Microfluidic methods for production of core/shell capsules using natural and synthetic biodegradable polymers

Biodegradable microcapsules can find many applications as carrier/delivery systems for active compounds such as essential nutrients, flavours, fragrances, drugs, and cells, or as ultrasound contrast agents for ultrasound contrast imaging and molecular imaging. In all these applications, it is essential to control and tune the average capsule size, the capsule size uniformity, and the shell thickness. The aim of this project is to develop new microfluidic strategies for production of microcapsules of controlled size and shell thickness with oil cores and shells composed of natural hydrogels and synthetic biodegradable polymers. The core/shell drops that will be used as templates for creation of capsules will be produced in microfluidic devices consisting of two round glass capillaries with tapered ends inserted into the outer square capillary. The inner fluid containing a core material (oil phase) will be pumped through the injection capillary tube and the middle fluid containing a shell material (gel-forming polymer or synthetic biodegradable polymer) will flow cocurrently through the outer square capillary. The continuous phase fluid will be supplied through the square capillary from the opposite side and all three liquid streams will be forced into the collection capillary tube, which will result in the rupture of the two coaxial jets and formation of discrete core/shell drops. These drops will be transformed into capsules by solvent evaporation-induced precipitation of synthetic biodegradable polymer (poly(lactic-co-glycolic acid)) or by ionotropic gelation of biopolymer (chitosan and sodium alginate) in the middle phase fluid. The effect of polymer concentration in the middle phase, the composition of the continuous phase and the operating parameters on the size and mondispersity of the fabricated capsules will be investigated in the processes will be optimised to obtain a maximum degree of monodispersity. The encapsulation of microparticles into core and shell regions of the capsules will be demonstrated by encapsulating fluorescent dye-labelled latex microparticles. The encapsulation efficiency will be estimated by observing the presence of latex particles in the continuous phase. Due to high degree of drop size uniformity and the ability to form drops in regular time intervals, the methods are convenient for single-cell encapsulation and encapsulation of controlled number of cells per capsule. The drop generation process will be recorded by a high-speed video camera for in situ optimisation of the operating conditions and emulsion formulation. Hydrogel delivery systems for omega-3 fatty acids will be developed by injecting oils rich in omega 3 fatty acids through the injection capillary. Omega 3 oils are highly susceptible to oxidation and the hydrogel shells formed around oil drops will act as a barrier to oxygen and light. Microencapsulation within hydrogel shells will also help to mask the undesirable taste and odour of some oils.The key advantages of microfluidic methods that will be developed in this project are that resultant capsules are highly uniform in size and that the shell thickness can precisely be controlled over a wide range by adjusting the flow rates of the liquid streams. Alternative strategies of engineering core-shell capsules are time consuming and require multi-stage operation such as electrostatic layer-by-layer deposition, do not allow precise control of the shell thickness such as interfacial complex coacervation, or lead to highly polydisperse capsules such as conventional emulsification and atomisation processes. The microfluidic methods that will be developed are highly flexible and can be used for preparation of different polymeric capsules, vesicles and hybrid multilayered microgel structures.

The equipment that will be bought and installed for the project such as the high-speed imaging system, micropipette puller and microforge will form the basis for intensive research training activities in the field of microfluidics at Loughborough, which will help to train and educate the next generation of UK scientists and engineers in microfluidics and microengineering. A long-term benefit to UK science is an increase of UK competitiveness in these rapidly expanding fields of science and engineering. Central industrial beneficiaries of this research will be companies in the food and healthcare sectors developing precision particle engineering technologies for encapsulation and controlled delivery applications, such as Unilever and a growing number of small and medium companies involved in the development of technologies and equipment for production of emulsions and functional microparticles, such as Micropore Technologies Ltd. Due to low fabrication costs of microcapillary devices, low consumption of chemicals and the ability to visualise drop formation process, microfluidic techniques that will be developed in this project can be used by these industries for improvements to their product formulations. The methods can help in better understanding the basic physical and physicochemical principles and the factors involved in drop generation, which may have wider implications in optimisation and modelling of industrial emulsification processes. New delivery systems for omega-3 fatty acids that will be developed in this project can be used to investigate the protective effect of hydrogel shells on omega 3 oils. The shell thickness and capsule size can be precisely tailored which opens up the opportunity for more systematic and fundamental investigation of the factors involved in omega 3-fatty acids stabilisation within microgel capsules. It may have wider implications because it is well known that higher intake of omega 3 oils reduces the risk of coronary heart disease and immune response disorders. Other potential beneficiaries are pharma/biotech companies working in the field of drug delivery, including targeted drug delivery, tissue engineering, and ultrasonic contrast agents (UCAs). UCAs are promising new tools in diagnosis and therapy of coronary heart disease, which is the leading cause of death for both sexes in England and Wales, according to a report published by the Office for National Statistics. Microfluidic processes that will be developed in this project can lead to the development of monodisperse UCAs, which have a greater percentage of their population optimised for ultrasound imaging than commercial polydisperse agents. The world market for contrast media for medical imaging applications is estimated to be more than 4 billion. For targeted imaging, in which only a small number of agents are retained at the site of pathology, it is even more important to use monodisperse UCAs. Although a drop production rate in microcapillary devices is insufficiant for practical applications, some of the processes that will be investigated can be scaled up in microchannel array devices. Microfluidic strategies for production of monodisperse hydrogel and polymeric capsules that will be developed in this project may have important implications in fundamental drug delivery investigations. Monodisperse capsules can ensure a predictable release rate and release profile of a drug and thereby a predictable therapeutic effect. The industrial dissemination of the project results will be promoted through contacts of the PI with Unilever Colworth (Dr Henelyta Ribeiro and Dr Shiping Zhu). Micropore Technologies Ltd, a Loughborough University spin out company, will help to promote the industrial dissemination through its well established contacts with the pharmaceutical, personal healthcare, and fine chemical industries.