PDF (Ahmed Chebbi PhD Thesis)

272 Pages·2011·5.65 MB·English

by  Ahmed Chebbi

Thermal Spray of a Drug Delivery System onto
Femoral Orthopaedic Implants

Ahmed Chebbi, B.Eng
A thesis submitted in fulfillment of the requirement for the degree
of
Doctor of Philosophy

Supervisor:
Dr Joseph Stokes
School of Mechanical and Manufacturing Engineering
Dublin City University, Ireland
i
Declaration

I hereby certify that this material, which I now submit for assessment on the programme of
study leading to the award of Doctor of Philosophy is entirely my own work, that I have
exercised reasonable care to ensure that the work is original, and does not to the best of my
knowledge breach any law of copyright, and has not been taken from the work of others
save and to the extent that such work has been cited and acknowledged within the text of
my work.
Signed: I.D. Number: 53145631 Date: 11/07/2011

ii
Dedication

TO MY BELOVED MOTHER&FATHER
The source of all the good in me

iii
Acknowledgements

First and above all, praise is due to almighty Allah for His everlasting blessing and
guidance in conceptualising, developing and completing this project.
I am to the highest degree thankful to my supervisor Dr. Joseph Stokes for his continual
support and guidance throughout the duration of this work. His innovative ideas,
constructive comments, suggestions and advice throughout the project were much
appreciated. I was very fortunate to have been able to work with him since undertaking my
final year project degree.
I very much thank the assistance of all the staff in the School of Mechanical and
Manufacturing Engineering, in particular Michael Tyrell for the technical support provided
throughout the course of my PhD. I extend my gratitude to the staff of other schools and
research centers for their technical support on a number of characterisation techniques. I
also greatly appreciate the support provided by many of the researchers in the department,
in particular the invaluable advice and suggestions of Dr Khaled Ben Younis on the Design
of Experiments work. Thanks also to Finbarr O’Sullivan in the National Institute for
Cellular Biotechnology for assistance with the in vitro experimental work.
I genuinely show gratitude to all my friends and colleagues in DCU for their
encouragement and support, in particular Elena Irina Pascu for the numerous scientific
discussions during the last year of my work. I cannot forget to be grateful to my office
mates Tuty, Aqida, Shadi, Joe and Jack for creating a perfectly pleasant study environment.
Thank you as well to my good friend Melanie Braune for all the tedious proof reading.
I offer heartfelt thanks to my loving wife, Faten Ben Ezzedine for her love, continued
patience, encouragement and understanding especially during the last stage of my PhD.
Special thanks to my family in Tunisia who always believed in me.
Finally, I would like to acknowledge the financial support provided by the Irish Research
Council for Science, Engineering and Technology, funded by the National Development
Plan, which made this project possible.
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Contents

Declaration ........................................................................................................................................... ii 
Dedication ........................................................................................................................................... iii 
Acknowledgements ............................................................................................................................. iv 
Contents ............................................................................................................................................... v 
List of Figures ..................................................................................................................................... ix 
Nomenclature .................................................................................................................................... xiv 
Abstract ................................................................................................................................................1 
1  Introduction ..................................................................................................................................2 
1.1  Objectives of the Research Project ......................................................................................4 
1.2  Structure of the Thesis ..........................................................................................................6 
2  Literature Review .........................................................................................................................7 
2.1  Bone Structure .....................................................................................................................7 
2.2  Orthopaedic Hip Implants ...................................................................................................9 
2.2.1  Hip Replacement: An Overview ..................................................................................9 
2.2.2  HA-Coated Hip Implants .......................................................................................... 10 
2.3  Biomaterials ...................................................................................................................... 13 
2.3.1  Biocompatible Polymers ........................................................................................... 15 
2.3.2  Polycaprolactone (PCL) ............................................................................................ 16 
2.3.3  Polymethylmethacrylate (PMMA) ............................................................................ 17 
2.3.4  Polyhydroxybutyrate/Polyhydroxyvalerate (PHBV) ................................................ 18 
2.3.5  Hydroxyapatite (HA) ................................................................................................ 19 
2.3.6  Biocomposites ........................................................................................................... 24 
2.3.7  Titanium (Ti) ............................................................................................................. 27 
2.4  Thermal Spraying .............................................................................................................. 30 
2.4.1  Flame Spraying ......................................................................................................... 33 
2.4.2  Atmospheric Plasma Spray ....................................................................................... 34 
2.5  Properties of Thermally Sprayed Coatings ....................................................................... 38 
2.5.1  Plasma Sprayed HA for Orthopaedic Coatings ......................................................... 38 
2.5.2  Thermally Sprayed Polymers .................................................................................... 44 
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2.6  Polymer Based Drug Delivery Systems ............................................................................. 50 
2.6.1  Polymer-Drug Attachment ........................................................................................ 54 
2.6.2  Polymers for Drug Delivery Purposes ...................................................................... 56 
2.6.3  Heat-Stable Antibiotics ............................................................................................. 59 
2.7  DoE Experiments .............................................................................................................. 60 
2.7.1  Factorial Experiments ............................................................................................... 61 
2.7.2  Response Surface Methodology ................................................................................ 62 
Summary: .......................................................................................................................................... 63 
3  Equipment, Materials and Procedures ...................................................................................... 64 
3.1  Thermal Spraying Equipment ........................................................................................... 64 
3.1.1  Flame Spray Equipment ............................................................................................ 64 
3.1.2  Flame Spray Procedure ............................................................................................. 66 
3.1.3  Plasma Spray Equipment .......................................................................................... 67 
3.1.4  Plasma Spraying Procedure ...................................................................................... 71 
3.2  Feed Stock Powders .......................................................................................................... 72 
3.2.1  Polycaprolactone (PCL) ............................................................................................ 72 
3.2.2  Polymethylmethacrylate (PMMA) ............................................................................ 73 
3.2.3  Polyhydroxybutyrate/Polyhydroxyvalerate (PHBV) ................................................ 73 
3.2.4  Hydroxyapatite (HA) ................................................................................................ 74 
3.3  Substrates .......................................................................................................................... 74 
3.4  Substrate Preparation ....................................................................................................... 75 
3.5  Surface Analysis ................................................................................................................ 76 
3.6  Powder Characterisation .................................................................................................. 77 
3.6.1  Powder Morphology ................................................................................................. 77 
3.6.2  Particle Size Distribution .......................................................................................... 78 
3.6.3  Powder Density ......................................................................................................... 78 
3.6.4  Powder Thermal Behaviour ...................................................................................... 79 
3.6.5  Powder Composition ................................................................................................. 80 
3.6.6  Powder Crystallinity ................................................................................................. 81 
3.7  Process Modelling............................................................................................................. 81 
3.8  Coating Characterisation ................................................................................................. 83 
3.8.1  Coating Morphology ................................................................................................. 83 
3.8.2  Cross-Section Metallographic Preparation ............................................................... 83 
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3.8.3  Coating Thickness ..................................................................................................... 84 
3.8.4  Coating Adhesion ...................................................................................................... 85 
3.8.5  Coating Wettability ................................................................................................... 86 
3.8.6  Coating Composition ................................................................................................ 87 
3.8.7  Coating Degradation ................................................................................................. 88 
3.8.8  pH and Conductivity ................................................................................................. 89 
3.9  Biological Testing ............................................................................................................. 89 
3.9.1  Powders Biological Assessment ............................................................................... 90 
3.9.2  Coating Biological Assessment ................................................................................ 91 
4  Results and Discussions ............................................................................................................ 93 
4.1  Materials Characterisation ............................................................................................... 93 
4.1.1  Substrate Material ..................................................................................................... 93 
4.1.2  Polycaprolactone (PCL) Powder ............................................................................... 94 
4.1.3  Polymethylmethacrylate (PMMA) Powder ............................................................... 97 
4.1.4  Polyhydroxybutyrate/Polyhydroxyvalerate (PHBV) Powder ................................. 100 
4.1.5  Hydroxyapatite (HA) Powder ................................................................................. 103 
4.2  Preliminary Process Investigation .................................................................................. 106 
4.2.1  PCL Screening ........................................................................................................ 106 
4.2.2  PMMA Screening ................................................................................................... 107 
4.2.3  PCL/PMMA Screening ........................................................................................... 110 
4.2.4  PHBV/PMMA Screening ........................................................................................ 113 
4.3  Parameter Space Investigation ....................................................................................... 115 
4.3.1  PCL/PMMA Parameters Range Selection .............................................................. 116 
4.3.2  PHBV/PMMA Parameters Range Selection ........................................................... 120 
4.4  Preliminary Biological Testing ....................................................................................... 125 
4.4.1  Powder Biological Testing ...................................................................................... 125 
4.4.2  Coating Biological Testing ..................................................................................... 126 
4.5  Response Surface Methodology Study ............................................................................ 127 
4.5.1  Coating Adhesion .................................................................................................... 127 
4.5.2  DoE Layout for PCL/PMMA .................................................................................. 129 
4.5.3  PCL/PMMA Thickness Model Validation .............................................................. 131 
4.5.4  PCL/PMMA Roughness Model Validation ............................................................ 139 
4.5.5  PCL/PMMA Adhesion Model Validation .............................................................. 146 
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4.5.6  PCL/PMMA Wettability Model Validation ............................................................ 154 
4.5.7  DoE Layout for PHBV/PMMA .............................................................................. 158 
4.5.8  PHBV/PMMA Thickness Model Validation .......................................................... 160 
4.5.9  PHBV/PMMA Roughness Model Validation ......................................................... 171 
4.5.10  PHBV/PMMA Adhesion Model Validation ........................................................... 180 
4.5.11  PHBV/PMMA Wettabilitty Model Validation ....................................................... 189 
4.5.12  RSM Experiment Summary .................................................................................... 194 
4.6  Optimisation Process for Polymer Coatings ................................................................... 195 
4.6.1  Thickness Requirements ......................................................................................... 195 
4.6.2  Roughness Requirements ........................................................................................ 196 
4.6.3  Adhesion Requirements .......................................................................................... 196 
4.6.4  Optimisation Summary ........................................................................................... 196 
4.6.5  Optimisation Validation .......................................................................................... 198 
4.6.6  Polymer Coatings Composition .............................................................................. 199 
4.7  Hydroxyapatite Coating Production ............................................................................... 202 
4.8  Mono-layer and Bi-layer Coatings as DDS .................................................................... 203 
4.9  Physio-Chemical Analysis ............................................................................................... 207 
4.9.1  Coating pH .............................................................................................................. 207 
4.9.2  Coating Conductivity .............................................................................................. 211 
4.9.3  Coating Weight Loss ............................................................................................... 214 
4.10  Biological Analysis ......................................................................................................... 219 
5  Conclusions and Recommendations for Future Work ............................................................ 220 
5.1  Conclusions ..................................................................................................................... 220 
5.2  Recommendations for Future Work ................................................................................ 222 
Publications Arising From This Work ............................................................................................ 224 
References ....................................................................................................................................... 225 
Appendix A- Statistical Measures.................................................................................................. 247 
Appendix B- Sample Holder Movement ........................................................................................ 250 
Appendix C- Plasma Equipment Operating Instructions ................................................................ 251 
Appendix D- Biological Analysis ................................................................................................... 256 

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List of Figures
Figure 1: Hierarchical structural organisation of bone [10] ......................................................... 7
Figure 2: Total hip replacement [18] .......................................................................................... 10
Figure 3: Schematic of bone-implant interface in the case of inert and bioactive surfaces
(adapted from [28]) ..................................................................................................................... 12
Figure 4: A schematic of the various human body parts, which can be potentially replaced by
synthetic biomaterials [34] ......................................................................................................... 13
Figure 5: Various applications of different polymer composite materials [37] .......................... 15
Figure 6: Ring opening polymerisation of Polycaprolactone [38] ............................................. 16
Figure 7: Free radical vinyl polymerisation [45] ........................................................................ 17
Figure 8: PHBV synthesis .......................................................................................................... 18
Figure 9: Illustration of a) crystal structure b) ac or bc face of hydroxyapatite [55] .................. 19
Figure 10: Implant materials requirements in orthopaedic applications [107] ........................... 29
Figure 11: Generic thermal spray process [111]......................................................................... 30
Figure 12: Thermal spray processes and subsets, adapted from [111] ....................................... 31
Figure 13: Cross section of a powder flame spray [112] ............................................................ 33
Figure 14: Sectional view of plasma torch [112] ....................................................................... 34
Figure 15: Input and output parameters ...................................................................................... 35
Figure 16: Typical cross section of a plasma sprayed coating ................................................... 36
Figure 17: Influence of particle trajectories along the jet on the degree of melting, adapted from
[111] ........................................................................................................................................... 37
Figure 18: Phase formation model for plasma sprayed HA coatings [54] ................................. 39
Figure 19: Cross-section of predicted three-dimensional spreading splats for 60, 90 and 120 µm
diameter particles [155] .............................................................................................................. 47
Figure 20: Microsphere preparation using the emulsion solvent evaporation technique ........... 55
Figure 21: Microsphere preparation using the spray drying technique ...................................... 55
Figure 22: Typical installation of a powder flame spray process [112] ..................................... 64
Figure 23: Ibeda MiniSprayJet Flame Spray System ................................................................. 65
Figure 24: Complete installation of a plasma spray system [112] .............................................. 68
Figure 25: Plasma Spray System ................................................................................................ 68
Figure 26: Sulzer Metco 9MB Plasma Gun ................................ Error! Bookmark not defined.
Figure 27: Sulzer Metco 9MCE Control Unit ............................................................................ 70
Figure 28: Sulzer Metco 9MPE Closed-Loop Powder Feeder ................................................... 71
Figure 29: Sample holder [82] .................................................................................................... 75
Figure 30: Stylus movement (right) and direction of pass (left) across the coating surface ...... 76
Figure 31: Fisherscope probe, principle of measurements [211] ............................................... 84
Figure 32: Pull-off stud for adhesion testing .............................................................................. 85
Figure 33: Contact angle θ of red tangent at the three phase boudary ........................................ 87
Figure 34: Idealised equilibrium between degradation rate of bone scaffold and bone
regeneration [216] ....................................................................................................................... 88
Figure 35: PCL powder morphology .......................................................................................... 94
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Figure 36: Particle size distribution for PCL .............................................................................. 95
Figure 37: TGA and DTA of PCL powder ................................................................................. 96
Figure 38: PMMA powder morphology ..................................................................................... 97
Figure 39: Particle size distribution for PMMA ......................................................................... 98
Figure 40: TGA and DTA of PMMA powder ............................................................................ 99
Figure 41: PHBV powder morphology .................................................................................... 100
Figure 42: Particle size distribution for PHB98%/PHV2% ...................................................... 100
Figure 43: TGA and DTA of PHBV powder ........................................................................... 101
Figure 44: Particle size distribution for HA ............................................................................. 103
Figure 45: HA powder morphology: a) at Mag=250X; b) at Mag=1000X .............................. 104
Figure 46: XRD pattern of CAPITAL 60 HA powder ............................................................. 105
Figure 47: PCL coating morphology: a) at Mag=420X; b) at Mag=1450X ............................. 107
Figure 48: Substrate following PMMA thermal spraying: a) at Mag=8X; b) at Mag=325X ... 108
Figure 49: Substrate following PMMA thermal spraying: a) at Mag=70X; b) at Mag= 720X 110
Figure 50: From left to right: orifice 4 used, orifice 3 used, bare Ti disc ................................. 112
Figure 51: Plume appearance with: a) Neutral flame; b) powder orifice 3 used; c) powder
orifice 4 used (excess powder) ................................................................................................. 112
Figure 52: PCL/PMMA coating using powder orifice 3 at: a) Mag = 370 X; b) Mag = 1900 X
.................................................................................................................................................. 113
Figure 53: PCL/PMMA coating using powder orifice 4 at: a) Mag = 370 X; b) Mag = 1900 X
.................................................................................................................................................. 113
Figure 54: PHBV/PMMA coating morphology at Mag=100X ................................................ 114
Figure 55: PCL/PMMA coatings classification chart ............................................................... 116
Figure 56: PHBV/PMMA coatings classification chart ........................................................... 120
Figure 57: Cell proliferation assay results ................................................................................ 125
Figure 58: Alkaline phosphatase assay results ......................................................................... 126
Figure 59: Cell proliferation study for the preliminary coating assessment ............................. 127
Figure 60: Pull-off test area showing cohesive failure ............................................................. 128
Figure 61: Pull-off test area showing adhesive failure ............................................................. 129
Figure 62: Predicted versus Actual values for PCL/PMMA coating thickness (1/õm) ......... 135
Figure 63: Average effect of traverse speed (A) (ips) on the thickness (1/õm) of PCL/PMMA
coatings ..................................................................................................................................... 136
Figure 64: Interaction effects of traverse speed (ips) and spraying distance (cm) on thickness
(µm) at a)6 passes, b)8 passes and c)10 passes ........................................................................ 137
Figure 65: Predicted versus Actual values for PCL/PMMA coating roughness (Ln/µm) ........ 142
Figure 66: Average effect of Traverse Speed (ips) (A) on the roughness (µm) of PCL/PMMA
coatings ..................................................................................................................................... 143
Figure 67: Average effect of number of passes (C) on the roughness (µm) of PCL/PMMA
coatings ..................................................................................................................................... 144
Figure 68: Roughness versus Thickness for PCL/PMMA coatings ......................................... 145
Figure 69: Predicted versus Actual values for PCL/PMMA coating adhesion (kg/cm2) ......... 150
x