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Proefschriften --- Thèses --- Academic collection --- #BIBC:T1999 --- Theses
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Despite the advances in the field of tissue engineering (TE), engineered tissue products that are part of routine medical treatments still do no t exist. What appears clear is that there is a need for a more controlle d environment for in vitro cell culture which in turn would lead t o a more robust, automated and cost effective production process. T he application of physical and chemical stimuli mimicking the ones perce ived by the cells in vivo would be essential to such an environment. Despite the introduction of bioreactors in order to help the monitoring and control of the 3D fluid dynamic environment, they are still often ap plied as "black boxes" containing the TE construct. Computational Fluid Dynamics (CFD) models, enabling the quantification o f the fluid dynamic variables, represent a valuable tool to understand t he effect of fluid flow and mass transport on cell behaviour. The general aim of this PhD project is twofold. Firstly, it aims at deve loping highly efficient computational tools in order to predict the flui d dynamic stimuli and mass transport inside regular scaffolds and, secon dly, it wants to illustrate how these models can assist bioreactor exper iments and the design of 3D regular scaffolds. In the first part of this work, a simplified one unit cell high regular scaffold is used as a test case. The fluid dynamic environment within th is scaffold is characterized through a bi-modular approach of modelling, by means of CFD, and experiments, using micro particle imaging velocime try (μ-PIV). Subsequently, the oxygen distribution within this simp lified scaffold is investigated and a computational 1D model is suggeste d as efficient tool for studying scaffold up-scaling as a function of gi ven oxygen constraints. Eventually, two approaches are presented to demo nstrate how the developed methods can be used to design perfusion experi ments. In the second part of this work, 3D additive manufactured (AM) Ti6Al4V s caffolds are used as test cases to (i) determine the accuracy of CFD mod els for the prediction of the permeability coefficient and (ii) to evalu ate the possibilities and drawbacks of computer aided design (CAD) and m icrofocus X-ray computed tomography (micro-CT) based models for the pred iction of the mechanical and transport parameters. Quantitative comparis ons with experimental results are performed: permeability measurements a re carried out to determine the scaffolds' permeability coefficients and compression tests are performed to measure the scaffolds elastic modulu s. In conclusion, the work shows that the developed computational models ca n accurately quantify the fluid dynamic environment within regular TE sc affolds. Furthermore it illustrates how, taking advantage of the regular ity of the scaffolds, the most efficient models can be effectively appli ed to guide scaffold and bioreactor design.
62 <043> --- Engineering. Technology in general--Dissertaties --- Theses
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Porous materials have very attractive properties because of their lightweight and unique geometry that lead to their shock or sound absorbing properties. Thus, porous materials are frequently used in many fields, such as lightweight sandwich manufacturing, packaging, crash worthiness and medicine. Most porous materials have a random morphology, however the request for porous structures with highly controlled properties, coming from different application areas within the industrial and scientific market, forced researchers to develop novel additive manufacturing (AM) production techniques like selective laser melting (SLM), selective laser sintering (SLS) or electron beam melting (EBM). A critical aspect in optimising these production techniques and their postproduction treatments is to allow control of the morphological and mechanical properties of manufactured porous structures on both meso- and microscale. Therefore, the main focus of this study was twofold, namely: i) optimisation of the porous structures towards novel engineering materials with fully customized morphological properties and ii) unravelling of the mechanical behaviour and failure of those porous structures subjected to the mechanical loading. Due to the large variety of porous structures, and their broad range of applications, this PhD study focuses on one specific production technique and material type. The prerequisite was that, within this specific manufacturing approach the porous structures with a well controlled macro-morphology can be produced based on the design input which can be modified according to the desired output. In practice a case study on open porous Ti6Al4V structures, produced by SLM, was performed.The dissertation consists mainly of two parts: one on material functionalization (chapters 2 and 4) and one on material characterization (chapter 3, 5 and 6). In chapter 2 a protocol for the surface topology improvement has been developed and applied to Ti6Al4V porous structures produced by SLM. Topology changes were introduced by several surface treatments consisting of chemical etching followed by electrochemical polishing. In that way the surface irregularities, typical for porous structures manufactured by SLM have been eliminated.In chapter 3 a novel tool for roughness measurements has been developed and validated for a quantitative characterization of the surface topology. For the first time, the micro-computed tomography (μCT) has been applied for quantification of the materials surface texture. Validity of this surface roughness analysis has been given by comparison to physical roughness measurementsperformed by conventional systems showing that the novel μCT image based tool for surface roughness analysis can be applied for quantitative surface characterization.The unique properties of porous structures strongly depend on the morphological properties, thus their thorough characterization is required. Therefore, in chapter 4 a relationship between thestructural properties and the μCT based analysis of porous Ti6Al4V structures has been investigated to define the most optimal characterization conditions. In this study, a basic, but systematic protocol for determination of the best acquisition parameters such as spatial resolution has been developed regarding the μCT based morphological characterization of the complex porous structures. The findings of this study can assist to increase the quality of 3D quantitative morphological analysis of any object in relation to its surface complexity as well to reduce the investigation time and costs by evolving towards a customised relationship of μCT settings versus morphological analysis level.In chapter 5, the surface modification protocol presented in chapter 2 has been developed further in order to manufacture Ti6Al4V porous structures with customized morphological properties. Application of the multi-factorial design of experiments led to a controlled, at both macro and micro level, morphological modification of the porous structures. This allowed to:i) eliminate the surface irregularities,ii) modify the surface roughness in a robust manner but, alsoiii) produce customized structures with desired global morphological propertiesAdditionally, the developed protocol can be applied for production of various porous structures with a final beam thickness that is lower than the resolution of the selected manufacturing process. Finally, modification of the beam surface can be used for controlling the biological cell behaviour seeded on 3D porous structures. In that way, the most optimal surface properties for future designs and production of 3D structures for orthopaedic application can be looked for and validated experimentally.Finally, a proof of concept case study was performed by using an automated non-rigid image registration to assess strain through analysis of μCT images acquired prior-to and after compressive loading of SLM made Ti6Al4V open porous structures. Additionally, the evaluation of the potential and limitations of the proposed approach was assessed based on the simulated deformation of the phantom object. It was shown that the µCT based strain mapping, performed by combining the in-situ loading and non-rigid image registration of the µCT images, provides a valuable tool to identify and analyze the critical sections in the porous structure having a higher strain concentration, eventually leading to sudden failure. Additionally, the local strain analysis revealed larger strain concentrations at the beam geometry imperfections. Experiments with the phantom object confirmed potential of the proposed approach for the local strain analysis as the computed strain corresponded with the deformation artificially applied to the tested object. However, obtained strain results showed dependency upon the applied grid spacing of the B-spline transformation. Therefore, further development of the non-rigid image registration approach as a tool for local strain analysis is required, although a qualitative analysis of the local deformation can already be performed to evaluate the volumetric changes in the porous Ti6Al4V structures.In conclusion, the work shows that combination of different tools was proven to be a valuable technique for thorough morphological characterization of complex porous structures, as well as their mechanical analysis. This resulted in production of novel porous Ti6Al4V structures with controlled morphological properties which can assist in more controlled evaluation of the combined effect of various functional properties. Furthermore, a novel characterization tool for surface analysis has been developed which can be beneficial for various research subjects dealing with surface engineering aspects.
669 --- academic collection --- Metallurgy --- Theses --- 669 Metallurgy
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Molecular transport phenomena underlie many of the processes that regulate cell behaviour during skeletal growth and development. This fundamental knowledge has largely originated from advances in imaging technologies that enabled the iterative interaction between experiments and theoretical models of mass transport. The demand for quantitative data that can be derived from imaging observations has hereby strongly increased, finding its application in rational experimental design. Quantitative descriptions of the mass transport environment have also become an obvious need in biomimetic tissue engineering approaches, aiming for the repair of skeletal tissue damage through recapitulation of embryonic tissue development. Gradually the tools for mass transport quantification are growing in this field, but the need for novel quantitative imaging technologies is still high. The research presented in this dissertation has combined quantitative luminescence techniques, microbead technology, and mathematical modelling with the aim of better understanding mass transport phenomena in tissue engineering constructs, with a central focus on the role of oxygen transport.To this end, photoluminescent oxygen sensitive microbeads were developed for the localized, in situ measurement of oxygen concentration. The microbead oxygen sensors were successfully calibrated in normal and turbid media, indicating that the ratiometric measurement principle in combination with a suitable intensity peak fitting algorithm could be applied to monitor oxygen concentrations in a wide variety of experimental setups. Oxygen transport within these setups was shown not to be influenced by the microscale dimensions of the oxygen sensors. Integration of the oxygen sensors into cell aggregates, mimics of skeletal cell condensations, was achieved by a binding method that relied on the non-covalent interactions between biotin and streptavidin. This binding method enabled the targeted and robust incorporation of microbeads into a specific environment. The non-invasive and non-interfering application of this method and sensor integration was corroborated experimentally.The use of fluorescence recovery after photobleaching was explored to provide a quantitative description of solute mobility within tissue engineering constructs. Tracer diffusion rates were shown to be significantly hindered by interactions with the bulk volume of a hydrogel and by the presence of cells. These results and use of the photobleaching technique were successfully validated by comparison with other methods for mass transport quantification. Oxygen transport within engineered constructs, and more specifically in cell aggregates, was quantified from microbead oxygen sensor measurements. Values for the oxygen consumption rate and induced oxygen concentration profiles were derived which could be correlated to observed changes in cell proliferation and differentiation behaviour.Finally, the influence of mass transport phenomena on bioluminescent reporter cell activity within a tissue engineering construct was explored. Oxygen concentration gradients were measured within the constructs that clearly interfered with the emitted bioluminescence signal. Using a model-based approach, oxygen-independent bioluminescence intensities could be obtained that were shown to be a more accurate and reliable representation of the active reporter cell population within the construct. These results revealed a dual role for the study of mass transport phenomena, as these transport phenomena do not only control many of the cellular and molecular processes during skeletal development, but they also are a basic requirement for the use of luminescent assays based on biochemical reactions.
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For almost two decades it is claimed that cell-based therapies will revolutionize the field of medicine. Albeit major scientific breakthroughs that present cells as the active ingredient of a clinical therapy are succeeding each other at increasing speed, today only few of these research successes are able to materialise their full clinical potential and develop into a widely available commercial cell-based treatment. Besides the remaining scientific challenges (e.g. exact mechanisms of action), costly product development, and a complex regulatory and reimbursement landscape, it is hypothesised that the lack of automated, controlled and cost-effective production strategies forms a major hurdle towards a wide-spread clinical translation of cell based therapies. This work therefore aims at creating enabling tools and knowledge for monitored and controlled large-scale stem cell production, with the ultimate goal of facilitating the manufacturing of qualitative and cost-effective cell-based therapies. Flask-based cell expansion processes are currently still the gold standard despite the disadvantage of their limited scale-up and automation potential. In a first phase the translation from flask-based cell production processes to a bioreactor-based process was investigated, without adversely influencing the properties of the cells. In parallel to the bioreactor-based scale-up, this work describes how the data from these bioreactor processes can be utilised to non-invasively monitor critical process parameters in real-time, then utilise this information for process control strategies that enable more informed process decisions, ultimately leading to an improved product quality.
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