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Applications of Hydroxyapatite Thermochemistry to Biomaterials Synthesis
R. E. Riman, C. Mossaad, M. Starr and D. T. Denhardt and L. Shimp
2010 OLI Simulation Conference
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Applications of Hydroxyapatite Thermochemistry to Biomaterials Synthesis
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Acknowledgements
• National Science Foundation/Rutgers IGERT on Biointerfaces, DGE 0333196
• Rutgers University Roger G. Ackerman Fellowship
• NASA GSRP Grant NNG04GO44H• Rutgers University Technology
Commercialization Fund• Osteotech, Inc.
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Outline
• Biomaterials• DBM-Hydroxyapatite nanocomposites• Thermodynamic simulations• Hydroxyapatite nanomaterials• Hydroxyapatite-collagen (DBM) nanocomposites
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Issues in Hard Tissue Replacement• Injury and Osteoporosis
- Cancer treatment- Celiac- Diabetes- Parathyroid issues
• Limited joint replacement lifetimes- Stress shielding causes loosening- Fibrous capsule causes loosening- Wear debris cause inflammation
• Current materials- Polymer/HA blends- Titanium alloy/HA coating- Stainless Steel- Cobalt alloy/HA coating- Pure polymers- Demineralized bone for non-load
bearing applicationsGoodman et. al. “Effects of orthopaedic wear particles on osteoprogenitor cells” Biomaterials 27 (2006) 6096-6101
Drees et. al. “Mechanisms of Disease: molecular insights into aseptic loosening of orthopedic implants” Nature Clinical Practice: Rheumatology 3(3) (2007) 165
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DBM-HA Nanocomposites
• Bone is made of Hydroxyapatite and collagen - Materials recognized and processed by native tissues
• DBM (Demineralized Bone Matrix) collagen forms- Matrix of collagen with residual proteins and mineral- Used in non-load bearing applications- High osteoinductivity (forms new bone)- Easily disintegrates in aqueous media
• Hydroxyapatite (Ca10(PO4)6(OH)2)- Implants, drugs, chromatography, supplements & toothpaste- Osteoconductive (forms bone on implant surface)- Possibly osteoinductive- Particle size very small in bone- Formed in aqueous environment
• Marry advantageous properties of both materials• Start with non-load bearing material 1emedicine.medscape.com
2http://www.graftondbm.com
Demineralized bone matrix1,2
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Paradigm hydroxyapatite synthesis system
• Precipitates at or below 37oC• Neutral pH (7-7.8)• Non-toxic precursors• Chemically robust• High yield• Scalable (>1 g/100 ml solution)• Short reaction time(< 4 h)• Can integrate process with collagen mats, fibers, and other
biomaterials• Current methods and chemistries do not meet all criteria
- Harsh chemical environment (ss rxn, hydrothermal, mechanochemical)- Low process yield and slow (simulated body fluid)- pH too high (aqueous precipitation, phase transition)
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Applications of Hydroxyapatite Thermochemistry to Biomaterials Synthesis
Rational Approach to Crystallization
• Compute thermodynamic equilibria as a function of the processing variables for phase of interest
• Generate equilibrium diagrams to map processing variable space for phase of interest
• Design hydrothermal experiments to test and validate computed diagrams
• Utilize processing variable space maps to explore opportunities for control of reaction and crystallization kinetics
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Applications of Hydroxyapatite Thermochemistry to Biomaterials Synthesis
Thermodynamic Modeling• List all relevant equilibrium species in the solid, aqueous and
vapor/gaseous state• Write k independent reactions for i species• Write the equation for the Gibbs free energy change for each
independent reaction, equations for respective equilibrium constants and collect the associated standard state thermochemical data tocompute these properties as a function of temperature
• Choose activity coefficient models and collect data for activitycoefficient computation
• Generate additional equations that invoke mass balance and charge neutrality to enable solution of all equations
• Solve all equations simultaneously using property minimization methods (e.g., Newton’s method) that minimize the free energy for the system
• Repeat this calculation for a wide range of processing variable space and plot the phase boundaries for the equilibrium diagram.
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Thermodynamic Modeling Search Criterion
• HA synthesis goals- Room Temperature synthesis (T=25oC)- Ambient Pressure (p=1 atm, no high pressure reactor needed)- Neutral pH- Low cost precursors- Non toxic ions produced in solution for ease of washing
• Tasks- Survey and model various calcium sources with a chosen phosphate- Survey and model various phosphates with a chosen calcium- Survey other reaction variables
Temperature, pH, composition- Analyze model outputs: Chemical/phase diagrams
Yield, Stability- Verify selected conditions with wet-chemical experiments
• Software used: OLI Stream Analyzer 2.0 by OLI Systems, Inc.
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Relevant Hydroxyapatite Chemical Equilibria
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Phase Equilibrium Systems for the Paradigm
Precursor (pH) K2HPO4 (9.00) H3PO4 (1.32) Na3PO4/K3PO4 (12.13/12.24)
CaCl2 (6.73) N N HCa(OH) 2 (12.39) H H H
Ca(C2H3O2)2 (8.92) N N H
• Ca/P=1.67, 0.5 m Ca-species, 0.3 m P-species, T= 25oC• H – Hydroxyapatite is the dominant phase somewhere• N – Hydroxyapatite not the dominant phase anywhere
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Modeling of the CaCl2-Na3PO4 System
12Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
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Modeling of the CaCl2-K2HPO4 System
13Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
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Applications of Hydroxyapatite Thermochemistry to Biomaterials Synthesis
Modeling of the Ca(OH)2-H3PO4 System
14Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
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Applications of Hydroxyapatite Thermochemistry to Biomaterials Synthesis
Ca(CH3COO)2-K3PO4-H2O System
15Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
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Universal pH dependent Stability Diagram
• Ca/P controls width of yield region
• Maintaining the pH above 6.2 avoids secondary products, but below 7-7.8 allow the co-processing with tissue
Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
Materials Science and EngineeringMaterials Science and Engineering
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Temperature Effects on Yield Diagram
Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
Materials Science and EngineeringMaterials Science and Engineering
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Validation of the Yield Diagram
Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
Materials Science and EngineeringMaterials Science and Engineering
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XRD of Verification Points on the Calcium Acetate/Tribasic Phosphate Model (Unwashed)
20 30 40 50 60
AP 6
AP 5
AP 4
AP 3
AP 1Inte
nsity
(Arb
itrar
y)
2 Theta (Degrees)
HA
Monetite
AP 2
Unwashed Powders as Prepared
20 30 40 50 60
APHT 6
APHT 5
APHT 4
APHT 3
APHT 2
Inte
nsity
(Arb
itrar
y)
2 Theta (Degrees)
HA
KCP
APHT 1
Unwashed Powders Heat Treated
Mossaad, C.; Starr, M.; Patil, S.; Riman, R. E., Chem. Mater., 22(1), 2010, 36-46.
Materials Science and EngineeringMaterials Science and Engineering
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TEM – Very Small Nanoparticles! Very Difficult to Isolate.
Mossaad, C.; Tan, M.C.; Starr, M.; Payzant, E.A.; Howe, J.Y..; Riman, R. E., Cryst. Growth Des., in press, 2010.
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Matrix Matrix with RU HA Surface Layer
Biomineralization of Hydroxyapatite onto DBM
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Micro-CT of Surface Mineralized DBM (10/6 mM)
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TEM of Mineralized DBM Fibers
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FTIR and XRD Confirms HA Presence
4000 3500 3000 2500 2000 1500 1000 500 0
1255
12581355
1560
1655
1656
1563 1407
1023
% T
rans
mitt
ance
(arb
itrar
y)
Wavenumber (cm-1)
DBM
HA+DBM
1019
10 20 30 40 50 60 70 80
Inte
nsity
(Arb
itrar
y)
2 Theta (Degrees)
Synthesized HA HA Standard
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TGA Studies show mineral content is similar to bone
7 wt%
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12 Bony-Site Sheep Study
Putty
Matrix
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Conclusions
• Thermodynamic computations were used to engineer a new mild process for synthesizing nanosized hydroxyapatite
• The process could be integrated with collagen fibers to make DBM-HA nanocomposites
• An aseptic adaptation of the synthesis method was accomplished
• A bioactive implant was prepared that stimulated bone growth- More stable interface afforded by preventing rapid aqueous dissociation
of the fibers- High surface area nanocomposite