The lung is an extraordinary organ responsible for vital respiratory functions, primarily the exchange of gases—oxygen intake and carbon dioxide expulsion—through the alveolar-capillary network. This exchange takes place at the air-liquid interface within the alveolar sacs, where air meets the blood in a thin, permeable barrier composed of alveolar epithelial cells and capillary endothelial cells. The effectiveness of this barrier is crucial for maintaining proper lung function, ensuring that oxygen efficiently enters the bloodstream while carbon dioxide is expelled.
Recent advancements in organ-on-a-chip technology, particularly lung-on-a-chip models, have provided an innovative platform for mimicking the complex physiological environment of the lung. These models have transcended traditional 2D cell cultures, incorporating a three-dimensional, dynamic air-liquid interface that better represents the in vivo conditions of the lung. This shift is pivotal in respiratory research, allowing scientists to study lung functions and pathologies with unprecedented accuracy 1 2.
The lung-on-a-chip technology, pioneered by researchers like Huh et al. at the Wyss Institute, has set a new standard in modeling lung physiology. These microfluidic devices consist of two primary chambers that simulate the air-filled alveolar sac and the blood-filled capillary lumen, separated by a thin, semi-permeable membrane that replicates the air-blood barrier. This design allows for the dynamic study of gas exchange, cellular interactions, and mechanical stresses encountered during breathing.
In these systems, alveolar epithelial cells are cultured on the air-exposed side of the membrane, while vascular endothelial cells are cultured on the blood-facing side. By introducing cyclic mechanical strain through vacuum channels, the model replicates the stretching and relaxing of lung tissues during respiration. This mechanical mimicry is crucial for forming tight junctions between cells, producing pulmonary surfactant, and maintaining the barrier’s porosity—key factors in preserving the lung’s physiological functions3 4.
For an air-liquid interface to be effective in a lung-on-a-chip model, it must support robust cell culture. The substrate should promote cell attachment, proliferation, differentiation, and interaction, while also enabling the replication of critical lung functions such as gas permeability, surfactant production, and ciliary motion. Designing these interfaces involves a careful balance of physical, biochemical, and mechanical properties to ensure that the microenvironment closely mimics that of the human lung5.
The porosity of the substrate is a fundamental feature that affects gas and nutrient permeability, as well as the ability of cells to migrate and interact across the membrane. Common materials like polycarbonate (PC) and polyethylene terephthalate (PET) are frequently used due to their availability in various pore sizes, which can be customized to meet specific experimental needs. Advanced techniques such as particle leaching, gas foaming, and photolithography can further fine-tune the porosity, allowing for precise control over gas exchange and cell behavior6.
The topography of the substrate plays a crucial role in modulating cell attachment, spreading, and alignment. Unlike the flat surfaces of traditional cell culture systems, the lung’s microenvironment is characterized by a highly convoluted and textured surface. By incorporating nanoscale roughness or patterned grooves into the substrate, researchers can create a more physiologically relevant surface that enhances cellular behavior. Techniques such as lithography and electrospinning allow for the fabrication of fibrous, three-dimensional scaffolds that mimic the extracellular matrix (ECM) of lung tissue.
Native lung tissue is inherently multi-layered, with complex three-dimensional architecture that facilitates cell-cell interactions and tissue organization. To replicate this, 3D scaffolds can be created using electrospinning techniques, where fibrous networks are generated to mimic the ECM. Additionally, sacrificial casting methods using materials like sugar cubes can transfer intricate 3D architectures to polydimethylsiloxane (PDMS) substrates, providing a more accurate representation of the lung’s structural complexity7 8.
PDMS, a common material used in microfluidic devices, is naturally hydrophobic, which can pose challenges for cell culture due to non-specific adsorption of small molecules and fluorescent dyes. Temporary treatments like plasma oxidation can render the surface hydrophilic, but for longer-lasting effects, more permanent modifications are needed. Coatings with poly-lysine, non-ionic surfactants, or immobilized ECM proteins such as collagen and fibronectin can significantly enhance cell attachment and proliferation on PDMS surfaces9.
To further enhance the biocompatibility of the air-liquid interface, various functional groups can be grafted onto the substrate. These groups facilitate the adsorption and sequestration of biomolecules such as glycoproteins and growth factors, which are essential for promoting cell growth and function. Techniques like surface plasma activation and chemical modification are commonly employed to introduce these functional groups, tailoring the substrate’s biochemical properties to the specific needs of the lung-on-a-chip model10.
Mechanical cues are critical modulators of cell behavior, influencing everything from stem cell differentiation to tissue remodeling. The stiffness of the substrate, often modulated by altering the base-to-curing agent ratio in PDMS, directly affects how cells grow and interact within the lung-on-a-chip system. Additionally, the application of cyclic mechanical stress, simulating the forces experienced during breathing, is essential for maintaining the functional integrity of the air-liquid interface.
Blending PDMS with other polymers or incorporating ECM proteins into the substrate can modulate its mechanical properties, such as tensile strength and elasticity, to better match the natural lung tissue. This approach not only enhances the physiological relevance of the model but also allows for the study of various disease states, where matrix stiffness may be altered, as seen in conditions like fibrosis or cancer11 12.
The development of air-liquid interfaces in lung-on-a-chip models represents a significant leap forward in respiratory research. By carefully tuning the physical, biochemical, and mechanical properties of these interfaces, researchers can create more accurate and physiologically relevant models of the lung. These advancements not only improve our understanding of lung function and disease but also provide a robust platform for testing new therapies and drugs in a controlled, in vitro environment.
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