The device was used to successfully deposit Poly I:C and corticosteroid drugs (fluticasone and dexamethasone) and the biological impact was comparable to pipetting. 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 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 TranswellsTM) and dynamic (airway barrier on a chip) culture systems. In Chapter 4, SAW technology was used to produce a miniaturised drug delivery system. 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. 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. 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 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. 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. Alongside the presentation of a drug delivery device based upon surface acoustic wave (SAW) technology. 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. 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). To replace animal models and better recapitulate the human in vivo environment, ‘Organ on a Chip’ technology is being globally developed. 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. The smoking airway-on-a-chip represents a tool to study normal and disease-specific responses of the human lung to inhaled smoke across molecular, cellular and tissue-level responses in an organ-relevant context.Ĭhronic 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. These studies led to identification of ciliary micropathologies, COPD-specific molecular signatures, and epithelial responses to smoke generated by electronic cigarettes. This technology enables true matched comparisons of biological responses by culturing cells from the same individual with or without smoke exposure. Here, we show that a small airway-on-a-chip device lined by living human bronchiolar epithelium from normal or COPD patients can be connected to an instrument that “breathes” whole cigarette smoke in and out of the chips to study smoke-induced pathophysiology in vitro. Smoking represents a major risk factor for chronic obstructive pulmonary disease (COPD), but it is difficult to characterize smoke-induced injury responses under physiological breathing conditions in humans due to patient-to-patient variability.
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