U.S. patent application number 10/557796 was filed with the patent office on 2008-06-26 for inorganic resorbable bone substitute material.
Invention is credited to Thomas Gerber.
Application Number | 20080152723 10/557796 |
Document ID | / |
Family ID | 33477513 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080152723 |
Kind Code |
A9 |
Gerber; Thomas |
June 26, 2008 |
Inorganic resorbable bone substitute material
Abstract
The invention relates in particular to a hydroxyl apatite/silica
granular material of defined morphology, a highly porous bone
substitute material based on this granular material and a glass
ceramic material based in turn thereon as bone substitute material
which is characterised by a variable mechanical strength, and
shaped bodies of this material, materials of different mechanical
strength being preferably used in the shaped body. The bone
substitute materials according to the invention are characterised
by a high resorbability in vivo.
Inventors: |
Gerber; Thomas; (Sildemow,
DE) |
Correspondence
Address: |
ARNOLD & PORTER LLP;ATTN: IP DOCKETING DEPT.
555 TWELFTH STREET, N.W.
WASHINGTON
DC
20004-1206
US
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20070059379 A1 |
March 15, 2007 |
|
|
Family ID: |
33477513 |
Appl. No.: |
10/557796 |
Filed: |
May 24, 2004 |
PCT Filed: |
May 24, 2004 |
PCT NO: |
PCT/EP04/05709 |
371 Date: |
August 25, 2006 |
Current U.S.
Class: |
424/602;
977/906 |
Current CPC
Class: |
A61L 2430/02 20130101;
A61P 19/10 20180101; A61L 27/58 20130101; A61L 27/12 20130101; A61L
27/427 20130101; A61L 27/56 20130101 |
Class at
Publication: |
424/602;
977/906 |
International
Class: |
A61K 33/42 20060101
A61K033/42 |
Foreign Application Data
Date |
Code |
Application Number |
May 22, 2003 |
DE |
10323079.3 |
Aug 22, 2003 |
DE |
10338634.3 |
Claims
1-61. (canceled)
62. A granular material comprising a crystalline calcium phosphate
embedded silica xerogel matrix, wherein said matrix comprises
calcium phosphate crystallites having a size of approximately 10 nm
to approximately 2000 nm and granule grains having a size of
approximately 1 .mu.m to approximately 1000 .mu.m, and the
proportion of said silica is approximately 2 to approximately 80%
by weight based on the total mass of said granule grains.
63. The granular material according to claim 62, wherein said
xerogel matrix comprises pores having an average diameter in the
region of 0.5 nm to 20 nm.
64. The granular material according to claim 62, wherein said
granule grains comprise pores that amount to approximately 10
volume % to approximately 60 volume %, based on the volume of the
granule grains.
65. The granular material according to claim 62, wherein the
calcium phosphate is hydroxyl apatite.
66. The granular material according to claim 62, wherein said
granular material further comprises soluble calcium phosphate.
67. The granular material according to claim 66, wherein said
soluble calcium phosphate is present in a proportion of
approximately 5% by weight to 50% by weight, based on the
proportion of calcium phosphate.
68. The granular material according to claim 66, wherein said
soluble calcium phosphate is .beta.-tricalcium phosphate.
69. The granular material according to claim 62, further comprising
a network modifier oxide.
70. The granular material according to claim 69, wherein the
network modifier oxide is present in a proportion of approximately
0.5 to approximately 35 mole %, based on the silica.
71. The granular material according to claim 70, wherein the
network modifier oxide is Na.sub.2O.
72. A highly porous bone substitute material comprising granule
grains of the granular material according to claim 62, wherein said
granule grains form a three-dimensional structure and said highly
porous bone substitute material exhibits pores that are
approximately the size of the granule grains.
73. The bone substitute material according to claim 72, wherein
said bone substitute material exhibits interconnecting macropores
in the region of approximately 100 .mu.m to several 1000 .mu.m.
74. The bone substitute material according to claim 72, wherein
said bone substitute material exhibits a total porosity of
approximately 30 to approximately 90 volume %.
75. The bone substitute material according to claim 72, wherein
said bone substitute material exhibits a fracture strength of
approximately 0.1 MPa to 15 MPa.
76. The bone substitute material according to claim 72, further
comprising a network modifier oxide.
77. The bone substitute material according to claim 76, wherein a
network modifier oxide is present in a proportion of approximately
0.5 to approximately 35 mole %, based on the silica.
78. The bone substitute material according to claim 76, wherein the
network modifier oxide is Na.sub.2O.
79. A bone substitute material comprising a crystalline calcium
phosphate embedded glass matrix, wherein said glass matrix
comprises approximately 2 to approximately 80% by weight of silica
based on the total mass of the bone substitute material and calcium
phosphate crystallites have a size of approximately 10 nm to
approximately 2000 nm.
80. The bone substitute material according to claim 79, further
comprising a network modifier oxide.
81. The bone substitute material according to claim 80, wherein the
network modifier oxide is present in a proportion of approximately
0.5 to approximately 35 mole %, based on the silica.
82. The bone substitute material according to claim 80, wherein the
network modifier oxide is Na.sub.2O.
83. The bone substitute material according to claim 79, wherein the
proportion of glass in the matrix is between 0 and 100 volume
%.
84. The bone substitute material according to claim 79, wherein
said glass matrix comprises sodium silicate.
85. The bone substitute material according to claim 79, wherein
said bone substitute material exhibits a mechanical strength of
approximately 30 MPa to 200 MPa.
86. The bone substitute material according to claim 79, wherein
said bone substitute material is a shaped body.
87. The bone substitute material according to claim 86, wherein
said shaped body is selected from the group consisting of a cube, a
plate, a hollow cylinder, or a wedge.
88. A shaped body of the porous bone substitute material according
to claim 72, wherein said shaped body comprises on at least one
side a layer of the bone substitute material comprising a
crystalline calcium phosphate embedded glass matrix, wherein said
glass matrix comprises approximately 2 to approximately 80% by
weight of silica based on the total mass of the bone substitute
material and calcium phosphate crystallites having a size of
approximately 10 nm to approximately 2000 nm, and said layer
further comprises holes with a diameter of approximately 0.5 to
approximately 5 mm which exhibit a proportion by volume of
approximately 5 to approximately 80% based on the total volume of
the layer and said holes are filled with a material selected from
the group of a granular material comprising a crystalline calcium
phosphate embedded silica xerogel matrix, wherein said matrix
comprises calcium phosphate crystallites having a size of
approximately 10 nm to approximately 2000 nm and granule grains
having a size of approximately 1 .mu.m to approximately 1000 .mu.m,
and the proportion of said silica is approximately 2 to
approximately 80% by weight based on the total mass of said granule
grains, a bone substitute material comprising a crystalline calcium
phosphate embedded silica xerogel matrix, wherein said matrix
comprises calcium phosphate crystallites having a size of
approximately 10 nm to approximately 2000 nm and granule grains
having a size of approximately 1 .mu.m to approximately 1000 .mu.m,
the proportion of said silica is approximately 2 to approximately
80% by weight based on the total mass of said granule grains, and
wherein said granule grains form a three-dimensional structure and
said bone substitute material exhibits pores that are approximately
the size of the granule grains, and combinations thereof.
89. A method of producing a shaped body using the granular material
according to claim 62.
90. The method according to claim 89, wherein said shaped body is
selected from the group consisting of a cube, a plate, a hollow
cylinder, and a wedge.
91. A method of coating implants using the granular material
according to claim 62.
92. The method according to claim 91, wherein said implant coating
is a plasma spray coating.
93. A method of stimulating healing of periodontal defects in a
patient, comprising mixing bone marrow fluid, the patient's own
blood, or saline with a granular material comprising a crystalline
calcium phosphate embedded silica xerogel matrix, wherein said
matrix comprises calcium phosphate crystallites having a size of
approximately 10 nm to approximately 2000 nm and granule grains
having a size of approximately 1 .mu.m to approximately 1000 .mu.m,
and the proportion of said silica is approximately 2 to
approximately 80% by weight based on the total mass of said granule
grains and implanting the mixture in said patient in need of
healing of periodontal defects.
94. A method of building up osteoporotic bone in a patient,
comprising mixing bone marrow fluid, the patient's own blood, or
saline with a granular material comprising a crystalline calcium
phosphate embedded silica xerogel matrix, wherein said matrix
comprises calcium phosphate crystallites having a size of
approximately 10 nm to approximately 2000 nm and granule grains
having a size of approximately 1 .mu.m to approximately 1000 .mu.m,
and the proportion of said silica is approximately 2 to
approximately 80% by weight based on the total mass of said granule
grains and implanting said mixture in said patient in need of
building up osteoporotic bone.
95. A medicine or medical product comprising a crystalline calcium
phosphate embedded silica xerogel matrix, wherein said matrix
comprises calcium phosphate crystallites having a size of
approximately 10 nm to approximately 2000 nm and granule grains
having a size of approximately 1 .mu.m to approximately 1000 .mu.m,
the proportion of said silica is approximately 2 to approximately
80% by weight based on the total mass of said granule grains, and
wherein said crystalline calcium phosphate embedded silica xerogel
matrix is mixed with bone marrow fluid or blood from a patient.
96. A method of producing a crystalline calcium phosphate embedded
silica xerogel matrix granular material, comprising: a)
precipitating hydroxyl apatite out of an aqueous solution wherein
said apatite has a Calcium/Phosphate ratio of 1.50 to 1.67; b)
forming crystallites of approximately 10 nm to approximately 2000
nm and granule grains of a size of approximately 1 .mu.m to
approximately 1000 .mu.m; c) forming a gel that has the
precipitated hydroxyl apatite homogenously embedded into a silicon
hydrogel without agglomerates in said aqueous solution; d) forming
a granulated hydrogel and subsequently; e) subjecting said hydrogel
to a drying process such that calcium phosphate crystallites are
embedded in a xerogel matrix.
97. The method of producing a crystalline calcium phosphate
embedded silica xerogel matrix granular material according to claim
96, wherein said hydrogel is stored in a closed vessel at room
temperature.
98. The method of producing a crystalline calcium phosphate
embedded silica xerogel matrix granular material according to claim
96, wherein the drying of said hydrogel is carried out at a
temperature of approximately 20.sup.0 C to approximately 150.sup.0
C.
99. A method of producing a granular material comprising
crystalline calcium phosphate embedded silica xerogel matrix
granular material, comprising: a) precipitating hydroxyl apatite
out of an aqueous solution wherein said apatite has a
Calcium/Phosphate ratio of 1.50 to 1.67; b) forming crystallites of
approximately 10 nm to approximately 2000 nm and granule grains of
a size of approximately 1 .mu.m to approximately 1000 .mu.m; c)
forming a gel that has the precipitated hydroxyl apatite
homogenously embedded into a silicon hydrogel without agglomerates
in said aqueous solution; and d) spray drying said aqueous solution
before gel formation.
100. A method of producing a crystalline calcium phosphate embedded
silica xerogel matrix granular material, comprising: a)
precipitating hydroxyl apatite out of an aqueous solution wherein
said apatite has a Calcium/Phosphate ratio of 1.50 to 1.67; b)
forming crystallites of approximately 10 nm to approximately 2000
nm and granule grains of a size of approximately 1 .mu.m to
approximately 1000 .mu.m; c) forming a gel that has the
precipitated hydroxyl apatite homogenously embedded into a silicon
hydrogel without agglomerates in said aqueous solution; d) cooling
said hydrogel to temperatures below the freezing point of the
solvent; and e) filtering the granular silica material and hydroxyl
apatite after said hydrogel is thawed.
101. The method of producing a crystalline calcium phosphate
embedded silica xerogel matrix granular material according to claim
96, comprising precipitating hydroxyl apatite with calcium nitrate
and ammonium hydrophosphate with a Calcium/Phosphate ratio of
1.67.
102. The method of producing a crystalline calcium phosphate
embedded silica xerogel matrix granular material according to claim
96, wherein the Calcium/Phosphate ratio of calcium nitrate and
ammonium hydrophosphate is equal to or more than 1.5 and less than
1.67 and the granular material comprises soluble .beta.-tricalcium
phosphate.
103. The method of producing a crystalline calcium phosphate
embedded silica xerogel matrix granular material according to claim
96, further comprising hydrolysed tetraethyl oxysilane to said
aqueous solution.
104. The method of producing a crystalline calcium phosphate
embedded silica xerogel matrix granular material according to claim
96, further comprising granular materials of 10 .mu.m or less by
altering the pressure, viscosity, and concentration.
105. The method of producing a crystalline calcium phosphate
embedded silica xerogel matrix granular material according to claim
104, wherein the kinematic viscosity is 0.5 to 50 cS.
106. A method of producing a highly porous bone substitute material
according to claim 72, comprising: a) precipitating hydroxyl
apatite out of an aqueous solution wherein said apatite has a
Calcium/Phosphate ratio of 1.50 to 1.67; b) forming crystallites of
approximately 10 nm to approximately 2000 nm and granule grains of
a size of approximately 1 .mu.m to approximately 1000 .mu.m; c)
forming a gel that has the precipitated hydroxyl apatite
homogenously embedded into a silicon hydrogel without agglomerates
in said aqueous solution; d) forming a granulated hydrogel; e)
subjecting said hydrogel to a drying process such that calcium
phosphate crystallites are embedded in a xerogel matrix and a
granule material is formed; f) stirring said granular material with
water to form a slip; g) adjusting the pH of said slip to between
approximately 2 and approximately 8; h) pouring said slip into a
mould; and i) drying said mould.
107. The method of producing a bone substitute material according
to claim 106, further comprising adding silicic acid to said
slip.
108. The method of producing a bone substitute material according
to claim 107, wherein said silicic acid is hydrolysed tetraethyl
oxysilane.
109. The method of producing a bone substitute material according
to claim 106, further comprising producing pore structures by
adding organic powder to said slip.
110. The method of producing a bone substitute material according
to claim 106, further comprising producing continuous pore
structures having a size of 100 .mu.m to the millimeter range by
adding organic fibers to said slip.
111. The method of producing a bone substitute material according
to claim 109, wherein said organic powder comprises wax.
112. The method of producing a bone substitute material according
to claim 111, further comprising drying said bone substitute
material at approximately 40.sup.0 C, subsequently burning the wax
residues, and removing the carbon formed during the reaction.
113. The method of producing a bone substitute material according
to claim 106, wherein said bone substitute material is treated at a
temperature of approximately 700.sup.0 C to approximately 900.sup.0
C if no network modifiers are present in the granular material or
are treated at a temperature of approximately 300.sup.0 C to
approximately 500.sup.0 C if network modifiers are present in said
granular material.
114. The method of producing a bone substitute material according
to claim 106, wherein a solution comprising network modifier oxides
is introduced into the pores of said bone substitute material such
that said network modifier oxides are present in a proportion of
approximately 0.5 to approximately 35 mole %, based on the
silica.
115. A method of producing a bone substitute material according to
claim 79, comprising: a) precipitating hydroxyl apatite out of an
aqueous solution wherein said apatite has a Calcium/Phosphate ratio
of 1.50 to 1.67; b) forming crystallites of approximately 10 nm to
approximately 2000 nm and granule grains of a size of approximately
1 .mu.m to approximately 1000 .mu.m; c) forming a gel that has the
precipitated hydroxyl apatite homogenously embedded into a silicon
hydrogel without agglomerates in said aqueous solution; d) forming
a granulated hydrogel; e) subjecting said hydrogel to a drying
process such that calcium phosphate crystallites are embedded in a
xerogel matrix and a granule material is formed; f) adding a
network modifier oxide to said granule material in a proportion of
approximately 0.5 to approximately 35 mole %, based on the silica;
g) stirring said granular material with water to form a slip; h)
adjusting the pH of said slip to between approximately 2 and
approximately 8; i) pouring said slip into a mould; j) drying said
mould thereby forming a highly porous bone substitute material; and
k) subjecting said highly porous bone substitute material to a
temperature treatment of approximately 350.sup.0 C to approximately
800.sup.0 C in order to convert the xerogel matrix into glass.
116. A method according to claim 115, comprising two granular
materials which differ by the proportion of the network
modifier.
117. A method according to claim 116, wherein one of said two
different granular materials comprises approximately 20 mol % of
Na.sub.2O, based on the xerogel, and the other granular material
does not contain Na.sub.2O.
118. A method according to claim 117, wherein said two different
granular materials are temperature treated at approximately
520.sup.0 C.
119. A method of producing the highly porous bone substitute
material according to claim 72.
120. The method according to claim 119, wherein said bone
substitute material is present in the form of small pieces.
121. The method according to claim 120, wherein said pieces are
cylinders with an average diameter of approximately 0.4 to
approximately 2 mm and a length of approximately 1 to approximately
6 mm.
122. A medicine or medical product comprising a bone substitute
material according to claim 72, wherein said bone substitute
material comprises pores that are filled with bone marrow fluid or
blood of a patient in need of treatment.
123. A method of stimulating bone build up, comprising mixing bone
marrow fluid, a patient's own blood, or saline with a granular
material comprising a crystalline calcium phosphate embedded silica
xerogel matrix, wherein said matrix comprises calcium phosphate
crystallites having a size of approximately 10 nm to approximately
2000 nm and granule grains having a size of approximately 1 .mu.m
to approximately 1000 .mu.m, and the proportion of said silica is
approximately 2 to approximately 80% by weight based on the total
mass of said granule grains and implanting the mixture in a patient
in need of said treatment.
124. The method of claim 123, wherein said implanting is at a
transition area of a loosened metal implant in said patient.
125. The method of claim 123, wherein said patient has
osteoporosis.
Description
[0001] The invention relates in particular to a granular hydroxyl
apatite/silica material of defined morphology, a highly porous bone
substitute material based on this granular material and a glass
ceramic material based thereon in turn as bone substitute material
which is characterised by a variable mechanical strength, and
shaped bodies of this material, materials of different mechanical
strength being preferably used in the shaped body. The bone
substitute materials according to the invention are characterised
by a high resorbability in vivo.
[0002] Bone grafts are the second most frequent type of transplant
in humans, second only to the administration of blood components
(Fox, R: New bone, The Lancet 339, 463 ff (1992)). Thus, 250,000
bone grafts were carried out in the USA in 1993 (Kenley et al:
Biotechnology and bone graft substitutes. Pharmaceut. Res. 10, 1393
(1993)). The replacement of congenital, post-traumatic and
osteoporotic bone defects occurring as a result of osteomyelitides
and tumour operations is of the utmost clinical significance since
a functionally comprehensive rehabilitation is possible only in
this way.
[0003] In the literature, numerous porous materials are described
as bone substitutes. In 1992, a ceramic material produced from
cattle bone was published, the entire organic matrix being removed
and the ceramic portion being annealed at temperatures of
1100.sup.0 C to 1500.sup.0 C (Bauer G, Vizethum, F., Process for
producing a bone substitute material. U.S. Pat. No. 5,133,756;
1992).
[0004] Some processes for the production of porous bone substitute
substances make use of the skeleton of natural corals (Pollick S,
Shors, E C, Holmes R E, Kraut R A. Bone formation and implant
degradation of coralline porous ceramics placed in bone and ectopic
sites. J. Oral Maxillofac Surg 1995; 53 (8): 915-23, White, E W.
Calcium phosphate bone substitute materials. U.S. Pat. No.
4,861,733; 1989) which exhibit an ideal pore structure (size
distribution, morphology) for the ingrowth of the bone tissue.
[0005] The decisive disadvantage of these ceramic materials is that
they are not resorbable (Jenssen S S, Aaboe M, Pinholt E M,
Hjorting-Hansen E, Melsen F, Ruyter I E. Tissue reaction and
material characteristics of four bone substitutes. Int J Oral
Maxillofac Implants. 1996; 11 (1): 55-66). The bone formed is
subject to continual restructuring, also called remodelling,
osteoclasts degrading the bone and osteoblasts rebuilding it. For
the materials described, this means that the bone tissue grows
excellently into the pore structure while the highly crystalline
hydroxyl apatite of the ceramic material, however, no longer
participates in bone remodelling. For this reason, it remains a
foreign body and unfavourably influences the mechanical properties
of the bone regenerate. In addition, an inflammation reaction
occurs in the interface area between the tissue and the ceramic
material (Gunther K P, Scharf H-P, Pesch H-J, Puhl W.
Einwachsverhalten von Knochenersatzstoffen (Ingrowth behaviour of
bone substitute materials) Orthopadie 1998; 27: 105-117, Sailer J
D, Weber F R. Knochenersatzmaterialien (Bone substitute materials)
Mund Kiefer Gesichts Chir 2000; 4 (Suppl. 1) 384-391).
[0006] Porous materials based on hydroxyl apatite (HA) are an ideal
bone substitute since they promote tissue regeneration as a result
of a special surface characteristic. However, in the literature, it
is generally stated that these ceramic materials do not have an
osteoinductive effect in the actual sense (Heymann D, Delecrin J,
Deschamps C, Gouin, F Padrines M, Passuti N. In vitro assessment of
associating osteogenic cells with macroporous calcium-phosphate
ceramics. Rev Chir Orthop Reparatrice Appar Mot 2001; 87 (1): 8-17,
Osborne J F, Newesely H. The material science of calcium phosphate
ceramics. Biomaterials 1980; 1: 108-112, Vuola J, Taurio R,
Goransson H, Asko-Seljavaara S. Compressive strength of calcium
carbonate and hydroxy apatite implants after bone-marrow-induced
osteogenesis. Biomaterials 1998; 19 (1-3): 223-7). Instead, close
fitting bonding to the bone takes place as a result of protein
adsorption and the addition of osteoblasts to a primary biological
apatite layer covering the implant (De Bruijn J D, Klein C P A T,
De Groot K, Van Blitterswijk C A. Ultrastructure of the
bone-hydroxyl apatite interface in vitro. J Biomed Mater Res. 1992;
26: 1365-1382, Donath K, Hormann, K, Kirsch A. Welchen Einfluss hat
Hydroxylapatitkeramik auf die Knochenbildung? (Which influence does
the hydroxyl apatite ceramic material have on bone formation?)
Dtsch Z Mund Kiefer Gesichtschir. 1985; 9 (6): 438-40).
[0007] Yuan et al., on the other hand (Yuan H, Kurashina K, de
Bruijn J D, Li Y, de Groot K, Zhang X. A preliminary study on
osteoinduction of two kinds of calcium phosphate ceramics.
Biomaterials 1999; 20 (19): 1799-806) has found that it is possible
to induce osteoinductive properties as a function of the
microstructure of the ceramic material with an identical chemical
and crystallographic structure of the calcium phosphate.
[0008] This means that these materials are capable of inducing a
dystopic bone formation, for example when they are implanted under
the skin or into the muscle tissue where no other osteoinductive
stimuli are present. These osteoinductive properties (bone
formation in extraosseal sites) is also caused in various hydroxyl
apatite ceramics (HA ceramics) if they have been saturated with
bone marrow cells (Heymann D, Delecrin J, Deschamps C, Gouin F
Padrines M, Passuti N. In vitro assessment of associating
osteogenic cells with macroporous calcium-phosphate ceramics. Rev
Chir Orthop Reparatrice Appar Mot 2001; 87 (1): 8-17, Vuola J,
Taurio R, Goransson H, Asko-Seljavaara S. Compressive strength of
calcium carbonate and hydroxy apatite implants after
bone-marrow-induced osteogenesis. Biomaterials 1998; 19 (1-3):
223-7).
[0009] Dagulsi describes the cell reaction, biodegradation and
bioresorption as well as the transformation to carbonate hydroxyl
apatite of a two-phase material (HA/TCP) which has been used as
shaped body, coating as well as injectable bone substitute material
(Dagulsi G. Biphasic calcium phosphate concept applied to
artificial bone, implant coating and injectable bone substitute.
1998, 19 (16): 1473-8).
[0010] Within the framework of the development of a resorbable bone
substitute substance, the influence of different calcium phosphates
and combinations of calcium phosphates on the development of
osteoblasts was examined in vitro. In a comparative study, Oonishi
et al implanted different bioceramic materials into the condyle of
the femur of adult Japanese white rabbits and indicate the
following resorption activities as being the result: HA with a low
degree of crystallinity, OCP>TeCP, TeDCPD, TeDCPA>.alpha.TCP,
.beta.TCP (Oonishi H, Hench L L, Wilson J, Sugihara F, Tsuji E,
Kushitani S, Iwaki H. Comparative bone growth behaviour in granules
of bioceramic materials of various sizes. J Biomed Mater Res 1999:
44 (1): 31-43).
[0011] Sun et al found that a combination of hydroxyl apatite and
.beta.-tricalcium phosphate (.beta.TCP) has an inhibiting effect on
the growth of the osteoblasts. The effect of calcium phosphate
particles on the growth of osteoblasts (Sun J S, Tsuang Y H, Liao C
J, Lui, HC, Hang, F K. The effects of calcium phosphate particles
on the growth of osteoblasts. J Biomed Mater Res 1997; 37 (3):
324-334).
[0012] The influence of different resorbable ceramics such as e.g.
CaNaPO.sub.4, CaNaPO.sub.4+MgNaPO.sub.4,
CaNaPO.sub.4+Mg.sub.2SiO.sub.4, among others, on the growth of the
osteoblasts was investigated in vitro (Knabe C, Gildenhaar R,
Berger G, Ostapowicz W, Fitzner R, Radlanski R J, Gross U.
Morphological evaluation of osteoblasts cultured on different
calcium phosphate ceramics. Biomaterials 1997; 18 (20): 1339-1347).
The best support for the growth of osteoblasts was found with
CaNaPO.sub.4+MgNaPO.sub.4 and Ca.sub.2KNa(PO.sub.4).sub.2. If too
many Ca.sup.2+ ions are released by the ceramic material, cell
growth is inhibited.
[0013] In a study of the condyles of the femur of fully grown
rabbits, Oonishi et al compare the ingrowth behaviour of granules
of a bioglass and synthetic temperature-treated hydroxyl apatite
(Oonishi H, Hench L L, Wilson J, Sugihara F, Tsuji E, Matsuura M,
Kin S, Yamamoto T, Mizokawa S. Quantitative comparison of bone
growth behaviour in granules of bioglass, A-W glass-ceramic, and
hydroxy apatite. J Biomed Mater Res 2000; 51 (1): 37-46). In
contrast to bioglass, synthetic hydroxyl apatite is not completely
resorbed.
[0014] Bioactive types of glass are also described as bone
substitute material (U.S. Pat. No. 6,054,400; 2000; U.S. Pat. No.
5,658,332; 1997). In this case, the inorganic material is present
as a glassy solid. Pores of the order of magnitude of the spongy
bone allow an ingrowth of the tissue. Smaller pores are not present
in the material.
[0015] Glass ceramics, too, are offered as bone substitute (e.g.
U.S. Pat. No. 5,981,412; 1999). They can be compared to the
bioactive types of glass, a crystalline component such as e.g.
Na.sub.2O2CaO-3SiO.sub.2 being incorporated into the glass matrix
which, in general, is a bioactive calcium silicate glass.
[0016] As a further substance group for use a bone substitute,
calcium phosphate cements have been developed (U.S. Pat. No.
5,997,624; 1999; U.S. Pat. No. 5,525,148; 1996). A decisive
disadvantage of this group of substances is that no defined
interconnecting pores are introduced into the material as a result
of which they are restricted to very small bone defects.
[0017] In the patents DE 198 25 419 and DE 100 03 824, processes
have been described by means of which highly porous calcium
phosphate ceramic materials based on hydroxyl apatite can be
produced by means of the sol-gel technique, which are intended
specifically for filling and the reconstruction of bone defects of
different size. The processes aim at producing highly porous
structures. Using the process of patent DE 198 25 419, a porosity
of up to 70% is achieved, the pores being in the range of 1-10
micrometers. In patent DE 100 03 824, a process is described which,
additionally, produces a pore structure of the order of magnitude
of 0.1 to approximately 1 millimetre, such as that which is present
also in natural spongiosa.
[0018] In DE 100 60 036, an inorganic resorbable bone substitute
material is described which possesses a loose crystal structure,
i.e. the crystallites are not tightly joined as in a solid body
(ceramic material) but connected only via some groups of molecules.
The volume which, in the natural bone, is taken up by collagen, is
present in the material as interconnecting pores in the nanometre
region. A second pore size, which is also interconnecting and in
the region of a few micrometers, permits an ingrowth of collagen
fibres during tissue formation. These fibres are nucleators for the
starting biomineralisation (formation of the body-inherent
biological apatite). The material contains a third interconnecting
pore category which imitates the spongiosa, is in the region of
approximately 100 .mu.m to 1000 .mu.m and consequently allows
ingrowth of blood vessels as a result of which resorption and
renewed bone formation occurs not only as a front of healthy bone
but also out of the entire defect.
[0019] In the case of this material, the promotion of osteogenesis
and the resorption property is in the foreground so that
remodelling of the bone is supported.
[0020] In the relevant specialist literature, it is pointed out
that bone substitute materials based on hydroxyl apatite are
practically not resorbed and permanently represent a foreign body.
In contrast to this, the material described in DE 100 60 036 which
consists essentially of hydroxyl apatite is highly satisfactorily
resorbed and, simultaneously, accelerates the renewed formation of
bone tissue. This property is determined by the loose crystal
structure of calcium phosphates described.
[0021] The mechanical strength of this material, however, is
relatively low. It cannot exercise any mechanical support function.
In addition, the possibilities of varying the bone substitute
material in order to be able to use it for replacing entire bone
fragments (e.g. parts of a tubular bone) are very limited.
[0022] In reconstructive surgery and in orthopaedic surgery, bone
substitute materials which contain components with a higher
mechanical strength are required in particular for relatively large
defects. In connection with computer tomography on the patient and
computer-supported production, substitute parts of the cranial
bone, for example, can be formed as an imitation.
[0023] In contrast, the present invention is based on the task of
providing a bone substitute which promotes a formation of bone
tissue (which is thus osteoconductive and/or osteoinductive) which
is resorbed via the natural processes of bone remodelling and
possesses a mechanical strength which can correspondingly be
adapted to the different applications. Defects in the bone, which
may arise e.g. as a result of inflammation, are usually surrounded
on several sides by healthy bone. For these defects, the mechanical
strength of the bone substitute material is insignificant. If,
however, entire bone segments are missing as a result of a
comminuted fracture or the removal of a bone tumour, the bone
substitute material must exert a supporting function. In this case,
a substitute bone is made from the bone substitute material (e.g. a
hollow cylinder for a missing piece of tubular bone) which is then
screwed with osteosynthesis plates (metal plates which are removed
after healing) to the remaining bone. The support function is now
assumed by the system of substitute bone of bone substitute
material and the osteosynthesis plate. Since it is certain that an
increased mechanical strength leads to a reduced resorption, a
compromise needs to be made regarding the material properties,
depending on the size of the defect and the mechanical stress.
[0024] To solve the task, granular materials, highly porous bone
substitute materials based on these granular materials, glass
ceramic materials based thereon as bone substitute materials with a
variable mechanical strength, uses, means, shaped bodies, processes
etc. are proposed. For solution purposes, the products of the
attached claims 1 to 27, 34 and 61, in particular, the processes of
the attached claims 35 to 57 and the use of the attached claim 28
to 33 and 58 to 60 are proposed.
[0025] According to the invention, the task is thus achieved by way
of a material which contains crystalline calcium phosphate embedded
in a xerogel matrix. This xerogel matrix consists of silica.
[0026] Xerogel is a dry gel which is characterised by a large
internal surface area and incomplete crosslinking of the structural
groups.
[0027] In this way a completely new type of material is available
which is comparable with a glass ceramic material, the matrix
containing the crystalline components not being glass in this case
but a xerogel with its typical porous structure. The xerogel matrix
should preferably occupy a proportion by weight of 4 to 80%, based
on the total mass of the bone substitute material. Since a silica
xerogel is a porous material in which SiO.sub.4/2 tetrahedra are
loosely joined and which has a large internal surface area with
--SiOH groups, it is possible to build a matrix even with low
proportions by weight, as a function of the size of the
crystallites of the calcium phosphate, which matrix encloses the
crystalline components. A reduction of the proportion of the matrix
to less than 5% by weight is possible as a function of the size of
the crystallites.
[0028] The xerogel matrix has different tasks. On the one hand, it
obviously binds the crystalline components of the material
together. The mechanical strength of the material is limited by the
relatively loose joining of the silica. The fracture strength is
typically in the region of 2 to 15 MPa (compare example 6). On the
other hand, the porosity of the xerogel allows the resorption of
the biomaterial and improves the bioactivity which is obviously
produced above all by the calcium phosphate components by
body-inherent proteins from the blood of the patient attaching
themselves to the high internal surface. Consequently, the cells do
not classify the biomaterial as foreign to the body.
[0029] Consequently, the subject matter of the invention is a
granular material and a group of bone substitute materials based
thereon which will be described below. The granular material is
based on calcium phosphate in which crystalline calcium phosphate
is embedded in a silica xerogel matrix, the crystallites having an
average diameter of approximately 10 nm to approximately 2000 nm,
preferably of 10 nm to 200 nm, wherein platelet-type crystallites
with a thickness of 2.5 nm to 10 nm and an average diameter of 10
nm to 200 nm are particularly preferably contained therein. The
granule grains exhibit an average diameter of approximately 1 .mu.m
to approximately 1000 .mu.m, and the proportion of silica is in the
region of approximately 2 to approximately 80% by weight,
preferably in the region of approximately 4 to approximately 50% by
weight.
[0030] The pores in the xerogel exhibit an average diameter in the
region of 0.5 nm to 20 nm. They represent approximately 10% by
volume to approximately 60% by volume, based on the volume of the
granule grain, in the granule grains.
[0031] Preferably, the calcium phosphate is hydroxyl apatite.
[0032] In a particular embodiment, the granular material can,
moreover comprise soluble calcium phosphate, the soluble calcium
phosphate being preferably present in a proportion of approximately
5% by weight to 50% by weight, based on the proportion of calcium
phosphate. The soluble calcium phosphate is .beta.-tricalcium
phosphate (.beta.TCP), in particular.
[0033] The xerogel of the granular material can, moreover, comprise
one or several network modifier oxides. The network modifier
oxide(s) is/are preferably present in a proportion of approximately
0.5 to approximately 35 mole %, preferably in a proportion of
approximately 17 mole % to approximately 30 mole %, based on
silica. The network modifier is in particular Na.sub.2O.
[0034] In FIG. 1, a granule particle according to the invention is
represented diagrammatically as an example. The crystallites (shown
in black) in the granular material are held together by the
SiO.sub.2 xerogel (shown in grey). At the surface of the granule
particles, SiO.sub.2 xerogel is present.
[0035] It should be briefly noted that a granule grain from the
preferred range of magnitude with a diameter of e.g. 1 .mu.m
contains crystallites of the order of magnitude of 104 if these are
e.g. platelets with a diameter of 100 nm and thickness of 10 nm and
the xerogel matrix takes up 40% by weight of the granule grain.
[0036] On the basis of the granular hydroxyl apatite/silica
material described, a highly porous bone substitute material as
well as a glass ceramic material are obtained as bone substitute
material with variable mechanical strength.
[0037] The starting point is a highly porous bone substitute
material which is characterised in that the granule grains are
bound together via the xerogel matrix and as a result of the
packing of the granule grains, pores are formed which are of the
order of magnitude of the granule grains. The highly porous bone
substitute material consequently has two categories of pores.
[0038] Apart from the pores just described which are formed by the
packing of the granule grains and are consequently in the
micrometer region, the pores which are within the granular material
and which have been described above are also present. These are the
pores in the xerogel which exhibit an average diameter in the
region of 0.5 nm to 20 nm.
[0039] Consequently, a porosity of preferably approximately 30% by
volume to approximately 80% by volume is present in the highly
porous bone substitute material.
[0040] In FIG. 2, the structure of the highly porous bone
substitute material is shown diagrammatically. An essential
difference in comparison with bone substitute material of the state
of the art consists in that the interior of the granule particles
(i.e. the crystallites) is held together in a defined manner by
SiO.sub.2. The structure can be described in such a way that every
individual crystallite is present in a xerogel matrix. The product
can be obtained by partly conventional ceramic manufacturing
processes when using the granular material described, as will be
described in further detail below.
[0041] Moreover, the invention relates to a highly porous bone
substitute material which comprises granule grains of the
above-mentioned granular material which form a 3-dimensional
structure which, apart from the pores present in the granule
grains, also exhibits pores of approximately the size of the
granule grains. Consequently, the pore diameter is in the region of
approximately 1 .mu.m to approximately 1000 .mu.m, preferably in
the region of approximately 1 .mu.m to approximately 50 .mu.m.
[0042] Small pieces (e.g. shaped bodies, particles, parts) of this
highly porous bone substitute material, preferably in the form of
cylinders with an average diameter of approximately 0.4 to
approximately 2 mm and a length of approximately 1 to approximately
6 mm are used to fill small bone defects, preferably up to a size
of 10 cm.sup.3, in particular if the defects are surrounded on two
sides by healthy bone.
[0043] Consequently, the invention also relates to a highly porous
bone substitute material which is characterised in that it
exhibits, moreover (i.e. additionally to the pores within the
individual granule grains and additionally to the pores which are
formed by the (3-dimensional) granule grain packing)
interconnecting macropores in the region of approximately 100 .mu.m
up to several 1000 .mu.m which have a volume proportion of
approximately 10 vol % to approximately 60 vol %. Consequently, the
highly porous bone substitute material preferably has an overall
porosity of approximately 30 vol % to approximately 90 vol %,
particularly preferably an overall porosity of approximately 60 vol
% to approximately 80 vol %.
[0044] The fracture strength of the highly porous bone substitute
material without the macropores described amounts to approximately
2 MPa to approximately 15 MPa, preferably approximately 3 to
approximately 10 MPa. As a result of the macropores, the fracture
strength of the material decreases and reaches values of only 0.1
MPa to 4 MPa.
[0045] According to a particularly preferred embodiment, the highly
porous bone substitute material also contains one or several
network modifier oxides. The network modifier oxide(s) is/are
preferably present in a proportion of approximately 0.5 to
approximately 35 mole %, preferably in a proportion of
approximately 17 to approximately 30 mole %, based on the silica.
Na.sub.2O is particularly preferred.
[0046] Moreover, the invention relates to a glass ceramic material
as bone substitute material (or -expressed differently, a bone
substitute material comprising a glass matrix) which is
characterised in that crystalline calcium phosphate is embedded
into a glass matrix, the crystallites exhibiting a size of
approximately 10 nm to approximately 2000 nm and the proportion of
glass being in the region of approximately 4 to approximately 80%
by weight (based on the total mass of the material), preferably in
the region of approximately 2 to approximately 50% by weight, the
glass containing silica as network modifier. Like the highly porous
bone substitute material, the bone substitute material can also
comprise one or several network modifiers. To avoid repetitions,
reference is made with respect to the network modifier oxides to
the full extent to the corresponding details provided above which
apply equally to the bone substitute material described here.
[0047] The glass ceramic material according to the invention as
bone substitute material is obtainable from an above-mentioned
highly porous bone substitute material by converting the silica
xerogel matrix with the network modifier, preferably sodium oxide,
into the glassy state.
[0048] By way of this modification process, the nanoporous xerogel
turns into a completely linked glass network which, having a
fracture strength of approximately 300 MPa to approximately 400
MPa, increases the mechanical stability of the bone substitute
material. The fracture strength of the bone substitute material
described is dependent on the residual porosity described below
such that the theoretical values are not achieved.
[0049] Consequently, the invention relates also to a bone
substitute material in the case of which the glass matrix consists
of sodium silicate. Preferably, it has a mechanical strength in the
region of approximately 30 MPa to approximately 200 MPa, preferably
approximately 50 MPa to approximately 120 MPa and exhibits a
residual porosity of approximately 5 to approximately 35%, the
pores having a diameter in the region of approximately 1 .mu.m to
approximately 200 .mu.m.
[0050] FIG. 3 shows the structure of the glass ceramic material
diagrammatically. The calcium phosphate crystallites drawn in black
have an identical structure to highly porous bone substitute
material; however, they are now present in a glass matrix which is
shown in grey. The residual porosity has not been represented in
the diagrammatic representation.
[0051] The process of converting gel into glass is associated with
sintering of the highly porous bone substitute material. The
nanoporosity is completely eliminated and the described porosity in
the micrometer region is reduced such that a residual porosity of
approximately 2 to approximately 35 vol % is retained.
[0052] As a result of the described proportion of calcium phosphate
in the glass matrix, the material is biocompatible. The process of
resorption, however, has changed completely since no nanoporosity
has remained.
[0053] Since the glass matrix preferably consists of sodium
silicate glass, the sodium ions are dissolved slowly when the glass
ceramic material is used as bone substitute material and the glass
is converted into a gel-type structure with nanopores. The residual
porosity in the micrometer region increases this effect. As a
result of this process, a resorption of this bone substitute
material is possible in the end.
[0054] Insofar as the process of the transition of the xerogel
matrix of the highly porous bone substitute material described into
the glass matrix takes place only partially, a bone substitute
material can be obtained which can be adjusted regarding the
mechanical properties and the resorption properties continually
between the two extremes, namely the highly porous bone substitute
material and the glass ceramic material as bone substitute
material.
[0055] (Consequently), the invention relates to a bone substitute
material which is characterised in that crystalline calcium
phosphate is embedded into a matrix, the crystallites having a size
of approximately 10 nm to approximately 2000 nm, the matrix
consisting of a xerogel and of a glass, the proportion of glass of
the matrix being between 0 and 100 vol %, preferably approximately
10 vol % to approximately 80 vol % and particularly preferably
between approximately 60 vol % and approximately 80 vol %, xerogel
and glass consisting of silica and a network modifier, preferably
in a proportion of approximately 0.5 to approximately 35 vol %,
preferably in a proportion of approximately 17 vol % to
approximately 30 vol %, based on the silica, the network modifier
preferably being sodium oxide and the matrix being in the region of
approximately 2 to approximately 80% by weight, preferably in the
region of approximately 4 to approximately 50% by weight of the
bone substitute material.
[0056] The partial transition from xerogel to glass is achievable
by heat treatment. Since the glass temperature of sodium silicate
glass is in the region of approximately 460.sup.0 C to
approximately 800.sup.0 C, depending on the sodium content, it is
clear that a heat treatment at above this temperature range leads
very rapidly to glass. It a temperature treatment is carried out
approximately 20% to approximately 5% below the glass temperature
determined for the composition, the process is slowed down and
requires several hours and can be broken off at any time.
[0057] A second possibility of carrying out the transition of
xerogel to glass only partially consists of the use of two granular
calcium phosphate/silica materials described above which differ by
their proportion of network modifier. Preferably, a granular
material without network modifier (Na.sub.2O) and a granular
material with approximately 20 mol % Na.sub.2O, based on the
xerogel, are selected. The highly porous bone substitute material
is produced from these granular materials according to the process
described below. If, subsequently, a heat treatment at
approximately 520.sup.0 C is carried out, the areas with the
Na.sub.2O are converted into the glassy state, the areas without
any Na.sub.2O remain in the state of the xerogel since temperatures
of approximately 1000.sup.0 C are required here.
[0058] According to a particular embodiment, the bone substitute
material is a shaped body, in particular a cube, a plate, a hollow
cylinder or a wedge.
[0059] Consequently, the subject matter of the invention is also a
shaped body of the highly porous bone substitute material described
which, on at least one side, comprises a layer of a bone substitute
material mentioned above with a higher mechanical strength,
preferably the glass ceramic material described, holes with a
diameter if approximately 0.5 to approximately 5 mm being contained
in this layer which holes exhibit a proportion by volume of
approximately 5 to approximately 80%, based on the total volume of
the layer, and these holes in turn being filled with the
above-mentioned granular material and/or with the above-mentioned
highly porous bone substitute material.
[0060] In the case of processes for the production of the materials
described above which are, moreover, a subject matter of the
invention, the starting point is the production of a granular
calcium phosphate material which is characterised in that the
crystallites are present in a xerogel matrix as described. Starting
out from this granular material, the highly porous bone substitute
material is produced which, in turn is a precondition for the
production of the glass ceramic material as bone substitute
material.
[0061] According to the invention, the production of the calcium
phosphate is combined with a gel formation process of the silica
during the production of the silica-containing granular material,
via a precipitation reaction during which a so-called slip is
formed. Only in this way can separate nanocrystallites be
incorporated into a xerogel matrix. The granular silica-containing
calcium phosphate materials are preferably hydroxyl apatite/silica
granular material comprising optionally also soluble calcium
phosphate.
[0062] In general, the synthesis for the production of calcium
phosphates and also in particular of hydroxyl apatite takes place
in an aqueous solution (C. P. A. T Klein, J. M. A. De
Blieck-Hogerworst, J. G. C. Wolke, K. De Groot, Biomaterials, 11,
509 (1190)). The hydroxyl apatite synthesis can take place in an
alkaline medium and provides thermally stable pure phase
crystallites (M. Asada, Y. Miura, A. Osaka, K. Oukami, S. Nakamura,
J. Mat. Sci. 23, 3202 (1988); S. Lazic, J. Cryst. Growth, 147, 147
(1995)). The hydroxyl apatite synthesis in a neutral or slightly
acidic environment is also possible but more difficult to control
(H. E. L. Madsen, G. Thodvadarson, J. Cryst. Growth, 66, 369
(1984)).
[0063] The starting point is e.g. calcium nitrate and ammonium
hydrophosphate with a ratio of calcium to phosphate of 10:6 if
hydroxyl apatite is to be obtained (U.S. Pat. No. 5,858,318). Other
starting materials are NaHCO.sub.3 and CaHPO.sub.4 (Th. Leventouri,
H. Y. Moghaddam, N. Papanearchou, C. E. Bunaciu, R. L. Levinson, O.
Martinez, Mat. Res. Soc. Symp. Proc. 599, 79 (2000)) or
Ca(H.sub.2PO.sub.4) and CaCl.sub.2 (M. Okido, R. Ichina, K. Kuroda,
R. Ohsawa, O. Takai, Mat. Res. Soc. Symp. Proc. 599, 153 (2000)).
Here, too, a ratio of calcium to phosphorus of 1.67 is chosen when
hydroxyl apatite is to be obtained.
[0064] It is also possible to carry out the precipitation reaction
with lime milk and phosphoric acid (DE 42, 32 443 C1, U.S. Pat. No.
4,274,879). If hydroxyl apatite, for example, is produced via these
starting materials, which can in turn be controlled by the ratio of
calcium to phosphorus of the starting products, dicalcium phosphate
is frequently formed as by-product, which is undesirable. It is
also advantageous to start out from pure soluble starting products
and not to use lime milk (a dispersion).
[0065] In the quoted literature it is described how the parameters
of pH, homogeneity of the mixture of the starting products and
temperature influence the size of the crystallites and the degree
of crystallinity of the end products. The connection between the pH
and the temperature of the solution, in particular, is important
(M. Okido, R. Ichina, K. Kuroda, R. Ohsawa, O. Takai, Mat. Res.
Soc. Symp. Proc. 599, 153 (2000)). It is remarkable that hydroxyl
apatite precipitates out in almost all solutions in a finely
crystalline manner, i.e. as nanocrystallites and that, for certain
applications e.g. as cleaning body in dental care, there is a
search under way for process steps leading instead to larger
crystallites (DE 43 32 443 C1).
[0066] The quantities of the starting products are selected in such
a way that a ratio of Ca/P of 1.50 to 1.67 arises. The
precipitation product in this range is always a so-called
"precipitated hydroxy apatite" (PHA,
Ca.sub.10-x(HPO.sub.4).sub.x(PO.sub.4).sub.6-x(OH).sub.2-x). In the
course of further treatment which includes also temperature
treatments, hydroxyl apatite is formed completely from the
"precipitated hydroxy apatite" at temperatures above approximately
650.sup.0 C if the ratio of calcium to phosphate (ratio of Ca/P) is
precisely 1.67. With a ratio of Ca/P of 1.5, almost the entire
hydroxyl apatite is converted into .beta.-tricalcium phosphate. By
way of a Ca/P ratio of between 1.5 and 1.67, a mixture of
.beta.-tricalcium phosphate and hydroxyl apatite is obtained whose
final composition is adjusted by the Ca/P ratio. A Ca/P ratio of
1.67 is preferably chosen in order to preferably obtain hydroxyl
apatite in the granular material exclusively. If a soluble calcium
phosphate (for the in vivo application, the pH value is 7) is to be
contained in the granular material, a Ca/P ratio of less than 1.67
is chosen and the soluble .beta.-tricalcium phosphate is formed in
the course of the process.
[0067] The crystals in the solution tend to agglomerate. If the
solid is isolated after precipitation the agglomeration of the
crystals, in particular the nanocrystals, is unavoidable (DE 42 32
443 C1). Consequently, granular materials are formed from calcium
phosphate crystallites from which the granular material according
to the invention, in which crystallites are present in a xerogel
matrix, can no longer be obtained.
[0068] According to the invention, this problem is solved by
homogenising the solution with the precipitated calcium phosphate
by stirring and supplying a highly concentrated silicic acid
solution, orthosilicic acid being preferably used. Preferably,
tetraethyl oxysilane (TEOS) is used which is hydrolysed completely.
For this purpose, TEOS and 0.1 molar hydrochloric acid are
preferably mixed in a preferred volume ratio of 30:9 with strong
stirring until hydrolysis occurs. The water necessary for
hydrolysis is provided by the hydrochloric acid solution.
[0069] The ratio of calcium phosphate in the precipitated solution
and the silicic acid added is selected in such a way that a
composition of the granular material according to the invention of
approximately 2% by weight to approximately 80% by weight of silica
is obtained. It should be noted in particular in this context that
270 g of silica are formed from 1 litre of TEOS. Should a granular
material, for example, be obtained which contains 30% by weight of
silica, 43 g of silica are required for a solution with 100 g of
calcium phosphate which in turn means that approximately 160 ml of
TEOS are used. This is independent of how much solvent is contained
in the precipitated solution.
[0070] According to the invention, the pH of the mixture of
precipitated calcium phosphate and silicic acid is adjusted within
a range of approximately 2 to approximately 8, preferably in a
range of approximately 5 to approximately 6.5.
[0071] The silicic acid in the slip begins to condense and the
viscosity of the mixture consequently to rise. Up to a viscosity of
preferably 210.sup.5 cP, sedimentation of calcium phosphates is
prevented in the mixture by stirring.
[0072] As a result of the beginning gel formation of the silica,
the mixture is fixed. The calcium phosphate crystallites are then
present in a matrix of silica hydrogel. By removing the solvent,
the hydrogel matrix becomes the xerogel matrix according to the
invention. Since a granular material according to the invention has
a granule grain size of approximately 1 .mu.m to approximately 1000
.mu.m, comminution is necessary. This comminution preferably takes
place in the hydrogel state.
[0073] The hydrogel is then stored in a closed vessel, preferably
at room temperature (if necessary also at temperatures of
approximately 60.sup.0 C to approximately 80.sup.0 C), preferably
over a period of approximately 24 h to 48 h. During this period,
ageing of the silica gel takes place, i.e. further condensation
reactions take place in the solid gel.
[0074] Subsequently, the gel with the calcium phosphate is dried in
order to remove solvent. The drying temperature is preferably
approximately 20.sup.0 C to approximately 150.sup.0 C, preferably
drying is carried out at approximately 120.sup.0 C.
[0075] By freezing the moist hydrogel, a granular calcium
phosphate/silica material (granular hydroxyl apatite/silica
material) is also obtained according to the invention. As a result
of the crystallisation of the water, the calcium phosphate and
silica of the hydrogel are compressed and granular material is thus
formed which can be filtered off after thawing of the ice. The
granular material filtered off is preferably dried at approximately
20.sup.0 C to approximate 150.sup.0 C, preferably at approximately
120.sup.0 C.
[0076] A particular embodiment of the production, according to the
invention, of the granular material is characterised in that the
mixture of precipitated calcium phosphate and silica whose pH is
adjusted within a range of approximately 2 to approximately 8,
preferably in a range of approximately 5 to approximately 6.5, is
spray dried before the gel formation which has the advantage that
granule grain sizes in the region according to the invention are
obtainable in a simple manner.
[0077] Spray drying is a process known in the state of the art
(compare e.g. K. Masters, "Spray Drying", 2.sup.nd ed., John Wiley
& Sons, New York, 1976).
[0078] During spray drying, liquid products are atomised into fine
droplets at the upper end of the drying tower. The droplets are
dried while falling freely through a stream of hot air in the
tower. The temperature of the stream of hot air is between
approximately 80.sup.0 C and approximately 200.sup.0 C and acts
onto the products only for a period of half to one second. After
freeze drying, spray drying is the second most gentle industrially
used drying method, in particular in the food industry.
[0079] If, as a result of the beginning condensation of the silicic
acid, a kinematic viscosity of preferably 0.5 to 10 cst is
achieved, the mixture is spray dried, the pressure being adjusted
to the concentration and the viscosity in such a way that granular
materials of 10 .mu.m and smaller are formed (compare in this
respect Masters, Spray Drying Handbook, (1979) George Godwin
Ltd;).
[0080] As a result of the evaporation of the solvent gel formation
is achieved and a transition from the wet gel to xerogel initiated.
Spray drying has the effect that, as a result of gel formation of
the small droplets and drying of the small droplets, granule grains
of a corresponding size are formed.
[0081] The granular material is characterised in that the calcium
phosphate crystallites (preferably HA crystallites) are held
together by a porous silica gel.
[0082] A characterisation of the granular material is effected by
electron microscopy and photocorrelation spectroscopy (E. R. Pike
and J. B. Abbiss eds. Light Scattering and Photo Correlation
Spectroscopy. Kluwer Academic Publisher, 1997).
[0083] A temperature treatment, in the region of approximately
200.sup.0 C to approximately 800.sup.0 C, of the granular material
obtainable according to one of the processes described above
guarantees that residual solvent is removed from the pores. In this
respect, it should be noted that any alcohol present, insofar as it
is used as a solvent, is removed as completely as possible before
the temperature treatment since it would otherwise subsequently
contaminate the product at elevated temperatures by forming
carbon.
[0084] A temperature treatment at preferably approximately
700.sup.0 C to approximately 900.sup.0 C (approximately 800.sup.0 C
in the presence of oxygen (normal air atmosphere)) removes the
carbon, which maybe present, by oxidation.
[0085] A particular embodiment of the granular material according
to the invention contains approximately 0.5 mole % to approximately
35 mole % of a network modifier in the xerogel, preferably
Na.sub.2O, as described above.
[0086] The network modifier is preferably introduced into the
finished nanoporous granular material by preferably using an
aqueous solution. A drying process at preferably approximately
120.sup.0 C to approximately 200.sup.0 C subsequently removes the
solvent (Example: for 100 g of a granular material with 30% by
weight of silica, 8 g of NaOH are dissolved in 50 ml of distilled
water. The porous granular material absorbs this solution and it is
dried immediately in order to prevent the dissolution of the
xerogel in the basic solution). Consequently, the network modifier
oxide is present in the granular material in a quantity of 21% by
weight, corresponding to 19.3 mole % of Na.sub.2O, based on the
xerogel.
[0087] Consequently, the invention also relates to a process for
the production of a granular material according to the invention in
which, by using corresponding orthophosphate compounds and calcium
compounds (such as e.g. calcium nitrate and ammonium
hydrophosphate) as a result of the reaction of the orthophosphate
group PO.sub.4.sup.3- and calcium ions in aqueous solution, a
hydroxyl apatite is precipitated out which, due to the ion
concentration fixed in the solution, exhibits a Ca/P ratio of 1.50
to 1.67, a Ca/P ratio of 1.67 being preferably selected if the end
product is to subsequently contain hydroxyl apatite as calcium
phosphate, and a Ca/P ratio of less than 1.67 being chosen if the
soluble .beta.-tricalcium phosphate is to be additionally present
in the end product.
[0088] The process is, moreover, characterised in that the
precipitated hydroxyl apatite is embedded homogeneously in a
silicon hydrogel, without forming agglomerates in the aqueous
solution, which can be achieved by supplying silicic acid,
preferably orthosilicic acid, in particular hydrolysed tetraethyl
oxysilane (TEOS) to the aqueous solution and adjusting the pH in
such a way that it is in the region of approximately 2 to
approximately 8, preferably of approximately 5 to approximately
6.5, such that a gel formation takes place. The quantity of TEOS
used is chosen in such a way that the proportion of silica is in
the region of approximately 4 to approximately 80% by weight,
preferably in the region of approximately 2 to approximately 50% by
weight, based on the total mass of the granule grains. As a result
of a drying process, a transition from hydrogel to xerogel takes
place as a result of which the calcium phosphate crystallites are
present in a xerogel matrix.
[0089] The granular calcium phosphate material (undissolved calcium
phosphate) which is preferably hydroxyl apatite produced according
to the invention, if necessary in combination with soluble calcium
phosphate, preferably .beta.-calcium phosphate, which contains
silica in a defined concentration and morphology, serves as
starting product for the production of a highly porous bone
substitute material, as has already been mentioned. The production
process will be described in further detail below. A use as
starting product for plasma spray coating (compare R. B. Heimann,
Plasma-Spray Coatings. Principles and Applications, Wiley-VCH
Verlag (1998)) of implants. In this case, parts coming in direct
contact with the bone, e.g. the shaft of a hip prosthesis is coated
with a material. An application in dental implants is also
possible.
[0090] If the granular material is mixed with bone marrow fluid or
with the patient's own blood it should be used as injectable
medicine or medicinal product having the purpose of building up
osteoporotic bones, of stimulating the build up of the bone in the
transition area to the loosened metal implants or of stimulating
the healing of parodontal defects.
[0091] The highly porous bone substitute material according to the
invention is produced from the granular material according to the
invention. In this case, a slip is produced from the granular
material described and preferably water. Preferably approximately
100 ml to approximately 300 ml of water are added to approximately
100 g of granular material. After adjusting the pH preferably such
that it is in the region of approximately 5 to 6.5, the slip is
poured into any desired mould and dried. In this way, a highly
porous bone substitute material is obtained. The shaped body
obtained is comparable to a green body such as it usually arises
with ceramic processes (compare in this respect: D. Richerson,
Modern Ceramic Engineering, Dekker Publ., J. Reed, Principles of
Ceramic Processing, Nanocrystalline Ceramics, M. Winterer, Springer
2002).
[0092] Since the calcium phosphate crystallites in the use of the
granular calcium phosphate material according to the invention are
present in a matrix of silica xerogel, the surface of the granular
material obviously consists of silica which, in the pH range
chosen, endeavours to effect a condensation reaction between the
--SiOH groups of the surfaces of touching granule grains. As a
result of the capillary pressure during the drying process, the
surfaces of the granule grains are pressed onto each other and
bonded by --SiOSi bonds. In this way, the highly porous bone
material receives its mechanical stability and the properties
according to the invention described above. Silicic acid, in
particular orthosilicic acid can be added to the slip as additional
binder. According to an embodiment of the invention, TEOS is
hydrolysed, for this purpose, with hydrochloric acid and added to
the slip. Preferably, 3 ml to 15 ml of TEOS are used per 100 g of
granular material.
[0093] Preferably, drying of the slip takes place at a temperature
of between room temperature and approximately 200.sup.0 C,
particularly preferably between approximately 80.sup.0 C and
approximately 130.sup.0 C. After drying, a further temperature
treatment takes place in order to solidify the highly porous bone
substitute material at a temperature which depends on the presence
of network modifiers in the xerogel of the granular material.
Without network modifier (pure silica xerogel), the temperature
treatment preferably takes place at approximately 700.sup.0 C to
approximately 900.sup.0 C, preferably at approximately 800.sup.0 C.
In the presence of a network modifier in the xerogel, the
temperature is preferably in the region between approximately
300.sup.0 C and approximately 500.sup.0 C.
[0094] As a result of the process described, the highly porous bone
substitute material receives its above-described structure and
consequently the described properties.
[0095] In addition to the nanopores in the xerogel, a category of
pores is formed which is determined by the packing of the granule
grains and their size. A further pore structure of the order of
magnitude of some hundred .mu.m to the mm range, which is to permit
the ingrowth of blood vessels, is produced in the shaped body by
additionally adding preferably organic powders with a grain size of
the pore size desired later on to the shaped body, which are burnt
out after the drying process.
[0096] Preferably, continuous pores (channels) (of an order of
magnitude of some hundred .mu.m to the mm range) are produced by
introducing organic fibres of the desired diameter into the slip,
which are burnt out after the drying process.
[0097] Material suitable for the powder or the fibres is in
particular wax since drying of the material which always entails a
certain amount of shrinkage can then be carried out at temperatures
at which the wax is soft and consequently prevents tearing of the
material. An advantageous drying temperature is consequently
approximately 40.sup.0 C. Subsequently, the wax can be removed from
the pores by centrifuging at approximately 100.sup.0 C. Residues of
the wax are subsequently burnt out and the carbon formed is removed
at approximately 800.sup.0 C.
[0098] The process for the production of the glass ceramics
materials according to the invention described is based on the
highly porous bone substitute material described.
[0099] In this case, the xerogel matrix of the highly porous bone
substitute material is converted into a glass matrix without
sintering together of the calcium phosphate crystals occurring.
This means that the interlinking of the silicon tetrahedra is
completed.
[0100] A gel-glass transition requires a relatively high
temperature of approximately 900.sup.0 C to approximately
1200.sup.0 C in the case of pure silica. Since the possibility
exists at these temperatures that the crystalline calcium phosphate
components undergo a phase transition, a highly porous bone
substitute material with a network modifier in the xerogel is
preferably used. The network modifiers have passed into the highly
porous bone substitute material either by the original use of a
granular material with a network modifier or the network modifiers
are introduced into the finished highly porous bone substitute
material by using the same method as for the granular material. In
this way, a gel-glass transition takes place at much lower
temperatures and the calcium phosphate component does not change.
Typical network modifier concentrations are in the region of
approximately 0.5 to approximately 35 mole %, preferably
approximately 17 to approximately 35 mole %, based on the
proportion of silica. A suitable network modifier is Na.sub.2O
since the glass phase is thus soluble in body fluids and
consequently can also be resorbed.
[0101] Since the glass temperature of sodium silicate glass is in
the region of approximately 460.sup.0 C to approximately 800.sup.0
C, depending on the sodium content, it is clear that a heat
treatment above this temperature range leads to glass very rapidly.
If a temperature treatment is carried out approximately 20% to
approximately 5% below the glass temperature determined for the
composition, the process is slowed down and requires several hours
and can be broken off at any time.
[0102] During resorption, the glass then goes the opposite way. In
other words, the glass turns again into a gel-type structure. The
granular calcium phosphate/silica material then provides the
possibility of optimising the strength and resorption properties of
the bone substitute material according to the invention. An
increase in strength will in any case always be accompanied by a
decrease in biodegradation.
[0103] Many applications are possible for the bone substitute
material according to the invention. For small defects such as
those partially occurring in surgery on the jaw bone, a granular
material of the highly porous bone substitute material can be used
for filling. In the case of greater defects where the remaining
bone still sufficiently stabilises the form of the defect, shaped
bodies of the highly porous bone substitute material must be
used.
[0104] Shaped bodies consisting of a combination of mechanically
relatively strong bone substitute materials (the matrix consists of
glass) and the highly porous bone substitute materials (the matrix
consists of xerogel), in particular, have an interesting
application in particular in the case of larger defects or also
defects in the case of which no native bone has remained as guiding
rail.
[0105] According to the invention, these shaped bodies possess, at
least on one side, a layer of the inorganic resorbable bone
substitute material with glass as matrix (increased strength) and
in this layer holes of an order of magnitude of 0.5 to 5
millimetres are present and these holes take up a proportion of the
volume in the layer of 5 to 80%. The entire volume, including the
holes in the more solid material, is taken up by the material which
has a xerogel as matrix. The hole structure in the solid layer is
to allow an ingrowth of blood vessels.
[0106] Consequently, the invention also relates to the use of the
granular materials and bone substitute materials according to the
invention for the production of shaped bodies, preferably a cube, a
plate, a hollow cylinder or a wedge.
[0107] Moreover, the invention permits the use of the
above-mentioned granular silica/calcium phosphate material for
coating implants (compare above). Particularly preferably, the
coating is effected by plasma spray coating.
[0108] Moreover, the invention relates to the use of a granular
material according to the invention for the production of a
medicine or medical product for building up osteoporotic bones, for
stimulating the bone build up in the transition area to loosened
metal implants or for stimulating healing of parodontal defects.
For this purpose, the granular material is preferably mixed with
bone marrow fluid or blood.
[0109] The subject matter of the invention moreover consists of a
medicine or medical product which comprises a granular material
according to the invention which is mixed with bone marrow fluid or
blood of the patient (consequently autologous).
[0110] The subject matter of the invention moreover consists of a
medicine or medical product which comprises a highly porous bone
substitute material according to the invention or a glass ceramic
material as bone substitute material, the bone substitute material
being brought into contact with the bone marrow fluid or blood of
the patient (consequently autologous) directly before implantation
such that the pores of the materials are completely filled.
[0111] The present invention will be explained in further detail in
the following examples and figures without being restricted
thereto.
EXAMPLES
Example 1
Production of Granular Calcium Phosphate Material
[0112] A solution of 3 mmole/m.sup.3 of Ca(H.sub.2PO.sub.4).sub.2
and a solution of 7 mmole/m.sup.3 of CaCl.sub.2 are stirred
together (giving a Ca/P ratio of 1.67) and a pH of 7 is adjusted
with NH.sub.4OH. The precipitated material is measured by powder
diffractometry. FIG. 4 shows the result. It is a pure phase
hydroxyl apatite which does not change even during the subsequent
process steps.
[0113] The solution with the precipitated hydroxyl apatite is
prevented from settling out by continuous stirring and concentrated
until 50 g of hydroxyl apatite remains per 100 ml of solvent. 60 ml
of tetraethyl oxysilane (TEOS) and 18 ml of 0.05 molar hydrochloric
acid are vigorously stirred until the hydrolysis of the TEOS has
been completed requiring a period of approximately 15 minutes and
detectable by a temperature increase from room temperature to
approximately 50.sup.0 C.
[0114] This solution is passed to the solution with the
precipitated homogenously distributed hydroxyl apatite and the pH
is adjusted to approximately 6.0 with NH.sub.4OH. This mixture is
stirred until a viscosity of approximately 2*10 5 cP is reached (as
a result of the beginning gel formation of the silica, the solution
becomes paste-like). Following the gel formation which sets in
immediately, the preparation is stored for 24 hours in a closed
vessel and subsequently granulated.
[0115] Subsequently, drying takes place at 80.sup.0 C for a period
of 2 hours. During this process, the transition from hydrogel to
xerogel takes place.
[0116] The granular material is rinsed in distilled water and
subsequently dried again. For this purpose, a temperature treatment
of 120.sup.0 C was chosen for a period of two hours.
[0117] The subsequent temperature treatment at 800.sup.0 C requires
a period of 1 hour. The granular material formed consists of
calcium phosphate to an amount of 75% by weight and of silica to an
amount of 25% by weight.
[0118] The granular material formed is characterised by scanning
electron micrographs as shown in FIG. 5. Granule grains within the
order of magnitude of 1 .mu.m to 5 .mu.m can be recognised.
[0119] From the granular material, a slip is produced with water
and the size distribution of the granule grains is determined by
dynamic light scattering (E. R. Pike and J. B. Abbiss eds. Light
Scattering and Photo Correlation Spectroscopy. Kluwer Academic
Publisher, 1997). The result is shown in FIG. 6.
[0120] FIGS. 7 and 8 show transmission electron micrographs of
cross sections through the granule grains. For this purpose, the
material was embedded in epoxide and sections approximately 60 nm
thick were prepared. The crystallites are platelets with an average
platelet diameter of approximately 150 nm and a platelet thickness
of approximately 10-20 nm. It can be seen very clearly how the
crystallites are embedded in the xerogel matrix even though the
contrast between the epoxide (embedding material) and the silica
xerogel is relatively weak. In FIG. 7, region A, for example, is a
pore filled with epoxide and region B is a typical area in which
the hydrogel apatite is embedded in xerogel.
Example 2
Production of Granular Calcium Phosphate Material
[0121] An aqueous solution of calcium nitrate and ammonium
hydrophosphate with a ratio of calcium to phosphate of 1.67 is
homogeneously mixed with a magnetic stirrer and a pH of 10 is
adjusted by means of NH.sub.4OH. The precipitated material is
washed four times with distilled water and centrifuged and
subsequently dispersed in ethanol.
[0122] Based on a proportion of solids of 72.9 g HA, 30 ml of TEOS
are mixed with 9 ml of an 0.1 mole/l HCl solution and 9 ml of
ethanol. Following the hydrolysis of the TEOS, this mixture is
introduced into the HA slip and distributed homogeneously and a pH
of 6.0 is adjusted.
[0123] Spray drying is carried out by pressing the homogenised slip
with compressed air at a pressure of between 50 and 100 kPa through
a nozzle and rapid drying takes place in a coaxial stream of air at
a temperature of 100.sup.0 C.
[0124] The subsequent temperature treatment at 800.sup.0 C requires
a time of 1 hour.
[0125] The granular material formed differs regarding the
properties from the granular material above all by the size of the
granule grains which has a considerably narrower distribution and a
maximum with a diameter of 18 .mu.m.
Example 3
Production of Granular Calcium Phosphate
[0126] An aqueous solution of 0.3 M orthophosphoric acid
(H.sub.3PO.sub.4) is mixed with an aqueous suspension of 0.1 M
calcium hydroxide (Ca(OH).sub.2) at room temperature. In this way,
a Ca/P ratio of 1.5 is obtained. A pH of 10 is adjusted with
Na.sub.4OH. The precipitated material is washed four times with
distilled water and centrifuged and subsequently dispersed in water
such that 50 g of calcium phosphate remain per 100 ml of solvent.
30 ml of TEOS and 9 ml of 0.05 molar hydrochloric acid are
vigorously stirred until the hydrolysis of the TEOS has been
completed, requiring a time of approximately 15 minutes and
detectable by a temperature increase from room temperature to
approximately 50.sup.0 C.
[0127] This solution is passed to the solution with the
precipitated, homogeneously distributed hydroxyl apatite and the pH
is adjusted to approximately 6.0 with Na.sub.4OH. This mixture is
stirred further until a viscosity of approximately 210.sup.5 cP is
reached (as a result of the gel formation of the silica setting in,
the solution becomes paste-like). Following the gel formation which
sets in immediately, the preparation is stored for 24 hours in a
closed vessel, subsequently granulated.
[0128] Subsequently, drying takes place at 80.sup.0 C over a period
of 2 hours. During this process, the transition from hydrogel to
xerogel takes place.
[0129] The granular material is rinsed in distilled water and
subsequently dried again. For this purpose, a temperature treatment
of 120.sup.0 C is chosen for a period of two hours.
[0130] The subsequent temperature treatment at 800.sup.0 C requires
a time of 1 hour. The granular material formed consists of calcium
phosphate to an amount of 86% by weight and of silica to an amount
of 14% by weight.
[0131] FIGS. 9 and 10 show scanning electron micrographs of a
granule grain. In FIG. 9, the interior of a ground granule grain
along a fracture line is visible. FIG. 10 shows the surface of a
granule grain. In this example, relatively large crystallites with
a diameter of approximately 1 .mu.m are present in the form of
.beta.-tricalcium phosphate. In the micrographs, the xerogel
appears as a compact material which is obviously attributable to
the resolution of the scanning micrographs which do not completely
resolve the porosity of the xerogel. However, it can been seen
fairly clearly how the xerogel forms a matrix in which the
crystallites are embedded and that entire granule grain is
surrounded by a xerogel layer.
Example 4
Production of the Highly Porous Bone Substitute Material
[0132] 100 g of the granular material, the production of which is
described in example 1 and which contains 25% by weight of silica
is mixed by stirring with 150 ml of distilled water and poured into
moulds of 8 mm15 mm30 mm respectively.
[0133] Drying takes place at 80.sup.0 C for 3 hours. During the
subsequent temperature treatment, the samples are maintained at
120.sup.0 C for 2 hours and, subsequently, the temperature is
increased to 800.sup.0 C and held for 1 hour.
[0134] The bone substitute material has a porosity of approximately
60%.
[0135] FIG. 11 shows the scanning electron micrograph of the
material. The granule grains whose original shape can be seen in
FIG. 5 now form a continuous 3-dimensional structure with pores in
the micrometer range.
[0136] The nanostructure in the interior of the granules remains
unchanged.
Example 5
Production of the Highly Porous Bone Substitute Material
[0137] 142 ml of water are mixed with 8 ml of hydrolysed TEOS
solution. For the hydrolysis, 18 ml of 0.05 molar hydrochloric acid
are added to 30 ml of TEOS and stirred until the hydrolysis is
completed which can be seen by a temperature increase from room
temperature to approximately 50.sup.0 C.
[0138] 100 g of granular material whose production is described in
example 1 are homogeneously distributed in this solution. A further
treatment follows as in example 4.
[0139] By additionally introducing the silica, the essential
structure of the material (micrometer pores and nanometapores) is
not altered. The granular materials are firmly bonded which
increases the overall strength of the highly porous bone substitute
material by approximately 50%.
Example 6
Production of the Highly Porous Bone Substitute Material But with
Macropores
[0140] Wax threads with a diameter of 0.2 mm are introduced into
moulds of example 4 in a completely random manner such that they
represent a volume fraction of 30% of the mould content. A slip of
silica-containing granular calcium phosphate material as described
in example 5 is introduced into these moulds. Drying now takes
place at 40.sup.0 C since the wax threads are soft in this case and
not yet liquid and are consequently not distributed in the
micrometer pores being formed, over a period of 4 hours.
[0141] During a temperature treatment at 800.sup.0 C over a period
of 1 hour, the wax is burnt out.
[0142] The macropores which have been formed instead of the wax
threads take up approximately 30 vol % such that an overall
porosity of 72% has been formed since the micrometer and nanometer
structure has not changed in comparison with example 5 or 6.
Example 7
Production of a Glass Ceramic Material
[0143] The starting point for the production of the glass ceramic
material as bone substitute material is the highly porous bone
substitute material produced in example 4.
[0144] A shaped body of this material has a density of 0.8
g/cm.sup.3 and consequently a porosity of approximately 60%. A
volume of 1000 ml of the shaped body contains 200 g of silica. In
order to introduce the network modifier into the xerogel of the
shaped body with the volume of 1000 ml, 50 g of NaOH are dissolved
in 600 ml of water and introduced into the pores of the shaped
body. The shaped body absorbs the solution completely and drying at
120.sup.0 C takes place. Consequently, the network modifier oxide
is present in the shaped body in a quantity of 20% by weight
corresponding to approximately 19 mole % of Na.sub.2O, based on the
xerogel.
[0145] Then follows a temperature treatment at 650.sup.0 C for two
hours. As a result, the xerogel passes into the state of glass.
Sodium silicate glass is formed. The shaped body shrinks and
retains a residual porosity of approximately 30%.
[0146] FIG. 12 documents the mechanical strength of the bone
substitute materials. Curve A in the stress-compressive strain
diagram shows the material with silicon xerogel as matrix. It is a
material with 24 percent by weight of silica and with hydroxyl
apatite as crystalline component.
[0147] Curve B in the diagram represents a material of identical
composition, the xerogel matrix having been converted into a glass.
The rupture strength has risen from approximately 3 to 50 MPa.
Example 7
In Vivo Testing of the Highly Porous Bone Substitute Material
[0148] Gottinger mini-pigs were used for the animal experiments in
order to test the properties of the material as bone substitute.
The animals were adult (1 year old) and weighed between 25 and 30
kg. The bone defects exceeded the critical size of 5 cm.sup.3;
their dimensions are approximately 3.0 cm1.5 cm1.5 cm. They were
implanted in the lower jaw, completely filled with the bone
substitute material and closed with the bone skin. After 8 months,
the pigs were killed and the lower jaws removed and x-ray,
histological and scanning microscopic investigations were carried
out.
[0149] FIG. 13 shows the lower jaw with the previous defect which
had been filled with the material of the example, 8 months after
the operation. The defective area has completely healed clinically.
Histological investigations show that less than 1% of the
biomaterial, taken as the mean value of several test animals, is
present in the defective area.
[0150] FIG. 14 shows a comparative study with a void defect. This
defect is encapsulated by connective tissue and has not healed.
[0151] FIG. 15 shows a comparative study with a commercial bone
substitute material based on hydroxyl apatite. Although the defect
has healed, the biomaterial has not been degraded and remains in
the bone as a foreign body.
[0152] FIG. 16 shows a light micrograph of a histological section.
It involves a demineralised histological section with hemalum
stain. A laguna (L) discernible in the biomaterial of example (B).
At the bottom of the laguna, osteoclasts (O) are seen decomposing
biomaterial. This means that the biodegradation of the material
takes place via osteoclasts which is of decisive importance for an
application.
Example 8
[0153] In FIG. 17, a shaped body is shown which combines the
properties of the two materials with different mechanical
properties and is intended for major bone defects. The material
with the glass as matrix forms a support layer on one side which
has a thickness of the order of magnitude of two mm, which is again
provided with a system of holes. The volume of the shaped body and
the holes in the stable layer are filled by the material with
xerogel as matrix since this material has the better bioactive
properties. FIG. 18 shows a further possible shaped body. The
cylinder has a jacket of the material with the glass as matrix.
This jacket also possesses a system of holes, which like the entire
volume, are filled with the material with xerogel as matrix.
* * * * *