Microwave synthesis of novel methacrylate monomers designed to reduce biofilm formation to surfaces

Rational design of biomaterials is hindered by the lack of quantitative structure-activity relationships (QSAR). Here we report the use of a QSAR to guide experimentation into a new chemical space; we predict and synthesize molecular structures for novel monomers that will reduce biofilm formation, and so identifying the lowest biofilm attachment polymer discovered to date. Cyclododecyl methacrylate was shown to reduce the formation of P. aeruginosa and P. mirabilis biofilms by up to 96 % and 97 % respectively compared to commercially available catheters. We believe that this is the first instance of a biomaterials screening program extending beyond the domain covered by the initial screen to predict a novel chemical entity with improved properties. This validates the QSAR approach for identifying polymers that resist biofilm formation beyond its chemical training domain. High throughput discovery of the non-commercially available material space is hindered by the ability to synthesize large numbers of materials in a controlled reaction process to keep up with supply demands. In this thesis we also present the production of a microwave single-well reactor capable of synthesizing novel methacrylate monomers using a transesterification process, where the design of the reactor has shown to outperform both conventional and standard microwave heating techniques. Powers as low as 40 W have been used to achieve reaction temperatures of 160 ˚C, showing great scale-out potential. With the approach of using QSAR for identifying potential biomaterials, monomer libraries can be judiciously chosen and then synthesised to enable high throughput discovery programs to have unprecedented access to the non-commercially available space

Mass wasting triggered by seasonal CO₂ sublimation under Martian atmospheric conditions: Laboratory experiments

Sublimation is a recognized process by which planetary landscapes can be modified. However, interpretation of whether sublimation is involved in downslope movements on Mars and other bodies is restricted by a lack of empirical data to constrain this mechanism of sediment transport and its influence on landform morphology. Here we present the first set of laboratory experiments under Martian atmospheric conditions which demonstrate that the sublimation of CO2 ice from within the sediment body can trigger failure of unconsolidated, regolith slopes and can measurably alter the landscape. Previous theoretical studies required CO2 slab ice for movements, but we find that only frost is required. Hence, sediment transport by CO2 sublimation could be more widely applicable (in space and time) on Mars than previously thought. This supports recent work suggesting CO2 sublimation could be responsible for recent modification in Martian gullies

Methodology for the synthesis of methacrylate monomers using designed single mode microwave applicators

© 2019 The Royal Society of Chemistry. A novel single-well prototype high throughput microwave reactor geometry has been produced and shown to be capable of synthesizing an array of non-commercially available methacrylate monomers. The reactor, which delivers the energy required via a dedicated coaxial line, has been shown experimentally to outperform other conventional/microwave formats. It is demonstrated to achieve significantly higher conversions than the alternative reactor types, whilst requiring (a) low levels of input power, (b) no additional energy for agitation/mass transfer, (c) no solvent and (d) no environmentally impacting thermos-fluids

Prediction of broad-spectrum pathogen attachment to coating materials for biomedical devices

Bacterial infections in healthcare settings are a frequent accompaniment to both routine procedures such as catheterization and surgical site interventions. Their impact is becoming even more marked as the numbers of medical devices that are used to manage chronic health conditions and improve quality of life increases. The resistance of pathogens to multiple antibiotics is also increasing, adding an additional layer of complexity to the problems of employing safe and effective medical procedures. One approach to reducing the rate of infections associated with implanted and indwelling medical devices is the use of polymers that resist the formation of bacterial biofilms. To significantly accelerate the discovery of such materials, we show how state of the art machine learning methods can generate quantitative predictions for the attachment of multiple pathogens to a large library of polymers in a single model for the first time. Such models facilitate design of polymers with very low pathogen attachment across different bacterial species that will be candidate materials for implantable or indwelling medical devices such as urinary catheters, cochlear implants and pacemakers

Ring opening polymerisation of ɛ-caprolactone with novel microwave magnetic heating and cyto-compatible catalyst

We report on the ring-opening polymerization of ε-caprolactone incorporated with a magnetic susceptible catalyst, FeCl 3, via the use of microwave magnetic heating (HH) which primarily heats the bulk with a magnetic field (H-field) from an electromagnetic field (EMF). Such a process was compared to more commonly used heating methods, such as conventional heating (CH), i.e., oil bath, and microwave electric heating (EH), which is also referred to as microwave heating that primarily heats the bulk with an electric field (E-field). We identified that the catalyst is susceptible to both the E-field and H-field heating, and promoted the heating of the bulk. Which, we noticed such promotion was a lot more significant in the HH heating experiment. Further investigating the impact of such observed effects in the ROP of ε-caprolactone, we found that the HH experiments showed a more significant improvement in both the product Mwt and yield as the input power increased. However, when the catalyst concentration was reduced from 400:1 to 1600:1 (Monomer:Catalyst molar ratio), the observed differentiation in the Mwt and yield between the EH and the HH heating methods diminished, which we hypothesized to be due to the limited species available that were susceptible to microwave magnetic heating. But comparable product results between the HH and EH heating methods suggest that the HH heating method along with a magnetic susceptible catalyst could be an alternative solution to overcome the penetration depth problem associated with the EH heating methods. The cytotoxicity of the produced polymer was investigated to identify its potential application as biomaterials

Achieving Microparticles with Cell-Instructive Surface Chemistry by Using Tunable Co-Polymer Surfactants

© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim A flow-focusing microfluidic device is used to produce functionalized monodisperse polymer particles with surface chemistries designed to control bacterial biofilm formation. This is achieved by using molecularly designed bespoke surfactants synthesized via catalytic chain transfer polymerization. This novel approach of using polymeric surfactants, often called surfmers, containing a biofunctional moiety contrasts with the more commonly employed emulsion methods. Typically, the surface chemistry of microparticles are dominated by unwanted surfactants that dilute/mask the desired surface response. Time of flight secondary ion mass spectrometry (ToF-SIMS) analysis of particles demonstrates that the comb-graft surfactant is located on the particle surface. Biofilm experiments show how specifically engineered surface chemistries, generated by the surfactants, successfully modulate bacterial attachment to both polymer films, and microparticles. Thus, this paper outlines how the use of designed polymeric surfactants and droplet microfluidics can exert control over both the surface chemistry and size distribution of microparticle materials, demonstrating their critical importance for controlling surface-cell response

A new particle mounting method for surface analysis

The chemical analysis of microparticles is challenging due to the need to mount the particles on a substrate for analysis; double sided adhesive tape is often used (sometimes conductive), however that is usually coated with poly(dimethyl siloxane) (PDMS) which is often used as a release agent. PDMS is a common surface contamination that can mask surface chemistries and hinder material performance where it is dependent on this contaminated interface. It is known that PDMS contains a very mobile oligomeric fraction that readily diffuses across surfaces resulting in the contamination of mounted particulate samples before and during surface chemistry analysis. This makes it impossible to determine whether the PDMS has arisen from the analysis procedure or from the sample itself. A new sample preparation method is proposed where polymer microparticles are mounted on a poly(hydroxyethyl methacrylate) (pHEMA) polymer solution, which we compare with particles that have been mounted on adhesive discs using time of flight secondary ion mass spectrometry (ToF-SIMS) and 3D OrbiSIMS analysis. Particles mounted on the pHEMA substrate results in a reduction of PDMS signal by 99.8% compared to microparticles mounted on adhesive discs. This illustrates how a simple, quick and inexpensive polymer solution can be used to adhere particles for analysis by ToF-SIMS, or other surface chemical analysis techniques such as XPS, without introduction of large amounts of silicone contaminant

Validating a Predictive Structure-Property Relationship by Discovery of Novel Polymers which Reduce Bacterial Biofilm Formation

ynthetic materials are an everyday component of modern healthcare yet often fail routinely as a consequence of medical‐device‐centered infections. The incidence rate for catheter‐associated urinary tract infections is between 3% and 7% for each day of use, which means that infection is inevitable when resident for sufficient time. The O'Neill Review on antimicrobial resistance estimates that, left unchecked, ten million people will die annually from drug‐resistant infections by 2050. Development of biomaterials resistant to bacterial colonization can play an important role in reducing device‐associated infections. However, rational design of new biomaterials is hindered by the lack of quantitative structure–activity relationships (QSARs). Here, the development of a predictive QSAR is reported for bacterial biofilm formation on a range of polymers, using calculated molecular descriptors of monomer units to discover and exemplify novel, biofilm‐resistant (meth‐)acrylate‐based polymers. These predictions are validated successfully by the synthesis of new monomers which are polymerized to create coatings found to be resistant to biofilm formation by six different bacterial pathogens: Pseudomonas aeruginosa, Proteus mirabilis, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus

Droplet Microfluidic Optimisation Using Micropipette Characterisation of Bio-Instructive Polymeric Surfactants

Droplet microfluidics can produce highly tailored microparticles whilst retaining monodispersity. However, these systems often require lengthy optimisation, commonly based on a trial-and-error approach, particularly when using bio-instructive, polymeric surfactants. Here, micropipette manipulation methods were used to optimise the concentration of bespoke polymeric surfactants to produce biodegradable (poly(d,l-lactic acid) (PDLLA)) microparticles with unique, bio-instructive surface chemistries. The effect of these three-dimensional surfactants on the interfacial tension of the system was analysed. It was determined that to provide adequate stabilisation, a low level (0.1% (w/v)) of poly(vinyl acetate-co-alcohol) (PVA) was required. Optimisation of the PVA concentration was informed by micropipette manipulation. As a result, successful, monodisperse particles were produced that maintained the desired bio-instructive surface chemistry

Modelled isotopic fractionation and transient diffusive release of methane from potential subsurface sources on Mars

We calculate transport timescales of martian methane and investigate the effect of potential release mechanisms into the atmosphere using a numerical model that includes both Fickian and Knudsen diffusion. The incorporation of Knudsen diffusion, which improves on a Fickian description of transport given the low permeability of the martian regolith, means that transport timescales from sources collocated with a putative martian water table are very long, up to several million martian years. Transport timescales also mean that any temporally varying source process, even in the shallow subsurface, would not result in a significant, observable variation in atmospheric methane concentration since changes resulting from small variations in flux would be rapidly obscured by atmospheric transport. This means that a short-lived 'plume' of methane, as detected by Mumma et al. (2009) and Webster et al. (2014), cannot be reconciled with diffusive transport from any reasonable depth and instead must invoke alternative processes such as fracturing or convective plumes. It is shown that transport through the martian regolith will cause a significant change in the isotopic composition of the gas, meaning that methane release from depth will produce an isotopic signature in the atmosphere that could be significantly different than the source composition. The deeper the source, the greater the change, and the change in methane composition in both δ13C and δD approaches -1000 ‰ for sources at a depth greater than around 1 km. This means that signatures of specific sources, in particular the methane produced by biogenesis that is generally depleted in 13CH4 and CH3D, could be obscured. We find that an abiogenic source of methane could therefore display an isotopic fractionation consistent with that expected for biogenic source processes if the source was at sufficient depth. The only unambiguous inference that can be made from measurements of methane isotopes alone is a measured δ13C or δD close to zero or positive implies a shallow, abiogenic source. The effect of transport processes must therefore be carefully considered when attempting to identify the source of any methane observed by future missions, and the severe depletion in heavier isotopologues will have implications for the sensitivity requirements for future missions that aim to measure the isotopic fractionation of methane in the martian atmosphere