Effect of cystic fibrosis sputum rheology on lungs drug delivery by inhalation

Cystic Fibrosis (CF), one of the most common lethal genetic diseases in people of Caucasian origin, causes a severe increase of mucus viscosity (due to water loss) in many organs, mainly the airways. As a consequence, increased viscosity impairs muco-ciliary clearance determining sputum (pathological mucus) stagnation, thus promoting bacterial lung infections. In the case of drugs administered by inhalation (usually, mucolytics, anti-inflammatory and antibiotics), the structure of the Airway Surface Liquid (ASL) lining the walls of the bronchial tree requires an in-depth understanding in order to improve the efficacy of the drugs. Indeed, ASL is composed by a thin inner water-like serous fluid named periciliary layer, where cells cilia beat, and by a thicker outer non-Newtonian viscoelastic fluid representing the Mucus Layer (ML). In particular, ML, is a heterogeneous medium made up of mainly physical cross-linked polymeric regions, embedded in a less viscous water-like fluid. Although drug transport inside ASL can depend on different factors, drug diffusion is one of the most important. Thus, the estimation of the drug diffusion coefficient (D) is a key factor: at this purpose the Lustig-Peppas model for not swelling systems represents an effective tool. Indeed, this model refers to both the network mesh size and the volume fraction of the solid (polymeric) network permeating the ML. Interestingly, based on the Flory, Chui and Schurz theories, it is possible to express D directly as a function of the ML shear modulus (G). Thus, assuming that ASL rheological properties are similar to those of sputum, it is possible evaluating D and the kinetics of drug penetration inside ASL. Therefore, this work provided to measure CF sputum G by fitting the generalized Maxwell model to frequency sweep data, to evaluate D and to simulate drug diffusion through the ASL layer by means of Fick's equation