a homogeneous
solution. Next, the polymer solution is subjected to a freezing and vacuum
drying
cycle. The freezing step phase separates the polymer solution and vacuum
drying
step removes the solvent by sublimation and/or drying, leaving a porous
polymer
structure or an interconnected open cell porous foam.
Suitable solvents that may be used ideally will have high vapor pressure at
temperatures below the freezing point of the solvent and a freezing point
reasonably obtainable by commercially available equipment.
The applicable polymer concentration or amount of solvent that may be
utilized will vary with each system. Generally, the amount of polymer in the
solution
õ_
CA 02461258 2004-03-18
=
- 18 -
can vary from about 0.5% to about 90% and, preferably, will vary from about
0.5%
to about 30% by weight, depending on factors such as the solubility of the
polymer
in a given solvent and the final properties desired in the foam.
In one embodiment, solids may be added to the polymer-solvent system to
modify the composition of the resulting foam surfaces. As the added particles
settle
out of solution to the bottom surface, regions will be created that will have
the
composition of the added solids, not the foamed polymeric material.
Alternatively,
the added solids may be more concentrated in desired regions (i.e., near the
top,
sides, or bottom) of the resulting tissue implant, thus causing compositional
changes in all such regions. For example, concentration of , solids in
selected
locations can be accomplished by adding metallic solids to a solution placed
in a
mold made of a magnetic material (or vice versa).
=
A variety of types of solids can be added to the polymer-solvent system.
Preferably, the solids are of a type that will not react with the polymer or
the solvent.
Generally, the added solids have an average diameter of less than about 1.0 mm
and preferably will have an average diameter of about 50 to about 500 microns.
Preferably the solids are present in an amount such that they will constitute
from
about 1 to about 50 volume percent of the total volume of the particle and
polymer-
solvent mixture (wherein the total volume percent equals 100 volume percent).
Exemplary solids include, but are not limited to, particles of demineralized
bone, calcium phosphate particles, calcium sulfate partides, Bioglass
particles or
calcium carbonate particles for bone repair, leachable solids for additional
pore
creation and particles of bioabsorbable polymers not soluble in the solvent
system
that are effective as reinforcing materials or to create pores as they are
absorbed
and non-bioabsorbable materials.
CA 02461258 2004-03-18
- 19 -
Suitable leachable solids include nontoxic leachable materials such as salts
(e.g., sodium chloride, potassium chloride, calcium chloride, sodium tartrate,
sodium citrate, and the like), biocompatible mono and disaccharides (e.g.,
glucose,
= fructose, dextrose, maltose, lactose and sucrose), polysaccharides (e.g.,
starch,
alginate, chitosan), water soluble proteins (e.g., gelatin and agarose). The
leachable materials can be removed by immersing the foam with the leachable
material in a solvent in which the particle is soluble for a sufficient amount
of time to
allow leaching of substantially all of the particles, but which does not
dissolve or
detrimentally alter the foam. The preferred extraction solvent is water, most
preferably distilled-deionized water. Preferably the foam will be dried after
the
leaching process is complete at low temperature and/or vacuum to minimize
hydrolysis of the foam unless accelerated absorption of the foam is desired.
Optionally, it may be desirable to not fully leach all the solid from the
scaffold before
implantation, for example if after implantation of the scaffold, the remainder
of
leachable solids can and provide a therapeutic effect at the implantation
site. For
example, calcium chloride is a well-known factor to active platelets. A
scaffold
containing calcium chloride may be able to cause platelet aggregation, which
will
cause release of growth factors, without the addition of thrombin.
Suitable non-bioabsorbable materials include biocompatible metals such as
stainless steel, cobalt chrome, titanium and titanium alloys, and bioinert
ceramic
particles (e.g., alumina, and zirconia). Further, the non-bioabsorbable
materials
may include particles made from polymers such as polyethylene,
polyvinylacetate,
polyethylene oxide, polymethylmethacrylate, silicone, polyethylene glycol,
polyurethanes, polypropylene, and natural biopolymers (e.g., cellulose
particles,
chitin, and keratin), and fluorinated polymers and copolymers (e.g.,
polyvinylidene
fluoride).
It is also possible to add solids (e.g., barium sulfate) that will render the
tissue implants radio opaque. The solids that may be added also include those
that
CA 02461258 2004-03-18
- 2 0 -
will promote tissue regeneration or regrowth, as well as those that act as
buffers,
reinforcing materials or porosity modifiers.
As noted above, porous, reinforced tissue implant devices of the present
invention are made by injecting, pouring, or otherwise placing, the
appropriate
polymer solution into a mold set-up comprised of a mold and the reinforcing
elements of the present invention. The mold set-up is cooled in an appropriate
bath
or on a refrigerated shelf and then lyophilized, thereby providing a
reinforced tissue
engineered scaffold. In the course of forming the foam component, it is
believed to
be important to control the rate of freezing of the polymer-solvent system.
The type
of pore morphology that is developed during the freezing step is a function of
factors such as the solution thermodynamics, freezing rate, temperature to
which it
is cooled, concentration of the solution, and whether homogeneous or
heterogenous nucleation occurs. One of ordinary skill in the art can readily
optimize
the parameters without undue experimentation.
The required general processing steps include the selection of the
appropriate materials from which the polymeric foam and the reinforcing
components are made. If a mesh reinforcing material is used, the proper mesh
density must be selected. Further, the reinforcing material must be properly
aligned
in the mold, the polymer solution must be added at an appropriate rate and,
preferably, into a mold that is tilted at an appropriate angle to minimize the
formation of air bubbles, and the polymer solution must be lyophilized.
In embodiments that utilize a mesh reinforcing material, the reinforcing
mesh advantageously has a certain density range. That is, the openings in the
mesh material must be sufficiently dense to render the construct suturable,
but not
so dense as to impede proper penetration of the foam material and cells
through
the reinforcing mesh openings. Without proper bonding across the reinforcing
CA 02461258 2012-07-30
- 21 -
element, the integrity of the layered structure is compromised leaving the
construct
fragile and difficult to handle.
Details of the processing steps currently used to make absorbable mesh
reinforced foam scaffolds with non-soluble reinforcing elements are discussed
in
previously mentioned U.S. Patent Applications Nos. 09/747488 and 09/747489,
now US Patents Nos. 6,852,330 and 6,599,323, respectively.
This disclosure specifically relates to a method of preparing such
biocompatible, bioabsorbable tissue implants using reinforcing elements that
are
soluble in the lyophilizing solvent.
There are five main components to this novel process: selection of
reinforcing elements based on diameter; annealing of reinforcing elements;
tensioning the reinforcing elements; constraining the elements during
processing;
and finally pre-cooling and quenching the reinforcing element/solution system
to
limit the exposure of the reinforcing element to liquid solvent prior to
lyophilization.
Briefly, the implants are made by placing a reinforcement material within a
stretcher and clamp apparatus in a desired position and orientation and if
need be,
under tension during processing. The stretcher and clamp apparatus is then
placed
in a mold to create a mold assembly. A solution of a desired polymeric
material in a
suitable solvent is prechilled prior to its addition to the mold assembly,
which may
also be prechilled, and the mold assembly is immediately quenched below the
melting point of the solvent. Finally, the solution in the mold assembly is
lyophilized
to obtain the implant in which a reinforcement material is embedded in a
polymeric
foam. Each of the steps in this process will be covered in more detail in the
following section.
The diameter of the reinforcing element will have a large impact on the
amount of surface area of reinforcing material that is directly exposed to the
CA 02461258 2004-03-18
- 22 - '
solvent. A larger diameter reduces the surface area that will be exposed to
the
solvent. For this reason, monofilament reinforcing elements may be preferred
over
yams. In preferred embodiments the fiber will have a diameter in the range of
50
micron to 2 mm.
Annealing the reinforcing elements prior to lyophilization will further
increase
the resistance of the reinforcing material to dissolution. Annealing schemes
that
enhance the crystallinity level of the reinforcing fibers are of particular
utility. For
95/5 poly(lactide-co-glycolide) reinforcing elements, an annealing cyle
containing a
=
o step that holds the reinforcing materials at 120 C under a nitrogen
atmosphere for
3 hours is a preferred way to process these constructs.
Constraining the soluble reinforcing elements during the lyophilization of the
reinforced foam is another way to produce implants with the desired integrity
and
mechanical properties. Preferably, the reinforcement material is substantially
flat
when placed in the mold. One method, known in the art, to ensure the proper
degree of flatness involves pressing flat the reinforcement material (e.g.,
mesh)
using a heated press prior to its placement within the mold. This inventive
method
involves the use of a stretcher and clamp apparatus that constrains the
reinforcement element flat. Such a stretcher and clamp apparatus 30 is
depicted in
FIG. 6.
Stretcher and clamp apparatus 30 is comprised of inner and outer frames
32,36. Inner frame 32 has outside surface 34, while outer frame 34 has inner
surface 38. Mesh 40 is placed between frames 32,36 such that, as shown in
Figure
7, mesh 40 is engaged between inner surface 38 of outer frame 34 and outside
surface 34 of inner frame 32.
Stretcher and clamp apparatus 30 keeps the reinforcement material flat,
level, and constrained, with the ability to add tension, during processing. In
addition,
=
CA 02461258 2004-03-18
- 23 -
stretcher and clamp apparatus 30 make it possible to use a wider range of
reinforcing materials, including those that have curled edges due to residual
stresses in their structure. Another advantage that apparatus 30 provides is
that
mesh 40 placement within the foam can be precisely controlled, and easily
changed, by using stretchers of different heights or by using a shim system.
As briefly aforementioned, it is not unexpected that a certain level of
tension
imparted on the mesh may play a role in strength retention of the
reinforcement.
This strength retention arises from the residual stresses imparted to the mesh
during loading. In order to retain such tension after removal from the
stretcher and
clamp device, it is preferred to anneal the mesh while under tension. This can
be
achieved by suspending the mesh in an annealing oven and loading the mesh
during annealing. After annealing but before removal of the suspended and
loaded
mesh, the stretcher and clamp apparatus can be affixed after which the
assembly is
subsequently removed from the oven. The optimum level of loading can be
determined by experimentation.
Quenching the reinforcing element/solution system is a critical step to
control the kinetics of the reinforcing element dissolution. This dissolution
is
dependent upon both exposure time and exposure temperature. To minimize these
factors, the stretcher and clamp apparatus, containing the optimized
reinforcing
element, is quenched immediately after being placed in the pre-chilled solvent
in
the pre-chilled mold. By adding the quenching step, the initial exposure of.
the
reinforcing fibers to the solvent can be limited.
The manner in which the polymer solution is added to the mold prior to
lyophilization also contributes to the creation of a tissue implant with
adequate
mechanical integrity. Assuming that a mesh reinforcing material will be used,
and
that it will be oriented and positioned at a desired depth in the mold, the
polymer
solution is then poured in a way that allows air bubbles to escape from
between the
CA 02461258 2012-07-30
- 24 -
layers of the foam component. Preferably, the mold is tilted at a desired
angle and
pouring is affected at a controlled rate to best prevent bubble formation. One
of
ordinary skill in the art will appreciate that a number of variables will
control the tilt
angle and pour rate. Generally, the mold should be tilted at an angle of
greater than
about 1 degree to avoid bubble formation. In addition, the rate of pouring
should be
slow enough to enable any air bubbles to escape from the mold, rather.than to
be
trapped in the mold.
A preferred composition for the reinforcing element is 95/5 poly(lactide-co
glycolide). Two fiber forms of this co-polymer were used in the examples
below: a
yarn with filaments with diameters on the order of 10 to 15 microns, and a
monofilament with a diameter of 125 pm.
When a mesh material is used as the reinforcing component, the density of
the mesh openings is an important factor in the formation of a resulting
tissue
implant with the desired mechanical properties. A low density, or open knitted
mesh
material, is preferred. The density or "openness" of a mesh material can be
evaluated using a digital photocamera interfaced with a computer. In one
evaluation, the density of the mesh was determined using a Nikon SMZ-U ZoomTM
with a Sony digital photocamera DKC-5000TM interfaced with an IBM 300PLTM
computer. Digital images of sections of each mesh magnified to 20x were
manipulated using Image-Pro Plus 4=0TM software in order to determine the mesh
density. Once a .digital image was captured by the software, the image was
thresholded such that the area accounting for the empty spaces in the mesh
could
be subtracted from the total area of the image. The mesh density was taken to
be.
the percentage of the remaining digital image. Implants with the most
desirable
mechanical properties were found to be those with a mesh density in the range
of
about 20% to 88% and more preferably about 20% to 55%. In this work, meshes
were knitted from these fibers with a density of 45%.
CA 02461258 2004-03-18
- 2 5 -
Another aspect of the present invention is providing a biocompatible tissue
implant in a method of repairing damaged tissue, particularly damaged soft
tissue.
The implant has a biocompatible polymeric foam component and a biocompatible
reinforcement member. The polymeric foam and the reinforcement member are
soluble in the same solvent. The implant is then placed in a desired position
at a
site relative to a tissue injury. The implant may be placed within a lesion
that
constitutes the tissue injury, or over the lesion, and may be of a size and
shape
such that it matches a geometry and dimension of the lesion.
1.13 FIG. 8 shows a patient's shoulder 50, with lesion 54 in rotator
cuff tendon
52. A method of repairing lesion 54, according' to the present invention, is
illustrated on FIG. 9. Here, implant 60 is placed over lesion 54, and affixed
in place.
The implant may also be placed within lesion 54 in an interference fit, or
adjacent to
lesion 54 that constitutes a tear such that the implant reinforces the tissue.
Also,
implant 60 may be wrapped around the tissue having lesion 54.
Affixing the implant to the damaged site may be accomplished by a number
of methods including, but not limited to, suturing, stapling, or using a glue
or a
device selected from the group consisting of suture anchors, tissue tacks,
darts,
screws, arrows, and combinations thereof. The glue may be selected from fibrin
glues, fibrin clots, platelet rich plasma, platelet poor plasma, blood clots,
biologically
compatible adhesives, and combinations thereof.
The following examples are illustrative of the principles and practice of this
invention although not limited thereto. Numerous additional embodiments within
the
scope and spirit of the invention will become apparent to those skilled in the
art.
The constructs made in each of the following examples are designated with a
construct identification code according to Table 1.
CA 02461258 2004-03-18
=
- 26 -
TABLE 1
Construct Identification Codes
95/5 poly(lactide-co-glycolide) yam mesh - unannealed, YUU
unquenched
95/5 poly(lactide-co-glycolide) yam mesh - unannealed, YUQ
quenched
95/5 poly(lactide-co-glycolide) yam mesh - annealed, YAU
unquenched
95/5 poly(lactide-co-glycolide) yam mesh - annealed, quenched YAQ
- 95/5 poly(lactide-co-glycolide) monofilament mesh - MUU
unannealed, unquenched
95/5 poly(lactide-co-glycolide) monofilament mesh - MUQ
unannealed, quenched
95/5 poly(lactide-co-glycolide) monofilament mesh - annealed, MAW
unquenched
95/5 poly(lactide-co-glycolide) monofilament mesh - annealed, MAQ
quenched
Example 1
Unannealed 95/5 poly(lactide-co-glycolide yam mesh unquenched and
quenched (constructs YUU and YUQ):
This example describes the preparation of a three-dimensional elastomeric
tissue implant with a 95/5 poly(lactide-co-glycolide) mesh reinforcement
produced
according to the methods described in the existing art and in the manner as
described in this work, namely quenching the mold assembly after adding the
polymer solution.
_
CA 02461258 2012-07-30
- 27 -
A solution of the polymer to be lyophilized to form the foam component of both
constructs was prepared. A 5% solution (by weight) of 60/40 poly(lactide¨co-
caprolactone) in 1,4-dioxane was made in a flask placed in a water bath
stirring at
60 C for 5 hours. The solution was filtered using an extraction thimble and
stored in
a flask.
The mesh used as the reinforcement in the constructs of this example was
made from 95/5 poly (lactide-co-glycolide) yarn. Pieces of the mesh, cut to
dimensions slightly larger than the stretcher and clamp apparatus (5-cm by 14-
cm),
were solvent-scoured to remove lubricant finishes and foreign materials that
accumulated during manufacturing using an agitated batch washing process in a
Bransonic Ultrasonic CleanerTM (Branson Ultrasonics Corp., Danbury, CT). For
scouring, the mesh was placed in a plastic tray filled with isopropyl alcohol
which
was put into the ultrasonic cleaner. The temperature of the cleaner was held
at 30 C.
The mesh was then agitated in the ultrasonic cleaner for 30 minutes, rinsed
with de-
ionized water 3 times, and then re-agitated in a plastic tray filled with de-
ionized
water for 30 minutes. The mesh was then removed from the plastic tray and
placed
under vacuum overnight. Mesh was then placed in a stretcher and clamp
apparatus
used to keep the mesh taut and flat. The mesh in the stretcher and clamp
apparatus
were then set aside in a cool, dry environment.
Room temperature polymer solution was then added to aluminum molds (15.3
X 15.3 crn2). Into each mold, 100 g of the polymer solution was poured,
ensuring that
the solution completely covered the bottom of the mold. To prepare unquenched
specimens (Code YUU), the mesh piece in its stretcher and clamp apparatus was
then placed in a mold to form a mold assembly. The mold assembly was then
transferred to a Virtis, Freeze Mobile GTM freezedryer (Virtis Inc., Gardiner,
NY) and
the assembly was lyophilized according to the following cycle: 1) -17 C for 15
minutes; 2) -15 C for 60 minutes; 3) -5 C for 60 minutes under vacuum 150
CA 02461258 2004-03-18 =
- 2 8
milliTorr; 4) 5 C for 60 minutes under vacuum 150 milliTorr, 5) 20 C for 60
minutes
under vacuum 150 milliTorr.
To prepare quenched specimens (Code YUQ), several modifications to the
above procedure were made. The mesh piece in its stretcher and clamp apparatus
was placed in the aluminum mold and was then submerged into a tray of liquid
nitrogen to quench the polymer solution and mesh to below 10 C. The mold
containing the frozen polymer solution surrounding the mesh was transferred to
the
aforementioned lyophilizer and lyophilized according to the aforementioned
cycle.
1.0
The mold assemblies were then removed from the freezer and placed in a
nitrogen box overnight. Following the completion of this process the resulting
= constructs were carefully peeled out of the mold in the form of a
foam/mesh sheet.
In this example, it was found that in the absence of the quenching step, a
=
significant quantity of the yam dissolved in the polymer solution in the time
that it
took for the lyophilizer to ramp down below the freezing point of the solvent.
With
the addition of the quenching step, the mesh survived exposure to the solvent
and
was present as a reinforcing element in the final construct. The minimization
or
substantial elimination of dissolution of the yam results in substantial
retention of
the mechanical strength of the reinforcing mesh, thereby providing for
sufficient
mechanical characteristics when used as a reinforcing implant. The mechanical
testing results are contained in Example 5 below.
Example 2
Annealed 95/5 poly(lactide-co-g)ycolide) yam mesh unquenched and
quenched (constructs YAU and YAQ):
. .
CA 02461258 2004-03-18
- 2 9 -
This example is identical to Example 1 with the exception that in this
example, the 95/5 poly(lactide-co-glycolide) yarn mesh was annealed prior to
processing.
The meshes were scoured according to the procedure delineated in
Example 1. The scoured meshes were placed in stretcher and clamp devices used
to hold the meshes flat and taut The mesh/device assemblies were then placed
in
an inert gas annealing oven and annealed at 120 C for 3 hours. The remainder
of '
the experiment was conducted in the same manner as Example 1 with one
3.0
annealed mesh being left unquenched and the other mesh being quenched. The
lyophilization cycle was also the same.
It was found that the addition of the quenching step resulted in reinforced
constructs in which less dissolution of the reinforcing fibers took place.
Without
quenching, regions of the mesh were observed to begin to dissolve in the
solvent.
The annealing step produced constructs with improved mechanical
characteristics
versus constructs without the annealing step. The testing of the mechanical
properties is contained in Example 5 below.
Example 3
Unannealed 95/5 poly(lactide-co-glycolide) monofilament mesh unquenched
and quenched (constructs MUU and MUQ):
The same procedure as described in Example 1 was used in this example
with the exception that 95/5 poly(lactide-co-glycolide) monofilament was used
to
make the mesh instead of multifilament yam. The only other difference was the
size
of the mold used. In this example, the same 5% (by weight) 60/40
poly(lactide¨co-
caprolactone) solution in 1,-4-dioxane was poured into smaller aluminum molds
(15.3 X 7 cm2). Therefore, 40 g of polymer solution was sufficient to fully
cover the
CA 02461258 2004-03-18
=
- 30 -
bottom of the mold. Again, the meshes were scoured according to the procedure
delineated in Example 1, and the scoured monofilament meshes constrained by
the
stretcher and clamp device were placed into the polymer-containing molds. One
mold was placed directly on the shelf of the lyophilizer after placement of
the mesh
and lyophilized according to the cycle delineated in Example 1 The other mesh
was first quenched by placing the mold in a stainless steel tray of liquid
nitrogen
before the mold was put on the shelf of the lyophilizer. The frozen assembly
was
then lyophilized according to the same cycle as described in Example 1.
It was found that the addition of the quenching step resulted in reinforced
constructs in which less dissolution of the reinforcing monofilaments took
place.
Without quenching, regions of the mesh were observed to begin to dissolve in
the
solvent, though the dissolution rate was much slower than that observed with
the
Example 1 yam reinforced constructs processed without quenching.Examole 4
Annealed 95/5 poly(lactide-co-glycolide) monofilament mesh unquenched
and quenched (constructs MAU and MAQ):
This example was almost identical to Example 3 with the exception that in
this example, the 95/5 poly(lactide-co-glycolide) monofilament ,mesh was
annealed
prior to processing. The meshes were scoured according to the procedure
delineated in Example 1. The scoured meshes were placed in stretcher and clamp
devices used to hold the meshes flat and taut. The mesh/device assemblies were
then placed in an inert gas annealing oven and annealed at 120 C for 3 hours.
One
annealed monofilament mesh was placed in a large aluminum mold containing 100
g of the 5% (by weight) 60/40 poly(lactide¨co-caprolactone) solution in 1,-4-
dioxane used in all of the examples, and this mold was placed on the shelf of
the
lyophilizer and lyophilized according to the cycle delineated in Example 1.
The
other monofilament mesh was placed in a small aluminum mold containing 40 g of
the 5% (by weight) 60/40 poly(lactide¨co-caprolactone) solution in 1,-4-
dioxane
CA 02461258 2004-03-18
=
- 31
and was immediately quenched after submersion in the polymer solution. This
frozen mold was then placed on the shelf of the lyophilizer and lyophilized
according to the cycle delineated in Example 1.
It was found that the addition of the quenching step resulted in reinforced
constructs in which less dissolution of the reinforcing elements took place.
Without
quenching, regions of the mesh were observed to begin to dissolve in the
solvent,
reducing the ability to act as a reinforcing element.
Example 5
Mechanical properties of constructs:
This example describes the testing of mechanical properties of the
reinforced meshes made in Examples 1 and 2. The components of the constructs
were tested as controls. It is noted that the mesh controls were scoured
according
to the procedure outlined in Example 1.
Peak loads of constructs described in Examples 1 and 2 were measured
using an Instron machine (Model 4501, lnstron, Inc., Canton, MA), outfitted
with a
20 lb. load cell. The specimens were cut (40 mm X 9.9 mm) using a die cutter
(with
the exception of the mesh controls that were cut with scissors), the thickness
of
each specimen was measured prior to testing. Seven specimens of each control
and construct type were measured. Pneumatic grips with rubber coated faces
were
used grip the samples such that a 20 mm gauge length, the length of the
construct
in between the grips, was present at the start of the experiment. The grip
pressure
was set at 50 psi. The cross-head speed was one inch per minute.
Table 2 shows the peak loads for the controls and constructs formed with
yam meshes. The table shows that the peak load of a construct formed without
the
=
CA 02461258 2004-03-18
- 32 -
annealing and quenching steps is equivalent to that of a non-reinforced foam
(0.9
lb). When a quenching step is added, the properties of a yam reinforced
construct
increase 44% (from 0.9 lb to 1.3 lb). The mechanical properties are further
improved when the reinforcing yam mesh is pre-annealed (7.0 lb). The addition
of
the annealing step without the quenching step also results in improved
properties
= (2.8 lb), although the improvement is not as great.
CA 02461258 2004-03-18
- 33 -
Table 2
Peak Idad (lb) STD (lb)
CONTROL
Foam 0.9 0.26 7
Yarn Mesh 12.5 2.13 7
Annealed Yam mesh 17.0 2.41 4
CONSTRUCTS
YUU 0.9 0.26 7
YUQ 1.3 0.51 7
YAU 2.8 0.49 7
YAQ 7.0 0.56 7
Example 6
A patient is prepared for surgery in a conventional manner using
conventional surgical preparatory procedures. The patient has a soft tissue
injury
o involving a tear in the supraspinatus tendon of the rotator cuff. In an
older patient,
the tendon is thin and degenerate and therefore the traditional methods for
reapproximation of the tendon edge to the insertion site on the humerus cannot
be
performed. Since the tendon is degenerate, the strength of the fixation will
not allow
for proper rehabilitation. The patient is anesthetized in a conventional
manner and
the operation is performed arthroscopically.
In a first surgical procedure, the implant of the present invention is used to
augment or reinforce the fixation. The bioabsorbable implant is cut to size
such that
the width of the implant is the same or slightly smaller than the width of the
native
=
-
CA 02461258 2012-07-30
- 34 -
supraspinatus tendon. The length of the implant is cut such that it spans the
degenerate portion of the tendon as well as some of the healthy portion of the
tendon. The implant is then sutured on top of the degenerate and healthy
portion of
the tendon. The medial wall of the greater tuberosity is then prepared with 3-
5 drill
holes. Suture anchors such as BioKnotlessTM brand suture anchors (Mitek,
Norwood, Massachusetts) threaded with No. 1 EthibondTM are inserted into the
holes. The sutures on the anchors pass through both the tendon and the implant
to
reattach the implant-reinforced supraspinatus tendon construct to the original
insertion site of the tendon.
In an additional surgical procedure, an implant of the present invention is
used as an extender to the tendon. This is necessary when there is too much
degeneration in the tendon or if there is retraction in the tendon. One end of
the
implant is sutured to the healthy portion of the supraspinatus tendon with
nonresorbable EthibondTM brand sutures (Ethicon, Somerville, New Jersey). The
other end is attached to the medial wall of the greater tuberosity using
suture
anchors. The implant is cut to match the width of the tendon and to properly
fill the
gap between the tendon and its insertion site. In this case, the implant will
serve as
a bridge between the tendon and the attachment site.. The surgical site is
closed
using conventional surgical techniques and the patient is removed from
anesthesia
and sent to a recovery room.
The reinforced implants of the present invention have numerous advantages.
In the past, traditional repair techniques have had failures due to inadequate
fixation of the tendon to bone or lack of tendon-to-bone healing. A slow-
resorbing
implant that has good mechanical strength will bear load at initial time
points and
allow for good fixation strength at the tendon-bone interface. The use of the
bioabsorbable implants of the present invention that support cell migration
and
growth will allow for the cells from neighboring tissue to migrate into the
implant site
and produce matrix that is similar to that of native tissue. When the
CA 02461258 2011-10-07
- 35 - '
implants of the present invention are used to augment the fixation, greater
area of
contact exists between the tendon-implant and bone and therefore may enhance
the healing response at the interface. When an implant of the present
invention is
used as an extender, the implant will support the migration of cells from the
native
tendon and bone and allow for biological healing of the tendon-tendon and
tendon-
bone interfaces.
Although this invention has been shown and described with respect to
detailed embodiments thereof, it will be understood by those skilled in the
art that
o various changes in form and detail thereof may be made.
