Bone is currently the second most transplanted tissue, second only to blood. However, significant hurdles including graft supply and implant failure continue to plague researchers and clinicians. Currently, standard clinical procedures include autologous and allogeneic grafting. Autologous grafts may achieve functional repair; yet, they are available in limited supply and are associated with donor site morbidity. Allogeneic grafts are available in greater supply, but have a higher risk of infection. To overcome the disadvantages of current grafts, tissue engineering has become a major focus for the regeneration of bone. The goal of tissue engineering is to use a multidisciplinary approach to create biomimetic constructs that stimulate osteogenic regeneration to heal bone defects and restore tissue function. Biodegradable scaffolds are used in tissue engineering strategies as an interim template for tissue regeneration. The scaffold architecture provides mechanical support for cell attachment and tissue regeneration. Biocompatible poly(lactic-co-glycolic acid) (PLGA) has been processed through a number of techniques to create porous 3D architectures. Hydroxyapatite (HAP) and tricalcium phosphate have been used in conjunction with polymer scaffolds due to their osteoconductivity and biocompatibility, but they often lack osteoinductivity and are resistant to biodegradation. Conversely, amorphous calcium phosphate (ACP) is a mineral that solubilizes under aqueous conditions, releasing calcium and phosphate ions, which have been postulated to enhance osteoblast differentiation and mineralization. Controlled dissolution can be achieved by stabilizing ACP with divalent cations such as zinc or copper. Furthermore, incorporation of such osteogenic ACPs within a biodegradable PLGA scaffold could enhance the osteoconductivity of the scaffold while providing calcium and phosphate ions to differentiating osteoprogenitor cells, thereby stimulating osteogenesis when implanted in vivo. In this research, the effect of zinc on the differentiation of osteoprogenitor cells was investigated. Zinc supplementation of the culture media had no stimulatory effect on cell proliferation or differentiation. ACPs were synthesized using zirconium (ZrACP) and zinc (ZnACP) as stabilizers to achieve sustained ion release. Elevated concentrations suggested sustained ion release over the course of 96 hours and enhanced solubility of ZrACP and ZnACP. X-ray diffraction analysis showed a conversion of ZrACP to a semi-crystalline material after 96 hours, but ZnACP showed no conversion after 96 hours. Composite scaffolds were fabricated by incorporating HAP, zirconium-stabilized ACP (ZrACP), or zinc-stabilized ACP (ZnACP) into a sintered PLGA microsphere matrix and then characterized to determine the effect of the minerals on the in vitro differentiation of MC3T3-E1 cells. Scanning electron microscopy revealed a porous microsphere matrix with calcium phosphate powders distributed on the surface of the microspheres. Measurements of mechanical properties indicated that incorporation of 0.5 wt% calcium phosphates resulted in a 30% decrease in compressive modulus. When cells were cultured in the scaffolds, composite ACP scaffolds stimulated proliferation and ALP activity, while HAP scaffolds stimulated osteoblast gene expression. Overall, the results of this work indicate the addition of calcium phosphate minerals to PLGA scaffolds supported cell growth and stimulated osteogenic differentiation, making the scaffolds a promising alternative for bone tissue regeneration. / Ph. D.

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No / The commercial success of hydroxyapatite (HA) filled polyethylene composite has generated growing interest in improving the processability of the composite. A number of synthetic procedures and post synthesis heat treatment of HA has lead to the availability of powders with widely varying morphological features. This paper addresses the effect of morphological features of HA on the rheology and processability of an injection-moulding grade HA-HDPE composite. The results showed that low surface area HA filled composite exhibited better injection processing characteristics through improved rheological responses. The effect of reducing the surface area of the filler is to require less polyethylene to wet the filler and allows more polyethylene to be involved in the flow processes. These changes reduced the temperatures and pressures required for successful processing.

no / The shear and extensional properties of injection moulding grade hydroxyapatite¿polyethylene composites developed for orthopaedic applications have been studied. The composite was prepared without processing aids owing to concerns over the potential biological responses to such additives. The composite containing 20 vol.-% hydroxyapatite filler showed typical pseudoplastic behaviour. However, that containing 40 vol.-% hydroxyapatite filler tended to exhibit yield. The Maron¿Pierce equation was found to be useful in predicting the viscosities of the composite systems. The activation energy of the composite and the unfilled polymer were equal, indicating that the 20 vol.-% system exhibits the same flow mechanism as the unfilled polymer. A qualitative assessment of extensional properties was made following Cogswell's method. The extensional stress of the unfilled polymer decreases with increasing temperature whereas the composites behave in a complex manner. For all the systems the Trouton ratios tend to increase with apparent shear rates. The Trouton ratio also indicates that at higher temperatures the flow of these composites is dominated by extensional properties.

Yes / Nanocrystalline hydroxyapatite (nanoHA) is the main hard component of bone and has potential to be used to promote osseointegration of implants and to treat bone defects. Here, using active pharmaceutical ingredients (APIs) like ibuprofen, we report on the prospects of combining nanoHA with biologically active compounds to improve the clinical performance of these treatments. In this study we designed and investigated the possibility of API attachment to the surface of nano-HA crystals via the formation of a hydrogen-bonded complex. The mechanistic studies of an ibuprofen/nanoHA complex formation have been performed using a holistic approach encompassing spectroscopic (FT-IR and Raman) and X-ray diffraction techniques as well as quantum chemistry calculations (DFT), while comparing the behaviour of the ibuprofen/nanoHA complex with that of a physical mixture of the two components. Whereas ibuprofen exists in dimeric form both in solid and liquid state, our study showed that the formation of the ibuprofen/nanoHA complex most likely occurs via the dissociation of the ibuprofen dimer into monomeric species promoted by ethanol, with subsequent attachment of a monomer to the HA surface. An adsorption mode for this process is proposed; this includes hydrogen bonding of the hydroxyl group of ibuprofen to the hydroxyl group of the apatite, together with the interaction of the ibuprofen carbonyl group to an HA calcium centre. Overall, this mechanistic study provides new insights into the molecular interactions between APIs and the surfaces of bioactive inorganic solids and sheds light on the relation between the non-covalent bonding and drug release properties. / Authors would like to acknowledge funding support from EPSRC (EP/L027011/1, EP/K029592/1). This research was performed in part at the MIDAS Facility, at the University of Sheffield, which was established with support from the Department of Energy and Climate Change.

Yes / Hydroxyapatite and fluorhydroxyapatite (F)HA nanoparticles were synthesised in the presence of branched poly(acrylic acid)s (PAA) synthesised via reversible addition–fragmentation chain transfer polymerisation and compared to those synthesised in the presence of linear PAA. Analysis of the resulting nanoparticles using Fourier transform infrared spectroscopy, powder X-ray diffraction and transition electron microscopy found that the polymer was included within the nanoparticle samples and affected their morphology with nanoparticles synthesised in the presence of branched PAA being more acicular and smaller overall.

Depuis une dizaine d'années, les procédés de granulation aérobie sont apparus comme une technologie prometteuse pour le traitement des effluents fortement chargés en azote, phosphore et carbone, tels que ceux issus de l'agro-industrie. La complexité microbienne de ces granules et les mécanismes qui leur donnent des propriétés exceptionnelles de décantation et de cohésion, constituent encore des axes de recherche importants. Dans cette thèse, le travail s'est axé sur un mécanisme encore non étudié : les processus de précipitation des phosphates au cœur des granules microbiennes. Différentes techniques d'analyses spectrales, parfois adaptés pour la première fois à ce type de systèmes, comme la spectroscopie Raman, ont permis de caractériser la nature de ces minéraux formés au cœur des granules. L'analyse menée sur des réacteurs de laboratoires a démontré la présence des phosphates de calcium sous forme d'hydroxyapatite [Ca5(PO4)3(OH)]. Cette précipitation est potentiellement induite par les variations locales de pH et de sursaturation provoqués par les réactions microbiennes à l'intérieur des granules. L'étude des phénomènes de biominéralisation à été étendu aux granules anaérobies issus des réacteurs de type UASB de l'industrie laitière. Un modèle physico-chimique sur les processus de précipitation sous forme matriciel sur AQUASIM®, couplé avec des bases de calcul de sursaturation (PHREEQC®), ont permis d'avancer des hypothèses sur les mécanismes influençant ces processus de biominéralisation, tels que la formation d'un précurseur amorphe de l'hydroxyapatite (ACP), ainsi que d'identifier les constantes de précipitation thermodynamiques (pKsp|20ºC=28.07±0.58) et cinétiques dans différentes conditions opératoires. Grâce au suivi d'un système biologique GSBR (Granular Sludge Sequenced Batch Reactor) pendant plus de 900 jours, la contribution de ce phénomène aux processus de déphosphatation a été estimé (46% dans les conditions testées). L'utilisation de ce processus pour immobiliser efficacement le phosphore et apporter des propriétés physiques stables aux granules a été également discutée. Une évaluation des performances et de la stabilité du réacteur à été mis en œuvre en alternant des cycles anoxies/aérobies ou anaérobies/aérobies vis-à-vis d'une future application industrielle. L'induction locale de la précipitation par les variations de pH et par le relargage des phosphates par les réactions microbiennes, nécessite une modélisation appropriée, qui a été également initiée dans cette thèse / Over the last decade, aerobic granulation processes have araised as a promising technology for treating wastewater effluents containing high nitrogen, phosphorus and carbon concentrations. The microbial complexity of granules and the mechanisms by which they acquire excellent settleability properties, still constitute important research goals to investigate. This thesis is focused on a mechanism that has been little addressed in literature, that is, phosphate precipitation in the core of aerobic granules. Different analytical techniques, sometimes adapted for the first time to this type of systems, like Raman spectroscopy, have let an exhaustive characterization of biominerals in the core of granules. Analyses performed on aerobic granules grown with synthetic fed in a lab-scale SBR (Sequential Batch Reactor), revealed a calcium phosphate core made of hydroxyapatite [Ca5(PO4)3(OH)]. This precipitation phenomenon is induced by local pH and supersaturation gradients issued of biological reactions inside granules. The study of the biomineralization phenomenon has been extended into anaerobic granules coming from UASB reactors at different cheese wastewater treatment plants. A physico-chemical model has been described in a form of matrix with AQUASIM® software, and coupled with a thermodynamic database (PHREEQC®), in an attempt to hypothesize the mechanisms that influence the biomineralization phenomena. It has been proposed the formation of an amorphous precursor (ACP) prior hydroxyapatite precipitation in the core of granules, suggesting the thermodynamic constant (pKsp|20ºC=28.07±0.58) and kinetic constants at different operating conditions. It has been also estimated the contribution of the biomineralization to the overall phosphorus removal process (up to 46% at the operating conditions tested), thanks to the development and study of a GSBR (Granular Sludge Batch Reactor) in labscale, for more than 900 days. The fate of the biomineralization process in granules, regarding the contribution to their stabilization and physical properties, has been also dealt in this thesis. The reactor stability and performances have been assessed by alternating anoxic/aerobic and anaerobic/aerobic cycles, in sights of a future industrial application. The induction of precipitation by local variation of pH and supersaturation issued of biological reactions has been here introduced, although it will need further investigation

L’objectif de ce travail est la mise au point de filtres garnis de laitiers d’aciéries destinés au traitement du phosphore (P) des eaux usées au sein de petites installations. Deux types de laitiers on été testés: laitiers de four à arc électrique (EAF), et laitiers d'aciérie de conversion (BOF). Une approche intégrée a été suivie, avec investigations à différentes échelles: (i) Des expériences en flacons ont été réalisées pour établir les capacités de rétention du P de laitiers produits en Europe, et ainsi sélectionner les échantillons les plus adaptés pour l’élimination du P; (ii)Des expériences en colonnes ont été menées pour étudier l'effet de divers paramètres, notamment la taille et la composition du laitier, sur les performances hydrauliques et épuratoires des filtres; (iii) Enfin, des expériences sur terrain ont été conduites afin d’évaluer les performances hydrauliques et épuratoires de deux unités démonstration conçues pour le traitement du P au sein d’un marais artificiel. Les résultats expérimentaux ont indiqué que le principal mécanisme d'élimination du P est lié à la dissolution du CaO des laitiers, suivie de la précipitation de phosphate de Ca et recristallisation en hydroxyapatite (HAP). Après 100 semaines d'alimentation avec une solution de P (concentration moyenne de P totale 10,2 mgP/L), les colonnes remplies de laitiers de petite taille (BOF6-12 mm et EAF 5-16 mm) ont retenu >98% du P total en entrée, tandis que les colonnes remplies de laitiers de grande taille (BOF 20-50 mm et EAF 20-40) ont retenu 56et 86% du P total en entrée, respectivement. Il apparaît que, plus la taille des laitiers est petite, plus la surface spécifique disponible pour la dissolution du CaO et pour l’adsorption des phosphates de Ca est grande. Les expériences sur terrain ont confirmé que les laitiers sont efficaces pour le traitement du P de l'effluent d'un marais artificiel (concentration moyenne du P totale 8,3 mg P/L). Sur une période de 85 semaines d'opération, de laitiers EAF ont retenu le 36% du P total en entrée, tandis que les laitiers BOF ont retenu le 59% du P total en entrée.L’efficacité de rétention du P apparaît augmenter avec la température et le temps de rétention hydraulique (HRT),très probablement parce que l'augmentation de la température et du HRT a favorisé la dissolution de la CaO et la précipitation de phosphate de Ca. Toutefois, il a été constaté que HRT >3 jours peuvent produire des pH élevés (>9), à la suite d’une excessive dissolution de CaO.Cependant, les résultats des unités démonstration ont montré que, à HRT de 1-2 jours, les filtres produisent des pH élevés seulement pendant les 5 premières semaines de fonctionnement, puis les pH se stabilisent en dessous de 9. Enfin, une équation de dimensionnement sur la base des résultats expérimentaux a été proposée. / This thesis aimed at developing the use of electric arc furnace steel slag (EAF-slag) and basic oxygen furnace steel slag (BOF-slag) in filters designed to upgrade phosphorus (P) removal in small wastewater treatment plants. An integrated approach was followed, with investigation at different scales: (i) Batch experiments were performed to establish an overview of the P removal capacities of steel slag produced in Europe, and then to select the most suitable samples for P removal; (ii)Continuous flow column experiments were performed to investigate the effect of various parameters including slag size and composition, and column design on treatment and hydraulic performances of lab-scale slag filters; (iii)Finally, field experiments were performed to investigate hydraulic and treatment performances of demonstration scale slag filters designed to remove P from the effluent of a constructed wetland. The experimental results indicated that the major mechanism of P removal was related toCaO-slag dissolution followed by precipitation of Caphosphate and recrystallisation into hydroxyapatite (HAP).Over 100 weeks of continuous feeding of a synthetic Psolution (mean inlet total P 10.2 mg P/L), columns filled with small-size slag (6-12 mm BOF-slag; 5-16 mm EAFslag)removed >98% of inlet total P, whereas columnsfilled with big-size slag (20-50 mm BOF-slag and 20-40mm EAF-slag) removed 56 and 86% of inlet total P,respectively. Most probably, the smaller was the size ofslag, the greater was the specific surface for CaO-slagdissolution and adsorption of Ca phosphate precipitates.Field experiments confirmed that EAF-slag and BOF-slagare efficient substrate for P removal from the effluent of aconstructed wetland (mean inlet total P 8.3 mg P/L). Overa period of 85 weeks of operation, EAF-slag removed 36%of inlet total P, whereas BOF-slag removed 59% of inlettotal P. P removal efficiencies increased with increasing temperature and void hydraulic retention time (HRTv),most probably because the increase in temperature and HRTv affected the rate of CaO dissolution and Caphosphate precipitation. However, it was found that longHRTv (>3 days) may produce high pH of the effluents(>9), as the result of excessive CaO-slag dissolution. However, the results of field experiments demonstrated that at shorter HRTv (1-2 days), slag filters produced pH that were elevated only during the first 5 weeks of operation, and then stabilized below a pH of 9. Finally, a dimensioning equation based on the experimental results was proposed.