U.S. patent application number 09/915997 was filed with the patent office on 2002-06-13 for bone graft substitute composition.
Invention is credited to Hagan, Cary P., Haggard, Warren Oliver, Petersen, Donald W., Randolph, Donald A., Richelsoph, Kelly Coupe.
Application Number | 20020071827 09/915997 |
Document ID | / |
Family ID | 23277952 |
Filed Date | 2002-06-13 |
United States Patent
Application |
20020071827 |
Kind Code |
A1 |
Petersen, Donald W. ; et
al. |
June 13, 2002 |
Bone graft substitute composition
Abstract
A bone graft substitute composition can include essentially of
calcium sulfate, a mixing solution, and a plasticizing substance. A
bone graft substitute composition can include calcium sulfate,
demineralized bone matrix, cancellous bone, a plasticizing
substance, and a mixing solution.
Inventors: |
Petersen, Donald W.;
(Bessemer, AL) ; Richelsoph, Kelly Coupe;
(Memphis, TN) ; Haggard, Warren Oliver; (Bartlett,
TN) ; Hagan, Cary P.; (Germantown, TN) ;
Randolph, Donald A.; (Wheaton, IL) |
Correspondence
Address: |
ROBERT C. NABINGER
Fish & Richardson P.C.
225 Franklin Street
Boston
MA
02110-2804
US
|
Family ID: |
23277952 |
Appl. No.: |
09/915997 |
Filed: |
July 26, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09915997 |
Jul 26, 2001 |
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09327761 |
Jun 7, 1999 |
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Current U.S.
Class: |
424/93.1 |
Current CPC
Class: |
C08L 1/26 20130101; A61K
2300/00 20130101; A61L 27/36 20130101; A61L 27/54 20130101; C08L
1/14 20130101; A61K 33/00 20130101; A61K 31/715 20130101; C08L 1/26
20130101; A61L 27/54 20130101; A61L 27/36 20130101; A61K 33/06
20130101; A61K 33/06 20130101; A61K 35/32 20130101; A61L 27/025
20130101; A61F 2002/2835 20130101; A61K 35/32 20130101; A61L 27/446
20130101; A61L 27/446 20130101; A61K 33/06 20130101; A61K 31/715
20130101; C08L 1/14 20130101; A61L 2430/02 20130101; A61K 2300/00
20130101; A61L 27/446 20130101; A61L 27/3608 20130101; A61L 27/446
20130101; A61L 27/365 20130101; A61L 27/446 20130101; A61K 35/32
20130101; A61K 33/06 20130101 |
Class at
Publication: |
424/93.1 |
International
Class: |
A61K 045/00 |
Claims
What is claimed is:
1. A bone graft substitute composition, consisting essentially of:
calcium sulfate; a mixing solution; and a plasticizing
substance.
2. The composition of claim 1, wherein the calcium sulfate
comprises calcium sulfate hemihydrate.
3. The composition of claim 1, wherein the plasticizing substance
comprises a cellulose derivative.
4. The composition of claim 1, wherein the plasticizing substance
is selected from a group consisting of sodium
carboxymethylcellulose, methylcellulose, hydroxypropyl methyl
cellulose, hydroxypropyl cellulose, ethylcellulose,
hydroxyethylcellulose, and cellulose acetate butyrate.
5. The composition of claim 1, wherein the plasticizing substance
comprises hydroxypropyl methyl cellulose.
6. The composition of claim 1, wherein the plasticizing substance
comprises hydroxypropyl cellulose.
7. The composition of claim 1, wherein the plasticizing substance
comprises hyaluronic acid.
8. The composition of claim 1, wherein the plasticizing substance
comprises methylcellulose.
9. The composition of claim 1, wherein the mixing solution is
selected from a group consisting of sterile water, inorganic salt,
and cationic surface active agent.
10. The composition of claim 9, wherein the cationic surface active
agent is selected from a group consisting of sodium chloride,
phosphate buffered saline, potassium chloride, sodium sulfate,
ammonium sulfate, ammonium acetate, and sodium acetate.
11. The composition of claim 1, wherein the mixing solution
comprises sterile water.
12. The composition of claim 1, wherein the composition does not
comprise a polymer matrix.
13. The composition of claim 1, wherein the composition does not
comprise bone.
14. The composition of claim 1, consisting essentially of: 100
parts by weight of the calcium sulfate; about 1.5 to about 8 parts
by weight of the plasticizing substance; and about 25 to about 65
parts by weight of the mixing solution.
15. The composition of claim 1, consisting essentially of: 100
parts of the calcium sulfate; about 5.25 parts by weight of the
plasticizing substance; and about 33.6 parts by weight of the
mixing solution.
16. A bone graft substitute composition, comprising: calcium
sulfate; demineralized bone matrix; cancellous bone; a plasticizing
substance; and a mixing solution.
17. The composition of claim 16, wherein the calcium sulfate
comprises calcium sulfate hemihydrate.
18. The composition of claim 16, wherein the plasticizing substance
comprises a cellulose derivative.
19. The composition of claim 16, wherein the plasticizing substance
is selected from a group consisting of sodium
carboxymethylcellulose, methylcellulose, hydroxypropyl methyl
cellulose, hydroxypropyl cellulose, ethylcellulose,
hydroxyethylcellulose, and cellulose acetate butyrate.
20. The composition of claim 16, wherein the mixing solution is
selected from a group consisting of sterile water, inorganic salt,
and cationic surface active agent.
21. The composition of claim 20, wherein the cationic surface
active agent is selected from a group consisting of sodium
chloride, phosphate buffered saline, potassium chloride, sodium
sulfate, ammonium sulfate, ammonium acetate, and sodium
acetate.
22. The composition of claim 16, wherein the mixing solution
comprises sterile water.
23. The composition of claim 16, comprising: about 80 to about 120
parts by weight of calcium sulfate; about 10 to about 100 parts by
weight of demineralized bone matrix; about 10 to about 100 parts by
weight of cancellous bone; about 1 to about 40 parts by weight of a
plasticizing substance; and about 21 to about 250 parts by weight
of a mixing solution.
24. The composition of claim 16, comprising: about 90 to about 110
parts by weight of calcium sulfate; about 10 to about 50 parts by
weight of demineralized bone matrix; about 15 to about 50 parts by
weight of cancellous bone; about 5 to about 20 parts by weight of a
plasticizing substance; and about 80 to about 120 parts by weight
of a mixing solution.
25. The composition of claim 16, comprising: about 98 to about 102
parts by weight of calcium sulfate; about 13 to about 23 parts by
weight of demineralized bone matrix; about 27 to about 33 parts by
weight of cancellous bone; about 15 to about 20 parts by weight of
a plasticizing substance; and about 95 to about 105 parts by weight
of a mixing solution.
26. The composition of claim 16, comprising: about 100 parts by
weight of calcium sulfate; about 18 to about 19 parts by weight of
demineralized bone matrix; about 27 to about 28 parts by weight of
cancellous bone; about 17 to about 18 parts by weight of a
plasticizing substance; and about 101 to about 102 parts by weight
of a mixing solution.
27. A bone graft substitute composition, comprising: about 80 to
about 120 parts by weight of calcium sulfate hemihydrate; about 10
to about 100 parts by weight of demineralized bone matrix; about 10
to about 100 parts by weight of cancellous bone; about 1 to about
40 parts by weight of a carboxymethylcellulose; and about 21 to
about 250 parts by weight of sterile water.
28. The composition of claim 27, comprising: about 90 to about 110
parts by weight of calcium sulfate hemihydrate; about 10 to about
50 parts by weight of demineralized bone matrix; about 15 to about
50 parts by weight of cancellous bone; about 5 to about 20 parts by
weight of carboxymethylcellulose; and about 80 to about 120 parts
by weight of sterile water.
29. The composition of claim 27, comprising: about 98 to about 102
parts by weight of calcium sulfate hydrate; about 13 to about 23
parts by weight of demineralized bone matrix; about 27 to about 33
parts by weight of cancellous bone; about 15 to about 20 parts by
weight of carboxymethylcellulose; and about 95 to about 105 parts
by weight of sterile water.
30. The composition of claim 27, comprising: about 100 parts by
weight of calcium sulfate hemihydrate; about 18 to about 19 parts
by weight of demineralized bone matrix; about 27 to about 28 parts
by weight of cancellous bone; about 17 to about 18 parts by weight
of carboxymethylcellulose; and about 101 to about 102 parts by
weight of sterile water.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of
and claims priority to U.S. application Ser. No. 09/327,761, filed
on Jun. 7, 1999, and entitled "Bone Graft Substitute Composition",
hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to bone graft substitute
compositions.
BACKGROUND
[0003] Calcium sulfate has been clinically used for many years as a
bone void filler with successful results. A preliminary
patentability search produced the following patents which appear to
be relevant to the present invention:
[0004] Hanker et al., U.S. Pat. No. 4,619,655, issued Oct. 28,
1986, discloses an animal implant comprising a scaffold material
composed of plaster of Paris and a non-bioresorbable calcium
material (such as calcium phosphate ceramic particles) bound with
the plaster of Paris; a method of inserting such a composition in
fluid or semisolid form into the appropriate body location of an
animal (e.g., about a fracture locus); and a method of inserting a
preform of such composition into the appropriate location of an
animal (e.g., at the locus of a fracture).
[0005] Gitelis, U.S. Pat. No. 5,147,403, issued Sep. 15, 1992,
discloses a method or technique for implanting a prosthesis
comprising the steps of first preparing the surface of a bone to
receive the prosthesis, then applying a calcium sulfate suspension
in free flowing form to the prepared bone surface, and then seating
the prosthesis to the coated bone surface.
[0006] Randolph, U.S. Pat. Nos. 5,614,206, issued Mar. 25, 1997,
and 5,807,567, issued Sep. 15, 1998, disclose processes for
preparing pellets by mixing of calcium sulfate, water and other
medicaments to provide controlled release of calcium sulfate and
medicaments.
[0007] Snyder, U.S. Pat. No. 5,425,769, issued Jun. 20, 1995,
discloses a composition for an artificial bone substitute material
consisting of collagen in a calcium sulfate matrix which can be
rendered porous by a foaming agent. The composition is adaptable
for osseous repair by adjusting the collagen and calcium sulfate in
varying ratios to suit particular applications and including
admixtures of growth factors.
[0008] Sottosanti, U.S. Pat. No. 5,366,507, discloses a composition
for use in bone tissue regeneration, the composition containing a
barrier material and a graft material. The barrier material can be
calcium sulfate, while the graft material may consist of a
composite graft material containing demineralized, freeze-dried,
allogeneic bone and calcium sulfate.
[0009] Sottosanti, U.S. Pat. No. 5,569,308, discloses a method for
use in bone tissue regeneration including first filling a graft
site with graft material, and then placing a layer of barrier
material over at least a portion of the graft material. The barrier
material can be calcium sulfate, while the graft material may
consist a composite graft material containing demineralized,
freeze-dried, allogeneic bone and calcium sulfate.
[0010] Hanker et al, "Setting of Composite Hydroxylapatite/Plaster
Implants with Blood 5 for Bone Reconstruction," Proceedings of the
44th Annual Meeting of the Electron Microscopy Society of America,
Copyright 1986, discloses using blood as the only moistening agent
in a plaster or plaster/HA mixture as long as accelerator salts are
utilized, and suggests that the putty-like consistency of such
compositions offers distinct advantages in moldability and
workability.
[0011] Osteotech, Inc., of Shrewsbury, N.J., markets a bone graft
substitute under the mark Grafton.RTM.. It is comprised of
demineralized bone matrix and glycerol as a carrier material. The
carrier material, glycerol, is a viscous, gel-like, weak alcohol
that is hydrophilic and water-soluble. It is recognized by the Food
and Drug Administration as a "Generally Regarded As Safe"
substance.
[0012] DePuy, Inc., of Warsaw, Ind., markets a bone graft
substitute under the mark DynaGraft.RTM.. It is comprised of
demineralized bone matrix and poloxamer as a carrier material.
Poloxamer is a reverse phase polymer which becomes more viscous
with increasing temperature.
[0013] Nothing in the known prior art discloses or suggests a bone
graft substitute composition including calcium sulfate, a mixing
solution such as sterile water, and a plasticizing substance such
as carboxymethylcellulose, and having an extended set time and
sufficient robustness to withstand fluid impact with minimal
erosion.
SUMMARY OF THE INVENTION
[0014] A basic concept of the present invention is to provide bone
graft substitute composition having an extended set time and
sufficient robustness to withstand fluid impact with minimal
erosion for expanded clinical applications.
[0015] The bone graft substitute composition of the present
invention comprises, in general, calcium sulfate; a mixing solution
such as sterile water; and a plasticizing substance such as
carboxymethylcellulose.
[0016] One object of the present invention is to provide a bone
graft substitute composition that can be mixed into a paste and
then loaded into a syringe and ejected for an extended period of
time (e.g., more than ten minutes).
[0017] Another object of the present invention is to provide a bone
graft substitute composition that can be mixed into a putty and
then handled and formed into desired shapes for an extended period
of time (e.g., more than ten minutes).
DETAILED DESCRIPTION
[0018] The bone graft substitute composition of the present
invention comprises, in general, a quantity of calcium sulfate, a
quantity of fluid (e.g., sterile water), and a quantity of a
plasticizing substance (e.g., carboxymethylcellulose) which
provides a resultant composition that is robust and has an extended
set time. The extended set time of the resultant composition
provides a useful working time of at least 5 minutes to allow
sufficient time for a surgeon to properly apply the bone graft
substitute composition, while the robustness of the resultant
composition allows the implanted composition to withstand the
typical pressure of body fluids, irrigation fluids and/or
suctioning with minimal material erosion, disintegration or
dissolution.
[0019] The bone graft substitute composition of the present
invention may comprise a mixture of calcium sulfate; a mixing
solution selected from the group consisting of sterile water,
inorganic salts, and cationic surface active agents including
sodium chloride, phosphate buffered saline, potassium chloride,
sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium
acetate, and sodium acetate, etc.; and a plasticizing substance
selected from the group consisting of cellulose derivatives
including sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl methylcellulose, hydroxypropylcellulose,
ethylcellulose, hydroxethylcellulose and cellulose acetate
butyrate, and higher molecular weight alcohols including glycerol
and vinyl alcohols, etc. The bone graft substitute composition may
include demineralized bone matrix. One formulation of the
composition may be approximately 100 parts calcium sulfate by
weight, 11.1 parts carboxymethylcellulose by weight, 185.2 parts
water by weight, and 69.4 parts demineralized bone matrix by
weight. Another formulation of the composition may be approximately
100 parts calcium sulfate by weight, 6.3 parts
carboxymethylcellulose by weight, and 31 parts water by weight.
Another formulation of the composition may be approximately 100
parts calcium sulfate by weight, 1.2 parts carboxymethylcellulose
by weight, and 31 parts water by weight. Another formulation of the
composition may be approximately 80-120 parts calcium sulfate by
weight, 1-40 parts carboxymethylcellulose by weight, and 21-250
parts water by weight. The composition may include a bioactive
agent selected from the group consisting of demineralized bone
matrix, growth factors, hyaluronic acid, bone morphogenic proteins,
bone autograft, and bone marrow, etc. The composition may include
sodium bicarbonate. For example, the composition may include 0.1-2%
sodium bicarbonate by weight for creating a porous structure in the
resultant composition. Possible embodiments of the bone graft
substitute composition of the present invention may include at
least one additive selected from the group consisting of antiviral
agent, antimicrobial agent, antibiotic agent, amino acid, peptide,
vitamin, inorganic element, protein synthesis co-factor, hormone,
endocrine tissue, synthesizer, enzyme, polymer cell scaffolding
agent with parenchymal cells, angiogenic drug, demineralized bone
powder, collagen lattice, antigenic agent, cytoskeletal agent,
mesenchymal stem cells, bone digester, antitumor agent, cellular
attractant, fibronectin, growth hormone, cellular attachment agent,
immunosuppressant, nucleic acid, surface active agent,
hydroxyapatite, penetration enhancer, bone allograft, and chunks,
shards, and/or pellets of calcium sulfate.
PREFERRED EMBODIMENT 1
[0020] An injectable bone graft substitute composition having the
following preferred formulation: 100 parts by weight of medical
grade calcium sulfate hemihydrate (MGCSH), 11.1 parts by weight of
carboxymethylcellulose (CMC), 69.4 parts by weight 15 of
demineralized bone matrix (DBM), and 162 parts by weight of sterile
water.
[0021] The preferred method for mixing this putty bone graft
substitute composition comprises the following steps: (1) dry blend
the powder components (i.e., the calcium sulfate hemihydrate,
carboxymethylcellulose, and demineralized bone matrix); (2) add the
sterile water; and (3) mix or stir all components for approximately
30 seconds to one minute or until the desired putty-like
consistency is achieved.
[0022] The resultant injectable bone graft substitute composition
has the following characteristic/criteria:
[0023] Handability - the resultant composition should: (a) be a
single cohesive bolus; (b) be able to be handled and manipulated
with minimal to no material transfer (sticking) to latex gloved
hand; (c) be able to be handled without material crumbling or
falling apart; and (d) exhibit minimal cracking or "tearing" with
extreme manipulation, e.g., hard squeezing;
[0024] Ejectability - the resultant composition should: (a) be able
to be easily manipulated, e.g., rolled into a long cylinder or
other suitable shape, so as to be manually placed into an
appropriate injection apparatus, e.g., a syringe; and (b) be able
to be ejected through a 1/8 inch (0.3175 centimeter) diameter
orifice with relatively little pressure required; and
[0025] Robustness - the resultant composition, after being placed
or injected into or onto the desired location, should be able to
withstand body fluids, reasonable irrigation fluids and/or
suctioning with minimal material erosion, disintegration or
dissolution.
PREFERRED EMBODIMENT 2
[0026] A putty bone graft substitute composition having the
following preferred formulation: 100 parts by weight of medical
grade calcium sulfate hemihydrate (MGCSH), 11.1 parts by weight of
carboxymethylcellulose (CMC), and 47 parts by weight of sterile
water.
[0027] The preferred method for mixing this putty bone graft
substitute composition comprises the following steps: (1) dry blend
the powder components (i.e., the calcium sulfate hemihydrate, and
carboxymethylcellulose); (2) add the sterile water; and (3) mix or
stir all components for approximately 30 seconds to one minute or
until the desired putty-like consistency is achieved.
[0028] The resultant putty bone graft substitute composition has
the following characteristic/criteria:
[0029] Handability - the resultant composition should: (a) be a
single cohesive bolus; (b) be able to be handled and manipulated
with minimal to no material transfer (sticking) to latex gloved
hand; (c) be able to be handled without material crumbling or
falling apart; and (d) exhibit minimal cracking or "tearing" with
extreme manipulation, e.g., hard squeezing; and
[0030] Robustness - the resultant composition, after being placed
or injected into or onto the desired location, should be able to
withstand body fluids, reasonable irrigation fluids and/or
suctioning with minimal material erosion, disintegration or
dissolution.
PREFERRED EMBODIMENT 3
[0031] A paste bone graft substitute composition having the
following preferred formulation: 100 parts by weight of medical
grade calcium sulfate hemihydrate (MGCSH), 1.2 parts by weight of
carboxymethylcellulose (CMC), and 31 parts by weight of sterile
water.
[0032] The preferred method for mixing this putty bone graft
substitute composition comprises the following steps: (1) dry blend
the powder components (i.e., the calcium sulfate hemihydrate, and
carboxymethylcellulose); (2) add the sterile water; and (3) mix or
stir all components for approximately 30 seconds to one minute or
until the desired putty-like consistency is achieved.
[0033] The resultant paste bone graft substitute composition has
the following characteristic/criteria:
[0034] Ejectability - the resultant composition should be able to
be ejected through a 1/8 inch (0.3175 centimeter)diameter orifice
with relatively little pressure required.
PREFERRED EMBODIMENT 4
[0035] A bone graft substitute composition having the following
preferred formulation: approximately 80-120 parts medical grade
calcium sulfate hemihydrate by weight; approximately 21-250 parts
sterile water by weight; and approximately 1-40 parts sodium
carboxymethylcellulose by weight. This preferred formulation may
include approximately 10-100 parts demineralized bone matrix by
weight.
[0036] The preferred method for mixing this bone graft substitute
composition comprises the following steps: (1) dry blend the powder
components (i.e., the calcium sulfate hemihydrate, and sodium
carboxymethylcellulose, and, if included, the demineralized bone
matrix); (2) add the sterile water; and (3) mix or stir all
components for approximately 30 seconds to one minute or until the
desired consistency is achieved.
[0037] The resultant bone graft substitute composition has the
following characteristic/criteria:
[0038] Handability - the resultant composition should: (a) be a
single cohesive bolus; (b) be able to be handled and manipulated
with minimal to no material transfer (sticking) to latex gloved
hand; (c) be able to be handled without material crumbling or
falling apart; and (d) exhibit minimal cracking or "tearing" with
extreme manipulation, e.g., hard squeezing;
[0039] Ejectability - the resultant composition should: (a) be able
to be easily manipulated, e.g., rolled into a long cylinder or
other suitable shape, so as to be manually placed into an
appropriate injection apparatus, e.g., a syringe; and (b) be able
to be ejected through a 1/8 inch (0.3175 centimeter) diameter
orifice with relatively little pressure required; and
[0040] Robustness - the resultant composition, after being placed
or injected into or onto the desired location, should be able to
withstand body fluids, reasonable irrigation fluids and/or
suctioning with minimal material erosion, disintegration or
dissolution.
PREFERRED EMBODIMENT 5
[0041] In some preferred embodiments, the bone graft substitute
composition includes calcium sulfate, e.g., calcium sulfate
hemihydrate; a mixing solution, e.g., sterile water; and a
plasticizing substance, e.g., hyaluronic acid or a cellulose
derivative such as methylcellulose. The plasticizing substance can
include, for example, sodium carboxymethylcellulose,
methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, ethylcellulose, hydroxyethylcellulose, and/or cellulose
acetate butyrate. The mixing solution can include, for example,
sterile water, inorganic salt, and/or cationic surface active
agent. The cationic surface active agent can include sodium
chloride, phosphate buffered saline, potassium chloride, sodium
sulfate, ammonium sulfate, ammonium acetate, or sodium acetate.
[0042] Generally, the bone graft substitute composition includes a
given amount of calcium sulfate, e.g., normalized to 100 parts by
weight of CaSO.sub.4.multidot.1/2H.sub.2O; an amount of the
plasticizing substance sufficient to provide a good biological
response, e.g., about 1 to about 10 parts, or about 1 to about 7
parts, or about 2 to about 6 parts, by weight; and a sufficient
amount of the mixing solution to provide good handability, e.g.,
about 20 to about 40 parts, or about 20 to about 35 parts, by
weight, such that the composition can be conveniently handled and
shaped. For a bone graft composition having
CaSO.sub.4.multidot.1/2H.- sub.2O and sterile water as the mixing
solution, specific compositions are a function of the plasticizing
substance used in the composition.
[0043] In an embodiment having hydroxypropyl cellulose (HPC) as the
plasticizing substance, the composition can include 100 parts by
weight of calcium sulfate, e.g., CaSO.sub.4.multidot.1/2H.sub.2O;
about 2 to about 7 parts, e.g., about 3 parts, by weight of HPC;
and about 26 to about 32 parts, e.g., about 28 parts, by weight of
the mixing solution, e.g., sterile water.
[0044] In an embodiment having hydroxypropyl methyl cellulose
(HPMC) as the plasticizing substance, the composition can include
100 parts by weight of calcium sulfate, e.g.,
CaSO.sub.4.multidot.1/2H.sub.2O; about 1 to about 6 parts, e.g.,
about 2 parts, by weight of HPMC; and about 23 to about 32 parts,
e.g., about 25 parts, by weight of the mixing solution, e.g.,
sterile water.
[0045] In an embodiment having hyaluronic acid as the plasticizing
substance, the composition can include 100 parts by weight of
calcium sulfate, e.g., CaSO.sub.4.multidot.1/2H.sub.2O; about 4 to
about 6 parts, e.g., about 5 parts, by weight of hyaluronic acid;
and about 23 to about 40 parts, e.g., about 30 to about 35 parts,
by weight of the mixing solution, e.g., sterile water.
[0046] In yet another embodiment, the composition can include about
100 parts by weight of the calcium sulfate hemihydrate, about 25 to
about 65 parts by weight of the mixing solution, e.g., water, and
about 1.5 to about 8 parts by weight of methylcellulose. For
example, the composition can include about 100 parts by weight of
the calcium sulfate, e.g., calcium sulfate hemihydrate, about 33.6
parts by weight of the mixing solution, e.g., water, and about 5.25
parts by weight of methylcellulose.
[0047] The compositions are formed according to the methods
described above. Powder components (e.g., calcium sulfate and
plasticizing substance) are dry blended. The mixing solution, e.g.,
water, is added to the powder components, and the mixture is mixed
or stirred for about 30-60 seconds or until a desired consistency
is achieved.
[0048] The resulting bone graft substitute composition is a paste
or putty having similar handability, ejectability and/or robustness
as described above.
[0049] The substitute composition can be handled and shaped such
that it can be conveniently positioned and secured into a surgical
site. The composition can set up relatively hard, e.g., it can be
used as an interoperative structural support, it can be resistant
to substantial collapse, or it can withstand fluid impact without
substantial erosion. The substitute composition has relatively low
to no risk of transmitting infectious disease because, for example,
it does not include biological materials such as materials from a
cadaver. The composition is relatively inexpensive to produce.
[0050] The resulting bone graft substitute can also be used as a
carrier, for example, by mixing it with other materials such as
allografts, antibiotics, and growth factors. This can the
composition with versatility and flexibility by allowing a user to
formulate a mixed composition according to a desired
application.
PREFERRED EMBODIMENT 6
[0051] Other preferred embodiments of a bone graft substitute
composition includes calcium sulfate, e.g., calcium sulfate
hemihydrate, demineralized bone matrix, allograft materials,
preferably, cancellous bone chips from a cadaver, a plasticizing
substance, and a mixing solution. The plasticizing substance can
include carboxymethylcellulose, e.g., sodium
carboxymethylcellulose, methylcellulose, hydroxypropyl methyl
cellulose, ethylcellulose, hydroxyethylcellulose, and/or cellulose
acetate butyrate. The mixing solution can include sterile water,
inorganic salt, and/or cationic surface active agent. The cationic
surface active agent can include sodium chloride, phosphate
buffered saline, potassium chloride, sodium sulfate, ammonium
sulfate, ammonium acetate, or sodium acetate.
[0052] Generally, the composition can include about 80 to about 120
parts by weight of calcium sulfate, about 10 to about 100 parts by
weight of demineralized bone matrix, about 10 to about 100 parts by
weight of allograft materials, about 1 to about 40 parts by weight
of a plasticizing substance, and about 21 to about 250 parts by
weight of a mixing solution. Preferably, the composition includes
about 90 to about 110 parts by weight of calcium sulfate, about 10
to about 50 parts by weight of demineralized bone matrix, about 15
to about 50 parts by weight of cancellous bone, about 5 to about 20
parts by weight of a plasticizing substance, and about 80 to about
120 parts by weight of a mixing solution. More preferably, the
composition includes about 98 to about 102 parts by weight of
calcium sulfate, about 13 to about 23 parts by weight of
demineralized bone matrix, about 27 to about 33 parts by weight of
cancellous bone, about 15 to about 20 parts by weight of a
plasticizing substance, and about 95 to about 105 parts by weight
of a mixing solution. Most preferably, the composition includes
about 100 parts by weight of calcium sulfate, about 18 to about 19
parts by weight of demineralized bone matrix, about 27 to about 28
parts by weight of cancellous bone, about 17 to about 18 parts by
weight of a plasticizing substance, and about 101 to about 102
parts by weight of a mixing solution.
[0053] The compositions are formed according to the methods
described above. Powder components (e.g., calcium sulfate
hemihydrate, demineralized bone matrix, cancellous bone chips, and
carboxymethylcellulose) are dry blended. The mixing solution, e.g.,
water, is added to the powder components, and the mixture is mixed
or stirred for about 30-60 seconds or until a desired consistency
is achieved.
[0054] The resulting bone graft substitute composition is a paste
or putty having similar handability, ejectability and/or robustness
as described above. The cancellous bone chips can provide the
composition with good structural support, and the relatively large
surface area of the cancellous bone chips can provide the
composition with good osteoconduction.
Tests
[0055] The majority of tests done to date on the bone graft
substitute composition of the present invention basically consist
of mixing a specific formulation and then assessing and recording
the mixing, handling, consistency, and injectability properties of
the resultant material.
Formulation Tests
[0056] Injectable Bone Graft Substitute Composition: Formulations
with various types and amounts of carboxymethylcellulose and
demineralized bone matrix have been tested. Specific examples
include: (1) carboxymethylcellulose percentages of 1-10% by weight;
(2) types of carboxymethylcellulose have included high viscosity,
medium viscosity, and low viscosity from 3 vendors (e.g.,
Aqualon.RTM. 7HF PH sodium carboxymethylcellulose from Hercules
Incorporated, Hercules Plaza, 1313 North Market Street, Wilmington,
Del. 19894-0001); (3) carboxymethylcellulose sterilized by gamma or
electronic beam sterilization (medium and low doses); (4)
demineralized bone matrix percentages up to 65% by volume; (5)
differently processed demineralized bone matrix, air dried and
freeze dried; (6) demineralized bone matrix from two vendors (e.g.,
human freeze dried demineralized bone matrix from AlloSource, 8085
E. Harvard Ave., Denver, Col. 80231); and (7) animal demineralized
bone matrix, including bovine and canine.
[0057] For all these formulations, varying amounts of water,
between 31-200 parts by weight, have been tested. The mixing,
handling, consistency, and injectability properties were assessed
and formulas chosen such that they met the mixing, handability,
ejectability, and robustness characteristics/criteria stated
hereinabove.
[0058] Paste And Putty Bone Graft Substitute Composition: These
were the first tests done and included formulations with
compositions having 100 parts by weight medical grade calcium
sulfate hemihydrate, and between 1-10% by weight
carboxymethylcellulose, and between 31-200 parts by weight water.
As was the case with the injectable bone graft substitute
composition, mixing, handability, consistency, injectability, and
robustness properties were assessed for the different formulations.
Specific tests have included: (1) varying the
carboxymethylcellulose percentages from 0.25% up to 10% by weight,
(2) using inorganic salt solutions including 2% sodium chloride
(NaCl) by weight, 2-4% sodium sulfate (Na.sub.2SO.sub.4) by weight,
and 2% potassium chloride (KCl)by weight.
[0059] As with the injectable bone graft substitute composition,
varying amounts of water, 31-200 parts by weight, were used.
EXAMPLE 1
[0060] The osteoinductive properties of the injectable bone graft
substitute composition have been studied using an athymic
mouse-intramuscular implantation model. This animal model is widely
accepted as the "gold standard" for assessing osteoinductive
characteristics of bone graft materials. In this model, a given
amount of material is surgically placed into a muscular site. After
an implantation period of four weeks, the osteoinductive response
is assessed using various analytical methods, including
radiography, biochemical analysis (alkaline phosphatase levels and
calcium content), and histomorphometry.
[0061] In this study, four athymic (nude) male mice (Harlan Sprague
Dawley, Inc.) were used for each material group. Two muscle pouches
were formed in the right and left gluteal muscles of each mouse and
implanted with either: (1) pellets which were manufactured using
the composition given in Preferred Embodiment 1, or (2) twenty (20)
5 mg of demineralized bone matrix which had been rehydrated with
isotonic saline (0.9% NaCl). The pellets made from Preferred
Embodiment 1 were 3.0 mm in diameter, 2.5 mm in height and 25 mg in
weight.
[0062] After twenty-eight (28) days the animals were sacrificed and
the materials explanted. The explants were analyzed for
osteoinductive potential by assessing the alkaline phosphatase
activity and for new bone growth by histomorphometric analysis of
histologic sections.
[0063] Samples to be analyzed for alkaline phosphatase activity
were minced, sonicated, and extracted with water saturated butanol.
The extracts were assayed for protein content using a Pierce BCA
Protein Assay Kit (Pierce Chemical Co.) and measuring the
conversion of para-nitrophenylphosphate (pNPP)to para-nitrophenol
(pNP) with time. The results were expressed as mole pNP formed/min/
g tissue protein.
[0064] Samples intended for histomorphometric analyses were
prepared using standard histological procedures. The percent viable
bone (new bone formation) was quantitated employing computer
software (Adobe Photo Shop 3.0.4 and HNIH 1.61), in conjunction
with a microscope equipped with a video camera. Data was reported
as percent viable bone relative to the total cross-sectional area
analyzed.
[0065] The alkaline phosphatase levels (.mu.mole pNP
formed/min/.mu.g tissue protein) and percent viable bone results
for the groups of mice implanted with DBM only and with injectable
putty manufactured using the composition given in Preferred
Embodiment 1 are shown in Table 1.
1TABLE 1 Osteoinductive Results Alkaline Phosphatase Levels and
Percent Viable Bone Alkaline Phosphatase Levels (.mu.mole pNP
formed/min/.mu.g Percent Viable Bone Group tissue protein) (%) DMB
only 2.1 .times. 10.sup.-5 .+-. 0.3 .times. 10.sup.-5 6.5% .+-.
1.0% Injectable Putty 3.0 .times. 10.sup.-5 .+-. 0.2 .times.
10.sup.-5 4.7% .+-. 0.9% (Preferred Embodiment 1)
EXAMPLE 2
[0066] A study was performed on canines to evaluate healing of bone
defects using materials with the composition given in Preferred
Embodiment 1. The DBM used in these compositions was fresh frozen
canine DBM (Veterinarian Transplant Services, Seattle, Wash.). Two
methods were used to produce the test materials. The first material
group consisted of a blend of DBM, calcium sulfate, and CMC powder
that was irradiated sterilized, while the second group mixed canine
DBM with the calcium sulfate-CMC blend at the time of surgery.
[0067] In this canine animal model, large medullary cylindrical
defects (13 mm diameter .times.50 mm length)were created
bilaterally in the proximal humeri by drilling axially through the
greater tubercle. Six to 7 cc of test material were injected into
prepared cavities using a large-bore catheter-tip syringe. Left
humeri received the premixed material that hand been sterilized and
the right humeri received the material mixed intraoperatively which
utilized non-irradiated canine DBM. Radiographs of the humeri were
obtained preoperative, immediately postoperative, and at 2, 3, and
6 weeks. Following euthanasia after 6 weeks, the explanted humeri
were sectioned transversely, radiographed, and processed for
plastic imbedded undecalcified histology. The histologic sections
were stained with basic fuchsin and toluidine blue and examined by
light microscopy.
[0068] Post-operative radiographs revealed all test materials to be
well contained in the prepared cavities. Normal would healing
occurred and there were no postoperative infections. Serial
clinical radiographs showed a progressive decrease in materials
density with time. No difference was evident between the right and
left sides.
[0069] Contact radiographs of the cut sections demonstrated no
difference in pattern or density of bone filling the right and left
defects, non-irradiated and irradiated canine DBM materials groups,
respectively. Serial sections for all the dogs showed between
30-100% filling of the defect, with one dog showing almost complete
filling for all sections.
[0070] Histologically, the nature of new bone formation and the
amount of residual material were similar in the right and left
defects. In the peripheral one-third of the defects, new bone was
present at the margins and haversian surfaces of abundant DBM
particles. Residual calcium sulfate was evident, incorporated
within slender bone trabeculae, independent of DBM particles. New
bone formation in the central aspect of the defects was more
variable, with some vascular fibrosus tissue shown. No foreign body
or inflammatory response was seen in any of the slides, indicating
that the materials had extremely good biocompatibilty.
[0071] Thus, materials with compositions given in Preferred
Embodiment 1 were shown to be well tolerated by the bone and to
heal a large medullary defect 30-100% at six 20 weeks with viable
new bone in a canine bone defect model.
[0072] Although the present invention has been described and
illustrated with respect to preferred embodiments and preferred
uses therefor, it is not to be so limited since modifications and
changes can be made therein which are within the full intended
scope of the invention.
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