Classification of calciumphosphate bone graft substitutes

Classification of calciumphosphate Classification of calciumphosphate bone graft substitutesbone graft substitutes

Ph.D. Patrizio SbornicchiaPh.D. Patrizio Sbornicchia

The skeleton apparatus is essential for vertebrates life, as it The skeleton apparatus is essential for vertebrates life, as it ensures ensures mechanical support,mechanical support, defencedefence andand energetic reservoir…energetic reservoir…

……and specially for human beings, it’s so specialised to reflect mand specially for human beings, it’s so specialised to reflect much of uch of the typical expressivity of the whole subject.the typical expressivity of the whole subject.

Dr. Patrizio Sbornicchia Ischia Porto, July 13th 2005

……so skeleton restoration stands for the recovery of aesthetic harso skeleton restoration stands for the recovery of aesthetic harmony mony and psychological equilibrium…beyond the preservation of generaland psychological equilibrium…beyond the preservation of generalphysiology…physiology…

……nevertheless,nevertheless, bone recovery can requirebone recovery can require big amount of tissue, which is big amount of tissue, which is not often availablenot often available in thein the patientpatient oror subjected to contagious risk between subjected to contagious risk between living beings.living beings.

…that’s nostalgic!Sigh!


ResearchResearch

IndustryIndustryMedicineMedicine

MarketMarket

SyntheticSyntheticbioceramicsbioceramics


The market of synthetic bioceramicsThe market of synthetic bioceramics

2001 2002 2003 2004 2005 20060

200

400

600

800

1000

1200M

ilion

i di d

olla

ri (U

SA)

Stati Uniti Europa Francia Giappone

Global market figures for synthetic bone graft substitutes.Global market figures for synthetic bone graft substitutes.


Bioceramics ClassificationBioceramics Classification

Functional criterionFunctional criterion Microstructural criterionMicrostructural criterion

Bioinert

Bioactive

Bioresorbable

Origin

Composition

Porosity

……danger of unpredictable responses!danger of unpredictable responses!

(based on behaviour)(based on behaviour) (based on chemical physical properties)(based on chemical physical properties)

……framing without response definition!framing without response definition!

……reaction to foreign material cannot be absolutely foreseen!reaction to foreign material cannot be absolutely foreseen!

Granulometry Osteoinductive

Osteoconductive…

…Osteointegrated… SSxx = implantation success rate


Microstructural ClassificationMicrostructural Classification

Natural Natural (autograft, allograft, xenograft)(autograft, allograft, xenograft)

OriginOrigin

Syntetic Syntetic (precipitation, solid state reaction, polimerization, hot pressi(precipitation, solid state reaction, polimerization, hot pressing…)ng…)

Hydroxyapatites

CompositionComposition

Other calcium phosphates

Composite bioceramics

CaCa1010(PO(PO44))66(OH)(OH)22 CaCa1010(PO(PO44))66(OH)(OH)22--xxFFxx CaCa1010(PO(PO44))66(OH)(OH)22--2x2x(CO(CO33))xx

CaCa33(PO(PO44))22 CaCa22PP22OO77 CaCa44PP44OO99 CaCa88(HPO(HPO44))22(PO(PO44))44·5H·5H22OO

Each category can be blended with biological components…Each category can be blended with biological components………BMPs, GFs, collagen, bone marrow, staminal cells, antibioticsBMPs, GFs, collagen, bone marrow, staminal cells, antibiotics


Microstructural ClassificationMicrostructural Classification

Size distribution of pores

Pores size

PorosityPorosity

(microporous, mesoporous, macroporous material)(microporous, mesoporous, macroporous material)

Total volume fraction of pores

Fraction of open porosity (hypoporous, meanporous, hyperporous material)(hypoporous, meanporous, hyperporous material)

(density of interconnected pores) (density of interconnected pores)

Granulometry.Granulometry.

Grains size (macrocrystalline, microcrystalline, nanocrystallyne)(macrocrystalline, microcrystalline, nanocrystallyne)


HydroxyapatiteHA

Other CalciumPhosphate Composites

Mesoporous10µm > d > 10-2µm

Macroporous103µm > d > 10µm

Nanoporous10-2µm > d > 10-4µm

Meanporous0.5 > xv > 0.1

Hyperporousxv > 0.5

Hypoporousxv < 0.1

Nanocrystalliner < 50 nm

Microcrystalliner < 100 µm

Macrocrystalliner > 100 µm

NN

SS

Ceramic T

ree

Ceramic T

reeAlberoceramico

Alberoceramico

3344 = 81 types!= 81 types!


NomenclatureNomenclature

Bioceramic composite constituted by 68%wt natural Bioceramic composite constituted by 68%wt natural hydroxyapatitehydroxyapatite and and 32%wt synthetic tricalcium phosphate, having a 110 32%wt synthetic tricalcium phosphate, having a 110 µµm mean pore diameter, m mean pore diameter, 60% total porosity, whose 45% interconnected. The success rate i60% total porosity, whose 45% interconnected. The success rate is 98% for s 98% for degradation.degradation.

(68)HA(32)(68)HA(32)CC33PP[60(45), 110, [60(45), 110, 9898dd] ]

Bioceramic composite constituted by 68%wt of natural Bioceramic composite constituted by 68%wt of natural hydroxyapatitehydroxyapatiteseparatelyseparately showing 60% total porosity, whose 45% interconnected, mean showing 60% total porosity, whose 45% interconnected, mean pores diameter 120 pores diameter 120 µµm and by 31%wt synthetic tricalcium phosphate, m and by 31%wt synthetic tricalcium phosphate, showing 45% total porosity, whose 25% interconnected and mean poshowing 45% total porosity, whose 25% interconnected and mean pores res diameter 85 diameter 85 µµm. The 1%wt bone morphogenetic proteins is also added.m. The 1%wt bone morphogenetic proteins is also added.

(68)HA[60(45), 120](68)HA[60(45), 120]--(31)(31)CC33PP[45(25), 85][45(25), 85]--(1)BMP(1)BMP

(microphasic or nanophasic composite)

(macrophasic composite)


MicrostructuresMicrostructures ofof Natural Bone TissueNatural Bone Tissue

TrabecularTrabecular CorticalCortical


Commercial CalciumphosphatesCommercial Calciumphosphates

GenGen--oxox®®

Baumer S.A. (Genius)Baumer S.A. (Genius)

Pure hydroxyapatite Pure hydroxyapatite without organic matrix.without organic matrix.

BiBi--OsteticOsteticTMTM

Berkeley Advanced BiomaterialsBerkeley Advanced Biomaterials

Hydroxyapatite and Hydroxyapatite and tricalciumphosphate granules.tricalciumphosphate granules.

EngiporeEngiporeTMTM

FIN CERAMICAFIN CERAMICA

Hydroxyapatite with Hydroxyapatite with intergranular porosityintergranular porosity

SkeliteSkeliteTMTM

Millenium BiologixMillenium Biologix

Corticotrabecular Corticotrabecular calciumphosphate graft.calciumphosphate graft.

CerasorbCerasorb®®OrthoOrthoCurasanCurasan

Granules and shaped blocks of Granules and shaped blocks of pure calciumphosphate.pure calciumphosphate.

OrthossOrthoss®®

Geistlich BiomaterialsGeistlich Biomaterials

Bovine hydroxyapatite.Bovine hydroxyapatite.


Commercial CalciumphosphatesCommercial Calciumphosphates

BiosorbBiosorb®®

SBMSBM

Preoperatory.Preoperatory.

Reduction of metacarpal defect by tough Reduction of metacarpal defect by tough tricalciumphosphates (45 MPa) synthetically derived.tricalciumphosphates (45 MPa) synthetically derived.

Postperatory.Postperatory. Six months.Six months. A year.A year.

EurocerEurocer®®

FH OrthopedicsFH Orthopedics

Fixation of traumatic defect, Fixation of traumatic defect, postoperatory and six months after.postoperatory and six months after.

Composite HAComposite HA--TCPTCP OrthossOrthoss®®

Geistlich BiomaterialsGeistlich Biomaterials

Treatment of mandible Treatment of mandible bone defect.bone defect.


Synthesis MethodologiesSynthesis Methodologies

1) Wet Precipitation1) Wet Precipitation

2) Calcium phosphate hydration2) Calcium phosphate hydration

3)3) Colloidal or microemulsion precipitationColloidal or microemulsion precipitation

4)4) Hydrothermal psedumorphosis of natural substrate Hydrothermal psedumorphosis of natural substrate ((∆∆,, MHz)MHz)

5) Silicon and fluorine doping5) Silicon and fluorine doping

6) Solid state reaction (6) Solid state reaction (∆∆33, , ∇∇FF33, , metalmetal, glass), glass)

8) Bioeutectic synthesis CaSiO8) Bioeutectic synthesis CaSiO33--CaCa33(PO(PO44))22

7) Polymers blending7) Polymers blending

9) Calciumphosphate cements9) Calciumphosphate cements

10) Glasses and glassceramics10) Glasses and glassceramics

12) Other calciumphosphates (DCP, TCP, OCP)…12) Other calciumphosphates (DCP, TCP, OCP)…

11) Biomimetic synthesis11) Biomimetic synthesis



10 CaCl10 CaCl2(emul)2(emul) + 6 (NH+ 6 (NH44))22HPOHPO4(sol)4(sol) + 2H+ 2H22O O →→ CaCa1010(PO(PO44))66(OH)(OH)2(s)2(s) + 12NH+ 12NH44ClCl(sol)(sol) + 8HCl+ 8HCl(sol)(sol)

Non polar solvents (ciclohexane) and surfactants (polyNon polar solvents (ciclohexane) and surfactants (poly--oxyethyleneoxyethylene--nonilphenolether)nonilphenolether)

Free nanometric grains, high sintering and homogeneity, fine micFree nanometric grains, high sintering and homogeneity, fine microstructures. rostructures.

Colloidal and microemulsion precipitation.Colloidal and microemulsion precipitation.

10 Ca(NO10 Ca(NO33))2(sol)2(sol) + 6NH+ 6NH44HH22POPO4(sol)4(sol) + 2NH+ 2NH44OHOH→→ CaCa1010(PO(PO44))66(OH)(OH)22(s) (s) + 8 NH+ 8 NH44NONO3(sol)3(sol) + 12HNO+ 12HNO3(sol)3(sol)

Glicerole acqueous suspension, 45°C. Glicerole acqueous suspension, 45°C.

Grain homogeneity, better sintering and high densification, lessGrain homogeneity, better sintering and high densification, less production production defects (1200°C 99%, 1100°C 94% E= 85MPa). defects (1200°C 99%, 1100°C 94% E= 85MPa).


Hydrothermal Pseudomorphosis of coral and eggs shell.Hydrothermal Pseudomorphosis of coral and eggs shell.

The marine specie The marine specie Goniopora Goniopora is made of calcium carbonate. is made of calcium carbonate.

The CHAp is highly osteogenic, as granule is reliable filler andThe CHAp is highly osteogenic, as granule is reliable filler and coating for coating for metallic grafts by using plasma spray. metallic grafts by using plasma spray.

10 CaCO10 CaCO3(coral)3(coral) + 6 (NH+ 6 (NH44))22HPOHPO4(sol)4(sol) →→ CaCa1010(PO(PO44))66(OH)(OH)2(s)2(s) + 10CO+ 10CO2(g)2(g) + 8H+ 8H22OO(g)(g) + 12NH+ 12NH3(g)3(g)


Goniopora HilliGoniopora Hilli and detail of a single calyx.and detail of a single calyx. The ratio HA/TCP dipends on phosphoric The ratio HA/TCP dipends on phosphoric acid concentration and Tacid concentration and Tcalcinizationcalcinization



10 Ca(OH)10 Ca(OH)2(sol)2(sol) + 6 H+ 6 H33POPO4(sol)4(sol) →→ CaCa1010(PO(PO44))66(OH)(OH)2(s)2(s) + 18 H+ 18 H22OO

Silicon and fluorine doping.Silicon and fluorine doping.Silicon is typically added as (CHSilicon is typically added as (CH33COCO22))44Si in ammonia solution. Si in ammonia solution.

It partially substitutes phosphorus (1.5%wt) and increases the oIt partially substitutes phosphorus (1.5%wt) and increases the osteointegration steointegration and resorption rate.and resorption rate.

The fluoroapatites are an accessory component into natural bonesThe fluoroapatites are an accessory component into natural bones..

The fluorine content tailors the solubility of hydroxyapatites aThe fluorine content tailors the solubility of hydroxyapatites and their nd their resistance in acid environment.resistance in acid environment.

10 Ca(NO10 Ca(NO33))22 + 6 (NH+ 6 (NH44))22HPOHPO44 + 8NH+ 8NH44F + HF + H22O O →→ CaCa1010(PO(PO44))66(OH)F(OH)F(s)(s) + 20 NH+ 20 NH44NONO3 3 + 7HF+ 7HF



Solid state reaction.Solid state reaction.

The The biphasicsbiphasics areare derived by calciumdeficient hydroxyapatites. derived by calciumdeficient hydroxyapatites.

CaCa1010--xxMMxx(PO(PO44))66--xx(HPO(HPO44)(OH))(OH)22 →→ CaCa1010(PO(PO44))66(OH)(OH)2(s)2(s) + + CaCa33(PO(PO44))2(s)2(s)∆

Weght ratio depends on calcium substitution and TWeght ratio depends on calcium substitution and Tsinteringsintering

This ratio modulate the resorption rate and the mechanical strenThis ratio modulate the resorption rate and the mechanical strength can be gth can be increased by mixing ZrOincreased by mixing ZrO22, Y, Y22OO33, CaSiO, CaSiO33… …

…preserving bioactivity and porosity.…preserving bioactivity and porosity.

The raw materials are generally calcium carbonate and phosphate The raw materials are generally calcium carbonate and phosphate salts. salts.

10 CaCO10 CaCO3(s)3(s) + 6 (NH+ 6 (NH44))33HPOHPO4(s)4(s) →→ CaCa1010(PO(PO44))66(OH)(OH)2(s)2(s) + 10 CO+ 10 CO2(g)2(g) + 12NH+ 12NH3(g) 3(g) + 8H+ 8H22OO(g)(g)

Highly pure and stoichometric hydroxyapatitesHighly pure and stoichometric hydroxyapatites (Ca/P)(Ca/P)stech.stech. = 1.67= 1.67



Solid state reaction with functional gradient.Solid state reaction with functional gradient.

CaCa1010(PO(PO44))66(OH)(OH)2(g)2(g) + + CC(diam)(diam) + + OO22 →→ 3Ca3Ca33(PO(PO44))2(s)2(s) + CaO + H+ CaO + H22OO(g)(g) + + COCO2(g)2(g)

The composition and microstructure vary along thickness, combiniThe composition and microstructure vary along thickness, combining different ng different properties and biomechanical response. The carbon combustion decproperties and biomechanical response. The carbon combustion decomposes the omposes the

mineral, leaving a tricalcium phosphate layer (mineral, leaving a tricalcium phosphate layer (αα--TCP).TCP).

The higher solubility of The higher solubility of αα--TCP guarantees a faster bone ingrowth!TCP guarantees a faster bone ingrowth!

These biphasics can be obtained by tapecasting, improving bone fThese biphasics can be obtained by tapecasting, improving bone fixation.ixation.



Solid state reaction with metal reinforcement.Solid state reaction with metal reinforcement.

CaCa1010(PO(PO44))66(OH)(OH)2(s)2(s) + + TiTi(s)(s) →→ TiTi--CaCa1010(PO(PO44))66(OH)(OH)2(s) 2(s)

The ductility of metal particles increases the strength and tougThe ductility of metal particles increases the strength and toughness hness ((crack bridgingcrack bridging), preserving good bioactivity.), preserving good bioactivity.

The bioceramic is premixed to the metal powder or metal carriersThe bioceramic is premixed to the metal powder or metal carriers, then , then pressed and sintered (1200°C).pressed and sintered (1200°C).

40%p Ti 40%p Ti

E =E = 80 GPa80 GPa

HV =HV = 33 GPaGPa

σσff == 92 MPa92 MPa

GGcc = 2.7 MPam= 2.7 MPam½½

(Human bone 2.0 MPam(Human bone 2.0 MPam½½))

P = 7%P = 7%



Polymers blending.Polymers blending.The polymers (HDPE, PMMA, PLLA) are reinforced by minerals.The polymers (HDPE, PMMA, PLLA) are reinforced by minerals.

Lubrificant (stearic acid) and coupling agents are needed (Si(CLubrificant (stearic acid) and coupling agents are needed (Si(C22HH55O)O)4,4,))

The low polymers blending temperature doesn’t affect bioceramic The low polymers blending temperature doesn’t affect bioceramic properties!properties!

The composite is The composite is injectable,injectable, osteoconductive and easily osteointegrated.osteoconductive and easily osteointegrated.

For example, PLA can be mixed to uncalcined For example, PLA can be mixed to uncalcined and unsintered hydroxyapatite (uand unsintered hydroxyapatite (u--HA, 3 HA, 3 µµm), m), derived from hydrolysis of hydrogenphosphate.derived from hydrolysis of hydrogenphosphate.

6CaHPO6CaHPO4(sol)4(sol) + 4CaCO+ 4CaCO3(s)3(s) →→ CaCa1010(PO(PO44))66(OH)(OH)2(s)2(s) + 4CO+ 4CO2(g)2(g) + 2H+ 2H22OO

The resulted materials is one of the highest resistant (The resulted materials is one of the highest resistant (σσff = 200 MPa) = 200 MPa) in vivo in vivo material, completely resorbable, bioactive, malleable e radioopamaterial, completely resorbable, bioactive, malleable e radioopaque. que.



The calciumphosphates develops at the surface of polymeric suppoThe calciumphosphates develops at the surface of polymeric support of different origins rt of different origins (chitosane, cotton fiber, PVA, PE, collagen), miming natural bio(chitosane, cotton fiber, PVA, PE, collagen), miming natural biomineralisation. mineralisation.

The previous treatment of support is needed (HThe previous treatment of support is needed (H33POPO44, urea, TEOS, Ca(OH), urea, TEOS, Ca(OH)22) to activate ) to activate surface and catalyse the growth of apatites once soaked into simsurface and catalyse the growth of apatites once soaked into simulated biological fluids. ulated biological fluids.

Biomimetic synthesis.Biomimetic synthesis.

Mechanical strength and bioactivity of biomimetic composite is rMechanical strength and bioactivity of biomimetic composite is remarkable!emarkable!

Natural cotton fibers.Natural cotton fibers. Activated cotton fibers and Activated cotton fibers and soaked into SBF.soaked into SBF.


ConclusionsConclusions

Nowadays, the fuctionality of calciumphosphate bioceramics fairlNowadays, the fuctionality of calciumphosphate bioceramics fairly ensures…y ensures…

1) Absence of systemic toxicity (biocompatibility).1) Absence of systemic toxicity (biocompatibility).

2) Tissue adhesion (bioactivity, osteointegration).2) Tissue adhesion (bioactivity, osteointegration).

3) Cells ingrowth (osteoconduction).3) Cells ingrowth (osteoconduction).

4) Cells differentiation (osteinduction).4) Cells differentiation (osteinduction).

5) Bone regeneration (resorption).5) Bone regeneration (resorption).

6) Mechanical support (composite).6) Mechanical support (composite).

……notwithstanding…the implantological failures are not yet negliginotwithstanding…the implantological failures are not yet negligible!...ble!...

Prof. Alan Boyde (University College, London)


……towards a bone graft substitute completely biomimetic!towards a bone graft substitute completely biomimetic!

«…«…Nature doesnNature doesn’’t make useless thingst make useless things!!»»Aristotele, 384Aristotele, 384--322 a.C.322 a.C.


……for high complexity of bone tissue, the bioceramics engineering for high complexity of bone tissue, the bioceramics engineering requires requires everlasting refinements…everlasting refinements…

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Classification of calciumphosphate bone graft substitutes