U.S. patent application number 16/117070 was filed with the patent office on 2018-12-27 for injectable, biodegradable bone cements and methods of making and using same.
This patent application is currently assigned to The University of Toledo. The applicant listed for this patent is The University of Toledo. Invention is credited to Anand K. Agarwal, Sarit B. Bhaduri, Vijay K. Goel, Huan Zhou.
Application Number | 20180369445 16/117070 |
Document ID | / |
Family ID | 48905811 |
Filed Date | 2018-12-27 |
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United States Patent
Application |
20180369445 |
Kind Code |
A1 |
Bhaduri; Sarit B. ; et
al. |
December 27, 2018 |
Injectable, Biodegradable Bone Cements And Methods Of Making And
Using Same
Abstract
Compositions of, methods of making, and methods of using
alkaline earth phosphate bone cements are disclosed.
Inventors: |
Bhaduri; Sarit B.; (Toledo,
OH) ; Zhou; Huan; (Toledo, OH) ; Agarwal;
Anand K.; (Toledo, OH) ; Goel; Vijay K.;
(Toledo, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The University of Toledo |
Toledo |
OH |
US |
|
|
Assignee: |
The University of Toledo
Toledo
OH
|
Family ID: |
48905811 |
Appl. No.: |
16/117070 |
Filed: |
August 30, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14375927 |
Jul 31, 2014 |
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PCT/US2013/024040 |
Jan 31, 2013 |
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16117070 |
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61593094 |
Jan 31, 2012 |
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61697059 |
Sep 5, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61C 5/62 20170201; A61L
24/0015 20130101; A61L 2420/04 20130101; A61L 24/0084 20130101;
A61L 2400/06 20130101; A61L 24/0063 20130101; A61L 2430/12
20130101; A61L 24/0084 20130101; A61L 24/0021 20130101; C08L 5/08
20130101; C23C 30/005 20130101; A61L 2430/02 20130101; A61L 24/08
20130101; A61L 24/0036 20130101; A61K 6/898 20200101; A61L 24/02
20130101; A61B 17/8805 20130101; A61L 27/32 20130101; C08L 5/08
20130101; A61K 6/864 20200101; A61K 6/74 20200101; A61L 24/0042
20130101 |
International
Class: |
A61L 24/00 20060101
A61L024/00; C23C 30/00 20060101 C23C030/00; A61C 5/62 20170101
A61C005/62; C08L 5/08 20060101 C08L005/08; A61B 17/88 20060101
A61B017/88; A61K 6/00 20060101 A61K006/00; A61K 6/06 20060101
A61K006/06; A61L 27/32 20060101 A61L027/32; A61L 24/08 20060101
A61L024/08; A61L 24/02 20060101 A61L024/02; A61K 6/097 20060101
A61K006/097 |
Claims
1. A kit for preparing a bone cement composition, the kit
comprising: a first container comprising a dry powder, wherein the
dry powder comprises newberyite and a biopolymer; and a second
container comprising an aqueous solution; wherein the kit comprises
silica, and the dry powder is combinable with the aqueous solution
to form a bone cement composition comprising silica.
2. The kit of claim 1, further comprising a syringe adapted to
inject a bone with the bone cement composition.
3. The kit of claim 1, wherein the dry powder further comprises
monetite.
4. The kit of claim 1, wherein the aqueous solution comprises
deionized water.
5. The kit of claim 1, wherein the bone cement composition is an
injectable paste.
6. A kit for preparing a bone cement composition, the kit
comprising: a first container comprising a dry powder, wherein the
dry powder comprises newberyite; and a second container comprising
an aqueous solution; wherein the kit comprises silica, and the dry
powder is combinable with the aqueous solution to form a bone
cement composition comprising silica.
7. The kit of claim 6, further comprising a syringe adapted to
inject a bone with the bone cement composition.
8. The kit of claim 6, wherein the dry powder further comprises
monetite.
9. The kit of claim 6, wherein the aqueous solution comprises
deionized water.
10. The kit of claim 6, wherein the bone cement composition is an
injectable paste.
11. A kit for preparing a bone cement composition, the kit
comprising: a first container comprising a dry powder, wherein the
dry powder comprises newberyite and a biopolymer; and a second
container comprising an aqueous solution; wherein the dry powder is
combinable with the aqueous solution to form a bone cement
composition.
12. The kit of claim 11, further comprising a syringe adapted to
inject a bone with the bone cement composition.
13. The kit of claim 11, wherein the dry powder further comprises
monetite.
14. The kit of claim 11, wherein the aqueous solution comprises
deionized water.
15. The kit of claim 11, wherein the bone cement composition is an
injectable paste.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of U.S.
application Ser. No. 14/375,927, filed under 35 U.S.C. .sctn. 371
on Jul. 31, 2014, now U.S. Pat. No. 10,064,972; which is the
national stage entry of international application
PCT/US2013/024040, filed under the authority of the Patent
Cooperation Treaty on Jan. 31, 2013, published; which claims
priority to U.S. Provisional Application No. 61/593,094, filed
under 35 U.S.C. .sctn. 111(b) on Jan. 31, 2012, and U.S.
Provisional Application No. 61/697,059, filed under 35 U.S.C.
.sctn. 111(b) on Sep. 5, 2012. The entire disclosures of all the
aforementioned applications are expressly incorporated herein by
reference for all purposes.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
[0002] This invention was made with no U.S. Government support and
the U.S. Government has no rights in this invention.
FIELD OF THE INVENTION
[0003] This invention generally relates to bone cement compositions
and methods of making, strengthening, and using bone cement
compositions.
BACKGROUND OF THE INVENTION
[0004] There is no admission that the background art disclosed in
this section legally constitutes prior art.
[0005] Conditions related to back pain account for more
hospitalizations than any other musculoskeletal condition. The back
is the body part most often involved in work-related disabilities.
Back pain is the most prevalent medical disorder in industrialized
societies. More than 75% of the United States population will be
affected by low back pain over the course of their lifetime.
According to the statistics from the National Institutes of Health,
back pain is the second most common medical condition for which
people seek treatment, accounting for more than 50 million
physician office visits annually. Low back pain is the leading
cause of disability in people younger than age 50.
[0006] In order to alleviate back pain, many people undergo
surgical intervention. Implanted instrumentation is used in many
types of spinal surgeries to help join vertebrae together and
restore stability. Additionally, implants such as plates, rods, and
screws help correct deformity and bridge spaces created by the
removal of damaged spinal elements. Bone cement is desired in
clinical situations to enable proper fixation of the implants. Bone
cement is also used in a wide variety of other medical and dental
applications, such as in the repair of cranio-maxillofacial
defects, tooth fillings, or spinal fusions.
[0007] The bone cements commonly used are poly methyl methacrylate
(PMMA) cements. Bone cements made from PMMA have several
disadvantages. Namely, methacrylates and methacrylic acid are known
irritants to living tissue. PMMA-based cements can generate free
radicals in vivo, which can damage surrounding tissue. PMMA-based
cements are also not biodegradable, and the polymerization reaction
involving PMMA is highly exothermic, possibly causing damage to
surrounding tissue when cured.
[0008] Another problem with many conventional bone cement
formulations is the necessity of mixing and storing two or more
solid powder ingredients, which reduces their batch-to-batch
reproducibility and shelf life. Homogeneous mixing of two solids is
not an easy task. Optimal cements should be able to set in a liquid
medium during the normal setting time without being washed away.
This is important for injectability and cohesiveness. Both of these
issues can be enhanced by incorporating a polymer in the setting
solution. However, cement compositions containing polymers with two
solid ingredients still have poor injectability because homogeneous
mixing of two solid ingredients is not easy.
[0009] Some possible alternatives to PMMA-based cements are cements
made from various alkaline earth phosphates. These include calcium
phosphate cements, magnesium phosphate cements, and strontium
phosphate cements. Of all alkaline earth phosphates, Ca--P cements,
or CPCs, are the most common. CPCs are based on different compounds
within the CaO--P.sub.2O.sub.5 (Ca--P) binary system. These
compounds include Ca-hydroxyapatite,
Ca.sub.10(PO.sub.4).sub.6(OH).sub.2 or simply hydroxyapatite, which
is most well known due to its similarity to natural bone mineral.
Other compounds in the Ca--P binary system include tetracalcium
phosphate (TTCP, Ca.sub.4(PO.sub.4).sub.2O), tricalcium phosphate
[.alpha.-TCP, .alpha.-Ca.sub.2(PO.sub.4).sub.2 and .beta.-TCP,
.beta.-Ca.sub.3(PO.sub.4).sub.2], dicalcium phosphate anhydrous
(DCPA, monetite, CaHPO.sub.4), di-calcium phosphate dehydrate
(DCPD, brushite, CaHPO.sub.4.2H.sub.2O), and octacalcium phosphate
(OCP, Ca.sub.8H.sub.2(PO.sub.4).sub.6.5H.sub.2O). CPCs offer
several advantages over PMMA-based cements, such as greater
malleability, allowing the cement to better adapt to a defect's
site and shape. CPCs also offer better biocompatibility,
bioactivity, osteoconductivity, and bioresorbability.
[0010] Mg--P cements (MPCs) in the market are mainly based on the
composition of MgNH.sub.4PO.sub.4, formed via reaction between acid
part (ammonia salts) and base part (MgO or Mg(OH).sub.2), resulting
in exothermic phenomena. However, the release of ammonia during
setting and degradation of MPCs compromises the biocompatibility of
the cements. Sr--P cements (SPCs) are Ca--P or Mg--P cements doped
with strontium. Strontium can promote cell growth and provides
radio opacity.
[0011] It would be desirable to formulate bone cement compositions
that are easily made and possess improved strength, mechanical
properties, and bioactivity. It would be further desirable if the
properties of such bone cements allow them to be readily used in
the surgical theater.
SUMMARY OF THE INVENTION
[0012] In a first aspect, there is provided herein a bone cement
composition made from mixing one powder component, a setting
solution, and a biocompatible polymer. The powder component
comprises a basic source of calcium, magnesium, or strontium. The
setting solution comprises phosphoric acid. A biocompatible polymer
is incorporated into the setting solution prior to mixing with the
powder. In certain embodiments, the biocompatible polymer is
chitosan and is surface-phosphorylated then incorporated into the
setting solution at a concentration ranging from about 0% to about
10% by weight of the setting solution. Upon mixing, a paste forms
that either (a) hardens into a solid mass some period of time after
mixing the powder with the setting solution, or (b) is irradiated
with electromagnetic radiation to form dry powders that are then
mixed with a second setting solution to form a bone cement paste
that sets into a hardened mass. In certain embodiments, the cement
has a setting time of from about 30 minutes to about 60
minutes.
[0013] In a second aspect, there is provided herein a method of
reducing the exothermicity of bone cement compositions. The method
involves irradiating a bone cement paste (made from acid-base
reactions) with electromagnetic radiation to form dry powders, then
mixing the dry powders with a setting solution comprising water,
saline, or nanosilica sol to form a bone cement paste that sets
into a hardened mass. The reaction does not change the pH and does
not release any heat. The method described herein also produces
strengthened bone cement compositions suitable for weight-bearing
applications.
[0014] Further disclosed herein are methods of making bone cement.
One method comprises mixing a single powder component with a
setting solution and a biopolymer to form a paste, and allowing the
paste to set into a hardened mass. Another method comprises forming
a bone cement paste from an acid-base reaction, irradiating the
bone cement paste with electromagnetic radiation to form dry
powders, and mixing the dry powders with a setting solution
comprising water, saline, or nanosilica sol to form a
radiation-assisted bone cement paste that sets into a hardened mass
after a period of time.
[0015] Further disclosed herein is a method of producing a settable
CPC/MPC/SPC with minimum exothermic properties. Further disclosed
are methods of using a bone cement to treat a subject, to deliver a
drug, to increase the biocompatibility of titanium implants, to
increase the strength of a calcium sulfate dehydrate cement, to
fill a tooth defect, to fill a hole or cavity in a bone, and to
replace or treat weakened or collapsed vertebrae.
[0016] Further disclosed are various kits for making a bone cement
composition as described herein.
[0017] Various aspects of the invention will become apparent to
those skilled in the art from the following detailed description of
the preferred embodiments, when read in light of the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0019] The following drawings may contain hidden features or
elements shown in dotted lines and may include phantom views of
various components or elements shown in dashed-dotted lines.
[0020] FIG. 1 is a comparison of XRD patterns for monetite cement
pastes formed between ten minutes and twelve hours of setting.
[0021] FIG. 2 illustrates the rheological properties of cements
with varying amounts of chitosan.
[0022] FIG. 3 is a series of SEM images of morphological structures
for chitosan monetite composites with various content of chitosan
by weight: 0% (A), 5% (B), 10% (C), and 20% (D).
[0023] FIG. 4 is an SEM image illustrating the in vitro response of
chitosan-containing cements.
[0024] FIG. 5 is a graph showing a comparison of the compressive
strength of monetite cement, monetite cement with commercially
available chitosan, and monetite cement with surface-phosphorylated
chitosan.
[0025] FIG. 6 shows SEM images of (a) monetite precursors formed
after microwave treatment; (b) monetite cement formed by direct
mixing with Ca(OH).sub.2 and H.sub.3PO.sub.4; and (c) hardened
monetite cement after microwave treatment.
[0026] FIG. 7 is a graph showing the injectability properties of
cements based on the percent of chitosan present in the cement.
[0027] FIG. 8 is a comparison of XRD patterns of a monetite cement
formed using a regular acid-base reaction, and a monetite cement
formed using the microwave-assisted approach disclosed herein.
[0028] FIG. 9 is an SEM image of preosteoblast cells on
monetite-silica cement samples 72 hours after seeding. The
biocompatibility of the surface is shown by cell spreading. Cement
particles are visible underneath the osteoblasts. This shows the
biocompatibility of the cement.
[0029] FIG. 10 shows compressive strength values of
monetite-silica, monetite, monetite (old), Chem-ostetic, and
calcibon cements. Microwave treatment can improve the compressive
strength of monetite cement, comparable to non-load bearing cements
on the market such as Chem-Ostetic. The addition of nanosilica sol
to monetite significantly improves its strength, making the
load-bearing of monetite-silica cement much higher than Calcibon, a
commercial weight-bearing CPC on the market.
[0030] FIG. 11 is a graph showing compressive strength values of
monetite-silica proceeding with time.
[0031] FIG. 12 is a graph of temperature over time, showing the
difference in heat generated during mixing of monetite cement made
with and without the microwave-assisted technique. As seen from
this graph, the microwave-assisted technique generates
significantly less heat.
[0032] FIG. 13 displays XRD patterns of Mg--P precursors formed
after microwave treatment, Mg--P cement formed by direct mixing
with Mg(OH).sub.2 and H.sub.3PO.sub.4, and hardened Mg--P cement
after microwave treatment.
[0033] FIG. 14 shows SEM images of (a) Mg--P precursors formed
after microwave treatment; (b) Mg--P cement formed by direct mixing
with Mg(OH).sub.2 and H.sub.3PO.sub.4; and (c) hardened Mg--P
cement after microwave treatment.
[0034] FIG. 15 is an SEM image of the Mg--P cement after 7 days
incubation in simulated body fluid. The Mg--P cement converted into
apatite with plate-like crystals and Mg.sup.2+, Ca.sup.2+,
Na.sup.+, and PO.sub.4.sup.3- ions.
[0035] FIG. 16 is an XRD pattern of the Mg--P cement after 7 days
incubation in simulated body fluid. The pattern indicates partial
newberyite (MgHPO.sub.4.3H.sub.2O) was converted into bobierrite
(Mg.sub.3(PO.sub.4).sub.2.8H.sub.2O).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
[0036] Throughout the entire specification, including the claims,
the word "comprise" and various of the word, such as "comprising"
and "comprises" as well as "have," "having," "includes," and
"including," and variations thereof, means that the named steps,
elements, or materials to which it refers are essential, but other
steps, elements, or materials may be added and still form a
construct within the scope of the claim or disclosure. When recited
in describing the invention and in a claim, it means that the
invention and what is claimed is considered to be what follows and
potentially more. These terms, particularly when applied to claims,
are inclusive or open-ended and do not exclude additional,
unrecited elements or method steps.
[0037] Various embodiments are described herein in the context of
composition, and method, formula, system, and/or process for
preparing, bone cements having improved mechanical properties.
Those of ordinary skill in the art will realize that the following
detailed description of the embodiments is illustrative only and
not intended to be in any way limiting. Other embodiments will
readily suggest themselves to such skilled persons having the
benefit of this disclosure. Reference to an "embodiment," "aspect,"
or "example" herein indicate that the embodiments of the invention
so described may include a particular feature, structure, or
characteristic, but not every embodiment necessarily includes the
particular feature, structure, or characteristic. Further, repeated
use of the phrase "in one embodiment" does not necessarily refer to
the same embodiment, although it may.
[0038] In the interest of clarity, not all of the routine features
of the implementations or processes described herein are shown and
described. It will, of course, be appreciated that in the
development of any such actual implementation, numerous
implementation-specific decisions will be made in order to achieve
the developer's specific goals, such as compliance with
application- and business-related constraints, and that these
specific goals will vary from one implementation to another and
from one developer to another. Moreover, it will be appreciated
that such a development effort might be complex and time-consuming,
but would nevertheless be a routine undertaking for those of
ordinary skill in the art having the benefit of this
disclosure.
[0039] A state-of-the-art bone cement composition should meet the
following criteria: (1) the composition should use one solid
component, thus enabling easy mixing; (2) the composition should
use solids that do not need high-temperature processing; (3) the
composition should use a setting solution of an aqueous nature; (4)
the hardening (setting) process should not be exothermic so that no
tissue necrosis takes place; (5) the final phosphate phase should
be biodegradable, for example MgP, SrP, TCP, DCPA, or DCPD, thus
enabling regeneration of bone tissues; (6) the composition should
be injectable (i.e., of the correct rheological property) to fill a
bone defect; (7) the composition should harden in a suitable
timeframe to give a surgeon an optimum window of opportunity to
inject the cement before hardening takes place; (8) the cement
should develop strength of the trabecular bone within a window of
ten minutes to two hours for the weight bearing of the patient and
ultimately developing even higher strength within 24 hours after
the operation; (9) the cement should be radio-opaque for quick
identification by X-rays; (10) the cement should be biocompatible
and biodegradable, as determined by in vitro testing; and (11) the
cement should maintain the above characteristics in vivo as
well.
[0040] In accordance with the above, provided herein is a bone
cement composition made from a single powder component comprising a
basic source of calcium, magnesium, or strontium, and a setting
solution comprising H.sub.3PO.sub.4. In certain embodiments, the
powder comprises Ca(OH).sub.2 or Mg(OH).sub.2, and the setting
solution further comprises a biocompatible polymer, deionized
water, a buffer such as NaHCO.sub.3, and citric acid monohydrate.
In particular embodiments wherein the powder is Ca(OH).sub.2, the
resulting bone cement is a dicalcium phosphate anhydrous
(CaHPO.sub.4, also known as monetite or DCPA) cement that dispenses
with several problems in conventional bone cement formulations. The
CPCs currently available commercially are either apatite CPCs (such
as .alpha.-BSM.RTM., BoneSource.RTM., Calcibon.RTM., and
Biopex.RTM.) or brushite CPCs (such as ChronOS Inject.RTM.,
Eurobone.RTM., and VitalOS.RTM.). However, monetite is a good
alternative to apatite and DCPD cements because it has similar
chemical composition and solubility to DCPD, it exhibits desirable
properties that support bone regeneration, and it does not
reprecipitate into apatite in vivo.
[0041] The monetite bone cement disclosed herein is based on an
acid-base reaction between H.sub.3PO.sub.4 and Ca(OH).sub.2, with
NaHCO.sub.3 as a pH buffer. The monetite cement is made from a
single powder component and a setting solution. The powder
comprises Ca(OH).sub.2, which is readily available commercially and
relatively inexpensive. The Ca(OH).sub.2 powder can be used without
any further treatments or additives, and is not subjected to high
temperatures during synthesis. The setting solution comprises
phosphoric acid (H.sub.3PO.sub.4). In certain embodiments, a
biocompatible polymer is incorporated into the setting solution to
provide cohesiveness to the composition. The biopolymer further
enhances the mechanical properties of the cement by providing a
toughening mechanism against the propagation of a crack.
[0042] In certain embodiments, the biocompatible polymer comprises
chitosan [(1-4)-2-amino-2-deoxy-.beta.-D-glucan] and is present
from about 0% to about 20% by weight of the total composition. More
particularly, the chitosan is present from about 1% to about 5% by
weight of the total composition. Chitosan is a compound found
primarily in the exoskeletons of arthropods and has several
desirable attributes for incorporation into cement compositions. It
has a polycationic carbohydrate structure similar to that of
hyaluronic acid, an extracellular matrix molecule. Chitosan's
cationic nature provides a suitable substrate for cell adhesion and
prevention of washout in a cavity. Chitosan is both biocompatible
and bioactive (e.g., osteoinductive), as well as haemostatic. While
liquid at room temperature, chitosan tends to gel at higher
temperature such as the physiological temperature of 37.degree. C.
These properties contribute to the cement composition's
injectability, bioactivity, cohesiveness, and improved mechanical
properties.
[0043] In certain embodiments, the chitosan is
surface-phosphorylated prior to being incorporated into the setting
solution. One method of achieving this surface modification is by
dissolving chitosan in orthophosphoric acid, urea, and N,N-dimethyl
formamide, heating and stirring the mixture, then pouring the
mixture into water and filtering it to collect
surface-phosphorylated chitosan particles. Phosphorylation improves
the adhesion of the chitosan to the cement.
[0044] The setting solution comprises H.sub.3PO.sub.4 but may
further comprise deionized water and a suitable buffer, such as
sodium bicarbonate (NaHCO.sub.3) dissolved in water, to increase
the pH of the setting solution, as well as citric acid monohydrate
(CAM) to improve the handling of the final paste. In some
embodiments, the powder component is mixed with deionized water to
form a basic solution which is then mixed with the setting
solution, while in other embodiments the powder component is mixed
directly with the setting solution. In one embodiment, the powder
and setting solution are mixed in a powder-to-liquid ratio of about
1 g per 0.4 mL. In another embodiment, the powder-to-liquid ratio
is about 1 g per 0.6 mL. Many other ratios are possible. The
powder-to-liquid ratio is easily changed by using different amounts
of deionized water in the setting solution.
[0045] Upon mixing with the setting solution, a paste is formed by
redox reactions between the H.sub.3PO.sub.4 and the Ca(OH).sub.2.
The paste is a monetite (DCPA) cement that sets into a hardened
mass between 30 and 60 minutes after mixing. The hardened monetite
cement is stable in deionized water at 37.degree. C. due to a thin
apatitic film on its surface, but converts to apatite readily in
carbonated solutions at a slightly elevated temperature of
95-100.degree. C. The monetite cement has a higher solubility at
neutral pH in physiological solutions than other CPCs and
stimulates apatite formation in simulated body fluids after a
relatively short time. Increased pH values also lead to hydrolysis
of monetite to form apatite.
[0046] Currently available CPCs are based on a powder component
comprising at least two or more CaP or Ca- or P-containing phases.
The components of these powder mixtures may undergo solid state
reactions that limit their shelf life and storage conditions. The
requirement of only one powder component for the monetite cement
disclosed herein is thus advantageous. The monetite cement also
exhibits a higher in vivo resorbability in comparison to apatitic
cements. Furthermore, unlike .alpha.-TCP and TTCP powders, the
monetite cement powders can be synthesized at room temperature,
alleviating the need to quench the cement phases to ambient
temperatures which may require delicate grinding and cause
contamination or undesired hydrolysis during grinding.
[0047] In addition to a variety of surgical applications discussed
below, the monetite bone cement disclosed herein can be used as a
coating on titanium implants that converts to apatite, making this
a useful technique for increasing the biocompatibility of titanium
implants. Also, the monetite bone cement can be added to calcium
sulfate dehydrate (CSD) cements to significantly increase the
mechanical properties of the CSD cements.
[0048] Further disclosed herein is a method of reducing the
exothermicity of alkaline earth phosphate bone cements such as the
monetite cement described above, and a series of alkaline earth
phosphate bone cements with significantly reduced exothermicity.
The method can be utilized with any cement paste formed from an
acid-base reaction and produces alkaline earth cements with minimum
exothermicity capable of use in weight-bearing applications. The
process involves subjecting a cement paste comprising reactants of
powder and liquid in an optimal ratio (before the paste sets) to
electromagnetic radiation with frequencies between about 10.sup.6
Hz to about 10.sup.22 Hz, such as microwaves, to produce dried
CPC/MPC/SPC powders. The irradiation preserves the cement in its
initial reaction stage and causes the paste to form a brittle mass.
The irradiation also removes water to stop the hydrolysis and
crystallization of CPC/MPC/SPC precursors, and renders all
CPC/MPC/SPC precursors inactive. The brittle mass is crushed into
fine powders. The fine powders are then mixed with a setting
solution comprising water, saline, or nanosilica sol. Upon contact
with the setting solution, hardening of the paste continues and the
cement strength increases. From this process, a viscous and
moldable paste is obtained with minimum exothermicity. The paste
sets to a firm mass after a period of time.
[0049] The cements produced using this electromagnetic
radiation-assisted technique have improved hardening and mechanical
properties with significantly minimized exothermicity and no change
in pH. When nanosilica sol is used as the setting solution, further
improvement to the mechanical properties of the cements compared to
water or other aqueous solution is achieved. This is due to the
nanosilica sol providing amorphous calcium silicate hydrate (CSH)
gel for initial strength reinforcement and increased bioactivity.
As time proceeds, the CSH gel polymerizes and hardens to provide a
solid network to support the cement, thereby providing more
strength and promoting bioactivity of the cement. It should be
noted that the addition of nanosilica, or any other additive, can
alter the desired powder-to-liquid ratio needed to produce the
final cement.
[0050] Some Si-containing CPCs/MPCs/SPCs are already available
commercially with adequate osteoconducitivty. However, commercially
available Si-containing cements are referred to as silicon or
silicate "substituted" cements. "Substitution" in this context
means Si enters into the relevant CPC/MPC/SPC lattice (crystal
structure), thus modifying osteoconductivity and osteoinduction.
Such cements are typically not suitable for orthopedic applications
because they are difficult to synthesize, have a long setting time,
show poor mechanical strength for load-bearing applications, and
may require high-temperature melting. (See Gibson I R, Best S M,
Bonfield W., Chemical Characterization of Silicon-Substituted
Hydroxyapatite, J Biomed Mater Res 1999; 44:422-428.) In the
CPC-SiO.sub.2, MPC-SiO.sub.2, and SPC-SiO.sub.2 compositions
presently disclosed, Si does not modify the lattice in any way.
Rather, as disclosed herein, Si provides a strong bond between the
cement particulates without deteriorating the osteoinduction or
osteoconductivity. The resulting composition shows enhanced
biocompatibility, bioactivity, and mechanical performance compared
to conventional CPCs/MPCs/SPCs. The osteoinduction and
osteoconductivity are mainly provided by the specific phosphate
phase formed. In certain embodiments, the cement is monetite
(DCPA), but the same mechanism applies to MPCs or SPCs.
[0051] The cements disclosed herein are useful for repairing a wide
variety of orthopedic conditions. By way of non-limiting example,
the cements may be injected into the vertebral body for treatment
of spinal fractures, injected into long bone or flat bone fractures
to augment the fracture repair or to stabilize the fractured
fragments, or injected into intact osteoporotic bones to improve
strength. The cements are useful in the augmentation of a
bone-screw or bone-implant interface. The cements may also be
formed into bone-filling granules to replace demineralized bone
matrix materials. The cements disclosed herein provide an elastic
modulus nearer to that of bone than conventional bone cements while
being biodegradable--allowing the cement to be replaced by natural
bone but at the same time mimicking the properties of normal bone
and being able to sustain weight-bearing. Because of their enhanced
weight-bearing capacity, the cements disclosed herein can provide
scaffold support for various types of vertebral fracture and could
be used in tibia plateau reconstruction, wrist fracture
reconstruction, calcaneal reconstruction, and prophylaxis
strengthening of the hip bone. Further, because of their enhanced
biocompatibility and bioactivity, the cements disclosed herein may
be used as delivery vehicles for drugs, genes, proteins, cells,
DNAs, or other molecules.
[0052] Additionally, the cements are useful as bone filler in areas
of the skeleton where bone may be deficient. In this context, the
cements are intended to fill, augment, and/or reconstruct
maxillofacial osseous bone defects, including periodontal, oral,
and cranio-maxillofacial applications. The cements are packed
gently into bony voids or gaps of the skeletal system (i.e.,
extremities, pelvis, and spine), including use in postero-lateral
spinal fusion or vertebral augmentation procedures with appropriate
stabilizing hardware. The cements may be used to fill defects which
may be surgically created osseous defects or osseous defects
created from traumatic injury to the bone. In certain embodiments,
the cements provide a bone void filler that resorbs and is replaced
by bone during the healing process.
[0053] Injectability and cohesiveness are clinically important
issues related to the use of any bone cement. When the repair of a
large defect is underway, a successful bone cement composition
should flow smoothly and homogeneously, resulting in eventual
uniform resorption. Embodiments of the bone cement formed from the
radiation-assisted technique wherein the setting solution comprises
nanosilica gel have improved injectability and cohesiveness. The
exothermic properties of a bone cement are also clinically
important. Because the silica-monetite cement disclosed herein
gives off little heat, the silica-monetite cement does not cause
necrosis of surrounding tissue and could be used as a drug delivery
device. Due to the cement's increase in strength from the
nanosilica bonding, the silica-containing cements described herein
can be used for weight-bearing applications. Examples of
weight-bearing applications include use in osteoporotic vertebral
compression fractures in the spine and other traumatic fractures
like tibia plateau fractures.
[0054] Various additives may be included in any of the compositions
described herein to adjust their properties and the properties of
the hardened cements produced. Examples of suitable additives
include proteins, osteoinductive and/or osteoconductive materials,
X-ray opacifying agents such as strontium phosphate or strontium
oxide, medicaments, supporting or strengthening filler materials,
crystal growth adjusters, viscosity modifiers, pore-forming agents,
antibiotics, antiseptics, growth factors, chemotherapeutic agents,
bone resorption inhibitors, color change agents, immersing liquids,
carboxylates, carboxylic acids, .alpha.-hydroxyl acids, metallic
ions, or mixtures thereof. Other suitable additives include
substances that adjust setting times (such as pyrophosphates or
sulfates), increase injectability or cohesion (such as hydrophobic
polymers like collagen), alter swelling time, or introduce
macroporosity (such as porogens).
[0055] If a reduced particle size of a particular cement
composition disclosed herein is desired for a certain application,
such particle reduction can be accomplished by using, for example,
an agate pestle and mortar, a ball mill, a roller mill, a
centrifugal-impact mill and sieve, a cutter mill, an attrition
mill, a chaser mill, a fluid-energy mill, and/or a
centrifugal-impact pulverizer. Particle size reduction may be
desired for treating bone defects through a method that involves
breaking up the hardened bone cement into pellets and filling a
hole or cavity in the bone with the pellets.
[0056] The cements disclosed herein may be supplied to the user in
a variety of forms, including as powders or as a powder mixture
which is later mixed with a solvent to make slurry or putty, or as
a pre-mixed putty which may a contain nonaqueous extender, e.g.,
glycerine and/or propylene glycol. The pre-mixed putty would allow
the cement to set upon contact with water. Also, any of the cements
disclosed herein can be delivered via injections. That is, a cement
paste can be transferred to a syringe for injection into a
mammalian body. Furthermore, the cements may be supplied with or in
the instrumentation which is used to introduce the cement into the
body. Examples of such instrumentation include, for example, a
syringe, percutaneous device, cannula, biocompatible packet,
dentula, reamer, file, or other forms which will be apparent to
those of ordinary skill in the art. It is further envisioned that
the bone cements disclosed herein could be delivered into the body
in such a form as to be converted by bodily processes into the bone
cement compositions disclosed herein.
[0057] It is contemplated that any of the cements disclosed herein
may be made available to practitioners such as surgeons,
veterinarians, or dentists via a kit containing one or more key
components. A non-limiting example of such a kit comprises the dry
and liquid components in separate containers, where the containers
may or may not be present in a combined configuration. Many other
kits are possible, such as kits comprising a source of
electromagnetic radiation in order to prepare a radiation-assisted
bone cement as described herein, kits comprising a pre-mixed putty
instead of the powder and setting solution, and kits including a
syringe or multiple syringes for injecting a bone cement
composition formed from the components of such kit. The kits
typically further include instructions for using the components of
the kit to practice the subject methods. The instructions for
practicing the subject methods are generally recorded on a suitable
recording medium. For example, the instructions may be present in
the kits as a package insert or in the labeling of the container of
the kit or components thereof. In other embodiments, the
instructions are present as an electronic storage data file present
on a suitable computer readable storage medium, such as a CD-ROM or
diskette. In other embodiments, the actual instructions are not
present in the kit, but means for obtaining the instructions from a
remote source, such as via the internet, are provided. An example
of this embodiment is a kit that includes a web address where the
instructions can be viewed and/or from which the instructions can
be downloaded. As with the instructions, this means for obtaining
the instructions is recorded on a suitable substrate.
[0058] Alternatively, the components to form a bone cement
composition as described herein may be present as a packaged
element. The cements are generally provided or employed in a
sterilized condition. Sterilization may be accomplished by several
methods such as radiation sterilization (e.g., gamma-ray
radiation), dry heat sterilization, or chemical cold
sterilization.
[0059] The bone cements disclosed herein may be further used for
drug delivery. A drug can be dissolved in a bone cement paste, or a
bone cement composition (before or after it sets) can be soaked in
a solution comprising a drug, before the composition is injected or
placed into or onto an anatomical location. The drug can then be
released into the subject from the cement matrix. Embodiments
resulting in sustained release of drugs are also envisioned, for
instance by coating the cement matrix with polymers including
PLA/PGA, polyacrylic acid, hydroxyl methylcellulose, and/or
chitosan.
Example 1
[0060] A 15 mL setting solution was prepared by mixing 0.0032 g
citric acid monohydrate, 6.0 g NaHCO.sub.3, 3.0 mL H.sub.2O, and 12
mL H.sub.3PO.sub.4(86.2%). The pH of the setting solution was
0.25.+-.0.01, and was stable over a shelf life of 6 months. The
setting solution was stored in a tightly-capped glass bottle.
[0061] The powder component of the cement comprised only
Ca(OH).sub.2 (>95%, Fisher Scientific). 1.235 g Ca(OH).sub.2 was
mixed with 0.8 mL H.sub.2O in an agate mortar using an agate
pestle. 1.5 mL of the setting solution was then added to the
mixture, and an agate pestle was used to manually mix the powder
and liquid, giving a paste-like substance at the end of 2.5 to 3
minutes. In a 37.degree. C. environment, the paste hardened after
33 minutes, showing a strength of about 10 MPa.
[0062] Surface modification of chitosan for better bonding to
monetite cement was achieved by mixing 3 g of 98% orthophosphoric
acid, 15 g urea, 15 mL N,N-dimethyl formamide, and 1 g of chitosan
microparticles or nanoparticles in a flask. The mixture was heated
to 120.degree. C. with magnetic stirring at 300 rpm for 1 hour. The
mixture was poured into water and filtered to collect
surface-phosphorylated chitosan particles.
[0063] Chitosan-incorporated monetite cement was prepared by adding
the surface-phosphorylated chitosan particles to the setting
solution with magnetic stirring at 300 rpm for 4 hours. When the
chitosan particles were uniformly dispersed in the setting
solution, the new setting solution was ready for further reaction.
1.235 g Ca(OH).sub.2 was mixed with 0.8 mL H.sub.2O in an agate
mortar using an agate pestle. 1.5 mL of the new setting solution
was then added to the mixture and the agate pestle was used to
manually mix the powder and liquid to form a paste. After
hardening, the monetite cement showed strength above 20 MPa.
[0064] FIG. 1 shows the formation of phases from the setting
solution (with 5% added chitosan as a representative composition)
at the intermediate time points 10 minutes, 20 minutes, 40 minutes,
and 12 hours, by stopping the reactions in ethanol. All the peaks
(other than Ca(OH).sub.2) are assigned to monetite (DCPA). FIG. 2
shows flow patterns of the injected cement paste with 0, 3, 5, and
10% by weight chitosan. The results show that with the addition of
10% chitosan, the cement paste does not flow continuously in spite
of using just one solid ingredient. A 10% composition will not fill
a bone defect cavity uniformly, resulting in non-uniform bone
growth. FIG. 3 is an SEM micrograph of the cement with different
chitosan content. FIG. 4 is an SEM micrograph of osteoblast cells
on cement samples after 72 hours of seeding. The biocompatibility
of the surface is shown by cell spreading, with cement particles
visible underneath the osteoblasts. This proves the
biocompatibility of the cement. FIG. 5 displays the compressive
strength improvement of the cement after the addition of surface
phosphorylated chitosan.
Example 2
[0065] Cement pastes were prepared by manually mixing Ca(OH).sub.2
with setting solution and DI water in an agate mortar by using an
agate pestle. For preparing 15 mL of the setting solution, 0.0032 g
of citric acid monohydrate (CAM, C.sub.6H.sub.8O.sub.7.H2O, 100%),
6 g of sodium bicarbonate (NaHCO.sub.3, >99.7%), 1.95 mL of DI
water for diluting the setting solution, and 13.05 mL of phosphoric
acid (H.sub.3PO.sub.4, 85%) solution as a source of phosphate, were
mixed respectively. Initially, 0.6175 g of Ca(OH).sub.2 was mixed
at least two minutes with 0.8 mL of DI water to form a paste with
Ca(OH).sub.2 uniformly dispersed in the water. Finally, 0.75 mL of
setting solution was added to the materials.
[0066] The mixed paste was transferred to a household microwave
with 1300 W energy input and baked for 5 minutes at maximum power.
The resulted mass was crushed into fine powders using a pestle. 1 g
of the monetite powders was then mixed with 0.5-0.8 mL water or
nanosilica sol. In both cases, the formed paste could be shaped and
injected, and was capable of self-setting at 45.degree. F.,
73.degree. F., and 98.6.degree. F. environments. The maximum
compressive strength of the monetite-silicate cement reached 65
MPa, ideal for weight-bearing applications. FIG. 8 shows XRD
patterns of monetite (DCPA) cements formed with and without using
this radiation-assisted technique. FIG. 9 shows a scanning electron
microscope (SEM) micrograph of preosteoblast cells on the
monetite-silica cement samples after 72 hours of seeding. FIG. 12
shows the difference in heat generated during mixing reactants with
water, with and without the microwave-assisted technique.
Example 3
[0067] Cement pastes were prepared by manually mixing Mg(OH).sub.2
with setting solution and DI water in an agate mortar by using an
agate pestle. For preparing 15 mL of the setting solution, 0.0032 g
of citric acid monohydrate (CAM, C.sub.6H.sub.8O.sub.7.H.sub.2O,
100%), 6 g of sodium bicarbonate (NaHCO.sub.3, >99.7%), 1.95 mL
of DI water for diluting the setting solution, and 13.05 mL of
phosphoric acid (H.sub.3PO.sub.4, 85%) solution as a source of
phosphate, were mixed respectively. 2.47 g of Mg(OH).sub.2 was
added to a mixture of 2 mL of DI water and 3 mL of setting solution
to form a paste.
[0068] The mixed paste was transferred to a household microwave
with 1300 W energy input and baked for 5 minutes at maximum power.
The resulted mass was crushed into fine powders using a pestle. 2 g
of the MPC powders were then mixed with 0.5-0.8 mL water or
nanosilica sol. In both cases, the formed paste could be shaped and
injected, and was capable of self-setting at 45.degree. F.,
73.degree. F., and 98.6.degree. F. environments.
Example 4
[0069] A cement paste was prepared by adding 1.235 g Mg(OH).sub.2
to a mixture of 0.5 mL DI water and 1.5 mL setting solution. The
paste hardened into disk samples. The same paste, freshly prepared,
was treated with microwaves for 10 minutes to prepare powders. The
1 g of synthesized powders was mixed with 0.4 mL DI water to form a
paste that set into a hardened mass. FIG. 13 compares the XRD
patterns of Mg--P precursors formed after microwave treatment,
Mg--P cement formed by direct mixing with Mg(OH).sub.2 and
H.sub.3PO.sub.4, and hardened Mg--P cement after microwave
treatment. FIG. 14 shows SEM images of the precursors, cement
formed from direct mixing, and cement formed after microwave
treatment. The formed Mg--P is newberyite
(MgHPO.sub.4.3H.sub.2O).
[0070] After 7 days incubation in simulated body fluid, the Mg--P
cement was converted into apatite with plate-like crystals and
Mg.sup.2+, Ca.sup.2+, Na.sup.+, and PO.sub.4.sup.3- ions. FIG. 15
shows an SEM image depicting this. FIG. 16 shows an XRD pattern of
the Mg--P cement after 7 days SBF incubation, indicating partial
newberyite (MgHPO.sub.4.3H.sub.2O) was converted into bobierrite
(Mg.sub.3(PO.sub.4).sub.2.8H.sub.2O).
Example 5
[0071] A strontium-containing cement was prepared using a setting
solution of DI water. The reactants were Mg(OH).sub.2 and
H.sub.3PO.sub.4 crystals. In the precursors' production, 3 g
Mg(OH).sub.2 and 3.36 g H.sub.3PO.sub.4 were mixed with 3 mL water.
After 1 minute of mixing, the formed paste was sent to a microwave
oven for 5 minutes of maximum power heating treatment. The formed
brittle material was crushed into fine powders. The powders were
mixed with water containing SrCl.sub.2 (0.01 g SrCl.sub.2 to 1 mL
water) at a weight/volume ratio of 3 g/mL to form a paste, which
set after 5 minutes. Since such a small amount of SrCl.sub.2 was
added, no change to the XRD pattern of the resulting cement can be
seen.
[0072] While various examples herein describe cements having Ca--P
phases as the predominant component, other alkaline earths such as
Sr can be added to synthesize doped Ca--P phases. In embodiments
with Sr-doped Ca--P or Mg--P phases, the resulting cement has radio
opacity and promotes cell growth. This will be readily apparent to
practitioners skilled in the art.
[0073] The term "cement" herein is used interchangeably with paste,
slurry, putty, cement formulation, and cement composition. The term
"between" is used in connection with a range that includes the
endpoints unless the context suggests otherwise. The term
"shelf-life" herein means that the calcium phosphate mineral(s)
will set when mixed with a solvent to form a cement after the
powder has been stored in a sealed container for a predetermined
period of time, most preferably for at least 6 months or more. The
term "setting solution" herein means the solution leading to redox
reactions. The term "injectable" as used in accordance with the
present disclosure refers to when the calcium phosphate minerals
are mixed with a solvent to form a cement paste and the paste is
transferred to a syringe for injection into a mammalian body. The
term "setting" means the hardening at room or body temperature of
the paste formed by mixing a powder component and a setting
solution as described herein.
[0074] Certain embodiments of the bone cement composition disclosed
herein are defined in the examples herein. It should be understood
that these examples, while indicating particular embodiments of the
invention, are given by way of illustration only. From the above
discussion and these examples, one skilled in the art can ascertain
the essential characteristics of this disclosure, and without
departing from the spirit and scope thereof, can make various
changes and modifications to adapt the compositions and methods
described herein to various usages and conditions. Various changes
may be made and equivalents may be substituted for elements thereof
without departing from the essential scope of the disclosure. In
addition, many modifications may be made to adapt a particular
situation or material to the teachings of the disclosure without
departing from the essential scope thereof.
* * * * *