(193af) Fabrication of in vitro Human Breathing Lung Model for Inhalation Drug Development

Drug discovery through animal testing has been proven inefficient in many instances. Even some pharmaceuticals that successfully pass clinical trials are later found to have serious side effects that can lead to unwanted suffering, costly lawsuits, or even worse, the death of patients. The current technology developed to emulate organ-level functions in miniaturized tissue-engineered models is known as “micro-physiological systems” or “organs-on-a-chip”. These models have been used to study the adsorption, distribution, metabolism, elimination, and toxicity (ADMET) of drugs in vitro. However, until now there are only a few such systems that can integrate both structures and flow mechanical features to recapitulate a complex lung with a physiological similar breathing motion. In this work, we developed a stepwise approach to construct a multilayered microfluidic platform that integrates both branched bronchiolar and deformed alveolar features to become a full lung model.

The device is composed of layers of acrylic, polyester (PET) and inflatable polydimethylsiloxane (PDMS) membranes that were pre-cut with a laser cutter followed by laminating with adhesive tapes. A water chamber was also integrated into the device to enable inflation of the flexible membrane that mimics the breathing motion by controlling the pressure difference in the water chamber. This non-pneumatic microfluidic aspiration mechanic that can stretch synthesized alveolar membranes and generate airflow in the airway. To realize the transport mechanism of inhalation drug in the breathing lung model, various sizes and charge properties of aerosolized drugs were generated and transported to the lung model through the breathing mechanism. The excessive aerosolized drugs were exhaled back to the aerosolization chamber while others remained in the in vitro lung model. To further improve the visualization ability, the aerosols were produced from fluorescein solution and observed using a fluorescent microscope. The distribution profile of the inhaled aerosols located in the different generation of bronchi was plotted by evaluating the remained aerosols. The in vitro lung model that mimics complex lung organ breathing mechanism is suitable to understand the transportation mechanism of drugs. These capabilities may be particularly useful in developing and accelerating clinical translation of inhalation drugs as well.