3D printing is an additive manufacturing technique that is rapidly gaining traction in health and medical applications. This technique could potentially benefit plastic and reconstructive surgeries by fabricating patient-specific tissue replacements with tissue-like functions and mechanical properties. One specific example in the field of plastic and constructive surgery is nose reconstruction. Current gold standard for nasal reconstruction after rhinectomy or severe trauma involves a three stage surgery that requires a minimum of three and maximum of seven operations to achieve an acceptable result. The surgical procedure require transposition of autologous cartilage grafts in conjunction with coverage using an autologous skin flap. Harvest of autologous rib cartilage requires a major additional procedure which creates donor site morbidity. Additionally, major nasal reconstruction also requires sculpting autologous cartilages to form a cartilage framework, which is complex, highly-skill demanding and time-consuming. These drawbacks of the current approach for nasal reconstruction are some of the reasons why facial plastic and reconstructive surgeons are interested in the application of tissue engineering and 3D printing for reconstructive surgeries. To address these clinical challenges, the aim of the work presented in this thesis was to fabricate a personalised 3D bioprinted composite scaffold for nasal reconstruction mimicking the mechanical properties and architecture of nasal cartilage. The composite consists of biodegradable thermoplastic polycaprolactone (PCL) to provide structural support, and cell-laden thermoresponsive and UV crosslinkable gelatin methacrylate (GelMA) to act as a cell carrier. We first investigated the appropriate cell source to use for cartilage tissue engineering and 3D bioprinting. Primary sheep articular chondrocytes (ShCh) and sheep bone marrow derived Mesenchymal Stem Cells (ShMSCs) were isolated, expanded and differentiated; followed by an assessment of the effects of the 3D printing process on cell viability and functionality. From these studies it was observed that ShCh were easier to isolate and expand than ShMSCs because less steps are required and the doubling time is 50% shorter. Additionally, 80% of the ShCh survived the printing process compared to a 50% of the ShMSCs, suggesting that chondrocytes were able to tolerate higher stress caused by the 3D printing process. PCL and poly (lactic-co-glycolic acid) (PLGA) scaffolds were printed and seeded with chondrocytes post-printing. The printing process and the 3D printed structures of these polymers were characterised before and after printing by measuring their molecular weight, thermal and mechanical properties. It was found that the printing process reduced the molecular weight of PLGA by 50% percent due to thermal degradation. Consequently, its glass transition temperature and young’s modulus decreased post printing. On the contrary, PCL’s molecular weight remain unchanged after printing. Characterisation of the chondrocytes showed that whilst both scaffold materials supported cell attachment the ECM secreted deformed the PLGA whilst the PCL scaffolds were unaffected. Due to superior mechanical properties PCL was selected to 3D print the personalised nose scaffolds. Additional studies on the 3D printed scaffolds showed that controlling the surface pores of scaffolds was important for cell infiltration and proliferation Scaffolds with larger surface pores were 3D printed and these resulted in increased cell seeding and proliferation demonstrated by DNA quantification. Moreover, the printing process of the cell carrier GelMA was optimised by utilising its thermoresponsive properties. A rheological study of three different concentrations of GelMA was performed in order to identify the most suitable for bioprinting. GelMA 15% and 20% at 15 °C and 18 °C respectively were found the appropriate ones. Finally, multi-material 3D bioprinting of PCL and chondrocyte-laden GelMA was utilised for making cartilage constructs. The 3D bioprinted constructs showed neocartilage formation and similar mechanical properties to nasal alar cartilage after a 50-day culture period. Neocartilage formation was evidenced by the presence of glycosaminoglycans and collagen type II after cultivation. The findings in this thesis therefore support the feasibility of using 3D bioprinted composite constructs for nasal reconstruction.

The repair of bone defects and non-union fractures is a significant challenge for clinicians as it requires tissue replacement. The current graft approaches used to treat these injuries have limitations with regard to quality and availability. This has resulted in research efforts to develop alternative synthetic materials that are able to aid tissue regeneration. These materials usually combined with biological factors to induce cells proliferation and differentiation. Transcription factors can provide specific regulatory effect, however, these transcription factors are very difficult to be delivered intracellularly. A recent work, conducted at Tissue Engineering group – University of Nottingham, has shown that recombinant transcription factors can be expressed, purified and delivered efficiently to control cell behaviour for further tissue engineering applications. Efficient delivery of these factors can be achieved by using Glycosaminoglycan-binding enhanced transduction (GET) peptides, which are multi-domain peptides comprising a GAG-binding peptide (to promote cell interaction) and a cell-penetrating peptide (CPP) for high efficiency membrane transduction. The aim of the work presented in this thesis was to develop a poly-(lactic-co-glycolic acid) (PLGA) based delivery system to release RUNX2 transcription factor, which is significantly involved in osteogenesis. GET peptide was utilised to enhance the intracellular delivery of RUNX2. The advantage of this system is to control the dose and localisation of the released RUNX2 as well as providing a biodegradable scaffold to support the newly formed tissue. Reproducible procedures were developed to manufacture spherical PLGA microparticles (MPs) using Solid-in-oil-in-water (S/O/W) emulsion method. Red florescent protein (RFP) coupled with GET peptide was used as model protein to evaluate the stability of peptide during microparticles fabrication and release. Efficient encapsulation (~65%) and tailored protein release profiles could be achieved, however intracellular transduction was significantly inhibited post-release. Co-encapsulation of L-Histidine, which may form a complex with the PLGA degradation products under acidic conditions, was used as a strategy to retain GET peptide activity. Simulations of the polymer microclimate showed that hydrolytic acidic PLGA degradation products directly inhibited GET peptide transduction activity, use of L-Histidine significantly enhanced released protein delivery. GET-RUNX2 was efficiently encapsulated (~60%) within PLGA MPs using the developed S/O/W method and release profile was adopted to match the optimal RUNX2 dose needed to induce osteogenesis of hMSCs (i.e. 60μg in the first 7 days of the study). GET-RUNX2 activity post release was evaluated. Results showed comparable transduction and transfection activities (compared to experimental control) throughout the release period. GET-RUNX2 loaded MPs were mixed with temperature-sensitive PLGA/PEG particles to provide scaffold structures. hMSCs were used for an in-vitro differentiation assessments. Osteogenesis gene markers were comparable to experimental controls for both early and late markers. Moreover, the scaffold formula was optimised to be 3D printable to provide complex and irregular shape scaffolds matching defect size. The ability to control intracellular transduction of functional proteins into cells will facilitate localised delivery of therapeutics, with minimised risk of systemic dosing that may lead to non-targeted activity, and allow approaches to direct cellular behaviour for regenerative medicine applications.

Introduction: Malignant Melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Breslow thickness remains the best predictor of metastasis and Sentinel Lymph Node Biopsy is the only method of detecting nodal spread in clinically node negative patients. Surgery is the only effective therapy. Angiogenesis – the growth of new vessels from pre-existing vasculature - is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. Anti- angiogenic isoforms of VEGF have been demonstrated previously to be protective with regard to metastasis. The aims of this thesis were to determine whether VEGF expression within the tumour may allow prediction of the nodal status. Furthermore another aim was to determine whether via the “Seed and Soil” theory, by examination of angiogenic and lymphangiogenic profiles of the tumour and node can we determine that the tumour may control the microenvironment around the Sentinel Node? Finally, as a cohort of false negative patients emerged with a higher mortality rate than their true negative and true positive patient cohort counterparts, could any further patterns be established by performing the same experiments on these patients? Methods: Archived human tumour and corresponding Sentinel Node samples were used and immunohistochemistry was used to investigate the role of pro and anti angiogenic isoforms of VEGF, VEGF-C, LYVE-1 and CD31 within these patients. Results: VEGF-C expression was significantly increased in the intranodal component of positive Sentinel Lymph Nodes (p < 0.01 Bonferroni). This increased expression appeared to be independent of tumoural influences and no strong evidence for the “Seed and Soil” theory was proved. A significantly higher number of lymphatic vessel counts were identified within node negative patients (p < 0.05 ANOVA). No further significant findings were defined on examination of the false negative cohort of patients. Conclusions: This study has shown that positive Sentinel Lymph Nodes exhibit high levels of intranodal VEGF-C. This expression does not appear to be related to tumoural influences. It would therefore appear that VEGF-C expression within Sentinel Nodes warrants further investigation and may aid diagnosis of spread or represent a target to slow or even prevent the onset of metastasis.

Colorectal cancer is the third most common cancer and the second most common cause of cancer death in the UK. Outcome is directly related to stage at diagnosis with over 90% of patients with Stage I disease surviving their disease to 5 years compared to less than 10% of those with Stage IV disease. Symptoms for colorectal cancer can be non-specific, particularly when the disease is at its early stage, and hence screening has been introduced. Population screening in the UK, using faecal occult blood testing (FOBt) has been introduced over the past 10 years following several major randomized control trials and a Cochrane review that has shown improved cancer specific mortality in the region of 15% in those individuals invited. This has been attributed to the detection of early stage disease with around 50% of all tumours detected through screening being Stage I. However, it has previously been shown that there are additional tumour and host prognostic factors outside of stage that can determine outcome. For example, the presence of venous invasion and the presence of an elevated host systemic inflammatory response have been associated with poorer cancer specific survival. These additional factors have not previously been studied within the context of a population screening programme or indeed within early stage disease. Moreover, the FOBt screening programme itself is not without its pitfalls. Uptake of the test is below that of other established cancer screening programmes and it is recognised that repeated screening rounds are required to achieve an acceptable sensitivity of the test. This thesis sought to examine the first round of the Scottish Bowel Screening Programme within the West of Scotland and assess its effect on tumour and host determinants of outcome. In Chapter 1 an overview of colorectal cancer and current determinants of outcome is provided. In addition, colorectal cancer screening is explored in detail including the evidence behind the current screening programme. Chapter 2 presents original data, utilising population databases, examining the changes in mode, site and stage of presentation across the West of Scotland that have accompanied the introduction of the national screening programme. It identifies that within non-metastatic disease there has been a shift towards a higher proportion of Stage I disease being present following screening introduction. Chapter 3 presents a detailed examination of the first round of screening in NHS Greater Glasgow &amp; Clyde (NHS GG&amp;C) emphasising the importance of the impact of deprivation throughout the screening programme. For example, deprived patients were less likely to take part, more likely to test positive, less likely to proceed to colonscopy following a positive test and less likely to have cancer detected at colonoscopy following a positive test. Chapters 4, 5 and 6 utilise an original dataset of over 4000 patients who underwent colonoscopy following a positive test in the first round of screening in NHS GG&amp;C generated through work from Chapter 3. Firstly, in Chapter 4, a theoretical model proposing a flexible sigmoidoscopy as a first line test, rather than a colonoscopy, is examined. It found a missed cancer rate of 17% and that around a third would require a completion colonoscopy, concluding that this would not be a desirable change to the current screening algorithm. Chapter 5 then examines the importance of potentially chemopreventative medications such as statins and aspirin, on the risk of neoplasia at colonoscopy, determining that patients on such medications did indeed have lower rates of neoplasia, significant neoplasia and cancer than those not on them. Chapter 6 then looks at symptoms in this population, identifying that around 40% had at least one bowel symptom however that these correlated poorly with the risk of significant neoplasia at colonoscopy. Chapter 7 explores outcomes in those who were invited but did not have a screen-detected cancer in order to examine the incidence of interval cancers (colorectal cancer within 2 years of a negative FOBt) and cancers in non-responders. Overall it identified a 30% interval cancer rate. The chapter then explores differences in tumour and host factors between screen-detected and non screen-detected disease reporting that stage for stage, patients with non screen-detected disease had higher rates of systemic inflammation. Furthermore it characterises the similarity between interval and non-responder tumours suggesting that rather than representing biologically more aggressive tumours, interval cancers arise due to limitations of the test itself. Chapter 8 presents long-term outcomes in patients who have undergone a resection for Stage I disease prior to the introduction of screening. The results report an excellent 5-year cancer specific survival of 95% however an overall survival of 76%. It identifies the presence of an elevated pre-operative host inflammatory response as being associated with a worse overall outcome. Tissue work exploring the local immune-cell microenvironment of both early stage and pre-malignant disease is the focus for Chapters 9 and 10. This characterisation of immune cell infiltrate identifies similar rates of peritumoural inflammation between T1 and T2 disease and validates a previously published automated scoring system. When exploring local inflammation within premalignant polyps there appears to be a change from low-grade to high-grade dysplasia signifying a specific response to early disease progression suggesting host immunosurveillance. Chapter 11 summarises the main findings of the thesis and presents future directions.

Introduction Prediction of soft tissue changes following orthognathic surgery has been frequently attempted in the past decades. It has gradually progressed from the classic “cut and paste” of photographs to the computer assisted 2D surgical prediction planning; and finally, comprehensive 3D surgical planning was introduced to help surgeons and patients to decide on the magnitude and direction of surgical movements as well as the type of surgery to be considered for the correction of facial dysmorphology. A wealth of experience was gained and numerous published literature is available which has augmented the knowledge of facial soft tissue behaviour and helped to improve the ability to closely simulate facial changes following orthognathic surgery. This was particularly noticed following the introduction of the three dimensional imaging into the medical research and clinical applications. Several approaches have been considered to mathematically predict soft tissue changes in three dimensions, following orthognathic surgery. The most common are the Finite element model and Mass tensor Model. These were developed into software packages which are currently used in clinical practice. In general, these methods produce an acceptable level of prediction accuracy of soft tissue changes following orthognathic surgery. Studies, however, have shown a limited prediction accuracy at specific regions of the face, in particular the areas around the lips. Aims The aim of this project is to conduct a comprehensive assessment of hard and soft tissue changes following orthognathic surgery and introduce a new method for prediction of facial soft tissue changes.   Methodology The study was carried out on the pre- and post-operative CBCT images of 100 patients who received their orthognathic surgery treatment at Glasgow dental hospital and school, Glasgow, UK. Three groups of patients were included in the analysis; patients who underwent Le Fort I maxillary advancement surgery; bilateral sagittal split mandibular advancement surgery or bimaxillary advancement surgery. A generic facial mesh was used to standardise the information obtained from individual patient’s facial image and Principal component analysis (PCA) was applied to interpolate the correlations between the skeletal surgical displacement and the resultant soft tissue changes. The identified relationship between hard tissue and soft tissue was then applied on a new set of preoperative 3D facial images and the predicted results were compared to the actual surgical changes measured from their post-operative 3D facial images. A set of validation studies was conducted. To include: • Comparison between voxel based registration and surface registration to analyse changes following orthognathic surgery. The results showed there was no statistically significant difference between the two methods. Voxel based registration, however, showed more reliability as it preserved the link between the soft tissue and skeletal structures of the face during the image registration process. Accordingly, voxel based registration was the method of choice for superimposition of the pre- and post-operative images. The result of this study was published in a refereed journal. • Direct DICOM slice landmarking; a novel technique to quantify the direction and magnitude of skeletal surgical movements. This method represents a new approach to quantify maxillary and mandibular surgical displacement in three dimensions. The technique includes measuring the distance of corresponding landmarks digitized directly on DICOM image slices in relation to three dimensional reference planes. The accuracy of the measurements was assessed against a set of “gold standard” measurements extracted from simulated model surgery. The results confirmed the accuracy of the method within 0.34mm. Therefore, the method was applied in this study. The results of this validation were published in a peer refereed journal. • The use of a generic mesh to assess soft tissue changes using stereophotogrammetry. The generic facial mesh played a major role in the soft tissue dense correspondence analysis. The conformed generic mesh represented the geometrical information of the individual’s facial mesh on which it was conformed (elastically deformed). Therefore, the accuracy of generic mesh conformation is essential to guarantee an accurate replica of the individual facial characteristics. The results showed an acceptable overall mean error of the conformation of generic mesh 1 mm. The results of this study were accepted for publication in peer refereed scientific journal. Skeletal tissue analysis was performed using the validated “Direct DICOM slices landmarking method” while soft tissue analysis was performed using Dense correspondence analysis. The analysis of soft tissue was novel and produced a comprehensive description of facial changes in response to orthognathic surgery. The results were accepted for publication in a refereed scientific Journal. The main soft tissue changes associated with Le Fort I were advancement at the midface region combined with widening of the paranasal, upper lip and nostrils. Minor changes were noticed at the tip of the nose and oral commissures. The main soft tissue changes associated with mandibular advancement surgery were advancement and downward displacement of the chin and lower lip regions, limited widening of the lower lip and slight reversion of the lower lip vermilion combined with minimal backward displacement of the upper lip were recorded. Minimal changes were observed on the oral commissures. The main soft tissue changes associated with bimaxillary advancement surgery were generalized advancement of the middle and lower thirds of the face combined with widening of the paranasal, upper lip and nostrils regions. In Le Fort I cases, the correlation between the changes of the facial soft tissue and the skeletal surgical movements was assessed using PCA. A statistical method known as ’Leave one out cross validation’ was applied on the 30 cases which had Le Fort I osteotomy surgical procedure to effectively utilize the data for the prediction algorithm. The prediction accuracy of soft tissue changes showed a mean error ranging between (0.0006mm±0.582) at the nose region to (-0.0316mm±2.1996) at the various facial regions.

Osteoarthritis (OA) is a chronic and highly prevalent degenerative disease of the synovial joint leading to cartilage destruction and bone remodelling. The current management of end-stage OA is joint replacement, however, this procedure is not suitable for a subset of patients hence there is a growing need for alternative treatments and technologies to address this limitation. One such approach to this problem is the application of cell-based therapies that regenerate areas of damaged cartilage. Recently discovered articular cartilage progenitor cells (CPC) have been hallmarked as a potential cell source for repair and/or regeneration of damaged articular cartilage. Initial focus was on the characterisation of human CPC isolated from healthy donors and compared with OA derived CPC and patient matched OA Bone Marrow Mesenchymal Stem Cells (BM-MSCs). Comparison of all cell types showed similar morphology and proliferative capacity. In addition, all cell types isolated showed positive expression of the putative mesenchymal stem cell makers; CD-90, CD-105 and CD-166 while lacking expression of CD-34. All cell types investigated showed successful osteogenic, chondrogenic and adipogenic differentiation, hence providing evidence of the mesenchymal stem cell properties of isolated CPC. A gene profiler array was used to identify the expression of Wnt pathway genes from RNA isolated from CPC cell lines originating from healthy and OA cartilage. Interestingly, the expression of Dkk-1 was observed to have the highest up-regulation in OA-derived CPC. The role of Dkk-1 was further studied in a number of CPC and chondrocyte cell lines from healthy and OA cartilage. It was found that normal CPC cell lines showed homogenously low expression and secretion of Dkk-1, however, OA-derived CPC cell lines exhibited a heterogeneous expression and secretion of Dkk-1. In a pellet culture model of chondrogenic differentiation, CPC cell lines secreting high levels of Dkk-1 failed to undergo chondrogenic differentiation, measured by diminished expression of chondrogenic differentiation markers, Type II collagen, ACAN and Sox-9 at both molecular and protein levels. Immunolocalisation of Dkk-1 in OA osteochondral plugs showed peri-cellular expression in chondrocytes located in all zones and around migratory endothelial cells invading articular cartilage where there was a quantifiable increase of blood vessel invasion. This later observation was further studied through a series of experiments to investigate the role of Dkk-1 in relation to endothelial cell migration and angiogenesis using an in vitro model of angiogenesis and migration/invasion assays. A novel finding emerged from these studies, which provides evidence for a pro-angiogenic and pro-migratory role of Dkk-1 and to a lesser extent Dkk-2 in human endothelial cell lines. A novel in vitro Transwell co-culture model was developed to study the interaction between chondrocytes and endothelial cells mimicking the osteochondral interface. A novel finding from these studies included the observation that normal or OA-derived chondrocytes appeared to induce an endothelial to mesenchymal transformation (EndMT) of the co-culture endothelial cells. This was assessed by a loss of the endothelial cobble stone morphology and a down-regulation of key factors implicated in endothelial cell phenotype, including VE-cadherin, Tie-2, e-NOS, PDGF-AA and PECAM-1. As endothelial cells lost their phenotype they adopted a spindle morphology and expressed mesenchymal cell markers including: Lumican, Snail, α-SMA, Vimentin and MMPs. Interestingly, this was also associated with an increase in Dkk-1 expression. To confirm a role for Dkk-1 in this process endothelial cells were cultured in the presence of Dkk-1 and were found to undergo EndMT when compared to the control. In summary, this thesis has uncovered several interesting differences in CPC phenotype. In addition, my results suggest that Dkk-1 has potential as a biomarker of OA pathology. This thesis highlights further the complex role of the Wnt Pathway and in particular Dkk-1 may play a role in the pathogenesis of osteoarthritis.

Total hip replacement is one of the most common surgical procedures carried out both in the UK and Worldwide. With an increasing number of younger patients undergoing the procedure, there is an emphasis on increasing the longevity of prostheses. The following reports on a number of component studies which, when combined give an insight into the mechanism of wear behind the loosening and failure of matt surface finish femoral stems. By examining stems which have been explanted from patients, a method of wear classification has been developed, and also 3D surface measurement techniques have been employed to quantify wear through parametric characterisation and also volume analysis. Initial findings suggested that the wear of matt finish femoral stems differs to that of smoother polished femoral stems. Studies also provide information regarding the nature of bone cement, its behaviour and the interaction between stem and cement following insertion of the stem. It was found that geometric change in bone cement occurred during polymerisation, and following curing. This geometric change presented itself in the form of differential shrinkage. This shrinkage of cement was observed initially through 3D surface topography analysis and later confirmed with geometric measurement techniques. The presence of voids between stem and cement give rise to the possibility of debris creation and transportation, adding to the evidence for a difference in wear mechanism between polished and matt surface finish femoral stems. Some progress was made towards replication of wear in vitro which has future possibilities for wear screening of materials and designs of future prostheses. The overall conclusion of the study suggests that the dominant wear mechanism which occurred between the stem and bone cement was abrasive in nature and this is likely to explain the accelerated wear of matt stems which has been reported by clinicians and researchers.

The design of materials for medical implants is continuously evolving to improve their performance to address clinical needs. The development of a fully bioresorbable material with properties similar to bone is desirable for the replacement of existing metallic implants. This thesis forms part of a recent interdisciplinary effort to develop a scalable manufacturing route for the next generation of melt-processable bioresorbable polymer nanocomposites based on poly (lactic acid) (PLA) and nanohydroxyapatite (nHA). Recent progress in nanoparticle synthesis has enabled large scale production of nHA with different morphologies, forming either nanorods or nanoplatelets. The nanoplatelets can also be surface-modified during production, allowing for different surface coatings to be added to aid the dispersion process. PLA has been selected as the matrix material as it is already a popular choice for commercialised bioresorbable medical implants like small screws and pins. The focus of this work is on the structural and mechanical properties of melt-compounded nHA/PLA nanocomposites from the point of production through to the end of useful implant life, and on the understanding of the degradation mechanism of the PLA and the influence of the nHA on material performance. The accelerated hydrolytic response in phosphate buffer solution (PBS) of three commercial Evonik Resomer® PLA grades, LR 704s, LR 706s, and LR 708, was investigated. It was found that the presence of acidic chain ends in LR 708 increased the rate of hydrolysis relative to ester chain ends in LR 704s and LR 706s, and as a result induced autocatalysis much faster; autocatalysis was visible after 14 d for LR 708 and after 21 d for LR 706s. The presence of low molecular weight species within the distribution was also identified as a factor leading to faster degradation, and grade LR 706s was selected for compounding with nanoparticles. The rate of diffusion of water into PLA was measured in LR 706s and shown to obey Fickian diffusion with an activation energy of 48.6 ± 2.3 kJ mol-1. Creep compliance was measured in bending and was shown to plateau after one day of hydrolytic saturation, but increased again after 10 d due to autocatalysis leading to localised degradation. The use of a pH sensitive dye and microCT imaging provided further insight into the phenomenon. It was also shown that the rate of molecular weight loss increased by 20 times when raising the temperature of the degradation medium from 37 to 50 °C, increased due to the increased energy to break the ester bond alongside the increased autocatalysis due to the chain scission occurring at a much faster rate than diffusion of the breakdown products. Nanocomposites were produced by melt-compounding LR 706s with 2.5, 5 and 10 wt. % of uncoated nHA nanorods, nanoplates and dispersant-coated nanoplates. The presence of water during extrusion caused significant molecular weight loss to the polymer as a result of the increased energy that extrusion at 210 °C would provide to the water to enable hydrolysis of the ester bonds to occur. The molecular weight in the polymer was shown to fall from 422.4 kDa to (187.8 ± 18.0) kDa after extrusion in an air atmosphere. Nitrogen fed through a cold trap was used to prevent this. A pre-drying stage applied to the uncoated nanoparticles also helped to reduce degradation during the extrusion, and polymer processed with dried nHA retained a higher molecular weight (378.6 ± 11.4) kDa than a polymer without the pre-drying stage (327.7 ± 3.1) kDa. Dry nanorod-filled materials exhibited a modulus of up to (5.1 ± 0.2) GPa (at 10 wt. %) compared with (3.8 ± 0.5) GPa for the unfilled polymer, but only moderate increases in strength, from (106 ± 3) MPa to (108.1 ± 2.2) MPa (at 2.5 wt. %), were observed in the nanofilled materials. Both nanorods and nanoplatelets offered a degree of control over the rate of degradation, with a rate of change of molecular weight almost 2.5 times faster possible with 10 wt. % addition of particles. This could be helpful in tuning the implants to transfer loads back to the healing bones in shorter times. The strength of the nanocomposites during degradation was shown to correlate with the molecular weight, remaining constant at ca (44.9 ± 0.7) MPa until the molecular weight dropped to below 58 kDa, when it reduced approximately linearly with molecular weight. In conclusion, the addition of nHA compounded with suitable care offers unique opportunities for the design of materials with some increases in dry mechanical properties, and controllable degradation timescales.

No description available.

[pt] O presente trabalho teve por objetivo mapear a logística na gestão do portfólio de projetos de pesquisa, desenvolvimento e inovação tecnológica do Programa regulado de P e D da ANEEL. Desenvolvido no contexto regulatório e empresarial, avalia em que medida a realização desses projetos resultam em benefícios econômicos para concessionária. O trabalho examinou (i) gargalos que dificultam a apropriação dos resultados dos projetos de P e D pela própria concessionária e (ii) os aspectos motivacionais induzidos pela introdução de políticas públicas de incentivo ao setor. Esse foi o caso da Lei 9991/2000 que cria condições favoráveis à sustentabilidade corporativa e à introdução de inovações no mercado das concessionárias distribuidoras de energia elétrica pela aplicação de um percentual da sua receita operacional líquida no desenvolvimento de projetos de P e D. Os resultados da pesquisa confirmam uma tendência de crescimento dos montantes anuais de investimento no Programa e uma determinação de concentrar recursos num número menor de projetos direcionados às linhas de pesquisa de maior relevância da concessionária. A maioria dos projetos foi desenvolvida por universidades, com ou sem parceria com outras instituições, por um valor médio mais baixo do que o praticado pelas demais instituições executoras. Já as indústrias não tomam a iniciativa de propor projetos de P e D, provavelmente por não disporem de laboratórios próprios. Como medida para evitar a pulverização dos recursos de pesquisa observou-se uma preocupação do gestor em concentrar recursos em iniciativas de centros de pesquisa comprometidos com a solução de temas relevantes que têm afligindo o setor. / [en] The present study aimed to map the logistics management of the portfolio of R, D and I (research, technological development and innovation) projects developed under the ANEEL regulated Program. Developed under the regulatory and business environment, it assesses the extent to which the realization of these projects results in economic benefits to the energy concessionaire. The study examined (i) bottlenecks that hinder the appropriation of the results achieved by the R, D and I projects contracted by the concessionaire and (ii) the motivational aspects induced by the introduction of public policies to incite the sector. This was the case of the 9991/2000-Act that created favourable conditions for corporate sustainability and the introduction of innovations in the market of electric energy operated by distribution concessionaires as it defines that a percentage of the net operating revenues must be applied in the development of R, D and I projects. The results of the survey carried out confirm a growing trend of the annual investment in the program and a determination to concentrate resources on fewer projects targeted to areas of research most relevant to the concessionaire. Most projects were developed by universities, with or without partnership with other institutions, for an average of investments lower than that charged by other executing agencies. The reason why industries do not take the initiative to propose R and D projects may be explained by the fact that they do not have their own laboratories. As a measure to avoid spraying of research resources there was a concern of the manager to concentrate resources on initiatives of research centres committed to the solution of important issues that have afflicted the sector.