Omolu, AMN; (2018) Evaluation of a novel intradermal delivery system for the treatment of pressure ulcers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Pressure ulcers, a form of chronic wound, represent a significant health and resource burden in elderly and immobilised patient populations. Pressure ulcers have been shown to exhibit high matrix metalloproteinase (MMP) activity which prevents normal wound healing and doxycycline, as an MMP inhibitor, offers a potential novel treatment. Intradermal delivery of doxycycline could help treat the earliest stages of wound development and prevent further wound progression. The skin, however, has a natural barrier function which prevents the diffusion of large exogenous molecules. Microneedle rollers offer a minimally invasive technique to transiently permeabilise the skin, creating microscopic pores that act as conduits for doxycycline diffusion. / Methods: The research described in this thesis focusses on the repurposing of existing microneedle rollers for the intradermal delivery of doxycycline as a pressure ulcer treatment. Firstly, the effect of microneedle length and application method on micropore formation and rate of drug permeation was investigated using the recently-launched artificial membrane Strat-MTM and compared with excised biological tissue. Next, the biological effects of doxycycline and its transmembrane delivery were modelled in a dermal tissue equivalent (DTE) model, formed from collagen and dermal fibroblasts, by assessing changes DTE contractile behaviour and matrix metalloproteinase (MMP) activity. This simplified in vitro model was further developed to better emulate the pressure ulcer microenvironment by introducing: (i) mechanical loading using a bespoke metal weight, (ii) glucose deprivation through the use of glucose-free media, and (iii) inflammatory cells, specifically macrophages, through co-culture. Investigations progressed to a preliminary in vivo surgical wound model using compression by magnets to determine the biological effects of pressure in a whole organism. This pre-existing model was established in our lab for future investigations of microneedle-mediated doxycycline delivery. Finally, the repurposing of the existing non-invasive imaging technology optical coherence tomography (OCT) for pressure ulcer evaluation was explored in an observational clinical audit. / Results: The results demonstrate that microneedle rollers significantly enhance the transmembrane delivery of doxycycline with significant effect on tissue-equivalent contraction and MMP activity. Results from the pressure ulcer models corroborate previous findings that the pressure ulcer microenvironment augments MMP activity. Lastly, OCT is shown to detect subsurface biomarkers of skin in the earliest stages of pressure ulcer development, most suitable for treatment with doxycycline.

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