Development of an ex vivo human-porcine respiratory model for preclinical studies

Abstract

Anatomical models to study aerosol delivery impose huge limitations and extrapolation to humans remains controversial. This study aimed to develop and validate an ex vivo human-like respiratory tract model easy to use and relevant to compare to in vivo human data. A human plastinated head is connected to an ex vivo porcine pulmonary tract ventilated artificially by passive expansion. A physiological study measures “pleural” depressions, tidal volumes, and minute ventilation for the respiratory rates chosen (10, 15, and 20 per minute) with three inspiratory/expiratory ratios (1/1, 1/2, and 1/3). Scintigraphy with 81mKrypton assesses the homogeneity of the ventilation. Forty different experiments were set for validation, with 36 (90%) ventilating successfully. At a respiratory rate of 15/minute with inspiratory/expiratory ratio of 1/2, the tidal volume average was 824 mL (standard deviation, 207 mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity to human physiological studies. Ratio of the peripheral to central count rates were equally correlated with human data published in the literature. This new model, combining research feasibility and human physiology likeness, provides a realistic approach to human inhalation and therefore can be an interesting tool in aerosol regional deposition studies.

Deposition pattern of aerosolized Legionella using an ex vivo human-porcine respiratory model

“…Physiological measurements for this model were consistent with the widely accepted human physiology (Perinel et al, 2017). Experimental conditions used were biomimetic with a breathing technological process simulating the intrapleural depressions.…”

“…A unique chimeric model was previously developed and well characterized (Perinel et al, 2017). It was adapted for this specific research on Legionella bioaerosol exposure by inhalation.…”

“…Experimental conditions used were biomimetic with a breathing technological process simulating the intrapleural depressions. Indeed, the chimeric model respired artificially by inflation with a negative pressure (passive expansion) applied inside an instrumented sealed enclosure (Perinel et al, 2017). The inhalation is due to the depression inside the instrumented sealed enclosure and the exhalation is passive by the return to atmospheric pressure by a pause of the depression generator.…”

“…Indeed, we paid attention to replace, reduce and refine our research approach by developing an alternative and very innovative experimental model. To that purpose, we adapted and optimized a chimeric respiratory model we previously developed and validated for other researches in the aerosol therapy field (Perinel et al, 2017). It consisted of a complete respiratory tract including a 3D replica of the human upper respiratory airways (nasal cavity, pharynx, sinuses) made by additive manufacturing allowing oro-nasal breathing.…”

“…It means that no animals were sacrificed specifically for this study since we used, for scientific research, organic wastes that are currently discarded by slaughterhouse. Lungs were ventilated by passive expansion as in human physiological ventilation allowing to reproduce inhalation exposure to aerosols (El Merhie et al, 2016;Le Guellec et al, 2014;Leclerc et al, 2014a;Perinel et al, 2016Perinel et al, , 2017. Previously, characterized Legionella aerosols generated upon nebulization using a fluorescent Legionella strain (Allegra et al, 2016).…”