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10 February 2018 Inhalation (ROI) for analysis of deposition in the different regions of the nasal cavity adds to the variability in the assessment of sprays using nasal airway models. Some models may have only one or two segments or ROIs, 33, 34 as shown in Figure 1. 34 In contrast, some anatomical models have multiple ROIs, 35 (see Figure 2) 35 with one model having 77 sections. 14 Models of this type can be used to assess parameters such as deposition with liquid or powder nasal drug delivery devices, or the effect of patient-use parameters such as delivery orientation or insertion angle. 12, 36-38 Quanti- tative assessments of regional drug deposition can be made using drug formulations, model compounds such as fluorescein, or radiolabels, together with the use of water-sensitive gels on the surface of the airway model to visualize deposition. 33, 35, 39, 40 It is important to recognize that there are some limita- tions of in vitro nasal airway models. Due to their rigid, inflexible structure, they are unable to simulate the forces present due to the Bernoulli principle during inhalation, which cause narrowing of the nasal valve with increasing inspiratory flow rate. 6 However, despite this drawback, the models appear useful to evaluate the initial site of drug deposition. e ability to investigate the fate of the deposited drug is limited in the physical model due to the lack of a mucociliary clearance (MCC) function. erefore, it is not possible to deter- mine the translocation of drug following deposition, which will ultimately control local nasal respiratory epithelial uptake and systemic drug absorption. Alter- native approaches include computational fluid dynamic modeling, which can be used to predict the fate of suspended drug particles in nasal spray droplets from the point of nasal deposition to the systemic absorption. Rygg et al., predicted spray droplet deposi- tion locations in a three-dimensional (3D) nasal cavity, which were then translated into a nasal dissolution absorption and clearance model (nasal-DAC) and cou- pled with an integrated compartmental pharmacoki- netic (PK) model to generate systemic plasma concen- tration/time profiles. e drug deposition prediction in the 3D model of the human nasal cavity was validated Patient nasal airway: Nasal models/casts Recently, anatomical nasal airway models or casts have been considered as effective tools for clinically relevant in vitro testing of nasal spray therapies. 12-14 Initially, the airway models were cadaver-based, which were casts or digitized copies of casts, however there was some con- cern that these geometries were inaccurate due to post-mortem changes in the airways. Guilmette et al., 15 described increases in airway passage volume that were attributed to shrinkage of the turbinates in the cadavers. With advancements in the speed and resolution of medical imaging (e.g. MRI and CT) and, more recently, rapid prototyping techniques, there are a growing number of airway models being developed for a variety of emerging applications, including drug deposition and toxicological dosimetry studies. 16-17 Delivery of nasal spray products in realistic airway phys- ical models can potentially allow determination of drug deposition efficiency or even equivalence between products for generic purposes, which may offer signifi- cant benefits in the product development process. However, as mentioned previously, there is significant inter-subject variability in the nasal airways of the patient population and capturing this variability using in vitro airway models poses a significant challenge. 18-21 Various approaches to building airway models have been employed including (i) the use of single anatomies from individuals 19-26 or (ii) development of a group of anatomies to represent a range of inter-subject variabil- ity or (iii) combined anatomies from several subjects to develop an idealized or average model. 9, 27-30 Two main approaches have been considered for developing ideal- ized/average nasal airway models. One approach is based on finding a characteristic dimension that reduces the inter-subject variability in nasal deposition among a population and making a nasal geometry that represents the average of the characteristic dimension of the population. 30 For example, Javaheri, et al. used hydraulic diameter as the primary dimension that was thought to determine deposition in an idealized infant nasal model. 30 Equally, once a mean characteristic dimension is identified, a patient-specific model can be selected from a group of models that satisfies the mean value. e second approach has been based on averag- ing the dimensions (mainly cross-sections through the length of nasal airway) of multiple subjects (e.g., 26 29 or 30 28 subjects) and developing a single model that rep- resents the average dimension. For instance, the most recent average nasal model was obtained using a deformable template method for aligning and averag- ing the nasal airway geometry from computed tomo- graphy (CT) scans of 26 individual adults. 29 For this approach, multiple subjects can be considered (e.g., 30) with several anatomies selected to represent a range of characteristic dimensions. 31, 32 In addition to the contribution of nasal anatomy to inter-subject variability, different approaches to seg- menting or defining the so-called regions of interest Figure 1 VCU's Human Nasal Model 1 34 Middle passage and nasopharynx regions Anterior nose