Lung-on-a-chip

Lung-on-a-chip (LoC), also known as Lung Chips, are micro- and millifluidic organ-on-a-chip devices designed to replicate the structure and function of the human lung, mimicking the breathing motions and fluid dynamics that occur during inhalation and exhalation.^[1] LoCs represent the most promising alternative to replace animal testing.

Schematic drawing of a lung-on-a-chip. The membrane in the middle can be stretched by vacuum in the two side chambers.

Concept

Huh et al. developed the first polydimethylsiloxane (PDMS)-based microfluidic system for culturing primary diseased small airway epithelial cells at the air-liquid interface (ALI). Despite its simplicity, this system successfully replicated crackling sounds associated with mechanical injury in the airway lumen.^[2]

The first LoC, published in the June 25, 2010, issue of Science, was developed by Dan Huh and Donald E. Ingber at the Wyss Institute using a microfabrication technique called soft lithography, which was pioneered by George M. Whitesides. A typical alveolus LoC comprises two microchannels primarily lined with epithelial cells on the apical side and endothelial cells on the basal side.^[3] Air is delivered to the lung lining cells, a culture medium flows in the capillary channel to mimic blood, and cyclic mechanical stretching is generated by a vacuum applied to the chambers adjacent to the cell culture channels to mimic breathing. The device is made using human lung and blood vessel cells and it can predict absorption of airborne nanoparticles and mimic the inflammatory response triggered by microbial pathogens. It can be used to test the effects of environmental toxins, absorption of aerosolized therapeutics, and the safety and efficacy of new drugs.

Since the introduction of LoCs in 2010, numerous advancements have been made to develop valid, functional, and clinically relevant models.^[4]

Shortcoming

The breathing movements in typical LoC such as Wyss platform occur in 2D, rather than the physiologically relevant three-dimensional (3D) format. Most organ-on-chip models, including LoC, are made from PDMS, which has several limitations.^[5] For example, the two-compartment platform chip, similar to the Wyss chip, is at least 10-15 times thicker than its in vivo counterpart (the commercial Wyss chip has a thickness of 50 μm according to its datasheet).^[6] This increased thickness is significant because it impedes the cross-talk between the two sides of the PDMS membranes.

The main issue with PDMS is its adsorption properties, which lead to unrealistic ADME and, consequently, inaccurate pharmacokinetics analysis.^[5][7] Other limitations of PDMS include biodegradation, leaching, cell delamination, and molecule absorption, all of which affect the accuracy and reliability of cell assays.^[8]