U.S. patent application number 14/300514 was filed with the patent office on 2015-01-08 for composition of a bone repair mixture.
This patent application is currently assigned to Vivex Biomedical, Inc.. The applicant listed for this patent is Tracy Scott Anderson, Timothy E. Taylor. Invention is credited to Tracy Scott Anderson, Timothy E. Taylor.
Application Number | 20150010642 14/300514 |
Document ID | / |
Family ID | 51177803 |
Filed Date | 2015-01-08 |
United States Patent
Application |
20150010642 |
Kind Code |
A1 |
Anderson; Tracy Scott ; et
al. |
January 8, 2015 |
COMPOSITION OF A BONE REPAIR MIXTURE
Abstract
A composition of a bone repair mixture has a quantity of
allograft particulate bone having a bone particle distribution of
particle sizes less than 700 micron and a quantity of biologic
carrier material intermixed with the particulate bone. The biologic
carrier material is one of collagen, porous collagen or a collagen
mixture. Preferably, the carrier material is exclusively
collagen.
Inventors: |
Anderson; Tracy Scott;
(Atlanta, GA) ; Taylor; Timothy E.; (Birmingham,
AL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Anderson; Tracy Scott
Taylor; Timothy E. |
Atlanta
Birmingham |
GA
AL |
US
US |
|
|
Assignee: |
Vivex Biomedical, Inc.
Marietta
GA
|
Family ID: |
51177803 |
Appl. No.: |
14/300514 |
Filed: |
June 10, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13934403 |
Jul 3, 2013 |
8784908 |
|
|
14300514 |
|
|
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|
Current U.S.
Class: |
424/499 ;
424/549; 604/218 |
Current CPC
Class: |
A61K 38/39 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 38/39 20130101;
A61K 35/32 20130101; A61K 35/32 20130101; A61K 9/146 20130101 |
Class at
Publication: |
424/499 ;
424/549; 604/218 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 35/32 20060101 A61K035/32 |
Claims
1. A composition of a bone repair mixture comprises: a quantity of
allograft particulate bone having a bone particle distribution of
particle sizes less than 700 micron; and a quantity of biologic
carrier material intermixed with the particulate bone.
2. The composition of a bone repair mixture of claim 1 wherein the
biologic carrier material is one of collagen, porous collagen or a
collagen mixture.
3. The composition of a bone repair mixture of claim 1 wherein the
carrier material is collagen.
4. The composition of a bone repair mixture of claim 3 wherein the
ratio by dry weight of biologic carrier to bone particle is 10% to
50%.
5. The composition of a bone repair mixture of claim 1 wherein the
particulate bone particle size distribution has a volumetric void
volume of 40% to 60% as measured by placing a predetermined
quantity of dry bone particles in a test tube and adding a volume
of water or saline solution to the top of the column of bone
particles the void volume represented the volume of liquid
added.
6. The composition of a bone repair mixture of claim 1 wherein the
quantity of biologic carrier is evenly mixed or dispersed with the
quantity of bone particles to form the repair mixture.
7. The composition of a bone repair mixture of claim 1 further
comprises: a quantity of saline solution; and wherein the
composition of bone repair mixture is dispersed and held in saline
in a container or a delivery syringe for use in a bone repair
procedure.
8. The composition of a bone repair mixture of claim 7 wherein the
composition is sterilized.
9. The composition of a bone repair mixture of claim 1 wherein the
biologic carrier is provided in a particle size of 10 microns or
greater.
10. The composition of a bone repair mixture of claim 9 wherein the
biologic carrier is provided in the form of chopped fibers or
strands of collagen.
11. The composition of a bone repair mixture of claim 1 wherein the
biologic carrier is provided in an average particle size of 150
microns.
12. A prefilled container or syringe comprising: a housing with a
delivery nozzle; a plunger; a volume of saline solution; and
wherein the composition of bone repair mixture is dispersed and
held in saline in a container or a delivery syringe for use in a
bone repair procedure.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 13/934,403 filed on Jul. 3, 2013 entitled, "A
Composition Of A Bone Repair Mixture".
TECHNICAL FIELD
[0002] The present invention relates to a composition for bone
repair, the composition having a quantity of allograft particulate
bone having a particle distribution of less than 700 microns and a
biological carrier material intermixed with the bone particle,
preferably collagen or a collagen mixture.
BACKGROUND OF THE INVENTION
[0003] The use of allograft bone particles to fill defects or
cavity repair in bone is well understood in the art. Its use has
had varying amounts of success dependent on how the bone particles
were cleaned, prepared, processed and sized.
[0004] Conventional wisdom believed new bone growth would be
facilitated by increasing the surface of the bone. That led to a
false belief that bone crushed into a fine powder of less than a
micron would be best. In practice, this simply was not the case.
The powder when packed into the defect had no void spaces to
facilitate new ingrowth.
[0005] In U.S. Pat. No. 7,335,381; it was determined that an array
of several different particle sizes would help induce new bone
growth if the bone was properly cleaned and prepared into particles
in a grinding procedure wherein the bone never is heated at or
above 40 degrees C. as a result of the grinding.
[0006] If the bone was non-demineralized and frozen or freeze dried
then the osteoinductive properties would not be degraded and a loss
of osteoinductive activity could be avoided.
[0007] The result was a superior bone particle mixture. The use of
this particle mixture 30 has been successful. Synthetic bone graft
material is being used, but these materials simply cannot duplicate
the porosity and ability to be resorbable when compared to natural
cellular materials.
[0008] The application of the bone particle mixture during a bone
defect repair is not ideal. Dry application of the bone mixture
while not difficult can be messy with some particles spilling out
of the defect cavity. Ideally, the bone mixture should be delivered
with no spillage and wasted material.
[0009] It is an objective of the present invention to provide a
non-synthetic bone defect repair composition that accelerates bone
growth and can be delivered in a more accurate convenient
manner.
SUMMARY OF THE INVENTION
[0010] A composition of a bone repair mixture has a quantity of
allograft particulate bone having a bone particle distribution of
particle sizes less than 700 micron and a quantity of biologic
carrier material intermixed with the particulate bone. The biologic
carrier material is one of collagen, porous collagen or a collagen
mixture. Preferably, the carrier material is exclusively
collagen.
[0011] The ratio by dry weight of biologic carrier to bone particle
is 10% to 50%. The particulate bone particle size distribution has
a volumetric void volume of 40% to 60% as measured by placing a
predetermined quantity of dry bone particles in a test tube and
adding a volume of water or saline solution to the top of the
column of bone particles the void volume represented the volume of
liquid added. The quantity of biologic carrier is evenly mixed or
dispersed with the quantity of bone particles to form the repair
mixture. The composition of a bone repair mixture further may have
a quantity of saline solution. The composition of bone repair
mixture is dispersed and held in saline in a container or a
delivery syringe for use in a bone repair procedure. The
composition is sterilized.
[0012] A prefilled container or syringe has a housing with a
delivery nozzle, a plunger and a volume of saline solution. The
composition of bone repair mixture is dispersed and held in saline
in a container or a delivery syringe for use in a bone repair
procedure.
[0013] The biologic carrier is provided in a particle size of 10
microns or greater. The biologic carrier is provided in the form of
particles, chopped fibers or strands of collagen. The biologic
carrier is provided in an average particle size of 150 microns.
DEFINITIONS
[0014] As used in this specification, the singular forms "a," "an"
and "the" include plural referents unless the context clearly
dictates otherwise. Thus, for example, the term "a material" is
intended to mean one or more materials, or a combination
thereof.
[0015] The term "biocompatible" refers to the ability (e.g., of a
composition or material) to perform with an appropriate host
response in a specific application, or at least to perform without
having a toxic or otherwise deleterious effect on a biological
system of the host, locally or systemically.
[0016] The term "osteoconductive" refers to the ability (e.g., of a
composition or material) to passively permit bone growth (e.g.,
onto and/or into the material). As such, osteoconduction can be
characterized as a passive process. A material (e.g., a graft or
implant) can be osteoconductive, for example, because it is
configured to passively permit growth of bone on a surface of the
material. In another example, a material can be osteoconductive
because it is configured to passively permit growth of bone into an
opening (e.g., a pore) of the material.
[0017] The term "osteoinductive" refers to the capability (e.g., of
a composition or material) to actively stimulate a biological
response which induces bone formation. As such, osteoinduction can
be characterized as an active process. Osteoinduction can include
the formation and/or stimulation of osteoprogenitor cells, such as
osteoprogenitor cells in bodily tissue surrounding or proximate to
a graft or implant.
[0018] The term "biodegradable" refers to the capability of a
material to be degraded, disassembled, and/or digested over time by
action of a biological environment (including the action of living
organisms, e.g., the patient's body) and/or in response to a change
in physiological pH or temperature.
[0019] The term "resorbable" refers to the capability of a material
to be broken down over a period of time and assimilated into the
biological environment.
[0020] The phrase "by weight" refers to a weight of components of a
composition described herein, such as the weight of the applicable
component prior to being added to or mixed with another different
component of the composition. For example, the weight can refer to
an initial weight of the component measured out before further
processing of the component into the bone repair composition.
[0021] The term "fibrillar" refers to being in the form of fibrils,
and not in the form of fibers. For example, a reference to collagen
in the fibrillar form includes collagen fibrils, but not native
collagen fibers.
[0022] The phrase "non-load bearing application" refers to an
application for repair of a void or gap in a bone or another bony
structure in which the void or gap to be repaired is not intrinsic
to the stability of the bone or bony structure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The invention will be described by way of example and with
reference to the accompanying drawings in which:
[0024] FIG. 1 is a view of a pre-filled syringe with a
predetermined amount of the repair mixture in a liquid, preferably
saline.
[0025] FIG. 2 is a view of a sealed container or vial containing a
mixture of bone particles, collagen and saline or other suitable
liquid or gel.
DETAILED DESCRIPTION OF THE INVENTION
[0026] As shown in FIGS. 1 and 2, the composition of a bone repair
mixture 30 is shown is a pre-filled syringe 10 and a sealed
container or vial 20, respectively. The mixture 30 has the bone
particles 24 dispersed uniformly in the collagen 26. In either
delivery system, the mixture 30 can also be filled with saline or
other suitable liquid or gel to facilitate placement in a bone
defect or bone cavity prepared for repair.
[0027] As shown in FIG. 1, the syringe 10 has a plunger 12 sealed
inside the housing 11 closed by a removable cap 13. The plunger 12
withdrawn to provide volumetric space for the pre-filled mixture
30. Once the cap 13 is removed, a nozzle is exposed to deliver the
mixture 30 to the target area.
[0028] Alternatively, the entire mixture 30 can be provided in a
sealed vial or container 20. An end cap 23 encircles an injectable
elastomeric stopper at one end or top of a housing 21. The mixture
30 of bone particles 24 and collagen 26 as well as saline 25 or any
other suitable fluid or gel is placed inside the container
housing.
[0029] A composition of a bone repair mixture 30 according to the
present invention is configured to facilitate repair or
regeneration of bone at a target repair site. For example, in some
embodiments, the composition can be osteoconductive,
osteoinductive, or both. In all cases, the composition includes a
mixture 30 of bone particles 24 and a biological carrier such as
collagen 26 or a collagen mixture.
[0030] The target repair site can be, for example, a void, gap, or
other defect in a bone or other bony structure in a body of a
patient. For example, as described in more detail below, the
composition can be configured to facilitate bone growth at a target
repair site in the spine, pelvis, an extremity, the cranium, or
another bone or bony structure in the patient's body. The
composition is configured to be disposed at the target repair site.
For example, in some embodiments, the composition is configured to
be disposed at the target repair site in a non-load bearing
application using a delivery device such as a syringe.
[0031] The composition can include various combinations of bone
particles 24 and collagen 26. The composition is biocompatible and
biodegradable. More specifically, the entire composition is
preferably resorbable.
[0032] The collagen 26 carrier can be or include soluble collagen
26, insoluble collagen 26, or a combination thereof. The collagen
26 can be or include type I collagen 26, type II collagen 26, type
III collagen 26, type VII collagen 26, another suitable type of
collagen 26, or a combination thereof. For example, in some
embodiments, the collagen 26 is or includes medical grade type I
collagen 26. In some embodiments, the collagen 26 includes type I
collagen 26 and up to about 5% of a type of collagen 26 different
than type I collagen 26. For example, the collagen 26 can include
type I collagen 26 and up to about 5% type III collagen 26.
Specifically, the collagen 26 can include about 5% type III
collagen 26 and the remainder of the collagen 26 is type I collagen
26. In another example, the collagen 26 can include type I collagen
26 and up to about 5% type VII collagen 26. The collagen 26 can be
human, equine, bovine or porcine. Preferably, the collagen 26 can
be derived from human tissue or bone.
[0033] In some embodiments, the collagen 26 is in fibrillar form.
In some embodiments, at least prior to being implanted into the
body of the patient, the collagen 26 is not mineralized. In some
embodiments, the collagen 26 is uncompressed.
[0034] The collagen 26 of the composition can be a matrix in and/or
on which the bone particles 24 are disposed. In this manner, the
collagen matrix facilitates delivery of the bone particles 24 to
the target repair site. The collagen matrix of the composition can
be in any suitable form. For example, in some embodiments, the
collagen matrix is in a flowable form. Suitable flowable forms
include a slurry, foam, gel, or paste. In this manner, the bone
particles 24 can be mixed with and/or embedded into the flowable
collagen matrix. In some embodiments, the collagen matrix is a
hardened, brittle, or otherwise dry material. For example, the
collagen matrix can be formed by drying the flowable collagen 26,
as described in more detail below. The dried collagen matrix can be
wetted with a suitable solution to form a sponge-like collagen
matrix. Suitable solutions include, but are not limited to saline,
phosphate buffered saline, gel, or another biocompatible fluid, or
any combination of the foregoing. In some embodiments, the collagen
26 can be wetted with a solution that includes at least one of the
bioactive glass or calcium phosphate. The collagen matrix, in any
suitable form generally and in the dry or sponge-like form
particularly, includes a surface configured to receive bone
particles 24, for example, in granular or particulate form.
[0035] The collagen matrix of the composition is porous. In some
embodiments, the collagen matrix defines a plurality of pores. At
least a portion of the pores can be configured to permit the
in-growth of bone. In this manner, the collagen matrix, and thus
the entire composition, is osteoconductive. The porosity of the
collagen matrix can be in any suitable range. For example, in some
embodiments, the collagen 26 has a porosity or volumetric void
volume within the range of about 50% to about 95%. In some
embodiments, the bone particles 24 have a porosity or void volume
within the range of about 50% to about 90%. More specifically, in
some embodiments, the overall bone repair composition is about 25%
to 70% porous.
[0036] The pores of the collagen matrix can be any suitable size(s)
for permitting bone growth therein. For example, in some
embodiments, the pores of the collagen matrix each have a nominal
or average diameter of 150 microns. The collagen matrix can define
pores of various sizes in the range of greater than about 100
microns to less than about 700 microns. In some embodiments, at
least a portion of the plurality of pores of the composition are
interconnected, which can further facilitate the in-growth of bone.
In this way, the bone particles 24 can fill or fit in these
pores.
[0037] The bone particle composition is configured to facilitate
the growth of new bone at the target repair site. The bone is an
osteoconductive agent. As described above, the bone can be disposed
in or embedded within, and or mixed with the collagen 26. In some
embodiments, the bone can be mixed with the collagen 26 such that
the bone is randomly, but uniformly dispersed throughout the
collagen 26. For example, the bone can be mixed with the collagen
26 to form a substantially homogenous mixture 30 (e.g., a slurry)
of collagen 26 and bone.
[0038] The bone particles 24 can be in any suitable form.
Preferably, the bone is in particulate form. In the particulate
form, the bone particles 24 are discrete and generally not
interconnected. The bone particles 24 can be generally irregular in
shape and can have a smooth or rough surface texture.
[0039] The bone particles 24 of the composition accelerate release
of BMP and/or other growth factors can be constructed based on a
unique particle size distribution of natural bone because the
particles 24 have multiple surfaces and are inherently three
dimensional. The bone particles 24 have a size of 700 microns or
less, the preferred compositions of this invention have a
distribution of bone particles 24 all below about 355 microns with
at least 30 wt. % of particles 24 having a particle size of less
than 180 microns. This particle size distribution provides a unique
particulate bone composition of either cancellous bone or cortical
bone or mixture 30s thereof with improved osteoinductive activity.
This particulate bone can be effectively used as a single
preparation or in mixture 30 with various biological carriers such
as collagen 26 matrices as described above. The method of bone
allograft/xenograft preparation described in the present invention
avoids extraction of lipids or inactivation of growth factors and
preserves bone composition in its native state.
[0040] The present invention is based on the use of
Non-demineralized (undecalcified) cortical bone or cancellous bone
or mixture 30s thereof in particle sizes less than about 355
microns repeatedly and reliably induces bone formation in defects
in bones. Moreover, new bone formation is induced at a rapid rate
with direct formation of new osteoid.
[0041] The present invention relates to a bone implant composition
including a distribution of particles 24 of bone having particle
sizes less than or equal to about 355 microns and preferably a
mixture 30s of particles 24 having particles 24 sizes between about
355 microns and about 250 microns, particles 24 having particles 24
sizes between about 250 microns and about 150 microns, and
particles 24 having particles 24 sizes below about 150 microns,
where the compositions have improved osteoinductive activity or
osteogenic capacity.
[0042] The present invention broadly relates to a method for making
a bone implant composition including a distribution of particles 24
of bone having particle sizes of about 355 microns and preferably a
mixture 30s of particles 24 having particles 24 sizes between about
355 microns and about 250 microns, particles 24 having particles 24
sizes between about 250 microns and about 150 microns, and
particles 24 having particles 24 sizes below about 150 microns,
where the compositions have improved osteoinductive activity or
capacity, where the method includes the step of periodically
grinding a bone sample into a composition of this invention, where
the periods between each grinding are sufficient to maintain a
temperature of the bone below 40 degrees C., preferably below about
33 degrees C.
[0043] The present invention broadly relates to a method for
treating bone defects including the step of administering one or
more therapeutically effective amount of a bone repair composition
including a distribution of particles 24 of bone having particle
sizes of about 355 microns to a bone defect, where composition
preferably is a mixture 30s of particles 24 having particles 24
sizes between about 355 microns and about 250 microns, particles 24
having particles 24 sizes between about 250 microns and about 150
microns, and particles 24 having particles 24 sizes below about 150
microns, where the compositions have improved osteoinductive
activity or capacity.
[0044] The present invention also broadly relates to particulate
bone composition including a particle size distribution of nascent
bone particles 24, autograft bone particles 24, xenograft bone
particles 24, allograft bone particles 24 or mixture 30s or
combinations thereof with improved osteoinductive capacity.
[0045] This micro-particulate bone has superior osteogenic capacity
and osteoinductive activity, and in fact, that the smaller the
particles the better the osteoinductive activity. Thus, preferred
embodiments of this invention include bone compositions having
particle sizes: (a) less than or equal to about 355 microns, (b)
less than or equal to 300 microns, (c) less than or equal to 250
microns, (d) less than or equal to 180 microns, (e) less than or
equal 106 microns, (f) less than or equal to 75 microns, (g) less
than or equal to 53 microns and (h) less than or equal to 25
microns. This composition having smaller particles 24 sizes or
particle size distributions including smaller sized particles 24
have superior osteogenic capacity and superior osteoinductive
activity.
[0046] The osteogenic capacity or osteoinductive activity of the
preparations of this invention depend primarily on particle size
and retention of unaltered growth factors and other substances. The
osteogenic capacity or osteoinductive activity of either cortical
bone or cancellous bone or mixture 30s thereof decreases if
particles 24 exceed the range of 355 microns. Likewise exposure of
the same preparations to hydrogen peroxide, ethyl alcohol or
isopropyl alcohol markedly decreases its osteoinductive capacity.
The invention is directed to the method of preparation of
non-demineralized osteoinductive bone particles 24 as well as to
the clinical application of these preparations.
[0047] The present invention is directed to implants for
stimulating osteoinduction, bone regrowth, and/or bone repair by
the implantation of a particulate bone preparation of this
invention in a bone defect in an animal including a human.
Moreover, the present invention can include particulate bone that
has been treated with additional bone growth factors to further
enhance and improve bone regeneration after implantation.
[0048] The process of particulate bone preparation is equally
applicable to allogeneic and xenogeneic bone. The particulate bone
preparations of this invention are unique because they avoid
entirely the need for harsh chemical treatments and extractions,
which alter inherent native properties of bone. The particulate
bone preparations of this invention can be produced either from
freeze-dried bone not subjected to any chemical treatment or from
frozen bone. The invention permits reproducible production of a
particulate bone preparation with optimal osteoinductivity clearly
demonstrable in higher animal models.
[0049] The present invention prepares particulate cortical bone or
cancellous bone or mixture 30s thereof without "undesirable
constituents." For the purposes of the present invention the term
"undesirable constituents" means any constituent other than osteoid
tissue normally present in bone or bone marrow. This includes
blood, bone marrow, free fat and soft connective tissue
elements.
[0050] Particulate bone of a powdery consistency can be prepared
from previously freeze-dried cortical bone or cancellous bone or
mixture 30s thereof. After freeze-drying and associated processing
which includes repeated washing in warm saline or other balanced
salt solutions to remove "undesirable constituents", the bone is
immersed directly into liquid nitrogen vapor and is then
freeze-dried in accordance with previously published procedures
(Malinin 1, 2, 3) to a residual moisture of 5 to 6% or less.
Residual moisture content was determined gravimetrically.
[0051] Freeze-dried bone is cut into cubes with a band saw, an
oscillating or a rotary saw without heating the bone preparation,
by avoiding pressure on the bone being cut and by limiting the time
of grinding to no more than 15 second for each surface being
cut.
[0052] Cut bone cubes, rectangles or other small configurations are
further cut in a turbo mill, micro hammer cutter mill, disc mill,
toothed disc mill, jet mill or other similar mills capable of
grinding bone or reducing bone to particles 24 having a particle
size less than about 355 microns. Although usually dry bone is
ground, cutting of wet bone preparation can be also
accomplished.
[0053] Any grinding process is associated with heat production.
Heating bone above about 45 degrees C. to about 50 degrees C. is
undesirable as the heat significantly reduces to completely
abolishes osteoinductive properties of bone. Continuous grinding
for 3 to 5 minutes in any of the conventional grinding mills will
raise the temperature to 70 degrees C. or above. The preferred
method uses defined interrupted grinding so that the temperature
exposure to the bone can be carefully controlled and kept below a
temperature which would not result in a loss of osteoinductive
activity. The mill is operated in cycles of about 8 seconds to
about 18 seconds, then the bone is sieved a duration of about 14
seconds to about 15 seconds. This does not allow the temperature of
bone or grinder to rise above about 33 degrees C. from the initial
temperature of the product of between about 18 degrees C. and about
20 degrees C. The cycle operates for no longer than 3 minutes with
an average operating time of about 2.5 minutes.
[0054] The above described procedures of repeated grinding and
sieving allows for the preparation of specific formulation of
non-decalcified particulate bone preparations with high
osteoinductive properties. One preferred embodiment of this
invention includes compositions having a particle size
distributions as follows: (1) from about 24.6 wt % to about 36.3 wt
% of particles 24 having a particle size between about 350 microns
and about 250 microns; (2) 22 wt % to about 25 wt % of particles 24
having a particle size between 25 microns and about 150 microns;
and (3) from about 36.7 wt % to about 46.7 wt % of particles 24
having a particle size less than 150 microns. Particularly, the
particles 24 having a particle size below about 25 microns should
have the following distribution: 35-65 wt % of particles 24 having
a particle size between about 250 microns and about 150 microns,
about 10 wt % to about 40 wt % of particles 24 having a particles
24 size between about 150 microns and about 100 microns, and about
10 wt % to about 40 wt % of particles 24 having a particle size
less than about 100 microns. More particularly, the particles 24
having a particle size below about 250 microns should have the
following distribution: 40 wt % to about 60 wt % of particles 24
having a particle size between about 250 microns and about 150
microns, about 15 wt % to about 35 wt % of particles 24 having a
particles 24 size between about 150 microns and about 100 g, and
about 15 wt % to about 35 wt % of particles 24 having a particle
size less than about 100 microns. Especially, the particles 24
having a particle size below about 250 microns should have the
following distribution: 50 wt % of particles 24 having a particle
size between about 250 microns and about 150 microns, about 25 wt %
of particles 24 having a particles 24 size between about 150
microns and about 100 microns, and about 25 wt % of particles 24
having a particle size less than about 100 microns.
[0055] Incorporation of particulate bone allografts is dependent on
the size of the particles 24 in the grafts and the method of its
preparation. Freeze-dried, microparticulate cortical bone
allografts first provide biomechanical support and most rapid
healing of the defect into which they are placed. They incorporate
by direct ossification, thus producing rapid new bone formation.
Demineralized cortical bone powder allografts stimulate the
surrounding bone, but by themselves do not undergo accretion.
Healing from the periphery is accomplished via as lower process of
endochondral ossification.
[0056] The bone particles 24, when prepared as described above, are
combined with collagen 26 to form a bone repair mixture 30.
[0057] In a similar fashion, the collagen 26 constituent in the
repair mixture 30 can be prepared into dry particles using a freeze
drying method. The collagen 26 can be prepared using the same
variety of sizes in the same proportions as described above for the
bone particles 24. The two components of bone 24 and collagen 26
can be blended together to form the repair mixture 30. The "dry
weight" proportions of the dry particles can be varied or can be
identical. It must be appreciated that the bone particles 24 when
freeze dried have a resultant density higher than the freeze dried
collagen particles 26. Accordingly, if the same dry weight of each
is used, the collagen 26 will have a much higher volume of dry
material in the order of 2 to 3 times or more than the bone 24. In
some cases, this is believed most desirable. Alternatively, in
other applications wherein a higher proportion of bone 24 is
preferred, the mixture 30 can be blended using equal volumes of
each bone 24 and collagen 26. In these mixtures, the dry weight of
the freeze dried collagen 26 is about 33% to 50% the weight of the
freeze dried bone 24. Regardless, when blended together a thorough
mixing and dispersion is believed essential to insure the best
performance in terms of new bone ingrowth in the repair procedure.
This dispersion is believed best achieved by having the particles
sized about the same regardless of the range of particle sizes used
in the components. By way of example, if the percentage of bone
particles 350-700 microns is 10%; 250-350 microns is 20%; 150-250
microns is 50% and 80-150 microns is 20%; then the collagen
particles should preferably be generally the same so upon mixing
the dispersion is the same. This means, by weight the bone
particles 24 will be 2 to 3 times heavier than the equal volume and
sized, but lighter weight collagen 26. This dry mixture can be
packaged and stored sterile and dry until use if so desired.
However, it is believed at the point of use, the mixture 30 should
preferably be rehydrated in sterile saline or other suitable
solution to facilitate filling the bone defect. Once hydrated, an
irrigation syringe with a large bore nozzle can be used to draw in
the mixture 30 and thereafter inject directly into the target or
bone repair cavity. Alternatively, if the surgeon prefers the
mixture 30 can be applied dry, however, this is believed less
desirable due to spillage and waste of the mixture 30 when dry
filling a cavity. Ideally, this rehydration is accomplished in a
sterile pre-packaged device well before, preferably at the location
where manufactured.
[0058] In some embodiments, the method optionally includes weighing
out at least one component to be included in the material. For
example, a desired dry weight of at least one component (e.g., the
bone particles 24) can be weighted out. In another example, in some
embodiments, the collagen 26 is in a flowable form (such as a
slurry of collagen 26 and water). As such, a desired dry weight of
collagen 26 is calculated based on the concentration, e.g., of the
slurry, and is weighed out volumetrically. For example, to obtain 2
grams of collagen 26 from a slurry having a concentration of 20 mg
of collagen 26 per 1 mL of liquid, a 100 mL collagen 26 slurry is
volumetrically weighed out.
[0059] The basic elements required for bone formation include a
three-dimensional, open-porosity tissue scaffold, cells, and
osteoinductive signaling molecules to stimulate cell
differentiation, proliferation and matrix formation. Successful
bone formation requires that these elements be combined in a
well-coordinated spatial and time dependent fashion. The relative
contribution of each element may vary, e.g., according to
differences in patient age, gender, health, systemic conditions,
habits, anatomical location, etc.
[0060] Embodiments for improved bone formation and healing include
the following: biocompatible, open-porous bone tissues scaffold,
enhanced local concentration of soluble bone mineral elements such
as calcium and phosphate. Each is subsequently analyzed.
[0061] A biocompatible, open-porous bone tissue scaffold restores
function and/or regenerates bone by providing a temporary matrix
for cell proliferation and extracellular matrix deposition with
consequent bone in-growth until new bony tissue is restored and/or
regenerated. The matrix may also provide a template for
vascularization of this tissue.
[0062] The macro and micro-structural properties of the scaffold
influence the survival, signaling, growth, propagation, and
reorganization of cells. They may also influence cellular gene
expression and phenotype preservation. The following properties
contribute to scaffold characteristics for bone formation: cell
biocompatiability, surface chemistry, biodegradability, porosity,
and pore size.
[0063] In one embodiment, the composition comprises mineralized
collagen 26. Mineralized collagen 26 is collagen matrix with bone
particles 24 dispersed in them in particular manner, simulating
natural bone structure. Collagen 26 is the main protein of
connective tissue in animals and the most abundant protein in
mammals. Bone is composed of strong, fibrillar bundles of collagen
26 encased within a hard matrix of a calcium phosphate known as
hydroxylapatite. Collagen 26 is also a constituent in cartilage,
tendon and other connective tissues.
[0064] Due to its high degree of biocompatibility with the human
body, collagen 26 has been successfully used in a variety of
medical and dental applications for many years with minimal adverse
responses. During its manufacture, potentially antigenic portions
of the collagen 26 molecule are removed, resulting in a product
that is highly biocompatible and well-tolerated by the tissue.
Collagen 26 is also chemotactic for fibroblasts and other cells
involved in bone tissue repair. Collagen 26 biocompatibility
ensures that the products are well integrated in the host tissue
without eliciting an immune response.
[0065] Collagen 26 used in the injectable composition may be from
any source. These include natural sources such as human and
mammalian tissues, and synthetic sources manufactured using
recombinant technologies. It may be of any type (e.g., collagen 26
Types I, II, III, X and/or gelatin). In one embodiment, collagen 26
used is Type I collagen 26. In one embodiment, collagen 26 is
derived from bovine dermis. In one embodiment, fibrillar collagen
26 is derived from bovine dermis manufactured by Kensey Nash
Corporation (Exton Pa.) under the name Semed F. In one embodiment,
the particles 24 comprise at least about 33 percent by dry weight
collagen 26. In another embodiment, the particles 24 comprise from
about 25 percent to about 75 percent dry weight collagen 26.
[0066] The surface chemistry of the scaffold can control and affect
cellular adhesion. It can also influence the solubility and
availability of proteins essential for intracellular signaling.
Intracellular signaling maximizes osteoinductivity through
controlled cellular differentiation, proliferation, and
stimulation.
[0067] Collagen 26 fabricates the disclosed structural scaffold and
provides a physical and chemical milieu favorable to bone
regeneration. Collagen 26 also provides a favorable extracellular
matrix for bone forming cells, e.g., osteoblasts, osteoclasts,
osteocytes, etc. The bone forming cells' natural affinity for the
collagen matrix has been demonstrated to favorably influence the
function and signaling required for normal cellular activity.
[0068] The degradation rate of the scaffold should ideally match
the bone-healing rate. Slower degradation rates can hinder the rate
of remodeled, load-bearing bone formation. Faster degradation can
result in unhealed defects.
[0069] The solubility and resorption of collagen 26 is affected by
its conformation and the degree of collagen 26 cross-linking. The
in vivo solubility and resorption of collagen 26 is also influenced
by the local concentration of proteolytic agents and vascularity at
the site.
[0070] Scaffolds desirably possess an open pore, fully
interconnected geometry to allow homogeneous and rapid cell
in-growth, and facilitate vascularization of the construct from the
surrounding tissue.
[0071] To this end, the total pore volume porosity of the scaffold
simulates that of cancellous bone. Cancellous bone is a highly
porous structure (about 50 vol. % to about 90 vol. %) arranged in a
sponge-like form, with a honeycomb of branching bars, plates, and
rods of various sizes called trabeculae. The synthetic scaffold
must ensure pore interconnectivity to allow for the diffusion of
nutrients and gases and for the removal of metabolic waste
resulting from the activity of the cells within the scaffold. It is
generally accepted by one skilled in the art that the pore
diameters should be within the range of about 200 microns to about
900 microns range for ideal bone formation. Smaller pores can
occlude and restrict cellular penetration, matrix production, and
tissue vascularization. Larger pores can detrimentally influence
the mechanical properties of the structural scaffold.
[0072] The disclosed method produces a composition that mimics the
natural structural design of bone for bone formation. In one
embodiment, the composition is fabricated using mineralized
collagen 26. Mineralized collagen 26 resembles the fundamental
element of natural bone, allows the formation of a composition with
high surface area and an interconnected network of high
porosity.
[0073] The disclosed composition and method supplements the local
availability of essential soluble bone components, e.g., calcium
and phosphate. Biologically compatible, sparingly soluble calcium
phosphates are suitable supplements to locally increase the supply
of soluble calcium [Ca.sup.2+] and phosphate [PO.sub.4.sup.3-]
ions.
[0074] Bone growth factor cytokines, also known as bone
morphogenetic proteins (BMPs), are entrapped at high concentration
within bone and are secreted by many bone-forming cell types. The
primary function of BMPs is cellular signaling. Intracellular
signaling occurs through the binding of a soluble growth factor to
a specific cell receptor site. This signal pathway stimulates
several different and important bone healing events, including the
proliferation, migration, and differentiation of bone forming
cells. The cells are, in turn, responsible for the synthesis of
other proteins and growth factors that are important for regulating
and controlling bone tissue formation. Although there is a vast
array of BMPs described and known to one skilled in the art, BMPs
2, 4, 6 and 7 are generally considered to be the most
osteoinductive.
[0075] In one embodiment, the composition forms an injectable fluid
paste that enhances the formation of bone tissue. It is provided at
a surgical site during reconstruction of a skeletal defect. For
example, the injectable composition may be used in spine, dental,
reconstructive, trauma, and other orthopedic surgeries. The
injectable composition may be used as a substitute for or additive
to autologous bone grafts. Although the composition is synthetic,
it may include natural components, e.g., bovine collagen 26, and/or
be combined with natural components, e.g., bone marrow
aspirate.
[0076] In one embodiment, the injectable composition is both
osteoinductive, i.e., it initiates or induces bone growth, and
osteoconductive, i.e., it facilitates already initiated bone growth
but does not itself initiate bone growth. Its osteoinductive effect
arises, for example, from osteoinductive factors present in the
liquid, e.g., bone marrow aspirate, used to make the paste.
[0077] In another embodiment, a method of using mineralized
collagen 26 and bone particles 24 is disclosed. The particulate
composition can be combined with a fluid, for example, water, to
create an injectable composition. The composition is then injected,
manually applied, or otherwise delivered to a site of a bone. In
one embodiment, the paste is an injectable bone void filler. The
composition provides improved handling and delivery capabilities,
allowing a surgeon to introduce the composition into complex
geometry bone defects. The composition components are fully
resorbable and stimulate bone regeneration in a manner similar to
that achieved with natural bone.
[0078] In one embodiment, the composition contains particulate,
mineralized collagen 26 and bone particles 24. The composition can
be combined with a liquid such as biological fluids (e.g., bone
marrow aspirate, whole blood, serum, plasma, etc.) to form an
injectable paste. The paste is then used as an injectable and/or
conformable (i.e., moldable) bone-grafting material for primary
applications in, e.g., spine fusion, dental furcation augmentation,
fracture repair, etc.
[0079] In one embodiment, where a collagen 26 component is combined
with a bone particle component to produce a mineralized collagen 26
component, porous particles 24 of the mineralized collagen 26
component may be prepared. In one embodiment, the mineralized
collagen 26 mixed with calcium sulfate in a ratio from about 0.5%
to 50%. In another embodiment, the mineralized collagen 26 mixed
with bone in a ratio from 5-30%.
[0080] In one embodiment, where a collagen 26 component is combined
with a bone particle component to produce a mineralized collagen 26
component, porous particles 24 of the mineralized collagen 26
component may be prepared.
[0081] The composition may further comprise additives such as
bioactive agents, e.g., agents that exhibit biologic activity, and
liquids. For example, agents that are osteoinductive and/or
osteogenic may be included. As previously stated, osteoinductive
agents stimulate bone growth. Examples of osteoinductive agents
include bone growth factors, bone marrow components, blood
components, and bone components. Bone growth factors may be
purified or recombinant and include bone morphogenetic protein
(BMP). Bone marrow aspirates (BMA) may be used in the composition
because they contain osteoinductive agents such as bone growth
factors and mesenchymal stem cells. Mesenchymal stem cells (MSCs)
are multi-potent cells capable of differentiating along several
lineage pathways to aid in the production of bone. MSCs are
considered as a readily available source of cells for many tissue
engineering and regenerative medicine applications. For these
reasons, osteoinductive proteins and MSCs have been used to
supplement the performance of osteoconductive bone formation
scaffolds as replacements for autologous and allogeneic bone
grafts.
[0082] Adding liquid to the composition results in an injectable
composition, defined as soft masses with physical consistencies
between a liquid and a solid. The liquid may be a biological fluid
such as blood, plasma, serum, bone marrow, etc., or may be a buffer
or may be capable of buffering to the physiological pH values of
human serum (pH 7.1 to pH 7.4). Examples of buffers are known to
one skilled in the art and include Tris and phosphate-buffered
saline. In one embodiment, the composition has a pH in the range of
about pH 5 to about pH 7.4. In another embodiment, the composition
has a pH in the range of about pH 5.5 to about pH 6.9. More than
one liquid may be included in the composition. For example, the
composition may include bone marrow aspirate and a buffering salt
solution. The liquid may also include biocompatible liquids such as
water, saline, glycerin, surfactants, carboxylic acids,
dimethylsulfoxide, and/or tetrahydrofuran. In one embodiment, the
liquid is greater than about 25 percent by volume of the
composition. In another embodiment, the liquid comprises from about
30 percent to about 55 percent by volume of the composition.
Additionally, natural and synthetic polymers such aliphatic
polyesters, polyethylene glycols, polyanhydrides, dextran polymers,
derivatized above mentioned polymers, and/or polymeric
orthophosphates may be included in the composition.
[0083] In one embodiment, a process for producing a particulate
mineralized collagen 26 composition comprising collagen 26 and
calcium sulfate is provided. In one embodiment, a mineralized
collagen 26 and calcium sulfate composition is prepared and is then
formed into particles 24, as shown in FIG. 3. The types of collagen
26 that may be used are described above and include bovine dermal
collagen 26. Suitable calcium phosphate includes acidic calcium
phosphate such as monocalcium phosphate
[Ca(H.sub.2PO.sub.4).sub.2], calcium hydrogen phosphate
[CaHPO.sub.4], and/or calcium pyrophosphate[2CaO.P.sub.20.sub.5].
Mineralized collagen 26 then can be further processed by freezing,
lyophilization, and the solid composition is formed into particles
24. Methods of forming particles 24 are known to one skilled in the
art and include, but are not limited to, grinding, milling,
chopping, and/or molding. In one embodiment, particles 24 are
formed by milling the solid composition. Milling may occur using a
Wiley mill (Thomas Scientific, Swedesboro N.J.). The mesh size on
the mill directs the size of the resultant particles 24. In one
embodiment, a -20 mesh is used that creates particles 24 in the
range of about 100 microns to about 840 microns. The particles 24
may be sized by, for example, sieving. At any point in the process,
additional components may be added to the composition, as described
above. For example, an osteoinductive component can be added prior
to forming the articles.
[0084] Upon combining the mineralized collagen 26 with bone
particles 24, the composition may be provided as a kit. In one
embodiment, the kit includes the composition described above, and
may further include other components. These include a receptacle
such as a plastic container in which to place the composition and
in which to add liquid to form the composition into a paste or
putty, a mixing implement such as a spatula, stir rod, etc., a
disposable syringe barrel without a needle in which to place and
deliver the mixed paste, instructions for formulating and/or using
the composition, etc.
[0085] In another embodiment, a method of facilitating bone growth
is provided. In one embodiment, the method includes adding at least
one osteoinductive component such as a purified bone growth factor,
a recombinant bone growth factor, a bone marrow component, a blood
component, demineralized bone, autologous bone, etc., to the
particulate composition previously described. In embodiments where
the osteoinductive component is bone marrow aspirate, blood, or a
blood component, it may be acutely obtained and added to the
composition (e.g., blood and/or bone marrow may be obtained from
the same surgical site for repairing the defect). Adding the
osteoinductive component(s) and/or another liquid to the
composition, with stifling, results in a paste or putty, which is
provided to the desired anatomical site of the patient.
[0086] In one embodiment, the paste is loaded into the barrel of a
disposable 5 cc syringe, without a needle attached, and is extruded
through the barrel aperture to the desired anatomical site. In
another embodiment, the putty is manipulated or formed into a
configuration of desired size, shape, length, etc., either manually
or by instrumentation, and gently pressed on and/or in the desired
anatomical site. The site is desirably prepared to expose healthy
bleeding bone, facilitating subsequent bone growth. The method may
be performed using minimally invasive procedures known to one
skilled in the art. The method may be used in at least partially
filling bone voids and/or gaps of the skeletal system (i.e.,
extremities, pelvis, spine, oral cavity) that are not intrinsic to
the stability of the bone structure. These voids and/or gaps may be
a result of trauma, either natural or by surgical creation. The
paste is gently provided on and/or in the void and/or gap. The
paste is resorbed by the body during the healing process (over
days, weeks, and months). The paste may be molded into the bone
void or defect by manipulating either manually or using an
instrument (e.g., spatula, syringe, probe, cannula, etc.).
[0087] Variations in the present invention are possible in light of
the description of it provided herein. While certain representative
embodiments and details have been shown for the purpose of
illustrating the subject invention, it will be apparent to those
skilled in this art that various changes and modifications can be
made therein without departing from the scope of the subject
invention. It is, therefore, to be understood that changes can be
made in the particular embodiments described, which will be within
the full intended scope of the invention as defined by the
following appended claims.
* * * * *