Engineering thermoresponsive materials via supracolloidal assembly in polymer-stabilised emulsions.

Stimuli-responsive materials have become very important in scientific research, allowing for "smart" control over material properties when triggered by external signals, such as changes in temperature or pH. This control has enabled ground-breaking scientific advances in fields such as tissue engineering, soft robotics, healthcare and diagnostics. One reported class of smart materials are "engineered emulsions", which use branched copolymer surfactants (BCSs) to stabilise emulsion droplets. These emulsions respond to changes in pH by solidifying into gels due to a change in the interactions between copolymers on adjacent emulsion droplets becoming attractive, leading to the self-assembly of the droplets into a hierarchical network structure. These "smart" materials are highly attractive, displaying stimulus-responsiveness combined with the availability of large hydrophobic and aqueous domains, which could be used as a reservoir or solubilisation locus for large payloads, released on demand. While the use of pH may be of interest for specific applications, temperature as a trigger offers wider applicability, particularly in biomaterials and food.

We have recently demonstrated that engineered emulsions stabilised by poly(ethylene glycol) - poly(N-isopropyl acrylamide) BCSs exhibit "thermothickening" behaviour, in other words, they respond to temperature as a stimulus and their viscosity dramatically increases upon warming. These new materials have many potential applications in advanced therapeutics, tissue engineering, and in emerging fields such as 3D printing. However, poly(N-isopropyl acrylamide), which is the most widely used polymers for thermothickening applications, is cytotoxic against some cell types, so a more biocompatible alternative must be found. In this project, candidate temperature-responsive materials with promising safety profiles have been identified, namely poly(N-vinylcaprolactam), poly(2-dimethylaminoethylmethacrylate), and poly(N,N-diethyl acrylamide), which could replace poly(N-isopropylacrylamide). In addition, the relationship between polymer block composition and thermothickening behaviour must be established to inform the design of future smart gelling materials. Finally, a better understanding of the mechanisms behind the thickening need to be achieved.

This project hypothesises that BCSs containing PEGMA and a temperature-responsive component may be used to engineer emulsions which thicken upon warming to body temperature, leading to the design of advanced functional materials. This project will explore the relationship between BCS structure and supracolloidal assembly in BCS-stabilised emulsions, to generate optimised materials with smart thermoresponsive thickening. Cutting-edge neutron scattering and reflectometry techniques will be used to understand morphology at the nanoscale relates to the gelling properties of the hierarchical assemblies, informing the design of future advanced materials.
Once developed, thermothickening BCS-stabilised emulsions have numerous potential applications, enhancing existing technologies and providing a platform for future advanced materials. Thermothickening materials could be used in mucosal drug delivery to sites such as the eye, vagina, and rectum, where a fluid containing drug may pass through an applicator, before forming a viscous gel at the site of administration, enhancing retention at sites where rapid clearance leads to poor therapeutic effect and low patient compliance. In tissue engineering, cellular medicines may be administered within a thickening material which forms a scaffold in situ in which the cells may grow and either replace damaged tissue or act as bioreactors. In 3D printing, these materials could be solidified using heat as a stimulus, creating scaffolds with microscale patterning. The temperature-responsive BCSs could also be impactful in areas such as cosmetics, chemically-enhanced oil recovery, and as flocculants.

Thermoresponsive BCS-stabilised emulsions have numerous potential uses in medicine, generating platforms for new healthcare technologies. Emulsions are attractive as drug delivery vehicles, allowing for the solubilisation of a large variety of bioactives. The thermoresponsive emulsions developed in this project enhance this functionality by allowing the emulsions to form a viscous gel upon contact with the body. This behaviour will allow passage through an applicator before hardening when warmed by the body, making the emulsions attractive to deliver drugs to topical sites such as the vagina, where the thickened material will resist shear forces that typically lead to poor retention of dose. The emulsions may also be used to form depot injections, where the material may flow through a needle then harden in a muscle, releasing drug in a controlled manner with time. Thermoresponsive materials may also be used in tissue engineering, where a material containing therapeutic cells may be used to fill a cavity, such as a damaged bone, and the warmth of the body leads to the formation of a gel scaffold for the cells to grow upon. In this context, emulsions allow for the incorporation of hydrophobic components, as well as the patterning of growth matrices, which can direct cell behaviour. Taken as a whole, these BCS-stabilised engineered emulsions could become a platform for the effective delivery of a variety of therapeutic entities, allowing for novel and improved medicines which positively impact the health and quality of life of the population.

This project will investigate the mechanisms by which BCS-stabilised emulsions undergo thickening at elevated temperature using a range of complementary techniques, including cutting-edge neutron scattering and reflectometry. The field of "engineered emulsions" is poorly explored, with the majority of studies attributable to pH-responsive systems by Weaver and co-workers. Expanding this field to emulsions which respond to temperature as a stimulus, and expanding beyond the widely used (but cytotoxic) PNIPAM, will impact knowledge in this innovative area of smart materials, enhancing scientists' capability to exploit materials properties to enhance therapies and processes, and also giving them tools to generate superior materials.

The patentable technologies developed in this project would offer significant value to the UK economy. The BCSs would, in the first instance, be explored as excipients for use in medicines, allowing for wealth-creation and inward investment into the U.K. by commercialisation via licencing to pharmaceutical companies or spin-out. The worldwide excipients market is valued at approximately $4.1 billion, with a compound annual growth rate of 6.02 % (Global Excipients Market Size, Share, Industry Trend Report 2018-2025, Grand View Research, 2018). Excipients with enhanced functionality have recently had successes in accessing this market, with notable examples including Captisol (Ligand, USA) and Soluplus (BASF, Germany). Licencing would also lead to exploitation of these polymers in other fields where surfactants are currently employed, such as cosmetics, textiles, and chemically-enhanced oil recovery. These materials may also be explored as flocculants in the water purification industry. All of these examples would generate wealth in the U.K., leading to economic impact.
This programme of work will lead to the training and development of a postdoctoral research assistant and advance the capability of the new investigator on the project. The multidisciplinary project will give the PDRA experience in polymer synthesis and characterisation by cutting edge techniques such as small-angle neutron scattering and neutron reflectometry. The new-investigator will gain experience of leading research projects, gain patentable technologies to pursue in his future career, and deliver academic outcomes which develop his career as an independent researcher.