Lab-on-a-chip model of mucociliary clearance for the treatment of Inflammatory Lung Diseases – MucOnChip

The Global Burden of Disease Study reports around 4 million deaths each year worldwide for inflammatory lung diseases, the large proportion of which occurring in low- and middle-income countries. Inflammatory lung diseases include asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and some late stages of the COVID-19 infection. For COPD, smoking is a major risk factor, leading to irreversible lesions in the bronchial and alveolar regions. This figure, compared to the 1.8 million deaths from SARS-CoV-2 infection in 2020, highlights the impact of inflammatory lung disease worldwide. Nowadays, advances in formulations and inhalation devices have made strides in the handling of these pathologies. However, it is clear from the above features that innovative treatments are still needed, especially to improve the drug delivery efficiency to the lungs. The expected benefits will have a major impact on the clinical outcome of patients, for example by slowing disease progression or delaying the use of multiple drugs when the disease worsens. MucOnChip addresses this public health challenge by proposing an original approach to the screening of anti-inflammatory drug formulations for lung delivery. To enhance local corticosteroid delivery to the bronchi, it is necessary to overcome a conceptual hurdle that is common to most inhalation therapies. On the one hand, the optimal particle size for drug carriers targeting the bronchial region is about 1-5 µm and on the other hand, the microcavities of mucus are such that drug particles in the micron range are arrested and eliminated by the defense mechanism of mucocilary clearance. Bypassing the mucociliary defense mechanism in the lungs through the use of smart drug nanocarriers is at the heart of our project, and its success could open doors for treatment of lung disorders beyond the pathologies mentioned.

In this project we design Trojan corticosteroid nanocarriers combining the advantages of nano- and microparticles, i.e. by inhalation the microparticles will deposit primarily in the bronchi, and will dissolve upon contact with mucus before being cleared. This in turn will lead to an enhanced release of 100 nm-corticosteroid nanoparticles capable of diffusing through the mucus barrier and reach target cells. The second important contribution of the project is that the synthetized drug carriers will be tested under conditions close to real life without going through small animal studies. For that we will fabricate a microchip that can induce mucus transport at its surface, as in the bronchi, and we will study in situ, using optical microscopy how drug particles translocate through the mucus layer.

The microfluidic device mimicking the mucociliary clearance to be developed here is indeed complementary to experiments performed In Vitro on lung epithelia and In Vivo on small animals. It has also significant advantages over the above approaches, as it does not require a specific cell biology environment, it is more ethical and its cost is very competitive. These differences should make our organ-on-chip, once implemented, very attractive to many players in the field, especially those in the pharmaceutical and nanotechnology industries. More generally, MucOnChip will impact our understanding of microparticle interaction and drug screening with the mucociliary clearance system, which is of crucial importance for the development of pulmonary nanomedicine. This knowledge has therefore a high prospect for industrial applications with developing innovative systems for medical and industrial relevant products.