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Polyacrylonitrile (PAN) is a linear polymer that is used in industry to produce carbon materials. While PAN-based carbon materials demonstrate excellent mechanical properties and promote bone cell growth along their surface, their porous properties are not sufficient for cell growth and proliferation. Carbon nanotubes (CNTs) are the one of strongest material available, which themselves posses some biological properties, and have the potential to extend clinical use of the carbon materials when manufactured in form of PAN-based composite and carbonized in order to form porous fibrous mat where nanotube-nanotube junctions are cemented with carbonized PAN. The work sought to develop and characterise PAN-CNT composites in main areas: 1) production of PAN-CNT composites, 2) carbonization of obtained composites, 3) investigation of reactivity of CNTs in order to improve interaction between polymer and nanotube in composite, and 4) assessment of the biological properties in vitro cell culture. PAN was synthesised via free-radical polymerization of acrylonitrile (AN) using azobisisobutyronitrile (AIBN) as initiator, and multi-walled CNTs were produced by chemical vapour deposition. Composites were produced by addition of acid-oxidized CNTs to AN solution as PAN was precipitating in form of loose powder or buckypaper. Characterization of the composite material with FTIR and I3C NMR found that the CNTs have no dramatic influence on AN polymerization. Composites made of buckypaper soaked in AN precursor solution were found to have better PAN distribution within composite. It was found that regardless of the synthesis approach, PAN-CNT composites were found to be non-porous and therefore unsuitable for cell growth, therefore silica-based CNT composites were synthesised as prospective candidates for the bone replacement material. It was found that silica forms a thin protecting layer around CNTs, when synthesised via sol-gel transformation of the 3-aminopropyltriethoxysilane, but was not thick enough to support a continuous CNT network. Furthermore this approach was used in synthesis of magnetic CNT -silica based composites for prospective application in magnetic driven adsorption and controlled drug delivery. To optimize the composite microstructure the CNT sidewall reactivity was investigated to determine its effect on porosity of the final composite. It was found that high temperature acid oxidation of pristine CNTs lead to an increase in the number of carboxylic groups' number and therefore contribute in the CNT's sidewall reactivity. In order to create porous carbonised materials, PAN and methylmethacrylate (MMA) was formed into a copolymer (PAN-co-MMA) in which mass content of MMA was 10% wt, was derived. Carbonisation of this copolymer in an inert atmosphere and in air leads to formation of the continuous open porous structure with a pore diameter in the range from 30 to 130μm, which is suitable for cell penetration. This was confirmed by in vitro cellular response to the PAN-co-MMA based carbon monolith was examined by culturing 3T3 mouse fibroblasts. It was also found that the copolymer under high heating rates lead to expansion and exfoliation. Examination of the resulting material shows that carbon nanomaterials produced are single- and multi- layered graphenes which may give a useful production route towards single layered graphene (SLG). This study has resulted in improved understanding of the processing of CNTs and the effect of a wide range of synthetic approaches on the final materials characteristics. The interesting preliminary results were obtained in the areas of CNTs reactivity, formation of magnetically driven adsorbents, and potential biological behaviour of porous carbonized PAN-co-MMA based monoliths

Distraction osteogenesis (DO) is a unique process of bone formation used for clinical correction of skeletal deformities. In DO, bone is osteotomised, and the cut ends are slowly pulled apart by mechanical means to induce de novo ossification. Despite the extensive current and historical use of DO, the .mechanisms involved are not well understood. A novel mouse model of DO featuring a custom-developed external fixator was validated and characterised by using radiography, immunohistochemistry, and micro array techniques. The in vivo model was subsequently studied in a whole-transcriptome time course micro array analysis of DO. Genes relevant to osteogenesis, angiogenesis, mechanotransduction, cytoskeletal signalling, and the Wnt pathway were highly expressed. Time course statistical methods applied to the micro array data enabled profiling of global gene expression throughout DO and identification of genes and functions that showed significant differential expression over time. Concurrently, a novel three-dimensional in vitro model of DO was developed to assess the mechanobiological effects of distraction. The system consists of two pieces of hard mineral scaffold held in a rigid distractor. A cell-seeded fibrin clot bridges the scaffold ends to simulate the in vivo distraction gap. Using this in vitro model, the effects of a single application of tensile strain on the model were assessed. Digital image correlation demonstrated that strain patterns in the stretched construct are similar to those in the distraction gap. Additionally, murine osteoblasts were viable and proliferated in the scaffold-fibrin construct. Following a single distraction, cells exhibited elongated morphology, greater alignment, and increased alkaline phosphatase activity. In conclusion, a new mouse model and a novel in vitro model were shown to be useful correlates to clinical DO. Additionally, time course statistical analyses and in situ 3D staining techniques provide new tools for understanding and improving surgical bone lengthening. These findings serve as a promising starting point for future investigations into the key mediators of the regenerative potential unleashed in DO.

Introduction Osteoporotic vertebral wedge fractures can lead to pain, disability and deformity. Strengthening ('augmenting') fractured vertebrae by injecting cement into them can provide analgesia and enable early mobilisation, but it remains unclear which of two procedures (vertebroplasty or kyphoplasty) is mechanically superior. This cadaveric study compared their ability to restore vertebral shape and function following severe wedge fractures. Methods Pairs of thoracolumbar "motion segments", aged 72•98 years, were overloaded to induce fracture, and then cyclically loaded to create severe wedge deformity. One of each pair underwent vertebroplasty and the other kyphoplasty. The following were measured before and after wedge fracture, after augmentation, and after cyclic loading: compressive stiffness, creep deformation, stress distributions within adjacent intervertebral discs, and vertebral height and shape. The stress distributions quantified intra-discal pressure (lOP) and neural arch load-bearing (FN). Treated vertebrae underwent micro-CT to assess regional cement fill and its relationship to mechanical and morphological outcomes. Results On average, following wedge fracture, FN increased by 58%,!DP fell by 96% and compressive stiffness fell by 44%. Anterior vertebral body height was reduced by 34%, and wedge angle increased from 5.0° to 11.4°. Both procedures were equally effective at restoring IDP, FN and compressive stiffness. Creep deformation was greatest anteriorly, and least posteriorly, but depended little on treatment type or experimental stage. Kyphoplasty restored anterior height loss by 97% (immediately) and by 79% (after creep loading). Values for vertebroplasty (59% and 47% respectively) were significantly less (p<O.OOl). Kypho plasty reduced vertebral wedging more than vertebroplasty, by 7.2° compared to 4.2° (p<O.02) following creep. For both treatments, reductions in wedge angle were proportional to % regional cement fi ll. Discussion When used to treat severe vertebral wedge fractures, both techniques provide similar restoration of mechanical function, but kyphoplasty reverses vertebral body wedging and height loss better than vertebroplasty.

The broad aim of this work was to investigate and optimise the properties of calcium phosphate bone cements (CPCs) for use in vertebroplasty to achieve effective primary fixation of spinal burst fractures. An in vitro sample production method was developed and the effect of CPCs on the pH and Ca concentration of culture medium assessed. The effect of collagen incorporation into CPCs was investigated in vitro, necessitating sterilisation of the samples. y irradiation was found to be the most effective technique. In vitro analysis of two CPCs found no significant difference in their biological properties, although their ability to promote differentiation was significantly higher than that seen in a PMMA control. Analysis of collagen augmented CPCs found that the incorporation of 1 wt% collagen resulted in slightly higher, though not clinically relevant, level of cytotoxicity. Despite this, cells were shown to proliferate equally well on each of the formulations. Incorporation of marine collagen did not significantly affect the level of differentiation observed; however, this level was significantly decreased when bovine collagen was considered. The CPCs investigated were better tolerated in vivo than PMMA. Significantly more bone apposition was observed on the surface of CPCs compared to PMMA and a small amount of remodelling was seen on the CPCs.

Bone is dynamic and adaptable. It has been suggested that each region has an intrinsic hypothetical 'mechanostat' (Frost, 1987), although the histological basis has yet to be clearly defined. To gain further insight, the phenomenon of connection and disconnection is explored within the calcifying protist Spirostomum ambiguum, and at three key structural hierarchical tissue levels of the human skeleton; the cancellous bone network, the osteocyte network and the periosteal Sharpey's fibre arrays. The tissue used was from elderly subjects; cadaveric vertebral bodies, and femoral heads after hip replacement for osteoporosis (OP) and osteoarthritis (OA). Established 20 histological techniques were inappropriate for reliable characterisation of 30 networks. In consequence, two novel methods were developed and two unusual models adopted. These methods combined histological techniques with image analysis, for 30 mapping and quantification of trabecular disconnection (ReTm) in vertebral cancellous bone, and characterisation of the osteocyte and its cytoplasmic interconnections within the hip and spine. Model one, utilised the Ligamentum teres insertion site to examine the fibrillar arrays of collagen III-rich Sharpey's fibres, by hard tissue microtomy and cryomicrotomy. Model two, combined light and confocal microscopy to observe the elements of a musculoskeletal system present within S. ambiguum. ReTm were heterogeneously distributed, with the caudal and cranial regions being of interest. Sex differences were evident. Measurements of bone 'quality' appeared independent of bone 'quantity' (R2<O.6, p<O .05). Osteocyte syncitia differed significantly in females (p<O.05), those from osteoporotic bone contained fewer cells, with fewer processes, which were more disconnected than their OA counterparts. No such significant differences were observed in the male hip. In an elderly female spine, significant differences (p<O.05) were observed between spinal levels. Again, these results appeared contrary to bone 'quantity'. In OP populations, Sharpey's fibres are depleted, thinner, truncated and fragmented in comparison to those in OA populations, whereby they penetrated deeper, appearing to coincide with osteocyte syncitia. S. ambiguum displayed environmentally driven 'remodelling', whereby interconnectivity of the musculoskeletal elements was essential for survival. The evidence above suggested that structural disconnection was a major feature for consideration in the evaluation of bone 'quality' and structural strength at the two major fracture sites of the spine and hip. Moreover the phenomenon of network disconnection at the three hierarchical levels, and the musculoskeletal elements within the calcifying protist observed, may not be expressed in isolation. This complex continuum may be the unknown histological basis for the 'mechanostat' hypothesis

Back pain is a common complaint and the origin of this frequently attributed to degenerative disc disease. In the most severe cases, the integrity of the disc and surrounding tissue is lost to such an extent that surgical intervention is necessary. Fusion procedures are commonly used to treat severely degenerated discs. Yet this is known to alter the biomechanics of the operated level, and may create a progression of degenerative decline. Total disc replacement has emerged as a viable treatment but the complexity of the spine is reflected in the clinical results, which trail far behind the success of hip and knee arthroplasty. This may be due to a failure of total disc replacement procedures to restore the natural biomechanics of the spine. The present study has led to the development of a dynamic pre-clinical testing protocol to quantitatively assess the efficacy of disc replacement devices. A six-axis spine simulator was designed and built, and the stiffness matrix testing of porcine lumbar specimens was completed, both with and without an axial preload. Intact specimens were tested, and the testing repeated after a total disc replacement procedure with a DePuy In Motion artificial disc. This is the first study to complete dynamic six-axis spinal testing of this kind. The testing demonstrated the disc replacement device compared favourably with the intact porcine disc both in shear and axial stiffness. However, the low-friction, double ball and socket design of the In Motion device lacks stiffness in the three rotational axes, and it is unstable in lateral bending. Rotations are the primary movements in the spine, and it is crucial if the natural biomechanics are to be restored, that a disc replacement device should replicate the stiffnesses of these axes. The next generation of disc replacement devices feature elastomeric materials that may more closely replicate the natural intervertebral disc. From patents registered with DePuy, this may also be true of the next generation of In Motion disc. This research provides a means to complete standardised performance tests of new spinal devices and lays the foundations for future comparison studies. Additionally, the spine simulator and testing protocol would provide valuable data during the design stage of new total disc replacements, aiding the development of the next generation of artificial discs.

Σκοπός της μελέτης είναι να συγκρίνει τα βραχυπρόθεσμα αποτελέσματα της άκαμπτης εναντίον ημιάκαμπτης και δυναμικής σπονδυλοδεσίας όσον αφορά: - τις αλλαγές της συνολικής και τμηματικής οσφυϊκής λόρδωσης, - την υποκειμενική αξιολόγηση του αποτελέσματος (SF-36, VAS) - τις σχετικές επιπλοκές. / -

Η παρούσα διδακτορική διατριβή περιγράφει το σχεδιασμό και την ανάπτυξη ενός εκπτυσσόμενου Ενδομυελικού Ήλου Επιμήκυνσης των Μακρών Οστών των Κάτω Άκρων. Η επιμήκυνση των κάτω άκρων είναι μία χειρουργική διαδικασία βαθμιαίας επιμήκυνσης των μακρών οστών των κάτω άκρων και των μαλακών μορίων που τα περιβάλουν. Γενικά, η επιμήκυνση των κάτω άκρων στοχεύει στην εξίσωση των σκελών ή αύξηση του μήκους των οστών και στα δύο άκρα. Η τεχνική αύξησης του μήκους των οστών των κάτω άκρων επινοήθηκε από τις αρχές του περασμένου αιώνα [1] και έχει καταξιωθεί στη μοντέρνα χειρουργική από τις αρχές του 1960, λόγω της ενασχόλησης του G.A.Ilizarov. Ο επιστήμονας και χειρουργός G.A.Ilizarov αφιέρωσε όλη τη θεωρητική και πρακτική του έρευνα [2] στη βελτίωση της διαδικασίας επιμήκυνσης των οστών και την ανάπτυξη εξωτερικής συσκευής σταθεροποίησης που φέρει το όνομα του. Η μέθοδος αυτή καθώς και η συσκευή Ilizarov χρησιμοποιήθηκαν πάρα πολύ για να διορθώσουν τόσο βλάβες όσο και παραμορφώσεις των κάτω άκρων. Η ευελιξία αυτής της συσκευής την κάνει ένα εξαιρετικό εργαλείο το οποίο μπορεί να χρησιμοποιηθεί για τη διόρθωση διαφόρων βλαβών όπως π.χ. σταθεροποίηση συνθέτων καταγμάτων, στροφικές διορθώσεις, διορθώσεις οστών με διαφορές μήκους. Τόσο όμως η συσκευή του Ilizarov όσο και οι υπόλοιποι μονόπακτοι εξωτερικοί σταθεροποιητές που παρουσιάσθηκαν αργότερα παρουσιάζουν μειονεκτήματα [3] όπως είναι π.χ. οι σύνθετες χειρουργικές διαδικασίες, οι συνδέσεις και οι βελόνες που διαπερνούν το δέρμα και που οδηγούν σε μολύνσεις, η μειωμένη δυνατότητα φόρτισης και η ταλαιπωρία λόγω του μεγέθους του σταθεροποιητή ειδικά στις περιπτώσεις εκείνες που η ευελιξία του σταθεροποιητή δεν είναι απαραίτητη. Πολλοί ασθενείς που χρειάζονται μία διόρθωση του μήκους ενός άκρου χωρίς άλλες παραμορφώσεις θα μπορούσαν να βοηθηθούν και από μία συσκευή μικρότερης ευελιξίας χωρίς τα μειονεκτήματα των εξωτερικών μονόπακτων σταθεροποιητών. / The technique to increase the length of the long bones is the subject of research for the orthopedic surgeons for many years. The technique is used for the treatment of a limb shortening due to malformation or to a deficit for other reasons e.g. the fracture of a long bone after a car accident, osteomyelitis, or malignancy. The procedure to increase the length of a bone is difficult and may become quite hazardous for the soft tissues surrounding the area. The two parts of the bone are stabilized to eliminate the possibility of relative torsion and bending. Then they align axially with respect to each other and move with a constant rate of elongation of 1mm per day. The elongation is usually achieved by 4 steps of 0,25mm every 6 hours. The application of internal distraction osteogenesis using shape memory alloys has all the advantages of internal osteosynthesis. The only part of these mechanisms that is found externally is the activation mechanism that is connected by the necessary cables of activation with the interior of the bone where the internal distraction device is placed. The basic problem of all designs is the high constructional complexity of activation and control of shift of the two parts of the bone, something that makes this systems non user friendly and with continuous fractures and blockings of the elements of the mechanisms. In the present work, all the advantages of the mechanism of internal distraction osteogenesis are combined with the fundamental advantage; the simplicity of manufacture of the mechanism and the simplicity of operation via the restriction of the moving elements.