U.S. patent application number 17/219763 was filed with the patent office on 2021-07-22 for kits for preparing a reactive graft material and injecting the graft material into a patient.
This patent application is currently assigned to Agnovos Healthcare, LLC. The applicant listed for this patent is Agnovos Healthcare, LLC. Invention is credited to Katie Harrigan, Jamie MacDougall, Jon P. Moseley.
Application Number | 20210220514 17/219763 |
Document ID | / |
Family ID | 1000005492973 |
Filed Date | 2021-07-22 |
United States Patent
Application |
20210220514 |
Kind Code |
A1 |
Moseley; Jon P. ; et
al. |
July 22, 2021 |
KITS FOR PREPARING A REACTIVE GRAFT MATERIAL AND INJECTING THE
GRAFT MATERIAL INTO A PATIENT
Abstract
Disclosed are kits for preparing a reactive graft material and
injecting the graft material into a patient. Kits may include a
first syringe containing a first powdered component and a second
syringe containing a second powdered component that is reactive
with the first powdered component when the first and second
powdered components are dispersed in a diluent solution. The kits
may further include a vial sealed by a septum and containing the
diluent solution. A syringe connector may be included that has a
connector at each end configured to make a fluidic connection to,
respectively, the first syringe and the second syringe, and also
comprises a passageway adapted to allow fluid to pass between the
syringes when the syringes are both fluidically connected to the
syringe connector. A vial adapter comprising a connector adapted
for fluidically connecting to at least one of the first syringe and
the second syringe, a passageway adapted to allow fluid to pass
from the vial into a syringe fluidically connected to the connector
of the vial adapter, and a spike in fluidic communication with the
passageway of the vial adapter may be included. The spike is
adapted for piercing the septum of the vial. Certain kits also
contain one or more needles for delivery of the graft material to a
site within a body of a patient.
Inventors: |
Moseley; Jon P.; (Alrington,
TN) ; MacDougall; Jamie; (Oakland, TN) ;
Harrigan; Katie; (Cordova, TN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Agnovos Healthcare, LLC |
Rockville |
MD |
US |
|
|
Assignee: |
Agnovos Healthcare, LLC
Rockville
MD
|
Family ID: |
1000005492973 |
Appl. No.: |
17/219763 |
Filed: |
March 31, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15238130 |
Aug 16, 2016 |
10973949 |
|
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17219763 |
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|
14568773 |
Dec 12, 2014 |
9446170 |
|
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15238130 |
|
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62031635 |
Jul 31, 2014 |
|
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61915837 |
Dec 13, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 2400/06 20130101;
A61L 27/3608 20130101; A61L 27/56 20130101; C04B 28/14 20130101;
A61L 2300/112 20130101; C04B 2111/00836 20130101; A61L 27/025
20130101; A61L 2300/414 20130101; A61L 27/12 20130101; A61L 27/58
20130101; A61L 24/0015 20130101; A61L 2430/02 20130101; A61L
2300/10 20130101; A61L 2300/102 20130101; C04B 28/34 20130101; A61L
27/3821 20130101; A61L 27/3641 20130101; A61L 27/54 20130101; A61L
24/02 20130101; A61L 27/3847 20130101 |
International
Class: |
A61L 27/12 20060101
A61L027/12; C04B 28/34 20060101 C04B028/34; A61L 24/02 20060101
A61L024/02; A61L 27/02 20060101 A61L027/02; A61L 27/36 20060101
A61L027/36; A61L 27/54 20060101 A61L027/54; A61L 27/56 20060101
A61L027/56; A61L 27/58 20060101 A61L027/58; A61L 24/00 20060101
A61L024/00; C04B 28/14 20060101 C04B028/14; A61L 27/38 20060101
A61L027/38 |
Claims
1. A kit for preparing a reactive graft material and injecting the
graft material into a patient, comprising: a first syringe
containing a first powdered component; a second syringe containing
a second powdered component that is reactive with the first
powdered component when the first and second powdered components
are dispersed in a diluent solution; a vial containing the diluent
solution and sealed by a septum; a syringe connector that includes
a connector at each end configured to make a fluidic connection to,
respectively, the first syringe and the second syringe, and also
comprises a passageway adapted to allow fluid to pass between the
syringes when the syringes are both fluidically connected to the
syringe connector; a vial adapter comprising a connector adapted
for fluidically connecting to at least one of the first syringe and
the second syringe, a passageway adapted to allow fluid to pass
from the vial into a syringe fluidically connected to the connector
of the vial adapter, and a spike in fluidic communication with the
passageway of the vial adapter, wherein the spike is adapted for
piercing the septum of the vial; and one or more needles for
delivery of the graft material to a site within a body of a
patient.
2. The kit of claim 1, wherein the connectors at each end of the
syringe connector are threaded connectors.
3. The kit of claim 2, wherein the connector of the vial adapter is
a threaded connector.
4. The kit of claim 1, further comprising at least two needles.
5. The kit of claim 4, wherein the at least two needles comprise
needles that differ from one another in length and/or gauge.
6. The kit of claim 4, wherein at least one needle is a Jamshidi
needle.
7. The kit of claim 6, wherein each of the one or more needles is a
Jamshidi needle.
8. The kit of claim 6, comprising an 11-gauge Jamshidi needle of a
first length and a 16-gauge Jamshidi needle of a second, shorter
length.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 15/238,130, filed Aug. 16, 2016, which is a
continuation of U.S. patent application Ser. No. 14/568,773, filed
Dec. 12, 2014, which application claims priority to U.S.
Provisional Patent Application Nos. 61/915,837, filed Dec. 13, 2013
and 62/031,635, filed Jul. 31, 2014, the disclosures of which are
incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] The invention is directed to a kit for preparing a reactive
graft material and injecting the graft material into a patient,
and, more specifically, a kit containing syringes containing
reactive graft materials, syringe connectors, a vial containing a
liquid diluent, a vial connector, and optionally needles.
BACKGROUND OF THE INVENTION
[0003] Defects in bone structure arise in a variety of
circumstances, such as trauma, disease, and surgery. There is a
need for effective repair of bone defects in various surgical
fields, including maxillo-craniofacial, periodontics, and
orthopedics. Numerous natural and synthetic materials and
compositions have been used to stimulate healing at the site of a
bone defect. As with compositions used to repair other types of
tissue, the biological and mechanical properties of a bone repair
material are critical in determining the effectiveness and
suitability of the material in any particular application.
[0004] After blood, bone is the second most commonly transplanted
material. Autologous cancellous bone has long been considered the
most effective bone repair material, since it is both
osteoinductive and non-immunogenic. However, adequate quantities of
autologous cancellous bone are not available under all
circumstances, and donor site morbidity and trauma are serious
drawbacks to this approach. The use of allograft bone avoids the
problem of creating a second surgical site in the patient, but
suffers from some disadvantages of its own. For instance, allograft
bone typically has a lower osteogenic capacity than autograft bone,
a higher resorption rate, creates less revascularization at the
site of the bone defect, and typically results in a greater
immunogenic response. The transfer of certain diseases is also a
danger when using allografts.
[0005] To avoid the problems associated with autograft and
allograft bone, considerable research has been conducted in the
area of synthetic bone substitute materials that can be used in
lieu of natural bone. For example, various compositions and
materials comprising demineralized bone matrix, calcium phosphate,
and calcium sulfate have been proposed.
[0006] Cements comprising calcium sulfate have a long history of
use as bone graft substitutes. Modern surgical grade calcium
sulfate cements offer high initial strength, good handling
properties, and are consistently replaced by bone in many
applications. However, calcium sulfate cements are characterized by
relatively rapid resorption by the body, which can be undesirable
in certain applications.
[0007] Hydroxyapatite is one of the most commonly used calcium
phosphates in bone graft materials. Its structure is similar to the
mineral phase of bone and it exhibits excellent biocompatibility.
However, hydroxyapatite has an extremely slow resorption rate that
may be unsuitable in certain applications. Other calcium phosphate
materials have also been used in the art, such as .beta.-tricalcium
phosphate, which exhibits a faster resorption rate than
hydroxyapatite, but has less mechanical strength. Certain calcium
phosphate materials that set in situ have also been attempted, such
as mixtures of tetracalcium phosphate and dicalcium phosphate
anhydrate or dihydrate, which react to form hydroxyapatite when
mixed with an aqueous solution.
[0008] The presently available synthetic bone repair materials do
not present ideal functional characteristics for all bone graft
applications. As noted above, some compositions exhibit a
resorption rate that is either too slow or too rapid. Further, many
bone graft cements are difficult to implant because they fail to
set or cannot be injected. Other drawbacks are inadequate strength
and difficulty in adding biologically active substances for
controlled release. Furthermore, certain bone graft cements
developed to address these concerns fail to completely set (harden)
in the presence of particular additives. For these reasons, there
remains a need in the art for bone graft cement compositions that
combine a desirable resorption rate with high mechanical strength,
ease of handling, osteoconductivity, and workable set time even in
the presence of additives.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention provides a particulate composition
adapted for forming a bone graft substitute cement upon mixing with
an aqueous solution, as well as a hardened bone graft substitute
cement made therefrom. The invention also relates to kits
comprising the particulate composition, and methods of making and
using the composition. In some embodiments, the particulate
composition of the invention comprises a calcium sulfate
hemihydrate powder in combination with calcium phosphate granules
with a porous morphology, and typically also in combination with a
brushite-forming calcium phosphate mixture. Upon mixing the
particulate composition with an aqueous mixing solution, a hardened
triphasic cement comprising brushite and calcium sulfate dihydrate
is typically formed. The calcium sulfate dihydrate provides good
mechanical strength and, due to its relatively fast resorption
rate, is rapidly replaced with bone tissue in the resulting cement,
while the brushite serves to reduce the overall resorption rate of
the cement as compared to a cement composition solely comprising
calcium sulfate dihydrate. Certain embodiments of the bone
substitute cement of the invention exhibit high mechanical
strength, such as high compressive strength and diametral tensile
strength, set into a hardened composition within a reasonable
period of time, facilitate development of high quality bone at the
site of the bone defect, and exhibit acceptable handling
characteristics. In certain embodiments, the bone substitute cement
of the invention is capable of hardening and setting in the
presence of biological additives.
[0010] In one aspect of the present invention is provided a
particulate composition adapted for forming a bone graft substitute
cement upon mixing with an aqueous solution, comprising: i) a
calcium sulfate hemihydrate powder, wherein the calcium sulfate
hemihydrate is present at a concentration of at least about 50
weight percent based on the total weight of the particulate
composition; ii) a monocalcium phosphate monohydrate powder; iii) a
non-porous .beta.-tricalcium phosphate powder; and iv) a porous
.beta.-tricalcium phosphate powder.
[0011] The calcium sulfate hemihydrate can be, for example,
.alpha.-calcium sulfate hemihydrate. In certain embodiments, the
calcium sulfate hemihydrate is present at a concentration of at
least about 70 weight percent based on the total weight of the
particulate composition. The calcium sulfate hemihydrate can, in
certain embodiments, have a bimodal particle distribution. The
calcium sulfate hemihydrate may have a median particle size of
about 5 microns to about 20 microns, for example. In some
embodiments, the calcium sulfate hemihydrate has a bimodal particle
distribution comprising about 30 to about 60 volume percent of
particles having a mode of about 1.0 to about 3.0 microns and about
40 to about 70 volume percent of particles having a mode of about
20 to about 30 microns, based on the total volume of the calcium
sulfate hemihydrate powder.
[0012] The porous .beta.-tricalcium phosphate powder can be
present, for example, at a concentration of between about 5 and
about 15 weight percent. In some embodiments, the porous
.beta.-tricalcium phosphate powder exhibits a bimodal particle size
distribution. For example, in certain embodiments, the porous
.beta.-tricalcium phosphate powder comprises less than 50% by
weight of particles having a particle size up to about 63 microns
and greater than 50% by weight of particles having a particle size
greater than about 63 microns. In certain embodiments, the porous
.beta.-tricalcium phosphate powder comprises about 25% by weight of
particles having a particle size up to about 63 microns and about
75% by weight of particles having a particle size greater than
about 63 microns.
[0013] In certain embodiments, the pore sizes of the porous
.beta.-tricalcium phosphate powder are in the range of about 100
microns to about 400 microns. The porous .beta.-tricalcium
phosphate powder can, in some embodiments, be characterized by an
interconnected, multidirectional porosity. The porosity of the
porous .beta.-tricalcium phosphate powder can vary and, in some
embodiments, the porous .beta.-tricalcium phosphate powder can have
a total porosity of at least about 50%.
[0014] The non-porous .beta.-tricalcium phosphate powder can have,
for example, a median particle size of less than about 20 microns.
In some embodiments, the non-porous .beta.-tricalcium phosphate
powder has a bimodal particle size distribution comprising about 30
to about 70 volume percent of particles having a mode of about 2.0
to about 6.0 microns and about 30 to about 70 volume percent of
particles having a mode of about 40 to about 70 microns based on
the total volume of the non-porous .beta.-tricalcium phosphate
powder. In some embodiments, the .beta.-tricalcium phosphate powder
has a bimodal particle size distribution comprising about 50 to
about 65 volume percent of particles having a mode of about 4.0 to
about 5.5 microns and about 35 to about 50 volume percent of
particles having a mode of about 60 to about 70 microns based on
the total volume of the non-porous .beta.-tricalcium phosphate
powder.
[0015] Various other components can be incorporated within the
compositions described herein. For example, in some embodiments,
the particulate composition can further comprise non-porous
.beta.-tricalcium phosphate granules having a median particle size
of at least about 75 microns (e.g., having a median particle size
of about 75 to about 1,000 microns). The non-porous
.beta.-tricalcium phosphate granules can be, for example, present
at a concentration of up to about 20 weight percent based on the
total weight of the particulate composition or present at a
concentration of up to about 12 weight percent based on the total
weight of the particulate composition.
[0016] The particulate composition can, in some embodiments,
further comprise an accelerant adapted for accelerating the
conversion of calcium sulfate hemihydrate to calcium sulfate
dihydrate. For example, the accelerant can be selected from the
group consisting of calcium sulfate dihydrate particles, potassium
sulfate particles, and sodium sulfate particles, wherein the
accelerant is optionally coated with sucrose. In some embodiments,
the accelerant may be present at a concentration of up to about 1
weight percent based on the total weight of the particulate
composition.
[0017] In one specific embodiment is provided a particulate
composition adapted for forming a bone graft substitute cement upon
mixing with an aqueous solution, comprising: i) a calcium sulfate
hemihydrate powder having a bimodal particle distribution and a
median particle size of about 5 to about 20 microns, wherein the
calcium sulfate hemihydrate is present at a concentration of at
least about 70 weight percent based on the total weight of the
particulate composition; ii) a monocalcium phosphate monohydrate
powder; iii) a non-porous .beta.-tricalcium phosphate powder having
a median particle size of less than about 20 microns, the
monocalcium phosphate monohydrate powder and the non-porous
.beta.-tricalcium phosphate powder being present at a combined
concentration of about 3 to about 20 weight percent based on the
total weight of the particulate composition; iv) non-porous
.beta.-tricalcium phosphate granules having a median particle size
of at least about 75 microns and present at a concentration of up
to about 20 weight percent based on the total weight of the
particulate composition; v) porous .beta.-tricalcium phosphate
powder, in an amount of up to about 15 weight percent based on the
total weight of the particulate composition; and vi) an accelerant
adapted for accelerating the conversion of calcium sulfate
hemihydrate to calcium sulfate dihydrate, the accelerant being
present at a concentration of up to about 1 weight percent based on
the total weight of the particulate composition.
[0018] In another specific embodiment is provided a particulate
composition adapted for forming a bone graft substitute cement upon
mixing with an aqueous solution, comprising: i) an
.alpha.-calciumsulfate hemihydrate powder having a bimodal particle
distribution and a median particle size of about 5 to about 20
microns, wherein the calcium sulfate hemihydrate is present at a
concentration of at least about 70 weight percent based on the
total weight of the particulate composition, and wherein the
calcium sulfate hemihydrate powder has a bimodal particle
distribution comprising about 30 to about 60 volume percent of
particles having a mode of about 1.0 to about 3.0 microns and about
40 to about 70 volume percent of particles having a mode of about
20 to about 30 microns, based on the total volume of the calcium
sulfate hemihydrate powder; ii) a monocalcium phosphate monohydrate
powder; iii) a .beta.-tricalcium phosphate powder having a median
particle size of less than about 20 microns, the monocalcium
phosphate monohydrate powder and the .beta.-tricalcium phosphate
powder being present at a combined concentration of about 3 to
about 20 weight percent based on the total weight of the
particulate composition; iv) .beta.-tricalcium phosphate granules
having a median particle size of about 100 to about 400 microns and
present at a concentration of up to about 12 weight percent based
on the total weight of the particulate composition; v) porous
.beta.-tricalcium phosphate powder, in an amount of up to about 15
weight percent based on the total weight of the particulate
composition, wherein the porous .beta.-tricalcium phosphate powder
comprises less than 50% by weight of particles having a particle
size up to about 63 microns and greater than 50% by weight of
particles having a particle size greater than about 63 microns; and
vi) an accelerant adapted for accelerating the conversion of
calcium sulfate hemihydrate to calcium sulfate dihydrate, the
accelerant being present at a concentration of up to about 1 weight
percent based on the total weight of the particulate
composition.
[0019] The particulate compositions described herein can, in some
embodiments, further comprise a biologically active agent.
Exemplary biologically active agents that can be useful in the
compositions include, but are not limited to, the group consisting
of cancellous bone chips, growth factors, antibiotics, pesticides
(e.g., antifungal agents and antiparasitic agents),
chemotherapeutic agents, antivirals, analgesics, and
anti-inflammatory agents. In some embodiments, the optional
biologically active agent comprises bone marrow aspirate. In some
embodiments, the optional biologically active agent comprises a
growth factor selected from the group consisting of fibroblast
growth factors, platelet-derived growth factors, bone morphogenic
proteins, osteogenic proteins, transforming growth factors, LIM
mineralization proteins, osteoid-inducing factors, angiogenins,
endothelins; growth differentiation factors, ADMP-1, endothelins,
hepatocyte growth factor and keratinocyte growth factor,
heparin-binding growth factors, hedgehog proteins, interleukins,
colony-stimulating factors, epithelial growth factors, insulin-like
growth factors, cytokines, osteopontin, and osteonectin.
[0020] The properties of the particulate compositions described
herein upon mixing with an aqueous solution can vary. For example,
in some embodiments, the particulate composition has a Vicat set
time upon mixing with an aqueous solution of about 3 to about 8
minutes. In some embodiments, the particulate composition has a
Gillmore set time upon mixing with an aqueous solution of about 6
to about 20 minutes.
[0021] In another aspect of the invention is provided a bone graft
substitute cement comprising the reaction product formed by mixing
a particulate composition as described herein with an aqueous
solution, the reaction product comprising calcium sulfate
dihydrate, brushite, and a porous .beta.-tricalcium phosphate
component. In some embodiments, the bone graft substitute cement
can further comprise non-porous .beta.-tricalcium phosphate
granules. The cement can, in some embodiments, be cast in a
predetermined shape (e.g., including, but not limited to, a pellet,
granule, wedge, block, or disk). The makeup of the aqueous solution
with which the particulate compositions are mixed can vary. For
example, in some embodiments, the aqueous solution comprises a
carboxylic acid (e.g., including, but not limited to, a hydroxy
carboxylic acid, such as glycolic acid). In some embodiments, the
carboxylic acid can be neutralized to a pH of about 6.5 to about
7.5. In certain embodiments, the aqueous solution further comprises
sodium chloride. For example, in some embodiments, the aqueous
solution comprises both a carboxylic acid and sodium chloride.
[0022] In another aspect of the present invention is provided a
bone graft substitute kit, comprising one or more containers
enclosing a particulate composition as described herein, a separate
container enclosing a sterile aqueous solution, and a written
instruction set describing a method of using the kit. The bone
graft substitute kit may optionally further comprise a mixing
apparatus adapted for mixing the particulate composition and the
aqueous solution. The bone graft substitute kit may optionally
further comprise a delivery device adapted for delivering a bone
graft substitute cement mixture to the site of a bone defect, such
as a Jamshidi needle. In certain embodiments, a portion of the
particulate composition is enclosed in a first syringe and a
portion of the particulate composition is enclosed in a second
syringe, and the kit further includes a syringe connector adapted
to connect the first and second syringe such that the contents of
each syringe can be mixed. In still further embodiments, the kit
includes at least one syringe containing at least a portion of the
particulate composition and a vial adaptor adapted to connect the
syringe to the container enclosing the sterile aqueous
solution.
[0023] In a still further aspect of the invention is provided a
method for treating a bone defect, comprising applying a bone graft
substitute cement as described herein to the site of the bone
defect.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Having thus described the invention in general terms,
reference will now be made to the accompanying drawings,
wherein:
[0025] FIG. 1 is a graph comparing the ejective force of an
inventive bone graft cement composition and a control
composition;
[0026] FIG. 2 is a graph comparing the diametral tensile strength
of an inventive bone graft cement composition and a control
composition;
[0027] FIG. 3 is a graph comparing the daily accelerated in vitro
dissolution properties of an inventive bone graft cement
composition and a control composition;
[0028] FIG. 4 is an example of a bone graft substitute kit of the
present invention; and
[0029] FIG. 5 illustrates a method of preparing a bone graft
substitute composition using the kit of FIG. 4.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present inventions now will be described more fully
hereinafter with reference to the accompanying drawings. The
invention may be embodied in many different forms and should not be
construed as limited to the embodiments set forth herein; rather,
these embodiments are provided so that this disclosure will satisfy
applicable legal requirements. As used in this specification and
the claims, the singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise.
[0031] The present invention provides a particulate composition
useful as a bone graft substitute cement that hardens or sets upon
mixing with an aqueous solution.
[0032] Advantageously, the particulate composition can provide a
bone graft substitute cement with a set time that is faster than
certain other commercially available bone graft substitute cements.
The particulate composition includes a calcium sulfate hemihydrate
(hereinafter "CSH") powder, a porous .beta.-tricalcium phosphate
(hereinafter ".beta.-TCP") component, and optionally a
brushite-forming calcium phosphate mixture comprising monocalcium
phosphate monohydrate (hereinafter "MCPM") powder and a non-porous
.beta.-TCP powder. Certain components useful according to the
present invention are described in U.S. Pat. Nos. 8,025,903 and
7,754,246 to Moseley et al. and U.S. Patent Application Publication
No. 2007/0128248 to Moseley et al., which are all incorporated
herein by reference.
[0033] Use of the particulate composition of the invention produces
a bone graft substitute cement comprising calcium sulfate dihydrate
(hereinafter "CSD"), which is the product of the reaction between
CSH and water. The CSD component of the cement confers good
mechanical strength to the cement, stimulates bone growth, and
provides a relatively fast resorption rate in vivo, such that a
porous structure in the cement is quickly created upon
implantation. Thus, the CSD component of the cement can be rapidly
replaced with bone tissue ingrowth into the implant site.
[0034] Certain preferred components of the composition (e.g., MCPM,
non-porous .beta.-TCP granules, and/or non-porous .beta.-TCP
powder) can react, at least in part, to form brushite upon mixing
with an aqueous solution. The presence of the brushite in the
cement slows the resorption rate of the bone graft substitute
cement as compared to a cement comprising CSD only. Thus, the bone
graft substitute cement of the invention provides a triphasic
resorption defined by the CSD component, the TCP component and the
brushite component.
[0035] In addition to a relatively slow resorption rate,
embodiments of the particulate composition of the invention can
provide a bone graft substitute cement that exhibits high
mechanical strength, good handling characteristics, and a
reasonable setting time, particularly a setting time that is
somewhat faster than certain other commercially available bone
graft substitute cements. Additionally, certain embodiments of the
bone graft substitute cement of the invention are capable of
producing high quality bone when used to treat bone defects.
Furthermore, certain embodiments described herein are uniquely able
to set in the presence of biologically active agents.
[0036] The CSH powder used in the present invention preferably has
a bimodal particle distribution. As understood in the art, a
bimodal particle distribution refers to a particle distribution
characterized by two peaks in a plot of particle size vs. the
volume percentage of particles of each size. In a preferred
embodiment, the bimodal particle distribution of the CSH powder is
characterized by about 30 to about 60 volume percent of particles
having a mode of about 1.0 to about 3.0 microns and about 40 to
about 70 volume percent of particles having a mode of about 20 to
about 30 microns, based on the total volume of the CSH powder. In
yet another embodiment, the bimodal particle distribution comprises
about 40 to about 60 volume percent of particles having a mode of
about 1.0 to about 2.0 microns and about 40 to about 60 volume
percent of particles having a mode of about 20 to about 25 microns.
The median particle size of the CSH powder is preferably about 5 to
about 20 microns, more preferably about 8 to about 15 microns, and
most preferably about 10 to about 15 microns.
[0037] As used herein, "median particle size" refers to the
particle size that divides a population of particles in half such
that half of the volume of particles in the population is above the
median size and half is below. Median particle size is measured
using linear interpolation of data acquired through a high
resolution laser diffraction method. More specifically, the laser
diffraction method is performed with parallel light with a constant
frequency of 632.8 nanometers and which exhibits 5 milliwatts of
power. Measurements of laser diffraction are acquired through a 32
channel detector array. Particle delivery to measurement system is
performed through a relatively constant mass flow rate using an
optimum dispersing media such as air flow creating a -3.5 bar gauge
pressure. A commercially available machine for laser-diffraction
particle analysis is the OASIS (Sympatec; Clausthal-Zellerfeld,
Germany) dispersing unit. The OASIS system is used in the dry mode
via the VIBRI model HDD200 and RODOS M. The VIBRI model is used
with a 75% feed rate and 3.0 mm gap. The -3.5 bar gauge pressure is
produced through a 4 mm injector. For measuring particle size of
calcium sulfate hemihydrate, the R2 lens (0.25/0.45 . . . 87.5
microns) is preferred, and for tricalcium phosphate components, the
R4 lens (0.5/1.8 . . . 350 microns) is preferred (both also from
Sympatec).
[0038] The particulate composition in the invention preferably
comprises a CSH powder in an amount of at least about 50 weight
percent based on the total weight of the particulate composition,
more preferably at least about 60 weight percent, and most
preferably at least about 70 weight percent. Typically, the CSH
powder is present in an amount of about 70 weight percent to about
99 weight percent, more preferably about 70 weight percent to about
90 weight percent, and most preferably about 70 weight percent to
about 80 weight percent (e.g., between about 70 weight percent and
about 75 weight percent).
[0039] The CSH is preferably .alpha.-calciumsulfate hemihydrate,
which exhibits higher mechanical strength as compared to the beta
form upon setting to form CSD. The CSH portion of the particulate
composition is important for providing mechanical strength to the
resulting bone graft substitute cement, as well as contributing to
the ability to set or harden in a relatively short period of time.
As is known in the art, CSH has the formula CaSO.sub.4.1/2H.sub.2O,
and will react with water to form calcium sulfate dihydrate
(CaSO.sub.4.2H.sub.2O). It is believed that the presence of CSD in
the bone graft substitute cement of the invention contributes to
rapid regeneration of bone tissue at the site of the bone
defect.
[0040] CSH powder can be formed by dehydration of the dihydrate
form by heating. Depending on the method of heating, the alpha or
beta form is obtained. The two forms exhibit crystallographic and
particle morphology differences. The preferred alpha form, which
has a higher density, is typically characterized by large,
hexagonal shaped rod-like primary crystals that are compact and
well formed with sharp edges.
[0041] In a preferred embodiment, the CSH powder is made by the
process disclosed in U.S. Pat. No. 2,616,789, which is incorporated
entirely herein by reference in its entirety. The process involves
immersion of calcium sulfate dihydrate in a solution of water and
an inorganic salt. Preferred salts include magnesium chloride,
calcium chloride, and sodium chloride. However, other inorganic
salts can be used without departing from the invention, such as
ammonium chloride, ammonium bromide, ammonium iodide, ammonium
nitrate, ammonium sulfate, calcium bromide, calcium iodide, calcium
nitrate, magnesium bromide, magnesium iodide, magnesium nitrate,
sodium bromide, sodium iodide, sodium nitrate, potassium chloride,
potassium bromide, potassium iodide, potassium nitrate, cesium
chloride, cesium nitrate, cesium sulfate, zinc chloride, zinc
bromide, zinc iodide, zinc nitrate, zinc sulfate, cupric chloride,
cupric bromide, cupric nitrate, cupric sulfate, and mixtures
thereof. Preferred salts are biocompatible, and any of the salts
can be used in their anhydrous or hydrate forms. Reference to the
salt is intended to encompass both anhydrous and hydrate forms. The
calcium sulfate dihydrate and the solution are heated to
substantially the boiling point at atmospheric pressure until a
substantial portion of the calcium sulfate dihydrate is converted
to CSH. The resulting CSH has a different crystalline structure
than CSH produced by other hydrothermal processes and has a lower
water-carrying capacity after being milled. In particular, the
crystalline structure of the CSH made according to this method is
characterized by thick, stubby, rod-like crystals.
[0042] In one embodiment, the CSH powder further includes an
accelerant capable of accelerating the conversion of CSH to the
dihydrate form, thereby causing the bone graft substitute cement
made therefrom to set more quickly. Although not wishing to be
bound by a theory of operation, it is believed that the accelerant
particles act as crystallization nucleation sites for the
conversion of CSH to calcium sulfate dihydrate. Examples of
accelerants include calcium sulfate dihydrate, potassium sulfate,
sodium sulfate, or other ionic salts. A preferred accelerant is
calcium sulfate dihydrate crystals (available from U.S. Gypsum)
coated with sucrose (available from VWR Scientific Products). A
process of stabilizing the dihydrate crystals by coating with
sucrose is described in U.S. Pat. No. 3,573,947, which is hereby
incorporated by reference in its entirety. The accelerant is
typically present in an amount of up to about 1.0 weight percent,
based on the total weight of the particulate composition. In some
embodiments, the particulate composition includes between about
0.001 and about 0.5 weight percent of the accelerant, more
typically between about 0.01 and about 0.3 weight percent (e.g.,
between about 0.05 and about 0.15 weight percent). Mixtures of two
or more accelerants can be used.
[0043] The non-porous calcium phosphate portion of the particulate
composition of the invention typically comprises a MCPM powder
(Ca(H.sub.2PO.sub.4).sub.2.H.sub.2O) and non-porous .beta.-TCP
powder (Ca.sub.3(PO.sub.4).sub.2). As understood in the art, the
main reaction product of MCPM and the non-porous .beta.-TCP powder
is brushite, otherwise known as dicalcium phosphate dihydrate
(CaHPO.sub.4.2H.sub.2O) (DCPD). The brushite-forming materials may
also participate in other reactions that would result in the
formation of certain calcium phosphates with a greater
thermodynamic stability than DCPD, such as hydroxyapatite,
octacalcium phosphate, and the like. A certain amount of the
non-porous .beta.-TCP powder may also remain unreacted in the
cement. In certain embodiments of the invention, one or both of the
brushite-forming components are not included in the inventive
composition.
[0044] The non-porous .beta.-TCP powder component preferably has a
median particle size of less than about 35 microns, and more
preferably a median particle size of less than about 30 microns,
and most preferably a median particle size of less than about 25
microns. Typically the non-porous .beta.-TCP powder will have a
median particle size of about 10 microns to about 30 microns (e.g.,
around 20 microns). The size of the non-porous .beta.-TCP powder
may affect the amount of brushite formed in the bone graft
substitute cement. It is believed that smaller particle sizes of
non-porous .beta.-TCP will result in an increased rate of brushite
formation, and larger particle sizes will result in a lower rate of
brushite formation. It is typically preferred to use smaller
non-porous .beta.-TCP particles in order to increase the
brushite-forming reaction rate.
[0045] The non-porous .beta.-TCP powder portion of the particulate
composition preferably has a bimodal particle size distribution
characterized by about 30 to about 70 volume percent of particles
having a mode of about 2.0 to about 6.0 microns and about 30 to
about 70 volume percent of particles having a mode of about 40 to
about 70 microns based on the total volume of the .beta.-tricalcium
phosphate powder. In one embodiment, the non-porous .beta.-TCP
powder has a bimodal particle size distribution characterized by
about 50 to about 65 volume percent of particles having a mode of
about 4.0 to about 5.5 microns and about 35 to about 50 volume
percent of particles having a mode of about 60 to about 70 microns
based on the total volume of the non-porous .beta.-tricalcium
phosphate powder.
[0046] The MCPM powder is relatively soluble in water, which means
particle size is relatively unimportant. Typically, the MCPM powder
will have a particle size of less than about 350 microns; however,
other particles sizes could be utilized without departing from the
invention. As would be understood, MCPM is the hydrate form of
monocalcium phosphate (MCP). As used herein, reference to MCPM is
intended to encompass MCP, which is simply the anhydrous form of
MCPM that releases the same number of calcium and phosphoric acid
ions in solution. However, if MCP is used in place of MCPM, the
amount of water used to form the bone graft substitute cement would
need to be increased to account for the water molecule missing from
MCP (if it is desired to produce precisely the same dissolution
product as formed when using MCPM).
[0047] As noted above, the brushite component of the bone graft
substitute cement of the invention serves to slow the in vivo
resorption of the bone graft substitute cement as compared to a
calcium sulfate cement. In turn, the slower resorption rate may
enable the bone graft substitute cement to provide structural
support at the site of the bone defect for longer periods of time,
which can aid the healing process in certain applications. Although
not bound by any particular theory of operation, it is believed
that the bone graft substitute cement of the invention will become
a highly porous matrix of calcium phosphate material after being
administered in vivo due to the relatively quick resorption of the
calcium sulfate component of the mixture. The remaining porous
matrix of calcium phosphate provides excellent scaffolding for bone
ingrowth during the natural healing process. The amount of MCPM
powder and non-porous .beta.-TCP powder present in the particulate
composition can vary and depends primarily on the amount of
brushite desired in the bone graft substitute cement. The
brushite-forming calcium phosphate composition (i.e., the combined
amount of MCPM and non-porous .beta.-TCP powders) will typically be
present at a concentration of about 3 to about 30 weight percent
based on the total weight of the particulate composition, more
preferably about 5 to about 10 weight percent, most preferably
about 8 weight percent. The relative amounts of MCPM and non-porous
.beta.-TCP can be selected based on their equimolar, stoichiometric
relationship in the brushite-forming reaction. In one embodiment,
the MCPM powder is present at a concentration of about 2 to about 5
weight percent, based on the total weight of the particulate
composition, and the non-porous .beta.-TCP is present in an amount
of about 3 to about 6 weight percent.
[0048] It has been discovered that the MCPM and non-porous
.beta.-TCP powders can react prematurely during storage in the
presence of residual moisture to form brushite and/or monetite, an
undesirable anhydrous analog of brushite. Thus, storage of the
brushite-forming calcium phosphate powders together in a homogenous
mixture can result in reduction in the amount of brushite produced
upon mixing the particulate composition with the aqueous mixing
solution to form the bone graft substitute cement, which in turn,
can alter the properties of the bone graft substitute cement in an
undesirable manner. As a result, in a preferred embodiment, the two
calcium phosphate components are either packaged together in a dry
environment and hermetically sealed against moisture invasion
during storage or are packaged separately during storage. In one
embodiment, the two calcium phosphate powders are packaged
separately, wherein each powder is either packaged alone with no
other components of the particulate composition of the invention or
in admixture with one or more of the remaining components (e.g.,
the CSH powder).
[0049] In certain embodiments, the particulate composition of the
invention will also include a plurality of non-porous .beta.-TCP
granules having a median particle size greater than the median
particle size of the non-porous .beta.-TCP powder. The non-porous
.beta.-TCP granules typically have a median particle size of about
75 to about 1,000 microns, more preferably about 100 to about 400
microns, and most preferably about 180 to about 240 microns. The
granules serve to further reduce the resorption rate of the bone
graft substitute cement and contribute to scaffold formation. The
non-porous .beta.-TCP granules are typically present at a
concentration of up to about 20 weight percent, based on the total
weight of the particulate composition, more preferably up to about
15 weight percent based on the total weight of the composition, and
most preferably up to about 12 weight percent. In one preferred
embodiment, the non-porous .beta.-TCP granules are present at a
concentration of about 8 to about 12 weight percent (e.g., about 10
weight percent). The non-porous .beta.-TCP granules can provide a
relatively inert third phase in the final cement that exhibits an
even slower resorption rate than the brushite formed by reaction of
the MCPM and the non-porous .beta.-TCP powder. Thus, the presence
of the granules can further alter the resorption profile of the
resulting bone graft substitute cement.
[0050] Both the non-porous .beta.-TCP granules and the non-porous
.beta.-TCP powder used in the present invention can be formed using
a commercially available non-porous .beta.-TCP powder as a starting
material, such as non-porous .beta.-TCP powder available from
Plasma Biotal Ltd. (Derbyshire, UK). In one embodiment, the
non-porous .beta.-TCP components of the particulate composition are
formed by first wet milling a commercially available non-porous
.beta.-TCP powder in a ball mill to a median particle size of less
than 1.0 micron and then draining the resulting slurry through a
strainer to remove the milling media. Thereafter, the solid cake of
non-porous .beta.-TCP can be separated from any remaining liquid
components using any of a variety of techniques known in the art,
such as centrifuging, gravity separation, filter pressing,
evaporation, and the like. The dry cake is then processed through a
series of sieves in order to produce two separate non-porous
.beta.-TCP components having different median particle sizes. The
dried cake of non-porous .beta.-TCP is typically milled either
during or prior to sieving in order to fragment the cake. In one
preferred embodiment, the system of sieves produces a non-porous
.beta.-TCP component having a particle size range of about 125 to
about 355 microns in a green (i.e., unfired) state and another
non-porous .beta.-TCP component having a particle size range of
about 75 to about 355 microns in a green state. Thereafter, the two
non-porous .beta.-TCP components are sintered, and thereby
densified, by heat treatment in a furnace. In one embodiment, the
furnace treatment involves heating the non-porous .beta.-TCP powder
components on an alumina plate at a temperature of about
1100-1200.degree. C. for about three hours. It is typical to ramp
the temperature up to the desired sintering temperature and ramp
the temperature back down during the cooling period at a rate no
greater than about 5-6.degree. C. per minute.
[0051] Following the sintering process, the densified non-porous
.beta.-TCP granules having had a green state particle size of about
125 to about 355 microns can be used as the granule component of
the particulate composition. The sintered non-porous .beta.-TCP
component having had a green (i.e., unfired) state particle size of
about 75 to about 355 microns can be dry milled in a ball mill for
approximately one to four hours in order to form the non-porous
.beta.-TCP powder having a median particle size of less than about
20 microns, which can then be used in the particulate composition
as described above.
[0052] The porous .beta.-TCP component comprises .beta.-TCP
particles that exhibit a relatively high degree of porosity as
compared with the non-porous .beta.-TCP component(s). Porous
.beta.-TCP can have various macrostructures and microstructures.
The size of the particles can vary and can be, e.g., in granular or
powder form. Also, the total surface area of the particles can vary
and the shapes and sizes of the pores present within the .beta.-TCP
particles can also vary. In some embodiments, the porous .beta.-TCP
component comprises .beta.-TCP particles having interconnected,
multidirectional porosity. In some embodiments, the porous
.beta.-TCP component comprises .beta.-TCP particles having a
multiplicity of unconnected pores. Pore sizes (e.g., diameters) can
range, for example, from about 100 microns to about 400 microns.
Accordingly, in some embodiments, the porous .beta.-TCP particles
can be characterized as microporous, in some embodiments, the
porous .beta.-TCP can be characterized as macroporous, and in some
embodiments, the porous .beta.-TCP can be characterized as both
microporous and macroporous. The total porosity can be at least
about 50%, at least about 60%, or at least about 70%. In exemplary
embodiments, the total porosity can range, e.g., from about 50% to
about 90%, such as between about 60% and about 90% or between about
70% and about 90%. The total porosity values of a given material
can be determined, e.g., by the measurement of the density by
weight of a sample of the material. It is noted that the non-porous
.beta.-TCP described herein can, in some embodiments, be described
as having a porosity of less than about 15% or less than about 10%
as determined by scanning electron microscopy (SEM) images. It is
noted that the porous .beta.-TCP incorporated into the compositions
described herein can, in certain embodiments, comprise some
percentage of an alpha TCP phase. For example, in some embodiments,
the porous .beta.-TCP can comprise up to about 40% alpha-TCP.
[0053] In one exemplary embodiment, the porous .beta.-TCP comprises
CELLPLEX.RTM. TCP from Wright Medical Technology, Inc. (Tennessee,
USA). See, for example, U.S. Pat. Nos. 6,136,029; 6,527,810; and
6,296,667, all to Johnson et al., which are all incorporated herein
by reference in their entireties. Other commercially available
porous .beta.-TCP powders/granules include, but are not limited to:
Conduit.RTM. TCP Granules (DePuy Synthes, Pa., USA); Ceros.RTM. TCP
Granules (Thommen Medical, Inc., Switzerland); .beta.-TCP Porous
Granules (Cam BioCeramics, the Netherlands); Osprolife .beta.-TCP
Granules (Eurocoating, Italy); and BoneSigma.TM. Porous TCP
(SigmaGraft, Inc., California, USA). Porous .beta.-TCP can also be
prepared as described, for example, in U.S. Pat. Nos. 7,390,498 and
6,949,251 to Dalal et al.; and U.S. Patent Application Publication
Nos. 2006/0292200 to Delaney; and 2003/0180376 to Brevetto et al.,
which are incorporated herein by reference in their entireties.
[0054] The amount of porous .beta.-TCP in the compositions
described herein can vary. In certain embodiments, porous
.beta.-TCP is present at a concentration of up to about 20 weight
percent, based on the total weight of the particulate composition
and more preferably up to about 15 weight percent based on the
total weight of the composition. In one preferred embodiment, the
porous .beta.-TCP is present at a concentration of about 5 to about
15 weight percent (e.g., about 10 weight percent).
[0055] The porous .beta.-TCP portion of the particulate composition
preferably has a bimodal particle size distribution characterized
by a minority (i.e., less than about 50%), e.g., about 25% by
weight, porous .beta.-TCP having a smaller particle size and a
majority (i.e., greater than about 50%), e.g., about 75%, porous
.beta.-TCP having a larger particle size. The particle sizes can
vary; however, in a representative embodiment, the smaller particle
size can be up to about 63 .mu.m (i.e., about 0-63 .mu.m) and the
larger particle size can be greater than about 63 .mu.m (e.g., from
about 63 .mu.m to about 250 .mu.m). Accordingly, one specific bone
substitute cement composition embodiment comprises porous
.beta.-TCP powder having a bimodal particle size distribution,
wherein less than about 50% of the porous .beta.-TCP powder has a
particle size of between about 0 microns and about 63 microns and
wherein greater than about 50% of the porous .beta.-TCP powder has
a particle size of between about 63 microns and about 250
microns.
[0056] The aqueous component that is mixed with the particulate
composition of the invention is selected in order to provide the
composition with a desired consistency and hardening or setting
time. Typically, the aqueous solution is provided in an amount
necessary to achieve a liquid to powder mass ratio (l/p) of at
least about 0.2, more preferably at least about 0.21, and most
preferably at least about 0.23. A preferred lip ratio range is
about 0.2 to about 0.3, more preferably about 0.2 to about 0.25.
Examples of suitable aqueous components include water (e.g.,
sterile water) and solutions thereof, optionally including one or
more additives selected from the group consisting of sodium
chloride, potassium chloride, sodium sulfate, potassium sulfate,
EDTA, ammonium sulfate, ammonium acetate, and sodium acetate. In
one preferred embodiment, the aqueous mixing solution used is a
saline solution or a phosphate buffered saline solution. An
exemplary aqueous solution is 0.9% NaCl saline solution available
from Baxter International (Deerfield, Ill.) and others.
[0057] In one embodiment, the aqueous solution further includes one
or more organic or inorganic carboxylic acid-containing compounds
(hereinafter carboxylic acids or carboxylic acid compounds) which
may or may not contain a hydroxyl group on the alpha carbon,
optionally titrated to a neutral pH using a suitable base (e.g.,
neutralized to a pH of about 6.5 to about 7.5 using an alkali metal
base such as sodium hydroxide or potassium hydroxide), which can
alter water demand, flowability, and/or viscosity of the bone graft
substitute cement composition upon mixing. Exemplary carboxylic
acids include glycolic acid and lactic acid. Preferred carboxylic
acids have a single carboxylic acid group, from 1 to about 10 total
carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms
including the carbonyl carbon), and 0-5 hydroxyl groups (e.g., 0,
1, 2, 3, 4, or 5) attached to the carbon chain. In one preferred
embodiment, the mixing solution comprises glycolic acid, sodium
hydroxide, and sodium chloride in water. Reference to the
carboxylic acid compound herein encompasses both the free acid and
salt forms.
[0058] It has been previously discovered, as detailed in U.S. Pat.
No. 7,754,246 to Moseley et al., which is incorporated herein by
reference, that the presence of the carboxylic acid component in
the aqueous solution prior to gamma radiation sterilization can
lead to inconsistent bone graft substitute cement properties, such
as "drift" in cement setting time, due to degradation of the acid
resulting from the radiation exposure. Thus, in one preferred
embodiment, the carboxylic acid compound discussed above in
connection with the aqueous mixing solution is packaged as a
crystalline powder (e.g., in free acid or salt form) with the
remaining particulate components of the kit, either in admixture
with one or more other powder components or in a separate
container, rather than in solution. Using the acid component in
powder form avoids degradation of the acid upon sterilization of
the composition with gamma radiation. Alternatively, the carboxylic
acid component is added to the aqueous solution after the solution
is sterilized by radiation so that the carboxylic acid is not
exposed to sterilizing radiation while in solution.
[0059] In one embodiment, the carboxylic acid for use in the
invention is neutralized to a pH of about 6.5 to about 7.5 in
solution using, for example, an alkali metal base as noted above,
and then isolated as a crystalline powder by evaporation of the
solvent (e.g., water). The crystalline powder is typically isolated
in a salt form, such as an alkali metal salt form (e.g., lithium,
sodium, or potassium salts). Exemplary dry crystalline powders of a
carboxylic acid, in salt form, for use in the invention include
sodium glycolate, potassium glycolate, sodium lactate, and
potassium lactate. The powdered carboxylic acid salt can be added
to any of the other powder ingredients that together form the
particulate portion of the bone graft substitute cement, such as
the CSH component or either of the calcium phosphate components.
However, in certain embodiments, the powdered carboxylic acid is
stored in a separate container so that it can be reconstituted with
the aqueous solution prior to mixing the solution with the
remaining particulate components of the composition.
[0060] Although brushite-forming components are preferred in the
inventive compositions of the invention, certain embodiments of the
invention do not include one or both brushite-forming components.
For example, in certain embodiment of the invention, the
composition includes CSH as described herein (in any of the amounts
noted herein), a porous .beta.-TCP component as described herein
(in any of the amounts noted herein), and a porous .beta.-TCP
granule component as described herein (in any of the amounts noted
herein). Such embodiments can be supplemented with one of the
brushite-forming components, such as the .beta.-TCP powder or the
MCPM powder as described herein (in any of the amounts noted
herein).
[0061] The bone graft substitute cement of the invention can
further include other additives known in the art. The additives can
be added as a solid or liquid to either the particulate composition
of the invention or the aqueous mixing solution. One example of an
additive for the calcium sulfate composition is a plasticizer
designed to alter the consistency and setting time of the
composition. Such a plasticizing ingredient can retard the setting
of calcium sulfate hemihydrate pastes, thereby increasing the time
it takes for the composition to set following mixing with an
aqueous solution. Exemplary plasticizers include glycerol and other
polyols, vinyl alcohol, stearic acid, hyaluronic acid, cellulose
derivatives and mixtures thereof. Alkyl celluloses are particularly
preferred as the plasticizer ingredient. Exemplary alkyl celluloses
include methylhydroxypropylcellulose, methylcellulose,
ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose
acetate butyrate, and mixtures or salts thereof.
[0062] Exemplary additives also include biologically active agents.
As used herein, the term "biologically active agent" is directed to
any agent, drug, compound, composition of matter or mixture that
provides some pharmacologic effect that can be demonstrated in vivo
or in vitro. Examples of biologically active agents include, but
are not limited to, peptides, proteins, enzymes, small molecule
drugs, dyes, lipids, nucleosides, oligonucleotides,
polynucleotides, nucleic acids, cells, viruses, liposomes,
microparticles, and micelles. It includes agents that produce a
localized or systemic effect in a patient.
[0063] Particularly preferred classes of biologically active agents
include osteoinductive or osteoconductive materials, antibiotics,
chemotherapeutic agents, pesticides (e.g., antifungal agents and
antiparasitic agents), antivirals, anti-inflammatory agents, and
analgesics. Exemplary antibiotics include ciprofloxacin,
tetracycline, oxytetracycline, chlorotetracycline, cephalosporins,
aminoglycocides (e.g., tobramycin, kanamycin, neomycin,
erithromycin, vancomycin, gentamycin, and streptomycin),
bacitracin, rifampicin, N-dimethylrifampicin, chloromycetin, and
derivatives thereof. Exemplary chemotherapeutic agents include
cis-platinum, 5-fluorouracil (5-FU), taxol and/or taxotere,
ifosfamide, methotrexate, and doxorubicin hydrochloride. Exemplary
analgesics include lidocaine hydrochloride, bipivacaine and
non-steroidal anti-inflammatory drugs such as ketorolac
tromethamine. Exemplary antivirals include gangcyclovir,
zidovudine, amantidine, vidarabine, ribaravin, trifluridine,
acyclovir, dideoxyuridine, antibodies to viral components or gene
products, cytokines, and interleukins. An exemplary antiparasitic
agent is pentamidine. Exemplary anti-inflammatory agents include
.alpha.-1-anti-trypsin and .alpha.-1-antichymotrypsin.
[0064] Useful antifungal agents include diflucan, ketaconizole,
nystatin, griseofulvin, mycostatin, miconazole and its derivatives
as described in U.S. Pat. No. 3,717,655, the entire teachings of
which are incorporated herein by reference; bisdiguanides such as
chlorhexidine; and more particularly quaternary ammonium compounds
such as domiphen bromide, domiphen chloride, domiphen fluoride,
benzalkonium chloride, cetyl pyridinium chloride, dequalinium
chloride, the cis isomer of
1-(3-chlorallyl)-3,5,7-triaza-1-azoniaadamantane chloride
(available commercially from the Dow Chemical Company under the
trademark Dowicil 200) and its analogues as described in U.S. Pat.
No. 3,228,828, the entire teachings of which are incorporated
herein by reference, cetyl trimethyl ammonium bromide as well as
benzethonium chloride and methylbenzethonium chloride such as
described in U.S. Pat. Nos. 2,170,111; 2,115,250; and 2,229,024,
the entire teachings of which are incorporated herein by reference;
the carbanilides and salicylanilides such
3,4,4'-trichlorocarbanilide, and 3,4,5-tribromosalicylanilide; the
hydroxydiphenyls such as dichlorophene, tetrachlorophene,
hexachlorophene, and 2,4,4'-trichloro-T-hydroxydiphenylether; and
organometallic and halogen antiseptics such as zinc pyrithione,
silver sulfadiazone, silver uracil, iodine, and the iodophores
derived from non-ionic surface active agents such as described in
U.S. Pat. Nos. 2,710,277 and 2,977,315, the entire teachings of
which are incorporated herein by reference, and from
polyvinylpyrrolidone such as described in U.S. Pat. Nos. 2,706,701,
2,826,532 and 2,900,305, the entire teachings of which are
incorporated herein by reference.
[0065] As used herein, the term "growth factors" encompasses any
cellular product that modulates the growth or differentiation of
other cells, particularly connective tissue progenitor cells. The
growth factors that may be used in accordance with the present
invention include, but are not limited to, fibroblast growth
factors (e.g., FGF-1, FGF-2, FGF-4); platelet-derived growth factor
(PDGF) including PDGF-AB, PDGF-BB and PDGF-AA; bone morphogenic
proteins (BMPs) such as any of BMP-1 to BMP-18; osteogenic proteins
(e.g., OP-1, OP-2, or OP-3); transforming growth factor-.alpha.-,
transforming growth factor-.beta. (e.g., .beta.1, .beta.2, or
.beta.3); LIM mineralization proteins (LMPs); osteoid-inducing
factor (OIF); angiogenin(s); endothelins; growth differentiation
factors (GDF's); ADMP-1; endothelins; hepatocyte growth factor and
keratinocyte growth factor; osteogenin (bone morphogenetic
protein-3); heparin-binding growth factors (HBGFs) such as HBGF-1
and HBGF-2; the hedgehog family of proteins including indian,
sonic, and desert hedgehog; interleukins (IL) including IL-1 thru
-6; colony-stimulating factors (CSF) including CSF-1, G-CSF, and
GM-CSF; epithelial growth factors (EGFs); and insulin-like growth
factors (e.g., IGF-I and -II); demineralized bone matrix (DBM);
cytokines; osteopontin; and osteonectin, including any isoforms of
the above proteins. Particulate DBM is a preferred osteoinductive
additive.
[0066] The biologically active agent may also be an antibody.
Suitable antibodies, include by way of example, STRO-1, SH-2, SH-3,
SH-4, SB-10, SB-20, and antibodies to alkaline phosphatase. Such
antibodies are described in Haynesworth et al., Bone (1992),
13:69-80; Bruder, S et al., Trans Ortho Res Soc (1996), 21:574;
Haynesworth, S. E., et al., Bone (1992), 13:69-80; Stewart, K., et
al, J Bone Miner Res (1996), 11(Suppl.):S142; Flemming J. E., et
al., in "Embryonic Human Skin. Developmental Dynamics,"
212:119-132, (1998); and Bruder S. P. et al., Bone (1997), 21(3):
225-235, the entire teachings of which are incorporated herein by
reference.
[0067] Other examples of biologically active agents include bone
marrow aspirate, platelet concentrate, blood, allograft bone,
cancellous bone chips, synthetically derived or naturally derived
chips of minerals such as calcium phosphate or calcium carbonate,
mesenchymal stem cells, and chunks, shards, and/or pellets of
calcium sulfate.
[0068] A bone graft substitute cement according to the invention
can be formed by mixing the particulate composition with the
aqueous solution using manual or mechanical mixing techniques and
apparatus known in the art. It is preferred to mix the components
of the cement at atmospheric pressure or below (e.g., under vacuum)
and at a temperature that will not result in freezing of the
aqueous component of the mixture or significant evaporation.
Following mixing, the homogenous composition typically has a
paste-like consistency, although the viscosity and flowability of
the mixture can vary depending on the additives therein. The bone
graft substitute cement material can be transferred to a delivery
device, such as a syringe, and injected into a target site, for
example, to fill in cracks or voids of a bone defect. In some
embodiments, the material can be injected through an 8- to 16-gauge
needle up to, for example, 10 cm long.
[0069] The bone graft substitute cements of the invention will
generally set, as defined by the Vicat needle drop test set forth
below, in about 3 to about 25 minutes, more preferably about 5 to
about 15 minutes (e.g., between about 5 and about 12 minutes). The
bone graft substitute cement material of the invention will
typically reach a hardness comparable to or greater than bone
within about 8 to about 60 minutes or about 10 to about 60 minutes
(e.g., having a Gillmore set time of between about 8 and about 30
minutes or about 12 to about 30 minutes, more preferably between
about 12 and about 20 minutes, e.g., between about 14 and about 17
minutes). Setting of the material can occur in a variety of
environments, including air, water, in vivo, and under any number
of in vitro conditions. It is noted that the presence of certain
biologically active agents in the material may retard the set time
of the material to some extent, as described in greater detail
below.
[0070] Although not intended to be limited by theory, it is
believed that, in certain embodiments, one or more of the specific
powder component ratios, the use of porous .beta.-TCP, and/or the
use of a mixing solution comprising sodium chloride in the glycolic
acid solution contribute, at least in part, to the enhanced setting
properties of the bone graft substitute here. By "enhanced setting
properties" is meant that such compositions set in the presence of
biologically active agents and set more quickly (with shorter Vicat
and Gillmore set times) than similar, commercially available
compositions (e.g., Pro-Dense.RTM., Wright Medical Technology,
Inc., Tennessee, USA).
[0071] In certain embodiments, the compositions described herein
are uniquely capable of achieving a relatively fast set time even
in the presence of various biologically active agents (e.g.,
including but not limited to, in the presence of bone marrow
aspirate or in the presence of platelet derived growth factors).
Interestingly, compositions described in the present disclosure can
exhibit improved properties as compared with a commercially
available composition (Pro-Dense.RTM., Wright Medical Technology,
Inc.) prepared as described in U.S. Pat. No. 7,754,246 to Moseley
et al., which is incorporated herein by reference in its entirety.
When biologically active agents are incorporated in the bone graft
substitute cements described herein, the cements may exhibit a
slight delay in setting as compared with identical bone graft
substitute cements that are free of biologically active agents.
However, the compositions described herein are uniquely capable of
hard setting even in the presence of various such biologically
active agents. For example, in certain embodiments, compositions as
described herein, further comprising one or more biologically
active agents can exhibit a Vicat set time of about 25 minutes or
less, about 20 minutes or less, about 15 minutes or less, or about
10 minutes or less (e.g., between about 7 and about 15 minutes or
between about 10 and about 15 minutes). In certain embodiments,
compositions as described herein, further comprising one or more
biologically active agents can exhibit a Gillmore set time of about
35 minutes or less, about 30 minutes or less, about 25 minutes or
less or about 20 minutes or less (e.g., between about 10 and about
20 minutes or between about 15 and about 20 minutes).
[0072] The hardened bone graft substitute cement preferably
exhibits certain mechanical strength properties, particularly as
characterized by diametral tensile strength and compressive
strength. Preferred embodiments of the cement exhibit a diametral
tensile strength of at least about 4 MPa after curing for one hour
in ambient air following mixing of the particulate composition with
an aqueous solution, more preferably a diametral tensile strength
of at least about 5 MPa, most preferably at least about 6 MPa.
Further, preferred embodiments of the bone graft substitute cement
exhibit a diametral tensile strength of at least about 8 MPa after
curing for 24 hours in ambient air following mixing of the
particulate composition with an aqueous solution, more preferably a
diametral tensile strength of at least about 9 MPa after curing for
24 hours, and most preferably at least about 10 MPa.
[0073] The bone graft substitute cement of the invention typically
exhibits a dissolution rate that is significantly slower than a
comparable bone graft substitute cement made substantially entirely
of calcium sulfate. In certain preferred embodiments, the cement of
the invention exhibits an average dissolution rate, expressed as an
average percentage of weight loss per day, that is at least about
25% lower than the average dissolution rate of a cement formed
using a particulate composition consisting of calcium sulfate, the
average dissolution rate measured by immersion of a 4.8 mm OD
pellet having a length of 3.3 mm in distilled water at 37.degree.
C. as described in greater detail below. More preferably, the bone
graft substitute cement of the invention has an average dissolution
rate that is at least about 30% lower than a calcium sulfate
cement, most preferably at least about 35% lower, and in some
embodiments, as much as 40% lower or more. A preferred range of
dissolution, expressed as an average percentage of weight loss per
day measured using the test procedure set forth below, is about 5%
to about 15%, more preferably about 7% to about 13%. Average
dissolution rates stated are determined by linear regression of %
weight loss per day using data from days 0, 1, 2, 3, and 4
determined using the procedure set forth below.
[0074] The present invention also provides a bone graft substitute
kit comprising the particulate composition of the invention.
Typically, the kit comprises one or more containers enclosing the
particulate composition as described above and a separate container
enclosing a sterile aqueous solution. The kit will typically
contain a written instruction set describing a method of using the
kit. In addition, the bone-graft substitute kit of the invention
will preferably comprise an apparatus for mixing the particulate
composition with the aqueous solution in order to form the bone
graft cement, such as a vacuum mixing apparatus. Additionally, the
kit will typically include a device for delivering the bone graft
cement to the site of the bone defect, such as an injection device
(e.g., a needle and syringe).
[0075] As noted previously, in certain embodiments, the kit of the
invention will separate the two calcium phosphate powder components
into different containers to avoid reaction during storage. There
are a number of packaging configurations that can accomplish this
goal. For example, in one embodiment, the kit includes one
container for CSH powder, one container for .beta.-TCP powder, and
one container for MCPM powder. In another embodiment, the kit
includes two containers for the particulate composition, one
including .beta.-TCP powder and a portion of the CSH component and
a second containing MCPM powder and a portion of the CSH component.
In yet another embodiment, the MCPM powder is packaged in a
separate container by itself, and the .beta.-TCP powder and the CSH
powder are packaged together. In a still further embodiment, the
.beta.-TCP powder is packaged in a separate container by itself,
and the MCPM powder and the CSH powder are packaged together. In
any of the above embodiments, any of the powder containers can
further include the crystalline powder of the carboxylic acid salt
component and/or the .beta.-TCP granules, or those components could
be packaged separately in their own containers. When present, the
accelerator adapted to accelerate conversion of CSH to CSD is
typically in admixture with the CSH powder. In one preferred
embodiment, the kit comprises one container enclosing the MCPM
powder, and a second container enclosing the remaining particulate
ingredients in admixture, such as one or more of the CSH powder,
the CSH accelerator, the .beta.-TCP powder, the .beta.-TCP
granules, and the carboxylic acid crystalline powder.
[0076] In certain embodiments, a dual syringe mixing system can be
incorporated in the kit. The dual syringe system may afford an
alternative means for separating the components of the kit as noted
above. For example, in one embodiment, one syringe can contain the
MCPM component and a second syringe can contain the remaining
powder components of the bone graft substitute composition. The
liquid component can be provided, for example, in a vial, such as a
crimp-top vial, which can be attached to the end of one syringe to
draw the liquid into either the MCPM component or the remaining
powder components of the composition. The two syringes can then be
connected (e.g., with a syringe connector), and the liquid material
can be passed back and forth between the two syringes to afford
complete mixing of the components. For injection, the mixture can
be drawn into one of the syringes, the syringe connector and other
syringe can be removed, and a needle can be applied to the end of
the mixture-containing syringe.
[0077] FIG. 4 illustrates one embodiment of a bone graft substitute
kit 100 suitable for use in the present invention, and FIG. 5
illustrates a method of preparing a bone graft substitute
composition using the kit of FIG. 4. As shown in FIG. 4, the kit
100 includes two syringes containing particulate material, a first
syringe 110 labelled "Part A" containing a majority of the powder
components of the kit and a second syringe 120 labelled "Part B"
containing a minor portion of the powder components of the kit.
Although the contents of each syringe can vary, in one embodiment,
the Part A syringe includes all powder/granular components except
the MCPM component and the Part B syringe contains the MCPM
component. The kit 100 also contains a liquid-containing vial 130
containing the mixing diluent solution, which can be, for example,
a saline solution containing glycolic acid. The vial 130 will
typically include a lid comprising a pierceable septum. The sizes
of the syringes, 110 and 120, as well as the vial 130 will depend
on the desired amount of bone graft substitute material to be made,
and will typically vary in size as needed to produce bone graft
substitute compositions in amounts ranging from about 1 cc to 10 cc
(e.g., about 2 cc to about 4 cc).
[0078] The illustrated kit 100 also contains a syringe connector
140 and a vial adaptor 150. The syringe connector 140 typically
includes a connector at each end for facilitating connection, such
as threaded connection, of the connector to a syringe and a
passageway adapted to allow fluid to pass from one connected
syringe to the other. The vial adaptor 150 typically includes a
connector for connecting to a syringe, such as through threaded
engagement, a passageway adapted to allow fluid to pass from a vial
into the syringe, and a spike adapted for piercing a septum of a
vial. Finally, the kit 100 may contain one or more, and preferably
multiple, needles for delivery of the bone graft substitute
composition to the bone site in need thereof. The illustrated kit
100 contains two needles, 160 and 170, which are shown as
advantageously being of the Jamshidi type, the two needles
differing in size (e.g., differing in length and/or gauge). As
shown, one exemplary kit 100 contains a 11-gauge Jamshidi needle
160 of a first length and a 16-gauge Jamshidi needle 170 of a
second, shorter length. Other sizes or needle types could be used
without departing from the invention. The kit will also typically
contain a written instruction set, such as a set of instructions
outlining the basic method set forth in FIG. 5 and explained
herein.
[0079] As set forth in FIG. 5, one method of using the kit 100 of
FIG. 4 involves the step 200 of attaching the vial adaptor 150 to
the Part A syringe 110 (after removing any cap present on the
syringe). The vial adaptor 150 can join the syringe 110 in any
manner, such as through threaded engagement. Thereafter, the method
can include the step 210 of attaching the mixing diluent vial 130
to the vial adaptor 150, which will result in the spike (not shown)
of the vial adaptor piercing the septum of the vial.
Advantageously, one can draw back the Part A syringe 110 to draw
air into the syringe before attaching the vial 130. The contents of
the vial 130 can then be withdrawn into the Part A syringe 110 in
step 220, which can be preceded by injection of the air optionally
drawn into the syringe into the vial. Multiple injection/withdrawal
steps may be required to withdraw all liquid from the vial 130.
Thereafter, the vial 130 and vial adaptor 150 can be removed from
the syringe 110 and the syringe connector 140 can be attached to
the Part B syringe 120 in step 230. Thereafter, the two syringes,
110 and 120, can be attached together via the syringe connector 140
in step 240. Application of an alternating plunging action to the
two syringes in step 250 will enable the materials in the two
syringes to mix well. In certain embodiments, the alternating
plunging of the syringes should occur at least about 20 times, such
as at least about 30 or at least about 40 times. To avoid loss of
injectability of the material, it is advantageous to inject the
bone graft substitute material within about 6 minutes (such as
within about 5 minutes or within about 3 minutes) of the time the
liquid is first added to the powder material.
[0080] Once the materials are thoroughly mixed, the two syringes
can be decoupled in step 260 (with all bone graft substitute
material in one syringe) and a delivery needle (e.g., needle 160 or
170) can be attached to the syringe containing the bone graft
material. Finally, in step 270, the bone graft substitute material
is delivered to the desired bone site using the syringe/needle
device.
[0081] The particular composition and the sterile aqueous solution
will typically be sterilized by irradiation prior to packaging in
the kit. In one preferred embodiment, the powdered form of the
carboxylic acid is packaged separately so that it can be
reconstituted in the aqueous solution, if desired, prior to mixing
the solution with the remaining particulate components. However, as
noted previously, the aqueous solution of the kit may also contain
the carboxylic acid component in solution form if the carboxylic
acid is added after radiation sterilization of the aqueous
component of the kit.
[0082] It can be important to utilize all of the aqueous solution
packaged in the kit in order to ensure that consistent setting
times are achieved. In one embodiment, the aqueous solution is
packaged in a highly hydrophobic container, such as a glass syringe
or other glass container, which is less prone to retention of
residual solution in amounts that will cause changes in the
performance characteristics of the bone graft substitute cement.
When mixing with a biologically active agent, it may in some
embodiments be beneficial to use a specified ratio of aqueous
solution to biologically active agent. For example, in one specific
embodiment, desirable results are achieved using bone marrow
aspirate in a ratio of 60:40 solution to bone marrow aspirate to
achieve an injectable, fast-setting material.
[0083] The present invention also provides a method for treating a
bone defect. The method of the invention involves applying a bone
graft substitute cement as described above to the site of the bone
defect. The bone graft substitute cement can be applied in flowable
farm following mixing of the particulate composition with the
aqueous solution. For example, methods of application include, but
are not limited to, applying the cement through an injection device
or digitally packing the cement, prior to setting of the
composition. Alternatively, the bone graft substitute cement can be
used in a precast hardened form, wherein the cement is provided in
predetermined shapes such as pellets, granules, wedges, blocks, or
disks, or used in the form of randomly-shaped shards created by
mechanically breaking a cement mass into smaller pieces. In a
further embodiment, the clinician can form the bone graft cement
mixture and manually mold the mixture into a desired shape, such as
the shape needed to fill a particular bone defect, prior to
application.
[0084] In another embodiment, the bone graft substitute cement of
the invention can be incorporated into an orthopedic implant, such
as any of the various devices adapted for joint replacement. The
bone graft substitute cement is typically incorporated into such
devices as an outer coating or as a filling material within the
pores of a porous outer component of the device. In this
embodiment, the bone graft substitute cement facilitates bone
in-growth in the area surrounding the implanted device. Exemplary
orthopedic implants include knee replacement devices (e.g.,
constrained or non-constrained knee implant devices, hinged knee
devices, metallic plateau knee devices, and patellar devices), hip
replacement devices (e.g., acetabular components and femoral
components), elbow replacement devices (e.g., constrained,
semi-constrained, and non-constrained devices), upper femoral
devices, upper humeral devices, wrist replacement devices (e.g.,
semi-constrained 2- and 3-part articulation devices), shoulder
devices, passive tendon devices, spinal devices (e.g.,
thoracolumbar spinal fixation devices, cervical spinal fixation
devices, and spinal fusion cages), finger/toe devices, and
diaphysis devices.
[0085] The present invention will be further illustrated by the
following non-limiting examples.
EXPERIMENTAL
Example 1
[0086] One exemplary embodiment of the presently disclosed
composition is provided as follows below in Table 1.
TABLE-US-00001 TABLE 1 Inventive Composition A Component Percent by
weight Particle size range Calcium sulfate hemihydrate 71.90% 5
.mu.m-10 .mu.m Accelerator 0.10% .ltoreq.595 .mu.m Non-porous
.beta.-TCP granules 10% 180 .mu.m-240 .mu.m Porous .beta.-TCP
granules (0-63 2.50% 0 .mu.m-63 .mu.m .mu.m) Porous .beta.-TCP
granules (63- 7.50% 63 .mu.m-250 .mu.m 250 .mu.m) Non-porous
.beta.-TCP powder 4.41% 13.3 .mu.m-15.7 .mu.m MCPM 3.59%
.ltoreq.350 .mu.m Glycolic acid in saline solution 0.25 1/p*
*liquid to powder mass ratio
[0087] The Inventive Composition A powder components, excluding
MCPM, are weighed out to the appropriate amount and mixed in a
V-shape blender for a minimum of ten minutes. The MCPM and glycolic
acid components are weighed out and set aside. After mixing, the
powder components are added to a mixer. The MCPM is then added, and
the powder and MCPM are stirred to combine. The glycolic
acid/saline solution is added, and a timer is started. The mixture
is mixed at a rate of 50 rotations per 30 seconds. The resultant
paste is then typically transferred to a syringe for immediate
use.
[0088] For use within a dual syringe system as described herein,
the blended powder components are located in one syringe and the
MCPM is located in the second syringe. The glycolic acid/saline
solution (present, e.g., in a vial having a puncturable septum) is
pulled into the blended powder-containing syringe via suction. This
syringe is then connected to the MCPM syringe via a connector, and
the mixture is mixed 30 times between the syringes.
[0089] A comparative composition (commercially available
Pro-Dense.RTM. material, Wright Medical Technology, Inc.,
Tennessee, USA) is prepared as described in U.S. Pat. No. 7,754,246
to Moseley et al., which is incorporated herein by reference, with
specific components and amounts as noted below in Table 2.
TABLE-US-00002 TABLE 2 Comparative Composition Component Percent by
weight Particle size range Calcium sulfate hemihydrate 74.906% 5
.mu.m-10 .mu.m Accelerator 0.094% .ltoreq.595 .mu.m Non-porous
.beta.-TCP granules 10.000% 180 .mu.m-240 .mu.m Non-porous
.beta.-TCP powder 8.30% 13.3 .mu.m-15.7 .mu.m MCPM 6.700%
.ltoreq.350 .mu.m Glycolic acid solution 0.25 1/p
Work Times/Set Times:
[0090] Inventive Composition A (Table 1) is compared against the
Comparative Composition (Table 2, which is a standard, commercially
available Pro-Dense.RTM. composition). Inventive Composition A
exhibits a work time (injection/delivery time) of 3-5 minutes, a
Vicat set time (point at which the composition is no longer
deformable without fracture) of 8-12 minutes, and Gillmore set time
(point at which a rock hard set is achieved) of 14-17 minutes. The
Comparative Composition exhibits a work time of 3-5 minutes, a
Vicat set time of 14-19 minutes, and a Gillmore set time of 30+
minutes.
[0091] Data for set times of both Inventive Composition A and the
Comparative Composition in the presence of various biologically
active agents are also provided. Table 3 illustrates set times for
trials with both compositions, incorporating a sodium acetate
buffer and/or recombinant human platelet derived growth factor
(rhPDGF-BB) in the buffer. As noted in the table, the Inventive
Composition exhibited lower set times as compared to the
Comparative Composition in the presence of certain biologically
active agents.
TABLE-US-00003 TABLE 3 Set Time Data for Inventive Composition A
and Comparative Composition in the presence of biologically active
agents rhPDGF- Sodium BB@ 0.3 acetate mg/mL Vicat Gillmore Graft
Graft 20 mM in set set Graft powder diluent (g) buffer time time
Trial material (g) (g) ("buffer") (g) (min) (min) 1 Comparative
22.0 2.2 3.0 23:30 Composition with sodium acetate buffer 2
Comparative 22.0 2.2 3.0 23:30 40:00- Composition 43:00 with
rhPDGF-BB 3 Inventive 25.0 3.4 3.0 15:00 .ltoreq.17:45 Composition
A with rhPDGF-BB 4 Inventive 25.0 6.4 13:00 16:50 Composition A 5
Inventive 25.0 3.4 3.0 12:30 14:00 Composition A with sodium
acetate buffer
[0092] Tables 4 and 5 illustrate set times for trials with the
Comparative Composition and various inventive compositions and
other comparative compositions incorporating antibiotics Tobramycin
(Table 4) or Vancomycin (Table 5). Bead set times, as shown in
Tables 4 and 5, are determined by preparing the bone graft pastes
(with or without antibiotics); and pressing the pastes into bead
molds to form beads of uniform size. "Bead set time" refers to the
amount of time required for the beads to remain in the mold so that
they will not deform once the bead mold is removed.
TABLE-US-00004 TABLE 4 Set Time Data for various compositions in
the presence and absence of Tobramycin No antibiotics Tobramycin
Vicat Gillmore Bead Vicat Gillmore Bead Set Set Set Set Set Set
Graft Time Time Time Time Time Time material (min) (min) (min)
(min) (min) (min) Comparative 19.5 47 47 38 54 46 Composition
Composition <10.5 <10.5 <10.5 11.5 17 15 A1 (75% CSH, 25%
non- porous TCP granules) Composition 13.25 17 17 13 15 15 A2 (85%
CSH, 10% non- porous TCP granules, 5% brushite (equimolar TCP
powder and MCPM)) Composition 17 21 21 12 16 19 A2 Deriv. (82% CSH,
10% non- porous TCP granules, 8% brushite (equimolar TCP powder and
MCPM)) Inventive 9.5 11.5 11.5 10.5 16 16 Composition A3 (75% CSH,
10% non- porous TCP granules, 15% porous TCP granules (<1 mm))
Inventive 7 9.5 8.5 12.5 23 17 Composition A4 (75% CSH, 15%
non-porous TCP granules, 10% porous TCP granules (<1 mm)
Inventive 16 19 19 13 21 21 Composition A5 (75% CSH, 14% non-porous
TCP granules, 6.6% porous TCP granules (<1 mm), 4.4% MCPM
Inventive 11 14.5 14.5 15 19 17 Composition A6 (75% CSH, 10% non-
porous TCP granules, 10% porous TCP granules (<1 mm), 5%
brushite (equimolar TCP powder and MCPM) Inventive 13.5 16.5 16.5
23 29 31 Composition A (Table 1)
TABLE-US-00005 TABLE 5 Set Time Data for various compositions in
the presence and absence of Vancomycin No antibiotics Vancomycin
Vicat Gillmore Bead Vicat Gillmore Bead Set Set Set Set Set Set
Graft Time Time Time Time Time Time material (min) (min) (min)
(min) (min) (min) Comparative 19.5 47 47 25 63 ~60 Composition
Composition <10.5 <10.5 <10.5 9.5 14 14 A1 (75% CSH, 25%
non- porous TCP granules) Composition 13.25 17 17 20.8 24.2 23.5 A2
(85% CSH, 10% non- porous TCP granules, 5% brushite (equimolar TCP
powder and MCPM)) Composition 17 21 21 24.0 28.0 28 A2 Deriv. (82%
CSH, 10% non- porous TCP granules, 8% brushite (equimolar TCP
powder and MCPM)) Inventive 9.5 11.5 11.5 12.5 17 17 Composition A3
(75% CSH, 10% non- porous TCP granules, 15% porous TCP granules
(<1 mm)) Inventive 7 9.5 8.5 12.75 19 19 Composition A4 (75%
CSH, 15% non-porous TCP granules, 10% porous TCP granules (<1
mm) Inventive 16 19 19 27.25 32.5 32.5 Composition A5 (75% CSH, 14%
non-porous TCP granules, 6.6% porous TCP granules (<1 mm), 4.4%
MCPM Inventive 11 14.5 14.5 16.75 19 20 Composition A6 (75% CSH,
10% non- porous TCP granules, 10% porous TCP granules (<1 mm),
5% brushite (equimolar TCP powder and MCPM) Inventive 13.5 16.5
16.5 17.5 21.5 20 Composition A (Table 1)
[0093] As noted in Tables 4 and 5, all of the tested compositions
exhibited an improvement in set time in the presence of antibiotics
as compared to the Comparative Composition (i.e., PRO-DENSE.RTM.
composition). However, some of the tested compositions, such as
Composition A1, Composition A2, and Composition A2 Deriv., did not
compare as favorably with PRO-DENSE.RTM. composition in other
properties, such as strength, ejection force, or dissolution
rate.
[0094] The inventive compositions comprising the porous granule
component were particularly advantageous compositions with respect
to a number of physical properties, with Inventive Compositions A,
A5, and A6 providing the best overall profile of properties such as
set time and diametral tensile strength (DTS).
Set Times:
[0095] Vicat set times described herein are measured using a Vicat
needle that is 1 mm in diameter, 5 cm long, and which possesses a
total weight of 300 g, all per ASTM C-472, which is incorporated by
reference herein in its entirety. The sample being tested should be
mixed in a manner that a homogeneous, flowable paste is created.
The sample size for the Vicat needle drop test is about 3 cc to
about 5 cc of material tapped down to a cake in an approximately 20
mL polyethylene cup; the sample is handled such that no agitation
is inflicted upon the material 1 minute after the aqueous solution
contacts the particulate composition other than the dropping and
removal of the Vicat needle. The cup is of such dimensions that the
cake is a short, flat cylinder measuring about 1/4'' to about 3/8''
in height.
[0096] Set time according to the Vicat needle drop test is defined
as the amount of time elapsed between the time the aqueous solution
contacts the particulate composition and the time the Vicat needle
will not pass through 50% of the height of a cement sample upon
being dropped from the upper surface of the sample. The needle is
allowed to fall under its own weight, under gravity alone, through
a line perpendicular to the top and bottom, flat faces of the
cylinder-shaped sample cake. The needle is dropped every 30 seconds
after the first drop. The needle shall not be dropped more than 6
times during the duration of the test. If after the 6.sup.th drop
the needle continues to pass through more that 50% of the height of
the sample, the test must be repeated with fresh material; a new,
clean cup; and a clean Vicat needle free of debris, especially that
which is left behind from previous tests. Cups, mixing equipment,
and material transfer equipment should not be reused. All materials
and equipment used during testing should be between 21-27.degree.
C. and exposed to an environment with a relative humidity between
20-50%.
[0097] Gillmore set times as described herein are tested based on
ASTM standard C266-08: Standard Test Method for Time of Setting of
Hydraulic-Cement Paste by Gillmore Needles. Similarly to Vicat set
time determination, a sample of material is prepared and placed
into a small cup. After determining the Vicat set time of the
sample, a 453.6 gram weight with a 1.06 mm diameter needle is
lightly placed onto the surface of the sample. The testing is
continued at 1 minute intervals until there is no appreciable
indentation left by the needle on the surface of the sample.
[0098] Work time as described herein is a description of the amount
of time from immediately after the fluid component is added to the
powder component until the material can no longer be reasonably
ejected from a syringe/needle. Accordingly, "work time" as used
herein includes the mixing time, the time to transfer the material
to a syringe and the time it takes to complete ejection the
material to its final placement.
Ejection Force:
[0099] The ejection force (measured 3 minutes after mixing the
solution and powder components of the compositions) for both the
Inventive Composition A (indicated as "FastSet") and the
Comparative Composition (indicated as "PRO-DENSE.RTM.") is provided
in FIG. 1. The left-most bar on the graph represents Inventive
Composition A, injected through an 11 gauge needle, the middle bar
represents Inventive Composition A, injected through an 8 gauge
needle, and the right-most bar on the graph represents the
Comparative Composition, injected through an 11-gauge needle. The
graph indicates that Inventive Composition A has acceptable values
of ejection force through 8-gauge and 11-gauge needles.
Diametral Tensile Strength:
[0100] The diametral tensile strength (DTS) of the Inventive
Composition A is tested and compared against the DTS of the
Comparative Composition in FIG. 2. As shown in FIG. 2, the DTS,
after 24 hours of cure time, is somewhat higher for Inventive
Composition A (indicated as "FastSet") than for the Comparative
Composition (indicated as "PRO-DENSE.RTM."). The difference in DTS
between the Comparative Composition and Inventive Composition A at
24 hours is statistically significant.
[0101] Diametral tensile strength is determined through the
following test methodology. A 1'' cube of 10 lb/ft.sup.3
closed-cell polyurethane foam (available as Last-A-Foam.RTM. from
General Plastics Manufacturing Company, Tacoma, Wash.) with an
approximately 5/8 in. (15.8 mm) outer diameter cylindrical void and
notches for side removal is used as the specimen mold. The
approximately 5/8 in. outer diameter cylindrical void is created by
drilling perpendicularly through opposite faces of the cube in one
depression of a drill press utilizing a 5/8 in. drill bit. The void
runs the entire length of the cube and is centered such that both
opposite, drilled faces share the same center as the circular voids
created in them from the drilling. Two opposite sides from the
remaining four full sides are designated to become the open sides
of the final specimen; these sides will be removed via the notches.
These sides are notched, two notches per side, in a manner such
that they can be removed immediately prior to testing and not
affect the sample integrity. The notches run the entire length of
the cube and are separated in a manner that upon removal, >50%
of the height of the specimen is exposed. Commonly the notches are
created using an upright band saw. Further details regarding
exemplary tensile test molds are provided in U.S. Pat. No.
7,754,246 to Moseley et al. and U.S. Patent Application Publication
No. 2007/0059281 to Carroll et al., which are incorporated herein
by reference.
[0102] The material to be tested is mixed to a homogeneous paste
and loaded into a device suitable for injection of the paste into
the 16 mm outer diameter cylindrical void. Commonly, a 30 cc
syringe with a 1 cm opening is used for this. The mold is held by
hand using the thumb and middle finger positioned on the opposite,
notched sides. The index finger of the hand used to hold the mold
is positioned over one of the circular openings. The material is
then injected into the void from the opposite side of the void from
the index finger; the entire face of the syringe exhibiting the 1
cm opening is lightly pushed up against the circular opening of the
mold. Upon injection of the material into the mold, pressure will
be felt on the index finger covering the back opening from the
ejected material. The index finger is slowly removed while filling
continues, allowing the paste to flow out of the rear of the mold
in an extrusion with the same 16 mm outer diameter as the void. The
syringe is slowly backed out from the front opening while back
filling of paste is performed through further ejection from the
syringe until the entire void is filled and excess material is
located outside the dimensions of the original cube of foam. The
front and rear sides of the specimen are wiped smooth, flush with
the front and rear sides of the mold using a spatula. All specimens
to be tested should be made within 2 minutes from the start of
mixing, defined by the aqueous solution coming into contact with
the particulate composition.
[0103] The specimens are allowed to cure horizontally in air in the
mold with the front and rear sides of the mold exposed to air at
room conditions (21-27.degree. C.; 20-50% relative humidity) for a
predetermined amount of time, normally 1 hr or 24 hrs. This
predetermined amount of time begins at the time at which the
aqueous solution comes into contact with the particulate
composition at the beginning of the mixing process. Testing is
performed on a mechanical test frame capable of displacement
control and of monitoring displacement and force through data
acquisition running at 20 Hz or faster. The sides of the specimen
mold are removed immediately prior to testing; only the areas
between the notches are removed.
[0104] Removal of the sides is normally performed with a knife. The
top and bottom of the mold are held between two fingers with slight
pressure to prevent specimen surface-to-mold interface damage. The
knife blade is placed into one of the notches and then twisted to
break the area between the notches free; this is repeated for the
other side in the same manner. The tops and bottom of the molds are
left in place to hold the specimen and prevent shear stresses on
the surface. The specimen is placed between two flat, parallel
platens; one of which is free to swivel to allow alignment with the
loading train. The swiveling platen assures an equally distributed
load across the specimen contact points. The specimen is loaded
transversely at a rate of 5 mm/minute until failure. Proper failure
will result in a vertical fracture completely through the length of
the specimen. The maximum force at failure is noted.
[0105] A loading curve of force versus displacement is created to
determine the maximum force at failure, in which displacement and
force are positive values. The first part of the loading curve
shows the loading of the foam followed by its compression. The
compression of the foam portion will be evident by continued
displacement with no substantial increase in force; this can also
be seen visually during the test. After the foam is completely
compressed, the force will begin to rise again, creating an
increasing slope on the loading curve followed by a constant slope
as the load is transferred to the specimen. The increasing slope is
commonly known as a "toe in". Failure is defined as a sudden drop
in load, a decrease in the slope of the loading curve after the
constant slope from specimen loading has been established, and/or
the force noted upon visual failure of the specimen while the test
is running.
[0106] The diametral tensile strength in MPa is then calculated as
followed: (2*Pmax)/(.pi.*L*H); where Pmax is the load at failure in
Newtons, .pi. is approximately equal to 3.14, L is the length of
the specimen in mm (25.4), and H is the height of the specimen in
mm (16). Specimens are disqualified for diametral tensile strengths
if any one or more of the following occur: fracture is not
vertical, fracture does not completely run the length of the
specimen, length of the specimen fails, or voids in the material
are seen on the fractured walls of the specimen.
Dissolution Rates:
[0107] Dissolution rates for Inventive Composition A and the
Comparative Composition are determined through the following
methodology. Specimens are cast in silicone molds to a size of 4.8
mm outer diameter and 3.3 mm tall cylinders. A 3.3 mm thick sheet
of silicone containing cylindrical voids is used as a mold.
Cylindrical voids are 4.8 mm in outer diameter and 3.3 mm tall, and
orientated such that the circular faces of the void are parallel
and in the same plane as the surfaces of the silicone sheet.
[0108] A thin sheet of polyethylene is laid on a table. A
polyethylene mesh is placed on top of the polyethylene sheet; sheet
and mesh are of same dimensions (excluding thickness) and
positioned such that the mesh masks the sheet from the top. Next a
silicone mold of smaller dimensions is placed on top of the mesh
(excluding thickness). No part of the mold hangs off the edge of
the mesh or sheet.
[0109] The material to be tested is then mixed together to form a
homogeneous paste. The paste is then wiped across the top of the
mold using a spatula in a manner that the voids are packed with the
material. The mesh will allow air to be displaced out of the void
as the mold is filled. Several wipes are performed to assure that
material has completely penetrated to bottom of the mold and
extruded out through the mesh and onto the lower polyethylene
sheet. A final wipe with the spatula across the top of the mold is
performed to remove the majority of excess material and produce
smooth top faces for the specimens. Another polyethylene sheet of
the same dimensions as the first is then placed across the top of
the mold, such that it completely covers the top of the mold. This
sheet is then gently pressed against the mold using a finger in a
gentle rubbing motion. An intimate contact between the top
polyethylene sheet and the specimens is created.
[0110] The entire system, sheet, mesh, mold, and sheet, is then
picked up as a whole and flipped over in a manner such that the
original top is now facing down. The system is held by hand and
slapped repeatedly onto table in a manner such that any air
entrapped in the molds will be displaced out by the material;
slapping of the system should not be excessive in force or
repetitions. Upon removal of the majority of the air the system is
returned to table in the upside down orientation, sheet and mesh
side up. The top polyethylene sheet, originally the bottom, and
mesh are removed and the spatula is again used to wipe material
into voids in the tops (previously bottoms) of the specimens
created from air removal. A final wipe with the spatula across the
top of the mold is performed to remove the majority of excess
material. The sheet (no mesh) is returned to the top of the mold.
The sheet is then pressed against the mold using a finger in a
gentle rubbing motion. An intimate contact between the top and
bottom polyethylene sheet and the specimens has now been
created.
[0111] The specimens are left in the mold to cure for a minimum of
8 hrs after the second polyethylene sheet has been placed in direct
contact with the specimens and mold (no mesh). After at least 8 hrs
have passed, the specimens are demolded by hand. Any flash
remaining attached to pellet faces are removed by rolling specimen
between fingers. All defective specimens are disqualified from the
test and discarded. A defective specimen is defined as a specimen
not exhibiting a cylindrical shape, which could be caused by
entrapped air, defects created upon demolding, and/or physical
damage to the specimen itself.
[0112] All specimens which are not defective are spread across a
stainless steel pan in a monolayer. The pan and specimens are then
dried in an oven at 40.degree. C. for a minimum of 4 hrs, and then
removed from oven and allowed to cool for 30 minutes in room
conditions (21-27.degree. C.; 20-50% relative humidity).
[0113] From the specimens created, five (5) specimens are
arbitrarily chosen to be used for dissolution testing. Each
specimen chosen is paired with a clean cylindrical fitted glass
extraction thimble of the following dimensions: 90.25 mm overall
height, 4 mm fitted glass base (40-60 micron pores) located 80 mm
from top of thimble, 25 mm outer diameter, and 22 mm inner
diameter. The mass of each extraction thimble is measured (0.01 mg)
and noted. The mass of each specimen in measured (0.01 mg) and
noted. A polyethylene bottle (300 mL) is designated to each pair
(specimen and thimble). The bottle has dimensions that allow
thimble and specimen to easily be placed in and removed from bottle
and upon filling with 275 mL of water will create a column of water
that is taller than the thimble. The bottle is filled with 275 mL
of distilled water at room temperature (21-27.degree. C.). The
specimen is placed into its corresponding thimble and the thimble
is lowered into the bottle; care is taken to keep any part of the
material from escaping from the thimble. The bottle is capped and
placed into a water bath at 37.degree. C. with no agitation and the
time is noted.
[0114] At 24 hrs after the specimen has been in the water, the
thimble containing the specimen is retrieved. The water is allowed
to drain out of the thimble through the fitted glass base. The
thimble containing the specimen is then dried for 4 hrs in a
40.degree. C. oven or until completely dried (determined
gravimetric ally). The thimble containing the specimen is then
allowed to cool down for 30 minutes at room conditions
(21-27.degree. C.; 20-50% relative humidity).
[0115] The thimble containing the pellet is then weighed to an
accuracy of 0.01 mg. Subtracting the known empty thimble mass from
the mass of the combination will result in the mass of the specimen
alone. Subtracting this mass from the initial specimen mass will
produce the mass lost to dissolution. This mass lost can be divided
by the specimen initial mass and the product of that multiplied by
100 will result in the % mass lost from dissolution.
[0116] At this point the thimble containing the pellet is returned
to the bottle containing fresh distilled water (275 mL) at room
temperature (21-27.degree. C.), and the bottle is capped and
returned to the water bath. After 24 hrs the drying and weighing
process is repeated. These actions are repeated with fresh
distilled water after every 24 hr soak until the test is terminated
or the material completely dissolves. The Inventive Composition A
(indicated as "FastSet" in FIG. 3) provided a slightly slower daily
accelerated dissolution than the Comparative Composition (indicated
as "PD" in FIG. 3).
Example 2
[0117] A second exemplary embodiment of the presently disclosed
composition is provided as follows, and was prepared specifically
for the purposes of characterization and evaluation of the
Inventive Composition against the Comparative Composition. It is
noted that "Inventive Powder Composition A" as referenced in Table
6 is comparable to "Inventive Composition A" as referenced in Table
1; however, "Inventive Powder Composition A" as referenced in Table
6 does not include the MCPM and glycolic acid/saline solution of
"Inventive Composition A." Table 7 indicates the relative mixing
amounts of Inventive Powder Composition A, MCPM, and glycolic
acid/saline solution to provide "Inventive Composition A."
TABLE-US-00006 TABLE 6 Inventive Powder Composition A Component
Percent by weight Particle size range Calcium sulfate hemihydrate
74.59% 5 .mu.m-10 .mu.m Accelerator (calcium sulfide) 0.10%
.ltoreq.595 .mu.m Non-porous .beta.-TCP granules 10.37% 180
.mu.m-240 .mu.m Porous .beta.-TCP granules (0-63 2.59% 0 .mu.m-63
.mu.m .mu.m) Porous .beta.-TCP granules (63- 7.78% 63 .mu.m-250
.mu.m 250 .mu.m) Non-porous .beta.-TCP powder 4.57% 13.3 .mu.m-15.7
.mu.m
[0118] The components of Inventive Powder Composition A as shown in
Table 6 were mixed. Inventive Powder Composition A, MCPM, and
glycolic acid/saline solution were separately sterilized by gamma
irradiation and combined in the amounts provided below in Table 7
for the tests indicated in the table.
TABLE-US-00007 TABLE 7 Inventive Composition A Makeup for Various
Tests Inventive Composition A Glycolic Inventive Powder Acid/Saline
Test Composition A (g) MCPM (g) Solution (g) FTIR 19.28 0.72 5.00
XRD Dissolution Maximum Exothermic 24.10 0.90 6.25 Temperature
Vicat and Gillmore Set 33.74 1.26 8.75 Time (wet) Vicat and
Gillmore Set 33.74 1.26 8.75 Time (dry) Dilute slurry pH 24.10 0.90
6.25 Density 24.10 0.90 6.25 Porosity 24.10 0.90 6.25 DTS (wet)
57.85 2.15 15.00 DTS (dry) 57.85 2.15 15.00 Injectability
(Ejection) 38.56 1.44 10.00
Chemical Composition (FTIR, XRD):
[0119] Inventive Powder Composition A, MCPM, and glycolic
acid/saline solution were mixed and the resulting paste was spread
onto a pellet mold and allowed to dry for a minimum of 8 hours at
room temperature to give a pellet. The pellet was then oven dried
at 40.degree. C. for 5 hours and crushed to a powder using a mortar
and pestle for analysis.
[0120] A ThermoScientific Nicolet i210g FTIR instrument was used
for FTIR analysis using a diffuse reflectance method. The spectrum
of Inventive Composition A exhibited peaks indicative of a calcium
sulfate dihydrate, calcium sulfate hemihydrate, and tricalcium
phosphate, correlating with the spectrum of the Comparative
Composition.
[0121] A Rigaku MiniFlex X-Ray Diffraction instrument was used for
XRD analysis. The Inventive Composition A demonstrated an almost
full conversion from calcium sulfate hemihydrate form (CaSO.sub.4
1/2H.sub.2O) to the dihydrate form (CaSO.sub.4.2H.sub.2O). Peaks of
tricalcium phosphate (Ca.sub.3(PO.sub.4).sub.2) and brushite
(CaHPO.sub.4.2H.sub.2O) were also identified.
Physical Properties (pH, Maximum Exothermic Temperature,
Dissolution, Porosity, and Density):
[0122] For pH determination, a loose slurry of the powder and
liquid components of Inventive Composition A was mixed continuously
for five minutes. At the end of the five minutes, pH was recorded.
Three separate slurries were prepared and tested in this way,
giving an average pH of 5.52 and a standard deviation of 0.02. The
pH of Inventive Composition A was determined to be not
significantly different than that of the Comparative Composition
(p=0.074), based on a two-sample T-Test.
[0123] For maximum exothermic temperature determination, Inventive
Powder Composition A and MCPM were mixed together, the glycolic
acid/saline solution was added to the mixer, and the materials were
mixed vigorously for 30 seconds under 22-25'' vacuum to give
Inventive Composition A. The paste was transferred to a
polyethylene mold containing a thermocouple to record the
temperature of the specimen. The temperature was recorded
continuously as the material cured and the maximum was determined
(based on ASTM F451). Three separate specimens were prepared and
tested in this way, giving an average maximum exothermic
temperature of 30.7 and a standard deviation of 0.1. The average
maximum exothermic temperature of Inventive Composition A was
determined to be significantly different than that of the
Comparative Composition (p=0.000). A slight increase in reaction
temperature is not unexpected due to the increased reaction rate
for the Inventive Composition A and for all materials tested, the
maximum temperature was advantageously well below the average body
temperature of 37.degree. C.
[0124] For dissolution testing, Inventive Powder Composition A and
MCPM were mixed together, the glycolic acid/saline solution was
added to the mixer, and the materials were mixed vigorously for 30
seconds under 22-25'' vacuum to give Inventive Composition A. The
resulting paste was spread onto a pellet mold and allowed to dry
for a minimum of 8 hours at room temperature to give a pellet. The
pellet was then oven dried at 40.degree. C. for 5 hours. Changes in
pellet weight were recorded after 96 hours of immersion in
deionized water. Five trials were done and the average percentage
of mass remaining in pellets comprising Inventive Composition A was
68.03%. The average dissolution of Inventive Composition A was
determined to be not significantly different than that of the
Comparative Composition (p=0.067), based on a Mann-Whitney
test.
[0125] For porosity testing, Inventive Powder Composition A and
MCPM were mixed together, the glycolic acid/saline solution was
added to the mixer, and the materials were mixed vigorously for 30
seconds under 22-25'' vacuum to give Inventive Composition A. The
resulting paste was loaded into a 10 cc syringe and the syringe was
tapped to remove air bubbles. The loaded syringe was air dried at
room temperature, the end of the syringe was cut, and the sample
was pushed out of the syringe. The resulting material was oven
dried at 40.degree. C. for 12 hours and broken in half by bending.
The fracture surface was wet ground with alcohol to produce a
smooth surface for analysis. The smoothed surface was examined with
a microscope and porosity was evaluated by examination of the
surface for visible pores at 7.5.times. The area of each void was
measured using software and the total void area was calculated by
summing the areas of all voids. The total void area of the section
was divided by the total area of the fracture surface to determine
percent porosity. The average percent porosity of Inventive
Composition A was determined to be not significantly different than
that of the Comparative Composition (p=1.00), based on a
Mann-Whitney test.
[0126] For density testing, Inventive Powder Composition A and MCPM
were mixed together, the glycolic acid/saline solution was added to
the mixer, and the materials were mixed vigorously for 30 seconds
under 22-25'' vacuum to give Inventive Composition A. The resulting
paste was loaded into a 15 cc open bore syringe and ejected into
specimens approximately 1.5'' long and 0.5'' wide. The resulting
specimen was dried at room temperature for 24 hours and then oven
dried at 40.degree. C. for 12 hours. After drying, the specimen was
weighed and then submerged into a 10 cc graduated cylinder
containing 5 mL deionized water and degassed in a sonicator for 3
minutes. The change in volume was measured visually on the
graduated cylinder and the ratio was calculated by dividing the
dried mass by the change in volume. The density of Inventive
Composition A was determined to be not significantly different than
that of the Comparative Composition (p=0.89), based on a two-sample
t-test.
[0127] Performance Characteristics (Vicat Set Time, Gillmore Set
Time, Injectability, and Diametral Tensile Strength):
[0128] For performance characteristic testing, Inventive Powder
Composition A and MCPM were mixed together, the glycolic
acid/saline solution was added to the mixer, and the materials were
mixed vigorously for 30 seconds under 22-25'' vacuum to give
Inventive Composition A.
[0129] For Vicat set time determination, the paste was transferred
to a small testing cup and evenly spread to create a material with
constant thickness. A 300 g weight with an attached probe of 1 mm
diameter was placed on the specimen and the specimen was considered
to be "Vicat set" when the probe penetrated half the specimen
thickness or less (as described in greater detail in Example 1).
Vicat set time was determined in both "dry" (cured in air) and
"wet" (cured in bovine serum) conditions. In both the dry and wet
environments, Inventive Composition A had a significantly faster
Vicat set time than the Comparative Composition (p=0.000 and
p=0.005, respectively), based on a two-sample t-test.
[0130] The dry Vicat set time averages for specimens prepared from
three different lots of Inventive Composition A (each lot used to
prepare four specimens and the Vicat set times of these four
specimens averaged to give a Lot Vicat set time average) were 12:38
(std. dev. 01:15), 10:38 (std. dev. 01:10), and 12:40 (std. dev.
01:26). The dry Vicat set time average for specimens prepared from
the Comparative Composition (four specimens prepared and the Vicat
set times of these four specimens averaged to give a Vicat set time
average) was 16:50 (std. dev. 00:46).
[0131] The wet Vicat set time averages for specimens prepared from
three different lots of Inventive Composition A (each lot used to
prepare three specimens and the Vicat set times of these three
specimens averaged to give a Lot Vicat set time average) were 13:40
(std. dev. 00:35), 11:40 (std. dev. 00:17), and 13:00 (std. dev.
00:17). The wet Vicat set time for the second lot of Inventive
Composition A was significantly faster setting in the wet
environment than the first and third lots (p=0.005, ANOVA);
however, the difference in set times was not large and
historically, wet testing has been more prone to variation within
samples. The wet Vicat set time average for specimens prepared from
the Comparative Composition (three specimens prepared and the Vicat
set times of these three specimens averaged to give a Vicat set
time average) was 18:15 (std. dev. 01:09).
[0132] For Gillmore set time determination, the paste was
transferred to a small testing cup and evenly spread to create a
material with constant thickness. The specimen was considered to be
"Gillmore set" when the probe left no appreciable indentation on
the surface of the specimen (as described in greater detail in
Example 1). Gillmore set time was evaluated immediately after Vicat
set time and was determined in both "dry" (cured in air) and "wet"
(cured in bovine serum) conditions. In the dry environment,
Inventive Composition A had a significantly faster Gillmore set
time than the Comparative Composition (p=0.002), based on a
two-sample t-test. In the wet environment, no data was available
for the Comparative Composition and the Comparative Composition is
typically not used under such conditions, so the Gillmore set time
of Inventive Composition A in a wet environment could not be
compared against that of the Comparative Composition.
[0133] The dry Gillmore set time averages for specimens prepared
from three different lots of Inventive Composition A (each lot used
to prepare four specimens and the Vicat set times of these four
specimens averaged to give a Lot Gillmore set time average) were
16:08 (std. dev. 2:25), 13:00 (std. dev. 01:21), and 14:30 (std.
dev. 02:05). The dry Vicat set time average for specimens prepared
from the Comparative Composition (four specimens prepared and the
Vicat set times of these four specimens averaged to give a Vicat
set time average) was 47:00 (std. dev. 05:37).
[0134] The wet Vicat set time averages for specimens prepared from
three different lots of Inventive Composition A (each lot used to
prepare three specimens and the Vicat set times of these three
specimens averaged to give a Lot Vicat set time average) were 17:50
(std. dev. 00:35), 15:20 (std. dev. 00:34), and 19:00 (std. dev.
01:30). The wet Vicat set time for the second lot of Inventive
Composition A was significantly faster setting in the wet
environment than the first and third lots (p=0.010, ANOVA);
however, the difference in set times was not large and
historically, wet testing has been more prone to variation within
samples.
[0135] For injectability (ejection) determination, the paste was
placed into a 20 cc syringe equipped with a 11 Ga, 6 cm Jamshidi
needle. A force was applied to the syringe/needle system at the
rate of 4.4 mm/sec until the specimen was ejected into a test cup.
The resistance to ejection force at 15 mm displacement was recorded
for the specimen at 3 minutes after initiation of mixing. The
injectability of Inventive Composition A was determined to be not
significantly different than that of the Comparative Composition
(p=0.098), based on a two-sample t-test.
[0136] For diametral tensile strength, specimens were prepared and
tested under dry conditions (as described in greater detail in
Example 1). Specimens were also prepared and tested under wet
conditions (i.e., a proteinaceous environment meant to simulate in
situ conditions) by curing the paste for one hour, immersing the
specimens in bovine serum, and heating the mixture at 37.degree.
C.+-.1.degree. C. A 2-hour test was performed by allowing the
specimens to cure for one hour in bovine serum before testing and a
24-hour test was performed by allowing the specimens to cure for 23
hours in bovine serum. Specimens were then placed between the
plates of a compression sub-press mounted in a test frame and
compressed at a constant rate of 1.5 mm/min until fracture
occurred.
[0137] The 2-hour diametral tensile strength of Inventive
Composition A in both dry and wet conditions was determined to be
significantly different (roughly a 20% increase in strength) than
that of the Comparative Composition (p=0.001 for the dry
conditions, based on a two-sample t-test and p=0.003 for the wet
conditions, based on a Kruskal-Wallis test). A higher initial
strength is consistent with the significantly faster set time of
Inventive Composition A as compared with the Comparative
Composition.
[0138] The 24-hour diametral tensile strength of Inventive
Composition A in dry conditions was determined not to be
significantly different than that of the Comparative Composition
(p=0.061), based on a two-sample t-test. The 24-hour diametral
tensile strength of Inventive Composition A in wet conditions was
determined to be significantly different (with Inventive
Composition A being stronger than the Comparative Composition) than
that of the Comparative Composition (p=0.012), based on a
two-sample t-test. The cause of this higher strength is not known,
but the difference is relatively small (1.9 MPa) and likely due to
known variation in data when materials are cured in a wet
environment.
[0139] Overall, Inventive Composition A is statistically equivalent
to the Comparative Composition both chemically and physically.
Inventive Composition A provides improvements in performance
characteristics by decreasing the Vicat and Gillmore set times
while maintaining the strength and injectability of the
material.
[0140] Many modifications and other embodiments of the inventions
set forth herein will come to mind to one skilled in the art to
which these inventions pertain having the benefit of the teachings
presented in the foregoing descriptions and the associated
drawings. Therefore, it is to be understood that the inventions are
not to be limited to the specific embodiments disclosed and that
modifications and other embodiments are intended to be included
within the scope of the appended claims. Although specific terms
are employed herein, they are used in a generic and descriptive
sense only and not for purposes of limitation.
* * * * *