Bio-inspired structured composites for load-bearing bone graft substitution

Natural composites, in particular nacre, often combine high strength and toughness thanks to highly ordered architectures and controlled geometries of the reinforcement components. However, combining strength, toughness and resorbability in synthetic materials remains a challenge in particular in the field of bone graft substitutes. In the present study, calcium phosphate-(CaP-)based materials with designed architectures inspired from natural composite materials were achieved. CaP platelets obtained by precipitation in organic medium were first aligned in chitosan matrices by solvent casting in ambient conditions. Efficient strengthening was obtained with 15 vol-% ceramic, reaching cortical bone strength (150 MPa) and preserving good ductility (5 % deformation). In a weak magnetic field, high spatial arrangement without percolation was maintained up to 20 vol-%. With directional freezing, good alignment of the platelets could be pushed up to 50 vol-%. In parallel, in situ recrystallization of CaP blocks in hydrothermal conditions led to hierarchical structures. The strength and the work-of-fracture were enhanced (300%) thanks to a change of failure mode.:Acknowledgements v Summary vii Background vii Thesis outline viii Part I: “Brick-and-mortar” structures with discrete reinforcement components ix Part II: “Textured” structures with continuous reinforcement components x Zusammenfassung xi Hintergrund xi Doktorarbeit Gliederung xii Teil I: “Ziegelmauer-Architektur” mit diskreten Verstärkungskomponenten xiii Teil II: “ Texturierte” Strukturen mit kontinuierlichen Verstärkungskomponenten xiv Chapter 1: General introduction 1 Bone grafting 1 CaP ceramics 1 How to improve toughness of CaP ceramics? 2 Importance of structure design: bio-inspiration 2 What mechanical properties should be reached? 5 Specific aims 5 Two general approaches to reach the goal 6 Nacre-inspired “brick-and mortar” structures (Part I) 6 Textured ceramic monoliths (Part II) 6 References 7 Chapter 2: Theoretical calculations 11 Introduction 12 Theoretical tensile strength of β-TCP platelets and critical size for flaw tolerance 13 Optimal aspect ratio 15 Composite strength and stiffness 17 Limitations 19 References 19 PART I: NACRE-INSPIRED “BRICK-AND-MORTAR” STRUCTURES Chapter 3: Synthesis of sub-micrometer calcium phosphate platelets 23 Introduction 24 ii Materials and Methods 25 Precipitation method 25 Reaction parameters 25 Characterization 26 Statistical analysis of results 28 Results 28 Reproducibility of standard experiments 28 Increase of the reagent volume to increase the productivity 30 Increase of the precursors concentration to increase the productivity and modify the particles 30 Increase of titration rate to simplify the process 32 Influence of temperature on the particles 35 Effect of the pH value on the particles 37 Effect of a longer reaction time on the particle stability 40 Study of the influence of variations of the Ca/P molar ratio 42 Discussion 43 Reproducibility 43 Productivity 44 CaP crystal shape 45 Crystal purity 47 Aspect ratio 48 Critical thickness 49 Uniformity of primary particles 50 Non agglomerated 51 General points 52 Conclusions 52 References 53 Chapter 4: Kinetics study of the calcium phosphate platelets growth 57 Introduction 58 Theory 58 Materials and methods 60 Materials and sample preparation 60 Characterization methods 61 Results 62 Visual observations during manipulations 62 SEM observations 62 XRD results 66 Size measurements 68 Kinetics calculations 70 Discussion 74 Nucleation and assembly mechanism 74 Reaction kinetics 76 Control of size and aspect ratio 76 Conclusions 77 References 78 Chapter 5: Structural design of bio-inspired composites by solvent casting 81 Foreword 82 Introduction 82 Experimental section 84 iii Synthesis of resorbable ceramic platelets 84 Solvent casting to prove the reinforcement efficiency of DCP platelets 84 Magnetization of the platelets 85 Maintaining the orientation during drying of an hydrogel matrix 86 Results 87 Synthesis of resorbable ceramic platelets 87 Solvent casting to prove the reinforcement efficiency of CaP platelets 87 Magnetization of the platelets 91 Maintaining the orientation during drying of an hydrogel matrix 93 Discussion 95 Detrimental effect of β-TCP platelets in chitosan 95 Efficient reinforcement with DCP platelets up to a given volume fraction 96 Threshold value for strength improvement 97 Fitting the experimental results with theoretical equations 98 Conclusions 101 References 101 Chapter 6: Biodegradable, strong and tough nacre-inspired structures obtained by freezecasting 105 Introduction 106 Experimental section 108 Synthesis of resorbable ceramic platelets 108 Preliminary freeze-casting tests with β-TCP-based slurries 108 Determination of adequate freeze-casting parameters for hydrogels-CaP slurries 108 Integration of CaP platelets and local planar alignment 109 Attempts to globally align porosity in two directions 109 Densification and consolidation 110 Tensile testing 110 Results 111 Preliminary freeze-casting tests with β-TCP-based slurries 111 Determination of adequate freeze-casting parameters for hydrogels-CaP slurries 112 Integration of CaP platelets and local planar alignment 113 Attempts to globally align porosity in two directions 119 Densification and consolidation 121 Tensile testing 121 Discussion 122 Conclusions 124 References 125 PART II: TEXTURED CERAMIC MONOLITHS Chapter 7: Micro-texturing by recrystallization of calcium phosphate blocks in hydrothermal conditions 127 Introduction 128 Materials and Methods 130 Samples characterization 132 Results 133 Macroscopic observations 133 Microstructural changes (SEM) 133 Crystalline phase conversion (XRD) 139 iv Mechanical properties 142 Fractured surfaces 142 Discussion 145 Conclusions 150 References 150 Chapter 8: Toughening of textured calcium phosphate blocks by polymer impregnation 155 Foreword 156 Introduction 156 Materials and Methods 157 Samples preparation 157 Characterization 158 Results 158 Porosity and microstructure 158 Composition 161 Mechanical properties 161 Discussion 162 Conclusions 164 References 164 Chapter 9: Synthesis and outlook 167 Curriculum Vitae 17

Laser Textured Calcium Phosphate Bio-Ceramic Coatings on Ti-6Al-4V for Improved Wettability and Bone Cell Compatibility

The interaction at the surfaces of load bearing implant biomaterials with tissues and physiological fluids is an area of crucial importance to all kinds of medical technologies. To achieve the best clinical outcome and restore the function of the diseased tissue, several surface engineering strategies have been discussed by scientific community throughout the world. In the current work, we are focusing on one such technique based on laser surface engineering to achieve the appropriate surface morphology and surface chemistry. Here by using a pulsed and continuous wave laser direct melting techniques we synthesize three dimensional textured surfaces of calcium phosphate (Ca-P) based surface chemistry on Ti-6Al-4V. The influence of each processing type on the micro texture and phase evolution and thereby its associated effect on wettability, in vitro bioactivity, and in vitro biocompatibility are systematically discussed. For samples processed using the pulsed laser, it was realized that with increasing laser scan speed and laser pulse frequency there was a transition from surface textures with sharp circular grooves to surface textures with radial grooves and thereby improved hydrophilicity. For CW laser processing the results demonstrated improved hydrophilicity for the samples processed at 100 μm line spacing as compared to the samples processed at 200 μm line spacing. Owing to the importance of Si for cartilage and hard tissue repair, a preliminary effort for synthesizing Ca-P-SiO2 composite coating on Ti-6Al-4V surface were also conducted. As a future potential technique we also explored the Laser Interference Patterning (LIP) technique to achieve the textured surfaces and developed understanding on their wetting behavior. In the current work, by adjusting the laser processing parameters we were able to synthesize textured coatings with biocompatible phases. The in vitro bioactivity and in vitro vi biocompatibility of the coatings were proved by the precipitation of an apatite like phase following immersion in simulated body fluid (SBF), and increased proliferation and spreading of the MC3T3-E1 like cells. The results and understanding of the current research is encouraging in terms of looking at other bio-ceramic precursor compositions and laser process parameter window for synthesizing better textured biocompatible coatings

Comprehensive quality control process for high precision intensity modulated adaptive proton therapy

The thesis focuses on development and clinical implementation of comprehensive and overlaying quality control process aimed at supporting introduction of high precision adaptive IMPT workflows. The thesis consists of seven chapters, covering topics on quality control for proton range accuracy, reconstruction, and accumulation of delivered dose distributions longitudinally throughout the proton therapy course and independent dose recalculation/predictive outcome-based patient specific quality assurance procedures. A proton range probing method as a quality control tool for range accuracy validation has been proposed and applied for range accuracy assessments in animal tissue samples covering a broad range of tissue types. A fraction-wise 4D dose reconstruction and accumulation procedure utilizing treatment delivery log files and patient-specific daily breathing patterns has been proposed and implemented in clinical practice. Validation of the procedure in controlled conditions with a 4D phantom revealed ability to spatially reconstruct the dose distributions with submillimeter accuracy. Eventually, an alternative approach for in-beam measurement-based patient specific quality assurance (PSQA) procedure has been investigated, developed, and introduced in clinical practice. By incorporating the developed range probing QC procedure as a validation tool for synthetic CTs and utilizing developed dose reconstruction and accumulation workflow, it enables possibility to establish a comprehensive longitudinal patient specific quality control process to monitor the treatment delivery in an environment of adaptive proton therapy. Introduction of more adaptive treatment procedures and availability of online adaptive workflows in proton therapy might be the next major advancement needed to take full advantage of the physical characteristics of the proton beam

Intrinsic osteoinduction and osteogenesis of biomimetic calcium phosphate scaffolds with different nano-, micro- and macroporosities : ectopic and orthotopic implantation in a canine model

The development of synthetic bone substitutes with enhanced osteogenic properties is urged by the global ageing population. Sintered calcium-phosphate (CaP) ceramics are the most widely used synthetic biomaterials for bone regeneration. However, their clinical performance is inferior to those of autografts, which are still considered the gold standard, despite the serious drawbacks associated with the need of a harvesting surgery. This thesis aims at providing new insights in the development of CaP biomaterials with osteoinductive properties, this is, with the capacity to foster the differentiation of mesenchymal stem cells to bone forming cells, without the need of adding exogenous growth factors. Previous studies pointed to chemical composition, macropore architecture, microstructural topography and specific surface area (SSA) as critical factors in the intrinsic osteoinduction of biomaterials. However, only sintered ceramics with a limited range of porosities and low SSAs had been analyzed so far. In the present thesis, we were able to extend this range to the nanoscale by using biomimetic low-temperature processing routes. Foaming and 3D-printing methods allowed producing biomimetic CaP scaffolds with tailored macropore architectures together with controlled micro and nanoporosity and, hence, high SSAs. In order to evaluate the intrinsic osteoinduction of this new family of biomimetic bone substitutes, nanostructured calcium deficient hydroxyapatite (CDHA) scaffolds with needle-like crystal morphology were implanted intramuscularly in a canine model, and compared with two sintered ceramics, namely biphasic calcium phosphate and beta-tricalcium phosphate (Study I). The results showed that the high reactivity of nanostructured biomimetic CDHA, combined with a spherical concave macroporosity of foamed scaffolds, accelerated and enhanced the osteoinduction potential beyond the limits of conventional, microstructured, sintered ceramics. As a second step, the effect of macropore geometry of nanostructured CDHA on the bone healing capacity was analyzed. The same foamed and 3D-printed CDHA scaffolds were implanted intraosseoulsy in a canine model (Study II). Whereas nanostructured CDHA was shown to be highly osteoconductive irrespective of macropore geometry, a superior osteogenic capacity was observed in the foamed scaffolds, which correlated well with the higher intrinsic osteoinductive potential demonstrated previously. Moreover, foams showed a higher cell-mediated degradation than the 3D-printed constructs, with a simultaneous and progressive replacement of the scaffold by new bone, demonstrating that the control of macropore architecture allows tuning both material degradation and new bone formation. Finally, aiming to further mimic the natural bone apatite, the effect of nanocrystal morphology (plate vs. needle) and carbonate doping on the intrinsic bioactivity of biomimetic CDHA was investigated. To this end, CDHA foams with different nanostructures (Coarse/Fine-CDHA) and carbonated CDHA foams were compared, both in canine ectopic and orthotopic implantation models (Study III). Fine-CDHA foams showed a superior osteoinduction and bone healing potential, as well as a higher degradation than Coarse-CDHA foams, suggesting that there is a threshold value in terms of SSA necessary to activate the cell-mediated resorption and the associated osteoinduction, which determines in turn the osteogenic capacity of the materials in a bony enviroment. Moreover, carbonate dopping of CDHA accelerated both intrinsic osteoinduction and bone healing, simultaneously increasing the cell-mediated resorption. Thus, the increased biomimetism of CDHA allowed the material to enter the natural bone remodelling cycle, this resulting in a tight synchronization between material degradation and bone formation, and ultimately, obtaining bone substitutes with enhanced bone regeneration potential.L’envelliment global de la població exigeix el desenvolupament de nous substituts ossis sintètics amb capacitats osteogèniques optimitzades. Tot i que les ceràmiques de fosfats de calci (CaP) sinteritzades són els biomaterials sintètics més utilitzats en regeneració òssia, la seva eficiència és inferior a la dels empelts d’ós autòleg, els quals continuen sent el tractament de primera elecció malgrat presentar inconvenients importants associats a la necessitat d’una segona cirurgia. Aquesta tesi té com a objectiu optimitzar el desenvolupament de biomaterials de CaP amb propietats osteoinductives, fet que estimula la diferenciació de cèl·lules mare mesenquimals a cèl·lules osteogèniques, sense l’ús de factors de creixement exògens. Estudis recents han identificat diferents factors crítics en l’osteoinducció intrínseca dels biomaterials com ara la composició química, la macroporositat, la microestructura i la superfície específica (SSA). Fins al moment, només s’han analitzat ceràmiques sinteritzades amb un rang limitat de porositats i SSAs. Tanmateix, en la present tesi s’ha aconseguit augmentar aquest rang a la nanoescala per mitjà de rutes de processament biomimètiques a baixes temperatures. L’escumat i la impressió 3D de CaP biomimètics, ha permès l’obtenció d’implants amb arquitectures macroporoses específicament modulades conjuntament amb micro i nanoporositats controlades, i per tant, amb SSAs significativament superiors. Per tal d'avaluar l'osteoinducció intrínseca d'aquests nous materials biomimètics, es van implantar intramuscularment materials nanoestructurats (cristalls tipus agulla) de hidroxiapatita deficient en calci (CDHA) en un model caní, i es van comparar amb dues ceràmiques sinteritzades (Estudi I). Els resultats van mostrar que la gran reactivitat de la CDHA nanoestructurada, combinada amb una macroporositat esfèrica còncava de les escumes, van incrementar el potencial d'osteoinducció més enllà dels límits oferts per les ceràmiques sinteritzades microestructurades. El segon pas va consistir en l’anàlisi de l'efecte de la geometria de la macroporositat dels materials de CDHA sobre la seva capacitat de consolidació òssia, implantant els materials escumats i els impresos en 3D a nivell intraossi en un model caní (Estudi II). Tot i que la CDHA nanoestructurada va demostrar ser altament osteoconductiva independentment de la geometria macroporosa, les escumes van mostrar una capacitat osteogènica superior, correlacionant-se directament amb el major potencial osteoinductiu intrínsec demostrat anteriorment. A més, les escumes van mostrar una reabsorció cel·lular superior als implants obtinguts per impressió 3D, substituint progressivament el material per nou os i, demostrant així que el control de l'arquitectura de la macroporositat permet adequar tant la degradació del material com fomentar la regeneració òssia. Finalment, amb l'objectiu de mimetitzar encara més la fase mineral òssia, es va investigar l’efecte de la morfologia dels nanocristalls (placa vs. agulla) i del dopatge amb ions carbonat sobre la bioactivitat intrínseca de la CDHA biomimètica, implantant escumes de CDHA amb diferents nanoestructures (Coarse/Fine-CDHA) i escumes carbonatades a nivell ectòpic i ortotòpic en gos (Estudi III). Les escumes Fine-CDHA van mostrar un potencial osteoinductiu i osteogènic superiors, i una degradació incrementada respecte a les escumes Coarse-CDHA, suggerint que existeix una SSA mínima per activar la degradació cel·lular dels materials i la conseqüent resposta osteoinductiva, fet que determina la capacitat osteogènica dels materials en un defecte ossi. La carbonatació de la CDHA va accelerar tant el potencial osteoinductiu i osteogènic, com la degradació cel·lular dels materials, suggerint que l’increment del biomimetisme de la CDHA afavoreix la introducció del material dins del cicle de remodelació òssi

Generating social media for the movie world: TweetMovies

PFC realitzat en el marc d'un programa de mobilitat amb la Helsinki Metropolia University of Applied Sciences.TweetMovies is a social network developed using edge web technologies, like Ruby on Rails, jQuery or Ruby on Rails. In the process, some advanced development techniques were used, like Test-Driven Development or Behavior-Driven Development. The basics of SEO are used and explained in the project

ReSCon '09, Research Student Conference: Book of Abstracts

The second SED Research Student Conference (ReSCon2009) was hosted over three days, 22-24 June 2009, in the Lecture Centre at Brunel University. The conference consisted of technical presentations, a poster session and social events. The abstracts and presentations were the result of ongoing research by postgraduate research students from the School of Engineering and Design at Brunel University. The conference is held annually, and ReSCon plays a key role in contributing to research and innovations within the School

The solar wind structures associated with cosmic ray decreases and particle acceleration in 1978-1982

The time histories of particles in the energy range 1 MeV to 1 GeV at times of all greater than 3 percent cosmic ray decreases in the years 1978 to 1982 are studied. Essentially all 59 of the decreases commenced at or before the passages of interplanetary shocks, the majority of which accelerated energetic particles. We use the intensity-time profiles of the energetic particles to separate the cosmic ray decreases into four classes which we subsequently associate with four types of solar wind structures. Decreases in class 1 (15 events) and class 2 (26 events) can be associated with shocks which are driven by energetic coronal mass ejections. For class 1 events the ejecta is detected at 1 AU whereas this is not the case for class 2 events. The shock must therefore play a dominant role in producing the depression of cosmic rays in class 2 events. In all class 1 and 2 events (which comprise 69 percent of the total) the departure time of the ejection from the sun (and hence the location) can be determined from the rapid onset of energetic particles several days before the shock passage at Earth. The class 1 events originate from within 50 deg of central meridian. Class 3 events (10 decreases) can be attributed to less energetic ejections which are directed towards the Earth. In these events the ejecta is more important than the shock in causing a depression in the cosmic ray intensity. The remaining events (14 percent of the total) can be attributed to corotating streams which have ejecta material embedded in them