Structural design of contact lens-based drug delivery systems; in vitro and in vivo studies of ocular triggering mechanisms

This study identifies and investigates the potential use of in-eye trigger mechanisms to supplement the widely available information on release of ophthalmic drugs from contact lenses under passive release conditions. Ophthalmic dyes and surrogates have been successfully employed to investigate how these factors can be drawn together to make a successful system. The storage of a drug-containing lens in a pH lower than that of the ocular environment can be used to establish an equilibrium that favours retention of the drug in the lens prior to ocular insertion. Although release under passive conditions does not result in complete dye elution, the use of mechanical agitation techniques which mimic the eyelid blink action in conjunction with ocular tear chemistry promotes further release. In this way differentiation between passive and triggered in vitro release characteristics can be established. Investigation of the role of individual tear proteins revealed significant differences in their ability to alter the equilibrium between matrix-held and eluate-held dye or drug. These individual experiments were then investigated in vivo using ophthalmic dyes. Complete elution was found to be achievable in-eye; this demonstrated the importance of that fraction of the drug retained under passive conditions and the triggering effect of in-eye conditions on the release process. Understanding both the structure-property relationship between drug and material and in-eye trigger mechanisms, using ophthalmic dyes as a surrogate, provides the basis of knowledge necessary to design ocular drug delivery vehicles for in-eye release in a controllable manner.

Computer simulation of form-roll design

Changes in modern structural design have created a demand for products which are light but possess high strength. The objective is a reduction in fuel consumption and weight of materials to satisfy both economic and environmental criteria. Cold roll forming has the potential to fulfil this requirement. The bending process is controlled by the shape of the profile machined on the periphery of the rolls. A CNC lathe can machine complicated profiles to a high standard of precision, but the expertise of a numerical control programmer is required. A computer program was developed during this project, using the expert system concept, to calculate tool paths and consequently to expedite the procurement of the machine control tapes whilst removing the need for a skilled programmer. Codifying the expertise of a human and the encapsulation of knowledge within a computer memory, destroys the dependency on highly trained people whose services can be costly, inconsistent and unreliable. A successful cold roll forming operation, where the product is geometrically correct and free from visual defects, is not easy to attain. The geometry of the sheet after travelling through the rolling mill depends on the residual strains generated by the elastic-plastic deformation. Accurate evaluation of the residual strains can provide the basis for predicting the geometry of the section. A study of geometric and material non-linearity, yield criteria, material hardening and stress-strain relationships was undertaken in this research project. The finite element method was chosen to provide a mathematical model of the bending process and, to ensure an efficient manipulation of the large stiffness matrices, the frontal solution was applied. A series of experimental investigations provided data to compare with corresponding values obtained from the theoretical modelling. A computer simulation, capable of predicting that a design will be satisfactory prior to the manufacture of the rolls, would allow effort to be concentrated into devising an optimum design where costs are minimised.

The design of contact lens based ocular drug delivery systems for single-day use:part (I) structural factors, surrogate ophthalmic dyes and passive diffusion studies

The poor retention and efficacy of instilled drops as a means of delivering drugs to the ophthalmic environment is well-recognised. The potential value of contact lenses as a means of ophthalmic drug delivery, and consequent improvement of pre-corneal retention is one obvious route to the development of a more effective ocular delivery system. Furthermore, the increasing availability and clinical use of daily disposable contact lenses provides the platform for the development of viable single-day use drug delivery devices based on existing materials and lenses. In order to provide a basis for the effective design of such devices, a systematic understanding of the factors affecting the interaction of individual drugs with the lens matrix is required. Because a large number of potential structural variables are involved, it is necessary to achieve some rationalisation of the parameters and physicochemical properties (such as molecular weight, charge, partition coefficients) that influence drug interactions. Ophthalmic dyes and structurally related compounds based on the same core structure were used to investigate these various factors and the way in which they can be used in concert to design effective release systems for structurally different drugs. Initial studies of passive diffusional release form a necessary precursor to the investigation of the features of the ocular environment that over-ride this simple behaviour. Commercially available contact lenses of differing structural classifications were used to study factors affecting the uptake of the surrogate actives and their release under 'passive' conditions. The interaction between active and lens material shows considerable and complex structure dependence, which is not simply related to equilibrium water content. The structure of the polymer matrix itself was found to have the dominant controlling influence on active uptake; hydrophobic interaction with the ophthalmic dye playing a major role. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Design and characterisation of novel blends of poly(lactic acid)

This thesis is concerned with the effect of polymer structure on miscibility of the three component blends based on poly(lactic acid) (PLA) with using blending techniques. The examination of novel PLA homologues (pre-synthesised poly(a-esters)), including a range of aliphatic and aromatic poly(a-esters) is an important aspect of the work. Because of their structural simplicity and similarity to PLA, they provide an ideal system to study the effect of polyester structures on the miscibility of PLA polymer blends. The miscibility behaviour of the PLA homologues is compared with other aliphatic polyesters (e.g. poly(e-caprolactone) (PCL), poly(hydroxybutyrate hydroxyvalerate) (P(HB-HV)), together with a series of cellulose-based polymers (e.g. cellulose acetate butyrate (CAB)). The work started with the exploration the technique used for preliminary observation of the miscibility of blends referred to as “a rapid screening method” and then the miscibility of binary blends was observed and characterised by percent transmittance together with the Coleman and Painter miscibility approach. However, it was observed that symmetrical structures (e.g. a1(dimethyl), a2(diethyl)) promote the well-packing which restrict their chains from intermingling into poly(L-lactide) (PLLA) chains and leads the blends to be immiscible, whereas, asymmetrical structures (e.g. a4(cyclohexyl)) behave to the contrary. a6(chloromethyl-methyl) should interact well with PLLA because of the polar group of chloride to form interactions, but it does not. It is difficult to disrupt the helical structure of PLLA. PLA were immiscible with PCL, P(HB-HV), or compatibiliser (e.g. G40, LLA-co-PCL), but miscible with CAB which is a hydrogen-bonded polymer. However, these binary blends provided a useful indication for the exploration the novel three component blends. In summary, the miscibility of the three-component blends are miscible even if only two polymers are miscible. This is the benefit for doing the three components blend in this thesis, which is not an attempt to produce a theoretical explanation for the miscibility of three components blend system.

A structural method for the design of fault tolerant distributed control systems

Distributed digital control systems provide alternatives to conventional, centralised digital control systems. Typically, a modern distributed control system will comprise a multi-processor or network of processors, a communications network, an associated set of sensors and actuators, and the systems and applications software. This thesis addresses the problem of how to design robust decentralised control systems, such as those used to control event-driven, real-time processes in time-critical environments. Emphasis is placed on studying the dynamical behaviour of a system and identifying ways of partitioning the system so that it may be controlled in a distributed manner. A structural partitioning technique is adopted which makes use of natural physical sub-processes in the system, which are then mapped into the software processes to control the system. However, communications are required between the processes because of the disjoint nature of the distributed (i.e. partitioned) state of the physical system. The structural partitioning technique, and recent developments in the theory of potential controllability and observability of a system, are the basis for the design of controllers. In particular, the method is used to derive a decentralised estimate of the state vector for a continuous-time system. The work is also extended to derive a distributed estimate for a discrete-time system. Emphasis is also given to the role of communications in the distributed control of processes and to the partitioning technique necessary to design distributed and decentralised systems with resilient structures. A method is presented for the systematic identification of necessary communications for distributed control. It is also shwon that the structural partitions can be used directly in the design of software fault tolerant concurrent controllers. In particular, the structural partition can be used to identify the boundary of the conversation which can be used to protect a specific part of the system. In addition, for certain classes of system, the partitions can be used to identify processes which may be dynamically reconfigured in the event of a fault. These methods should be of use in the design of robust distributed systems.

Structural behaviour and design of load-bearing falsework

Tne object of this research was to investigate the behaviour of birdcage scaffolding as used in falsework structures, assess the suitability of existing design methods and make recommendations for a set of design rules. Since excessive deflection is as undesirable in a structure as total collapse, the project was divided into two sections. These were to determine the ultimate vertical and horizontal load-carrying capacity and also the deflection characteristics of any falsework. So theoretical analyses were developed to ascertain the ability of both the individual standards to resist vertical load, and of the bracing to resist horizontal load.Furthermore a model was evolved which would predict the horizontal deflection of a scaffold under load using strain energy methods. These models were checked by three series of experiments. The first was on individual standards under vertical load only. The second series was carried out on full scale falsework structures loading vertically and horizontally to failure. Finally experiments were conducted on scaffold couplers to provide additional verification of the method of predicting deflections. This thesis gives the history of the project and an introduction into the field of scaffolding. It details both the experiments conducted and the theories developed and the correlation between theory and experiment. Finally it makes recommendations for a design method to be employed by scaffolding designers.

Design of improved membrane protein production experiments:quantitation of the host response

Eukaryotic membrane proteins cannot be produced in a reliable manner for structural analysis. Consequently, researchers still rely on trial-and-error approaches, which most often yield insufficient amounts. This means that membrane protein production is recognized by biologists as the primary bottleneck in contemporary structural genomics programs. Here, we describe a study to examine the reasons for successes and failures in recombinant membrane protein production in yeast, at the level of the host cell, by systematically quantifying cultures in high-performance bioreactors under tightlydefined growth regimes. Our data show that the most rapid growth conditions of those chosen are not the optimal production conditions. Furthermore, the growth phase at which the cells are harvested is critical: We show that it is crucial to grow cells under tightly-controlled conditions and to harvest them prior to glucose exhaustion, just before the diauxic shift. The differences in membrane protein yields that we observe under different culture conditions are not reflected in corresponding changes in mRNA levels of FPS1, but rather can be related to the differential expression of genes involved in membrane protein secretion and yeast cellular physiology. Copyright © 2005 The Protein Society.

Exchange rate exposure : do size and foreign operations matter?

Purpose – The purpose of this paper is to examine the effect of firm size and foreign operations on the exchange rate exposure of UK non-financial companies from January 1981 to December 2001. Design/methodology/approach – The impact of the unexpected changes in exchange rates on firms’ stock returns is examined. In addition, the movements in bilateral, equally weighted (EQW) and trade-weighted and exchange rate indices are considered. The sample is classified according to firm size and the extent of firms’ foreign operations. In addition, structural changes on the relationship between exchange rate changes and individual firms’ stock returns are examined over three sub-periods: before joining the exchange rate mechanism (pre-ERM), during joining the ERM (in-ERM), and after departure from the ERM (post-ERM). Findings – The findings indicate that a higher percentage of UK firms are exposed to contemporaneous exchange rate changes than those reported in previous studies. UK firms’ stock returns are more affected by changes in the EQW, and US$ European currency unit exchange rate, and respond less significantly to the basket of 20 countries’ currencies relative to the UK pound exchange rate. It is found that exchange rate exposure has a more significant impact on stock returns of the large firms compared with the small and medium-sized companies. The evidence is consistent across all specifications using different exchange rate. The results provide evidence that the proportion of significant foreign exchange rate exposure is higher for firms which generate a higher percentage of revenues from abroad. The sensitivities of firms’ stock returns to exchange rate fluctuations are most evident in the pre-ERM and post-ERM periods. Practical implications – This study provides important implications for public policymakers, financial managers and investors on how common stock returns of various sectors react to exchange rate fluctuations. Originality/value – The empirical evidence supports the view that UK firms’ stock returns are affected by foreign exchange rate exposure.

Impact of liberalization on efficiency and productivity of sugar industry in Kenya

Purpose – The data used in this study is for the period 1980-2000. Almost midway through this period (in 1992), the Kenyan government liberalized the sugar industry and the role of the market increased, while the government's role with respect to control of prices, imports and other aspects in the sector declined. This exposed the local sugar manufacturers to external competition from other sugar producers, especially from the COMESA region. This study aims to find whether there were any changes in efficiency of production between the two periods (pre and post-liberalization). Design/methodology/approach – The study utilized two methodologies to efficiency estimation: data envelopment analysis (DEA) and the stochastic frontier. DEA uses mathematical programming techniques and does not impose any functional form on the data. However, it attributes all deviation from the mean function to inefficiencies. The stochastic frontier utilizes econometric techniques. Findings – The test for structural differences in the two periods does not show any statistically significant differences between the two periods. However, both methodologies show a decline in efficiency levels from 1992, with the lowest period experienced in 1998. From then on, efficiency levels began to increase. Originality/value – To the best of the authors' knowledge, this is the first paper to use both methodologies in the sugar industry in Kenya. It is shown that in industries where the noise (error) term is minimal (such as manufacturing), the DEA and stochastic frontier give similar results.

Design and synthesis of potential antimicrobial agents

Tuberculosis is one of the most devastating diseases in the world primarily due to several decades of neglect and an emergence of multidrug-resitance strains (MDR) of M. tuberculosis together with the increased incidence of disseminated infections produced by other mycobacterium in AIDS patients. This has prompted the search for new antimycobacterial drugs. A series of pyridine-2-, pyridine-3-, pyridine-4-, pyrazine and quinoline-2-carboxamidrazone derivatives and new classes of carboxamidrazone were prepared in an automated fashion and by traditional synthesis. Over nine hundred synthesized compounds were screened for their anti mycobacterial activity against M. fortutium (NGTG 10394) as a surrogate for M. tuberculosis. The new classes of amidrazones were also screened against tuberculosis H37 Rv and antimicrobial activities against various bacteria. Fifteen tested compounds were found to provide 90-100% inhibition of mycobacterium growth of M. tuberculosis H37 Rv in the primary screen at 6.25 μg mL-1. The most active compound in the carboxamidrazone amide series had an MIG value of 0.1-2 μg mL-1 against M. fortutium. The enzyme dihydrofolate reductase (DHFR) has been a drug-design target for decades. Blocking of the enzymatic activity of DHFR is a key element in the treatment of many diseases, including cancer, bacterial and protozoal infection. The x-ray structure of DHFR from M. tuberculosis and human DHFR were found to have differences in substrate binding site. The presence of glycerol molecule in the Xray structure from M. tuberculosis DHFR provided opportunity to design new antifolates. The new antifolates described herein were designed to retain the pharmcophore of pyrimethamine (2,4- diamino-5(4-chlorophenyl)-6-ethylpyrimidine), but encompassing a range of polar groups that might interact with the M. tuberculosis DHFR glycerol binding pockets. Finally, the research described in this thesis contributes to the preparation of molecularly imprinted polymers for the recognition of 2,4-diaminopyrimidine for the binding the target. The formation of hydrogen bonding between the model functional monomer 5-(4-tert-butyl-benzylidene)-pyrimidine-2,4,6-trione and 2,4-diaminopyrimidine in the pre-polymerisation stage was verified by 1H-NMR studies. Having proven that 2,4-diaminopyrimidine interacts strongly with the model 5-(4-tert-butylbenzylidene)- pyrimidine-2,4,6-trione, 2,4-diaminopyrimidine-imprinted polymers were prepared using a novel cyclobarbital derived functional monomer, acrylic acid 4-(2,4,6-trioxo-tetrahydro-pyrimidin-5- ylidenemethyl)phenyl ester, capable of multiple hydrogen bond formation with the 2,4- diaminopyrimidine. The recognition property of the respective polymers toward the template and other test compounds was evaluated by fluorescence. The results demonstrate that the polymers showed dose dependent enhancement of fluorescence emissions. In addition, the results also indicate that synthesized MIPs have higher 2,4-diaminopyrimidine binding ability as compared with corresponding non-imprinting polymers.

Some studies relating to the design of shallow, fluidized bed boilers

The concept of shallow fluidized bed boilers is defined and a preliminary working design for a gas-fired package boiler has been produced. Those areas of the design requiring further study have been specified. Experimental investigations concerning these areas have been carried out. A two-dimensional, conducting paper analog has been developed for the specific purpose of evaluating sheet fins. The analog has been generalised and is presented as a simple means of simulating the general, two-dimensional Helmholtz equation. By recording the transient response of spherical, calorimetric probes when plunged into heated air-fluidized beds, heat transfer coefficients have been measured at bed temperatures up to 1 100°C. A correlation fitting all the data to within ±10% has been obtained. A model of heat transfer to surfaces immersed in high temperature beds has been proposed. The model solutions are, however, only in qualitative agreement with the experimental data. A simple experimental investigation has revealed that the effective, radial, thermal conductivities of shallow fluidized beds are an order of magnitude lower than the axial conductivities. These must, consequently, be taken into account when considering heat transfer to surfaces immersed within fluidized beds. Preliminary work on pre-mixed gas combustion and some further qualitative experiments have been used as the basis for discussing the feasibility of combusting heavy fuel oils within shallow beds. The use of binary beds, within which the fuel could be both gasified and subsequently burnt, is proposed. Finally, the consequences of the experimental studies on the initial design are considered, and suggestions for further work are made.

Applications of Reissner's principle to structural dynamics

The analysis and prediction of the dynamic behaviour of s7ructural components plays an important role in modern engineering design. :n this work, the so-called "mixed" finite element models based on Reissnen's variational principle are applied to the solution of free and forced vibration problems, for beam and :late structures. The mixed beam models are obtained by using elements of various shape functions ranging from simple linear to complex cubic and quadratic functions. The elements were in general capable of predicting the natural frequencies and dynamic responses with good accuracy. An isoparametric quadrilateral element with 8-nodes was developed for application to thin plate problems. The element has 32 degrees of freedom (one deflection, two bending and one twisting moment per node) which is suitable for discretization of plates with arbitrary geometry. A linear isoparametric element and two non-conforming displacement elements (4-node and 8-node quadrilateral) were extended to the solution of dynamic problems. An auto-mesh generation program was used to facilitate the preparation of input data required by the 8-node quadrilateral elements of mixed and displacement type. Numerical examples were solved using both the mixed beam and plate elements for predicting a structure's natural frequencies and dynamic response to a variety of forcing functions. The solutions were compared with the available analytical and displacement model solutions. The mixed elements developed have been found to have significant advantages over the conventional displacement elements in the solution of plate type problems. A dramatic saving in computational time is possible without any loss in solution accuracy. With beam type problems, there appears to be no significant advantages in using mixed models.

A biological-inspired support frame for an artificial cornea

Bilateral corneal blindness represents a quarter of the total blind, world-wide. The artificial cornea in assorted forms, was developed to replace opaque non-functional corneas and to return sight in otherwise hopeless cases that were not amenable to corneal grafts; believed to be 2% of corneal blind. Despite technological advances in materials design and tissue engineering no artificial cornea has provided absolute, long-term success. Formidable problems exist, due to a combination of unpredictable wound healing and unmanageable pathology. To have a solid guarantee of reliable success an artificial cornea must possess three attributes: an optical window to replace the opaque cornea; a strong, long term union to surrounding ocular tissue; and the ability to induce desired host responses. A unique artificial cornea possesses all three functional attributes- the Osteo-odonto-keratoprosthesis (OOKP). The OOKP has a high success rate and can survive for up to twenty years, but it is complicated both in structure and in surgical procedure; it is expensive and not universally available. The aim of this project was to develop a synthetic substitute for the OOKP, based upon key features of the tooth and bone structure. In doing so, surgical complexity and biological complications would be reduced. Analysis of the biological effectiveness of the OOKP showed that the structure of bone was the most crucial component for implant retention. An experimental semi-rigid hydroxyapatite framework was fabricated with a complex bone-like architecture, which could be fused to the optical window. The first method for making such a framework, was pressing and sintering of hydroxyapatite powders; however, it was not possible to fabricate a void architecture with the correct sizes and uniformity of pores. Ceramers were synthesised using alternative pore forming methods, providing for improved mechanical properties and stronger attachment to the plastic optical window. Naturally occurring skeletal structures closely match the structural features of all forms of natural bone. Synthetic casts were fabricated using the replamineform process, of desirable natural artifacts, such as coral and sponges. The final method of construction by-passed ceramic fabrication in favour of pre-formed coral derivatives and focused on methods for polymer infiltration, adhesion and fabrication. Prototypes were constructed and evaluated; a fully penetrative synthetic OOKP analogue was fabricated according to the dimensions of the OOKP. Fabrication of the cornea shaped OOKP synthetic analogue was also attempted.

Problem solving in architectural design

This thesis is presented in two parts. The first part is an attempt to set out a framework of factors influencing the problem solving stage of the architectural design process. The discussion covers the nature of architectural problems and some of the main ways in which they differ from other types of design problems. The structure of constraints that both the problem and the architect impose upon solutions are seen as of great importance in defining the type of design problem solving situation. The problem solver, or architect, is then studied. The literature of the psychology of thinking is surveyed for relevant work . All of the traditional schools of psychology are found wanting in terms of providing a comprehensive theory of thinking. Various types of thinking are examined, particularly structural and productive thought, for their relevance to design problem solving. Finally some reported common traits of architects are briefly reviewed. The second section is a report of u~o main experiments which model some aspects of architectural design problem solving. The first experiment examines the way in which architects come to understand the structure of their problems. The performances of first and final year architectural students are compared with those of postgraduate science students and sixth form pupils. On the whole these groups show significantly different results and also different cognitive strategies. The second experiment poses design problems which involve both subjective and objective criteria, and examines the way in which final year architectural students are able to relate the different types of constraint produced. In the final section the significance of all the results is suggested. Some educational and methodological implications are discussed and some further experiments and investigations are proposed.

The design of novel antifolates against pneumocystis carinii

The pneumonia caused by Pneumocystis carinii is ultimately responsible for the death of many acquired immunodeficiency syndrome (AIDS) patients. Large doses of trimethoprim and pyrimethamine in combination with a sulphonamide and/or pentamidine suppress the infection but produce serious side-effects and seldom prevent recurrence after treatment withdrawal. However, the partial success of the aforementioned antifolates, and also trimetrexate used alone, does suggest dihydrofolate reductase (DHFR) as a target for the development of antipneumocystis agents. From the DHFR inhibitory activities of 3'-substituted pyrimethamine analogues it was suggested that the 3'-(3'',3''-dimethyltriazen-1''-yl) substituent may be responsible for the greater activity for the P.carinii over the mammalian enzyme. Crystallographic and molecular modeling studies revealed considerable geometrical and electronic differences between the triazene and the chemically related formamidine functions that may account for the differences in DHFR inhibitory profiles. Structural and electronic parameters calculated for a series of 3'-(3'',3''-disubstitutedtriazen-1''-yl) pyrimethamine analogues did not correlate with the DHFR inhibitory activities. However, the in vitro screening against P.carinii DHFR revealed that the 3''-hydroxyethyl-3''-benzyl analogue was the most active and selective. Models of the active sites of human and P.carinii DHFRs were constructed using DHFR sequence and structural homology data which had identified key residues involved in substrate and cofactor binding. Low energy conformations of the 3'',3''-dimethyl and 3''-hydroxyethyl-3''-benzyle analogues, determined from nuclear magnetic resonance studies and theoretical calculations, were docked by superimposing the diaminopyrimidine fragment onto a previously docked pyrimethamine analogue. Enzyme kinetic data supported the 3''-hydroxyethyl-3''-benzyl moiety being located in the NADPH binding groove. The 3''-benzyl substituent was able to locate to within 3 AA of a valine residue in the active site of P.carinii DHFR thereby producing a hydrophobic contact. The equivalent residue in human DHFR is threonine, more hydrophilic and less likely to be involved in such a contact. This difference may account for the greater inhibitory activity this analogue has for P.carinii DHFR and provide a basis for future drug design. From an in vivo model of PCP in immunosuppressed rats it was established that the 3"-hydroxyethyl-3"-benzyl analogue was able to reduce the.P.carinii burden more effectively with increasing doses, without causmg any visible signs of toxicity. However, equivalent doses were not as effective as pentamidine, a current treatment of choice for Pneumocystis carinii pneumonia.