U.S. patent application number 15/185482 was filed with the patent office on 2016-11-24 for bioabsorbable fixation devices.
This patent application is currently assigned to Smith & Nephew, Inc.. The applicant listed for this patent is Smith & Nephew, Inc.. Invention is credited to Nicholas John Cotton, Melissa Jane Egan.
Application Number | 20160339153 15/185482 |
Document ID | / |
Family ID | 43306621 |
Filed Date | 2016-11-24 |
United States Patent
Application |
20160339153 |
Kind Code |
A1 |
Cotton; Nicholas John ; et
al. |
November 24, 2016 |
BIOABSORBABLE FIXATION DEVICES
Abstract
A new material was assessed in a patellar reattachment model in
sheep and evaluated using histology and biomechanical testing.
Overall, these materials showed they produced minimal reactivity
histologically. The new material had higher failure strength
overall compared to a previous study with the control material as
repairs completed with PLG/CS/TCP anchors were significantly
stronger compared to repairs with PLLA anchors.
Inventors: |
Cotton; Nicholas John;
(Westborough, MA) ; Egan; Melissa Jane; (Plympton,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Smith & Nephew, Inc. |
Memphis |
TN |
US |
|
|
Assignee: |
Smith & Nephew, Inc.
Memphis
TN
|
Family ID: |
43306621 |
Appl. No.: |
15/185482 |
Filed: |
June 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14857948 |
Sep 18, 2015 |
9387274 |
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15185482 |
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14010931 |
Aug 27, 2013 |
9173981 |
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14857948 |
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12847511 |
Jul 30, 2010 |
8545866 |
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14010931 |
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11262336 |
Oct 28, 2005 |
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12847511 |
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60623645 |
Oct 29, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 24/02 20130101;
A61L 31/128 20130101; C08K 2003/3045 20130101; A61K 31/765
20130101; A61K 31/765 20130101; A61K 33/10 20130101; A61P 19/00
20180101; A61P 17/02 20180101; A61L 31/06 20130101; A61K 33/06
20130101; A61L 31/128 20130101; C08K 3/26 20130101; A61L 31/127
20130101; A61L 27/446 20130101; A61L 31/026 20130101; C08K 3/30
20130101; A61L 24/046 20130101; A61L 31/16 20130101; C08L 67/04
20130101; C08L 67/04 20130101; C08L 67/04 20130101; A61L 27/425
20130101; C08L 67/04 20130101; A61L 31/148 20130101; A61L 2430/34
20130101; C08L 67/04 20130101; A61P 19/02 20180101; A61L 27/446
20130101; A61L 24/0042 20130101; A61L 31/127 20130101; A61K 33/10
20130101; A61L 27/425 20130101; A61K 2300/00 20130101; C08K
2003/265 20130101; A61K 2300/00 20130101 |
International
Class: |
A61L 31/12 20060101
A61L031/12; A61L 31/14 20060101 A61L031/14; A61L 31/06 20060101
A61L031/06; A61L 31/02 20060101 A61L031/02 |
Claims
1. An internal fixation device made from a bioabsorbable polymer
composition comprising: about 50 to 80 percent by weight of a
copolymer, based on the weight of said bioabsorbable polymer
composition, wherein said copolymer is selected from the group
consisting of poly 1-lactide:co-glycolide, poly
1-lactide:d,l-lactide, and mixtures thereof; and about 20 to 50
percent by weight of a ceramic filler, based on the weight of the
bioabsorbably polymer composition, wherein said ceramic filler
comprises calcium carbonate.
2. The internal fixation device of claim 1, comprising: (a) about
50 percent by weight of a copolymer, based on the weight of said
bioabsorbable polymer composition, wherein said copolymer is
selected from the group consisting of poly 1-lactide:co-glycolide,
poly 1-lactide:d,l-lactide, and mixtures thereof; and (b) about 50
percent by weight of a ceramic filler, based on the weight of the
bioabsorbably polymer composition, wherein said ceramic filler
comprises calcium carbonate.
3. The internal fixation device of claim 1, wherein the copolymer
comprises poly(lactide-coglycolide) in a ratio of about 85:15
lactide and glycolide units.
4. The internal fixation device of claim 1, comprising only
poly(lactide-coglycolide) in a ratio of about 85:15 lactide and
glycolide units and about 20 to 50 percent calcium carbonate by
weight.
5. A method comprising securing soft tissue to a bone using at
least one suture anchor comprising an internal fixation device made
from a bioabsorbable polymer composition, the composition
comprises: (a) from 20 to 80 percent by weight of a copolymer,
based on the weight of said bioabsorbable polymer composition,
wherein said copolymer is selected from the group consisting of
poly 1-lactide:co-glycolide, poly 1-lactide:d,l-lactide, and
mixtures thereof; and (b) from 20 to 50 percent by weight of a
ceramic filler, based on the weight of the bioabsorbable polymer
composition, wherein said ceramic filler comprises calcium sulphate
and optionally tricalcium phosphate.
6. The method of claim 5, wherein the soft tissue is selected from
the group consisting of ligament, tendon, muscle, and
cartilage.
7. The method of claim 5, wherein the bone is patella bone.
8. The method of claim 5, wherein the ceramic filler comprises
material purified from natural sources.
9. The method of claim 5, wherein the ceramic filler comprises
synthetic material.
10. The method of claim 5, wherein the ceramic filler comprises a
mixture of synthetic material and material purified from natural
sources.
11. The method of claim 5, wherein the composition comprises: (a)
about 50 percent by weight of a copolymer, based on the weight of
said bioabsorbable polymer composition, wherein said copolymer is
selected from the group consisting of poly 1-lactide:co-glycolide,
poly 1-lactide:d,l-lactide, and mixtures thereof; and (b) about 50
percent by weight of a ceramic filler, based on the weight of the
bioabsorbably polymer composition, wherein said ceramic filler
comprises calcium carbonate.
12. The method of claim 5, wherein the copolymer comprises
poly(lactide-coglycolide) in a ratio of about 85:15 lactide and
glycolide units.
13. The method of claim 5, wherein the composition comprises only
poly(lactide-coglycolide) in a ratio of about 85:15 lactide and
glycolide units and about 20 to 50 percent calcium carbonate by
weight.
14. An internal fixation device made from a bioabsorbable polymer
composition comprising only poly(lactide-coglycolide) in a ratio of
about 85:15 lactide and glycolide units and about 20 to 50 percent
calcium carbonate by weight.
15. The internal fixation device of claim 14, wherein said
poly(lactide-coglycolide) comprises poly
1-lactide:co-glycolide.
16. The internal fixation device of claim 14, comprising: (a) about
50 percent by weight of a copolymer, based on the weight of said
bioabsorbable polymer composition, wherein said copolymer is
selected from the group consisting of poly 1-lactide:co-glycolide,
poly 1-lactide:d,l-lactide, and mixtures thereof; and (b) about 50
percent by weight of a ceramic filler, based on the weight of the
bioabsorbably polymer composition, wherein said ceramic filler
comprises calcium carbonate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/857,948 filed Sep. 18, 2015, which is a continuation of U.S.
application Ser. No. 14/010,931 filed Aug. 27, 2013, now U.S. Pat.
No. 9,173,981, issued Nov. 3, 2015, which is a continuation of U.S.
application Ser. No. 12/847,511, filed Jul. 30, 2010, now U.S. Pat.
No. 8,545,866, issued Oct. 1, 2013 which is a continuation-in-part
of U.S. application Ser. No. 11/262,336, filed Oct. 28, 2005, now
abandoned, which claims the benefit of U.S. provisional application
No. 60/623,645, which was filed Oct. 29, 2004. The entire content
of these prior applications is hereby incorporated by reference in
the present application.
TECHNICAL FIELD
[0002] Described herein are compositions that include a
biodegradable copolymer such as poly(lactide-co-glycolide) (PLGA),
and methods of making and using devices containing such
compositions.
BACKGROUND
[0003] Tissue fixation devices are used extensively to repair
traumatic injuries, for example, those sustained during sporting
events. Such "sports medicine fixation devices" are typically used
to fix soft tissue and sometimes hard tissue back to bone. Sports
medicine implants may be used to repair bone, chondral and/or
osteochondral defects.
[0004] Bioabsorbable materials are used in both types of
applications. For example, interference screws are used to fixate
autologous grafts during anterior cruciate ligament (ACL) repair.
The devices are often made from a semicrystalline polymer,
poly(I-lactic acid) (PLLA) or copolymers of PLLA with
poly(d,l-lactic) acid (PDLA) or poly(glycolic) acid (PGA). These
bioabsorbable polymers produce acidic products upon degradation,
and others have suggested inclusion of a buffering compound to
neutralize the breakdown products (see, e.g., U.S. Pat. No.
6,741,329). Although appropriate for soft tissue repair, these
materials can also be used in the event of orthopedic trauma or
reconstructive surgery to fixate bone to bone.
[0005] The ideal bioabsorbable has sufficient mechanical properties
to perform its primary function but over time the implant should
ideally get replaced by natural tissue that is surrounding the
implant. It certain embodiments the material releases compounds
that aid the repair and replacement process.
SUMMARY
[0006] Described herein are biocompatible compositions that contain
a copolymer and a filler material. For example, the compositions
can include a copolymer that includes lactic acid and/or glycolic
acid monomers and a filler such as calcium carbonate (e.g., about
30-40% CaC03 by weight {i.e., by weight of the composition as a
whole).
[0007] In specific embodiments, the copolymer can be
poly(lactide-co-glycolide) (PLGA), with a lactide: glycolide ratio
of about 85:15 and the filler can be, for example, calcium
carbonate or tricalcium phosphate. Alternatively, the copolymer can
be poly 1-lactide:d,llactide (PLDL), with an 1-lactide:d,l-lactide
ratio of 70:30. We may refer to compositions containing calcium
carbonate as Poly Lactide Carbonate or "PLC." The compositions
described herein are also referred to herein as "materials" or
"biomaterials" or, when the compositions are fashioned for a
particular use, such as implantation, as "devices" or "implants."
Further, where the devices are suitable for attaching one tissue to
another (e.g., attaching soft tissue to bone or attaching bone to
bone), we may refer to them as internal fixation devices. Such
devices include screws, pins, rods, plates, sutures, suture
anchors, staples, clips, rings, and the like. When fashioned to
repair an injured bone (e.g., when used to replace lost bone
fragments), the device can be described as a bone prosthesis.
[0008] The compositions described herein can be amorphous (i.e.,
they can be compositions in which the polymer chains are not
ordered) or semi-crystalline {i.e., compositions in which there is
some order to the polymer chains). On a macroscopic level, the
compositions can have a pulverized or pelletized form (for example,
the compositions described herein can be formulated as a powder or
paste, or as pellets, granules, or interlocking shapes), or they
can be shaped for use in a particular surgical procedure (for
example, as a tissue fixation device or synthetic bone substitute
or prosthesis). In any event, the compositions can be sterile. The
compositions can also be fashioned as porous implants or devices.
Methods for making such implants or devices are known in the art
and can be carried out with the compositions described herein. For
example, processes are known in the art for using porogens,
leaching agents, supercritical C02, gas generating additives,
and/or sintering techniques to fuse smaller shapes. The
compositions described herein can also be molded into essentially
any shape, whether regular (such as a cylinder or square) or
irregular.
[0009] The compositions described herein are useful in a wide
variety of methods in which tissue is altered, including methods in
which the primary site of repair is bone per se. The methods
encompass any type of tissue modification, including tissue repair,
reconstruction, remodeling, and tissue-guided regeneration. In
addition to their use as tissue fixation devices or synthetic bone
substitutes or prostheses, the compositions described herein can be
used as devices for attachment of orthopedic hardware (e.g., as
screws for bone plates or screws to temporary secure hip stems) or
in the context of reconstructive or cosmetic surgery.
[0010] In one embodiment, the composition may include a polymer
formulation based on lactide and glycolide units that has a
moderate degradation rate of 1-3 years. Into this polymer is
blended both tricalcium phosphate (TCP) and calcium sulphate. The
calcium sulphate will provide soluble calcium ions to aid repair.
Local increases in calcium ions are known to increase bone
formation which is critical in both getting the implant replaced by
bone and to increase the tendon to bone repair. The TCP is a good
osteoconductive agent and will enable longer term bone attachment
and eventual replacement by bone.
[0011] In an alternative embodiment, the composition is
biocompatible (i.e., substantially non-toxic) and includes a filler
such as calcium carbonate, calcium sulphate, and/or tricalcium
phosphate, and a copolymer formed from lactic acid monomers and/or
glycolic acid monomers. The filler (e.g., calcium carbonate) can
constitute more than 30% but less than 40% of the weight of the
composition, regardless of the composition's form, the copolymer
selected, or the inclusion of other components (e.g., a therapeutic
agent, as described below). For example, the filler (e.g., calcium
carbonate) can constitute more than 30% but less than about 34%;
more than 30% but less than about 35%; or about 36% to less than
40% of the weight of the composition. The filler can constitute
more than 30%; about 31%; about 32%; about 33%; about 34%; about
35%; about 36%; about 37%; about 38%; about 39%; or an amount
therein between (e.g., an amount between 31 and 32%; an amount
between 32 and 33%; and so forth). Where calcium carbonate is used,
it can have the crystalline structure of calcite, and it may be
present as calcium carbonate particles of a substantially uniform
size (e.g., a majority of the calcium carbonate particles can be
about 0.1-0.5; 0.5-2.5; 2.5-5.0; 5.0-7.5; or about 7.5-10.0/lJm in
size (size being measured across the particles' largest diameter)).
Alternatively, the filler particles can vary in size (e.g., ranging
in size in a uniform or non-uniform way from about 0.01/lm to about
10.0/lJm).
[0012] Any of the fillers, including CaC03, can be combined with a
PLGA copolymer in which the lactic acid monomers are in the L-form
or the D-form, or are a mixture of the L- and D-forms. More
specifically, the copolymer can be poly(dl-lactideco-glycolide).
The ratio of lactic acid and glycolic acid monomers within the
polymer can also vary. For example, the copolymer can contain from
about 50:50 lactide: glycolide units to about 90:10
lactide:glycolide units (e.g., about 85:151actide:glycolide units).
It will be understood by one of ordinary skill in the art that
these ratios can, and often do, vary due to manufacturing
limitations. For example, the ratio can vary by about .+-.5%. Thus,
it is to be understood that all references herein to the ratio of
polymer units encompasses copolymers in which that ratio varies to
an expected extent. In a specific embodiment, the composition
includes (and may include only) a copolymer of lactide and
glycolide units and more than 30% but less than 40% calcium
carbonate by weight. In another specific embodiment, the
composition includes (and may include only)
poly(lactide-coglycolide) at 85:15 lactide:glycolide units and
about 20-50% calcium carbonate by weight (e.g., about 20-30% (e.g.,
25%), 30-40%, 40-50% (e.g., 45%), 30-34%, 35%, or 36-40%).
Regardless of the precise components or their amounts, the
copolymer can be amorphous or crystalline and the filler (e.g.
CaC03) and the copolymer (e.g., PLGA) can form a substantially
homogeneous mixture (e.g., the filler can be evenly or about evenly
distributed within the copolymer; dispersed). Thus, the composition
of any device, as a whole, fashioned from a substantially
homogeneous mixture can also be homogeneous (e.g., the composition
of a device at the proximal and distal ends of a screw or the
opposite faces of a plate can be substantially indistinguishable in
content).
[0013] The compositions described herein can, but do not
necessarily, contain one or more additional components, which may
be bioactive agents (e.g., therapeutic agents). For example, the
compositions can contain a growth factor, including growth factors
such as those from the fibroblast growth factor family,
transforming growth factor family, or platelet derived growth
factor family that act as chemoattractants and/or growth
stimulators, a hormone such as human growth hormone, an antibiotic,
an antiviral agent, an antifungal agent, an anti-inflammatory
agent, an inflammatory mediator such as an interleukin, tumor
necrosis factor, a prostaglandin, nitric oxide, an analgesic agent,
an osteogenic factor such as a bone morphogenetic protein, or a
matrix molecule such as hyaluronan. Other agents include angiogenic
factors, which are capable of directly or indirectly promoting
angiogenesis. Examples include angiogenic peptide growth factors in
autologous, xenogenic, recombinant, or synthetic forms (e.g., a
member of the vascular endothelial growth factor family}. Further
examples are blood clot breakdown products, such as thrombin and
heparin including autologous, allogeneic, xenogeneic, recombinant
and synthetic forms of these materials. Compositions based around
butyric acid, including butyric acid (butanoic acid, C4H80 2) and
butyric acid salts, including sodium, potassium, calcium, ammonium
and lithium salts, a-monobutyrin (1-glycerol butyrate; 1-(2,3
dihydroxypropyl) butanoate; C7H1404) and hydroxybutyrate can also
be incorporated. Where the bioactive or therapeutic agent is a
polypeptide, one can incorporate the polypeptide in its naturally
occurring form or a fragment or other mutant thereof that retains
sufficient biological activity to confer a benefit on the patient
to whom it is administered. The polypeptides can be autologous in
the sense that, where the recipient is a human patient, the
polypeptide can have the sequence of a human polypeptide or a
biologically active fragment or other mutant thereof.
Alternatively, or in addition, the additional component can be a
nutraceutical, such as a vitamin or mineral.
[0014] The bioactive material is included in an amount that is
therapeutically effective for the organism (e.g., a human patient)
in question. Inclusion of one or more bioactive materials may, for
example, increase the rate of tissue repair, decrease the risk of
infection, or otherwise aid the healing or post-operative
process.
[0015] Also described herein are methods of making devices (e.g.,
internal fixation devices) with the compositions described herein.
In one embodiment, the method can be carried out in steps that
include the following: (a) providing a filler (e.g., calcium
carbonate); (b) providing a copolymer (e.g., a copolymer formed
from lactic acid monomers and glycolic acid monomers); (c)
combining the filler and the copolymer to produce a composition in
which the amount of the filler constitutes about 20-50% of the
composition (e.g., more than 30% and less than 40% of the
composition (e.g., about 35%); and (d) molding the composition to
produce a device (e.g., an internal fixation device). In a specific
embodiment, the method will produce a composition that includes
(and may include only) a copolymer of lactide and glycolide units
and more than 30% but less than 40% calcium carbonate by weight. In
another specific embodiment, the method will produce a composition
that includes (and may include only) poly(lactidecoglycolide) at
85:15 lactide and glycolide units and about 20-50% calcium
carbonate by weight (e.g., about 20-30%, 30-40%, 40-50%, 30-34%,
35%, or 36-40%). The methods can further include a step of
sterilizing the device by, for example, exposing it to radiation
(e.g., gamma radiation), treating it with gases (e.g., chemical
sterilization such as exposure to ethylene oxide gas), exposing it
to heat (e.g., from steam, as in autoclaving), or exposing it to an
electronic beam (e beam), or light (e.g., white light). Methods of
sterilizing devices are known in the art, and one of ordinary skill
in the art can select methods appropriate for a given device.
[0016] Optionally, the filler and copolymer can be combined with a
bioactive agent (e.g., a therapeutic agent) including, but not
limited to, any of those described herein. The therapeutic agent
can be mixed or otherwise combined with the copolymer and filler or
it can be added to the surface of the device or otherwise localized
within the device.
[0017] If desired, one can omit the molding process of step (d).
Thus, the methods described herein encompass those comprising steps
(a)-(c) above, but not step (d). Therapeutic agents can also be
included, and the composition can be sterilized and packaged, just
as molded compositions can be sterilized and packaged.
[0018] The materials within the composition or device can be
combined by any method that produces a satisfactory mixture that
can be, if desired, formed into a shaped device. For example, a
device can be formed by an extrusion process (e.g., a single screw,
twin screw, disk, ram, or pulltrusion process); a molding process
(e.g., an injection, intrusion, compression, or thermoforming
process); a solvent based process (e.g., mixing or casting); a
welding process (e.g., an ultrasonic or hermetic process); a
polymerization process (e.g., reaction injection molding, bulk
polymerization, and solvent polymerization); or by other methods
(e.g., fiber spinning or electrospinning). The components within
the compositions or devices can have the properties described
herein. For example, where the filler is calcium carbonate, it can
have the particle size described above, the lactic acid monomers
used can be in the 0-form, L-form, or a mixture of D and L-forms,
and so forth.
[0019] The compositions or devices can be packaged as kits, with
instructions for further processing them or using (e.g.,
implanting) them. The instructions can be, but are not necessarily,
printed instructions (e.g., the instructions can be supplied as an
audio- or videotape or on a compact disc or similar medium). The
kits can optionally contain materials suitable for processing or
using the compositions or devices.
[0020] Also described herein are methods of using the compositions
and devices to repair or remodel tissue. For example, the
compositions and devices can be used in treating a patient who has
sustained an injury in which a soft tissue within their body has
become detached (wholly or partly) from bone. The methods can be
carried out by using an internal fixation device as described
herein (or made according to the methods described herein) to
reattach the soft tissue to the bone. The soft tissue can be a
ligament, (e.g., the ACL), a tendon, a muscle, cartilage, or other
soft or connective tissue. In other embodiments, the compositions
and devices described herein can be used to repair or reshape a
bone or to attach bone to bone.
[0021] Also described herein are methods of treating a patient who
has, or who is at risk for developing, osteomyelitis (an acute or
chronic bone infection, usually caused by bacteria, and frequently
associated with trauma, diabetes, and any condition associated with
frequent disruption of the skin (e.g., hemodialysis, intravenous
therapy, and drug abuse)). The method can be carried out by
administering to the patient a composition or device described
herein that includes an antibiotic. For example, where a patient
has developed osteomyelitis in connection with a traumatic injury,
the injury can be repaired with a suitable device that includes an
antibiotic. Also described herein are methods of treating a patient
who has bone cancer by administering to the patient (e.g., at the
site from which a tumor has been excised) a composition comprising
a composition or device described herein that includes a
chemotherapeutic agent. For example, a patient having a bone cancer
can be treated with a composition or device that includes any of
the components described herein (e.g., poly(lactide-co-glycolide)
and calcium carbonate) and a chemotherapeutic agent. As noted in
connection with the compositions, the poly(lactide-co-glycolide)
can include lactide:glycolide units at a ratio of 85:15, and the
calcium carbonate can constitute about 20-50% of the composition by
weight (e.g., more than 30% but less than 40% of the weight of the
composition).
[0022] As copolymers such as PLGA degrade in vivo by hydrolysis
into natural metabolic products, the compositions of the present
invention and devices or implants made as described herein are
biocompatible and may also be referred to as bioabsorbable (i.e.,
as able to degrade over time in a biological environment such as
the human body to compounds that are removed during normal
metabolic processes). Moreover, devices fashioned with the present
compositions can degrade over a period of time that allows a
desirable shift in weight bearing from the device to the patient's
own tissues. While the compositions described herein are not
limited to those having any particular advantage, we believe the
inclusion of calcium carbonate decreases the rate of acid catalyzed
hydrolysis, allowing for greater strength retention suitable for
orthopedic repair devices. The release of calcium may stimulate
bone cells and accelerate bone repair. The filler may also increase
or enhance biocompatibility or dimensional stability, facilitate
processing, and/or improve the appearance of the composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a table depicting % mass loss on days 1, 2, 4, and
5 from various compositions prepared as described in Example 1.
[0024] FIG. 2a is a table depicting molecular weight loss for the
compositions listed after 1, 2, and 4 days, as described in Example
1.
[0025] FIG. 2b is a line graph representing the tabular data of
FIG. 2a.
[0026] FIG. 3 is a table indicating the pass/fail rating for four
compositions (PDLG, PLCI5, PLC35, and PLC50) in a standard industry
torsional test.
[0027] FIG. 4 is a line graph depicting the degradation of
molecular weight for four compositions (PDLG, PLCI5, PLC35, and
PLC50) over 26 weeks in vitro.
[0028] FIG. 5 is a line graph depicting the degradation of mass for
four compositions (PDLG, PLCI5, PLC35, and PLC50) over 52 weeks in
vitro.
[0029] FIG. 6 is a bar graph comparing the results of strength
retention testing with PLC and PLLA over 24 weeks (as described in
Example 3).
[0030] FIG. 7 is a series of three photographs of an implanted PLC
screw at six weeks, 26 weeks, and 52 weeks (left to right)
following implantation into the femur of a sheep.
[0031] FIG. 8 is a pair of photographs of an implanted PLC screw
(left-hand photograph) and a PLLA screw (right-hand photograph) one
year following implantation into the femur of a sheep.
[0032] FIG. 9 is a pair of CT scans. The left-hand scan shows the
location of a PLC screw in the femur of a sheep after 52 weeks
implantation (the screw was replaced by normal cancellous bone).
The right-hand scan shows a PLLA screw after the same period of
time. The PLLA screw is still present.
[0033] FIG. 10 is a pair of photographs of the sites of
implantation of a PLC screw six weeks after implantation (left-hand
photograph) and 26 weeks after implantation (right hand
photograph).
[0034] FIG. 11 is a photograph illustrating central placement of a
screw completely surrounded by a tendon graft.
[0035] FIG. 12 is a bar graph comparing the tensile strength (N) in
the reconstructed tibial-femoral complex in animals treated with
PLC screws and animals treated with PLLA screws.
[0036] FIG. 13 is a pair of photographs illustrating the ability of
a PLC screw to stimulate graft ossification (presumably by calcium
release) after 26 weeks implantation (left-hand photograph) and
after 52 weeks implantation (right-hand photograph).
[0037] FIG. 14 is a photograph illustrating a PLLA screw after 52
weeks implantation under the same conditions as the PLC screw shown
in FIG. 13 (and described in Example 5).
[0038] FIG. 15 is a series of CT sections through the planes shown
as Z1, Z2, and Z3, showing the progression of bone integration in
both the graft and PLC screw domains.
[0039] FIG. 16 shows peak load for the Osteoraptor 2.3 and Lupine
BR suture anchor during in vitro degradation.
[0040] FIG. 17a-17d shows histology from sheep implanted with
screws made from poly l lactide-co-glycolide, calcium sulphate,
p-tricalcium phosphate [PLG (85/15), CaS04, TCP 65:20:15], compared
to empty defect controls. FIG. 17a shows representative fresh and
stained sections from an implanted subject at 6 months postsurgery;
FIG. 17b shows representative fresh and stained sections from an
emptydefect control at 6 months post-surgery; FIG. 17c shows
representative fresh and stained sections from an implanted subject
at 12 months post-surgery; FIG. 17d shows representative fresh and
stained sections from an empty-defect control at 12 months
post-surgery.
[0041] FIG. 18: 40.times. representative image of PLG/CS/TCP anchor
interphase with bone. A thin layer of fibrous tissue containing
scant macrophages is present, indicating a mild foreign-body
response with no reactivity tissue/implant nor tissue/bone.
[0042] FIG. 19: 3.2.times. image show a representative section from
the PLG/CS/TCP group.
[0043] FIG. 20: Representative histology of the Bioraptor (PLLA)
anchor implantation site at 12 weeks post-surgery. Panels A and 8
represent higher magnification photomicrographs of the areas
designated in the large upper panel. In each panel the areas of
bone and soft tissue are as denoted.
[0044] FIG. 21: Comparison of failure strengths using historical
control data (PLLA) and current study data (PLG/CS/TCP).
DETAILED DESCRIPTION
[0045] As noted, the compositions described herein can include a
co-polymer and a filler material. These components, as well as
additional components and methods of use are described further
below.
[0046] Copolymers: As noted, the compositions described herein can
include a copolymer, including copolymers produced from lactide and
glycolide monomers. Lactide monomers can be present in the D-form
or the L-form. Alternatively, the copolymer can include a
combination of monomers in both the D- and L-forms (e.g.,
poly-llactide:d,llactide). For example, 20-28% of the lactide
monomers (e.g., 25-75%, 30-70%, 40-60%, or about 50%) can be
D-lactide monomers. As noted, where the copolymer includes monomers
of lactic and glycolic acids, we may refer to it as PLGA, and where
both isoforms are present, we may refer to
poly(dl-lactide-co-glycolide) (PDLGA). Moreover, the ratio of
monomers (e.g., the ratio of lactide to glycolide units) can vary.
For example, the copolymer can contain about 50:50
lactide:glycolide units to about 90:10 lactide: glycolide units
(e.g., about 85: 151actide:glycolide units; as noted above, the
ratio can vary from these absolute numbers due to the manufacturing
process). The copolymer can be manufactured by methods known to
those of ordinary skill in the art or purchased from a commercial
supplier.
[0047] Filler material: Materials suitable for inclusion as fillers
with any of the copolymers described herein (e.g., with PLGA or
PDLGA, for example where the ratio of lactide:glycolide units is
about 85:15) include basic organic and inorganic metal compounds,
such as acetates, lactates, glycolates, hydroxides, carbonates,
phosphates, and halides. For example, the filler can be sodium
acetate, potassium acetate, sodium lactate, potassium lactate,
calcium lactate, potassium glycolate, calcium glycolate, calcium
propionate, calcium oxide, calcium hydroxide, calcium carbonate,
calcium phosphate family, calcium fluoride, calcium sulphate,
magnesium oxide, magnesium hydroxide, magnesium carbonate,
magnesium phosphate, sodium phosphate, sodium fluoride, potassium
phosphate, potassium fluoride, or combinations thereof. A single
filler such as calcium carbonate may be used as the sole filler or
in combination with another filler material. Alternatively,
combinations of two or more fillers can be used such as, for
example, calcium sulphate and tricalcium phosphate. When a
combination of fillers is used, the individual fillers may be, but
need not be, present in equal amounts. For example, four parts
calcium sulphate may be mixed with three parts tricalcium
phosphate.
[0048] Like the copolymer, the filler material can be purchased
from commercial suppliers or may be synthesized or purified from
natural sources. For example, calcium carbonate is found in nature
(e.g., in natural coral or other marine life). The filler may be
pure or substantially pure, or it may contain contaminants. For
example, the calcium carbonate may be pure or may contain small
amounts (e.g., "trace" amounts) of another compound such as MgC03,
Si03, or [FeAl2]03. With respect to form, the calcium carbonate may
be particulate, and the particles can be roughly spherical, cubical
or tetrahedral measuring in size from very small (e.g., less than
about 0.10 1 Jm) to quite large (e.g., about 10.0 1 Jm or more).
For example, the particles can have a diameter of about 0.1-0.51
Jm; about 0.5-2.51 Jm; about 2.5-5.0 lJm; about 5.0-7.51 Jm; about
7.5-10.0 1 Jm; or sizes within the ranges provided (e.g., about
8.0-9.0 1 Jm). The particles, or a majority of the particles, can
be of approximately the same size or they can be of a range of
different sizes (e.g., the smallest can be about 0.01, 0.05, 0.10,
0.25, 0.50, 0.75, 1.0, 1.25, 1.50, 1.75, 2.00, or 2.50 1 Jm and the
largest can be about 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 1 Jm).
Regardless of size, the particles can be solid or can contain a
hollow core, or can be porous in nature.
[0049] The amount of the filler within the composition can vary.
For example, where the composition contains only a copolymer and
filler, the filler can constitute about 20-50% of the composition
(e.g., about 30-40% (e.g., about 35%)) by weight. For example,
where the total weight of a composition is 100 g, it can include
60-70 g of a copolymer and 30-40 g of filler (e.g., 65 g of PLGA
(e.g., PLGA at 85:15 lactide: glycolide units) and 35 g CaC03).
Where one or more additives are included, as described below, the
amount of the filler can nevertheless remain the same (i.e., about
20-50% (e.g., 30-40% (e.g., about 35%))) of the composition as a
whole. Alternatively, the filler can constitute about 20-50% (e.g.,
30-40% (e.g., about 35%)) by weight of the weight of the
copolymer.
[0050] Additives: If desired, any of the compositions described
herein (e.g., a mixture of PLGA (e.g., 85:15 lactide:glycolide
units) and calcium carbonate), regardless of form, can contain one
or more additives (e.g., therapeutic agents such as biotherapeutics
or pharmaceuticals). For example, a calcium carbonate-PLGA
composition (e.g., Poly Lactide Carbonate (PLC)) fashioned as a
tissue fixation device or material for orthopedic application
(e.g., a bone graft substitute) can include one or more additives
(e.g., therapeutic agents). The additive(s) can be released as the
device degrades or absorbs in vivo. Alternatively, or in addition,
an additive can diffuse away from an intact device or can be
positioned on the surface of the device so that it exerts an effect
(e.g., an effect on surrounding tissue) after implantation.
Accordingly, an additive may be incorporated throughout the device
(e.g., it may form part of a substantially homogeneous device) or
it may be spatially segregated (e.g., in an inner compartment or on
the device's surface).
[0051] The therapeutic agent can be, or can include, a growth
factor, including growth factors such as those from the fibroblast
growth factor family, transforming growth factor family, or
platelet derived growth factor family that act as chemoattractants
and/or growth stimulators, a hormone such as human growth hormone,
an antibiotic, an antiviral agent, an antifungal agent, an
anti-inflammatory agent, an inflammatory mediator such as an
interleukin, tumor necrosis factor, a prostaglandin, nitric oxide,
an analgesic agent, an osteogenic factor such as a bone
morphogenetic protein, or a matrix molecule such as hyaluronan.
Other agents include angiogenic factors that are materials capable
of directly or indirectly promoting angiogenesis. Examples include
angiogenic peptide growth factors in autologous, xenogenic,
recombinant, or synthetic forms (e.g., a member of the vascular
endothelial growth factor family}. Further examples are blood clot
breakdown products, such as thrombin and heparin including
autologous, allogeneic, xenogeneic, recombinant and synthetic forms
of these materials. Compositions based around butyric acid,
including butyric acid (butanoic acid, C4H80 2) and butyric acid
salts, including sodium, potassium, calcium, ammonium and lithium
salts, a-monobutyrin (l-glycerol butyrate; 1-(2,3 dihydroxypropyl)
butanoate; C7H140 4) and hydroxybutyrate can also be incorporated.
The therapeutic agent can also be a chemotherapeutic, cytotoxic, or
immunotherapeutic agent. For example, the compositions can contain
doxorubicin hydrochloride (Adriamycin), methotrexate with
citrovorum, cisplatin, vincristine, cyclophosphamide, and/or
dacarbazine.
[0052] Where antibiotics are incorporated, the compositions
described herein can be used to treat osteomyelitis and may be
administered prophylactically (e.g., in the event of bone
surgery).
[0053] These therapeutic agents and other additives can be provided
in physiologically acceptable carriers, including within
sustained-release or timed-release formulations. Acceptable
pharmaceutical carriers are well known in the art and are
described, for example, in Remington's Pharmaceutical Sciences (Mac
Publishing Co., A. R. Gennaro Ed.). Carriers are non-toxic to
recipients at the dosages and concentrations employed, and include
diluents, solubilizers, lubricants, suspending agents,
encapsulating materials, solvents, thickeners, dispersants, buffers
such as phosphate, citrate, acetate and other organic acid salts,
anti-oxidants such as ascorbic acid, preservatives, low molecular
weight peptides (e.g., peptides having less than about 10 residues)
such as polyarginine, proteins such as serum albumin, gelatin or an
immunoglobulin, hydrophilic polymers such as
poly(vinylpyrrolindinone), amino acids such as glycine, glutamic
acid, aspartic acid or arginine, monosaccharides, disaccharides,
and other carbohydrates including cellulose or its derivatives,
glucose, man nose or dextrines, chelating agents such as EDT A,
sugar alcohols such as mannitol or sorbitol, counter-ions such as
sodium, and/or non-ionic surfactants such as tween, pluronics, or
polyethyleneglycol (PEG). Moreover, the additives can be linked to
agents that facilitate their delivery. For example, an additive can
be linked to an antibody or antigen-binding fragment thereof,
including a single chain antibody, a growth factor, hormone, or
other ligand that specifically binds a target (e.g., a cell surface
receptor).
[0054] The substances within the compositions can be combined in
any order. For example, the calcium carbonate and PLGA can be
combined before the additive is introduced or all three types of
ingredients (the filler, the copolymer, and the additive) can be
combined at essentially the same time. The additive may be
dissolved in a carrier (including those described above) and
combined with a stabilizer or other agent (e.g., the targeting
agents described above) before it is combined with another
component.
[0055] The amount of additive incorporated into the composition can
vary, but will be a therapeutically effective amount (i.e., an
amount that confers a therapeutic benefit on the subject treated
with the composition). To help preserve the composition, it can be
packaged and stored under conditions in which the activity of the
additive is likely to be preserved (e.g., ambient or cool
temperatures (e.g., 4.degree. C.)).
[0056] Therapeutically effective dosages may be determined by
studies conducted in vitro or in vivo. Determining effective dosage
levels (i.e., the dosage required to achieve a desired result) is
well within the abilities of one of ordinary skill in the art. The
position of the additive within the device and the rate at which it
is released can also be varied to determine an optimal or
acceptable rate of delivery. A typical additive dosage can range
from about 0.001 mg/kg to about 1000 mg/kg, alternatively from
about 0.01 mg/kg to about 100 mg/kg, or from about 0.10 mg/kg to
about 20 mg/kg. The additives may be used alone or in combination
with one another or with diagnostic agents.
[0057] Manufacturing: The filler material (e.g., calcium carbonate)
and, optionally, an additive can be incorporated into the copolymer
by any means known in the art (e.g., mixing, stirring, shaking,
milling, melt blending or any other blending technique). Once
incorporated, the combined materials can be formed into a device
(e.g., a medical device, implant, or prosthesis, such as those
described above). The device can be a tissue fixation device or it
can be a material or device suitable for orthopedic application
(e.g. the compositions described herein can be used as bone graft
substitutes, spinal fusions, bone plates, bone plate screws, and
the like). We may refer to bone substitute materials as "synthetic
bone substitutes." The device can be fabricated by any method that
involves a physical or phase change of the material or its
components in order to form a specific resin, geometry, or product.
For example, a device can be formed by an extrusion process (e.g.,
a single screw, twin screw, disk, ram, or pulltrusion process); a
molding process (e.g., an injection, intrusion, compression, or
thermoforming process); a solvent based process (e.g., mixing or
casting); a welding process (e.g., an ultrasonic or hermetic
process); a polymerization process (e.g., reaction injection
molding, bulk polymerization, and solvent polymerization); or by
other methods (e.g., fiber spinning or electrospinning). Pellets,
powders, or other physical forms of the copolymer (e.g., pellets,
granules, or interlocking shapes) can be coated with powders of the
filler (e.g., calcium carbonate) with blending occurring in an
extruder, which may be employed in the subsequent processing of the
polymer to provide a useful medical device. Such devices include
screws, pins, rods, plates, sutures, suture anchors, staples,
clips, rings, and the like. In the case of a suture, the
construction can produce a monofilament or multifilament suture
(e.g., a braided, twisted, or spun suture made by conventional
techniques such as those described in U.S. Pat. No. 5,019,093).
[0058] When intended for use as a synthetic bone substitute or an
"infilling" item, the compositions can be fashioned into a
paste-like product, which can be readily used to fill bone cavities
or irregularities. The compositions described herein can be used as
synthetic bone substitutes to treat injuries that result from
trauma, surgery, or degenerative conditions that affect bone. Such
substitutes provide an alternative to the use of autologous or
allogeneic bone, and they can provide a matrix to facilitate bone
growth and healing. We mention "infilling" above. The compositions
described herein can be used to fill a donor site when an
autologous bone graft is taken for use in another anatomical
location. More specifically, the compositions described herein can
be used in, or fashioned for use in, joint fusions, fracture
treatment (e.g., fresh and nonunion), revision hip procedures, and
osteotomies.
[0059] In one embodiment, the filler (e.g., a CaC03 powder) can be
added to a solution of the copolymer in an organic solvent, which
is subsequently evaporated. Evaporation of the solvent (e.g.,
chloroform) can be facilitated by stirring or otherwise agitating
the solution. Any residual solvent can then be removed in a vacuum
oven. The sold mixture obtained may then be compression molded at a
temperature at least equal to the softening temperature. The molded
solid items can, if necessary or desired, be machined to a
particular shape (e.g., the shape of a bone fragment they are meant
to replace).
[0060] Compositions (e.g., amorphous compositions) and
polymer-based devices used for medical purposes should also be
sterile. Sterility may be readily accomplished by conventional
methods such as irradiation or treatment with gases or heat, an
electronic beam (e beam), or light (e.g., white light). For
example, the polymer-based compositions described herein can be
sterilized through steam sterilization (e.g., by autoclaving),
treatment with ethylene oxide (EtO) gas, or exposure to radiation
(e.g., y irradiation) (see, e.g., Athanasiou et al., Biomaterials
17:93-102, 1996; Baker et al., J. Biomed. Mat. Res. 46:573-581,
1999; Besong et al., J. Bone Joint Surg. 80-8:340-344, 1998;
Buchanan et al., Biomaterials 20:823-837, 1999; Costa et al.,
Biomaterials 19:659-668, 1998; Dillow et al., Proc. Natl. Acad.
Sci. USA 96:10344-10348, 1999; Gogolewski and Mainii-Varlet,
Biomaterials 17:523-528, 1996; Gogolewski and MainiiVarlet,
Biomaterials 18:251-255, 1997; Kurtz et al., J. Biomed. Mat. Res.
46:112-120, 1999; Kurtz et al., Biomaterials 20:1659-1688, 1999;
Pascaud et al., Biomaterials 18:727-735, 1997; Ratner et al., Eds.,
Biomaterials Science: An Introduction to Materials in Medicine,
Academic Press, pp. 415-420, 1996; and Sauer et al., Biomaterials
17:1929-1935, 1996).
[0061] Steam sterilization is a common form of sterilization that
sterilizes materials by exposing them to high temperature steam
(over about 121 oc), under pressure (about, or more than, two
atmospheres), for about 15-30 minutes. As autoclaving can harm
polymeric biomaterials, an alternate method of sterilization may be
used. As noted, the compositions described herein can also be
sterilized by exposure to EtO gas, which kills microorganisms by
alkylating the amine groups on nucleic acids. To prevent or reduce
toxicity (EtO can attack the same amine groups in humans that it
attacks in microorganisms), materials sterilized with EtO can be
washed (e.g., washed 2-10 times with air) (Kurtz et al.,
Biomaterials 20:1659-1688, 1999 and Ratner et al., Eds., supra).
Radiation (e.g., y radiation) sterilizes materials by ionizing the
nuclei acids of any contaminating microorganisms. A typical
application is of 60Co at 25-40 kGy). If required, more detailed
procedures for sterilizing materials by these methods are readily
available, and one of ordinary skill in the art is easily able to
perform them. Accordingly, the methods of manufacturing a
polymer-based composition (e.g., a PLGA/CaC03 containing
composition) can include the step of sterilizing the
composition.
[0062] Regardless of the precise method by which the compositions
are sterilized, the goal is to remove (or destroy or disable)
living organisms (e.g., bacteria) or other disease-causing agents
(e.g., viruses, fungi, yeast, molds, and prions) from (or within)
the composition. Sterility is generally quantified using the
sterility assurance limit (SAL) and process conditions determined
by performing fractional sterilization runs. The SAL is the
probability that a given implant will remain nonsterile following a
sterilization run, and the accepted minimum value for the SAL is
10-6. At that value, one implant in one million may be
nonsterile.
[0063] Use: The compositions and devices can be used in a wide
variety of situations to treat patients who have experienced an
injury (exemplary tissue fixation devices and materials for
orthopedic application are described above). While human patients
are clearly candidates for treatment, the invention is not so
limited. Veterinary application is also possible (the animals may
be domesticated pets (such as dogs or cats), farm animals (e.g.,
horses, cows, goats, pigs, or sheep), laboratory animals (such as
rodents or non-human primates), or wild animals (e.g., a nonhuman
primate or other mammal (e.g., an animal kept in a zoo>>. The
compositions can also be used in the event of elective surgery,
including cosmetic surgery. The method may be one in which soft
tissue is attached to bone or one in which the primary site of
repair is bone per se. The process can encompass any type of tissue
modification, including tissue repair, reconstruction, remodeling,
and tissue-guided regeneration, including wholly internal processes
as well as processes that include or affect the skin or an orifice
such as the mouth or nose (e.g., the compositions described herein
can be used in dental procedures).
EXAMPLES
Example 1
Poly-dl-lactide-co-glycolide (PDLG) (85:15) with CaC03 or CaS04
[0064] The studies described here were designed to evaluate the
hypothesis that basic fillers such as calcium carbonate and calcium
sulfate delay the degradation rate of amorphous polymers, including
PDLG having about 85% lactide units and 15% glycolide units. We
used dried PDLG 85:15 with an initial intrinsic viscosity (I. V.)
of 1.16. The calcium carbonate and calcium sulfate had a purity of
over 99%.
[0065] To mix the copolymer and filler, we began by dissolving
various components in a solvent. Each of the following were
dissolved in 150 ml chloroform: (1) 15 g of PDLG; (2) 9 g of PDLG
and 6 g of calcium carbonate; and (3) 9 g of PDLG and 6 g of
calcium sulphate. The materials were allowed to dissolve in the
solvent over several hours. The solutions were agitated
periodically and then emptied out onto a glass tray. As the solvent
evaporated, a thin film of mixed polymer and filler formed on the
tray. The film was peeled off the tray and compression molded as
described below. PDLG resin was also compression molded
directly.
[0066] To compression mold the materials, we preheated a
compression molder to 150.degree. C. We placed the mold onto the
lower mold plate, and filled the cavity with approximately 15 grams
of material before inserting it into the compression molder. The
material sat for approximately five minutes or until the polymer
resin began to adhere to itself. We then increased the heat to
approximately 180.degree. C. and let the material sit until a
consistent melt had formed. The top mold plate was placed onto the
bottom mold plate, and the mold clamp was screwed down to compress
the sample. After 10 seconds, we released the pressure to allow
gases to escape, then reapplied the pressure and let sample cure
for 30-60 seconds. The mold was removed, quenched under cold water,
and opened using a rubber mallet. We used a band saw to cut the
disc into parts (0.5''.times.0.75''), which were placed in 100 ml
of a buffer solution at 6rC. Samples were removed from the solution
at time zero and after 1, 2, 4, 7, or 9 days, and dried to constant
weight at 50.degree. C. under vacuum. Mass loss was recorded before
the samples were subjected to GPC analysis. Their thickness was
also measured before and after degradation.
[0067] The percentage mass loss is shown through day five in the
table of FIG. 1, and the loss of molecular weight is presented in
tabular and graphical form in FIGS. 2a and 2b, respectively. The
results clearly demonstrate that the degradation of poly dl lactide
co-glycolide is retarded by the addition of calcium sulphate and
calcium carbonate. This can be seen in both the molecular weight
loss and the mass loss of the polymer. Calcium carbonate was more
effective in slowing the degradation rate than calcium
sulphate.
Example 2
Degradation Studies of Molded Implants
[0068] The purpose of this study was to evaluate
poly(dl-lactide-co-glycolide (85:15)) (PDLG) blended with calcium
carbonate, as a material for bioabsorbable medical devices,
specifically interference screws. We evaluated in vitro degradation
characteristics to determine the effect of calcium carbonate on the
rate of degradation of these polymers in a molded form and assessed
the materials for initial torsional strength.
[0069] The pure polymer was molded following drying using a
standard molding procedure into an interference fixation screw. We
produced filled material by blending calcium carbonate into PDLG.
The weight of the filler, as a percentage of the polymer, was 15,
35, or 50%. The resulting material is designated poly lactide
carbonate (PLC); materials containing 15% calcium carbonate are
designated PLC15; those containing 35% are designated PCL35; and
those containing 50% are designated PLC50. The materials were
molded according to standard molding procedures into an
interference fixation screw and tested for torsional strength. A
pass/fail criteria based on industry specifications was used to
determine if the materials had sufficient torsional strength to be
used as interference screws.
[0070] For in vitro degradation testing, each screw was placed in
phosphate buffered saline (PBS) and maintained at a temperature of
3rC. The incubated samples were assessed for molecular weight, and
for mass loss, at 0, 2, 4, 6, 8, 10, 12, 26, and 52 weeks. The
molecular weight of the degraded samples was analyzed using
chloroform GPC and compared with the starting material to evaluate
degradation during in vitro conditioning.
[0071] The torsional test results shown in FIG. 3 indicate that
that PDLG and PLC15 and PLC35 have acceptable torsional strength.
PLC50 failed this test indicating that the filler level is too high
and this material is not well suited for bio-medical screw
applications.
[0072] The loss in molecular weights, depicted in FIG. 4, clearly
shows the effect of calcium carbonate on the degradation rate. The
rate is slowed down by addition of calcium carbonate. This is
proportional to the mass ratio of the calcium carbonate in the PLC
until 35% is reached. No difference could be seen between PLC35
(35% calcium carbonate) and PLC50 (50% calcium carbonate). Mass
loss data (shown in FIG. 5) also clearly demonstrates the effect of
calcium carbonate on PDLG. Samples of PDLG showed considerable mass
loss (88%) after 10 weeks in vitro. For samples of PLC15, mass loss
began between 12 and 26 weeks in vitro, as 20% massloss was
realized at 26 weeks. No significant mass loss was shown at 26
weeks for samples of PLC35, and PLC50. Samples of all three PLC
blends showed significant mass loss at 52 weeks (70%, 54%, and 30%,
for PLC15, PLC35, and PLC50, respectively). An ASH test was
performed on the degraded materials and, assuming no mass loss was
attributed to calcium carbonate, the materials had all lost nearly
90% of their polymer portion. Our conclusions from this study are
as follows: (1) the degradation rate of poly(dl
lactide-co-glycolide) is too fast for fixation device applications
that require strength retention to 12 weeks; (2) the addition of
calcium carbonate decreases the rate of degradation in proportion
to the amount of calcium carbonate in the polymer until around
35-40% by weight; (3) Initial torsion testing indicated torsion
strength for this design device is below acceptable levels for the
composition with 50% calcium carbonate. Based on these studies, we
considered further analysis of PLC with about 35% calcium
carbonate. This formulation contained enough calcium carbonate to
slow the degradation rate and thereby enhance strength retention,
but not so much calcium carbonate that the initial mechanical
properties of the compositions were compromised.
Example 3
Further Degradation Studies (Strength Retention)
[0073] This study was designed to evaluate the in vitro mechanical
characteristics of a sterilized tibial fixation screw
(7.times.9.times.25 mm) produced from Poly Lactide Carbonate (PLC);
poly-dllactide-coglycolide (85:15) blended with calcium carbonate
65:35 w/w. We evaluated the material for strength retention
characteristics and used poly-1-lactide (PLLA) tibial fixation
screws as controls.
[0074] To test strength retention, we cut saw bone (20 pet) into
cubes (4.times.4.times.4 em) and drilled an 11 mm hole through the
center of each cube. We then cut leather straps (25.5.times.1.5 em)
from standard 1.5 mm thick leather (natural vegetable KIP, grade
A), folded it in half, and inserted it through the hole to form a
loop coming out the other side of the cube. We took care to
position the leather within the hole to ensure the strap followed
the circumference of the hole, forming a channel in the center of
the strap. The screw was then inserted down this channel until the
head of the screw was just below the surface of the saw bone.
[0075] We placed each saw bone block containing a screw and leather
strap into a 500 ml sealed jar filled with PBS, and placed the jar
in a water bath at 37.degree. C. Samples were removed one day, 6,
12, 14, 16, 20, 24 weeks later for mechanical testing. For both the
experimental (PLC) screw and the control (PLLA) screw, ten
replicates were performed at each time point.
[0076] The samples were tested to failure by placing the bone block
under a standard Instron base grip. The loop of the leather was
attached to a hook fixed to the load cell of the Instron and pulled
to failure at 1 mm/second. The results are shown in FIG. 6. No
significant difference (p=0.01) was seen between the two materials
at any of the three time points to 12 weeks. Therefore, mechanical
pull-out testing has shown that screws made from PLC retain
fixation strength comparable to that of screws made from PLLA for
at least 12 weeks.
Example 4
Evaluation of a Tapered Screw in an Ovine Model
[0077] PLC and PLLA screws were implanted directly into the
cancellous bone of the left medial distal femur of an ovine model.
Histology and computed tomography (CT) were performed over time to
assess biocompatibility and bone integration into the screws.
[0078] The histological analysis performed on the PLC screw
revealed new bone formation at all time points examined, starting
with new bone formation and attachment around the margin of the
screw at six and 12 weeks (FIG. 7, left-hand photograph). At 26
weeks the PLC screw was partially integrated with bone (FIG. 7,
center photograph), and at 52 weeks, the screw was replaced with
new bone (FIG. 7, righthand photograph). In contrast, the PLLA
screw was still present and surrounded by fibrous tissue even after
52 weeks implantation. These results indicate that the PLC screw is
osteoconductive. The amount of bone formation increased with time
in the group of animals that received the PLC screw, as the screw
degraded and was replaced by cancellous bone. At one year, the
implant site was fully healed with normal cancellous bone. Even
after this extended period of time, the PLLA screw was fully
present; there was no sign of resorption (FIG. 8). These results
are consistent with our prior studies demonstrating that PLLA
degrades extremely slowly and is not replaced by bone.
[0079] Computed tomography results for the PLC screw showed
extensive bone integration at 26 weeks and new bone formation by 52
weeks. The new bone formation was so extensive that no evidence of
the screw could be seen. These results support our belief that the
PLC screw is osteoconductive. The PLLA screw was still present at
52 weeks in all animals tested (see FIG. 9).
[0080] Macroscopically, the PLC screws were easily seen at 6 and 12
weeks following implantation. It was difficult to identify the PLC
screw after 26 weeks, and it was not possible after 52 weeks due to
the extent of bone integration. We believe the slight swelling of
the PLC screw improves surface-bone contact and closes down
cannulation (see FIG. 10, left-hand photograph). After 26 weeks,
the PLC screw was in the process of being replaced by rapidly
maturing bone (see FIG. 10, right-hand photograph).
[0081] Based on this study, we concluded that: (1) when placed
directly in cancellous bone, the PLC screw was gradually replaced
with normal bone and is, therefore, osteoconductive; (2) PLLA
screws remain present in cancellous bone for at least 52 weeks; (3)
the PLC material is biocompatible (bone attachment was seen at the
earliest time point studied); and (4) the combination of an
amorphous bioabsorbable polymer and calcium carbonate is ideal for
use in devices such as sports medicine fixation devices.
Example 5
In Vivo ACL Study
[0082] A PLC screw was compared to a PLLA interference screw in a
soft tissue ACL model. The screws were placed in the center of a
four-stranded graft, which represents the worst-case scenario for
bone integration, as the screw is fully encapsulated with tendon
tissue (see FIG. 11). This model is unlike many fixation
techniques, where the screw is placed alongside the graft and in
contact with bone that will enhance bone integration.
[0083] Mechanical testing was performed to assess overall repair
strength and failure modes to 12 weeks {n=10). This time point was
chosen because it is well established that graft/tunnel healing and
fixation occurs in approximately four weeks using bone-tendon-bone
(BTB) grafts and before 12 weeks using soft tissue grafts in ACL
repair (Grana et al., Am. J Sports Med. 22:344-351, 1994; Rodeo et
al., J Bone Joint Surg. 75-A:17951803, 1993; Weiler et al.,
Arthroscopy 18:113-123, 2002).
[0084] Histology and CT were used to assess biocompatibility,
tendon-bone integration and bone formation. These tests were
performed at 6, 12, 26, and 52 weeks following implantation, with
six replicates at each time point.
[0085] We did not observe any difference in mechanical properties
of the repaired ACL in animals treated with the PLC screw and
animals treated with the PLLA interference screws (the results
obtained at 12 weeks are shown in the graph of FIG. 12).
[0086] Our histological analysis demonstrated that, within one
year, the PLC screw was replaced by bone, and the material also
stimulated bone formation in the tendon graft within the tunnel.
FIG. 13 illustrates the stimulating effect the PLC screw has on the
surrounding graft tissue. Ossification of the graft can clearly be
seen in the tunnel containing the PLC screw, but no ossification
was seen around the PLLA screw. Ossification was stimulated in the
PLC-repaired graft by 26 weeks and both the PLC screw and the
surrounding ACL graft were ossified by 52 weeks (FIG. 13). New bone
formation was noted within the tendon graft in only the PLC-treated
group. The PLLA screw remained intact and inert at 52 weeks (FIG.
14).
[0087] The PLC screw also stimulated the ossification of the tendon
graft away from the screw position but still within the tunnel.
This ossification was not seen in animals treated with the PLLA
screw (FIG. 14). Thus, our histological analyses support the
hypotheses that the PLC screw is replaced by bone when placed in an
osseous site; is an osteoconductive material; and actively
stimulates ossification of the tendon graft within the bone
tunnel.
[0088] CT was performed to examine bone formation with the bone
tunnel for both the PCL and PLLA screws. The PLLA screws were
present at all time points examined with no demonstrable in vivo
resorption. The PLC screws were replaced by bone and bone formation
was noted throughout the tunnel within the graft indicating the
bone stimulating effect of PLC. CT sections in three planes,
showing the progression of bone integration in both the graft and
screw domains are shown in FIG. 15.
[0089] These studies support the following conclusions: (1) PLC
screws are biocompatible and exhibit fixation strength equivalent
to the PLLA screws {both providing adequate mechanical fixation
until healing had occurred); (2) the PLC material was
osteoconductive, facilitating in-growth of bone into the implant
material; and (3) the PLC screws actively stimulated bone formation
with a tendon graft that was present in the bone tunnel. Further,
the intra-articular portion of the graft, articular cartilage and
synovium was normal throughout the study for both PLC-treated and
PLLA-treated animals. Thus, the PLC screws are useful as a healing
material and may be ideal for use in interference screws used for
ACL reconstruction.
Example 6
In Vivo ACL Study
[0090] The formulation, broadly classified as a composite, is
composed of a polymer and ceramic filler. Two polymers, poly
1-lactide-co-glycolide 85:15 (PLG) and poly 1-lactide:d,l-lactide
70:30 (PLDL), were separately blended into the same percentage of
ceramics. The ceramic portion of the formulation is composed of two
different ratios of tricalcium phosphate (TCP) and calcium
sulphate.
[0091] Within the total formulation, the polymer is at a loading
level of 65% and the ceramics are at a loading level of 35%. One
formulation has 65% poly l lactide:coglycolide 85:15, 20% calcium
sulphate, and 15% tricalcium phosphate. The other formulation is
composed of 65% poly 1-lactide:d,l-lactide 70:30, 20% calcium
sulphate, and 15% tricalcium phosphate (note: all percentages are
weight-percentages).
Example 7
In Vitro Degradation Study the Comparing Suture Anchors Made from
the Formulation of Poly L Lactide-Co-Glycolide, Calcium Sulphate,
Tricalclum Phosphate [PLG (85/15), Ca504, TCP 65:20:15] with a
Commercialized Suture Anchor, the LUPINE BR
[0092] To evaluate the fixation strength, molecular weight and mass
loss during in vitro degradation of poly llactide-co-glycolide,
calcium sulphate, tricalcium phosphate [PLG (85/15), CaS04, TCP
65:20:15] also called the Osteoraptor 2.3, and Lupine BR
instability suture anchors (control) at 3JOC.
[0093] Each anchor was inserted into the prepared holes of a
polyurethane block using the appropriate instrumentation and
technique recommended for respective suture anchor. Each bone block
with inserted anchor and was placed in a plastic jar and filled
with phosphate buffered saline. The jar was then be placed in an
oven at 3JOC and samples removed at the following time points of 0,
6, 12, 18, 26 weeks for mechanical testing. The Osteoraptor suture
anchor was additionally tested at the following time points, 2, 4,
8, 10, 14, 16, 20, 24 weeks. The sample number was nine. The suture
anchors was mechanically evaluated on the electromechanical testing
machine and the molecular weight will also be determined at each
time point.
[0094] The peak load of the suture anchors was evaluated over
twenty-six weeks. Results showed that within twenty-six weeks the
fixation strength of the Osteoraptor 2.3 suture anchor increased
79%. It was shown that the twenty-six week results were
significantly greater (p-value <0.05) than baseline results. At
thirty-nine weeks the peak load decreased, but was statistically
equivalent (p-value=0.940) to baseline results. The results were
analyzed by a two student t-test with 95% confidence intervals. The
Lupine BR suture anchor was stable from baseline to eighteen weeks
with a slight decline by week twenty-six and an increase at
thirty-nine weeks. (Error! Reference source not found. FIG. 16)
[0095] The molecular weight of the Osteoraptor 2.3 and Lupine BR
suture anchor was also evaluated over fifty-two weeks. It was shown
that the initial weight average molecular weight of the Advanced
Osteoraptor 2.3 suture anchor was lower than the Lupine BR suture
anchor. However, between six and twelve weeks similar values were
reached. The values continued to decline, when the formal
mechanical evaluation ceased, through twenty-six weeks and at
thirty-nine weeks. At fifty-two weeks the overall Osteoraptor 2.3
suture anchor weight average molecular weight loss was 93.3%, while
the Lupine BR loss was 97.6%.
Example 8
Summary of the Histological Evaluation of Specimens from Resorbable
Screw Study 6, 12 and 18-Month Post-Implantation
[0096] The objective of this animal study was to evaluate a new
bioresorbable material molded into screws compared to empty defect
in an ovine direct-in-bone model. An empty defect control was used
as to demonstrate the critical size nature of the defect in this
model. Screws (9.times.1 Omm) were manufactured to the out of the
formulation of poly l lactide-co-glycolide, calcium sulphate,
p-tricalcium phosphate [PLG (85/15), CaS04, TCP 65:20:15].
[0097] The ovine direct-in-bone model is bilateral; each leg
received an implant in the distal medial femur and proximal medal
tibia for a total of 4 implantation sites per animal. An
8.5.times.9 mm defect was created in each site and either filled
with a 9.times.10 mm implant or left empty. Implants were left 1 mm
proud to the surrounding bone. A 1.5 mm fully threaded,
self-tapping cortical screw was inserted approximately 1-1.5 cm
caudal to each implant to mark placement for histological
preparation. Each time point sample size was 6 animals. Twenty-four
adult Merino whethers underwent surgery without complication and
with adequate pain management.
[0098] All animals survived until their respective time points were
reached. They were sacrificed at 6, 12, and 18 months and were
noted to have unremarkable necropsies. Samples were collected and
were processed for histological analysis.
Histology Summary
6 Months
[0099] The screws were intact and had retained their shape. Surface
has an uneven appearance and may be due to slight expansion of the
screws. Bone was visible penetrating into the thread of the screw
and in contact with the surface. Minimal fibrous tissue is evident
at the screw/bone interface. Minimal cellular reaction to the
screws was noted. Empty defects were all noted to have new bone
growth, with bridging across the gap at the cortical surface.
12 Months
[0100] The majority of the implants were highly fragmented. Ceramic
particles were evident. There was evidence of bone growth into the
threads of most of the specimens.
[0101] In the empty group, two of the defects had entered the
medullary cavity and in the remaining specimens repair had not
progressed. Although new bone growth was evident at the cortical
surface, large spaces filled with marrow were noted deeper in the
defect.
18 Months
[0102] The majority of the screws were degraded and what remained
was highly fragmented. In areas of the defect the fragments had
become enveloped by new bone growth. New bone growth tended to
occur at the periphery of the defect whereas at the surface, and
extending deeper into the central aspect of the defect, fibrous
tissue was evident. Empty defects were difficult to identify in
tibial sites, but voids in femoral sites were noted in a few
samples.
[0103] Histomorphometry analysis noted that there was an increase
in new bone growth surrounding the screw, which was still present
at 6 months. At this time, this new bone growth around the screw
averaged about 14.3%. The empty defect averaged at 18.5% new bone
growth. At 12 months, new bone surrounding the screw material as it
started to degrade averaged about 16%. At 18 months, bone in-growth
into the defect site was noted with about 24.3% new bone formation,
which is nearly a 2-fold increase from the 6 month data. The empty
defects tended not to heal.
CONCLUSIONS
[0104] PLG (85/15), CaS04, TCP 65:20:15 bioabsorbable screws when
placed in bone degraded slowly over an 18 month time period. By the
18 month time point the defect, where the implant had been present,
was slowly being ingrown with bone. Example 9: In vivo Study
Summary: Evaluation of a new suture anchor in an ovine patellar
tendon reattachment model
[0105] The objective of this animal study was to evaluate a new
bioresorbable material molded into suture anchors and compare to
results from a previous study. Suture anchors were manufactured to
the 2.3 mm BIORAPTOR design out of poly-Llactide-co-glycolide,
calcium sulphate, and tricalcium phosphate (PLG/CSffCP). The
control group used from the previous study was composed of
Poly-L-lactide (PLLA).
[0106] The ovine patellar-tendon reattachment model utilizes an
external fixator to immobilize the stifle (knee) joint of the sheep
over a 3-week period relieving a reattached major extensor tendon,
the patellar tendon, time to heal and regain adequate strength.
Once the fixator was placed, each of 10 sheep had surgery that
sharply dissected the patellar tendon and reattached it to the
decorticated tibial tuberosity utilizing two anchors. There were 5
sheep in each material group. All sheep survived the surgery
without complication for the 3-week period while in fixators. The
animals had no surgery-related complications up to the 12 week time
point.
[0107] Animals at time of sacrifice were noted to have unremarkable
necropsies. Common findings for groups were small patella-femoral
lesions from the K-wire penetrating the joint. No evidence of
arthritic change was present in this joint, the femorotibial joint,
or the patellar tendon enthesis grossly. Four animals were noted to
have a minor reduction in range-of-motion. Histology was performed
on mechanically tested samples (FIGS. 18-20). Tissue reactions
showed minimal reactivity. Mechanically, the PLG/CS/ITCP had higher
failure strengths to the historical control from the previous
study. Repairs using PLG/CS/TCP anchors in fact had significantly
higher failure strength than those made of PLLA (FIG. 21).
* * * * *