Tissue engineering of co-cultured skin substitutes using biocomposite membranes based on collagen and polycaprolactone

The preparation and characterisation of collagen: PCL, gelatin: PCL and gelatin/collagen:PCL biocomposites for manufacture of tissue engineered skin substitutes are reported. Films of collagen: PLC, gelatin: PCL (1:4, 1:8 and 1:20 w/w) and gelatin/collagen:PCL (1:8 and 1:20 w/w) biocomposites were prepared by impregnation of lyophilised collagen and/or gelatin mats by PCL solutions followed by solvent evaporation. In vitro assays of total protein release of collagen:PCL and gelatin: PCL biocomposite films revealed an expected inverse relationship between the collagen release rate and the content of synthetic polymer in the biocomposite samples that may be exploited for controlled presentation and release of biopharmaceuticals such as growth factors. Good compatibility of all biocomposite groups was proven by interaction with 3T3 fibroblasts, normal human epidermal keratinocytes (NHEK), and primary human epidermal keratinocytes (PHEK) and dermal fibroblasts (PHDF) in vitro respectively. The 1:20 collagen: PCL materials exhibiting good cell growth curves and mechanical characteristics were selected for engineering of skin substitutes in this work. The tissue-engineered skin model based on single-donor PHEK and PHDF with differentiated confluent epidermal layer and fibrous porous dermal layer was then developed successfully in vitro proven by SEM and immunohistochemistry assay. The following in vivo animal study on athymic mice revealed early complete wound healing in 10 days and good integration of co-cultured skin substitutes with adjacent mice skin structures. Thus the co-cultured skin substitutes based on 1:20 collagen: PCL biocomposite membranes was proven in principle. The approach to skin modelling reported here may find application in wound treatment, gene therapy and screening of new pharmaceuticals.

The planning and management of health for development:a model for Zimbabwe

In this thesis, I view the historical background of Zimbabwe to show the patterns of traditional life that existed prior to settlerism. The form, nature, pace and impact of settlerism and colonialism up to the time of independence are also discussed to show how they affected the health of the population and the pace of development of the country. The political, social and economic underdevelopment of the African people that occurred in Zimbabwe prior to independence was a result of deliberate, politically motivated and controlled policy initiatives. These led to inequatable, inadequate, inappropriate and inaccessible health care provision. It is submitted that since it was the politics that determined the pace of underdevelopment, it must be the politics that must be at the forefront of the development strategy adopted. In the face of the amed conflict that existed in Zimbabwe, existing frameworks of analyses are shown to be inadequate for planning purposes because of their inability to provide indications about the stability of future outcomes. The Metagame technique of analysis of options is proposed as a methology that can be applied in such situations. It rejects deterministic predicative models as misleading and advocates an interactive model based on objective and subjective valuation of human behaviour. In conclusion, the search for stable outcomes rather than optimal and best solutions strategies is advocated in decision making in organisations of all sizes.

Comparison and characterisation of ribozyme delivery in cultured glial and neuronal cells in vivo and in vitro

Ribozymes are short strands of RNA that possess a huge potential as biological tools for studying gene expression and as therapeutic agents to down-regulate undesirable gene expression. Successful application of ribozymes requires delivery to the target site in sufficient amounts for an adequate duration. However, due to their large size and polyanionic character ribozymes are not amenable to transport across biological membranes. In this study a chemically modified ribozyme with enhanced biological stability, targeted against the EGFR mRNA has been evaluated for cellular delivery to cultured glial and neuronal cells with a view to developing treatments for brain tumours. Cellular delivery of free ribozyme was characterised in cultured glial and neuronal cells from the human and rat. Delivery was very limited and time dependent with no consistent difference observed between glial and neuronal cells in both species. Cellular association was largely temperature and energy-dependent with a small component of non-energy dependent association. Further studies showed that ribozyme cellular association was inhibited with self and cross competition with nucleic and non-nucleic acid polyanions indicating the presence of cell surface ribozyme-binding molecules. Trypsin washing experiments further implied that the ribozyme binding surface molecules were protein by nature. Dependence of cellular association on pH indicated that interaction of ribozyme with cell surface molecules was based on ionic interactions. Fluoresence studies indicated that, post cell association, ribozymes were sequestered in sub-cellular vesicles. South-Western blots identified several cell surface proteins which bind to ribozymes and could facilitate cellular association. The limited cellular association observed with free ribozyme required the development and evaluation of polylactide-co-glycolide microspheres incorporating ribozyme for enhanced cellular delivery. Characterisation of microsphere mediated delivery of ribozyme in cultured glial and neuronal cells showed that association increased by 18 to 27-fold in all cell types with no differences observed between cell lines and species. Microsphere mediated delivery was temperature and energy dependent and independent of pH. In order to assess the potential of PLGA micro spheres for the CNS delivery of ribozyme the distribution of ribozyme entrapping microspheres was investigated in rat CNS after intracerebroventricular injection. Distribution studies demonstrated that after 24 hours there was no free ribozyme present in the brain parenchyma, however microsphere entrapped ribozyme was found in the CNS. Microspheres remained in the ventricular system after deposition and passed from the lateral ventricles to the third and fourth ventricle and in the subarachnoid space. Investigation of the influence of microsphere size on the distribution in CNS demonstrated that particles up to 2.5 and O.5f.lm remained in the ventricles around the choroid plexus and ependymal lining.

A semantic web environment for component model

Component-based development (CBD) has become an important emerging topic in the software engineering field. It promises long-sought-after benefits such as increased software reuse, reduced development time to market and, hence, reduced software production cost. Despite the huge potential, the lack of reasoning support and development environment of component modeling and verification may hinder its development. Methods and tools that can support component model analysis are highly appreciated by industry. Such a tool support should be fully automated as well as efficient. At the same time, the reasoning tool should scale up well as it may need to handle hundreds or even thousands of components that a modern software system may have. Furthermore, a distributed environment that can effectively manage and compose components is also desirable. In this paper, we present an approach to the modeling and verification of a newly proposed component model using Semantic Web languages and their reasoning tools. We use the Web Ontology Language and the Semantic Web Rule Language to precisely capture the inter-relationships and constraints among the entities in a component model. Semantic Web reasoning tools are deployed to perform automated analysis support of the component models. Moreover, we also proposed a service-oriented architecture (SOA)-based semantic web environment for CBD. The adoption of Semantic Web services and SOA make our component environment more reusable, scalable, dynamic and adaptive.

A pre-post test evaluation of the impact of the PELICAN MDT-TME development programme on the working lives of colorectal cancer team members

Background - The PELICAN Multidisciplinary Team Total Mesorectal Excision (MDT-TME) Development Programme aimed to improve clinical outcomes for rectal cancer by educating colorectal cancer teams in precision surgery and related aspects of multidisciplinary care. The Programme reached almost all colorectal cancer teams across England. We took the opportunity to assess the impact of participating in this novel team-based Development Programme on the working lives of colorectal cancer team members. Methods - The impact of participating in the programme on team members' self-reported job stress, job satisfaction and team performance was assessed in a pre-post course study. 333/568 (59%) team members, from the 75 multidisciplinary teams who attended the final year of the Programme, completed questionnaires pre-course, and 6-8 weeks post-course. Results - Across all team members, the main sources of job satisfaction related to working in multidisciplinary teams; whilst feeling overloaded was the main source of job stress. Surgeons and clinical nurse specialists reported higher levels of job satisfaction than team members who do not provide direct patient care, whilst MDT coordinators reported the lowest levels of job satisfaction and job stress. Both job stress and satisfaction decreased after participating in the Programme for all team members. There was a small improvement in team performance. Conclusions - Participation in the Development Programme had a mixed impact on the working lives of team members in the immediate aftermath of attending. The decrease in team members' job stress may reflect the improved knowledge and skills conferred by the Programme. The decrease in job satisfaction may be the consequence of being unable to apply these skills immediately in clinical practice because of a lack of required infrastructure and/or equipment. In addition, whilst the Programme raised awareness of the challenges of teamworking, a greater focus on tackling these issues may have improved working lives further.

A fuzzy AHP based integer linear programming model for the multi-criteria transshipment problem

Purpose – The purpose of this research is to develop a holistic approach to maximize the customer service level while minimizing the logistics cost by using an integrated multiple criteria decision making (MCDM) method for the contemporary transshipment problem. Unlike the prevalent optimization techniques, this paper proposes an integrated approach which considers both quantitative and qualitative factors in order to maximize the benefits of service deliverers and customers under uncertain environments. Design/methodology/approach – This paper proposes a fuzzy-based integer linear programming model, based on the existing literature and validated with an example case. The model integrates the developed fuzzy modification of the analytic hierarchy process (FAHP), and solves the multi-criteria transshipment problem. Findings – This paper provides several novel insights about how to transform a company from a cost-based model to a service-dominated model by using an integrated MCDM method. It suggests that the contemporary customer-driven supply chain remains and increases its competitiveness from two aspects: optimizing the cost and providing the best service simultaneously. Research limitations/implications – This research used one illustrative industry case to exemplify the developed method. Considering the generalization of the research findings and the complexity of the transshipment service network, more cases across multiple industries are necessary to further enhance the validity of the research output. Practical implications – The paper includes implications for the evaluation and selection of transshipment service suppliers, the construction of optimal transshipment network as well as managing the network. Originality/value – The major advantages of this generic approach are that both quantitative and qualitative factors under fuzzy environment are considered simultaneously and also the viewpoints of service deliverers and customers are focused. Therefore, it is believed that it is useful and applicable for the transshipment service network design.

A nested Petri net framework for modeling and analyzing multi-agent systems

In the past two decades, multi-agent systems (MAS) have emerged as a new paradigm for conceptualizing large and complex distributed software systems. A multi-agent system view provides a natural abstraction for both the structure and the behavior of modern-day software systems. Although there were many conceptual frameworks for using multi-agent systems, there was no well established and widely accepted method for modeling multi-agent systems. This dissertation research addressed the representation and analysis of multi-agent systems based on model-oriented formal methods. The objective was to provide a systematic approach for studying MAS at an early stage of system development to ensure the quality of design. ^ Given that there was no well-defined formal model directly supporting agent-oriented modeling, this study was centered on three main topics: (1) adapting a well-known formal model, predicate transition nets (PrT nets), to support MAS modeling; (2) formulating a modeling methodology to ease the construction of formal MAS models; and (3) developing a technique to support machine analysis of formal MAS models using model checking technology. PrT nets were extended to include the notions of dynamic structure, agent communication and coordination to support agent-oriented modeling. An aspect-oriented technique was developed to address the modularity of agent models and compositionality of incremental analysis. A set of translation rules were defined to systematically translate formal MAS models to concrete models that can be verified through the model checker SPIN (Simple Promela Interpreter). ^ This dissertation presents the framework developed for modeling and analyzing MAS, including a well-defined process model based on nested PrT nets, and a comprehensive methodology to guide the construction and analysis of formal MAS models.^

The early development and pilot -testing of a case management intervention with victims of stalking: An evaluation study

This study evaluated the early development and pilot-testing of Project IMPACT, a case management intervention for victims of stalking. The Design and Development framework (Rothman & Thomas, 1994) was used as a guide for program development and evaluation. Nine research questions examined the processes and outcomes associated with program implementation. ^ The sample included all 36 clients who participated in Project IMPACT between February of 2000 and June of 2001, as well as the victim advocates who provided them with services. Quantitative and qualitative data were drawn from client case files, participant observation field notes and interview transcriptions. Quantitative data were entered into three databases where: (1) clients were the units of analysis (n = 36), (2) services were the units of analysis (n = 1146), and (3) goals were the units of analysis (n = 149). These data were analyzed using descriptive statistics, Pearson's Chi-square, Spearman's Rho, Phi, Cramer's V, Wilcoxon's Matched Pairs Signed-Ranked Test and McNemar's Test Statistic. Qualitative data were reduced via open, axial and selective coding methods. Grounded theory and case study frameworks were utilized to analyze these data. ^ Results showed that most clients noted an improved sense of well-being and safety, although residual symptoms of trauma remained for numerous individuals. Stalkers appeared to respond to criminal and civil justice-based interventions by reducing violent and threatening behaviors; however, covert behaviors continued. The study produced findings that provided preliminary support for the use of several intervention components including support services, psycho-education, safety planning, and boundary spanning. The psycho-education and safety planning in particular seemed to help clients cognitively reframe their perceptions of the stalking experience and gain a sense of increased safety and well-being. A 65% level of satisfactory goal achievement was observed overall, although goals involving justice-based organizations were associated with lower achievement. High service usage was related to low-income clients and those lacking in social support. Numerous inconsistencies in program implementation were found to be associated with the skills and experiences of victim advocates. Thus, recommendations were made to further refine, develop and evaluate the intervention. ^

Genetic markers, birth characteristics, and childhood leukemia risk

The cause for childhood acute lymphoblastic leukemia (ALL) remains unknown, but male gender is a risk factor, and among ethnicities, Hispanics have the highest risk. In this dissertation, we explored correlations among genetic polymorphisms, birth characteristics, and the risk of childhood ALL in a multi-ethnic sample in 161 cases and 231 controls recruited contemporaneously (2007-2012) in Houston, TX. We first examined three lymphoma risk markers, since lymphoma and ALL both stem from lymphoid cells. Of these, rs2395185 showed a risk association in non-Hispanic White males (OR=2.8, P=0.02; P interaction=0.03 for gender), but not in Hispanics. We verified previously known risk associations to validate the case-control sample. Mutations of HFE (C282Y, H63D) were genotyped to test whether iron-regulatory gene (IRG) variants known to elevate iron levels increase childhood ALL risk. Being positive for either polymorphism yielded only a modestly elevated OR in males, which increased to 2.96 (P=0.01) in the presence of a particular transferrin receptor (TFRC) genotype for rs3817672 (Pinteraction=0.04). SNP rs3817672 itself showed an ethnicity-specific association (P interaction=0.02 for ethnicity). We then examined additional IRG SNPs (rs422982, rs855791, rs733655), which showed risk associations in males (ORs=1.52 to 2.60). A polygenic model based on the number of polymorphic alleles in five IRG SNPs revealed a linear increase in risk (OR=2.00 per incremental change; P=0.002). Having three or more alleles compared with none was associated with increased risk in males (OR=4.12; P=0.004). Significant risk associations with childhood ALL was found with birth length (OR=1.18 per inch, P=0.04), high birth weight (>4,000g) (OR=1.93, P=0.01), and with gestational age (OR=1.10 per week, P=0.04). We observed a negative correlation between HFE SNP rs9366637 and gestational age (P=0.005), again, stronger in males ( P=0.001) and interacting with TFRC (P interaction=0.05). Our results showed that (i) ALL risk markers do not show universal associations across ethnicities or between genders, (ii) IRG SNPs modify ALL risk presumably by their effects on iron levels, (iii) a negative correlation between an HFE SNP and gestational age exists, which implicates an iron-related mechanism. The results suggest that currently unregulated supplemental iron intake may have implications on childhood ALL development.

Evaluating Effects of Everglades Restoration on American Crocodile Populations in South Florida Using a Spatially-Explicit, Stage-Based Population Model

The distribution and abundance of the American crocodile (Crocodylus acutus) in the Florida Everglades is dependent on the timing, amount, and location of freshwater flow. One of the goals of the Comprehensive Everglades Restoration Plan (CERP) is to restore historic freshwater flows to American crocodile habitat throughout the Everglades. To predict the impacts on the crocodile population from planned restoration activities, we created a stage-based spatially explicit crocodile population model that incorporated regional hydrology models and American crocodile research and monitoring data. Growth and survival were influenced by salinity, water depth, and density-dependent interactions. A stage-structured spatial model was used with discrete spatial convolution to direct crocodiles toward attractive sources where conditions were favorable. The model predicted that CERP would have both positive and negative impacts on American crocodile growth, survival, and distribution. Overall, crocodile populations across south Florida were predicted to decrease approximately 3 % with the implementation of CERP compared to future conditions without restoration, but local increases up to 30 % occurred in the Joe Bay area near Taylor Slough, and local decreases up to 30 % occurred in the vicinity of Buttonwood Canal due to changes in salinity and freshwater flows.

Fuzzy Modeling and Control Based Virtual Machine Resource Management

Virtual machines (VMs) are powerful platforms for building agile datacenters and emerging cloud systems. However, resource management for a VM-based system is still a challenging task. First, the complexity of application workloads as well as the interference among competing workloads makes it difficult to understand their VMs’ resource demands for meeting their Quality of Service (QoS) targets; Second, the dynamics in the applications and system makes it also difficult to maintain the desired QoS target while the environment changes; Third, the transparency of virtualization presents a hurdle for guest-layer application and host-layer VM scheduler to cooperate and improve application QoS and system efficiency. This dissertation proposes to address the above challenges through fuzzy modeling and control theory based VM resource management. First, a fuzzy-logic-based nonlinear modeling approach is proposed to accurately capture a VM’s complex demands of multiple types of resources automatically online based on the observed workload and resource usages. Second, to enable fast adaption for resource management, the fuzzy modeling approach is integrated with a predictive-control-based controller to form a new Fuzzy Modeling Predictive Control (FMPC) approach which can quickly track the applications’ QoS targets and optimize the resource allocations under dynamic changes in the system. Finally, to address the limitations of black-box-based resource management solutions, a cross-layer optimization approach is proposed to enable cooperation between a VM’s host and guest layers and further improve the application QoS and resource usage efficiency. The above proposed approaches are prototyped and evaluated on a Xen-based virtualized system and evaluated with representative benchmarks including TPC-H, RUBiS, and TerraFly. The results demonstrate that the fuzzy-modeling-based approach improves the accuracy in resource prediction by up to 31.4% compared to conventional regression approaches. The FMPC approach substantially outperforms the traditional linear-model-based predictive control approach in meeting application QoS targets for an oversubscribed system. It is able to manage dynamic VM resource allocations and migrations for over 100 concurrent VMs across multiple hosts with good efficiency. Finally, the cross-layer optimization approach further improves the performance of a virtualized application by up to 40% when the resources are contended by dynamic workloads.

A dosimetry and radiobiological model for intravascular brachytherapy treatment planning with radioisotope emitting stents

The aim of this study was to develop a practical, versatile and fast dosimetry and radiobiological model for calculation of the 3D dose distribution and radiobiological effectiveness of radioactive stents. The algorithm was written in Matlab 6.5 programming language and is based on the dose point kernel convolution. The dosimetry and radiobiological model was applied for evaluation of the 3D dose distribution of 32P, 90Y, 188Re and 177Lu stents. Of the four, 32P delivers the highest dose, while 90Y, 188Re and 177Lu require high levels of activity to deliver a significant therapeutic dose in the range of 15-30 Gy. Results of the radiobiological model demonstrated that the same physical dose delivered by different radioisotopes produces significantly different radiobiological effects. This type of theoretical dose calculation can be useful in the development of new stent designs, the planning of animal studies and clinical trials, and clinical decisions involving individualized treatment plans.

A framework for experimental determination of localised vertical pedestrian forces on full-scale structures using wireless attitude and heading reference systems

A major weakness among loading models for pedestrians walking on flexible structures proposed in recent years is the various uncorroborated assumptions made in their development. This applies to spatio-temporal characteristics of pedestrian loading and the nature of multi-object interactions. To alleviate this problem, a framework for the determination of localised pedestrian forces on full-scale structures is presented using a wireless attitude and heading reference systems (AHRS). An AHRS comprises a triad of tri-axial accelerometers, gyroscopes and magnetometers managed by a dedicated data processing unit, allowing motion in three-dimensional space to be reconstructed. A pedestrian loading model based on a single point inertial measurement from an AHRS is derived and shown to perform well against benchmark data collected on an instrumented treadmill. Unlike other models, the current model does not take any predefined form nor does it require any extrapolations as to the timing and amplitude of pedestrian loading. In order to assess correctly the influence of the moving pedestrian on behaviour of a structure, an algorithm for tracking the point of application of pedestrian force is developed based on data from a single AHRS attached to a foot. A set of controlled walking tests with a single pedestrian is conducted on a real footbridge for validation purposes. A remarkably good match between the measured and simulated bridge response is found, indeed confirming applicability of the proposed framework.

Web-based museum trails on PDAs for university-level design students: Design and evaluation

This paper describes the development and evaluation of web-based museum trails for university-level design students to access on handheld devices in the Victoria and Albert Museum (V&A) in London. The trails offered students a range of ways of exploring the museum environment and collections, some encouraging students to interpret objects and museum spaces in lateral and imaginative ways, others more straightforwardly providing context and extra information. In a three-stage qualitative evaluation programme, student feedback showed that overall the trails enhanced students’ knowledge of, interest in, and closeness to the objects. However, the trails were only partially successful from a technological standpoint due to device and network problems. Broader findings suggest that technology has a key role to play in helping to maintain the museum as a learning space which complements that of universities as well as schools. This research informed my other work in visitor-constructed learning trails in museums, specifically in the theoretical approach to data analysis used, in the research design, and in informing ways to structure visitor experiences in museums. It resulted in a conference presentation, and more broadly informed my subsequent teaching practice.

INVESTIGATIONS INTO MECHANISMS UNDERLYING EXTREME WAVE FORMATIONS AND COMPUTATIONALLY INTENSIVE SIMULATIONS

Various mechanisms have been proposed to explain extreme waves or rogue waves in an oceanic environment including directional focusing, dispersive focusing, wave-current interaction, and nonlinear modulational instability. The Benjamin-Feir instability (nonlinear modulational instability), however, is considered to be one of the primary mechanisms for rogue-wave occurrence. The nonlinear Schrodinger equation is a well-established approximate model based on the same assumptions as required for the derivation of the Benjamin-Feir theory. Solutions of the nonlinear Schrodinger equation, including new rogue-wave type solutions are presented in the author's dissertation work. The solutions are obtained by using a predictive eigenvalue map based predictor-corrector procedure developed by the author. Features of the predictive map are explored and the influences of certain parameter variations are investigated. The solutions are rescaled to match the length scales of waves generated in a wave tank. Based on the information provided by the map and the details of physical scaling, a framework is developed that can serve as a basis for experimental investigations into a variety of extreme waves as well localizations in wave fields. To derive further fundamental insights into the complexity of extreme wave conditions, Smoothed Particle Hydrodynamics (SPH) simulations are carried out on an advanced Graphic Processing Unit (GPU) based parallel computational platform. Free surface gravity wave simulations have successfully characterized water-wave dispersion in the SPH model while demonstrating extreme energy focusing and wave growth in both linear and nonlinear regimes. A virtual wave tank is simulated wherein wave motions can be excited from either side. Focusing of several wave trains and isolated waves has been simulated. With properly chosen parameters, dispersion effects are observed causing a chirped wave train to focus and exhibit growth. By using the insights derived from the study of the nonlinear Schrodinger equation, modulational instability or self-focusing has been induced in a numerical wave tank and studied through several numerical simulations. Due to the inherent dissipative nature of SPH models, simulating persistent progressive waves can be problematic. This issue has been addressed and an observation-based solution has been provided. The efficacy of SPH in modeling wave focusing can be critical to further our understanding and predicting extreme wave phenomena through simulations. A deeper understanding of the mechanisms underlying extreme energy localization phenomena can help facilitate energy harnessing and serve as a basis to predict and mitigate the impact of energy focusing.