U.S. patent application number 10/149052 was filed with the patent office on 2003-10-23 for mineral-polymer hybrid composition.
Invention is credited to Chaput, Cyril, Rodrigues El Zein, Anabelle.
Application Number | 20030199615 10/149052 |
Document ID | / |
Family ID | 22617898 |
Filed Date | 2003-10-23 |
United States Patent
Application |
20030199615 |
Kind Code |
A1 |
Chaput, Cyril ; et
al. |
October 23, 2003 |
Mineral-polymer hybrid composition
Abstract
The present invention relates to self-setting compositions
consisting in admixed liquid and solid components enable the
formation of hardened bio-materials having a broad range of
properties and performances. The present invention proposes a) a
thermo-sensitive self-gelling liquid component, being water-based,
comprising at least a polycationic and a phosphate source, wherein
the liquid component is a thermo-gelling solution at a pH ranging
from 6.5 to 7.4; b) a powder component consisting in at least two
calcium phosphate sources. The preferred calcium phosphate source
includes apatites, tricalcium phosphates, tetracalcium phosphates
and dicalcium phosphates. Both solid and liquid components are
admixed to form a flowable slurry that sets in situ into a hardened
calcium phosphate based bio-material.
Inventors: |
Chaput, Cyril; (Montreal,
CA) ; Rodrigues El Zein, Anabelle; (Montreal-Nord,
CA) |
Correspondence
Address: |
Nixon Peabody
101 Federal Street
Boston
MA
02110
US
|
Family ID: |
22617898 |
Appl. No.: |
10/149052 |
Filed: |
November 22, 2002 |
PCT Filed: |
December 8, 2000 |
PCT NO: |
PCT/CA00/01489 |
Current U.S.
Class: |
524/2 |
Current CPC
Class: |
A61K 47/02 20130101;
A61L 24/08 20130101; A61L 24/0063 20130101; A61P 19/00 20180101;
C08L 5/08 20130101; C08L 5/08 20130101; C08L 5/08 20130101; A61L
27/425 20130101; A61K 9/0024 20130101; A61L 27/52 20130101; A61L
24/08 20130101; A61L 27/32 20130101; A61L 27/20 20130101; A61K
47/36 20130101; A61L 27/20 20130101; A61L 27/24 20130101; A61L
24/0084 20130101; C08L 5/08 20130101; A61L 24/0084 20130101; A61L
2400/06 20130101 |
Class at
Publication: |
524/2 |
International
Class: |
C08K 003/00 |
Claims
What is claimed is:
1. An injectable self-setting composition comprising: a) a
water-based liquid component comprising at least one cationic
polymer and one mono-phosphate salt; said liquid component having a
pH ranging from 6.5 to 7.4, said liquid component having an
endothermally gelling character and being free of insoluble
particles; and b) a powder component comprising at least two
calcium phosphate sources selected from apatites and apatitic
calcium phosphates, octacalcium phosphates, amorphous calcium
phosphates, tetracalcium phosphates, tricalcium phosphates,
dicalcium phosphates and monocalcium phosphates, wherein when said
components of step a) and b) are intimately and uniformly mixed
together, said components of step a) and b) form an injectable
thermo-setting slurry, said slurry when heated turns into a solid
material.
2. The composition of claim 1, wherein said cationic polymer is a
polysaccharide, a polypeptide or a synthetic polymer.
3. The composition of claim 1, wherein said cationic polymer has a
concentration in said liquid component between 0.1 and 5.0% wt.
4. The composition of claim 1, wherein said cationic polymer is
chitosan or collagen, or a mixture of chitosan and collagen.
5. The composition of claim 1, wherein said cationic polymer is a
partially-deacetylated chitin or chitosan with a degree of
deacetylation between 30 and 99%.
6. The composition of claim 1, wherein said cationic polymer is a
polylysine.
7. The composition of claim 1, wherein said monophosphate salt has
a basic character.
8. The composition of claim 1, wherein said liquid component
comprises a first phosphate source selected from the group
consisting of Na.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
Fe.sub.2PO.sub.4C.sub.3H.sub.5(- OH).sub.2,
K.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
MgPO.sub.4C.sub.3H.sub.5(OH).sub.2,
MnPO.sub.4C.sub.3H.sub.5(OH).sub.2,
Ca.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
Na.sub.2PO.sub.7C.sub.3H.sub.7, Na.sub.2PO.sub.7C.sub.4H.sub.7,
K.sub.2PO.sub.7C.sub.4H.sub.7, NaPO.sub.7C.sub.4H.sub.8,
K.sub.2PO.sub.7C.sub.4H.sub.8, Na.sub.2PO.sub.8C.sub.5H.sub.9,
K.sub.2PO.sub.8C.sub.5H.sub.9, NaPO.sub.8C.sub.5H.sub.10,
KPO.sub.8C.sub.5H.sub.10, Na.sub.2PO.sub.9C.sub.6H.sub.11,
NaPO.sub.9C.sub.6H.sub.12, K.sub.2PO.sub.8C.sub.6H.sub.14,
KPO.sub.9C.sub.6H.sub.12, Na.sub.2PO.sub.8C.sub.6H.sub.13,
K.sub.2PO.sub.8C.sub.6H.sub.13, NaPO.sub.8C.sub.6H.sub.14,
KPO.sub.8C.sub.6H.sub.14, Na.sub.2PO.sub.9C.sub.6H.sub.12,
K.sub.2PO.sub.9C.sub.6H.sub.12, NaPO.sub.9C.sub.6H.sub.13,
KPO.sub.9C.sub.6H.sub.13, Na.sub.2PO.sub.8C.sub.10H.sub.11,
K.sub.2PO.sub.8C.sub.10H.sub.11, NaPO.sub.8C.sub.10H.sub.12,
KPO.sub.8C.sub.10H.sub.12 and the like, or a derivative
thereof.
9. The composition of claim 1, wherein said monophosphate salt is a
sodium, magnesium, potassium, ferric and/or calcium alpha- or
beta-glycerophosphate salt, or a mixture thereof.
10. The composition of claim 1, wherein said monophosphate salt is
glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate or
fructose-6-phosphate salt, or a mixture thereof.
11. The composition of claim 1, wherein said liquid component has a
pH between 6.8 and 7.2.
12. The composition of claim 1, wherein said liquid component has a
viscosity superior to 200 mPa.s.
13. The composition of claim 1, wherein said liquid component
further comprises at least one other water-soluble polymer selected
from the group consisting of polypeptides, cellulosics and
synthetic polymers, including methyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxyethyl propylcellulose,
hydroxymethyl propylcellulose, poly(ethylene oxide), poly(propylene
oxide), poly(ethylene glycol), poly(vinylpyrrolidone), poly(vinyl
alcohol), and derivatives thereof.
14. The composition of claim 1, wherein said liquid component
further comprises at least one organic polyol, including
sugar-polyol, saccharide-polyol and glycol, selected from the group
consisting of glycerol, mannitol, sorbitol, ethylene glycol
oligomers, propylene glycol oligomers, saccharose, fructose,
glucose, maltose, and the like.
15. The composition of claim 1, wherein said liquid component
further comprises at least one water-soluble amino acid having a
basic character and a pKa between 6.5 and 8.5.
16. The composition of claim 1, wherein said liquid component
further comprises a water-soluble sulfonate or carboxylate salt
having a basic character and a pKa between 6.5 and 8.5.
17. The composition of claim 1, wherein the liquid component and
the powder component has a ratio liquid/powder component from 0.05
to 1.50 mug.
18. The composition of claim 1, wherein the composition has a final
molar ratio of calcium/phosphorus between 1.20 and 1.80.
19. The composition of claim 1, wherein said powder component
comprises alpha-tricalcium phosphate and an apatitic calcium
phosphate.
20. The composition of claim 1, wherein said powder component
comprises alpha-tricalcium phosphate, dicalcium phosphate and an
apatitic calcium phosphate.
21. The composition of claim 1, wherein said powder component
comprises alpha-tricalcium, monocalcium phosphate and an apatitic
calcium phosphate.
22. The composition of claim 1, wherein said powder component
comprises at least alpha-tricalcium phosphate and an amorphous
calcium phosphate.
23. The composition of claim 1, wherein said powder component
comprises tetracalcium phosphate and dicalcium phosphate.
24. The composition of claim 1, wherein said powder component
comprises tetracalcium phosphate and monocalcium phosphate.
25. The composition of claim 1, wherein said powder component
comprises less than 40% wt. of an apatitic calcium phosphate.
26. The composition of claim 1, wherein said powder component
further comprises at least one fluoride selected from the group
consisting of NaF, Na.sub.2Si.sub.6F, KF, KSi.sub.6F, CaF.sub.2,
MgF.sub.2, ZnF.sub.2, and sodium fluorophosphates, and the like, or
derivatives thereof.
27. The composition of claim 1, wherein said powder component
further comprises at least one carbonate selected from the group
consisting of Na.sub.2CO.sub.3, CaCO.sub.3, K.sub.2CO.sub.3,
MgCO.sub.3, ZnCO.sub.3, Ca.sub.9K(PO.sub.4).sub.5(CO.sub.3).sub.2,
Ca.sub.8.5Na.sub.1.5(PO.sub.4)- .sub.4.5(CO.sub.3).sub.2.5,
Ca.sub.9(PO.sub.4).sub.4.5(CO.sub.3).sub.1.5, and the like.
28. The composition of claim 1, wherein said powder component
comprises a strontium salt including strontium carbonate.
29. The composition of claim 1, wherein said powder component
comprises at least one calcium phosphate selected from the group
consisting of fluoride, strontium, carbonate, magnesium, zinc, and
barium containing calcium phosphates.
30. The composition of claim 1, wherein said powder component
comprises at least one inorganic salt including sodium phosphates
and disodium glycerophosphate, or the like.
31. The composition of claim 1, wherein said powder component
comprises at least one organic salt including oxalate, citrate,
malate, gluconate, lactate, lactobionate, or the like.
32. The composition of claim 1, wherein said powder component
comprises at least one organic salt including oxalic, citric,
malic, gluconic, lactic, lactobionic acids, or the like.
33. The composition of claim 1, wherein said powder component is a
powder having a size ranging from 0.1 to 100 micrometers.
34. The composition of claim 1, further comprising a bioactive
ingredient such as a drug, a protein, a peptide, a synthetic
molecule or an inorganic molecule.
35. The composition of claim 1, which further comprises at least
one osteoinductive agent selected from the group consisting of
hormones, bone proteins and mixtures of osteoinductive proteins,
demineralized bone matrix (DBM) or powder (DBP), bone morphogenic
proteins (BMP), sialoproteins, osteonectin, osteopontin,
osteocalcin, calcitonin.
36. The composition of claim 1, which further comprises at least
one growth factor selected from the group consisting of IGF, EGF,
a-FGF, b-FGF, PDGF-A, PDGF-B and TGF-beta.
37. The composition of claim 1, which further comprises an
antiresorptive, antibiotic, antiviral, antitumor, or an
immunosupressive agent.
38. Use of the composition of claim 1 for injection into a defect,
cavity or interface of a body's tissue, said composition setting in
situ into a hardened filling material.
39. Use of the composition of claim 1 for injection into a defect,
cavity or interface of a cancellous, cortical or corticocancellous
bone, said composition setting in situ into a hardened filling
material.
40. Use of the composition of claim 1 for injection into the
metaphysis or diaphysis of a bone, said composition setting in situ
into a filling hardened material.
41. Use of the composition of claim 1 for injection into a
fractured bone, between the bone fragments of fractured bone, said
composition setting in situ into a filling hardened material.
42. An injectable self-setting composition comprising: a) a liquid
component, free of insoluble material, comprising, an organic
and/or inorganic acid, a partially N-deacetylated chitosan and/or a
collagen, and a glycerophosphate; said liquid component having a pH
ranging from 6.5 to 7.4, said liquid component having an
endothermally gelling character, said partially N-deacetylated
chitosan having a final concentration ranging between 0.5 to 3.0%
w/v, and said glycerophosphate salt having a final concentration
ranging between 1.0 to 10.0% w/v, and b) a powder component
comprising a dry mixture of a tricalcium phosphate with a calcium
deficient apatite or an octacalcium phosphate, and with at least
one of an inorganic salt, an organic salt, an organic acid source
and an organic compound, wherein when said components of step a)
and b) are intimately and uniformly mixed together, said components
of step a) and b) form an injectable thermo-setting slurry, said
slurry when heated turns into a solid material.
43. An injectable self-setting composition comprising: a) a liquid
component, free of insoluble particle, comprising an organic and/or
inorganic acid, a partially N-deacetylated chitosan and/or a
collagen, and a glycerophosphate; said liquid component having a pH
ranging from 6.5 to 7.4, said liquid component having an
endothermally gelling character, said partially N-deacetylated
chitosan has a concentration ranging between 0.5 to 3.0% w/v, and
said glycerophosphate salt has a concentration ranging between 1.0
to 10.0% w/v, and b) a powder component comprising a dry mixture of
a tetracalcium phosphate with a calcium deficient apatite or an
octacalcium phosphate, and with at least one of an inorganic salt,
an organic salt, an organic acid source and an organic compound,
wherein when said components of step a) and b) are intimately and
uniformly mixed together, said components of step a) and b) form an
injectable thermo-setting slurry, said slurry once heated setting
into a solid material.
44. A composition as described in claim 42 or 43, wherein said
inorganic salt is selected from carbonate, phosphate, strontium,
fluoride salts, and the like.
45. A composition as described in claim 42 or 43, wherein said
organic salt is selected from citrate, malate, lactate, gluconate
salts, and the like.
46. A composition as described in claim 42 or 43, wherein said
organic acid is selected from citric acid, malic acid, lactic acid,
gluconic acid, and the like.
47. A composition as described in claim 42 or 43, wherein said
organic compound is selected from the group consisting of
biological fluids and components, water-soluble or miscible organic
polyols, drugs, amino-acids, proteins, and the like.
48. A composition as described in claim 42 or 43, which further
comprises a water-soluble or miscible organic polyol, including
sugar-polyol, saccharide-polyol and glycol, selected from the group
consisting of glycerol, mannitol, sorbitol, ethylene glycol
oligomers, propylene glycol oligomers, saccharose, fructose,
glucose, maltose, and the like.
49. A composition as described in claim 42 or 43, which further
comprises glucosamine and/or histidine.
50. A composition as described in claim 42 or 43, which further
comprises a strontium containing compound.
51. A composition as described in claim 42 or 43, which further
comprises a carbonate containing compound.
52. A composition as described in claim 42 or 43, which further
comprises a fluoride containing compound.
53. Use of a composition as described in claim 42 or 43 for
injection into a defect, cavity or substance of a mammalian or
human hard-tissue, said composition setting in situ.
54. Use of a composition as described in claim 42 or 43, for
injection in association with a permanent or biodegradable fixative
device, said composition setting in situ.
55. A method of preparation of an injectable self-setting
composition, said method comprising the step of admixing a
water-based liquid component comprising at least one cationic
polymer and one monophosphate salt with a powder component
comprising at least two calcium phosphate sources selected from
apatites and apatitic calcium phosphates, octacalcium phosphates,
amorphous calcium phosphates, tetracalcium phosphates, tricalcium
phosphates, dicalcium phosphates and monocalcium phosphates,
wherein said liquid component comprising at least one cationic
polymer and one mono-phosphate salt; said liquid component having a
pH ranging from 6.5 to 7.4, said liquid component having an
endothermally gelling character and being free of insoluble
particles, said admixing thus forming an injectable thermo-setting
slurry, said slurry when heated turns into a solid material.
56. A method of preparation of an injectable self-setting
composition, said method comprising admixing a liquid component,
free of insoluble material, comprising, an organic and/or inorganic
acid, a partially N-deacetylated chitosan and/or a collagen, and a
glycerophosphate, with a powder component comprising a dry mixture
of a tricalcium phosphate with a calcium deficient apatite or an
octacalcium phosphate, and with at least one of an inorganic salt,
an organic salt, an organic acid source and an organic compound,
said liquid component having a pH ranging from 6.5 to 7.4, said
liquid component having an endothermally gelling character, said
partially N-deacetylated chitosan having a final concentration
ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt
having a final concentration ranging between 1.0 to 10.0% w/v, said
admixing thus forming an injectable thermo-setting slurry, said
slurry when heated turns into a solid material.
57. A method of preparation of an injectable self-setting
composition, said method comprising admixing a liquid component,
free of insoluble particle, comprising an organic and/or inorganic
acid, a partially N-deacetylated chitosan and/or a collagen, and a
glycerophosphate with a powder component comprising a dry mixture
of a tetracalcium phosphate with a calcium deficient apatite or an
octacalcium phosphate, and with at least one of an inorganic salt,
an organic salt, an organic acid source and an organic compound,
said liquid component having a pH ranging from 6.5 to 7.4, said
liquid component having an endothermally gelling character, said
partially N-deacetylated chitosan has a concentration ranging
between 0.5 to 3.0% w/v, and said glycerophosphate salt has a
concentration ranging between 1.0 to 10.0% w/v, said admixing thus
forming an injectable thermo-setting slurry, said slurry when
heated turns into a solid material.
Description
BACKGROUND OF THE INVENTION
[0001] (a) Field of the Invention
[0002] The invention relates generally to the preparation and use
of an injectable self-setting mineral-polymer composition for
repairing, replacing or therapeutically treating tissues and body
parts. More particularly, the present invention includes the
injectable self-setting mineral-polymer composition.
[0003] (b) Description of Prior Art
[0004] A large quantity of biomaterials has been introduced for
hard-tissue repair and formation, including natural or synthetic
materials, pure organic or inorganic materials, and
organo-inorganic biohybrid or hybrid materials.
[0005] Conductive hard-tissue implants are passive biomaterials
that provide a matrix to favor and support a new hard-tissue
ingrowth and repair. They generally do not provide any osteogenesis
property, in the meaning that such materials do not supply, by
themselves, any osteogenesis or hard-tissue inductive factors, or
any hard-tissue healing accelerators. Conductive structures have
typically to favor the own ingrowth and reorganization of
hard-tissues (Ex: osteoconductive materials).
[0006] The main constituent of hard-tissues is biological apatite
that is commonly found in bone and teeth (65-98%). Calcium and
phosphate ions are commonly contained in body fluids and mineral
contents of hard tissues, including bones, dentine and dental
enamel. They may also additionally contain other constituents such
as carbonates, magnesium or sodium. Hydroxyapatite is generally
recognized as being a calcium phosphate material with a crystal
structure very close to biological apatite. Calcium phosphates, and
some other ceramics, were found to be very useful biocompatible
materials for hard-tissue repair. Today, a large family of ceramic
biomaterials having different forms is available for repairing
hard-tissues, and includes calcium phosphates, calcium carbonates,
bioglasses and pure natural minerals.
[0007] Bone Repair and Formation
[0008] Conductive matrices for hard-tissue repair are designed to
provide adequate compositions and architectures that favor the
ingrowth of hard-tissue by its own. They are inserted into a
defect, thus contacting mature hard-tissue cells that are capable
of invading the repairing matrix and forming mineral networks to
complete tissue ingrowth. Typical examples are generally related to
osteoconductive materials for bone tissues.
[0009] Conductive hard-tissue implants have received a considerable
attention, particularly in bone surgery. Grafting materials for
defect filling and bone repair include autografts, xenografts,
demineralized bone matrix, porous ceramics such as calcium
phosphates, calcium carbonates, coral, nacre, bioglasses, organic
matrices (polymers, collagen and other biological macromolecules)
as well as organo-inorganic biohybrid or hybrid materials such as
organo-apatites.
[0010] Implants for filling and repairing defects are currently
solids, sometimes gels and hydrogels that enable the ingrowth and
conduction of the hard-tissue. Porous or plain solids may be used.
Plain solid implants stimulate hard-tissue ingrowth through their
own resorption. Porosity may be inherent to the material
architecture (true porosity), or be interstitial. Calcium
phosphates have been the preferred bone biomaterials. In a large
number of animal and human studies, they have been shown to be
biocompatible, and bone growth promoters. Targeted calcium
phosphate ceramics are tricalcium phosphates, amorphous calcium
phosphate, octacalcium phosphate, and apatitic compounds.
Hydroxyapatite [Ca.sub.10(PO.sub.4).sub.6(OH).sub.2],
calcium-deficient apatite, fluorinated apatite
[Ca.sub.10(PO.sub.4).sub.6F.sub.2], and carbonated apatite
[Ca.sub.10-xH.sub.ax(PO.sub.4).sub.6-x(CO.sub.3).sub.x(OH).sub.2]
are the most representative apatitic compounds. Synthetic or
sintered apatites may be prepared.
[0011] Most calcium phosphate ceramics are prepared as granules or
block materials. Block materials can be prepared in various
geometries such as rods, cylinders, rectangular shapes, etc.
However, ceramic blocks must be re-shaped before implantation to
fit exactly the defect size and geometry, which makes heavier and
longer the handling and clinical application. Furthermore, calcium
phosphate blocks are very brittle and difficult to shape, and
consequently the interface between the bone tissue and ceramic
implant is not perfectly continuous which may impair the
osteoconduction efficiency. Calcium phosphate granules are
currently produced with a wide size distribution, and available
from 10 microns to 2.5 mm, but preferably used with a size between
90 and 400 microns. Granules can be injected, or at least
administered through less invasive techniques, so as to fulfill the
tissue defect. But granules have a mobility problem in situ, which
limits their use and efficiency.
[0012] Ceramics such as calcium carbonates, coral or nacre are
equally proposed under granular or block form, and present similar
problems. Bioglasses are generally under granular or microspheric
form (Bioglass.RTM., USBiomaterials; Biogran.RTM., Orthovita;
Perioglass.RTM.).
[0013] Collagen, a component of soft- and hard-tissues, and Bone
Demineralized Matrix (BDM) are the current organic materials for
filling hard-tissue defects. Collagen was associated with mineral
to form composite materials such as Collapat.RTM. or
Collagraft.RTM. (NeuColl), Cerapatite-Collagen.RTM.
(Ceraver-Osteal), Ossatite.RTM. composite (MCP). Polymeric
materials such as polylactic acid, polyglycolic acid,
polylactic-co-glycolic acid microspheres, etc were also proposed
for bone defect filling and repair, but are less current than
calcium phosphate granular materials. One new development is
Immix.RTM. (Osteobiologics) bone-grafting material based on
PLA/GA.
[0014] Injectable Bone Substitutes
[0015] Inorganic or organo-inorganic bone cements and/or
remineralizing systems form another family of promising injectable
self-setting or self-hardening osteoarticular materials.
Self-setting cements were typically composed of a solid mineral
component mixed with a liquid component. Solid mineral components
generally contain calcium phosphates, such as monocalcium
phosphates [Ca(H.sub.2PO.sub.4).sub.2.H.sub.2O], dicalcium
phosphates [CaHPO.sub.4, CaHPO.sub.4.2H.sub.2O], tricalcium
phosphates [.alpha.-Ca.sub.3(PO.sub.4).sub.2,
.beta.-Ca.sub.3(PO.sub.4).s- ub.2] and tetracalcium phosphates
[Ca.sub.4(PO.sub.4)O], with or without other calcium sources and/or
phosphate sources, calcium carbonates and/or organic or inorganic
additives.
[0016] Calcium phosphate remineralizing and cement systems differ
by the liquid to solid ratio. Cements are produced from calcium
phosphate powder that was finely ground, typically around 5
microns. Calcium phosphate solid component was also mixed with much
less liquid, thus forming a paste rather than a slurry.
Remineralization was generally promoted by using particles of
greater size since they slow the remineralization rate and prolong
the remineralization potential.
[0017] Porosity of the resulting self-setting calcium phosphate
materials may benefit to the hard-tissue repair. It is reached by
adding a highly soluble porogen ingredient to the calcium phosphate
composition. The composition, including the water-soluble
inclusions, is subjected to pressure to form compact materials. Hot
water may be used to dissolve the porogenic compound. Others
suggested that cement porosity is controlled by the size of dry
ingredients. Large-size calcium phosphate granules (0.7-1.0 mm) in
the cement composition were found to provide larger pores than
small-size granules (0.1-0.3 mm).
[0018] Self-setting calcium phosphate composition is transformed
following the reaction in situ of calcium phosphate ingredients
which is a dissolution/reprecipitation process. The reactivity in
situ of calcium phosphates is controlled by chemical and physical
conditions. Chemical purity of calcium phosphates may greatly alter
the reactivity. Tetracalcium phosphate (TTCP) purity was showed to
influence setting and performances of calcium phosphate cements,
for example the cement setting time and mechanical strength. TTCP
is highly reactive to water, such as air moisture, thus forming
calcium oxide or hydroxide, and hydroxyapatite at the TTCP granule
surface. Formulation pH and temperature influence the reactivity of
calcium phosphates. The size of calcium phosphate particles was
also reported to significantly control the reactivity, thus
possibly slowing the reaction and retarding the hardening or
setting rate when too large. Granule size is related to the exposed
surface area, and possibly influences the initial composition of
the ingredients, the final dry product composition, and hence the
mixing, mechanical and physical properties.
[0019] Single calcium phosphate cements cannot set in
hard-consistency materials. They were also reported not to be able
to maintain a constant pH, and to lack of mineralizing capacity.
Driskell et al. (U.S. Pat. No. 3,913,229) described a mixture of
tricalcium phosphates and dicalcium phosphate that does not
self-harden, and has insufficient remineralizing capacity.
[0020] Brown and Chow (U.S. Pat. Nos. 4,612,053; 4,518,430; and
Re33,221) proposed a self-setting composition based upon an aqueous
mixture of tetracalcium phosphate (TTCP) with at least another
calcium phosphate component in excess, selected from dicalcium
phosphate or brushite, tricalcium phosphates and modified
tricalcium phosphates, octacalcium phosphate
[Ca.sub.8H.sub.2(PO.sub.4).sub.6.5H.sub.2O] which was able to
self-harden into a cement at an ambient temperature. Additional
calcium or phosphate sources consisted mainly in CaCl.sub.2,
Ca(C.sub.2H.sub.3O.sub.2), NaH.sub.2PO.sub.4 and
NH.sub.4H.sub.2PO.sub.4. The slurry containing calcium phosphates
in excess had a pH in the vicinity of 7.4. This cement paste was
proposed first for dental restorative applications although many
orthopedic indications were proposed. Later, Chow and Takagi (U.S.
Pat. No. 5,545,254) showed that the preparation of TTCP free of
surface calcium oxide or hydroxyapatite greatly improved the
quality of such bone cements for dental and orthopedic
applications. Remineralization and cement compositions were
biocompatible precursors of hydroxyapatite, having two properties:
a) they were self-hardening and form materials with sufficient
strengths for medical and dental applications; b) they were
resorbed in situ and progressively replaced by new
hard-tissues.
[0021] Liu and Chung (U.S. Pat. No. 5,149,368) proposed other
TTCP-based cement formulations where TTCP was admixed with water
and acidic citrate to form a paste having a pH greater than 5. The
weight ratio of powder to liquid was between 2:1 and 15:1.
Constantz et al. (U.S. Pat. No. 5,053,212) developed a composition
precursor of hydroxyapatite by admixing a calcium source with an
acidic phosphate source. In the preferred embodiment, TTCP was
mixed with calcium oxides, calcium carbonates (typically
CaCO.sub.3), monocalcium phosphate monohydrate (MCPM) and/or
orthophosphoric acid. Calcium to phosphate ration was about
1.25-2.0 to 1.0. Later, another bone cement was described where a
dry component was admixed with a compatible lubricant and an
anti-microbial agent (U.S. Pat. No. 5,968,253). Its dry component
was made of reactive .alpha.-tricalcium phosphate (60-95% dry wt.),
monocalcium phosphate monohydrate (1-20% dry wt.) and calcium
carbonate (5-25% dry wt.), and admixed to a phosphate buffer having
a pH between 4.0 and 11.0. The anti-microbial agent such as
gentamycin or vancomycin was added to the liquid component at 0.001
to 3.0% wt. This flowable composition was the basis of the Norian
SRS.RTM. bone cement. This composition involved conversion of MCPM
into dicalcium phosphate, then formation of hydroxyapatite by
reaction of dicalcium phosphate with TTCP. It was setting in
approximately 15 minutes, and reached a compression strength about
40 MPa. Another proposed cement composition gave a 2-10% wt.
carbonated apatite (U.S. Pat. No. 5,900,254). Dry composition
includes a partially neutralized phosphoric acid such as the MCPM
and a calcium phosphate source such as the TCP. Calcium carbonate
(9-70% dry wt.) was added to the dry component. The liquid
component was a 0.01 to 2.0M phosphate buffer, either a sodium
phosphate or sodium carbonate, with a pH between 6.0 and 11.0. This
composition had the properties of a) having a calcium to phosphate
molar ratio of 1.33 to 2.0; b) being not sintered or hydrothermally
prepared; and c) having a compression strength above 5500 psi.
[0022] Granular bone cements were proposed by admixing a
monocalcium phosphate and/or dicalcium phosphates to a
.alpha.-tricalcium phosphate or a tetracalcium phosphate (U.S. Pat.
No. 5,338,356). Calcium to Phosphate ratio was between 1.39 and
1.45, and calcium phosphate granules were 0.1 to 1.0 mm in size.
Liquid to Solid ratio varied from 0.3 to 30. Hirano and Hanno (U.S.
Pat. No. 5,152,836) also proposed a hydraulic cement made of a
mixture of tricalcium phosphates and dicalcium phosphates with a
calcium to phosphate ratio between 1.4 and 1.5. Water was used as
the hardening liquid component, and water containing soluble sodium
was preferred for short hardening times and enhanced cement
strengths.
[0023] A calcium phosphate cement was proposed and prepared from a
TCP/TTCP dry mixture in a liquid component containing calcium and
phosphate sources. Liquid component typically contained phosphoric
acid, and calcium hydroxide or calcium carbonate. Additives were
optionally added to the cement composition, preferably lactic acid
(<4% wt.), alginate or gum (<2% wt.), and/or magnesium or
potassium glycerophosphate (<15% wt.). Calcium to phosphate
ratio of the dry component was about 1.70 to 1.85 while the one of
the liquid component was between 0.2 and 0.5. This cement gave a
crystalline hydroxyapatite biomaterial with a compressive strength
about 15 to 25 MPa.
[0024] A calcium orthophosphate composition that hardens in 100%
humidity environments into a calcium phosphate cement was composed
of a mixture of three to four calcium sources with water. The
composition had a pH ranging between 6.5 and 8.0. Calcium sources
were selected preferably among monocalcium phosphate monohydrate
(MCPM), dicalcium phosphate or brushite, tricalcium phosphates, and
modified tricalcium phosphates, octacalcium phosphate, apatites,
and other calcium compounds such as
Ca.sub.8.5Na.sub.1.5(PO.sub.4).sub.4.5(CO.sub.3).sub.2.5,
Ca.sub.9(PO.sub.4).sub.4.5(CO.sub.3).sub.1.5,
Ca.sub.4Mg.sub.5(PO.sub.4).- sub.6, CaZn.sub.2(PO.sub.4).sub.2,
CaKPO.sub.4, CaNaPO.sub.4, Ca.sub.10Na(PO.sub.4).sub.7,
Ca.sub.2PO.sub.4Cl, CaO, Ca(OH).sub.2, CaMgO.sub.2 and
Ca.sub.10(PO.sub.4).sub.6Cl.sub.2.
[0025] Basic calcium phosphate cements self-setting in
hydroxyapatite were developed by Chow and Takagi (U.S. Pat. Nos.
5,525,148 and 5,954,867). Liquid components contained liquid
phosphate component having a pH above 12.5 (phosphate >0.2
mol/l). Solid calcium phosphate component had a Calcium to
Phosphate between 3.0 and 5.0, included various calcium phosphates,
except TTCP, and a calcium source. Proposed calcium phosphates were
dicalcium phosphates, tricalcium phosphates, octacalcium phosphate
and/or amorphous calcium phosphate. Additional sources of calcium
were selected typically among calcium carbonates, calcium oxides,
and calcium hydroxides. Additional minerals were also added in
minor concentrations. The pH of the composition was potentially
adjusted above 12.5 by adding sodium hydroxide.
[0026] Commercial developments in calcium phosphate bone cements
are given by SRS.RTM. (Norian), BoneSource.RTM.
(Stryker/Howmedica), alpha-BSM.RTM. (ETEX Corp.), all three giving
carbonated apatite in situ, and Cementek.RTM. (Teknimed SA).
[0027] Most common calcium phosphates in self-setting cements were
selected from monocalcium phosphate monohydrate
[Ca(H.sub.2PO.sub.4)2.H.s- ub.2O], dicalcium phosphate (DCP) or
brushite [CaHPO.sub.4, CaHPO.sub.4.2H.sub.2O], tricalcium phosphate
(TCP) [.alpha.-Ca.sub.3(PO.sub.4).sub.2,
.beta.-Ca.sub.3(PO.sub.4).sub.2], tetracalcium phosphate
(TTCP)[Ca.sub.4(PO.sub.4)O], amorphous calcium phosphate (ACP)
[Ca.sub.3(PO.sub.4)2.H.sub.2O], octacalcium phosphate (OCP)
[Ca.sub.8H.sub.2(PO.sub.4).sub.6.5H.sub.2O], and apatites
[Ca.sub.10(PO.sub.4).sub.6(OH).sub.2].
[0028] All calcium phosphates have different dissolution rate at a
given pH. For a calcium to phosphate molar ratio above 1.5, the
dissolution rate can be defined (at least up to a pH about 10) as
follows: Tetracalcium phosphate>.alpha.-tricalcium
phosphate>.beta.-tricalci- um phosphate>hydroxyapatite.
[0029] Calcium phosphates have also a relative acidic or basic
character, thus increasing acidity or basicity.
[0030] Acidic components generally include, in an acidity order:
monocalcium phosphate monohydrate>dicalcium
phosphate>octacalcium phosphate>amorphous calcium phosphate
.beta.-tricalcium phosphate=.alpha.-tricalcium
phosphate=calcium-deficient apatite. Monocalcium phosphate
monohydrate is generally used as acidic calcium phosphate source
when necessary.
[0031] Basic calcium phosphates generally include, in a basicity
order: tetracalcium phosphate>precipitated
hydroxyapatite=sintered hydroxyapatite>.alpha.-tricalcium
phosphate=calcium-deficient apatite=.beta.-tricalcium
phosphate=amorphous calcium phosphate. Calcium sources such as
calcium oxides and hydroxides are more basic than tetracalcium
phosphate.
[0032] Exothermic setting reactions may be damageable to living
tissues and cells in situ. High temperatures generated by the
cement setting being undesirable, it is thus desirable to keep the
setting temperature well below 50-60.degree. C. Exothermic effects
in calcium phosphate cements are typically obtained by reacting
calcium oxides with acidic phosphate sources. The transformation of
calcium oxide into calcium hydroxide is recognized to be
exothermic. Pressure level of cement composition may also change
during the setting reaction. Calcium carbonate [CaCO.sub.3] is for
neutralizing and buffering the formulation, but generates carbon
dioxide gas. In situ formation of carbon dioxide gas is susceptible
of pressure elevation, and may induce unexpected structural
modifications or changes of the resulting material. Calcium
carbonate, and other carbonates, in cement composition must be
specially considered for this gas supply and pressure increase in
situ.
[0033] Incorporation of polymer in cement composition was proposed
to give some specific properties: a) to improve the handling
properties and wettability of the cement; b) to avoid the cement
composition to disintegrate in aqueous media such as the
physiological fluids, and allow to pre-shape the composition; as a
consequence, this reduced the need for removal of body fluid,
hemostasis, or the like.
[0034] Polyacid or polyol polymers, polysaccharides and
polypetidics were preferentially chosen for incorporation in
calcium phosphate cement compositions. Polycarboxylics
(polycarboxylic acid), poly(ethylene glycol), poly(propylene
glycol), methyl cellulose, poly(vinyl alcohol), carboxymethyl
cellulose, hydroxypropyl methylcellulose, and the like, were
proposed as polymeric components. Collagen was optionally
introduced in a cement composition by Constantz et al. (U.S. Pat.
No. 5,053,212). Chitin, chitosan, starch, gum, pectic acid, alginic
acid, hyaluronic acid, chondroitin sulfuric acid, dextran sulfuric
acid and their salts were reported as potent polysaccharide
ingredient (U.S. Pat. Nos. 5,152,836; and 5,980,625; and European
patent application publication No. EP-899,247 A1).
[0035] Chitosan was admixed in many liquid components of calcium
phosphate cement compositions. Chitosan in citric, malic, or
phosphoric acid aqueous medium was the liquid component of a
self-setting TCP or TCP/TTCP cement (U.S. Pat. Nos. 5,281,404 and
5,180,426). Chitosan in bone cements or substitutes was also
studied in the scientific literature, as reported by Leroux et al.
(Bone, Vol. 25, No 2, supplement, 1999:31S-34S), Hidaka et al. (J.
Biomed. Mat. Res., 46:418-423, 1999), Ito (Biomaterials, 12:41-45,
1991). It has also been reported the use of chitosan in calcium
phosphate compositions. Typically, chitosan 0.05% wt. in an acidic
aqueous medium (acid 25-55% wt.) was used as lubricant for a solid
component consisting in a mixture of TCP and TTCP. Chitosan was
chosen to prevent the powder dispersion and cement
disintegration.
[0036] Osteoconduction and osteogenic performances of chitosan
based materials were reviewed, and applied to biomaterials
development. Chitosan with immobilized polysaccharides such as
heparin, heparan sulfate, chondroitin sulfate and dextran sulfate
was reported for stimulating hard-tissue regeneration by Hansson et
al. (International Patent Application publication WO96/02259).
Osteoinductive compositions were also developed by admixing
hydroxyapatite and bone-derived osteoinductive gelatin to chitosan
solutions (U.S. Pat. No. 5,618,339).
[0037] It would be highly desirable to be provided with a
self-hardening mineral polymer hybrid composition with attractive
performance for biomedical uses.
[0038] It would also be highly desirable to be provided with a
gel-forming liquid component that enables to enhance the handling
and cohesion properties of a new self-hardening material.
[0039] It would still be highly desirable to be provided with a
liquid component that contains a chitosan solution, free of
insoluble particle, with a pH close to 7.0 and a thermo-gelling
character. This would be innovative and allow developing an in-situ
self-hardening material based upon a mineral composition.
SUMMARY OF THE INVENTION
[0040] One aim of the present invention is to provide a
self-setting mineral-polymer composition that can be applied to
defects or cavities of hard-tissues, or to an anatomical structure
of hard-tissues, or a body cavity, thus enabling the formation in
situ of a group of bio-materials having distinct compositions,
functions and properties.
[0041] In accordance with the present invention there is provided a
new injectable in situ self-setting mineral-polymer composition
that can be conveniently used for hard-tissue repair, replacement
or treatment in mammalians or humans.
[0042] Also in accordance with the present invention, there is
provided an injectable self-setting composition comprising:
[0043] a) a water-based liquid component comprising at least one
cationic polymer and one mono-phosphate salt; said liquid component
having a pH ranging from 6.5 to 7.4, said liquid component having
an endothermally gelling character and being free of insoluble
particles; and
[0044] b) a powder component comprising at least two calcium
phosphate sources selected from apatites and apatitic calcium
phosphates, octacalcium phosphates, amorphous calcium phosphates,
tetracalcium phosphates, tricalcium phosphates, dicalcium
phosphates and monocalcium phosphates,
[0045] wherein when said components of step a) and b) are
intimately and uniformly mixed together, said components of step a)
and b) form an injectable thermo-setting slurry, said slurry when
heated turns into a solid material.
[0046] The cationic polymer may be a polysaccharide, a polypeptide
or a synthetic polymer. The cationic polymer may have a
concentration in said liquid component between 0.1 and 5.0% wt. The
cationic polymer is preferably chitosan or collagen, or a mixture
of chitosan and collagen. The cationic polymer can also be a
partially-deacetylated chitin or chitosan with a degree of
deacetylation between 30 and 99%. The cationic polymer can further
be a polylysine.
[0047] The monophosphate salt may have a basic character.
[0048] The liquid component can comprise a first phosphate source
selected from the group consisting of
Na.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
Fe.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
K.sub.2PO.sub.4C.sub.3H.sub.5(O- H).sub.2,
MgPo.sub.4C.sub.3H.sub.5(OH).sub.2, MnPO.sub.4C.sub.3H.sub.5(OH)-
.sub.2, Ca.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
Na.sub.2PO.sub.7C.sub.3H- .sub.7, Na.sub.2PO.sub.7C.sub.4H.sub.7,
K.sub.2PO.sub.7C.sub.4H.sub.7, NaPO.sub.7C.sub.4H.sub.8,
K.sub.2PO.sub.7C.sub.4H.sub.8, Na.sub.2PO.sub.8C.sub.5H.sub.9,
K.sub.2PO.sub.8C.sub.5H.sub.9, NaPO.sub.8C.sub.5H.sub.10,
KPO.sub.8C.sub.5H.sub.10, Na.sub.2PO.sub.9C.sub.6H.sub.11,
NaPO.sub.9C.sub.6H.sub.12, K.sub.2PO.sub.9C.sub.6H.sub.11,
KPO.sub.9C.sub.6H.sub.12, Na.sub.2PO.sub.8C.sub.6H.sub.13,
K.sub.2PO.sub.8C.sub.6H.sub.13, NaPO.sub.8C.sub.6H.sub.14,
KPO.sub.8C.sub.6H.sub.14, Na.sub.2PO.sub.8C.sub.6 H.sub.12,
K.sub.2PO.sub.9C.sub.6H.sub.12, NaPO.sub.9C.sub.6H.sub.13,
KPO.sub.9C.sub.6H.sub.13, Na.sub.2PO.sub.8C.sub.10H.sub.11,
K.sub.2PO.sub.8C.sub.10H.sub.11, NaPO.sub.8C.sub.10H.sub.12,
KPO.sub.8C.sub.10H.sub.12 and the like, or a derivative
thereof.
[0049] The monophosphate salt is a sodium, magnesium, potassium,
ferric and/or calcium alpha- or beta-glycerophosphate salt, or a
mixture thereof.
[0050] The monophosphate salt may be glucose-1-phosphate,
glucose-6-phosphate, fructose-1-phosphate or fructose-6-phosphate
salt, or a mixture thereof.
[0051] The liquid component preferably has a pH between 6.8 and 7.2
and a viscosity superior to 200 mPa.s.
[0052] The liquid component can further comprise at least one other
water-soluble polymer selected from the group consisting of
polypeptides, cellulosics and synthetic polymers, including methyl
cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxyethyl propylcellulose, hydroxymethyl propylcellulose,
poly(ethylene oxide), poly(propylene oxide), poly(ethylene glycol),
poly(vinylpyrrolidone), poly(vinyl alcohol), and derivatives
thereof.
[0053] The liquid component can also further comprise at least one
organic polyol, including sugar-polyol, saccharide-polyol and
glycol, selected from the group consisting of glycerol, mannitol,
sorbitol, ethylene glycol oligomers, propylene glycol oligomers,
saccharose, fructose, glucose, maltose, and the like.
[0054] The liquid component can further comprise at least one
water-soluble amino acid having a basic character and a pKa between
6.5 and 8.5, or alternatively the liquid component can further
comprise a water-soluble sulfonate or carboxylate salt having a
basic character and a pKa between 6.5 and 8.5.
[0055] The liquid component and the powder component preferably
have a ratio liquid/powder component from 0.05 to 1.50 mL/g.
[0056] The composition preferably has a final molar ratio of
calcium/phosphorus between 1.20 and 1.80.
[0057] The powder component can comprise alpha-tricalcium phosphate
and an apatitic calcium phosphate, or alpha-tricalcium phosphate,
dicalcium phosphate and an apatitic calcium phosphate.
[0058] The powder component can comprise alpha-tricalcium,
monocalcium phosphate and an apatitic calcium phosphate.
[0059] The powder component can comprise at least alpha-tricalcium
phosphate and an amorphous calcium phosphate.
[0060] The powder component can comprise tetracalcium phosphate and
dicalcium phosphate, or tetracalcium phosphate and monocalcium
phosphate. Preferably, the powder component comprises less than 40%
wt. of an apatitic calcium phosphate.
[0061] The powder component can further comprise at least one
fluoride selected from the group consisting of NaF,
Na.sub.2Si.sub.6F, KF, KSi.sub.6F, CaF.sub.2, MgF.sub.2, ZnF.sub.2,
and sodium fluorophosphates, and the like, or derivatives
thereof.
[0062] The powder component can further comprise at least one
carbonate selected from the group consisting of Na.sub.2CO.sub.3,
CaCO.sub.3, K.sub.2CO.sub.3, MgCO.sub.3, ZnCO.sub.3,
Ca.sub.9K(PO.sub.4).sub.5(CO.sub- .3).sub.2,
Ca.sub.8.5Na.sub.1.5(PO.sub.4).sub.4.5(CO.sub.3).sub.2.5,
Ca.sub.9(PO.sub.4).sub.4.5(CO.sub.3).sub.1.5, and the like.
[0063] The powder component preferably comprises a strontium salt
including strontium carbonate or at least one calcium phosphate
selected from the group consisting of fluoride, strontium,
carbonate, magnesium, zinc, and barium containing calcium
phosphates.
[0064] The powder component can comprise at least one inorganic
salt including sodium phosphates and disodium glycerophosphate, or
the like, or alternatively, it can comprise at least one organic
salt including oxalate, citrate, malate, gluconate, lactate,
lactobionate, or the like.
[0065] The powder component can comprise at least one organic salt
including oxalic, citric, malic, gluconic, lactic, lactobionic
acids, or the like.
[0066] The powder component is preferably a powder having a size
ranging from 0.1 to 100 micrometers.
[0067] Preferably, the composition further comprises a bioactive
ingredient such as a drug, a protein, a peptide, a synthetic
molecule or an inorganic molecule, or it can comprise at least one
osteoinductive agent selected from the group consisting of
hormones, bone proteins and mixtures of osteoinductive proteins,
demineralized bone matrix (DBM) or powder (DBP), bone morphogenic
proteins (BMP), sialoproteins, osteonectin, osteopontin,
osteocalcin, calcitonin. Preferably, the composition further
comprises at least one growth factor selected from the group
consisting of IGF, EGF, a-FGF, b-FGF, PDGF-A, PDGF-B and
TGF-beta.
[0068] The composition can also further comprise an antiresorptive,
antibiotic, antiviral, antitumor, or an immunosupressive agent.
[0069] In accordance with the present invention, there is also
provided the use of the composition as defined above for injection
into a defect, cavity or interface of a body's tissue, said
composition setting in situ into a hardened filling material, or
for the manufacture of a medicament for injection. The composition
may be injected into a defect, cavity or interface of a cancellous,
cortical or corticocancellous bone. The composition may also be
injected into the metaphysis or diaphysis of a bone or into a
fractured bone, between the bone fragments of fractured bone. The
composition once injected sets in situ into a filling hardened
material.
[0070] Further in accordance with the present invention, there is
also provided an injectable self-setting composition
comprising:
[0071] c) a liquid component, free of insoluble material,
comprising, an organic and/or inorganic acid, a partially
N-deacetylated chitosan and/or a collagen, and a glycerophosphate;
said liquid component having a pH ranging from 6.5 to 7.4, said
liquid component having an endothermally gelling character, said
partially N-deacetylated chitosan having a final concentration
ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt
having a final concentration ranging between 1.0 to 10.0% w/v,
and
[0072] d) a powder component comprising a dry mixture of a
tricalcium phosphate with a calcium deficient apatite or an
octacalcium phosphate, and with at least one of an inorganic salt,
an organic salt, an organic acid source and an organic
compound,
[0073] wherein when said components of step a) and b) are
intimately and uniformly mixed together, said components of step a)
and b) form an injectable thermo-setting slurry, said slurry when
heated turns into a solid material.
[0074] Still in accordance with the present invention, there is
provided an injectable self-setting composition comprising:
[0075] a) a liquid component, free of insoluble particle,
comprising an organic and/or inorganic acid, a partially
N-deacetylated chitosan and/or a collagen, and a glycerophosphate;
said liquid component having a pH ranging from 6.5 to 7.4, said
liquid component having an endothermally gelling character, said
partially N-deacetylated chitosan has a concentration ranging
between 0.5 to 3.0% w/v, and said glycerophosphate salt has a
concentration ranging between 1.0 to 10.0% w/v, and
[0076] b) a powder component comprising a dry mixture of a
tetracalcium phosphate with a calcium deficient apatite or an
octacalcium phosphate, and with at least one of an inorganic salt,
an organic salt, an organic acid source and an organic
compound,
[0077] wherein when said components of step a) and b) are
intimately and uniformly mixed together, said components of step a)
and b) form an injectable thermo-setting slurry, said slurry once
heated setting into a solid material.
[0078] Preferably, the inorganic salt is selected from carbonate,
phosphate, strontium, fluoride salts, and the like, and the organic
salt is preferably selected from citrate, malate, lactate,
gluconate salts, and the like.
[0079] The organic acid can be selected from citric acid, malic
acid, lactic acid, gluconic acid, and the like, and the organic
compound can be selected from the group consisting of biological
fluids and components, water-soluble or miscible organic polyols,
drugs, amino-acids, proteins, and the like.
[0080] The composition can also further comprise a water-soluble or
miscible organic polyol, including sugar-polyol, saccharide-polyol
and glycol, selected from the group consisting of glycerol,
mannitol, sorbitol, ethylene glycol oligomers, propylene glycol
oligomers, saccharose, fructose, glucose, maltose, and the
like.
[0081] The composition can still comprise glucosamine and/or
histidine.
[0082] The composition can further comprise a strontium containing
compound, a carbonate containing compound or a fluoride containing
compound.
[0083] Also in accordance with the present invention, there is
provided a method of preparation of an injectable self-setting
composition, said method comprising the step of admixing a
water-based liquid component comprising at least one cationic
polymer and one mono-phosphate salt with a powder component
comprising at least two calcium phosphate sources selected from
apatites and apatitic calcium phosphates, octacalcium phosphates,
amorphous calcium phosphates, tetracalcium phosphates, tricalcium
phosphates, dicalcium phosphates and monocalcium phosphates,
wherein said liquid component comprising at least one cationic
polymer and one mono-phosphate salt; said liquid component having a
pH ranging from 6.5 to 7.4, said liquid component having an
endothermally gelling character and being free of insoluble
particles, said admixing thus forming an injectable thermo-setting
slurry, said slurry when heated turns into a solid material.
[0084] In one embodiment of the invention, there is provided a
method of preparation of an injectable self-setting composition,
said method comprising admixing a liquid component, free of
insoluble material, comprising, an organic and/or inorganic acid, a
partially N-deacetylated chitosan and/or a collagen, and a
glycerophosphate, with a powder component comprising a dry mixture
of a tricalcium phosphate with a calcium deficient apatite or an
octacalcium phosphate, and with at least one of an inorganic salt,
an organic salt, an organic acid source and an organic compound,
said liquid component having a pH ranging from 6.5 to 7.4, said
liquid component having an endothermally gelling character, said
partially N-deacetylated chitosan having a final concentration
ranging between 0.5 to 3.0% w/v, and said glycerophosphate salt
having a final concentration ranging between 1.0 to 10.0% w/v, said
admixing thus forming an injectable thermo-setting slurry, said
slurry when heated turns into a solid material.
[0085] In a further embodiment of the invention, there is also
provided a method of preparation of an injectable self-setting
composition, said method comprising admixing a liquid component,
free of insoluble particle, comprising an organic and/or inorganic
acid, a partially N-deacetylated chitosan and/or a collagen, and a
glycerophosphate with a powder component comprising a dry mixture
of a tetracalcium phosphate with a calcium deficient apatite or an
octacalcium phosphate, and with at least one of an inorganic salt,
an organic salt, an organic acid source and an organic compound,
said liquid component having a pH ranging from 6.5 to 7.4, said
liquid component having an endothermally gelling character, said
partially N-deacetylated chitosan has a concentration ranging
between 0.5 to 3.0% w/v, and said glycerophosphate salt has a
concentration ranging between 1.0 to 10.0% w/v, said admixing thus
forming an injectable thermo-setting slurry, said slurry when
heated turns into a solid material.
[0086] For the purpose of the present invention the following terms
are defined below.
[0087] In the present invention, the term "endothermally sensitive"
solution refers herein to a solution turning into a gel material
with an increasing temperature. In that meaning, endothermally
sensitive may be easily replaced by "endothermally gelling" and
"thermo-gelling".
[0088] In accordance with the present invention, the composition
comprises a liquid component and a solid component, such components
being intimately mixed together; said liquid component being
endothermally sensitive as previously defined.
[0089] The term "mineral-polymer hybrid" refers herein to a
biphasic system where a mineral component is associated to a
polymer component, whatever said mineral and polymer components are
liquid or solid.
[0090] The term "liquid component (or phase)" refers herein to the
component that is a water-based solution, and particularly a
water-based polymeric solution.
[0091] The term "powder component (or phase)" refers herein to the
component that is a solid material, said solid materials being
preferably a powder, particulate or granular material. Also used
for solid component is "mineral component or phase".
[0092] The term "dry ingredient" refers to a dry solid material
that enters in the preparation of the solid component and
mineral-polymer hybrid composition. In most cases, it is a mixture
of solid particulates made of minerals or organics.
[0093] "Apatitic" refers herein to a compound that has mainly an
apatite-related crystallographic phase.
[0094] "Bioactive agent" refers herein to a substance that presents
an established biological activity of interest for the use of the
hybrid composition. "Non-bioactive agent" corresponds to a
substance used without any consideration for a possible biological
activity of the hybrid composition.
[0095] "Self-setting" refers herein to a reaction that occurs in
the hybrid composition between the components of the liquid and
solid components. It is basically a dissolution and reprecipitation
of the minerals of the solid component in the liquid component. It
results in macroscopic and characteristics changes of the hybrid
composition.
[0096] "Self-hardening" refers herein to the formation of a
continuous solid material or network within the hybrid composition.
This material or network is built from minerals, but may
incorporate organic (mineral-polymer). Self-hardening excludes
self-gelling. Self-hardened materials are not highly hydrated, and
do not correspond to gels.
[0097] "Self-gelling" refers herein to the sol-gel transition
associated to the liquid component, resulting in the formation of
uniform three-dimensional hydrated network (mainly organic). The
self-gelling reaction is a reaction intrinsic to the polymer in the
liquid component. Herein, gelling exclude hardening.
[0098] "Gel-like" refers to a material that has the appearance of a
homogeneous highly hydrated gel.
[0099] In the present invention, the new in situ self-setting
mineral-polymer composition refers specially to a composition and
bio-material, described by an injectable self-forming hard-tissue
composition and substitute wherein the material formation in situ
is related to solid-like materials; said compositions and
substitutes are defined herein by "self-setting (self-hardening)
mineral-polymer hybrid compositions, biomaterials" or "self-setting
cement-like materials".
BRIEF DESCRIPTION OF THE DRAWINGS
[0100] FIG. 1 illustrates a general view of self-setting
mineral-polymer hybrid materials in accordance with the present
invention, after setting in vitro, wherein hybrid materials have
been shaped prior to self-setting at 37.degree. C. in a moist
environment;
[0101] FIG. 2 illustrates X-ray diffraction graphs of self-setting
mineral-polymer hybrid compositions (mineral), wherein signs
.tangle-solidup., .circle-solid., and .quadrature. correspond to
bands for apatite, dicalcium phosphate (anhydrous) or tricalcium
phosphate (beta);
[0102] FIG. 3 illustrates micro-structural view (scanning electron
microscopy) of self-setting mineral-polymer hybrid materials with
apatite crystals;
[0103] FIG. 4 illustrates the pH evolution during the setting of a
mineral-polymer hybrid composition of the present invention;
and
[0104] FIG. 5 illustrates the evolution of the ultimate compression
strength (Megapascals, Mpa) of a mineral-polymer hybrid composition
(calcium deficient apatite with a Ca/P ratio of 1.50) as a function
of US and percent charge (weight).
DETAILED DESCRIPTION OF THE INVENTION
[0105] In one embodiment, a self-setting mineral-polymer
composition comprises a thermo-gelling liquid component and a
mineral powder component that gives a self-setting (self-hardening)
composition at the body temperature. Various composition of the
present invention can be self-hardening to various levels, which
give potent high strengths, mainly ceramic-composed, solid
bio-materials with a plain or porous structure.
[0106] The composition of the present invention is preferably used
with hard-tissues of the body, typically bone, dentine and
enamel.
[0107] Preparation of the Liquid Component
[0108] In the present invention, the liquid component is an
endothermally sensitive solution, and consists in a polymeric
aqueous solution. In a preferred embodiment, the liquid component
comprises water, and an acid-soluble organic and/or inorganic acid,
at least one acid-soluble cationic polymer, and at least one
water-soluble phosphate source. In other embodiments, the
composition comprises water, and an acid-soluble organic and/or
inorganic acid, at least one acid-soluble cationic polymer, at
least one of a water-soluble phosphate, and one of water-soluble
sulfonate and carboxylate salt. The acid-soluble cationic polymer
is defined as being a hydrophilic cationic polymer that is soluble
in an acidic aqueous medium with a pH inferior to 6.5.
[0109] The liquid component is characterized by its endothermal
sensitivity which means generally that it presents a sol-gel
transition temperature (SGTT), a liquid state (sol state) at a
temperature lower than the SGTT, and a gel state comprising a gel
which is substantially water-insoluble at a temperature higher than
the SGTT.
[0110] In the liquid component, the acid-soluble polymer is
dissolved by using organic and/or inorganic acids, including malic
acid, propionic acid, phosphoric acid, glycerophosphoric acid,
orthophosphoric acid, lactic acid, hydrochloric acid, ascorbic
acid, formic acid, acetic acid, and the like. The polymer is
dissolved in an acidic aqueous medium having a pH ranging between
1.0 and 5.0, preferentially between 1.0 and 4.0. The acid-soluble
cationic polymer is a hydrophilic polysaccharide, including
partially deacetylated chitins and chitosans, and an
amino-substituted polysaccharide having the desired properties. It
can also be an amino-substituted dextran. The acid-soluble cationic
polymer can also be a polypeptidic or poly(amino acids) including
collagens and polylysine, and a synthetic cationic polymer
including polyacrylamide, and the like. The content in the
acid-soluble polymer is ranging between 0.1% and 10% w/v,
preferentially between 0.5 and 5.0% w/v, and more preferably
between 0.5% and 3.0% w/v.
[0111] The cationic polymer may be optionally combined with another
polymer selected from polysaccharides, polypeptides, cellulosics
and synthetic polymers, including modified chitin, modified
chitosans, collagen, methylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxyethylpropyl cellulose,
hydroxymethyl propylcellulose, poly(ethylene oxide), poly(ethylene
glycol), poly(propylene oxide), poly(vinyl alcohol), poly(vinyl
pyrrolidone), and the like, or a mixture thereof. The content in
this other polymer varies between 0.01% and 5.0% w/v,
preferentially between 0.01% and 2.5% w/v, and more preferably
between 0.01% and 1.0% w/v. A typical example of other polymer is a
N,O-carboxymethylchitosan or a N,O-glycolic-chitosan or
N,O-lactic-chitosan, a poly(ethylene oxide), poly(ethylene
oxide-co-propylene oxide-co-ethylene oxide), or methyl cellulose.
In one embodiment, a preferred other polymer is a collagen
solubilized at a concentration between 0.5 to 10% w/v.
[0112] In one embodiment, the water-soluble phosphate source of the
liquid component is defined as being an organic mono-phosphate
basic salt. It has a moderate basic character, and a pKa between
6.0 and 7.4. This phosphate source is preferentially a (di)sodium,
(di)potassium, magnesium, manganese or (di)ferric salt, and more
preferably a disodium, dipotassium or magnesium salt, or a mixture
thereof. The concentration of the phosphate source of the liquid
component is between 0.1% and 20% w/v, and ideally between 0.5% and
10% w/v. The phosphate source is preferably selected in a group
comprising Na.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
Fe.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
K.sub.2PO.sub.4C.sub.3H.sub.5(O- H).sub.2,
MgPO.sub.4C.sub.3H.sub.5(OH).sub.2, MnPO.sub.4C.sub.3H.sub.5(OH)-
.sub.2, Ca.sub.2PO.sub.4C.sub.3H.sub.5(OH).sub.2,
Na.sub.2PO.sub.7C.sub.3H- .sub.7, Na.sub.2PO.sub.7C.sub.4H.sub.7,
K.sub.2PO.sub.7C.sub.4H.sub.7, NaPO.sub.7C.sub.4H.sub.8,
K.sub.2PO.sub.7C.sub.4H.sub.8, Na.sub.2PO.sub.8C.sub.5H.sub.9,
K.sub.2PO.sub.8C.sub.5H.sub.9, NaPO.sub.8C.sub.5H.sub.10,
KPO.sub.8C.sub.5H.sub.10, Na.sub.2PO.sub.9C.sub.6H.sub.11,
NaPO.sub.9C.sub.6H.sub.12, K.sub.2PO.sub.9C.sub.6H.sub.11,
KPO.sub.9C.sub.6H.sub.12, Na.sub.2PO.sub.8C.sub.6H.sub.13,
K.sub.2PO.sub.8C.sub.6H.sub.13, NaPO.sub.8C.sub.6H.sub.14,
KPO.sub.8C.sub.6H.sub.14, Na.sub.2PO.sub.9C.sub.6H.sub.12,
K.sub.2PO.sub.9C.sub.6H.sub.12, NaPO.sub.9C.sub.6H.sub.13,
KPO.sub.9C.sub.6H.sub.13, Na.sub.2PO.sub.8C.sub.10H.sub.11,
K.sub.2PO.sub.8C.sub.10H.sub.11, NaPO.sub.8C.sub.10H.sub.12,
KPO.sub.8C.sub.10H.sub.12, and the like, and derivatives thereof or
a mixture thereof. Ideally, the phosphate source is alpha- or
beta-glycerophosphate (glycerol-2-phosphate, glycerol-2-phosphate),
glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate or
fructose-6-phosphate disodium or dipotassium, magnesium, or a
mixture thereof.
[0113] The liquid component may optionally comprise at least one
sulfonate source, in a proportion of 0.1 to 10% w/v, selected among
N-[carbamoylmethyl]-2-aminoethane sulfonate (ACES),
N,N-bis[2-hydroxyethyl]-2-aminoethane sulfonate (BES),
3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy propanesulfonate
(DIPSO), N-[2-hydroxyethyl]piperazine-N'-3-propane-sulfonate
(EPPS), N-[2-hydroxyethyl]piperazine-N'-3-propanesulfonate (HEPES),
2-[N-morpholino]ethanesulfonate (MES),
4-[N-morpholino]butane-sulfonate (MOBS),
N-tris[hydroxymethyl]methyl-2-minoethanesulfonate (TES), and the
like, or a mixture thereof.
[0114] The liquid component may optionally comprise other molecules
such as water-soluble molecules having one acid and at least two
amino groups, or more amino groups than acid groups, or at least
one amino groups and multiple alcohol groups; said molecules having
a moderate basic character and a pKa between 6.0 and 7.4. This
molecule is generally selected among amino-acid residues or
sequences, including histidine (HIS) or lysine (LYS) residues or
sequences, and/or among a group comprising
bis[2-hydroxyethyl]iminotris[hydroxymethyl]methane (BIS-TRIS),
Tris[hydroxy-methyl]amino-methane (TRIZMA), and the like, or a
mixture thereof.
[0115] All proposed liquid components have a pH ranging between 6.5
and 7.4, an intrinsic viscosity ranging between 5 and 100,000 mPa.s
at 21.degree. C. All liquid components, being endothermally
sensitive, have a sol-gel transition temperature, and form
homogeneous solid aqueous gels at a temperature, between 15.degree.
C. and 60.degree. C., preferably between 25.degree. C. and
45.degree. C., and more preferably at 35-40.degree. C.
[0116] Other organic compounds being non-bioactive may be admixed
to the liquid component so as to provide specific chemical or
physical properties. Representative compounds include sugar-polyols
such as glycerol, mannitol or sorbitol, and saccharide-polyols such
as fructose, glucose, lactose or maltose, and glycols such as
ethylene glycol oligomers, propylene glycol oligomers, and the
like. Sugar-polyols, saccharide-polyols and glycols may be
incorporated alone or in combination. The final concentration of
sugar-polyols, saccharide-polyols and glycols in the liquid
component is typically below 20% wt., preferably between 1.0 and
15.0% wt.
[0117] Other water-soluble salt may be added to the liquid
component as required and permitted by the thermo-gelling property.
This includes water-soluble fluoride, phosphate and carbonate
salts, generally at a concentration below 0.1 mol/l.
[0118] In one embodiment, the liquid component is composed of
chitosan and disodium glycerophosphate, has a pH above the pKa of
chitosan (6.3-6.4), generally between 6.5 and 7.4, and a reduced
content in acid. Typically, chitosan-glycerophosphate solutions at
pH=-7.0, prepared from chitosan, hydrochloric acid and disodium
glycerol-phosphate, mainly contain water, chitosan-glycerophophate
and NaCl.
[0119] Preparation of the Powder Component
[0120] In the invention, the solid component is a mixture of dry
mineral powders or particles, also called "dry ingredients". The
size of the particles is not particularly crucial in the invention,
although there exist preferred ranges of sizes to have optimal
particle surface area, surface reactivity, dissolution rate, etc.
The dry ingredient of the present invention comprises at least two
calcium phosphates, but optionally comprises also a calcium source,
a sodium phosphate, other minerals and organics.
[0121] The solid component consists in a dry powder mixture that
comprises at least two calcium phosphate sources. The two calcium
phosphate sources are selected among apatitic calcium phosphates,
octacalcium phosphates, amorphous calcium phosphates, tetracalcium
phosphates, tricalcium phosphates, dicalcium phosphates and
monocalcium phosphates. Apatites comprise sintered hydroxyapatite
Ca.sub.10(PO.sub.4).sub.6(OH).sub.2-2xO.- sub.x (SHA, Ca/P=1.67),
precipitated hydroxyapatite Ca.sub.10(PO.sub.4).sub.6(OH).sub.2
(PHA, Ca/P=1.67), all calcium-deficient apatites such as the
apatite of formula Ca.sub.9(HPO.sub.4)(PO.sub.4).sub.5OH (CDA,
Ca/P=1.5), and the like, and derivatives thereof. Calcium deficient
apatites are apatitic calcium phosphates with Ca/P molar ratio in
the range 1.66 to 1.5 or less. Compounds including interlayers of
octacalcium phosphate are included.
[0122] The calcium phosphates can be selected in a group comprising
Ca(H.sub.2PO.sub.4).sub.2.H.sub.2O, CaHPO.sub.4.2H.sub.2O,
CaHPO.sub.4, CaZn.sub.3(PO.sub.4).sub.2, CaZnPO.sub.4,
CaNaPO.sub.4, Ca.sub.2PO.sub.4Cl, alpha-Ca.sub.3(PO.sub.4).sub.2,
beta-Ca.sub.3(PO.sub.4).sub.2, Ca.sub.3(PO.sub.4).sub.2.H.sub.2O,
Ca.sub.4(PO.sub.4).sub.2O,
Ca.sub.8H.sub.2(PO.sub.4).sub.6.5H.sub.2O,
Ca.sub.9(HPO.sub.4)(PO.sub.4).sub.5OH,
Ca.sub.10(PO.sub.4).sub.6(OH).sub.- 2-2xO.sub.x,
Ca.sub.10(PO.sub.4).sub.6(OH).sub.2, and derivatives thereof.
Calcium phosphate sources may comprise natural mineral components
including hard-tissue, enamel or dental apatite, coral or nacre.
Calcium phosphate sources may also be selected among apatitic and
nonapatitic calcium phosphates containing fluoride, strontium or
carbonate (calcium fluoride phosphates, calcium strontium
phosphates, carbonated calcium phosphates, fluorinated and
carbonated calcium phosphates, fluorinated calcium strontium
phosphates, fluorinated and carbonated calcium strontium
phosphates, and the like).
[0123] The solid component may also comprise a phosphate source
such as a sodium phosphate compound.
[0124] The solid component may also comprise a calcium source
selected in a group comprising CaO, Ca(OH).sub.2, CaCO.sub.3,
CaCl.sub.2, CaMgO.sub.2, CaF.sub.2,
CaPO.sub.4C.sub.3H.sub.5(OH).sub.2,
Ca(H.sub.2PO.sub.4).sub.2.H.sub.2O, CaHPO.sub.4.2H.sub.2O,
CaHPO.sub.4, alpha-Ca.sub.3(PO.sub.4).sub.2,
beta-Ca.sub.3(PO.sub.4).sub.2, Ca.sub.3(PO.sub.4).sub.2.H.sub.2O,
Ca.sub.4(PO.sub.4).sub.2O,
Ca.sub.8H.sub.2(PO.sub.4).sub.6.5H.sub.2O,
Ca.sub.9(HPO.sub.4)(PO.sub.4).- sub.5OH,
Ca.sub.4Mg.sub.5(PO.sub.4).sub.6CaO, Ca.sub.10(PO.sub.4).sub.6Cl.-
sub.2, Ca.sub.10(PO.sub.4).sub.6(OH).sub.2-2xO.sub.x,
Ca.sub.10(PO.sub.4).sub.6(OH).sub.2, and derivatives thereof.
[0125] The solid component may comprise other mineral ingredients
such as a carbonate, strontium, fluoride, magnesium, zinc or barium
source, or other minerals. Carbonates may be typically selected
among Na.sub.2CO.sub.3, CaCO.sub.3, K.sub.2CO.sub.3, MgCO.sub.3,
ZnCO.sub.3, Ca.sub.9K(PO.sub.4).sub.5(CO.sub.3).sub.2,
Ca.sub.8.5Na.sub.1.5(PO.sub.4)- .sub.4.5(CO.sub.3).sub.2.5,
Ca.sub.9(PO.sub.4).sub.4.5(CO.sub.3).sub.1.5, and the like. The
fluoride source may be selected among NaF, Na.sub.2Si.sub.6F, KF,
KSi.sub.6F, CaF.sub.2, MgF.sub.2, ZnF.sub.2, and the like.
Strontium compounds may be strontium salts (strontium chloride,
oxides and the like), strontium phosphate salts. Other ingredient
may be oxides and/or hydroxides such as MgO, Mg(OH).sub.2, ZnO, and
the like.
[0126] The solid component may also comprise an organic salt source
such as oxalate, lactate, malate, citrate, lactobionate compounds,
and the like. The solid component may also comprise an acid source
such as oxalic acid, lactic acid, malic acid, citric acid,
lactobionic acid, and the like. The solid component may also
comprise an organic compound such as an amino-acid, a polyol, a
sugar, and the like.
[0127] The size of calcium phosphate particles was reported to
significantly control the reactivity, thus possibly slowing the
reaction and retarding the hardening or setting rate when too
large. Granule size is related to the exposed surface area, and
possibly influences the initial composition of the ingredients, the
final dry product composition, and hence the mixing, mechanical and
physical properties. Particle size, herein defined as an average
particle size, may range from 0.2 microns to 100 microns,
preferably is below 50 microns, and more preferentially varies from
0.1 to 20 microns.
[0128] Dry ingredients are combined together by physico-mechanical
mixing techniques and instruments. This may be reached by a single
mixing step, or by a series of mixing steps. The physico-mechanical
mixing is not critical, may be operated with various techniques and
instruments, but has to provide an intimate mixing of the dry
ingredients. The mixing may be combined with a milling of solid
minerals. Physico-mechanical mixing techniques include mortar,
shaker mixing, ball planetary mixing, rolling mixing, vibratory
mixing, and the like. A selection of the dry powder mixture may be
operated following the dry mixing, for example by sieving into an
appropriate ingredient size. Shaker (rotary) mixing and ball mixing
was preferentially used in the present invention.
[0129] It is important that the dry ingredient mixing is achieved
without chemically altering the ingredient reactivity, and without
inducing unexpected reactions between the mixed ingredients. The
intimate ingredient mixing regulates the further reactions between
the different dry ingredients. Mixing must be performed until
occurrence of a uniform dry mixture. To ensure anhydrous
conditions, the mixing of dry ingredients may be operated under
strict anhydrous conditions (gas, environment control), or in
anhydrous non-aqueous liquids, for example solvents such as hexane
or absolute alcohols, all traces of water being preliminarily
eliminated from this liquid. Identically, the dry mixture is
preferentially stored under strict anhydrous conditions so as to
avoid any contamination or cross-reaction with water. Solid
additives, being organic or inorganic, may be admixed with the dry
ingredients at the dry mixing step. Incorporation of bioactive
agents in the solid component may be performed during the dry
mixing, or later, during a second mixing step.
[0130] Preparation of Self-Setting Hybrid
Compositions/Bio-Materials
[0131] In the present invention, self-setting compositions are
prepared by intimately mixing the liquid component and the powder
component. Mixing may be performed manually by kneading, or
physico-mechanically by using homogenizers, mixers or mills. There
is no special preference for the mixing instruments, but the
composition must be as uniform and homogeneous as possible. A
specially designed instrument may be used as well as to mix and
deliver the composition before use.
[0132] The liquid component is one selected among those previously
described. One preferred basic liquid components comprise water,
acid, chitosan and a first source of phosphate, glycerophosphate.
Acid is generally selected among hydrochloric acid,
glycerophosphoric acid, phosphoric acid, citric acid, acetic acid,
lactic acid, and the like. The starting acidic aqueous medium is
generally a 0.05 to 1 N acid/water solution, and preferably a 0.05
to 0.5N solution. Chitosan is generally selected among partially
N-deacetylated poly(glucosamine) having a deacetylation degree
between 60 and 100%, preferably between 30 and 99% and more
preferentially between 84 and 98%. It is present in the liquid
component at a concentration ranging from 0.1% to 10% w/v, and more
preferably between 0.1% and 2.0% w/v. The source of phosphate is
generally an organic monophosphate dibasic salt, such as
glycerol-2-phosphate and/or glycerol-3-phosphate sodium or
magnesium salts, at a concentration between 0.1% and 20% w/v, and
ideally between 1.0% and 10% w/v. The pH of the liquid component
varies between 6.5 and 7.4, and preferably between 6.8 and 7.2. The
viscosity of the liquid component is ranging between 5 mPa.s to
100,000 mPa.s, and preferably between 10 mPa.s and 1,000 mPa.s. As
previously described, additional reagents may be an organic
monosulfonate salt and/or a second hydrophilic polymer, and/or an
organic molecules, and/or a bioactive agent. The liquid component
is preferably stored at cool temperatures, ideally between 0 and
4.degree. C.
[0133] The preferred calcium phosphates of the powder component
comprise dry mixtures of apatitic calcium phosphate and/or
tetracalcium phosphate, and/or tricalcium phosphate (alpha, beta,
others), and/or dicalcium phosphate (hydrated or anhydrous) and/or
monocalcium phosphate (hydrated or anhydrous). Apatites comprise
sintered hydroxyapatite
Ca.sub.10(PO.sub.4).sub.6(OH).sub.2-2xO.sub.x (SHA, Ca/P=1.67),
precipitated hydroxyapatite Ca.sub.10(PO.sub.4).sub.6(OH).sub.2
(PHA, Ca/P=1.67), all calcium-deficient apatites such as the
apatite of formula Ca.sub.9(HPO.sub.4)(PO.sub.4).sub.5OH (CDA,
Ca/P=1.5), and the like or derivatives thereof. Calcium deficient
apatites are apatitic calcium phosphates with Ca/P molar ratio in
the range 1.66 to 1.5 or less. Compounds including interlayers of
octacalcium phosphate are included.
[0134] In one embodiment, the solid component comprises a dry
mixture of alpha-tricalcium phosphate and an apatitic calcium
phosphate.
[0135] In another embodiment, the solid component comprises a dry
mixture of alpha-tricalcium phosphate and an octacalcium
phosphate.
[0136] Still in another embodiment, the solid component comprises
alpha-tricalcium phosphate and an apatitic calcium phosphate and
one of dicalcium phosphate and monocalcium phosphate.
[0137] In another embodiment, the solid component comprises a
noncalcium phosphate salt.
[0138] In yet another embodiment, the solid component comprises a
carbonated and/or a fluorinated and/or a strontium-containing
and/or a magnesium-containing and/or a zinc-containing and/or a
barium containing compound. This includes carbonate, fluoride or
strontium, magnesium, zinc, barium salts with no calcium and
phosphate as well as apatitic and nonapatitic calcium phosphates
containing carbonate and/or fluoride and/or strontium and/or
magnesium and/or zinc and/or barium.
[0139] The solid component also comprises an organic salt source
such as oxalate, lactate, malate, citrate, gluconate compounds, and
the like. The solid component also comprises an acid source such as
oxalic acid, lactic acid, malic acid, citric acid, gluconic acid,
and the like. The solid component also comprises an organic
compound, being not an acid or a salt, such as an amino-acid, a
polyol, a sugar, and the like.
[0140] In one embodiment, the solid component comprises a dry
mixture of alpha-tricalcium phosphate and calcium deficient
apatite. In another embodiment, the solid component comprises a dry
mixture of alpha-tricalcium phosphate and calcium deficient apatite
with at least one of an organic acid, an organic salt, an organic
(nonacid, nonsalt) compound and a noncalcium phosphate salt.
[0141] The mineral ingredients of the solid component are dry-mixed
as previously described so as to obtain a homogeneous dry mixture.
This dry mixture can be performed in several distinct sequences.
Preferentially, the dry minerals or ingredients were mixed-milled
in a ball mill so as to obtain a mineral powder mixture homogeneous
and of the adequate size. This mixing/milling may be performed in
acetone or hexane solvent to avoid any moisture. An appropriate
size of dry ingredient ranges between 1 and 250 .mu.m, generally
between 1 and 50 .mu.m, and preferably between 1 and 20 .mu.m.
[0142] The calcium to phosphate ratio of the solid component
generally varies between 1.0 and 4.0, and typically between 1.0 and
2.0, and preferably between 1.2 and 1.8.
[0143] The mixing of liquid (L) and solid (S) components is
performed at a liquid/solid weight ratio between 0.05 and 1.50
(mL/g), and preferably between 0.2 and 1.0 (mL/g).
[0144] The liquid component is endothermally sensitive, but the
resulting paste is self-setting with time, thus self-hardening at
37.degree. C. and 100% humidity into a solid bio-materials that
looks like a ceramic or cement-like materials. The cement-like
materials have higher compression strengths: after two days ageing
in a water solution, the wet ultimate compression strength reaches
typically 5-10 MPa and up. Resulting mineral composition includes
apatite. The material is resorbable in situ over a period of 18
months.
[0145] Bioactive Ingredients
[0146] Any bioactive ingredients may be incorporated and released
from self-setting compositions and bio-materials. The incorporation
can be assessed out via the liquid or solid component. Bioactive
agents include drugs, therapeutic agents, osteogenic agents and
anti-resorptive agents. Bioactive agents of interest are typically
osteoinductive agents selected from a group comprising growth
factors, hormones, individual osteoinductive proteins and mixtures
of osteoinductive proteins, bone derived materials including
demineralized bone matrix (DBM) or powder (DBP), growth factors
selected from a group comprising IGF, EGF, a-FGF, b-FGF, PDGF-A,
PDGF-B and/or TGF-beta, bone morphogenic proteins (BMP),
sialoproteins, osteonectin, osteopontin, osteocalcin, calcitonin,
or a mixture thereof. Other agents include antibiotic, antiviral,
antitumor, and/or immuno-supressive agent.
[0147] Mode of Administration--Application
[0148] The administration of the composition to hard-tissue
defects, cavities, or any anatomical structures is performed
percutaneously by injection through a cannula, trocar or needle of
a gauge ranging from 7 to 27, preferably from 14 to 22, and more
ideally from 16 to 22, and with the use of syringe or a pressure
injecting device, or by the use of endoscopic technique and
instrument or during the course of an open surgical operation.
[0149] The compositions may be useful for medical and dental
indications, in human or veterinarian procedures. They may be used
in one of the following procedures:
[0150] a) to favor and promote regeneration and/or repair of bone
lost due to disorders, diseases or deficiencies; to replace bone
that is surgically removed or lost during a trauma;
[0151] b) to reconstruct, (re)shape and/or replace partly or
totally hard-tissues;
[0152] c) to favor the repair of fractured bones; to fix bone
fragments;
[0153] d) to ensure retention and strength in situ of other
orthopaedic devices (pin, prosthesis, fixation);
[0154] e) to protect or cap the dental pulp;
[0155] f) to fill permanently or temporarily enamel and dentin;
[0156] g) to fill root canals;
[0157] h) to implant or replant a teeth; and
[0158] i) to act a luring cement in dentistry and orthopaedic
surgery.
[0159] More generally, the compositions may be useful for all
repair, regeneration, filling, replacement procedures associated to
hard-tissues as well as for delivering drugs or bioactive agents to
hard-tissues.
[0160] The composition can be injected to the filling and repair of
internal bone cavity, of local treatment of osteoporotic bones, and
other demineralized bones and demineralization disorders; of bone
defects or cavities, for example in the case of periodontal defects
with bone loss, augmentation of the alveolar ridge or
surgically-performed hard-tissue defects following resection of
diseased hard-tissue parts; of bone fractures for repairing
fractures, fixing bone fragments, delivering agents that accelerate
the sequence of fracture healing.
[0161] Self-setting mineral-polymer compositions are to be used in
orthopaedic, cranio-maxillofacial or dental surgery.
[0162] The present invention will be more readily understood by
referring to the following examples, which are given to illustrate
the invention rather than to limit its scope.
EXAMPLE I
Preparation of Liquid Phases
[0163] The liquid phase of bone composition is an endothermally
self-forming aqueous solution made of one hydrophilic biopolymer
and at least one water-soluble phosphate source.
[0164] A representative liquid phase is a
chitosan/glycero-phosphate [chitosan-GP] aqueous solution. An
acidic chitosan aqueous solution (2.0% w/v) was made with a
chitosan previously deacetylated at 83-97%, filtered and dialyzed,
and was prepared from a 0.097M (0.10M) HCl solution. A
chitosan/glycerophosphate aqueous solution was prepared from the
2.0% (w/v) chitosan in HCl aqueous solution and a 8.4% (w/v)
disodium glycerophosphate in distilled water solution. Final
concentrations (w/v) in the self-gelling chitosan/glycerophosphate
systems was approximately 1.6-2.0% (chitosan) and 6.75-8.2%
(glycerol-phosphate).
[0165] Glycerophosphate salts act herein as
buffering/thermo-gelling agents for the chitosan solution. Other
buffering/thermogelling phosphate sources may be used, typically
organic monobasic phosphate salts, such as glucose-phosphate or
fructose-phosphate salts. Other buffering agents may be also
associated with glycerophosphate salts so as to enhance the
buffering/thermogelling action such as amino acids or organic
sulfonate salts. Table 1 summarizes the potent composition of
liquid phases.
1TABLE 1 Buffering/thermogelling agents for liquid phases having
1.0-2.0% by weight of chitosan Buffering/ Example Thermogelling
contents agents (% w/v) Remarks Glycero-phosphate 4-10 salts
Glucose-phosphate 6-12 salts Fructose-phosphate 1-6 salts Histidine
2-10 Histidine and glucosamine used as co- Glucosamine 2-10
buffering agent with glycero-phosphate. BIS-TRIS 1-8 Used alone or
mixed with glycero-phosphate. MES 1-4 Used alone or mixed with
(sulfonate) salt glycero-phosphate. HEPES 1-4 Used alone or mixed
with (sulfonate) salt glycero-phosphate. TES 1-4 Used alone or
mixed with (sulfonate) salt glycero-phosphate.
[0166] Histidine was typically admixed with GP in the chitosan
solution (Ex: 1.5% w/v chitosan, 4.0% w/v GP+4.0% w/v histidine).
BIS-TRIS may be used alone as a buffering/thermogelling agent (Ex:
1.5% w/v chitosan+2.0% w/v BIS-TRIS). HEPES, TES or MES sulfonate
agent may be used alone as a buffering/thermogelling agent (Ex:
1.5% w/v chitosan+2.0% w/v HEPES, TES or MES).
[0167] a) Addition of a Second Water-Soluble Polymer in the Liquid
Phase
[0168] A second water-soluble polymer may be dissolved in the
chitosan-GP aqueous solution. Table 2 gives the composition of
liquid phase consisting in chitosan-GP plus a water-soluble
polymer. Glycerophosphate may be added prior to the dissolution of
the second polymer, or after the dissolution of the second
polymer.
[0169] Thermosensitive polymers such as the methyl cellulose,
hydroxypropyl methyl cellulose or Pluronic.RTM. were found to be
the more sensitive to the concentration in glycerophosphate salts.
Those salts were found to affect the gelling or precipitating
temperature of the polymer, thus leading to a precipitation of the
chitosan/GP/polymer (2) system.
2TABLE 2 Liquid phase compositions having an admixed second
water-soluble polymer Polymer Chitosan GP content content content
Polymer (2) (w/v) (w/v) (w/v) Remarks Hydroxyethyl 1.0% 2.0% 8.0%
Form gels. Cellulose Hydroxypropyl 0.55% 1.0% 4.5% Form gels.
Methyl Cellulose Polyethylene 1.0% 2.0% 8.0% Form gels. glycol
Methyl Cellulose 1.0-2.0% 1.0-2.0% 4.0-6.0% Form gels.
Precipitation may occur with higher GP contents. Pluronic .RTM.
1.0% 2.0% 2.0% Form gels. Precipitation may occur with higher GP
contents. Collagen (type I) 1.0% 1.0% 8.0% Form gels. All presented
concentrations (%, mol/l . . . ) are final.
[0170] All polymers (2) were dissolved in a prepared chitosan-GP
solution, except for collagen, and more generally polyamines, that
are dissolved in combination with the chitosan.
[0171] b) Addition of Water-Soluble Ingredients of Interest
[0172] Some organic molecules that are soluble or miscible with
water may be added to the chitosan-based liquid phase to give
modified or improved physico-chemical characteristics, mechanical
or handling performances, or biological properties. This includes
polyols, sugars, amino-acids, polysaccharides, and other
biochemicals.
[0173] Polyols & Sugars
[0174] Of particular interest may be the polyols such as polyols
having diol hydrocarbon moieties, which may be useful for the
processing, or the performances of the liquid phase. Among those
polyols, glycerol, mannitol, sorbitol and ethylene glycol compounds
such as the triethylene glycol, tetraethylene glycol (Table 3) were
found to be good representative examples, being attractive and
bringing modifications or improvements to the liquid phase or
resulting thermo-formed gel. Sugars such as fructose, glucose, etc
may be used similarly.
3TABLE 3 Liquid phase compositions having added water- soluble
non-polymeric ingredient (Polyols) Ingredient Chitosan GP Polymer
content content content (2) (w/v) (w/v) (w/v) Remarks Glycerol
0.1-1.0 2.0% 8.0% Form gels. Changed rheological parameters of
gels. Stabilize chitosan sol viscosity. Sorbitol 0.1-1.0 1.0% 4.0%
Form gels. Changed (Mannitol) rheological parameters of nonsterile
gels. Stabilize chitosan sol viscosity. Ethylene 0.1-1.0 2.0% 8.0%
Form gels. Changed glycol rheological parameters of nonsterile
gels. Stabilize chitosan sol viscosity. Tri- 0.1-1.0 2.0% 8.0% Form
gels. Changed (Tetra-) rheological parameters of ethylene gels.
Stabilize chitosan glycol sol viscosity. All presented
concentrations (%, mol/l . . . ) are final.
[0175] Polysaccharides (GAGs)
[0176] Other water-soluble (bio)chemical ingredients may be of
interest to be added to the chitosan-GP liquid phase. However, such
ingredients must not disturb the chitosan-GP composition
(ingredient) and its thermogelling property.
[0177] Glycoaminoglycans may be added to the chitosan-GP solution
to a certain extent. It must be taken care of not inducing
precipitation of chitosan. Heparin (see Table 4) was used as the
GAGs to be added. Chitosan solutions were 4.0% w/v chitosan
(deacetylation 95%) in 0.19M HCl. GP solutions were 54.6% w/v in
water. Heparin in water solutions was at 1 mg/mL (A), 0.1 mg/mL
(B), 10 .mu.g/mL (C) and 1 .mu.g/mL (D).
4TABLE 4 Liquid phase compositions having added water- soluble
non-polymeric ingredient (Heparin) # Composition pH Remarks 1. 500
.mu.L chitosan + 150 .mu.L GP 7.04 Gels. 250 .mu.L water + 100
.mu.L Heparin (B) 2. 500 .mu.L chitosan + 250 .mu.L water 7.01
Gels. 150 .mu.L GP + 100 .mu.L Heparin (C) 3. 500 .mu.L chitosan +
250 .mu.L water 6.87 Gels. 150 .mu.L GP + 100 .mu.L Heparin (B) 4.
500 .mu.L chitosan + 250 .mu.L water 6.97 Reduced precipitation.
150 .mu.L GP + 100 .mu.L Heparin (A) Gels.
[0178] c) Addition of a Second Water-Soluble Phosphate Source to
the Liquid Phase
[0179] An acidic chitosan aqueous solution (2.0-4.0 w/v) was made
with a chitosan deacetylated at 83-85%, filtered and dialyzed, and
was prepared from a 0.1 M HCl solution (see Table 5).
5TABLE 5 Composition of liquid phases supplemented with a second
source of water-soluble phosphate [Phos- Gelling Chitosan:GP phate]
time Precip- Composition pH (% w/v) mol/l (initial) itation 10 ml
chitosan-GP 7.0 2.0:8.2 0 30 No minutes 8 ml chitosan-GP + 6.9
1.6:6.6 0.0014 30 No 2 ml phosphate (1) minutes 7 ml chitosan-GP +
6.9 1.4:5.7 0.0021 30 No 3 ml phosphate (1) minutes 5 ml
chitosan-GP + 6.9 1.0:4.1 0.0035 30 No 5 ml phosphate (1) minutes 8
ml chitosan-GP + 6.9 1.6:6.6 0.04 Slow No 2 ml phosphate (2)
gelation 1:1 7 ml chitosan-GP + 6.9 1.4:5.7 0.06 Slow No 3 ml
phosphate (2) gelation 1:1 5 ml chitosan-GP + 6.95 1.0:4.1 0.001
30-40 No 5 ml phosphate (2) minutes precip- 1:100 itation
[0180] All presented concentrations (%, mol/l . . . ) are
final.
[0181] A chitosan-GP aqueous solution was prepared from a
pre-cooled (4.degree. C.) chitosan in HCl solution and a 54-55%
(w/v) disodium glycerophosphate (GP) in distilled water solution.
The pH of the resulting liquid chitosan-GP solution was measured at
21.degree. C.
[0182] A phosphate solution (1) was prepared with 0.144 g/l
KH.sub.2PO.sub.4.7H.sub.2O potassium dihydrogen phosphate hydrated)
and 0.795 g/l Na.sub.2HPO.sub.4 disodium hydrogen phosphate) and
had a pH of 7.4 at 20.degree. C. Amounts of the chitosan-GP
solution and phosphate solution (1) were admixed homogeneously,
then the pH of the resulting solutions was measured (Table 6). The
solutions were finally disposed at 37.degree. C. for gelation, all
signs of precipitation being noted. All chitosan-GP+phosphate
solution (1) (80:20 to 50:50, vol) showed no signs of
precipitation, and gelled within 30 minutes at 37.degree. C.
6TABLE 6 Composition of liquid phases supplemented with a second
source of water-soluble phosphate [Phos- Gelling Chitosan:GP phate]
time Precip- Composition pH (% w/v) mol/l (initial) itation 10 ml
chitosan-GP 7.0 4.0:8.2 0 30 No minutes 9 ml chitosan-GP + 6.7
3.6:7.4 0.05 More 1 ml phosphate (3) turbid 8 ml chitosan-GP + 6.7
3.2:6.6 0.1 Highly 2 ml phosphate (3) turbid; Gels hetero-
geneously
[0183] A concentrated phosphate solution (2) was prepared from
283.92 .mu.l of Na.sub.2HPO.sub.4 (0.2 mol/l disodium hydrogen
phosphate) and 239.96 g/i of NaH.sub.2PO.sub.4 (0.2 mol/l sodium
dihydrogen phosphate) and had a pH of 7.4 at 37.degree. C. This
phosphate solution was used with dilutions at 1:1, 1:10, 1:100 and
1:1000. Equal volumes (50:50) of the diluted to concentrated
phosphate solution (2) and chitosan-GP solution were mixed
homogeneously. The pH of the resulting solutions was measured, and
the solutions disposed at 37.degree. C. for gelation, all signs of
precipitation being noted. All chitosan-GP/phosphate (2) gelled
with various rates at 37.degree. C.
[0184] A more concentrated phosphate solution (3) was prepared: 0.5
mol/l NaH.sub.2PO.sub.4 (600 g/l) and 0.5 mol/l Na.sub.2HPO.sub.4
(709.8 g/l). Volumes of the concentrated phosphate solution (3) was
added to chitosan-GP solutions, and mixed homogeneously. The pH of
the resulting solutions was measured, and the solutions disposed at
37.degree. C. for gelation, all signs of precipitation being noted.
Chitosan-GP is fully compatible with 5 mM PBS solution at pH
7.2-7.4. Compatibility depends upon the phosphate content (Tables
2-4): the addition of highly concentrated phosphate solutions
(especially dibasic phosphates) renders the chitosan-GP system more
turbid and prone to precipitation or heterogeneous gelation.
[0185] d) Addition of a Water-Soluble Carbonate Source to the
Liquid Phase
[0186] The chitosan-GP solutions were prepared as in Example 1c). A
carbonate solution was prepared from a 0.2 mol/l solution of
monosodium carbonate, having a pH of 8.16 at 21.degree. C. Equal
volumes (50:50) of the diluted (1/10) to concentrated carbonate
solution and chitosan-GP solution were mixed homogeneously. A
carbonate (0.1 mol/l)+phosphate (0.1 mol/l) solution was also used.
The pH was measured, and the solutions were disposed at 37.degree.
C. for gelation, all signs of precipitation being noted.
Chitosan-GP systems are fully compatible with carbonate buffer such
as a 5 mM phosphate/carbonate buffer at a pH of 8.8. But, this
compatibility will decline for too high carbonate contents.
[0187] In Examples 1e) and 1f) below, liquid chitosan-GP
formulations supplemented with water-soluble phosphates and/or
carbonates (Table 7) present a reduced shell-life and stability,
even at low temperatures (4.degree. C.). This is dose-dependent,
the more concentrated is the content of water-soluble phosphate
and/or carbonate in the chitosan-GP formulation, the less stable is
the resulting solution.
7TABLE 7 Composition of liquid phases supplemented with a source of
water-soluble carbonate Gelling [Carbonate] time Precipitation/
Composition pH mol/l (initial) Remarks 10 ml chitosan-GP 7.0 0 30
No minutes 8 ml chitosan-GP + 7.0 0.04 30 No 2 ml carbonate minutes
6 ml chitosan-GP + 7.1 0.08 30 No. Some sparse 4 ml carbonate
minutes complexes may occur by the surface. 5 ml chitosan-GP + 7.1
0.10 30 No. Fibrous 5 ml carbonate minutes complexes occur sparsely
at the upper level. 5 ml chitosan-GP + 6.95 0.01 30 No 5 ml
carbonate 1:10 minutes All presented concentrations (%, mol/l . . .
) are final.
[0188] e) Typical Preparation of Sterile Liquid Phase
[0189] Sterile Liquid Phases
[0190] Sterilization of liquid phase can be performed during the
preparation and processing of the chitosan-GP solutions. The
chitosan-GP systems can not be sterilized by energizing methods,
due to unexpected and undesirable thermal gelling. Chitosan
solutions (no GP) and GP solutions (no chitosan) are to be
sterilized separately. GP aqueous solutions have no viscosity and
are sterilized by filtration in all cases, without any noticeable
adverse effects. Chitosan materials (solid) or chitosan solutions
(acidic aqueous medium) must be sterilized while avoiding the
occurrence of degradative effects on both chitosan polymer and
chitosan-GP systems. Table 8 illustrates the effects of sterilizing
on Chitosan-GP systems (no additive).
8TABLE 8 Effects Of Sterilizing On Chitosan-Gp Systems (No
Additive) Effects on chitosan Effect of thermogelling Chitosan
sterilization biopolymer Chitosan-GP systems. Autoclaving of
Controlled Gels (slightly decreased chitosan solutions in
modification; gelling rate). acidic media. Autoclaving of
Controlled Modify gel properties. chitosan suspension in
modification; water. Irradiation of chitosan Controlled Gels
(slightly decreased materials (40.degree. C.). modification;
gelling rate). Irradiation of chitosan Stronger Gels (affect the
materials (20.degree. C.). modification; gelling rate).
EXAMPLE II
Cement-Like Compositions and Bio-Materials
[0191] Compositions for cement-like bio-materials were prepared
from liquid and solid (mineral) phases, liquid phases being
prepared typically as described in Examples 1 and being thermally
sensitive. The solid phase is a powder phase, generally containing
minerals such as calcium phosphates or carbonates, and optionally
solid organics. Liquid and solid phases are intimately mixed
together before reaching a cement-like self-setting composition
that has a hardening characteristic.
[0192] Tetracalcium phosphate (TTCP) was from Clarkson
Chromatography Products Corp. (NY, USA). Dicalcium phosphate and
Tricalcium phosphate (alpha or beta) were from Fluka Chemical
Company (Germany) and Clarkson Chromatography Products Corp. (NY,
USA). Monocalcium phosphates were from American & Chemical
(USA) and Aldrich Chemical Company.
[0193] a) TCP Cement-Like Compositions and Resulting
Bio-Materials
[0194] TCP/MCP Calcium Phosphate Content
[0195] Liquid phases were composed of pure water or phosphate
aqueous buffer (used as control for normal cement-like materials),
pure chitosan-GP aqueous systems (see Example 1) or
chitosan-GP/phosphates, chitosan-GP/carbonates or
chitosan-GP/phosphates-carbonates aqueous systems (see Examples
1a-1 d).
[0196] Solid TCP/MCP phases were prepared from tri-calcium
phosphates (.alpha.- or .beta.-TCP) and mono-calcium phosphates
(anhydrous or hydrated), but optionally also contained other
mineral ingredients (carbonated, fluorinated) (see Table 9).
9TABLE 9 Composition of liquid and solid phases for TCP/MCP/CC
based cement-like bio-materials Mineral Phase Ca/P Liquid Phase L/S
ml/g Observations .beta.TCP/MCPM 1.45 Water 0.6 Set.: 3 h; hard.: 4
(24 h) Gelling CGP (1% C) 0.6 Set.: 3 h; hard.: 4 (24 h)
.beta.TCP/MCPM 1.45 NaPO4 0.01 M 0.45 Set.: 1 h; hard.: 5 (20 h)
Gelling CGP (1% C), 0.45 Set.: 1 h; hard.: 4 (20 h) NaP 0.01 M
.beta.TCP/MCPM/ 1.59 Gelling CGP (1% C) 1 Set.: 4 h; hard.: 2 (24
h) HAP Gelling CGP (1% C), 1 Set.: 2 h; hard.: 3 (24 h) NaP 0.01 M
.beta.TCP/MCPM/ 1.59 Gelling CGP (1% C) 0.40 Set.: 1 h; hard.: 5
(24 h) CaCO.sub.3 Gelling CGP (1% C), 0.40 Set.: 1 h; hard.: 5 (24
h) NaP 0.01 M .beta.TCP/MCPM 1.33 Water 0.3 Set.: 30 s; hard.: 5 (2
min) Gelling CGP (1% C) 0.3 Set.: 30 s; hard.: 5 (2 min)
.beta.TCP/MCPM/ 1.45 Water 1.4 Set.: 1 h; hard.: 2 (24 h) HAP
Gelling CGP (1% C), 1 Set.: 1 h; hard.: 2 (24 h) .beta.TCP/MCPM/
1.41 Water 0.4 Set.: 1 h; hard.: 5 (4 h) CaCO.sub.3 Gelling CGP (1%
C) 0.4 Set.: 1 h; hard.: 3 (2 h) .beta.TCP/MCPM/ 1.00 Gelling CGP
(1% C) 0.40 Set.: 1 h; hard.: 5 (1 h) DCPA .beta.TCP/Citric ac.
1.50 Gelling CGP (1% C) 0.40 Set.: 20 h; hard.: 5 (24 h)
.beta.TCP/MCPM/ 1.45 Gelling CGP (1% C) 0.40 Set.: 3 h; hard.: 5
(24 h) Citric ac. .beta.TCP/MCPM/ 1.45 Gelling CGP (1% C) 0.30
Set.: 1 h; hard.: 3 (24 h) NaH.sub.2PO.sub.4 S/L ratio: is given in
ml of liquid phase per gram of solid phase. Ca/P*: Total Ca/P ratio
for solid phase. Hardness: from 0 (liquid) to 5 (very hard).
[0197] In given examples (see Table 9), a composition was
consisting in TCP, MCP and calcium carbonate (CC), thus giving at
the end a carbonated apatite material that can be represented by
Ca.sub.9-x(HPO.sub.4).sub.1-1-
.5x(PO.sub.4).sub.5-2.5x(CO.sub.3).sub.3.5x(OH).sub.1+1.5x. Typical
solid TCP powder phase compositions were made of 100% TCP, and
80-90% wt. TCP (Ex: 7.77 g), 5-10% wt. MCP (Ex: 0.869) and 5-10%
wt. CC (Ex: 0.86 g). Another typical example consisted in 4.2 g
TCP, 1.3 g MCP and 1.2 g Calcium Sulfate dihydrate (CS). Ca/P ratio
varied from 1.54 to 2.64. TCP was .beta. or .beta. (here for
example, .beta.-TCP was selected), .alpha.-TCP being potentially
more reactive.
[0198] Solid TCP based phases were obtained by dry-mixing of
mineral powders, either by manual mixing or rotative mixing. Manual
mixing was done by using a mortar and pestle. Rotative mixing was
performed at low speeds in closed 50 cc chambers that contained 10
cc to 30 cc of mineral materials (.about.50% free volume). Powder
mixture was stored under strict anhydrous conditions (<10% HR).
The liquid phase was added to the solid powder phase in a glass or
agate recipient. Typically, 1 gram of solid minerals was admixed
with the required amount of liquid phase (see Table 10). Intimate
mixing was reached manually by kneading, or mechanically (shear
mixing, ball mill mixing). Once being well-homogeneized, the
resulting paste or suspension was shaped in a mold, with a size:
approximately mm long.times.mm width.times.mm deep, and disposed in
a closed humid chamber (.about.100% humidity) at 37.degree. C.
10TABLE 10 Composition of liquid and solid phases for TCP/MCP based
cement-like bio-materials Mineral L/S Phase Ca/P Liquid Phase ml/g
Observations .beta.TCP/ 1.45 Water 0.45 Set.: 5 h; hard.: 3 (24 h)
DCPA Gelling CGP (C 1%) 0.45 Set.: 2 h; hard.: 2 (24 h) .beta.TCP/
1.45 NaPO4 0.01 M 0.40 Set.: 19 h; hard.: 1 (24 h) DCPA Gelling CGP
0.40 Set.: 2 h; hard.: 2 (24 h) (C 1%), NaP 0.01 M .beta.TCP/ 1.59
Gelling CGP (C 1%) 1.0 Set.: 2 h; hard.: 2 (24 h) DCPA/ Gelling CGP
1.0 Set.: 2 h; hard.: 2 (24 h) HAP (C 1%), NaP 0.01 M .beta.TCP/
1.59 Gelling CGP (C 1%) 0.40 Set.: 1 h; hard.: 4 (24 h) DCPA/
Gelling CGP 0.40 Set.: 1 h; hard.: 4 (24 h) CaCO.sub.3 (C 1%), NaP
0.01 M
[0199] S/L ratio: is given in ml of liquid phase per gram of solid
phase.
[0200] Ca/P*: Total Ca/P ratio for solid phase.
[0201] Hardness: from 0 (liquid) to 5 (very hard).
[0202] TCP/DCP Calcium Phosphate Content
[0203] The composition and preparation were identical to those
described previously in Example 2a, except that monocalcium
phosphate (MCP anhydrous or hydrated) was replaced by di-calcium
phosphate (DCP anhydrous or hydrated). One typical example
comprises 3.10 g TCP and 0.30 g DCP. Other mineral ingredients may
be incorporated in the solid phase: in the Examples (see Table 11),
calcium carbonate minerals were added, thus giving carbonated
apatites. The Ca/P ratio of compositions was between 1.40 and
1.60.
[0204] b) TTCP Cement-Like Compositions and Bio-Materials
[0205] TTCP/MCP Calcium Phosphate Contents
[0206] Liquid phases were composed of pure phosphate aqueous buffer
(control), chitosan-GP aqueous systems (see Examples 1),
chitosan-GP/phosphates, chitosan-GP/carbonates or
chitosan-GP/phosphates-- carbonates aqueous systems (see Examples 1
a-1d).
[0207] Phosphate buffer was 0.2 mol/l sodium or potassium hydrogen
phosphates (Ex: NaH.sub.2PO.sub.4+K.sub.2HPO.sub.4). Phosphate
addition to chitosan-GP systems was done with sodium or potassium
hydrogen phosphates (Ex: NaH.sub.2PO.sub.4+K.sub.2HPO.sub.4) (see
Examples 1). Carbonate addition to chitosan-GP systems was done
with sodium bicarbonate (NaHCO.sub.3) (see Examples 1).
11TABLE 11 Composition of liquid and solid phases for TTCP/DCP
based cement-like bio-materials Mineral L/S Phase Ca/P Liquid Phase
ml/g Observations TTCP/ 1.66 Water 0.70 Set.: 1 h; hard.: 5 (5 h)
MCPM Gelling CGP (C 1%) 0.70 Set.: 1 h; hard.: 5 (5 h) TTCP/ 1.66
NaP 0.01 M 0.60 Set.: 1 h; hard.: 5 (4 h) MCPM Gelling CGP (C 1%),
0.60 Set.: < 1 h; hard.: 5 NaP 0.01 M (4 h) TTCP/ 1.66 Gelling
CGP (C 1%) 1.00 Set.: < 1 h; hard.: 4 (24 h) MCPM/ 1.66 Gelling
CGP (C 1%), 1.00 Set.: < 1 h; hard.: 5 (5 h) HAP NaP 0.01 M
TTCP/ 1.75 Gelling CGP (C 1%) 0.6 Set.: 1 h; hard.: 5 (4 h) MCPM/
1.75 Gelling CGP (C 1%), 0.6 Set.: 1 h; hard.: 5 (4 h) CaCO.sub.3
NaP 0.01 M
[0208] S/L ratio: is given in ml of liquid phase per gram of solid
phase.
[0209] Ca/P*: Total Ca/P ratio for solid phase.
[0210] Hardness: from 0 (liquid) to 5 (very hard).
[0211] Solid TTCP/MCP phases were prepared from tetra-calcium
phosphates (TTCP) and monocalcium phosphates (MCP Anhydrous or
Dihydrated), but optionally also contained other mineral
ingredients (calcium, carbonated, fluorinated). Seeding of
hydroxyapatite (HA) was also used (Ex: 40% wt.). In typical
Examples, solid phases included 3.26 g TTCP and 0.71 g MCPM, or
3.26 g TTCP and 2.04 g MCPM. Ca/P ratio was ranging from 1.33 to
1.80. Solid TTCP/MCP phases were obtained by dry-mixing, either
manual mixing or rotative mixing, of mineral powders. Manual mixing
was done with a mortar and pestle. Rotative mixing was performed at
low speeds in closed 50 cc chambers that contained 10-30 cc of
mineral materials (.about.50% free volume).
[0212] TTCP/DCP Calcium Phosphate Contents
[0213] TTCP/DCP mineral phases were also used to prepare
cement-like compositions and bio-materials. TTCP/DCP based phases
were prepared from tetra-calcium phosphates (TTCP) and di-calcium
phosphates (DCP Anhydrous or Di-hydrated), but optionally also
contained other mineral ingredients (carbonated, fluorinated).
Powder mixture of TTCP and DCP was equimolar (see Table 12).
12TABLE 12 Composition of liquid and solid phases for TTCP/DCP
based cement-like bio-materials Mineral Liquid L/S Phase Ca/P Phase
ml/g Observations TTCP/DCPA 1.66 Water 0.60 Set.: 24 h; hard.: 1
(24 h) Gelling 0.50 Set.: 3 h; hard.: 3 (24 h) CGP (C 1%) TTCP/DCPA
1.66 NaP 0.01 M 0.40 Set.: 3 h; hard.: 2 (20 h) Gelling 0.40 Set.:
3 h; hard.: 2 (20 h) CGP (C 1%), NaP 0.01 M TTCP/DCPA/ 1.66 Gelling
0.75 Set.: 2 h; hard.: 5 (5 h) HAP CGP (C 1%) Gelling 1.00 Set.: 2
h; hard.: 3 (24 h) CGP (C 1%), NaP 0.01 M TTCP/DCPA/ 1.75 Gelling
0.50 Set.: 19 h; hard.: 2 (24 h) CaCO.sub.3 CGP (C 1%) Gelling 0.50
Set.: 19 h; hard.: 2 (24 h) CGP (C 1%), NaP 0.01 M TTCP/DCPA/ 1.66
Gelling 0.30 Set.:1 h; hard.: 6 (1 h) Citric ac. CGP (C 1%)
TTCP/DCPA/ 1.66 Gelling 0.80 Set.: 1 h; hard.: 5 (1 h)
NaH.sub.2PO.sub.4 CGP (C 1%)
[0214] S/L ratio: is given in ml of liquid phase per gram of solid
phase.
[0215] Ca/P*: Total Ca/P ratio for solid phase.
[0216] Hardness: from 0 (liquid) to 5 (very hard).
[0217] Example solid phases contained 3.26 g TTCP and 1.36 g DCPA.
A 40% (wt.) seeding of hydroxyapatite (HA) was also used with 1.63
g TTCP and 0.68 g DCPD. Ca/P ratio was about 1.67. Solid TTCP/DCP
phases were obtained by dry-mixing, either manual mixing or
rotative mixing, of mineral powders. Manual mixing was done with a
mortar and pestle. Rotative mixing was performed at low speeds in
closed 50 cc chambers that contained 10-30 cc of mineral materials
(.about.50% free volume)(see FIG. 2).
[0218] c) TTCP/TCP Cement-Like Compositions and Bio-Materials
[0219] A solid mineral phase was prepared on the basis of a
dry-mixture of TTCP and TCP minerals, by incorporating mono-calcium
phosphate (MCP anhydrous or hydrated) or di-calcium phosphate (DCP
anhydrous or hydrated). In Examples, 1.55 g TTCP and 3.1 g TCP were
admixed for one composition (Ca/P ratio: 1.67)(see Table 13).
13TABLE 13 Composition of liquid and solid phases for TTCP/TCP
based cement-like bio-materials Mineral L/S Phase Ca/P Liquid Phase
ml/g Observations TTCP/ 1.66 Water 0.45 Set.: 3 h; hard.: 3 (24 h)
.beta.TCP Gelling CGP 0.45 Set.: 3 h; hard.: 3 (24 h) (C 1%) TTCP/
1.66 NaP 0.01M 0.40 Set.: 19 h; hard.: 2 (24 h) .beta.TCP Gelling
0.40 Set.: 19 h; hard.: 1 (24 h) CGP (C 1%), NaP 0.01M TTCP/ 1.66
Gelling 1.0 Set.: 4 h; hard.: 1 (24 h) .beta.TCP/HAP CGP (C 1%)
Gelling 1.0 Set.: 2 h; hard.: 2 (24 h) CGP (C 1%), NaP 0.01M TTCP/
1.75 Gelling 0.40 Set.: 19 h; hard.: 2 (24 h) .beta.TCP/ CGP (C 1%)
CaCO.sub.3 Gelling 0.40 Set.: 19 h; hard.: 2 (24 h) CGP (C 1%), NaP
0.01M
[0220] S/L ratio: is given in ml of liquid phase per gram of solid
phase.
[0221] Ca/P*: Total Ca/P ratio for solid phase.
[0222] Hardness: from 0 (liquid) to 5 (very hard).
[0223] TCP was either .alpha.- or .beta.-tricalcium phosphate. Dry
mixing was achieved as previously described in Example 2a-2b.
Liquid phases were pure water or chitosan-GP aqueous systems.
Admixing and homogenization of liquid and solid phases was done as
previously reported in Examples 2a-2b.
[0224] d) Other Cement-Like Compositions and Bio-Materials
[0225] Other combinations of calcium phosphate minerals were
performed to prepare the solid phase. Some given examples report
the use of hydroxyapatite (HAP) crystal or other seeding (see Table
14).
[0226] Most compositions contains MCP, OCP calcium phosphates
and/or calcium/zinc sources (oxides). Octa-calcium phosphate may be
used, combined with calcium phosphates or calcium sources, in the
solid mineral phase. OCP (4.91 g) was admixed with Ca(OH).sub.2
(0.37 g) and a 40% wt. HAP seeding, or with 3.26 g TTCP and a 40%
wt. HAP seeding. Mixing of mineral powders and homogenization of
liquid and solid phases were performed as previously described.
Mono-calcium phosphate may be incorporated as a major calcium
phosphate source. In typical Examples, 2.52 g MCPM was admixed with
1.31 g CaO (40% wt. HAP seeding), or with 3.10 g TCP (10% wt. DCPD
seeding). Ca/P ratio varied from 1.0 to 1.67. Mixing of mineral
powders and homogenization of liquid and solid phases were
performed as previously described.
14TABLE 14 Composition of liquid and solid phases for cement-like
bio-materials Mineral Phase Ca/P Liquid Phase L/S ml/g Observations
.beta.TCP/OCP 1.45 Gelling CGP (C 1%) 1.0 Set.: 1 h; hard.: 3 (24
h) Gelling CGP (C 1%), 1.0 Set.: 1 h; hard.: 3 (24 h) NaP 0.01M
TTCP/OCP 1.66 Gelling CGP (C 1%) 1.20 Set.: 1 h; hard.: 4 (16 h)
TTCP/OCP 1.66 Gelling CGP (C 1%), 1.20 Set.: 1 h; hard.: 4 (16 h)
NaP 0.01M Gelling CGP (C 1%) 1.20 Set.: 1 h; hard.: 4 (16 h)
Gelling CGP (C 1%), 1.20 Set.: 1 h; hard.: 4 (16 h) NaP 0.01M
MCPM/OCP/HAP 1.25 Gelling CGP (C 1%) 0.9 Set.: 3 h; hard.: 3 (5 h)
MCPM/OCP/ 1.45 Gelling CGP (C 1%) 2.4 Set.: 1 h; hard.: 2 (5 h)
CaO/HAP MCPM/OCP/ 1.46 Gelling CGP (C 1%) 2.0 Set.: 1 h; hard.: 2
(5 h) CaCO3/HAP MCPM/CaO/ 1.56 Gelling CGP (C 1%) 1.4 Set.: < 1
h; hard.: 3 (1 h) HAP Gelling CGP (C 1%), 1.4 Set.: < 1 h;
hard.: 3 (1 h) NaP 0.01M MCPM/CaO/ 1.56 Gelling CGP (C 1%) 1.4
Set.: < 1 h; hard.: 3 (1 h) HAP Gelling CGP (C 1%), 1.4 Set.:
< 1 h; hard.: 3 (1 h) NaP 0.01M MCPM/ 1.48 Gelling CGP (C 1%)
1.0 Set.: 1 h; hard.: 4 (20 h) CaCO.sub.3/HAP MCPM/CaO/ 1.47
Gelling CGP (C 1%) 1.4 Set.: 1 h; hard.: 4 (20 h) CaCO.sub.3/HAP
HAP/CaO/ 1.50 Gelling CGP (C 1%) 1.6 Set.: 1 h; hard.: 4 (20 h)
ZnO/MCPM DCPA/CaO/ 1.46 Gelling CGP (C 1%) 0.8 Set.: 1 h; hard.: 2
(24 h) HAP Gelling CGP (C 1%), 0.8 Set.: 1 h; hard.: 2 (24 h) NaP
0.01M DCPA/CaO/ 1.66 Gelling CGP (C 1%) 0.8 Set.: 1 h; hard.: 2 (24
h) CaCO.sub.3/HAP Gelling CGP (C 1%), 0.8 Set.: 1 h; hard.: 2 (24
h) NaP 0.01M HAP/CaO/ZnO 1.73 Gelling CGP (C 1%) 1.6 Set.: 1 h;
hard.: 2 (20 h) HAP/CaO/ 1.73 Gelling CGP (C 1%) 1.6 Set.: 1 h;
hard.: 2 (20 h) ZnO/cit. ac
[0227] S/L ratio: is given in ml of liquid phase per gram of solid
phase.
[0228] Ca/P*: Total Ca/P ratio for solid phase.
[0229] Hardness: from 0 (liquid) to 5 (very hard).
[0230] e) Typical Cement-Like Hybrid Compositions/Bio-Materials
[0231] Representative hybrid compositions for self-setting
cement-like biomaterials are given in Tables 15-22.
[0232] Solid phases were calcium phosphates and calcium
phosphates+organic powders grounded by ball milling, and mixed
together by rotating or ball mixing. Liquid phase were
thermo-gelling chitosan-GP solutions at 1 or 2% w/v chitosan.
Liquid and solid phases were mixed homogeneously by hand mixing
(spatula), then disposed in cylindrical flat-ended silicone molds
(D.times.L=8 mm.times.16 mm) (see FIGS. 1 and 3).
[0233] Ultimate compressive strength of cement-like hybrid
materials were determined on specimens that were shaped in
cylindrical flat-ended silicone molds (D.times.L=8 mm.times.16 mm).
Compositions were not compressed in molds prior to formation at
37.degree. C. and mechanical testing (free formation). Specimens
were aged for 15 days in an aqueous medium, and the specimen ends
were flattened and paralleled by polishing. The cylindrical
specimens were tested in compression to rupture on a MTS hydraulic
mechanical testing machine, at a cross-head rate of 1 mm/min.
15TABLE 15 Composition of liquid and solid phases for self-setting
hybrid compositions and bio-materials (TCP and TTCP based) Liquid
phase L/S # Solid phase (% in w/v) Ca/P (mL/g) Setting/Hardening 1
TTCP + CGP, C 1%. 1.66 0.55 Suspension with limited MCPM
homogeneity; Injectability difficult; Setting; Hardening (0-4 hrs).
Hard after ageing. 2 TTCP + CGP, C 1%. 1.50 0.6 Fine & workable
slurry; DCPA + Injectability difficult; MCPM Setting Hardening (0-4
hrs). Hard after ageing. 3 TTCP + CGP, C 1%. 1.66 0.32 Fine &
workable slurry; DCPA + Injectability must be rapid; Citric ac.
Setting rapid; Hardening (1 min). Hard after ageing. 4 .beta.TCP +
CGP, C 1%. 1.33 0.3 Fine & workable slurry; MCPM Injectability
must be rapid; Setting rapid; Hardening (1 min). Hard after ageing.
5 .alpha.TCP + CGP, C 1%. 1.37 0.7 Suspension with limited MCPM +
HA homogeneity; Injectability difficult; Setting; Hardening (0-6
hrs). Hard after ageing. 6 .alpha.TCP + CGP, C 1%. 1.33 0.5 Fine,
flowable & workable slurry; DCPA + HA Injectable; Setting;
Hardening (0-6 hrs). Hard after ageing. 7 .alpha.TCP + CGP, C 1%.
1.50 0.4 Fine, flowable & workable slurry; citric ac. +
Injectable; HA Setting; Hardening (0-10 min.). Hard after
ageing.
[0234]
16TABLE 16 Ultimate compressive strengths (MPa) of self-setting
hybrid materials (uncompressed specimens, TCP and TTCP based)
Liquid Phase: Liquid Phase: Liquid Phase: # Solid phase Pure water
CGP, 1% chitosan CGP, 2% chitosan 1 TTCP + MCPM ND 3.5 (0.2) 3.20
(0.75) 2 TTCP + DCPA + ND 2.9 (1.0) 3.4 (0.7) MCPM 3 TTCP + DCPA +
5.7 Mpa (0) 6.8 (0.4) 8.2 (2.3) citric ac. 4 .beta.TCP + MCPM ND
2.2 (0.5) 1.3 (0.1) 5 .alpha.TCP + MCPM + HA ND 11.85 (2.00) 13.4
(1.7) 6 .alpha.TCP + DCPA + HA 10.1 Mpa (3.3) 7.75 (1.50) 17.85
(4.9) 7 .alpha.TCP + citric ac. + HA 17.1 Mpa (2.5) 29.00 (8.45)
21.0 (8.0) ND: not determined; (): standard deviation
[0235] ND: not determined; ( ): standard deviation
17TABLE 17 Composition of liquid and solid phases for self-setting
hybrid alpha- TCP based compositions and bio-materials (changes of
apatitic charge) pH range Solid phase Liquid phase L/S (start.-
Setting/ # (% wt.) (% in w/v) Ca/P (mL/g) final) Hardening 1
.alpha.TCP + CGP, 1.50 0.40 4.80- Initial set.: 4 min citric ac.
Chitosan 1%. 5.46 Final set.: 8-10 min (11.7%) + CDAc (10.0%) 2
.alpha.TCP + CGP, 1.50 0.40 5.76- Initial set.: 6 min citrate
(9.0%) + Chitosan 1%. 6.60 Final set.: 30 min CDAc (10.0%) 3
.alpha.TCP + CGP, 1.50 0.40 5.75- Initial set.: 7 min citrate
(11.7%) + Chitosan 1%. 6.30 Final set.: 30 min CDAc (10.0%) 4
.alpha.TCP + CGP, 1.50 0.40 6.13- Cohesion time: 8 min citrate
(9.0%) + Chitosan 1%. 6.62 Initial set.: 9 min CDAc (10.0%) Final
set.: 33 min Injectability is 100% 5 .alpha.TCP + CGP, 1.50 0.40
6.02- Cohesion time: 7 min citrate (9.0%) + Chitosan 1%. 6.59
Initial set.: 9 min SHA (10.0%) Final set.: 33 min Injectability is
100% CDAc: Calcium Deficient Apatite, commercial, Ca/P = 1.5; CDAh:
Calcium Deficient Apatite, home synthesized, Ca/P = 1.5; SHA:
Sintered Hydroxyapatite, commercial; pH (start.-final): pH after
preparation of slurry-pH after setting (>8 hrs)
[0236] CDAc: Calcium Deficient Apatite, commercial, Ca/P=1.5;
[0237] CDAh: Calcium Deficient Apatite, home synthesized,
Ca/P=1.5;
[0238] SHA: Sintered Hydroxyapatite, commercial;
[0239] pH (start.-final): pH after preparation of slurry--pH after
setting (>8 hrs)
18TABLE 18 Setting and injectability of an alpha-TCP based
self-setting Composition Solid phase (charge, # % wt.) L/S = 0.30
mL/g L/S = 0.40 mL/g L/S = 0.50 mL/g 1 CDAc CT: 2.5 min CT: 8.0 min
CT: 24.0 min 0.0% In. set.: 2.5 min In. set.: 10.5 min In. set.:
44.0 min Fin set.: 9.5 min Fin set.: 32 min Fin set.: 110 min Inj.:
0% Inj.: 100% Inj.: 100% 2 CDAc CT: 3.0 min CT: 8.0 min CT: 30.0
min 5.0% In. set.: 3.5 min In. set.: 11.5 min In. set.: 33.0 min
Fin set.: 8.0 min Fin set.: 32 min Fin set.: 85 min Inj.: 0% Inj.:
80-100% Inj.: 100% 3 CDAc CT: 8.0 min CT: ND CT: 17.0 min 10.0% In.
set.: 4.0 min In. set.: 7 min In. set.: 22.0 min Fin set.: 6.5 min
Fin set.: 30 min Fin set.: 44 min Inj.: 0% Inj.: ND Inj.: 100% 4
CDAc CT: 3.0 min CT: 5.0 min CT: 11.0 min 15.0% In. set.: 5.5 min
In. set.: 10.0 min In. set.: 12.0 min Fin set.: 14.0 min Fin set.:
28 min Fin set.: 34 min Inj.: 70% Inj.: 90-100% Inj.: 90-100% 5
CDAc CT: 3.0 min CT: 3.0 min CT: ND 20.0% In. set.: 4.5 min In.
set.: 5.0 min In. set.: 13.0 min Fin set.: 11.0 min Fin set.: 23
min Fin set.: 40 min Inj.: 0% Inj.: 0% Inj.: 80-100% 6 CDAc CT: 4.0
min 50.0% In. set.: 8.5 min Fin set.: 36 min Inj.: 0%
[0240] (Liquid: chitosan-glycerophosphate-water, chitosan 1%
w/v);
[0241] (Solid: alpha-TCP, CDAc 10% wt., citrate 9% wt.).
19TABLE 19 pH change of an alpha-TCP based self-setting Composition
(see FIG. 4) Solid phase L/S = L/S = L/S = # (charge, % wt.) 0.30
mL/g 0.40 mL/g 0.50 mL/g 1 CDAc 0.0% pH start: 6.09 pH start: 6.27
pH start: 6.02 pH final: 6.70 pH final: 6.75 pH final: 6.65 2 CDAc
5.0% pH start: 6.11 pH final: 6.66 3 CDAc 10.0% pH start: 6.06 pH
start: 5.76 pH start: 5.97 pH final: 6.70 pH final: 6.60 pH final:
6.55 4 CDAc 15.0% pH start: 6.04 pH final: 6.68 5 CDAc 20.0% pH
start: 5.84 pH start: 5.76 pH final: 6.62 pH final: 6.56 6 CDAc
50.0% pH start: 5.73 pH final: 6.30
[0242] CDAc: Calcium Deficient Apatite, commercial, Ca/P=1.50;
[0243] CT: cohesion time (in min)
[0244] In set.: initial setting (in min)
[0245] Fin set.: final setting (in min)
[0246] Inj.: injectability (capacity to be injected)
[0247] (start.-final): pH after preparation of slurry--pH after
setting (>8 hrs)
20TABLE 20 Ultimate compression strengths of an alpha-TCP based
self-setting Composition (see FIG. 5) Solid phase L/S = L/S = L/S =
# (charge, % wt.) 0.30 mL/g 0.40 mL/g 0.50 mL/g 1 CDAc 0.0% 7.67
(1.58) 7.36 (2.25) 11.74 (1.79) 2 CDAc 5.0% 6.18 (0.84) 11.50
(1.61) 2-days 11.30 (4.87) 7.75 (2.60) 7-days 9.50 (3.33) 28-days 3
CDAc 10.0% 6.28 (3.70) 7.66 (1.78) 7.86 (2.53) 4 CDAc 15.0% 6.23
(1.28) 10.47 (2.73) 2-days 8.26 (1.02) 9.50 (3.92) 7-days 11.06
(2.47) 28-days 5 CDAc 20.0% 6.88 (2.34) 12.26 (4.00) 7.26 (2.49) 6
CDAc 50.0% ND 3.55 (0.56) ND CDAc: Calcium Deficient Apatite,
commercial, Ca/P = 1.50; ND: not determined; (): standard
deviation
[0248] CDAc: Calcium Deficient Apatite, commercial, Ca/P=1.50;
[0249] ND: not determined; ( ): standard deviation
[0250] (Liquid: chitosan-glycerophosphate-water, chitosan 1%
w/v);
[0251] (Solid: alpha-TCP, CDAc 10% wt., citrate 9% wt.).
21TABLE 21 Setting and injectability of an alpha-TCP/Calcium
Carbonate based self-setting Composition Solid phase 1 2 3 4 Liquid
phase* CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 # (charge, %
wt.) 5.9% 10.0% 9.15% 20.0% 1 .alpha.TCP CT: 9.0 min CDAc 15.0% In.
set.: 12.0 min Citrate 9.0% Fin set.: 44.0 min L/S = 0.4 mL/g Inj.:
0% pH: 5.7-6.6 2 .alpha.TCP CT: 5.0 min CDAc 15.0% In. set.: 13.0
min Citrate 9.0% Fin set.: 27.0 min L/S = 0.4 ml/g Inj.: 100% 3
.alpha.TCP CT: 6.0 min CDAc 15.0% In. set.: 4.0 min Citric ac.
11.7% Fin set.: 12.0 min L/S = 0.4 mL/g Inj.: 5-10%% pH: 4.8-6.03 4
.alpha.TCP CT: 5.0 min CDAc 15.0% In. set.: 4.0 min Citric ac.
11.7% Fin set.: 12.0 min L/S = 0.4 mL/g In.: 100% PH: 4.7-6.3 CDAc:
Calcium Deficient Apatite, commercial, Ca/P = 1.50; CT: cohesion
time (in min) In. set.: initial setting (in min) Fin set.: final
setting (in min) Inj.: injectability (capacity to be injected) pH
(start.-final): pH after preparation of slurry-pH after setting
(>8 hrs) (Liquid: chitosan-glycerophosphate-water, chitosan 1%
w/v);
[0252] CDAc: Calcium Deficient Apatite, commercial, Ca/P=1.50;
[0253] CT: cohesion time (in min) In. set.: initial setting (in
min) Fin set.: final setting (in min) Inj.: injectability (capacity
to be injected) pH (start.-final): pH after preparation of
slurry--pH after setting (>8 hrs) (Liquid:
chitosan-glycerophosphate-water, chitosan 1% w/v);
22TABLE 22 pH change of an alpha-TCP/Calcium Carbonate based
self-setting Composition Solid phase 1 2 3 4 Liquid Phase
CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 CaCO.sub.3 # (charge, % wt.) 5.9%
10.0% 9.15% 20.0% 1 .alpha.TCP 4.55 CDAc 15.0% (1.22) Citrate 9.0%
L/S = 0.4 mL/g 2 .alpha.TCP 4.94 CDAc 15.0% (0.33) Citrate 9.0% L/S
= 0.4 mL/g 3 .alpha.TCP 17.35 CDAc 15.0% (3.07) Citric ac. 11.7%
L/S = 0.4 mL/g 4 .alpha.TCP 12.85 CDAc 15.0% (3.96) Citric ac.
11.7% L/S = 0.4 mL/g CDAc: Calcium Deficient Apatite, commercial,
Ca/P = 1.50; ND: not determined; (): standard deviation
[0254] CDAc: Calcium Deficient Apatite, commercial, Ca/P=1.50;
[0255] ND: not determined; ( ): standard deviation
[0256] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practice within the art to which the
invention pertains and as may be applied to the essential features
hereinbefore set forth, and as follows in the scope of the appended
claims.
* * * * *