The stability of solid state particulate formulations which include bio-molecules are critical in the healthcare, food and consumer product markets. Whether the product it is an enzyme containing cleaning formulation or a protein based therapeutics, the stability of the product is important for the effective delivery of the relevant healthcare, nutritional or consumer benefits. An improved understanding of the stability of such products will support improved healthcare and as well as the more efficient and environmentally sound delivery of a range of consumer products from washing machine powders through to food products. This project will examine the stability both model and real world proteins and enzymes using a range of advanced experimental techniques. This work will include gravimetric and thermal analysis approaches. Of specific interest will be the effects of moisture and temperature on material performance/behaviour including diffusion and permeability, equilibrium moisture content as well as the impact on Tg. The factors that determine the intrinsic stability of the selected proteins and enzymes will be determined prior to moving into complex powder mixtures which incorporate these specific biologic species. In these bio-formulations we will look to map spectroscopically the moisture distribution through the materials using FTIR or NIR image under controlled moisture conditions. This behaviour will then be correlated with the final powder performance. Here the relationship between moisture stability and common powder problems such as caking and agglomeration will be established. This information will allow rational design principles to be applied to the preparation of bio-formulations. It is anticipated that the close relationship with Procter and Gamble and Imperial College will facilitate the maximum opportunity for commercial exploitation should such opportunities arise within the scope of this project. This in return allows the best possible change of improvements to the quality of like in the UK following on from this work programme. Where appropriate, commercially relevant intellectual property will be protected by patent applications, which may be licensed or spun-out through IC Innovations Ltd., the commercial exploitation arm of Imperial College in line with the standard terms for BBSRC studentship grants. Scientific results will be communicated via range of national and international relevant conferences, such as the UK Particle Technology Forum, following appropriate internal discussions between Procter and Gamble and Imperial College. It would be normal practice at Imperial College for a PhD student to give a number of posters and, in the later stages of their PhD, oral presentations, of their research results at such meetings. The proposed work is targeted at understanding the key relationship between formulation, processing conditions and product stability for solid state bio-formulations.

The proposed work involves an experimental and modelling investigation of vertically downwards gas-liquid annular flows. These are the key components in a wide variety of industrial applications, prime examples of which are, condensers and chemical reactors used in the production of detergents. In the latter case, a liquid feedstock is injected as a film onto the inside of a bundle of tubes and undergoes an exothermic sulphonation by contact with air containing SO3 which flows down the tubes co-currently with the films on the tube walls. To obtain the required quality of the product, the temperature of the reacting liquid must be rigidly controlled; otherwise, undesirable by-products are formed. Industry has made good progress in modelling these systems but such modelling is limited by the complexity of the underlying physics. First, a complex pattern of waves is formed on the interface and these affect the interaction between the gas and liquid and also the reaction and heat transfer processes. Secondly, liquid droplets are torn off the film and react with the SO3 in the gas in an uncontrolled way. Knowing which flow regime occurs under which conditions, and being able to predict the flow regimes in a systematic manner is crucial for the efficient and optimal operation of reactors that exploit downwards annular gas-liquid flows. Whereas vertically upwards annular flows have received considerable attention in the literature (see e.g. the work of Hewitt and Hall Taylor1a, Hewitt1b, Hewitt and Govan1c and Barbosa et al.1d), there has been very little work on vertically downwards annular flows. This is surprising given the early studies of Webb and Hewitt1e, whose work in this area has shown that the interactions between the turbulent gas core and the thin liquid film, particularly when both gravity and interfacial shear are significant, give rise to many complex phenomena and rich dynamics, which are not well-understood. The current state of modelling of downwards annular flows in general is insufficient. Hence, there is a need for a substantially improved understanding of the coupling between the liquid film and gas turbulence through the interfacial stress exerted by the gas onto the liquid which is responsible for wave formation and drop entrainment; achieving such an understanding is the aim of the proposed work. The project proposed here is a well-balanced synergistic approach adopting recent, advanced experimental methods, results of the detailed numerical and analytical studies conducted in other EPSRC-funded projects, EP/D031222 and EP/E021468, unavailable at the time of earlier studies, and advanced theoretical and modelling methodologies to develop efficient and accurate methods for the systematic prediction of flow interfacial behaviour and flow regimes in downwards annular flows.

The skin is our largest organ. Ageing of the skin leads to its thinning, loss of barrier function, loss of wound healing efficiency and increased irritability. These are not just 'cosmetic' problems but are extremely important for health and wellbeing in adult and old age. Recent progress in the field including work from the applicants has indicated a major role for cellular ageing (cell senescence) as a cause of age-associated dysfunction and disease in many organs. In fact, this research has shown that suppressing cellular senescence or outright killing the senescent cells that accumulate during ageing can prolong healthy life expectancy in mice. However, it is neither clear whether such a senolytic approach can actually 'rejuvenate' skin nor whether it might work in man. The present project aims to answer these questions. It is well known that senescent cells accumulate in ageing skin. Previously, in work together with Procter&Gamble, largely funded by BBSRC, we have generated a suite of human-based in-vitro and ex-vivo skin models, in which we can modify the numbers of senescent cells. We will now use these tools to examine the consequences of senescent skin cell accumulation for skin function. We know already that skin containing more senescent cells becomes thinner and less able to act as an efficient barrier. We hypothesize that this occurs because senescent cells compromise the differentiation capabilities of the two major cell types in skin: fibroblasts in the dermis and keratinocytes in the epidermis. We will test whether reduction of senescent cell numbers results in more 'youthful' (papillary) dermal fibroblasts and in better proliferation and/or differentiation of epidermal keratinocytes. We will develop and validate a very novel technology to identify senescent cells and to characterize their interactions with neighbouring cells in tissues by combination of an unprecedented number of functional markers in a single image at subcellular resolution. We will examine whether prior reduction of senescent cell numbers in samples of aged skin improves their ability to heal after wounding. Finally, we will test novel candidate substances for senolytic drugs in our human skin models. Presently, not more than a handful of such candidate drugs are known. Our collaboration partner used an in-silico systems pharmacology approach to predict novel senolytics, which we validate in a cell culture screen in a separate industry collaboration. Promising novel candidates will be transferred into the present project and their effect onto skin cell differentiation, skin thickness, barrier function and wound healing efficiency will be established. Our project will show for the first time whether it is possible to ameliorate ageing in a human organ (model) by reducing numbers of senescent cells. It will develop a novel technique to visualise senescent cells in their tissue context with unprecedented specificity and thus improve the understanding of their tissue-specific impact. The project will further provide improved screening tools for the development of scientifically evidence-based skin anti-ageing interventions, and it will validate novel senolytic drugs for use in human skin.

In designing new chemical manufacturing processes, the molecules or materials required (e.g., solvents or catalysts) are often chosen prior to optimising the topology or operating conditions of the product or process. This sequential decision-making process can lead to poor performance of the overall process because all these factors are intrinsically linked. For example, what is the best solvent for a reaction in a pharmaceutical manufacturing process depends on the temperature and pressure of the reactor, but also on what comes next in the process. If it is another reaction, it may be best to find a solvent which works reasonably well for both reactions, in order to avoid expensive additional processing steps such as swapping one solvent for another. By making decisions simultaneously, we can significantly improve the economics of a process and reduce its environmental impact through decreased material use and increased energy efficiency. Such an approach is referred to as integrated product and process design. There are three elements needed for integrated product and process design: predictive models that can relate changes in the materials and in the process to performance; optimisation formulations that capture mathematically the trade-offs inherent in such complex systems; reliable algorithms that can solve the resulting design problems efficiently. In recent years, we have developed predictive models that have opened up new possibilities in design. The aim of this proposal is therefore to propose new formulations and algorithms for integrated product and process design and to apply them to a series of design problems. The key challenge in problem formulation is to ensure that innovative (but unknown) solutions are embedded within the optimisation problem so that they can be uncovered. One way to do this is to allow the structure of the molecules or the materials to be part of the decision process by representing them through discrete decisions. Another complementary approach is to develop formulations that allow the identification of optimal mixtures. By mixing known molecules, one can tune the performance of the process. We will propose generic formulations for such problems. We will also tackle the simultaneous design of molecules/mixtures and processes. In the optimisation algorithms used to solve these design problems, the main issue is to identify the very best (global) solution reliably and in a reasonable amount of time. This is difficult due to the nature of the integrated product and process design problem: it is nonlinear and combinatorial, which means that many local solutions may exist. We will develop robust algorithms for such problems, tackling the different types of mathematics that may be encountered, such as differential equations and/or discrete variables. These generic algorithms will be applicable to large classes of problems and will therefore be useful to solve other optimisation problems. The findings of this research will be implemented and tested on a set of design case studies we have gathered in recent years through collaboration with industrial partners and other academic groups. Ongoing collaborations will ensure that our formulations and approaches are captured in software tools and suitable to tackle realistic design problems.

This proposal seeks to obtain funding for partially supporting the first UK-China Particle Technology Forum (1-3 April 2007) initiated by the investigators in collaboration with the Particle Technology Subject Group (PTSG) of the Institution of Chemical Engineers (IChemE) and The Particle Characterisation Interest Group (PCIG) of the Royal Society of Chemistry (RSC), supported by a number of industrialists representing various industrial sectors. The aims of the UK-China Particle Technology Forum are to enhance communications between scientists and engineers from both academic institutions and industrial companies of the two countries, to establish a platform to foster new and substantial collaborations, and to identify and address common challenges in the area of particle technology.The UK-China Particle Technology Forum is timely and aligns very well with the government strategies to establishing a partnership in various areas including education, energy, environment, aerospace, e-science and drug development, where particle technology plays key roles.