Nasal nitric oxide flux from the paranasal sinuses.

PURPOSE OF REVIEW: Upper airway nitric oxide (NO) is physiologically important in airway regulation and defense, and can be modulated by various airway inflammatory conditions, including allergic rhinitis and chronic rhinosinusitis - with and without polyposis. Paranasal sinuses serve as a NO 'reservoir', with concentrations typically exceeding those measured in lower airway (fractional exhaled NO or FeNO) by a few orders of magnitude. However, the dynamics of NO flux between the paranasal sinuses and main nasal airway, which are critical to respiratory NO emission, are poorly understood. RECENT FINDINGS: Historically, NO emissions were thought to be contributed mostly by the maxillary sinuses (the largest sinuses) and active air movement (convection). However, recent anatomically-accurate computational modeling studies based on patients' CT scans showed that the ethmoid sinuses and diffusive transport dominate the process. SUMMARY: These new findings may have a substantial impact on our view of nasal NO emission mechanisms and sinus physiopathology in general.

Use of computational fluid dynamics (CFD) to model observed nasal nitric oxide levels in human subjects.

BACKGROUND: Upper airway nitric oxide (NO) is physiologically important in airway regulation and defense, and nasal NO (nNO) levels typically exceed those in exhaled breath (fractional exhaled NO [FeNO]). Elevated concentrations of NO sampled from the nose, in turn, reflect even higher concentrations in the paranasal sinuses, suggesting a "reservoir" role for the latter. However, the dynamics of NO flux within the sinonasal compartment are poorly understood. METHODS: Data from 10 human subjects who had previously undergone both real-time nNO sampling and computed tomography (CT) scanning of the sinuses were analyzed using computational fluid dynamics (CFD) methods. Modeled and observed nNO values during the initial 2-s transient ("spike") during nasal exhalation were then compared. RESULTS: Examining the initial 2-s transient spike for each subject (as well as the pooled group), there was a statistically significant correlation between modeled and observed nNO levels, with r values ranging from 0.43 to 0.89 (p values ranging from <0.05 to <0.0001). Model performance varied between subjects, with weaker correlations evident in those with high background (FeNO) levels. In addition, the CFD simulation suggests that ethmoid sinuses (>60%) and diffusion process (>54%) contributed most to total nasal NO emissions. CONCLUSION: Analysis of this dataset confirms that CFD is a valuable modeling tool for nNO dynamics, and highlights the importance of the ethmoid sinuses, as well as the role of diffusion as an initiating step in sinonasal NO flux. Future model iterations may apply more generally if baseline FeNO is taken into account.

Evidence of Nasal Cooling and Sensory Impairments Driving Patient Symptoms With Septal Deviation.

OBJECTIVES/HYPOTHESIS: About 260,000 septoplasties are performed annually in the US to address nasal septal deviation (NSD). Yet, we do not consistently understand what aspects of NSD result in symptoms. STUDY DESIGN: Blinded cohort study. METHODS: Two fellowship-trained surgeons blindly reviewed computerized tomography (CTs) of 10 confirmed NSD patients mixed with 36 healthy controls. All patients were correctly identified, however, 24/36 controls were falsely identified by both surgeons as patients (33.3% specificity), which were grouped as asymptomatic NSD (aNSD), while the remaining controls as non-NSD (healthy). Acoustic rhinometry, rhinomanometry, individual CT-based computational fluid dynamics and nasal sensory testing were applied to address the puzzling questions of why these aNSD had no symptoms and, more fundamentally, what caused symptoms in sNSD patients. RESULTS: aNSD reported no nasal symptoms - Nasal Obstruction Symptom Evaluation score (sNSD: 60.50 ± 13.00; aNSD: 5.20 ± 5.41; non-NSD: 6.66 ± 7.17, P < .05); 22-item Sino-Nasal Outcome Test score (sNSD: 32.60 ± 14.13; aNSD: 10.04 ± 10.10; non-NSD: 9.08 ± 12.42, P < .001). No significant differences in measured nasal resistance, minimum cross-sectional area (MCA), degree of septal deviation, and nasal airflow distributions were found between sNSD and aNSD groups. Only three variables differentiate sNSD versus aNSD: anterior averaged heat flux on deviated side, inferior turbinate peak heat flux on non-deviated side, and nasal cool sensitivity measured by menthol lateralization threshold, with no significant differences among these variables found between the two healthy groups (aNSD vs. non-NSD). These variables by themselves or combined can differentiate sNSD from controls with higher specificity than the physicians (ROC area under the curve = 0.84 with 70% sensitivity and 91.6% specificity). CONCLUSIONS: This study sheds light on the potential mechanisms of NSD symptomatology: distorted nasal cooling due to NSD exacerbated by poorer nasal mucosal sensitivity. It further supports our previous hypothesis that nasal obstruction complaints do not result directly from obstruction, rather from the capacity of our nose to subjectively sense airflow cooling. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:509-517, 2022.

Tissue-engineered composite tracheal grafts create mechanically stable and biocompatible airway replacements.

We tested composite tracheal grafts (CTG) composed of a partially decellularized tracheal graft (PDTG) combined with a 3-dimensional (3D)-printed airway splint for use in long-segment airway reconstruction. CTG is designed to recapitulate the 3D extracellular matrix of the trachea with stable mechanical properties imparted from the extraluminal airway splint. We performed segmental orthotopic tracheal replacement in a mouse microsurgical model. MicroCT was used to measure graft patency. Tracheal neotissue formation was quantified histologically. Airflow dynamic properties were analyzed using computational fluid dynamics. We found that CTG are easily implanted and did not result in vascular erosion, tracheal injury, or inflammation. Graft epithelialization and endothelialization were comparable with CTG to control. Tracheal collapse was absent with CTG. Composite tracheal scaffolds combine biocompatible synthetic support with PDTG, supporting the regeneration of host epithelium while maintaining graft structure.

Computational modeling of nasal nitric oxide flux from the paranasal sinuses: Validation against human experiment.

BACKGROUND: Nitric oxide (NO) is important in respiratory physiology and airway defense. Although the paranasal sinuses are the major source of nasal NO, transport dynamics between the sinuses and nasal cavities are poorly understood. METHODS: Exhaled nasal NO tracings were measured in two non-asthmatic subjects (one with allergic rhinitis, one without) using NO analyzer connected via face mask. We subsequently performed computational fluid dynamics NO emission simulations based on individual CT scans and compared to the experimental data. RESULTS: Simulated exhaled NO tracings match well with experimental data (r > 0.84, p < 0.01) for both subjects, with measured peaks reaching 319.6 ppb in one subject (allergic-rhinitis), and 196.9 ppb in the other. The CFD simulation accurately captured the peak differences, even though the initial sinus NO concentration for both cases was set to the same 9000 ppb based on literature value. Further, the CFD simulation suggests that ethmoid sinuses contributed the most (>67%, other sinuses combined <33%) to total nasal NO emission in both cases and that diffusion contributes more than convective transport. By turning off diffusion (setting NO diffusivity to ~0), the NO emission peaks for both cases were reduced by >70%. CONCLUSION: Historically, nasal NO emissions were thought to be contributed mostly by the maxillary sinuses (the largest sinuses) and active air movement (convection). Here, we showed that the ethmoid sinuses and diffusive transport dominate the process. These findings may have a substantial impact on our view of nasal NO emission mechanisms and sinus physiopathology in general.

Inferior meatus augmentation procedure (IMAP) normalizes nasal airflow patterns in empty nose syndrome patients via computational fluid dynamics (CFD) modeling.

BACKGROUND: Empty nose syndrome (ENS) is a controversial upper airway disorder most commonly associated with tissue loss from the inferior turbinates. The inferior meatus augmentation procedure (IMAP) has been shown to effectively reduce ENS symptoms in a durable manner, but the precise mechanisms that may govern this symptomatic improvement remain unknown. METHODS: Five patients with ENS who underwent bilateral IMAP via submucosal costal cartilage implant were assessed. Pre-implant and 6 months post-implant computed tomography (CT) imaging for each ENS patient was analyzed in a blinded fashion using computational fluid dynamics (CFD) modeling to investigate intrapatient changes in airflow parameters. RESULTS: Following surgery, ENS patients have significantly improved symptoms as indexed by Empty Nose Syndrome 6-Item Questionnaire (ENS6Q) scoring (pre-implant: 14.00 ± 4.06 [mean ± standard deviation]; 95% confidence interval [CI], 10.44 to 17.56; post-implant: 4.8 ± 2.77; 95% CI, 2.37 to 7.23; Cohen's d = 2.64; p = 0.02). Using CFD, a significant shift in nasal airflow patterns was observed, where airflow deviates away from the middle meatus upon hitting the implant (pre-implant: 67.13% ± 11.14%; 95% CI, 60.22% to 74.04%; post-implant: 46.18% ± 12.81%; 95% CI, 38.23% to 54.12%; d = 1.74; p < 0.05) toward the inferior meatus (pre-implant: 30.55% ± 11.29%; 95% CI, 23.55% to 37.55%; post-implant: 42.59% ± 9.60%; 95% CI, 36.63 to 48.54%; d = 1.14; p < 0.05). No significant changes were found in nasal resistance (pre-implant: 0.102 ± 0.015; 95% CI, 0.092 to 0.112 Pa*s/mL; post-implant: 0.105 ± 0.041; 95% CI, 0.081 to 0.130 Pa*s/mL). In addition, the improvement of ENS6Q scoring significantly correlated with percent reduction in aberrant airflow through the middle meatus (R2 = 0.60, p = 0.04). CONCLUSION: This study supports our prior working hypothesis that disordered vectors of nasal airflow congregate in the middle meatus contribute to ENS symptoms, not nasal resistance. Moreover, these data illuminate a paradoxical, but consistent, restoration of nasal airflow to the inferior meatus following the replacement of turbinate tissue volume in the inferior meatus via IMAP surgery, potentially due to the Coanda effect.

Regional Peak Mucosal Cooling Predicts Radiofrequency Treatment Outcomes of Nasal Valve Obstruction.

OBJECTIVES/HYPOTHESIS: Low energy radiofrequency may offer effective treatment for narrow or obstructed nasal valve, yet its precise mechanism is not fully understood. STUDY DESIGN: Prospective, nonrandomized, case series. METHODS: Twenty prospective patients with internal nasal valve obstruction underwent office-based Vivaer treatment (Aerin Medical, Inc) under local anesthesia. Computational fluid dynamics (CFD) models were constructed based on the pre- and 90 days post-procedure computed tomography (CT) scans to identify salient changes in nasal airflow parameters. RESULTS: Patients' Nasal Obstruction Symptom Evaluation score (NOSE: pre-treatment 78.89 ± 11.57; post-treatment 31.39 ± 18.30, P = 5e-7) and Visual Analog Scale of nasal obstruction (VAS: pre-treatment 6.01 ± 1.83; post-treatment 3.44 ± 2.11, P = 1e-4) improved significantly at 90 days after the minimally invasive approach. Nasal airway volume in the treatment area increased ~7% 90 days post-treatment (pre-treatment 5.97 ± 1.20, post-treatment 6.38 ± 1.50 cm3 , P = .018), yet there were no statistically significant changes in the measured peak nasal inspiratory flowrate (PNIF, pre-treatment: 60.16 ± 34.49; post-treatment: 72.38 ± 43.66 ml/s; P = .13) and CFD computed nasal resistance (pre-treatment: 0.096 ± 0.065; post-treatment: 0.075 ± 0.026 Pa/(ml/s); P = .063). As validation, PNIF correlated significantly with nasal resistance (r = 0.47, P = .004). Among all the variables, only the peak mucosal cooling posterior to the nasal vestibule significantly correlated with the NOSE at baseline (r = -0.531, P = .023) and with post-treatment improvement (r = 0.659, P = .003). CONCLUSION: Minimal remodeling of the nasal valve (7% in this study) may have a profound effect on perceived nasal obstruction, despite little effect on nasal resistance, or PNIF. The results corroborated our previous findings that subjective relief of nasal obstruction correlates with regional mucosal cooling rather than nasal resistance or peak flow rate, a potential target for future effective, personalized therapeutic approaches. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1760-E1769, 2021.

Regeneration of partially decellularized tracheal scaffolds in a mouse model of orthotopic tracheal replacement.

Decellularized tracheal scaffolds offer a potential solution for the repair of long-segment tracheal defects. However, complete decellularization of trachea is complicated by tracheal collapse. We created a partially decellularized tracheal scaffold (DTS) and characterized regeneration in a mouse model of tracheal transplantation. All cell populations except chondrocytes were eliminated from DTS. DTS maintained graft integrity as well as its predominant extracellular matrix (ECM) proteins. We then assessed the performance of DTS in vivo. Grafts formed a functional epithelium by study endpoint (28 days). While initial chondrocyte viability was low, this was found to improve in vivo. We then used atomic force microscopy to quantify micromechanical properties of DTS, demonstrating that orthotopic implantation and graft regeneration lead to the restoration of native tracheal rigidity. We conclude that DTS preserves the cartilage ECM, supports neo-epithelialization, endothelialization and chondrocyte viability, and can serve as a potential solution for long-segment tracheal defects.