Impermeable metal microcapsules for diagnostic/ therapeutic applications

Until recently, small, volatile actives could not be efficiently encapsulated for timescales longer than a few days, due to the inherent porosity of the polymeric membranes used as the capsule shell material. Using electro-less deposition of metals, we have developed a method for preventing undesired loss of encapsulated actives using a simple 3 step process.1 The addition of a continuous metal shell prevents loss of the core into a solvent for the core over a period of 90 days, as opposed to polymeric capsules which lose their entire core in less than 30 minutes under the same conditions. Polymer shell – oil core microcapsules are produced using oil-in-water emulsification followed by co-solvent extraction to precipitate a polymeric shell around the oil core, as first described in the work of Vincent et al.2, 3 Metallic catalytic nanoparticles are then physically adsorbed onto the microcapsule polymeric shells. Subsequently, this nanoparticle coating is used to catalyze the growth of a secondary metallic film.4 Here we investigate an exciting application of these metal microcapsules, as a vehicle for drug delivery, the rationale being that once a material is encapsulated in our capsules it cannot escape, until the capsules are broken by an external trigger. Thus, with a drug molecule that exhibits undesirable side effects trapped in the capsules, we can target the delivery site and fracture the capsules by application of an external force once they arrive at that location, removing the unwanted side effects which normally are associated with, for example, off-target effects of drug delivery in cancer treatment. Previously poly(methyl methacrylate) (PMMA) has been utilized as the polymeric shell. However, in this work we demonstrate that PMMA can be substituted for poly(lactic-co-glycolic acid) (PLGA) a biocompatible and biodegradable polymer suitable for use as a drug carrier. We encapsulate perfluorooctyl bromide (PFOB), a tracer for ultrasound, as our model system, and then follow the steps described previously for growth of the metal shell. We demonstrate that by using acoustic pulsed signals of varying intensity and time intervals, we can control the rupture of our metal capsules in an aqueous environment, to trigger release of PFOB into the external environment. 1. Hitchcock, J. P.; Tasker, A. L.; Baxter, E. A.; Biggs, S.; Cayre, O. J., Long-Term Retention of Small, Volatile Molecular Species within Metallic Microcapsules. Acs Applied Materials & Interfaces 2015, 7 (27), 14808-14815. 2. Dowding, P. J.; Atkin, R.; Vincent, B.; Bouillot, P., Oil Core/Polymer Shell Microcapsules by Internal Phase Separation from Emulsion Droplets. Ii: Controlling the Release Profile of Active Molecules. Langmuir 2005, 21 (12), 5278-5284. 3. Loxley, A.; Vincent, B., Preparation of Poly(Methylmethacrylate) Microcapsules with Liquid Cores. Journal of Colloid and Interface Science 1998, 208 (1), 49-62. 4. Horiuchi, S.; Nakao, Y., Platinum Colloid Catalyzed Etchingless Gold Electroless Plating with Strong Adhesion to Polymers. Surface & Coatings Technology 2010, 204 (23), 3811-3817

Particle-Stabilized Fluid-Fluid Interfaces: The Impact of Core Composition on Interfacial Structure

The encapsulation of small molecule drugs in nanomaterials has become an increasingly popular approach to the delivery of therapeutics. The use of emulsions as templates for the synthesis of drug impregnated nanomaterials is an exciting area of research, and a great deal of progress has been made in understanding the interfacial chemistry that is critical to controlling the physicochemical properties of both the encapsulated material and the templated material. For example, control of the interfacial tension between an oil and aqueous phase is a fundamental concern when designing drug delivery vehicles that are stabilized by particulate surfactants at the fluid interface. Particles in general are capable of self-assembly at a fluid interface, with a preference for one or the other of the phases, and much work has focussed on modification of the particle properties to optimize formation and stability of the emulsion. An issue arises however when a model, single oil system is translated into more complex, real-world scenarios, which are often multi-component, with the incorporation of charged active ingredients and other excipients. The result is potentially a huge change in the properties of the dispersed phase which can lead to a failure in the capability of particles to continue to stabilize the interface. In this mini-review, we will focus on two encapsulation strategies based on the selective deposition of particles or proteins on a fluid-fluid interface: virus-like particles and polymer microcapsules formed from particle-stabilized emulsion templates. The similarity between these colloidal systems lies in the fact that particulate entities are used to stabilize fluid cores. We will focus on those studies that have described the effect of subtle changes in core composition on the self-assembly of particles at the fluid-fluid interface and how this influences the resulting capsule structure

Micropalaeontology reveals the source of building materials for a defensive earthwork (English Civil War?) at Wallingford Castle, Oxfordshire

Microfossils recovered from sediment used to construct a putative English Civil War defensive bastion at Wallingford Castle, south Oxfordshire, provide a biostratigraphical age of Cretaceous (earliest Cenomanian) basal M. mantelli Biozone. The rock used in the buttress – which may have housed a gun emplacement – can thus be tracked to the Glauconitic Marl Member, base of the West Melbury Marly Chalk Formation. A supply of this rock is available on the castle site or to the east of the River Thames near Crowmarsh Gifford. Microfossils provide a unique means to provenance construction materials used at the Wallingford site. While serendipity may have been the chief cause for use of the Glauconitic Marl, when compacted, it forms a strong, almost ‘road base’-like foundation that was clearly of use for constructing defensive works. Indeed, use of the Glauconitic Marl was widespread in the area for agricultural purposes and its properties may have been well-known locally

The effect of surfactant chain length on the morphology of poly(methyl methacrylate) microcapsules for fragrance oil encapsulation

The solvent evaporation method for producing microcapsules relies upon the correct wetting conditions between the three phases involved in the synthesis to allow core-shell morphologies to form. By measuring the interfacial tensions between the oil, polymer and aqueous phases, spreading coefficients can be calculated, allowing the capsule morphology to be predicted. In this work we explore the effect of surfactant chain length on capsule morphology using poly(methyl methacrylate) as the polymer and hexadecane as the core. We compared the predicted morphologies obtained using the polymer as a solid, and the polymer dissolved in dichloromethane to represent the point at which capsule formation begins. We found that using the polymer in its final, solid form gave predictions which were more consistent with our observations. The method was applied to successfully predict the capsule morphologies obtained when commercial fragrance oils were encapsulated

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Water resistance properties of water-based biopolymer films

This thesis addresses both the theory and simulation of diffusion of moisture in water-based biopolymer films, whose preliminary use is as adhesives on glass bottles in the labelling industry. The first part explores the kinetics of dehydration of thin films of these biopolymer materials. The second part of the thesis deals with moisture intake into both dried thin films and into the wet biopolymer gel network. Mathematical simulations based on Fick's laws of diffusion have been developed as a tool to understand the underpinning mechanisms of diffusion and of evaporation to discover which, if either plays a more dominant role in controlling the dehydration process. By inputting a series of different initial and final moisture contents, a full spectra of scenarios has been examined to aid understanding of the dehydration process. Numerical calculations where diffusion is the controlling mechanism as well as simulations where evaporation controls the process have been considered and discussed. Models in which a combination of both diffusion and evaporation are equally important are also studied. Fixed and moving boundary conditions are applied to the models and compared with dehydration results obtained experimentally. A simple method has been developed to assess the rehydration process of a dried biopolymer film and similar simulations have also been constructed to describe the rehydration of a water droplet into the thin, dried films. A novel method to investigate the migration of water into casein biopolymer gels using acoustic techniques has been developed and validated. The preliminary results are promising, highlighting the potential capability of the method. As the composition of a material changes, the speed of a wave of sound being passed through the material changes, so by monitoring this change as a function of time, concentration profiles of the biopolymer material can be constructed. Simulated concentration profiles were successfully produced based on Fick's second law of diffusion, to obtain a diffusion coefficient dependent on both time and position.. By fitting these curves to the experimental data, diffusion coefficients are obtained with values of the same order of magnitude as those calculated from the experiments on a dehydrating thin film of the same composition

The provenance of Chalk Tesserae from selected sites in Roman Britain

Microfossil analysis of chalk tesserae from mosaics at five sites in Roman Britain (Caerleon, Colchester, the Isle of Wight, Leicester and London) was undertaken in order to ascertain the biostratigraphical age of the chalk used and thereby to determine its lithostratigraphical position within the Chalk Group. This information was then used to determine its most likely geographical provenance. The foraminiferal evidence presented in this thesis strongly suggests that the source of the chalk used to manufacture the tesserae within the Roman province varied with time. Comparison of the results obtained with previous micropalaeontological analyses of chalk tesserae from Silchester, Norden (Dorset) and elsewhere in London suggest that Dorset may have acted as a regional source of chalk tesserae supply for mosaics dating to the first or early second century AD. This confirms previous suggestions that a ‘geomaterials complex’ was operating in the Poole-Purbeck area of south-east Dorset at this time. Chalk tesserae dating to later periods did not display this same pattern of supply and appear to have been derived from elsewhere in the province. Kent and Sussex are suggested as possible sources for chalk tesserae dating to the second and third centuries AD, whereas Baldock in Hertfordshire emerges as a possible source in the fourth. The geological evidence also shows that harder members of the Chalk Group do not seem to have been preferentially selected for use in tesserae manufacture. The results obtained confirm the value of the ‘microfossil approach’ to the problem of provenance in archaeological studies. It is suggested that the extension of this technique to chalk tesserae from other sites might enable some wider aspects of mosaic manufacture in Roman Britain to be investigated and two areas are put forward for future consideration

Editorial Introduction and "Pre-Raphaelitism and Australia"

Overview of the origins and contents of the issue, Acknowledgements, and a short essay providing an overview of the study of Pre-Raphaelitism in Australia

Editorial Introduction

Front matter: Introductory essay by Alison Inglis, Editorial Acknowledgements by Meg Taske