Design and evaluation of novel microencapsulation technologies to enhance delivery of Ciclosporin

Drug delivery systems influence the various processes of release, absorption, distribution and elimination of drug. Conventional delivery methods administer drug through the mouth, the skin, transmucosal areas, inhalation or injection. However, one of the current challenges is the lack of effective and targeted oral drug administration. Development of sophisticated strategies, such as micro- and nanotechnology that can integrate the design and synthesis of drug delivery systems in a one-step, scalable process is fundamental in advancing the limitations of conventional processing techniques. Thus, the objective of this thesis is to evaluate novel microencapsulation technologies in the production of size-specific and target-specific drug-loaded particles. The first part of this thesis describes the utility of PDMS and silicon microfluidic flow focusing devices (MFFDs) to produce PLGA-based microparticles. The formation of uniform droplets was dependent on the surface of PDMS remaining hydrophilic. However, the durability of PDMS was limited to no more than 1 hour before wetting of the microchannel walls with dichloromethane and subsequent swelling occurred. Critically, silicon MFFDs revealed very good solvent compatibility and was sufficiently robust to withstand elevated fluid flow rates. Silicon MFFDs facilitated experiments to run over days with continuous use and re-use of the device with a narrower microparticle size distribution, relative to conventional production techniques. The second part of this thesis demonstrates an alternative microencapsulation technology, SmPill® minispheres, to target CsA delivery to the colon. Characterisation of CsA release in vitro and in vivo was performed. By modulating the ethylcellulose:pectin coating thickness, release of CsA in-vivo was more effectively controlled compared to current commercial CsA formulations and demonstrated a linear in-vitro in-vivo relationship. Coated minispheres were shown to limit CsA release in the upper small intestine and enhance localised CsA delivery to the colon.

Finding our way through phenotypes.

Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.

Does an incremental filling technique reduce polymerization shrinkage stresses

It is widely accepted that volumetric contraction and solidification during the polymerization process of restorative composites in combination with bonding to the hard tissue result in stress transfer and inward deformation of the cavity walls of the restored tooth. Deformation of the walls decreases the size of the cavity during the filling process. This fact has a profound influence on the assumption-raised and discussed in this paper-that an incremental filling technique reduces the stress effect of composite shrinkage on the tooth. Developing stress fields for different incremental filling techniques are simulated in a numerical analysis. The analysis shows that, in a restoration with a well-established bond to the tooth-as is generally desired-incremental filling techniques increase the deformation of the restored tooth. The increase is caused by the incremental deformation of the preparation, which effectively decreases the total amount of composite needed to fill the cavity. This leads to a higher-stressed tooth-composite structure. The study also shows that the assessment of intercuspal distance measurements as well as simplifications based on generalization of the shrinkage stress state cannot be sufficient to characterize the effect of polymerization shrinkage in a tooth-restoration complex. Incremental filling methods may need to be retained for reasons such as densification, adaptation, thoroughness of cure, and bond formation. However, it is very difficult to prove that incrementalization needs to be retained because of the abatement of shrinkage effects.

Monotone scheme and boundary conditions for finite volume simulation of magnetohydrodynamic internal flows at high Hartmann number

A monotone scheme for finite volume simulation of magnetohydrodynamic internal flows at high Hartmann number is presented. The numerical stability is analysed with respect to the electromagnetic force. Standard central finite differences applied to finite volumes can only be numerically stable if the vector products involved in this force are computed with a scheme using a fully staggered grid. The electromagnetic quantities (electric currents and electric potential) must be shifted by half the grid size from the mechanical ones (velocity and pressure). An integral treatment of the boundary layers is used in conjunction with boundary conditions for electrically conducting walls. The simulations are performed with inhomogeneous electrical conductivities of the walls and reach high Hartmann numbers in three-dimensional simulations, even though a non-adaptive grid is used.

Staggered-mesh computation for aerodynamic sound

For the numerical solution of the linearized Euler equations, an optimized computational scheme is considered. It is based on fully staggered (in space and time) regular meshes and on a simple mirroring procedure at the stepwise solid walls. There is no need to define ghost points into the solid ohjects that reflect the sound waves. Test results demonstrate the accuracy of the method that may be used for aeroacoustic problems with complex geometries.

An experimental and numerical CFD study of turbulence in a tundish container

This paper describes work performed at IRSID/USINOR in France and the University of Greenwich, UK, to investigate flow structures and turbulence in a water-model container, simulating aspects typical of metal tundish operation. Extensive mean and fluctuating velocity measurements were performed at IRSID using LDA to determine the flow field and these form the basis for a numerical model validation. This apparently simple problem poses several difficulties for the CFD modelling. The flow is driven by the strong impinging jet at the inlet. Accurate description of the jet is most important and requires a localized fine grid, but also a turbulence model that predicts the correct spreading rates of jet and impinging wall boundary layers. The velocities in the bulk of the tundish tend to be (indeed need to be) much smaller than those of the jet, leading to damping of turbulence, or even laminar flow. The authors have developed several low-Reynolds number (low-Re) k–var epsilon model variants to compute this flow and compare against measurements. Best agreement is obtained when turbulence damping is introduced to account not only for walls, but also for low-Re regions in the bulk – the k–var epsilon model otherwise allows turbulence to accumulate in the container due to the restricted outlet. Several damping functions are tested and the results reported here. The k–ω model, which is more suited to transitional flow, also seems to perform well in this problem.

Characterisation of weldpool shapes in the laser welding of thick plates

We consider the problem of finding the heat distribution and the shape of the liquid fraction during laser welding of a thick steel plate using the finite volume CFD package PHYSICA. Since the shape of the keyhole is not known in advance, the following two-step approach to handling this problem has been employed. In the first stage, we determine the geometry of the keyhole for the steady-state case and form an appropriate mesh that includes both the workpiece and the keyhole. In the second stage, we impose the boundary conditions by assigning temperature to the walls of the keyhole and find the heat distribution and the shape of the liquid fraction for a given welding speed and material properties. We construct a fairly accurate approximation of the keyhole as a sequence of include sliced cones. A formula for finding the initial radius of the keyhole is derived by determining the radius of the vaporisation isotherm for the line heat source. We report on the results of a series of computational experiments for various heat input values and welding velocities.

Dynamics of magnetically suspended fluid

Magnetic suspension is a technique for processing pure or reactive materials without contact to walls. This work is concerned with the flow in the rapidly deforming liquid volume, suspended in an AC magnetic field. Intense flow motion due to the induced electromagnetic force distorts dynamically the droplet envelope. The relative positional change between the liquid surface and the surrounding coil means that fluid flow and magnetic field computations need to be closely coupled. The computed results are compared against a physical experiment and nearly spherical analytic solutions. A comparison between the "magetic pressure" approximation and the full electromagnetic force solutions shows fundamental differences; the full electromagnetic force is necessary for accurate results in most practical applications of this technique. The physical reason for the fundamental discrepancy is the difference in the electromagnetic force representation: only the gradient part of the full force is accounted for in the "magnetic pressure" approximation.

Modelling induction skull melting design modifications

Induction Skull Melting (ISM) is a technique for heating, melting, mixing and, possibly, evaporating reactive liquid metals at high temperatures with a minimum contact at solid walls. The presented numerical modelling involves the complete time dependent process analysis based on the coupled electromagnetic, temperature and turbulent velocity fields during the melting and liquid shape changes. The simulation model is validated against measurements of liquid metal height, temperature and heat losses in a commercial size ISM furnace. The observed typical limiting temperature plateau for increasing input electrical power is explained by the turbulent convective heat losses. Various methods to increase the superheat within the liquid melt, the process energy efficiency and stability are proposed.

Experimental and numerical study of the cold crucible melting process

The cold crucible, or induction skull melting process as is otherwise known, has the potential to produce high purity melts of a range of difficult to melt materials, including Ti–Al and Ti6Al4V alloys for Aerospace, Ti–Ta and other biocompatible materials for surgical implants, silicon for photovoltaic and electronic applications, etc. A water cooled AC coil surrounds the crucible causing induction currents to melt the alloy and partially suspend it against gravity away from water-cooled surfaces. Strong stirring takes place in the melt due to the induced electromagnetic Lorentz forces and very high temperatures are attainable under the right conditions (i.e., provided contact with water cooled walls is minimised). In a joint numerical and experimental research programme, various aspects of the design and operation of this process are investigated to increase our understanding of the physical mechanisms involved and to maximise process efficiency. A combination of FV and Spectral CFD techniques are used at Greenwich to tackle this problem numerically, with the experimental work taking place at Birmingham University. Results of this study, presented here, highlight the influence of turbulence and free surface behaviour on attained superheat and also discuss coil design variations and dual frequency options that may lead to winning crucible designs.

Modelling induction skull melting design modifications

Induction Skull Melting (ISM) is used for heating, melting, mixing and, possibly, evaporating reactive liquid metals at high temperatures when a minimum contact at solid walls is required. The numerical model presented here involves the complete time dependent process analysis based on the coupled electromagnetic, temperature and turbulent velocity fields during the melting and liquid shape changes. The simulation is validated against measurements of liquid metal height, temperature and heat losses in a commercial size ISM furnace. The often observed limiting temperature plateau for ever increasing electrical power input is explained by the turbulent convective heat losses. Various methods to increase the superheat within the liquid melt, the process energy efficiency and stability are proposed.

Nonlinear MHD stability of aluminium reduction cells

An industrial electrolysis cell used to produce primary aluminium is sensitive to waves at the interface of liquid aluminium and electrolyte. The interface waves are similar to stratified sea layers [1], but the penetrating electric current and the associated magnetic field are intricately involved in the oscillation process, and the observed wave frequencies are shifted from the purely hydrodynamic ones [2]. The interface stability problem is of great practical importance because the electrolytic aluminium production is a major electrical energy consumer, and it is related to environmental pollution rate. The stability analysis was started in [3] and a short summary of the main developments is given in [2]. Important aspects of the multiple mode interaction have been introduced in [4], and a widely used linear friction law first applied in [5]. In [6] a systematic perturbation expansion is developed for the fluid dynamics and electric current problems permitting reduction of the three-dimensional problem to a two dimensional one. The procedure is more generally known as “shallow water approximation” which can be extended for the case of weakly non-linear and dispersive waves. The Boussinesq formulation permits to generalise the problem for non-unidirectionally propagating waves accounting for side walls and for a two fluid layer interface [1]. Attempts to extend the electrolytic cell wave modelling to the weakly nonlinear case have started in [7] where the basic equations are derived, including the nonlinearity and linear dispersion terms. An alternative approach for the nonlinear numerical simulation for an electrolysis cell wave evolution is attempted in [8 and references there], yet, omitting the dispersion terms and without a proper account for the dissipation, the model can predict unstable waves growth only. The present paper contains a generalisation of the previous non linear wave equations [7] by accounting for the turbulent horizontal circulation flows in the two fluid layers. The inclusion of the turbulence model is essential in order to explain the small amplitude self-sustained oscillations of the liquid metal surface observed in real cells, known as “MHD noise”. The fluid dynamic model is coupled to the extended electromagnetic simulation including not only the fluid layers, but the whole bus bar circuit and the ferromagnetic effects [9].

Maximising heat transfer efficiency in the cold crucible induction melting process

Induction heating is an efficient method used to melt electrically conductive materials, particularly if melting takes place in a ceramic crucible. This form of melting is particularly good for alloys, as electromagnetic forces set up by the induction coil lead to vigorous stirring of the melt ensuring homogeneity and uniformity in temperature. However, for certain reactive alloys, or where high purity is required, ceramic crucibles cannot be used, but a water-cooled segmented copper crucible is employed instead. Water cooling prevents meltdown or distortion of the metal wall, but much of the energy goes into the coolant. To reduce this loss, the electromagnetic force generated by the coil is used to push the melt away from the walls and so minimise contact with water-cooled surfaces. Even then, heat is lost through the crucible base where contact is inevitable. In a collaborative programme between Greenwich and Birmingham Universities, computer modelling has been used in conjunction with experiments to improve the superheat attainable in the melt for a,number of alloys, especially for y-TiAl intermetallics to cast aeroengine turbine blades. The model solves the discretised form of the turbulent Navier-Stokes, thermal energy conservation and Maxwell equations using a Spectral Collocation technique. The time-varying melt envelope is followed explicitly during the computation using an adaptive mesh. This paper briefly describes the mathematical model used to represent the interaction between the magnetic field, fluid flow, heat transfer and change of phase in the crucible and identifies the proportions of energy used in the melt, lost in the crucible base and in the crucible walls. The role of turbulence is highlighted as important in controlling heat losses and turbulence damping is introduced as a means of improving superheat. Model validation is against experimental results and shows good agreement with measured temperatures and energy losses in the cooling fluid throughout the melting cycle.

Experimental and numerical study of the cold crucible melting process

The cold crucible, or induction skull melting process as is otherwise known, has the potential to produce high purity melts of a range of difficult to melt materials, including Ti–Al and Ti6Al4V alloys for Aerospace, Ti–Ta and other biocompatible materials for surgical implants, silicon for photovoltaic and electronic applications, etc. A water cooled AC coil surrounds the crucible causing induction currents to melt the alloy and partially suspend it against gravity away from water-cooled surfaces. Strong stirring takes place in the melt due to the induced electromagnetic Lorentz forces and very high temperatures are attainable under the right conditions (i.e., provided contact with water cooled walls is minimised). In a joint numerical and experimental research programme, various aspects of the design and operation of this process are investigated to increase our understanding of the physical mechanisms involved and to maximise process efficiency. A combination of FV and Spectral CFD techniques are used at Greenwich to tackle this problem numerically, with the experimental work taking place at Birmingham University. Results of this study, presented here, highlight the influence of turbulence and free surface behaviour on attained superheat and also discuss coil design variations and dual frequency options that may lead to winning crucible designs.

The study of flow and temperature fields in conducting droplets suspended in a DC/AC combination field

Electromagnetic Levitation (EML) is a valuable method for measuring the thermo-physical properties of metals - surface tensions, viscosity, thermal/electrical conductivity, specific heat, hemispherical emissivity, etc. – beyond their melting temperature. In EML, a small amount of the test specimen is melted by Joule heating in a suspended AC coil. Once in liquid state, a small perturbation causes the liquid envelope to oscillate and the frequency of oscillation is then used to compute its surface tension by the well know Rayleigh formula. Similarly, the rate at which the oscillation is dampened relates to the viscosity. To measure thermal conductivity, a sinusoidally varying laser source may be used to heat the polar axis of the droplet and the temperature response measured at the polar opposite – the resulting phase shift yields thermal conductivity. All these theoretical methods assume that convective effects due to flow within the droplet are negligible compared to conduction, and similarly that the flow conditions are laminar; a situation that can only be realised under microgravity conditions. Hence the EML experiment is the method favoured for Spacelab experiments (viz. TEMPUS). Under terrestrial conditions, the full gravity force has to be countered by a much larger induced magnetic field. The magnetic field generates strong flow within the droplet, which for droplets of practical size becomes irrotational and turbulent. At the same time the droplet oscillation envelope is no longer ellipsoidal. Both these conditions invalidate simple theoretical models and prevent widespread EML use in terrestrial laboratories. The authors have shown in earlier publications that it is possible to suppress most of the turbulent convection generated in the droplet skin layer, through use of a static magnetic field. Using a pseudo-spectral discretisation method it is possible compute very accurately the dynamic variation in the suspended fluid envelope and simultaneously compute the time-varying electromagnetic, flow and thermal fields. The use of a DC field as a dampening agent was also demonstrated in cold crucible melting, where suppression of turbulence was achieved in a much larger liquid metal volume and led to increased superheat in the melt and reduction of heat losses to the water-cooled walls. In this paper, the authors describe the pseudo-spectral technique as applied to EML to compute the combined effects of AC and DC fields, accounting for all the flow-induced forces acting on the liquid volume (Lorentz, Maragoni, surface tension, gravity) and show example simulations.