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Inhalation February 2023 15 interfaces, physicochemical microenvironments and vascular perfusion of the lungs, which is not possible with conventional 2-D or 3-D culture systems [57]. ey also enable high-resolution, real-time imaging for in vitro analysis of biochemical, genetic and met- abolic activities of living cells of the lung, making them an ideal tool for pharmacokinetics studies and toxicity tests [58]. To recreate the physiological con- ditions of the respiratory system, microfluidic plat- forms with a dual-chamber system were developed to enable the manipulation of air-liquid interfaces and flow conditions [59-61]. Further, these microfluidic devices can be integrated with a computer-controlled vacuum to produce cyclic stretching of the tissue/tis- sue interface to mimic physiological breathing move- ments [62]. Generally, the design and the fabrication of the microfluid platforms comprise microchannels made of polydimethylsiloxane (PDMS), sandwich- ing a semi-permeable membrane, and bonded with two plexiglass covers. In addition, integration with a microsensor system within the devices can enable high throughput screening of novel inhalation thera- pies. However, challenges with these models include the level of complexity in set up and operation, the requirement for highly trained operators and the inability to test aerosolized formulations. Integrated models for deposition to study interactions of aerosols with biological barriers in the respiratory tract Conventional, in vitro, cell model testing to evaluate toxicity and efficacy is still performed using a solution or suspensions of test compounds. is may be rep- resentative of the environment in organs such as the gastrointestinal tract, brain, kidney and liver. How- ing how well a drug product can permeate through a mass, such as those prevalent in disease states like fibrosis and cancer. Scaffolded models e scaffolded models of 3-D cell culture involve using biomaterials to generate structures that can support cell growth and provide a physical structure for cell organization and differentiation. In the con- text of the respiratory system, the biomaterials are very often components of the extracellular matrix (ECM), hydrogels or commercially available bio-inks such as GelMA (gelatin methacrylate) and PEGDA (poly (ethylene glycol) diacrylate). Recent develop- ments in 3-D bioprinting technologies have enabled the ability to generate biologically accurate structures of the airways onto which cells can be seeded and grown. Scaffolds can simulate cell/ECM and cell/cell interactions. ey can also help elucidate ECM and tight cell junctions that influence the cytotoxic effect of inhalable products [56]. Unlike 2-D cell culture, these 3-D cell culture tech- niques can reproduce some of the hallmarks of in vivo models, which can be very beneficial in drug discovery and development studies. However, it is important to note the disadvantages of these models, which include a complex and labor-intensive process, a high degree of variability that makes reproducibility difficult, high costs associated with producing these models and the inability to test aerosolized products. Microfluidic platforms A lung- or organ-on-a-chip (Figure 3) is a microflu- idic device in which cells are seeded and perfused in a chip-like array. e aim of these devices is to reca- pitulate the multicellular architectures, tissue/tissue Figure 4 Integrated models that assess aerodynamic distribution in the lungs, as well as responses of epithelial layers. (A) Andersen cascade impactor (ACI) modified model (B) Next Generation Impactor (NGI) modified model. Adapted from Cidem, et al. 2020 [4]. 1 2 3 4 5 6 7 A B Throat pMDI Air flow Deposition Drug particles Uptake Pharmacological interaction Lung epithelium Transport buffer Snapwell or Transwell inserts Vacuum flow Absorption Front profile of mNGI Air flow Throat Vacuum flow Deposition Drug particles Aerial profile of mNGI lower panel Air flow Lung epithelium Transport buffer Absorption Uptake Pharmacological interaction 1 2 3 4 5 6 7 8