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Indiana University-Purdue University Indianapolis (IUPUI) / Calcium phosphate-filled restorative materials were developed to provide calcium (Ca) and phosphate (PO4) ions, which have been proposed to enhance remineralization of demineralized tooth structure. Recently, tricalcium phosphate (TCP)-filled restorative materials were introduced as an alternative to amorphous calcium phosphate. The TCP filler has a more crystalline structure than ACP and is therefore potentially stronger. The aim of the present study was to examine TCP-filled restorative resins at different concentration levels at different time intervals to characterize the concentrations of Ca and PO4 ions released, and to measure the water sorption (WS) of these resins. An in vitro study was conducted by formulating resin composite using TCP as the filler mixed with EBPADMA, HmDMA, and HEMA as the resin matrix. One-hundred- sixty samples were prepared, 40 samples of each filler concentration (30 percent, 40 percent, 50 percent, and 60 percent) by weight. From each filler concentration, 5 samples of each of the 8 time points (time intervals of 4 h, 8 h, 12 h, 24 h, 3 d, 7 d, 14 d, and 21 d) were immersed in 100-ml deionized water. Calcium and PO4 ions were measured using atomic absorption spectroscopy and light spectroscopy, respectively. Water sorption (WS) was measured according to ISO 4049 specification and then the WS and the diffusion coefficient were calculated. The significance level was set at p = 0.001. The results indicated that Ca and PO4 ion release increased with increasing filler level at a rate faster than being linear. In addition, WS results were very high and failed to meet the ISO 4049 specification requirement. Diffusion coefficient results were also high. One-way ANOVA test for only 21-day data revealed that there is a statistically significant difference in filler level percent, and two-way ANOVA testing revealed that there is a statistically significant interaction between time and filler level percent on the Ca, PO4 released and WS. It can be concluded that the concentrations of Ca and PO4 released and WS were affected by composition of the monomers, filler level and type, dispersion, and the absence of coupling agent. Although this TCP-filled restorative material may release Ca and PO4, it cannot serve as a restorative material due to high WS values. Further study is needed to improve the material and evaluate its ability in promoting remineralization of the tooth structure in order for it to serve its purpose.

Avec plus de 2 millions d’interventions chirurgicales par an dans le monde, les actes de chirurgie osseuse sont les plus fréquents, ce qui pousse les entreprises du secteur des biomatériaux pour la régénération osseuse à investir massivement pour sans cesse améliorer leurs produits. Cette thèse est issue d’un contrat CIFRE effectué avec l’entreprise Kasios afin de l’aider dans le développement de céramiques et polymères poreux principalement pour des applications en chirurgie maxillo-faciale. Les travaux réalisés s’articulent autour du développement de biomatériaux biphasiques à base de phosphate tricalcique béta (β-TCP). En premier lieu, des microfibres de polycaprolactone (PCL) incorporant des particules élémentaires de β-TCP ont été fabriquées par électrospinning. Les principales applications des fibres concernent la régénération osseuse guidée pour la préservation alvéolaire ou les opérations de relevés de sinus. L’électrospinning des fibres a utilisé des solvants ne présentant pas de toxicité aiguë. Les fibres ont formé des membranes manipulables qui peuvent être facilement découpées et suturées même en environnement humide. Les études in vitro n’ont révélé aucune cytotoxicité et les membranes ont permis la prolifération de cellules ostéoblastiques. La seconde étude a permis la fabrication d’éponges de gélatine et d’acide hyaluronique saturées ou recouvertes en surface de granules de β-TCP pour le comblement alvéolaire. Les éponges étaient facilement façonnables pour correspondre à l’alvéole du patient. Le chirurgien pourrait alors bénéficier de la nature biphasique du dispositif médical afin de faciliter l’implantation et éviter la manipulation séparée des éponges et des granules. L’utilisation des éponges permettrait par ailleurs d’assurer un positionnement idéal des granules pour la cicatrisation alvéolaire. La troisième étude, plus fondamentale, porte sur l’interaction des cellules osseuses avec le β-TCP et sa résorption. Des études de biomécanique et de biodégradation ainsi que de biodissolution ont également été réalisées sur des biomatériaux produits par l’entreprise. / With more than 2 million surgeries per year, bone tissue is one of the most concerned tissues and biomaterial companies have developed massive investments to continually improve bone regeneration.This thesis was conducted during a CIFRE contract (a tripartite contract linking a student, a university and acompany) and was done in association with the company Kasios for the development of new porous polymers and ceramics. This thesis was specifically centered in the development of biphasic biomaterials based upon beta tricalcium phosphate (β-TCP). First, polycaprolacton (PCL) microfibers incorporating β-TCP elementary particles were produced using electrospinning. These fibers were developed to provide membranes for guided bone regeneration usable in alveolar preservation and sinus lifting. Electrospinning of the fibers did not require any high toxicity solvent. Our fibers formed membranes that could easily be handled, cut and sutured in dry and wet environment. In vitrocytotoxicity studies confirmed the non-toxic nature of the material and showed the ability of the membranes to encourage survival and proliferation of osteoblastic cells. Secondly, freeze-dried gelatin and hyaluronicacid sponges saturated or embedded with β-TCP granules were developed for alveolar filling. Theses ponges could easily be shaped to fit the patient’s dental socket. The biphasic nature of the sponges could make the implantation easier and faster by avoiding surgeons to handle separately the granules and the sponges. This medical device could also insure a correct and optimal positioning of the granules for the patient healing. Lastly, a fundamental study was conducted on resorption of β-TCP and the interaction between bone cells and the biomaterial. Biomechanical and biodegradation/biodissolution studies were also done on different types of biomaterials produced by the company.

Surfaces and interfaces are of fundamental importance from the nucleation to growth of crystals formed under different conditions such as vapor phase, liquid phase including biomineralisation conditions. Recently there is lot of interest in controlling the shape of nanoparticles during the synthesis due to their excellent shape dependent properties. Understanding the role of surfaces and interfaces is vital for such shapecontrolled synthesis of nanomaterials. On the surface, coordination number, structure, density and composition are different from that of bulk and hence the properties are completely different in the surfaces and interfaces of any crystalline material. Especially when the length scale become nanoscale, the surface and interface play a dominant important role and leads to several new and interesting phenomena. In this dissertation, the role of surfaces and interfaces on the synthesis and the properties of inorganic functional nanostructures have been studied. The work primarily relies on basic chemistry to synthesize nanostructures that brings the importance of surfaces/interfaces into the picture. Though several basic characterization techniques have been used, electron microscopy has been the emphasis and has been used extensively through the work to probe and explore the materials for characterizing the structures over a variety of length scales. The entire thesis based on the results and findings obtained from the present investigation are organized as follows: Chapter1 gives a general introduction to the surfaces and interfaces to create a background for the investigation. This emphasizes the role of surfaces and interfaces in several aspects starting from nucleation, growth to the properties of inorganic crystals. It gives some exposure in to the different type of surface phenomenon which is common in nanoscale materials. Chapter 2 deals with the materials and methods which essentially gives the information about the materials used for the synthesis and the techniques utilized to characterize the materials chosen for the investigation. Chapter 3 deals with predicting the morphology of 2D nanostructures by combining the crystal growth theory into chemical thermodynamics. Morphology diagrams have been developed for Au, Ag, Pt and Pd to predict conditions under which two-dimensional nanostructures form as a result of a chemical reaction. In addition, it provides the general understanding of shape control in 2D nanostructures with atomistic mechanism. The validity of the morphology diagram has been tested for various noble metals by carrying out critical experiments. As a result, 2D nanostructures of metals projecting the lowest energy facet resulted in a complete novel way in the absence of any capping/reducing agents. Chapter 4 deals with predicting the formation of 2D nanostructures of inorganic crystals formed as a result of precipitation reaction. Morphology diagram has been developed for the case of hydroxyapatite, an inorganic part of the human bone. This answers some of the long standing question related to the shape of the HA crystals formed in the bone by biomineralisation. The generality of the method has been tested to few other inorganic crystals such as CaCO3, ZnO and CuO formed through precipitation reaction. The key finding of the above two chapter is that the low driving force of the chemical reactions results in two dimensional nanostructures. On contrary, high chemical driving force combined with the optimum zeta potential results in porous aggregate of nanoparticles. Chapter 5 discusses the formation of porous clusters of metals and ceramics at specific conditions. The mechanism behind the formation of monodisperse aggregates are investigated based on the interaction energies of nanoparticles in aqueous medium. This chapter reveals the role of surface charge and the surface energy in controlling the stability of nanoparticles in aqueous medium. In addition, it provides the simple methodology to produce well controlled porous clusters by exploiting the competition between surface charge and surface energy during the aggregation. The application of the porous clusters of Pt has been tested for methanol oxidation which is essential for fuel cell applications. Chapter 6 deals with the development of porous biphasic scaffolds through the morphology transition of nanorods. Rod shape is not stable when subjected to high temperature due to instability and spherodisation takes place to minimize the surface energy. Here in this chapter, by exploiting spherodisation along with the phase transition, highly interconnected porous structure of hydroxyapatite and tricalcium phosphate is achieved. Combined with the morphology transition, by adding naphthalene as a template, the possibility of achieving hierarchical porous structure also presented. The mechanical strength of the biphasic porous scaffold has been tested by microindentation. Mechanical properties of apatite are generally poor and there are lots of efforts to improve the mechanical properties apatite by the composite approach. Chapter 7 deals with the HA-Alumina and HA-TCP composites. In spite of much attention given to the mechanical properties of the composites, the interfacial phenomenon that takes place between the components of the nanocomposite has not been studied in detail. In the present study, interfacial reactions in hydroxyapatite-alumina nanocomposites have been investigated and new reaction mechanism also proposed. The degradation of densification process has been observed for the HATCP composites due to the creation of porous interface between HA crystals and TCP matrix. Mechanical properties of these two composites have been studied using microindentation. The mechanical properties of HA and TCP single crystals are important for developing the biphasic composites with reliable mechanical properties. Chapter8deals with the mechanical behavior of hydroxyapatite and tricalcium phosphate single crystals. The mechanical properties of HA and TCP have been studied by performing nanoand microindentation on specific crystallographic facets. In case of hydroxyapatite, the anisotropy in mechanical properties has been explored by performing indentation on its prism and basal planes. Nanoscale plasticity is observed in both HA and TCP crystals which arise due to the easy movement of surface atoms with lesser coordination compared to the bulk. Nanoindentation has been performed in the calciumdeficient HA platelets provides important clues about the role of calcium deficiency on the mechanical behavior of bone and has implications for the properties of osteoporotic bones.

Les bioverres du système quaternaire SiO2-CaO-Na2O-P2O5 obtenus par fusion doivent être coulés à 1400°C, ce qui ne permet pas la mise en forme de matériaux complexes comme par exemple des composites macroporeux en biocéramiques (HA et TCP) recouverts d’une couche uniforme de bioverre. Pour contourner cette limitation, la voie sol-gel a été utilisée dans cette étude. Le but principal a été de synthétiser par le procédé sol-gel, deux compositions quaternaires du système SiO2-CaO-Na2O-P2O5 habituellement obtenues par fusion. Il s’agit des compositions 45S5® de L.L. Hench et 47Q de C. Duée. Ces verres sont inversés, c’est à dire qu’ils contiennent plus d’éléments modificateurs (calcium et sodium) que d’éléments formateurs (silicium et phosphore). Pour la synthèse sol-gel, du TEOS (TétraEthylOrthoSilicate) et du TEP (TriEthylPhosphate) ont été utilisés pour introduire les formateurs. En utilisant des précurseurs minéraux pour le calcium et le sodium, il existe des difficultés à maintenir le gel amorphe lors de son séchage. En effet, les précurseurs minéraux sont le siège de mécanismes de dissolution-précipitation liés entre autres aux solvants choisis, à la nature et à la concentration des anions dans le milieu. L’étude s’est donc orientée vers l’utilisation d’autres précurseurs des modificateurs afin de limiter la part des anions qui contribuent au phénomène de précipitation non souhaité. Deux procédés de synthèse originaux ont été alors mis au point avec des précurseurs alcoolates, acétates et du glycérol. Avec ces procédés, la nature amorphe des composés a été confirmée et leurs caractéristiques thermiques ont été ensuite étudiées. Tous les verres sol-gel réalisés sont bioactifs. Les compositions de base, 45S5® et 47Q, ont été ensuite dopées avec de l’argent afin de doter les bioverres d’une action antibactérienne. Des cellules L132 ont été utilisées pour évaluer la toxicité des poudres des deux procédés solgel. Le procédé le moins toxique a été conservé pour la suite de l’étude. Les bioverres dopés et non dopés ont été alors déposés à la surface d’échantillons plats et macroporeux en HA et TCP par une technique de trempage-retrait. Des tests de prolifération et de formation de biofilms par Pseudomonas aeruginosa ont été réalisés sur des pastilles de TCP recouvertes et ont mis en évidence un effet toxique des dépôts contenant de l’argent. Des mesures de prolifération et de vitalité sur des cellules humaines MG63 ont été également réalisées et ont permis d’observer également un effet toxique. Cet effet n’est pas souhaitable dans ce cas car il affecte la biocompatibilité de l’implant. Il devrait cependant être confirmé par d’autres tests réalisés avec d’autres lignées cellulaires. / Bioglasses of quaternary system SiO2-Na2O-CaO-P2O5 obtained by melting are cast at 1400 ° C, which does not allow the shape of complex materials, for example macroporous bioceramics composites (HA and TCP) coated with an uniform layer of bioglass. To overcome this limitation, the sol-gel process has been used in this study. The aim has been to synthesize by sol-gel process, two quaternary compositions usually obtained by melting in the SiO2- CaO-Na2O-P2O5 system. These are two compositions: 45S5® of L.L. Hench and 47Q made by C. Duée. These glasses are reversed, ie they contain more modifiers elements (calcium and sodium) as formers elements (silicon and phosphorus). For the sol-gel synthesis, TEOS (TetraEthylOrthoSilicate) and TEP (TriEthylPhosphate) have been used to introduce the formers. When minerals precursors are used for calcium and sodium, there are difficulties to maintain amorphous the gel during its drying. Indeed, minerals precursors have some dissolution-precipitation mechanisms linked to the selected solvents and the nature and concentration of anions in the medium. The use of other modifiers precursors has been made in the study to limit the proportion of anions contributing to the undesired precipitation phenomenon. Two original synthesis methods have been developed with alkoxide precursors, acetates and glycerol. With these processes, the amorphous nature of the compounds has been confirmed and their thermal characteristics have been studied. All sol-gel glasses are bioactives. The compositions, 45S5® and 47Q, have been doped with silver to add an antibacterial action to the bioglasses. L132 cells have been used to test the toxicity on the powders of the two sol-gel processes. The least toxic process is has been retained for the other tests. Doped and undoped bioglasses have been coated on the surface of flat and macroporous samples of HA and TCP by a dip-coating technique. Proliferation tests and biofilms formation by Pseudomonas aeruginosa have been made on coated TCP and show toxic effects of silver. Proliferation and vitality tests have been also made on MG63 human cells and have allowed to observe a toxic effect. This effect is not suitable in this case because it affects the biocompatibility of the implant. It would, however, be confirmed by other tests with other cell lines.

Despite the recent development in PLA and PLGA based medical devices, there are still needs to further improve the mechanical performance of bioresorbable medical implants and their bioactivity. This is normally done by optimizing the filler compositions in selected groups ofbiodegradable polymer matrices. In this study, the effects of various filler levels on mechanical strength and thermal properties of PLA and PLGA composites were investigated. Composites containing different dosage of osteoconductive HAp with various particles size (0-5μm, 0-50 μm, nano size), β-TCP, bioactive glass and biodegradable Poly-L-lactide and Polylactide-glycolic acid was manufactured with melt blending, using a twin-screw extruder.The samples were investigated by Differential Scanning Calorimetry (DSC), thermo gravimetric analysis (TGA), Scanning Electron Microscopy (SEM), viscometer, three points bending machine, and Optical Microscopy (OM). The Extruder produced a porous profile. The result from TGA and SEM indicated that there was homogenous filler dispersion in the matrix after compounding.The result from DSC and Viscometer shows that there was some degradation duringcompounding. Mechanical properties of composites were modified by adding filler to matrix. The addition of Bioactive glass, as a filler, increases the degradation of the polymer matrix. The best filler that was applied is 0-5μm and nano HAp. Also in in-vitro degradation part of this thesis work, the effects of calcium phosphate materialsare investigated on degradation process.