U.S. patent application number 14/312276 was filed with the patent office on 2014-10-09 for sodium containing sol-gel derived bioactive glasses and uses thereof including hemostasis.
The applicant listed for this patent is Cecilia Cao, Roy Layne Howell, Gregory J. Pomrink, Zehra Tosun, Jipin Zhong. Invention is credited to Cecilia Cao, Roy Layne Howell, Gregory J. Pomrink, Zehra Tosun, Jipin Zhong.
Application Number | 20140302165 14/312276 |
Document ID | / |
Family ID | 51528100 |
Filed Date | 2014-10-09 |
United States Patent
Application |
20140302165 |
Kind Code |
A1 |
Pomrink; Gregory J. ; et
al. |
October 9, 2014 |
SODIUM CONTAINING SOL-GEL DERIVED BIOACTIVE GLASSES AND USES
THEREOF INCLUDING HEMOSTASIS
Abstract
A sol-gel bioactive glass precursor, method for making sol-gel
glasses, resultant sol-gel bioactive glasses, and methods of use
thereof, which include introducing Na.sub.2O into the glass network
during the sol-gel process through the use of Na-ethoxide, NaCl, or
sodium silicate rather than sodium nitrate. Medical and industrial
uses of such glasses.
Inventors: |
Pomrink; Gregory J.;
(Newberry, FL) ; Zhong; Jipin; (Gainesville,
FL) ; Tosun; Zehra; (Gainesville, FL) ;
Howell; Roy Layne; (Gainesville, FL) ; Cao;
Cecilia; (Gainesville, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pomrink; Gregory J.
Zhong; Jipin
Tosun; Zehra
Howell; Roy Layne
Cao; Cecilia |
Newberry
Gainesville
Gainesville
Gainesville
Gainesville |
FL
FL
FL
FL
FL |
US
US
US
US
US |
|
|
Family ID: |
51528100 |
Appl. No.: |
14/312276 |
Filed: |
June 23, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14204816 |
Mar 11, 2014 |
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14312276 |
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61782849 |
Mar 14, 2013 |
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61786991 |
Mar 15, 2013 |
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Current U.S.
Class: |
424/602 |
Current CPC
Class: |
A61L 27/10 20130101;
A61L 26/0004 20130101; A61L 27/12 20130101; A61K 31/415 20130101;
A61L 27/54 20130101; A61L 27/52 20130101; A61K 31/4439 20130101;
A61K 8/25 20130101; A61K 31/65 20130101; A61K 33/14 20130101; C03C
2204/00 20130101; A61K 31/454 20130101; A61K 33/42 20130101; A61Q
11/00 20130101; A61K 33/22 20130101; A61L 27/56 20130101; A61K
45/06 20130101; A61K 31/58 20130101; A61L 2400/04 20130101; C03C
3/097 20130101; C03C 4/0007 20130101; A61K 33/08 20130101; A61L
26/0085 20130101; C03B 19/02 20130101; A61P 3/00 20180101; A61K
31/216 20130101; A61L 2430/02 20130101; A61L 26/0066 20130101; C03C
2203/26 20130101; A61K 33/08 20130101; A61K 2300/00 20130101; A61K
33/42 20130101; A61K 2300/00 20130101; A61K 33/22 20130101; A61K
2300/00 20130101; A61K 33/14 20130101; A61K 2300/00 20130101; A61K
31/65 20130101; A61K 2300/00 20130101; A61K 31/58 20130101; A61K
2300/00 20130101; A61K 31/415 20130101; A61K 2300/00 20130101; A61K
31/216 20130101; A61K 2300/00 20130101; A61K 31/4439 20130101; A61K
2300/00 20130101; A61K 31/454 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/602 |
International
Class: |
A61K 33/42 20060101
A61K033/42 |
Claims
1. A sol-gel bioactive glass precursor including a source of Si,
Ca, P, and Na, wherein the sodium source is selected from the group
consisting of sodium methoxide, sodium tert-butoxide, sodium
hydroxide, sodium oxalate, sodium nitrate, sodium sulfate, sodium
thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash,
baking soda, and sodium acetate.
2. The sol-gel bioactive glass precursor of claim 1, wherein the Si
source is selected from the group consisting of
tetraethylorthosilicate (TEOS), tetramethylorthosilicate (TMOS),
fumed silica, colloidal silica, silica gel, sodium silicate, and
silicon tetrachloride.
3. The sol-gel bioactive glass precursor of claim 1, wherein the Ca
source is selected from the group consisting of calcium methoxide,
calcium chloride diydrate, calcium hydroxide, calcium oxolate
hydrate, and calcium citrate tetrahydrate, calcium sulfate
dehydrate, calcium carbonate, calcium acetate hydrate.
4. The sol-gel bioactive glass precursor of claim 2, wherein the Ca
source is selected from the group consisting of calcium methoxide,
calcium chloride diydrate, calcium hydroxide, calcium oxolate
hydrate, and calcium citrate tetrahydrate, calcium sulfate
dehydrate, calcium carbonate, calcium acetate hydrate.
5. The sol-gel bioactive glass precursor of claim 1, wherein the P
source is triethylphosphate or sodium hexametaphosphate.
6. The sol-gel bioactive glass precursor of claim 1, wherein the
source of Na is present in an amount to provide for 20-30% by
weight of Na.sub.2O in a sol-gel bioactive glass.
7. The sol-gel bioactive glass precursor of claim 2, wherein the
source of Si is present in an amount to provide for 20-30% by
weight of SiO.sub.2 in a sol-gel bioactive glass.
8. The sol-gel bioactive glass precursor of claim 3, wherein the
source of Ca is present in an amount to provide for 20-30% by
weight of CaO in a sol-gel bioactive glass.
9. The sol-gel bioactive glass precursor of claim 4, wherein the
source of Ca is present in an amount to provide for 20-30% by
weight of CaO in a sol-gel bioactive glass.
10. The sol gel bioactive glass precursor of claim 5, wherein the
source of phosphate is triethylphosphate and is present in an
amount to provide for 20-30% by weight of P.sub.2O.sub.5 in a
sol-gel bioactive glass.
11. The sol-gel bioactive glass of claim 1, wherein the bioactive
sol-gel glass is in a granular form, particulate form, matt form,
fiber form, hemostatic sponge form, foam form, paste or putty form,
or sphere or bead form, or a combination thereof.
12. A sol-gel bioactive glass comprising Si, Ca, P, and Na, wherein
the sol-gel bioactive glass is derived from a mixture including a
sodium source selected from the group consisting of sodium
methoxide, sodium tert-butoxide, sodium hydroxide, sodium oxalate,
sodium nitrate, sodium sulfate, sodium thiosulfate, sodium dodecyl
sulfate, sodium bicarbonate, soda ash, baking soda, and sodium
acetate.
13. A method of making a sol-gel bioactive glass including Si, Ca,
P, and Na comprising: mixing a sol-gel bioactive glass precursor
including a source of Si, Ca, P, and Na, wherein the sodium source
is selected from the group consisting of sodium methoxide, sodium
tert-butoxide, sodium hydroxide, sodium oxalate, sodium nitrate,
sodium sulfate, sodium thiosulfate, sodium dodecyl sulfate, sodium
bicarbonate, soda ash, baking soda, sodium silicate, and sodium
acetate; aging the mixture, and drying the mixture to form the
sol-gel bioactive glass.
14. The method of claim 13, wherein said aging is conducted at a
temperature of 50-80.degree. C. for 40-70 hours.
15. The method of claim 13, further comprising sintering at
500-900.degree. C. for 15 to 50 hours.
16. A method for achieving hemostasis in a patient in need of
treatment thereof comprising contacting the patient with the
sol-gel bioactive glass of claim 12.
17. A method of inducing rapid coagulation in a bleeding patient
comprising contacting the patient with the sol-gel bioactive glass
of claim 12.
18. A method for achieving hemostasis in a patient in need of
treatment thereof comprising contacting the patient with the
sol-gel bioactive glass made from the sol-gel bioactive glass
precursor of claim 1.
19. The sol-gel bioactive glass of claim 12, wherein Si, Ca, P, and
Na are present in their oxide form of SiO.sub.2, Ca.sub.2O,
P.sub.2O.sub.5, and NaO.
20. The sol-gel bioactive glass of claim 19, further comprising one
or more of K, Mg, Zn, B, F, or Ag.
21. A method of making a sol-gel bioactive glass including Si, Ca,
P, and Na comprising: mixing a sol-gel bioactive glass precursor
including a source of Si, Ca, P, and Na, wherein the sodium source
is selected from the group consisting of sodium methoxide, sodium
tert-butoxide, sodium hydroxide, sodium oxalate, sodium nitrate,
sodium sulfate, sodium thiosulfate, sodium dodecyl sulfate, sodium
bicarbonate, soda ash, baking soda, and sodium acetate, and drying
the mixture at a temperature of 100.degree. C. or lower.
22. The method of claim 21, further comprising adding a
biologically active molecule.
23. A method of treating wounds in a patient comprising contacting
the patient with the sol-gel bioactive glass of claim 12.
24. A method of repairing bone in a patient comprising contacting
the bone in need of treatment with the sol-gel bioactive glass of
claim 12.
25. A method for achieving hemostasis in a patient in need of
treatment thereof comprising contacting the patient with the
sol-gel bioactive glass comprising Si, Ca, P, and Na, wherein the
sol-gel bioactive glass is derived from a mixture including a
sodium source, wherein the sodium source is selected from the group
consisting of sodium methoxide, sodium tert-butoxide, sodium
hydroxide, sodium oxalate, sodium nitrate, sodium sulfate, sodium
thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash,
baking soda, and sodium acetate.
Description
RELATED APPLICATIONS
[0001] The present patent document is a continuation-in-part
application of U.S. application Ser. No. 14/204,816, filed on Mar.
11, 2014, which claims the benefit of the filing date under 35
U.S.C. .sctn.119(e) of Provisional U.S. Patent Application Ser. No.
61/782,849, filed Mar. 14, 2013 and Provisional U.S. Patent
Application Ser. No. 61/786,991, filed March 15, 2013, which are
hereby incorporated by reference in their entirety.
BACKGROUND
[0002] This invention relates generally to novel sol-gel derived
bioactive glasses containing sodium and uses thereof.
[0003] Sol-gel processes for making, bioactive glass using sol-gel
technology are generally known. For example, U.S. Pat. No.
5,074,916 (the "'916 patent"), the subject matter of which is
incorporated herein by reference, discloses sol-gel processing
techniques used to produce alkali-free bioactive glass compositions
based on SiO.sub.2, CaO.sub.2 and P.sub.2O.sub.5. The '916 patent
discloses that by varying the SiO.sub.2 content a range of
hydroxyapatite production rates can be obtained. Also, varying the
time of exposure to actual or simulated in vivo solutions permits
use of a range of allowable proportions of SiO.sub.2. The sol-gel
derived compositions disclosed in the '916 patent can be chosen to
achieve target values for a thermal expansion coefficient, elastic
modulus and volume electrical resistivity. Methods of manufacturing
near equilibrium dried sol-gel bioactive glasses are described in
U.S. Pat. No. 6,171,986 herein incorporated by reference in its
entirety.
[0004] The '916 patent explains that one of the advantages of
sol-gel derived bioactive glasses over melt derived, is that the
use of alkali metal oxides such as Na.sub.2O can be avoided in
sol-gel derived bioactive glasses. Such alkali metal oxides serve
as a flux or aid in melting or homogenization. The '916 patent
points out that the presence of alkali metal oxide ions results in
a high pH at the interface between the glass and surrounding fluid
or tissue in vivo, and that this can induce inflammation and shut
down repair. The '916 patent avoids such issues by using only
SiO.sub.2, CaO.sub.2 and P.sub.2O.sub.5 and eliminating the
traditional need for sodium or other alkali metal compounds to
assist in producing bioactivity.
[0005] Patent Application Publication U.S. 2009/0208428 states that
the presence of the alkali metals, sodium and potassium, at high
concentrations in the bioactive glasses can reduce the usefulness
of the bioactive glass in vivo. The preferred sol-gel derived glass
disclosed in U.S. 2009/0208428 includes strontium and is
alkali-metal free.
[0006] Bioglass, melt-derived with code name 45S5, contains 45%
SiO.sub.2 in weight percent with 24.5% CaO, 24.5% Na.sub.2O and 6%
P.sub.2O.sub.5, and provides a rapid biological response, or in
other words, fast bioactivity, when implanted in living tissue as
compared to other bioactive glass formulations.
[0007] It has been well recognized that the surface reactivity of
Bioglass is attributed to its bioactivity. In the early of 1990s,
sol-gel bioactive glasses have been reported with higher specific
surface area from their porous structure. Since then, 49S, 58S,
68S, 77S, 86S sol-gel compositions have been reported with
corresponding 50%, 60%, 70%, 80% and 90% SiO.sub.2 in mole percent,
respectively. The specific surface area of all of these
compositions is more than 100 times greater than melt-derived 45S5
Bioglass. These compositions typically do not contain Na.sub.2O due
to the difficulty in incorporating the Na.sub.2O into the glass
network.
[0008] Some hemostasis products used worldwide, such as Zeolite and
starch powders derived products, owe their hemostatic effect to
high specific surface area. It is believed that materials with high
surface area adsorb water from the blood rapidly and concentrate
clotting proteins and platelets to promote instantaneous clot
formation. Sol-gel bioactive glasses possess much higher specific
surface area, and should be ideal hemostasis materials in addition
to their recognized properties of enhancing bone growth, soft
tissue growth and healing as well as oral care in applications such
as tooth desensitization, anti-gingivitis and tooth whiting. U.S.
Patent Application Publication Nos. 2009/0186013 and 2009/0232902,
herein incorporated by reference in their entirety, claim that
sol-gel made bioactive silica gel with porous structure and high
specific surface area, possessed hemostatic effect. But all of the
silica gels reported were made from Si, Ca and P precursors or
their inorganic compounds and none of silica gels were reported
with a sodium precursor.
[0009] A few articles have been published recently on sol-gel
derived 45S5 Bioglass containing Na.sub.2O. See Q Z Chen, Y Lia, L
Y Jina, J M W Quinnc, P A Komesaroffe, "A new sol-gel process for
producing Na2O-containing bioactive glass ceramics", Acta
Biomaterialia V6(10), 4143-53, 2010; R L Siqueira, O P Edgar and D
Zanotto, "Gel-derived SiO2-CaO--Na2O--P2O5 bioactive powders:
Synthesis and in vitro bioactivity", Materials Science and
Engineering: C V 31(5), 983-91, 2011; Q Z Chen, G A Thouas,
"Fabrication and Characterization of Sol-gel Derived 45S5
Bioglass-Ceramic Scaffolds", Acta Biomaterialia, 7, 3636-26, 2011;
I Cacciotti, M Lombardi, A Bianco rt al., "Sol-gel Derived 45S5
Bioglass: Synthesis, Microstructural Evolution and Thermal
Behaviour", J Mater Sci: Mater Med, 23:1849-66, 2012. All of those
works used NaNO.sub.3 (sodium nitrate) to introduce Na.sub.2O into
the Bioglass system during the sol-gel processing. As explained
below, a comparative experiment demonstrated that the precipitation
could be seen visually on the gel's surface prepared with sodium
nitrate after aging, which could result in possible non-homogenous
composition. The exact compositions of the reported sol-gel 45S5
Bioglass materials remain a question since no data has been
reported in those published works. Also, all of those articles
describe the use of high temperature sintering from 700.degree. C.
to 1100.degree. C. to prepare the sol-gel 45S5 glass. The high
temperature sintering could enable the preparation of a homogenous
composition, however this process could reduce the surface area
dramatically to yield a dense 45S5 Bioglass. The authors do not
provide any porosity and surface area data in these
publications.
SUMMARY
[0010] In one aspect, the present invention is directed to a
sol-gel bioactive glass precursor including a source of Si, Ca, P,
and Na, wherein the sodium source is selected from the group
consisting of sodium methoxide, sodium tert-butoxide, sodium
hydroxide, sodium oxalate, sodium nitrate, sodium sulfate, sodium
thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash,
baking soda, and sodium acetate. The Si source may be selected from
the group consisting of tetraethylorthosilicate (TEOS),
tetramethylorthosilicate (TMOS), fumed silica, colloidal silica,
silica gel, sodium silicate, and silicon tetrachloride. The Ca
source may be selected from the group consisting of calcium
methoxide, calcium chloride diydrate, calcium hydroxide, calcium
oxolate hydrate, and calcium citrate tetrahydrate, calcium sulfate
dehydrate, calcium carbonate, calcium acetate hydrate. The P source
may be triethylphosphate or sodium hexametaphosphate. The source of
Na may be present in an amount to provide for 20-30% by weight of
Na.sub.2O in a sol-gel bioactive glass. The source of Si may be
present in an amount to provide for 20-30% by weight of SiO.sub.2
in a sol-gel bioactive glass. The source of Ca may be present in an
amount to provide for 20-30% by weight of CaO in a sol-gel
bioactive glass. The source of Ca may be present in an amount to
provide for 20-30% by weight of CaO in a sol-gel bioactive glass.
The source of phosphate may be triethylphosphate and may be present
in an amount to provide for 20-30% by weight of P.sub.2O.sub.5 in a
sol-gel bioactive glass. The bioactive sol-gel glass may be in a
granular form, particulate form, matt form, fiber form, hemostatic
sponge form, foam form, paste or putty form, or sphere or bead
form, or a combination thereof.
[0011] Another embodiments relates to a sol-gel bioactive glass
comprising Si, Ca, P, and Na, wherein the sol-gel bioactive glass
is derived from a mixture including a sodium source selected from
the group consisting of sodium methoxide, sodium tert-butoxide,
sodium hydroxide, sodium oxalate, sodium nitrate, sodium sulfate,
sodium thiosulfate, sodium dodecyl sulfate, sodium bicarbonate,
soda ash, baking soda, and sodium acetate.
[0012] Further embodiment relates to a method of making a sol-gel
bioactive glass including Si, Ca, P, and Na, the method including
mixing a sol-gel bioactive glass precursor including a source of
Si, Ca, P, and Na, wherein the sodium source is selected from the
group consisting of sodium methoxide, sodium tert-butoxide, sodium
hydroxide, sodium oxalate, sodium nitrate, sodium sulfate, sodium
thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash,
baking soda, sodium silicate, and sodium acetate; aging the
mixture, and drying the mixture to form the sol-gel bioactive
glass. In the method, the aging may be conducted at a temperature
of 50-80.degree. C. for 40-70 hours. The method may further include
the step of sintering at 500-900.degree. C. for 15 to 50 hours.
[0013] Yet further embodiment relates to a method for achieving
hemostasis in a patient in need of treatment thereof comprising
contacting the patient with a sol-gel bioactive glass.
[0014] Another embodiment relates to a method of inducing rapid
coagulation in a bleeding patient comprising contacting the patient
with a sol-gel bioactive glass.
[0015] Yet further embodiment relates to a method for achieving
hemostasis in a patient in need of treatment thereof comprising
contacting the patient with the sol-gel bioactive glass made from
the sol-gel bioactive glass precursor including a source of Si, Ca,
P, and Na, wherein the sodium source is selected from the group
consisting of sodium methoxide, sodium tert-butoxide, sodium
hydroxide, sodium oxalate, sodium nitrate, sodium sulfate, sodium
thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash,
baking soda, and sodium acetate. In the method, Si, Ca, P, and Na
may be present in their oxide form of SiO.sub.2, Ca.sub.2O,
P.sub.2O.sub.5, and NaO. The sol-gel bioactive glass may further
include one or more of K, Mg, Zn, B, F, or Ag.
[0016] Further embodiment relates to a method of making a sol-gel
bioactive glass including Si, Ca, P, and Na that includes mixing a
sol-gel bioactive glass precursor including a source of Si, Ca, P,
and Na, wherein the sodium source is selected from the group
consisting of sodium methoxide, sodium tert-butoxide, sodium
hydroxide, sodium oxalate, sodium nitrate, sodium sulfate, sodium
thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash,
baking soda, and sodium acetate, and drying the mixture at a
temperature of 100.degree. C. or lower. The method may further
include adding a biologically active molecule.
[0017] Yet further embodiment relates to a patient comprising
contacting the patient with a sol-gel bioactive glass.
[0018] Another embodiment relates to a method of repairing bone in
a patient comprising contacting the bone in need of treatment with
a sol-gel bioactive glass.
[0019] Further embodiment relates to a method for achieving
hemostasis or inducing rapid coagulation in a patient in need of
treatment thereof comprising contacting the patient with the
sol-gel bioactive glass comprising Si, Ca, P, and Na, wherein the
sol-gel bioactive glass is derived from a mixture including a
sodium source, wherein the sodium source is selected from the group
consisting of sodium methoxide, sodium tert-butoxide, sodium
hydroxide, sodium oxalate, sodium nitrate, sodium sulfate, sodium
thiosulfate, sodium dodecyl sulfate, sodium bicarbonate, soda ash,
baking soda, and sodium acetate.
[0020] Other systems, methods, features and advantages of the
invention will be, or will become, apparent to one with skill in
the art upon examination of the following figures and detailed
description. It is intended that all such additional systems,
methods, features and advantages be within the scope of the
invention, and be encompassed by the following claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains.
[0022] A sol-gel bioactive glass precursor, method for making
sol-gel glasses, and resultant sol-gel bioactive glasses are
disclosed herein which include introducing Na.sub.2O into the glass
network during the sol-gel process through the use of Na-ethoxide
or NaCl rather than sodium nitrate. The precursor includes
organometallic or inorganic salts of elements such as, for example,
Si, Ca, Na, P, Ca, and/or B that are converted to their respective
oxides after heat treatment. The resultant gels provide a
homogenous material. This gel may be heat treated at relatively low
temperature of 100.degree. C. or less to preserve the porous
structure with a high specific surface area thereby avoiding a
sintering step and providing the possibility of adding biologically
active molecules such as disclosed in 5,830,480, the contents of
which is hereby incorporated by reference in its entirety. The
sol-gel glasses are optionally sintered at 500-1000.degree. C. or
preferably 500-900.degree. C., or more preferably, 550-650.degree.
C. Bioactive sol-gels made in accordance with the present invention
provide significantly improved hemostatic properties as compared to
melt-derived 45S5 Bioglass, and other sol-gel compositions. In
addition, bioactive sol-gels made in accordance with the present
invention exhibited equivalent or better hemostatic properties as
compared to some current commercially available hemostasis
products.
[0023] In certain embodiments, a sol-gel bioactive glass precursor
in accordance with the present invention is a mix of ingredients
that provide sources of Si, Ca, and Na to provide a phosphate-free
sol-gel derived bioglass.
[0024] In certain other embodiments, a sol-gel bioactive glass
precursor in accordance with the present invention is a mix of
ingredients that provide sources of Si, Ca, P, and Na. Many
organometallic compounds or inorganic salts (other than sodium
nitrate) providing a source of Si, Ca, P, or Na can be used. For
example, an alkoxysilane such as tetraethoxy silane may be used as
a source of silica, calcium methoxide may be used as a source of
calcium and triethylphoshpate may be used as a source of
phosphorous. Sodium chloride or sodium ethoxide may be used as a
source of sodium. Sol-gel bioactive precursors and sol-gels made
therefrom may further contain K, Mg, Zn, B, F, Ag, Cu, Fe, Mn, Mo,
Sr, and Zn.
[0025] Silicon oxide is typically present in amounts of 20-86%, or
30-60%, or 30-45% by weight of the bioactive sol gel glass. Many
organosilicon or silicon salts may be used as precursors and may be
present in amounts sufficient to yield 0-86% by weight SiO.sub.2 in
the bioactive glass. Colloidal silica or salycic acid may also be
used. Other precursors of silica include sodium organometallics
(e.g., tetraethylorthosilicate (TEOS) and tetramethylorthosilicate
(TMOS)), fumed silica, colloidal silica, silica gel, sodium
silicate, and silicon tetrachloride.
[0026] The sol gel bioactive glass may further contain sodium. Many
organosodium or inorganic sodium salts may be used as a precursor
including but not limited to sodium chloride, sodium ethoxide or
sodium silicate. Other precursors of sodium include other sodium
organometallics (e.g., sodium methoxide, and sodium tert-butoxide),
sodium salts (e.g., sodium hydroxide, and sodium oxalate), sodium
nitrates (e.g., sodium nitrate), sodium sulfates (e.g., sodium
sulfate, sodium thiosulfate, and sodium dodecyl sulfate), sodium
carbonates (e.g., sodium bicarbonate, soda ash, and baking soda)
and others, such as sodium silicates and sodium acetate.
[0027] Such precursors may be used in an amount sufficient to yield
0-40%, 1-55%, 5-15%, 25-30%, or about 10% by weight Na.sub.2O in
the bioactive sol gel glass.
[0028] The sol-gel bioactive glass may further comprise potassium.
The potassium precursors may include but are not limited to
organopotassium compounds or inorganic potassium salts such as
potassium nitrate (KNO.sub.3), potassium sulphate (K.sub.2SO.sub.4)
and potassium silicates. It is advantageous to provide a bioactive
glass composition in which the potassium content is low. If a
potassium precursor is included, it may be present in amounts
sufficient to yield 0-8 K.sub.2O in the bioactive glass.
[0029] The bioactive glass of the present invention preferably
comprises calcium. Calcium precursors include but are not limited
to organocalcium compounds or inorganic salts of calcium such as
calcium nitrate (Ca(NO.sub.3).sub.2), calcium nitrate tetrahydrate
(Callo.sub.3.4H.sub.2O), calcium sulphate (CaSO.sub.4), calcium
silicates or a source of calcium oxide (Lime). Other precursors of
calcium include calcium organometallics (e.g., calcium methoxide),
calcium salts (e.g., calcium chloride diydrate, calcium hydroxide,
calcium oxolate hydrate, and calcium citrate tetrahydrate), calcium
nitrates (e.g., calcium nitrate tetrahydrate), calcium sulfates
(e.g., calcium sulfate dehydrate), calcium carbonates (e.g.,
calcium carbonate) and other precursors, such as calcium acetate
hydrate. A source of calcium oxide includes any compound that
decomposes to form calcium oxide. Release of Ca.sup.2+ ions from
the surface of the bioactive glass aids the formation of the
calcium phosphate-rich layer on the surface of the glass. The
provision of calcium ions by the bioactive glass can increase the
rate of formation of the calcium phosphate-rich layer. However it
should be appreciated that the calcium phosphate-rich layer can
form without the provision of calcium ions by the bioactive glass,
as body fluid itself contains calcium ions. Thus, for the purposes
of this invention, bioactive glasses containing no calcium can be
used. The calcium precursor may be present in the precursor in an
amount sufficient to yield at least 5%, 0-40%, 10-20%, 20-30% or
about 25% CaO in the resultant sol-gel glass.
[0030] The bioactive glass of the present invention preferably
comprises P.sub.2O.sub.5. Phosphate precursors include many
organophosphates and inorganic phosphate salts including but not
limited to triethylphosphate and/or polyphosphates, such as, e.g.
sodium hexametaphosphate. Release of phosphate ions from the
surface of the bioactive glass aids in the formation of
hydroxycarbonated apatite. While hydroxycarbonated apatite can form
without the provision of phosphate ions by the bioactive glass, as
body fluid itself contains phosphate ions, the provision of
phosphate ions by the bioactive glass increases the rate of
formation of hydroxycarbonated apatite. The phosphate precursor may
be present in an amount sufficient to yield at 0-80%, 0-50%,
20-70%, 20-30%, 25-30%, or about 25% P.sub.2O.sub.5 in the
resultant glass.
[0031] The sol-gel bioactive glass of the present invention may
comprise zinc. Zinc precursors include but are not limited to
organozinc compounds or inorganic salts containing zinc such as
zinc nitrate (Zn(NO.sub.3).sub.2), zinc sulphate (ZnSO.sub.4), and
zinc silicates and any such compounds that decompose to form zinc
oxide. When present, the zinc precursor should be present in
amounts sufficient to yield 0.01-5% ZnO in the glass.
[0032] The bioactive glass of the present invention may comprise
magnesium. Magnesium precursors include but are not limited to
organomagnesium compounds or inorganic magnesium salts such as
magnesium nitrate (Mg(NO.sub.3).sub.2), magnesium sulphate
(MgSO.sub.4), magnesium silicates and any such compounds that
decompose to form magnesium oxide. When included the magnesium
source should be present in an amount sufficient to yield 0.01 to
5% MgO in the bioactive glass.
[0033] The sol-gel bioactive glass of the present invention also
includes boron. The boron precursors include but are not limited to
organoborate compounds, inorganic borate salts, boric acid, and
trimethyl borate. A sufficient amount of boron precursor may be
used sufficient to provide B.sub.2O.sub.3 in amounts of at least
25%, 30% to 50%, 35-45%, or up to 80% by weight in the glass.
[0034] The bioactive glass of the present invention may comprise
fluorine. Fluorine precursors include but are not limited to
organofluorine compounds or inorganic fluorine salts such as
calcium fluoride (CaF.sub.2), strontium fluoride (SrF.sub.2),
magnesium fluoride (MgF.sub.2), Sodium fluoride (NaF) or potassium
fluoride (KF). Fluoride stimulates osteoblasts, and increases the
rate of hydroxycarbonated apatite deposition. When present, an
amount of fluorine precursor is used to provide 0-35% or 0.01-5%
calcium fluoride.
[0035] The bioactive sol-gels may further comprise sources of Cu,
Fe, Mn, Mo, or Sr. When present, such sources include
organometallic and inorganic salts thereof. Each may be present to
provide in 0.01 to 5% or more by weight of the respective oxide in
the glass.
[0036] Bioactive sol-gels in accordance with the present invention
are hemostatic materials that are bioabsorbable, that provide for
superior hemostasis, and may be fabricated into a variety of forms
suitable for use in controlling bleeding from a variety of wounds,
both internal and external. Bioactive sol-gel glasses may be in
granular or particulate form, matt or fiber form, a hemostatic
sponge, incorporated into a foam, or in the form of a paste or
putty. The sol-gel glasses may also be in a form of a sphere or a
bead, or a combination of all the forms. Exemplary spherical forms
were described in U.S. Provisonal Application No. 61/786,991, filed
Mar. 15, 2013, content of which is incorporated by reference in its
entirety. They may also be formulated into settable and
non-settable carriers.
[0037] Sol-gel bioactive glass is suitable for use in both surgical
applications as well as in field treatment of traumatic injuries.
For example, in vascular surgery, bleeding is particularly
problematic. In cardiac surgery, the multiple vascular anastomoses
and cannulation sites, complicated by coagulopathy induced by
extracorporeal bypass, can result in bleeding that can only be
controlled by topical hemostats. Rapid and effective hemostasis
during spinal surgery, where control of osseous, epidural, and/or
subdural bleeding or bleeding from the spinal cord is not amenable
to sutures or cautery, can minimize the potential for injury to
nerve roots and reduce the procedure time. In liver surgery, for
example, live donor liver transplant procedures or removal of
cancerous tumors, there is a substantial risk of massive bleeding.
An effective hemostatic material can significantly enhance patient
outcome in such procedures. Even in those situations where bleeding
is not massive, an effective hemostatic material can be desirable,
for example, in dental procedures such as tooth extractions, as
well as the treatment of abrasions, burns, and the like. In
neurosurgery, oozing wounds are common and are difficult to
treat.
[0038] The bioactive sol-gels may be further combined with a
bioactive agent. The bioactive agent comprises one of antibodies,
antigens, antibiotics, wound sterilization substances, thrombin,
blood clotting factors, conventional chemo- and radiation
therapeutic drugs, VEGF, antitumor agents such as angiostatin,
endostatin, biological response modifiers, and various combinations
thereof. The bioactive sol-gels may also be combined with polymers
to provide further structural support. For example, porous
bioactive glass hemostatic agents may be prepared by a sol gel
process described herein that further uses a block copolymer of
ethyleneoxide and propylene oxide.
[0039] Other uses for the sol-gel compositions of the present
invention include filling bone defects, bone repair/regeneration,
limb salvage, drug delivery, repair of osteochondral defects,
reparing osseous defects, dental hypersensitivity, tooth whitening,
and guided tissue regeneration.
EXAMPLES
Preparation of Sol-Gels
[0040] Sol Gel Bioactive glasses were prepared with the
compositions set forth in Table 1 and as described in 1-1 through
1-6 below:
TABLE-US-00001 TABLE 1 Compositions of Sol-gel Bioactive Glasses
Sample ID SiO2 (wt %) CaO (wt %) P2O5 (wt %) Na2O (wt %) 45S5
(melt) 45 24.5 6 24.5 45S5 (Sol- 45 24.5 6 24.5 gel) 58S 58 33 9 0
77S 77 14 9 0 100S 100 0 0 0
[0041] Preparation of 1-1. 100S gel (Comparative--no Na, Ca, or P
source): the gel was prepared by mixing D. I. water, HCl, TEOS
(Tetraethoxysilane) followed by mixing for 60 minutes to facilitate
the completion of hydrolysis reaction. Then, the mixture was
transferred into a polypropylene mold for aging at 60.degree. C.
for 55 hours. After aging, the gel was transferred into drying
vessel for drying to 180.degree. C., then heated at 700.degree. C.
in the same procedures as reported in U.S. Pat. No. 5,074,916 (the
contents of which are hereby incorporated by reference in its
entirety). The heat treated gels were ground to <300 .mu.m
powders for analysis and testing.
[0042] Preparation of 1-2. 77S gel (Comparative--no Na source): the
gel was prepared by mixing D. I. water, HCl, TEOS
(Tetraethoxysilane) for 30 minutes, adding TEP (Triethylphosphate)
into the solution and mixing for another 20 minutes, then adding
CaNO.sub.3.4H.sub.2O (Calcium Nitrate tetra-hydrate) while mixing
for an additional 60 minutes to complete the dissolution of the
Calcium Nitrate. Then, the mixture was transferred into a
polypropylene mold for aging at 60.degree. C. for 55 hours. After
aging, the gel was transferred into drying vessel for drying to
180.degree. C., and then heated at 700.degree. C. in the same
procedures as reported in the U.S. Pat. No. 5,074,916. The heat
treated gels were ground to <300 .mu.m powders for analysis and
testing.
[0043] Preparation of 1-3 (Comparative--no Na source). 58S gel: the
gel was prepared by mixing D. I. water, HCl, TEOS
(Tetraethoxysilane) for 30 minutes, adding TEP (Triethylphosphate)
into the solution and mixing another 20 minutes, then adding
CaNO3.4H2O (Calcium Nitrate tetra-hydrate) while mixing for an
additional 60 minutes to complete the dissolution of the Calcium
Nitrate. Then, the mixture was transferred into a polypropylene
mold for aging at 60.degree. C. for 55 hours. After aging, the gel
was be transferred into drying vessel for drying to 180.degree. C.,
and then heated at 700.degree. C. in the same procedures as
reported in the U.S. Pat. No. 5,074,916. The heat treated gels were
ground to <300 .mu.m powders for analysis and testing.
[0044] Preparation of 1-4. 45S5 gel #1 (Includes sodium ethoxide as
Na source): the gel was prepared by mixing half the amount of D. I.
water, HCl, TEOS (Tetraethoxysilane) for 30 minutes, adding TEP
(Triethylphosphate) into the solution and mixing another 20
minutes, then adding the rest of D. I. water, Calcium Methoxide,
and Sodium Ethoxide, while mixing for 60 minutes to complete the
hydrolysis reaction. Then, the mixture was transferred into a
polypropylene mold for aging at 60.degree. C. for 55 hours. After
aging, the gel was transferred into drying vessel for drying to
180.degree. C., and then heated at 550.degree. C. in the same
procedures as reported in the U.S. Pat. No. 5,074,916. The heat
treated gels were ground to <300 .mu.m powders for analysis and
testing.
[0045] Preparation of 1-5. 45S5 gel #2 (Includes NaCl as Na
source): the gel was prepared by mixing D. I. water, HCl, TEOS
(Tetraethoxysilane) for 30 minutes, adding TEP (triethylphosphate)
into the solution and mixing another 20 minutes, then adding
CaNO.sub.3.4H.sub.2O (Calcium Nitrate tetra-hydrate) and NaCl while
mixing for an additional 60 minutes to complete the dissolution of
the Calcium Nitrate and NaCl. Then, the mixture was transferred
into a polypropylene mold for aging at 60.degree. C. for 55 hours.
After aging, the gel was transferred into drying vessel for drying
at 180.degree. C., and then heated to 550.degree. C. using the same
procedure as reported in U.S. Pat. No. 5,074,916.
[0046] Preparation of 1-6. 45S5 gel #3 (Comparative--includes
sodium nitrate as Na source): the gel was prepared by mixing D. I.
water, HCl, TEOS (Tetraethoxysilane) for 30 minutes, adding TEP
(triethylphosphate) into the solution and mixing another 20
minutes, then adding CaNO.sub.3.4H.sub.2O (Calcium Nitrate
tetra-hydrate) and NaNO.sub.3 (Sodium Nitrate), while mixing for an
additional 60 minutes to complete the dissolution of the Calcium
Nitrate and Sodium Nitrate. Then, the mixture was transferred into
a polypropylene mold for aging at 60.degree. C. for 55 hours. After
aging, the precipitation could be seen visually. After aging, the
gel was transferred into drying vessel for drying at 180.degree.
C., and then heated to 550.degree. C. using the same procedure as
reported in U.S. Pat. No. 5,074,916.
[0047] The following porous structure data was obtained from the
foregoing compositions:
TABLE-US-00002 Specific Surface Pore Size Area Diameter Sample ID
m.sup.2/gram (Angstroms) Standard 216 203 Specifications 45S5
(Melt) 0.1 0 45S5 (Sol-gel) 31 98 58S 166 96 77S 414 30 100S 561
40
Hemostasis Studies
[0048] The male adult Wistar rats were anesthetized by
intraperitoneal injection of pentobarbital (40 mg/kg). An abnormal
incision was made and the left kidney was isolated. A thin flexible
plastic tray was placed under the kidney and the kidney is wrapped
with pre-weighted degrease cotton. Heparin sodium (300 IU/kg) was
then intravenous injected. Five minutes later, an atraumatic clamp
was placed across the renal vascular pedicle, the caudal pole of
the kidney was extruded through the ring about 4 mm protruded above
the plate and the tissue was severed with a scalpel blade. The
hemostatic agent was applied to the cutting surface of the kidney
before the clamp was removed. Bleeding time and the amount of blood
dropped (Blood Wt) were measured.
[0049] 4-1. Study #1 [0050] The tested samples: 45S5(Melt), Sol-gel
58S [0051] Control group: FloSeal, Starch (both are commercially
available products used in the worldwide market) [0052] Blank
Control: No material applied [0053] Each test article was tested in
50 mg, and conducted 6 tests.
TABLE-US-00003 [0053] TABLE 3 Test Results Bleeding Time and Blood
Drop for Study #1 in the Rat Model of Partial Nephrectomy Bleeding
time Blood dropped Group Number (Seconds) (ml) No-treatment Control
5 624 .+-. 36 4.3 .+-. 0.4 Edible starch 5 408 .+-. 24 3.0 .+-. 0.5
Melt-derived 45S5 5 264 .+-. 24 2.1 .+-. 0.3 Bioglass Bioglass 58S
Gel 5 216 .+-. 12 1.0 .+-. 0.1 FloSeal 5 186 .+-. 12 1.0 .+-.
0.1
[0054] Based on the statistic results of this test, the sol-gel 58S
demonstrated a comparable hemostatic effect to FloSeal, a
commercial available product in the market. The order is,
58S>melt 45S5>Starch. All of the test materials are better
than No-treatment control.
[0055] 4-2. Study #2 [0056] The tested samples: 45S5(Melt),
45S5(Sol-gel), 58S, 77S, 100S [0057] Control group: NexStat
(Hemostasis, LLC), [0058] Blank Control: No material applied [0059]
Each test article was tested in 3 doses: 5 .mu.l, 15 .mu.l and 50
.mu.l, and each dose was conducted 6 tests.
[0060] Test Results
TABLE-US-00004 TABLE 4 Blank Control Bleeding time (s) Blood Wt
Collected (g) 647 .+-. 25.57 5.35 .+-. 0.17
TABLE-US-00005 TABLE 5 Bleeding Time and Blood Drop for Study #2 in
the Rat Model of Partial Nephrectomy Materials NexStat
45S5(Sol-gel) 1-4 58S 77S 100S Bleeding Blood Bleeding Blood
Bleeding Blood Bleeding Blood Bleeding Blood Dose Time (s) Wt (g)
Time (s) Wt (g) Time (s) Wt (g) Time (s) Wt (g) Time (s) Wt (g) 5
.mu.l 341 .+-. 17.5* 3.22 .+-. 0.16* 220.6 1.9 552 .+-. 16.7 4.68
.+-. 0.21 466 .+-. 32.3* 4.10 .+-. 0.18 587 .+-. 16.7 4.90 .+-.
0.13 15 .mu.l 166 .+-. 9.7* 1.65 .+-. 0.10* 178 1.12 396 .+-. 9.6*
3.83 .+-. 0.24 240 .+-. 16.2* 2.43 .+-. 0.15* 450 .+-. 13.3* 3.67
.+-. 0.20* 50 .mu.l 80 .+-. 7.2* 1.00 .+-. 0.08* 78 0.66 216 .+-.
7.7* 2.15 .+-. 0.20* 92 .+-. 7.8* 0.98 .+-. 0.07* 286 .+-. 8.5*
2.48 .+-. 0.18*
[0061] Based on the statistic results of this test, the sol-gel
45S5 demonstrated the best hemostatic effect. The order is, sol-gel
45S5>NexStat>77S>58S>77S>melt 45S5.
[0062] Sol-gel 45S5 demonstrated the best hemostatic effect
compared with other tested materials, even some commercially
available hemostasis products. Sol-gel 45S5, with porous structure,
has 30 times higher surface area then melt derived 45S5 Bioglass.
The high surface is functions to adsorb water from the blood
rapidly and concentrate clotting proteins and platelets to promote
instantaneous clot formation. In addition, calcium ions release
from the glass function to complex with the carboxylic acid
functional groups of the proteins within the site to facilitate
clot formation. Although sol-gel 45S5 specific surface area is not
the highest compared with other sol-gel materials such as the 58S,
77S and 100S, it can be assumed that the ionic exchange between Na+
inside sol-gel 45S5 and OH-- would create a large amount of silanol
groups on the sol-gel 45S5 surface or inside pores, which would
facilitate the physical and chemical absorption of water onto the
surface of the glass.
[0063] Due to its fast surface activity, Ca.sup.2+ release from
sol-gel 45S5 would also be very dramatic. As previously described
the calcium ions will complex with the surrounding proteins most
notably fibrin acting as a type of glue to hold the fibrin monomers
to each other to form the polymeric fiber. The resultant fibrin
fibers form a loose meshwork, which functions to entrap
erythrocytes, thus forming a clot that stops the flow of blood. All
of these factors contribute to the hemostatic effect exhibited by
the sol-gel 45S5 Bioglass.
[0064] Throughout this specification various indications have been
given as to preferred and alternative embodiments of the invention.
However, the foregoing detailed description is to be regarded as
illustrative rather than limiting and the invention is not limited
to any one of the provided embodiments. It should be understood
that it is the appended claims, including all equivalents, that are
intended to define the spirit and scope of this invention.
* * * * *