Development of an integrated aerosol drug delivery device for an in vitro airway barrier on a chip platform

Abstract

Chronic respiratory diseases account for 4 million premature deaths per annum with constant mortality rates predicted for another decade with no cures and few newly developed treatments. The development of new compounds is highly inefficient due to safety and efficacy concerns paired with lengthy timescales and high expenses which can be attributed to the current models (animals or static cell cultures) that are used to mimic human specific diseases. To replace animal models and better recapitulate the human in vivo environment, ‘Organ on a Chip’ technology is being globally developed. This thesis focuses upon the modelling of the airway epithelial barrier and associated drug delivery, as impairment of barrier function is implicated in many respiratory diseases such as asthma or Chronic Obstructive Pulmonary Disease (COPD). A co-developed “airway barrier on chip” has been described that combines microfluidic flow with real-time measurements of barrier function using electrical impedance spectroscopy, providing an advantage over current available technologies. Alongside the presentation of a drug delivery device based upon surface acoustic wave (SAW) technology. The drug delivery device can be integrated with the airway barrier on a chip platform to deliver aerosolised drugs mimicking the way we inhale viruses and compounds to create a more physiologically relevant challenge model. The majority of drug delivery devices interface only with traditional models, the few that do interact with “lung on a chip” platforms are bulky, waste compounds through non-specific deposition and can lead to sample shearing and degradation. Results presented in Chapter 3 using the airway barrier on chip platform demonstrate the monitoring of bronchial epithelial cell barrier formation with different support membranes, and barrier integrity following challenge with a synthetic dsRNA analogue (Poly I:C, a mimic of viral infection) and treatment with a corticosteroid. The user friendly and multi-channel system uses integrated electrodes to measure electrical impedance in real time and is made from biocompatible materials that are easily machined and do not leach and absorb molecules. The impedance electrodes provide an ability to measure cellular ionic barrier integrity without disruption, whilst the microfluidic flow removes waste, provides nutrients simulating in vivo forces and pressures. In Chapter 4, SAW technology was used to produce a miniaturised drug delivery system. The SAW chip design was inspired from the literature and further optimised to generate an aerosol of a respirable size, whilst maintaining a low surface temperature and incorporating a continuous fluidic supply and integration mechanisms to facilitate pairing with both static (commercial Transwells^TM) and dynamic (airway barrier on a chip) culture systems. In Chapter 5, the ability of the drug delivery device to aerosolise compounds without impacting their biological function was investigated using bronchial epithelial cells grown at a liquid-liquid and air-liquid interface. The device was used to successfully deposit Poly I:C and corticosteroid drugs (fluticasone and dexamethasone) and the biological impact was comparable to pipetting. The ability of extracellular vesicles to modulate bronchial barrier function and reduce inflammatory cytokine release was also investigated using pipetted and nebulised delivery in response to poly I:C challenge. The work presented in this thesis hopes to provide the basis for a more appropriate method of developing and testing new therapeutic compounds. To create better compounds that can be administered to patients faster to improve their quality of life, paving the way towards personalised medication, whilst also addressing the replacement and reduction of animal testing through the bridging of in vitro specificity and in vivo complexity to unlock previously unobtainable information.

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Identifiers

ORCID for Nikita Karra: orcid.org/0000-0003-2250-7438

ORCID for Hywel Morgan: orcid.org/0000-0003-4850-5676

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