Elsayed, Mohamed; (2020) Novel manufacturing of drug delivery devices using soft processing techniques. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Novel processing of advanced drug delivery carriers with enhanced efficacy is required for the 21st century healthcare. In the study, a ‘soft’ T- junction microfluidic processing technique to improve drug delivery has been developed and systematically evaluated and characterized. An advanced electrohydrodynamic atomization (EHDA) technique was utilized to obtain alginate-based nanoparticles. The influences of processing parameters, such as applied voltage, solution flow rate, nozzle diameter and collection distance, on the formation of cone-jet mode were investigated and correlated with production of nanoparticles with narrow size distribution. In addition, the effect of the properties of the alginate solutions, such as the viscosity, electrical conductivity and solvent mixture (ethanol/water) on EHDA processing and the particles size was evaluated. The results showed that the size of alginate nanoparticles can be controlled from 92 nm to 440 nm through varying the processing conditions. The bioactivity of trypsin, a model enzyme, in an alginate solution after EHDA processing was compared under different voltages and flow rates. It was found that the flow rate of the liquid, in the range of 50 to 150 µl/min has limited influence on the bioactivity of trypsin. However, almost 50% of bioactivity was lost at higher voltages (i.e. 15 kV and 20 kV), while 73% of the bioactivity of the enzyme could be retained at the lowest voltage (i.e. 10 kV). An aerodynamically assisted T- junction microfluidic method has been developed as a soft processing technique to minimise the degradation of biomolecules. Using T-geometry capillaries with 100-200 µm in diameters, the formation of microbubbles was controlled by varying the flow rate of the liquid and the bubbling pressure. Alginate-based nanoparticles with an average size ranging from 80 to 200 nm were produced through controlling shell hinning and bursting of microbubbles. This technique can also be used to obtain polymeric films with uniform/spherical pores, (i.e. with pore sizes ranged from 2 µm to 240 µm), and nano-patterned surfaces by carefully controlling the thinning of the bubble shell. Particularly, a high encapsulation efficiency of trypsin-loaded alginate porous films was prepared using T-junction microfluidic processing, which was able to maintain a high bioactivity of the encapsulated enzyme, such as retaining at least 80% of bioactivity after processing when capillaries with inner diameters of 200 µm and a flow ratio (i.e. ratio between gas and liquid flow rates) of 0.38 were used. The release profile of trypsin from the films was found to depend on the pore size, with smaller pore sizes leading to extended trypsin release compared to those with larger pores. The results show that the T-junction microfluidic method has offered an excellent potential for the preparation of nanoparticles and porous films/scaffolds that incorporate sensitive entities, such as enzymes. This work explored the utilization of microbubbles in new biomedical applications, through producing nanoparticles and highly-uniform porous films.

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