| Abstract | Microneedles are promising devices for transdermal drug delivery and biofluid sampling. Microneedle devices provide a non-invasive and painless insertion, which has the potential for self-administration. Despite recent advances, microneedle technology suffers from time-consuming manufacturing processes, inefficient penetration, and unreliable drug delivery. Hence, therapeutic activities are often associated with uncertainties in the reliability and repeatability of the results. To address these research gaps, the initial approach of this thesis is to reduce the fabrication time without compromising accuracy by optimising the fabrication techniques, such as stereolithography, micro moulding, and soft embossing. Moreover, to improve the skin penetration efficiency and drug diffusion of microneedles, the study investigates the effects of microneedle geometrical parameters and external stimulants, such as skin strains and vibrations. This is coupled with applications of artificial skin models, simulation of microneedle and microblade insertion, plus drug diffusion modelling as a validation tool to usher fidelity and reliability to the experimental outcome.
Throughout the thesis, microneedle arrays and microblade masters were made with a photoresist using the two-photon polymerisation, followed by fabrication of polydimethylsiloxane moulds for soft embossing thermoplastic samples. Two approaches were used to reduce the fabrication and replication times of microneedle masters and replicas. Firstly, through modifications to stereolithography codes, multiple master microblades were printed on a single substrate. Hence, the approach for printing six microblades on a single substrate reduced the two-photon polymerisation fabrication time by ~ 63.3 % compared to the fabrication of a 9 × 9 microneedle array on the identical substrate. Secondly, the thermoplastic replicas were further considered secondary masters for simultaneous centrifugation of multiple polyvinyl alcohol/polyvinylpyrrolidone dissolving microneedle patches. This later approach to employing primary (IP-photoresist) and secondary (Zeonor 1060R) masters reduced the overall fabrication time by ~ 86.9 %.
In the next stage, mechanical and insertion tests are conducted to determine the safety margin of the replicated microblades and microneedles. A series of mechanical compression and transverse tests are conducted on thermoplastic microneedles, dissolving patches, and microblades. For the case of microblade devices, the compression test results indicated that the microblade tip angle and test speed were directly related to the initial stiffness and failure point. In addition, increasing the microblade blade eccentricity resulted in the reduction of initial stiffness and failure point. The margin of safety for both microblades and microneedles is then ii determined based on the peak insertion forces using experiments and computer simulations. Insertion tests were conducted experimentally by inserting single microneedles on the polydimethylsiloxane model (strain: 0 - 20 %, vibration: 0 - 250 Hz). These tests are coupled with a novel finite element analysis paradigm, which integrates a series of analyses to model the microneedle insertion on a multi-layered hyperelastic skin model incorporating skin surface strains and vibrations. The results showed an inverse relationship between increasing skin strains (0 - 10 %) and vibrations (0 - 250 Hz) with the peak insertion force. Thus, applying skin strains and vibrations improved the insertion safety of microblades and microneedles.
According to the outcome of the skin strains and vibrations, a novel multifeatured impact applicator is designed, manufactured, and provisionally patented. The prototype impact applicator can be adjusted using the pre-set or manual regulation of impact velocities from 1.5 to 5.5 m/s. The applicator can also enable a range of skin surface stretching utilising a pair of side arms controlled with compression springs for height adjustment and torsion springs for the actual strains of up to 22 N. The applicator can stimulate a range of rotational and linear vibrations with frequency ranges of 0 to 250 Hz and 0 to 200 Hz, respectively.
During the experiments, skin insertion tests were conducted on the porcine back and abdominal skins using fluorescein sodium salt as the model drug coated on solid thermoplastic microneedle arrays and microblades and encapsulated in dissolving patches. Increasing the frequency for two modes of vibrations (0 - 250 Hz) on dissolving patches resulted in higher drug concentrations. The model drug diffusion flux and concentrations were also simulated for different microblades. The results indicated a direct relationship between increased blade angle and higher diffusion flux and concentration. However, finite element analysis results showed that a higher blade angle was associated with reducing microblade penetration depth. The current thesis introduced new techniques for time and cost-effective fabrication of solid and dissolving microneedles. The study also gave insight into the new methods of application systems for improving insertion safety, penetration efficiency, and drug diffusion. The reliability of the results was validated by coupling the in vitro experiments on porcine skin with artificial models and computer simulations. This research also investigated the potential application of microblades for biomedical applications, focusing on geometrical parameters, such as blade angle and eccentricity level. Furthermore, the effects of skin stimulants, such as strain and vibration, were evaluated by studying the mechanics of microneedle insertion/extraction phases. These techniques were introduced into a novel provisionally patented impact applicator capable of regulatable impact speeds, skin strains, and two modes of induced vibrations. |
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