Classification of calciumphosphate bone graft substitutes. Ph.D. Patrizio Sbornicchia

Transcription

1 Classification of calciumphosphate bone graft substitutes Ph.D. Patrizio Sbornicchia

2 The skeleton apparatus is essential for vertebrates life, as it ensures mechanical support, defence and energetic reservoir and specially for human beings, it s so specialised to reflect much m of the typical expressivity of the whole subject.

3 so skeleton restoration stands for the recovery of aesthetic harmony and psychological equilibrium beyond the preservation of general physiology that s nostalgic! Sigh! nevertheless, bone recovery can require big amount of tissue, which is not often available in the patient or subjected to contagious risk between living beings.

4 Research Medicine Synthetic bioceramics Industry Market

5 The market of synthetic bioceramics Milioni di dollari (USA) Stati Uniti Europa Francia Giappone Global market figures for synthetic bone graft substitutes.

6 Bioceramics Classification Functional criterion (based on behaviour) Bioinert Bioactive Bioresorbable Osteoinductive Osteoconductive Osteointegrated Microstructural criterion (based on chemical physical properties) Origin Composition Porosity Granulometry framing without response definition! S x = implantation success rate danger of unpredictable responses! reaction to foreign material cannot be absolutely foreseen!

7 Microstructural Classification Origin Natural (autograft, allograft, xenograft) Syntetic (precipitation, solid state reaction, polimerization, hot pressing ) Syntetic Composition Hydroxyapatites Ca 10 (PO 4 ) 6 (OH) 2 Ca 10 Other calcium phosphates Ca 3 (PO 4 ) 2 Ca 2 P 2 O 7 Composite bioceramics Ca 10 (PO 4 ) 6 (OH) 2-x F x Ca 10 Ca 4 P 4 O 9 Ca 10 (PO 4 ) 6 (OH) Ca 10 (OH) 2-2x Ca 8 (HPO 4 ) 2 (PO 4 ) 4 5H 2 O 2x(CO 3 ) x Each category can be blended with biological components BMPs, GFs, collagen, bone marrow, staminal cells, antibiotics

8 Porosity Pores size Size distribution of pores Microstructural Classification Total volume fraction of pores (hypoporous, meanporous, hyperporous material) Fraction of open porosity (density of interconnected pores) (microporous, mesoporous, macroporous material) Granulometry. Grains size (macrocrystalline, microcrystalline, nanocrystallyne)

9 Ceramic Ceramic Tree Tree Nanocrystalline r < 50 nm Microcrystalline r < 100 µm Macrocrystalline r > 100 µm Alberoceramico Hyperporous x v > 0.5 Meanporous 0.5 > x v > 0.1 Hypoporous x v < 0.1 Macroporous 10 3 µm > d > 10µm Mesoporous 10µm > d > 10-2 µm Nanoporous 10-2 µm > d > 10-4 µm Other Calcium Phosphate Hydroxyapatite HA Composites N 3 4 = 81 types! S

10 Nomenclature Bioceramic composite constituted by 68%wt natural hydroxyapatite and 32%wt synthetic tricalcium phosphate, having a 110 µm m mean pore diameter, 60% total porosity, whose 45% interconnected. The success rate is 98% for degradation. (68)HA(32)C 3 P[60(45), 110, 98 d ] (microphasic or nanophasic composite) Bioceramic composite constituted by 68%wt of natural hydroxyapatite separately showing 60% total porosity, whose 45% interconnected, mean pores diameter 120 µm m and by 31%wt synthetic tricalcium phosphate, showing 45% total porosity, whose 25% interconnected and mean pores diameter 85 µm. The 1%wt bone morphogenetic proteins is also added. (68)HA[60(45), 120]-(31) (31)C 3 P[45(25), 85]-(1)BMP (macrophasic composite)

11 Microstructures of Natural Bone Tissue Trabecular Cortical

12 Commercial Calciumphosphates Gen-ox Baumer S.A. (Genius) Bi-Ostetic TM Berkeley Advanced Biomaterials Engipore TM FIN CERAMICA Pure hydroxyapatite without organic matrix. Skelite TM Millenium Biologix Hydroxyapatite and tricalciumphosphate granules. Cerasorb Ortho Curasan Hydroxyapatite with intergranular porosity Orthoss Geistlich Biomaterials Corticotrabecular calciumphosphate graft. Granules and shaped blocks of pure calciumphosphate. Bovine hydroxyapatite.

13 Commercial Calciumphosphates Biosorb SBM Reduction of metacarpal defect by tough tricalciumphosphates (45 MPa) synthetically derived. Preoperatory. Postperatory. Six months. A year. Eurocer FH Orthopedics Composite HA-TCP Orthoss Geistlich Biomaterials Fixation of traumatic defect, postoperatory and six months after. Treatment of mandible bone defect.

14 Synthesis Methodologies 1) Wet Precipitation 2) Calcium phosphate hydration 3) Colloidal or microemulsion precipitation 4) Hydrothermal psedumorphosis of natural substrate (, MHz) 5) Silicon and fluorine doping 6) Solid state reaction ( ( 3, F 3, metal,, glass) 7) Polymers blending 8) Bioeutectic synthesis CaSiO 3 -Ca 3 (PO 4 ) 2 9) Calciumphosphate cements 10) Glasses and glassceramics 11) Biomimetic synthesis 12) Other calciumphosphates (DCP, TCP, OCP)

15 Synthesis Methodologies Colloidal and microemulsion precipitation. Glicerole acqueous suspension, 45 C. 10 Ca(NO 3 ) 2(sol) + 6NH 4 H 2 PO 4(sol) + 2NH 4 OH Ca 10 (PO 4 ) 6 (OH) (OH) 2(s) (s) + 8 NH 4 NO 3(sol) + 12HNO 3(sol) Grain homogeneity, better sintering and high densification, less production defects (1200 C 99%, 1100 C 94% E= 85MPa). Non polar solvents (ciclohexane) and surfactants (poly-oxyethylene oxyethylene-nonilphenolether) nonilphenolether) 10 CaCl 2(emul) + 6 (NH 4 ) 2 HPO 4(sol) + 2H 2 O Ca 10 (PO 4 ) 6 (OH) 2(s) + 12NH 4 Cl (sol) + 8HCl (sol) Free nanometric grains, high sintering and homogeneity, fine microstructures.

16 Synthesis Methodologies Hydrothermal Pseudomorphosis of coral and eggs shell. The marine specie Goniopora is made of calcium carbonate. 10 CaCO 3(coral) + 6 (NH 4 ) 2 HPO 4(sol) Ca 10 (PO 4 ) 6 (OH) 2(s) + 10CO 2(g) + 8H 2 O (g) + 12NH 3(g) The CHAp is highly osteogenic, as granule is reliable filler and coating for metallic grafts by using plasma spray. Goniopora Hilli and detail of a single calyx. The ratio HA/TCP dipends on phosphoric acid concentration and T calcinization

17 Synthesis Methodologies Silicon and fluorine doping. Silicon is typically added as (CH 3 CO 2 ) 4 Si in ammonia solution. 10 Ca(OH) 2(sol) + 6 H 3 PO 4(sol) Ca 10 (PO 4 ) 6 (OH) 2(s) + 18 H 2 O It partially substitutes phosphorus (1.5%wt) and increases the osteointegration o and resorption rate. The fluoroapatites are an accessory component into natural bones. 10 Ca(NO 3 ) (NH 4 ) 2 HPO 4 + 8NH 4 F + H 2 O Ca 10 (PO 4 ) 6 (OH)F (s) + 20 NH 4 NO 3 + 7HF The fluorine content tailors the solubility of hydroxyapatites and a their resistance in acid environment.

18 Synthesis Methodologies Solid state reaction. The raw materials are generally calcium carbonate and phosphate salts. 10 CaCO 3(s) + 6 (NH 4 ) 3 HPO 4(s) Ca 10 (PO 4 ) 6 (OH) 2(s) + 10 CO 2(g) + 12NH 3(g) + 8H 2 O (g) Highly pure and stoichometric hydroxyapatites (Ca/P) stech. = 1.67 (Ca/P) stech. The biphasics are derived by calciumdeficient hydroxyapatites. Ca 10-x M x (PO 4 ) 6-x (HPO 4 )(OH) 2 Ca 10 (PO 4 ) 6 (OH) 2(s) + Ca 3 (PO 4 ) 2(s) Weght ratio depends on calcium substitution and T sintering This ratio modulate the resorption rate and the mechanical strength can be increased by mixing ZrO 2, Y 2 O 3, CaSiO 3 preserving bioactivity and porosity.

19 Synthesis Methodologies Solid state reaction with functional gradient. The composition and microstructure vary along thickness, combining ng different properties and biomechanical response. The carbon combustion decomposes the mineral, leaving a tricalcium phosphate layer (α-tcp).( Ca 10 (PO 4 ) 6 (OH) Ca 10 (OH) 2(g) + C (diam) + O 2 3Ca 3 (PO 4 ) 2(s) + CaO + H 2 O (g) + CO CO 2(g) The higher solubility of α-tcp guarantees a faster bone ingrowth! These biphasics can be obtained by tapecasting, improving bone fixation. f

20 Synthesis Methodologies Solid state reaction with metal reinforcement. The bioceramic is premixed to the metal powder or metal carriers,, then pressed and sintered (1200 C). Ca 10 (PO 4 ) 6 (OH) Ca 10 (OH) 2(s) + Ti (s) Ti-Ca 10 (PO 4 ) 6 (OH) (OH) 2(s) 40%p Ti E = 80 GPa HV = 3 GPa σ f = 92 MPa G c = 2.7 MPam ½ (Human bone 2.0 MPam ½ ) P = 7% The ductility of metal particles increases the strength and toughness (crack bridging), preserving good bioactivity.

21 Synthesis Methodologies Polymers blending. The polymers (HDPE, PMMA, PLLA) are reinforced by minerals. Lubrificant (stearic acid) and coupling agents are needed (Si(C 2 H 5 O) O) 4, ) The low polymers blending temperature doesn t affect bioceramic properties! The composite is injectable, osteoconductive and easily osteointegrated. For example, PLA can be mixed to uncalcined and unsintered hydroxyapatite (u-ha, 3 µm), derived from hydrolysis of hydrogenphosphate. 6CaHPO 4(sol) + 4CaCO 3(s) Ca 10 (PO 4 ) 6 (OH) 2(s) + 4CO 2(g) + 2H 2 O The resulted materials is one of the highest resistant (σ( f = 200 MPa) in vivo material, completely resorbable, bioactive, malleable e radioopaque.

22 Synthesis Methodologies Biomimetic synthesis. The calciumphosphates develops at the surface of polymeric support of different origins (chitosane, cotton fiber, PVA, PE, collagen), miming natural biomineralisation. The previous treatment of support is needed (H 3 PO 4, urea, TEOS, Ca(OH) 2 ) to activate surface and catalyse the growth of apatites once soaked into simulated biological fluids. Natural cotton fibers. Activated cotton fibers and soaked into SBF. Mechanical strength and bioactivity of biomimetic composite is remarkable! r

23 Conclusions Nowadays, the fuctionality of calciumphosphate bioceramics fairly y ensures 1) Absence of systemic toxicity (biocompatibility). 2) Tissue adhesion (bioactivity, osteointegration). 3) Cells ingrowth (osteoconduction). 4) Cells differentiation (osteinduction). 5) Bone regeneration (resorption). 6) Mechanical support (composite). Prof. Alan Boyde (University College, London) notwithstanding the implantological failures are not yet negligible!...

24 for high complexity of bone tissue, the bioceramics engineering requires everlasting refinements towards a bone graft substitute completely biomimetic! «Nature doesn t t make useless things!» Aristotele, a.c.