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Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols

There are many advantages of direct nose-to-brain drug delivery in the treatment of neurological disorders. However, its application is limited by the ...

California Baptist University

Hygroscopic growth within the human respiratory tract can be significant, which may notably alter the behavior and fate of the inhaled aerosols. The objective of this study is to evaluate the hygroscopic effects upon the transport and deposition of nasally inhaled fine-regime aerosols in children. A physiologically realistic nasal-laryngeal airway model was developed based on magnetic resonance imaging of a 5-year-old boy. Temperature and relative humidity field were simulated using the low Reynolds number k - ε turbulence model and chemical specie transport model under a spectrum of four thermo-humidity conditions. Particle growth and transport were simulated using a well validated Lagrangian tracking model coupled with a user-defined hygroscopic growth module. The subsequent aerosol depositions for the four inhalation scenarios were evaluated on a multiscale basis such as total, subregional, and cellular-level depositions. Results of this study show that a supersaturated humid environment is possible in the nasal turbinate region and can lead to significant condensation growth (d / d(0)  > 10) of nasally inhaled aerosols. Depositions in the nasal airway can also be greatly enhanced by condensation growth with appropriate inhalation temperature and humidity. For subsaturated and mild inhalation conditions, the hygroscopic effects were found to be nonsignificant for total depositions, while exerting a large impact upon localized depositions.

Dynamic growth and deposition of hygroscopic aerosols in the nasal airway of a 5-year-old child.

Direct nose-to-brain drug delivery has multiple advantages over conventional intravenous deliveries. However, demonstration of its clinical feasibility is still in adolescence due to the lack of devices that effectively deliver medications to olfactory epitheliums. The objective of this study is to numerically evaluate two olfactory delivery protocols in a MRI-based nasal airway model: (1) pointed drug release in the vestibule (i.e., vestibular intubation), and (2) deep intubation with mediation released close to the olfactory mucosa. Influences of breathing maneuvers on olfactory delivery were also studied. It was observed that the front vestibular release gave higher olfactory dosage than the posterior vestibular release, and deep intubations yielded better outcomes than vestibular intubations. Specifically, the optimal olfactory dosage was achieved with deep intubation during inhalation. Breath-holding or exhalation, which was initially considered advantageous, resulted in unfocused depositions throughout the nasal turbinate region. Results of this study have implications for developing new olfactory delivery devices and for optimizing delivery protocols specific to patients' ventilations.

Modeling of release position and ventilation effects on olfactory aerosol drug delivery.

The deposition of hygroscopic aerosols is highly complex in nature, which results from a cumulative effect of dynamic particle growth and the real-time size-specific deposition mechanisms. The objective of this study is to evaluate hygroscopic effects on the particle growth, transport, and deposition of nasally inhaled aerosols across a range of 0.2-2.5 μm in an adult image-based nose-throat model. Temperature and relative humidity fields were simulated using the LRN k-ω turbulence model and species transport model under a spectrum of thermo-humidity conditions. Particle growth and transport were simulated using a well validated Lagrangian tracking model coupled with a user-defined hygroscopic growth module. Results of this study indicate that the saturation level and initial particle size are the two major factors that determine the particle growth rate (d/d0), while the effect of inhalation flow rate is found to be not significant. An empirical correlation of condensation growth of nasally inhaled hygroscopic aerosols in adults has been developed based on a variety of thermo-humidity inhalation conditions. Significant elevated nasal depositions of hygroscopic aerosols could be induced by condensation growth for both sub-micrometer and small micrometer particulates. In particular, the deposition of initially 2.5 μm hygroscopic aerosols was observed to be 5-8 times that of inert particles under warm to hot saturated conditions. Results of this study have important implications in exposure assessment in hot humid environments, where much higher risks may be expected compared to normal conditions.

Hygroscopic aerosol deposition in the human upper respiratory tract under various thermo-humidity conditions.

Intranasal olfactory drug delivery provides a non-invasive method that bypasses the Blood-Brain-Barrier and directly delivers medication to the brain and spinal cord. However, a device designed specifically for olfactory delivery has not yet been found.

Electrophoretic particle guidance significantly enhances olfactory drug delivery: a feasibility study.

How the facial interface affects particle inhalability and depositions within the airway is not well understood. Previous studies of inhalation dosimetry are limited to either inhalability or deposition, rather than the two studied in a systematic way.

Effects of the facial interface on inhalation and deposition of micrometer particles in calm air in a child airway model.

Exhaled aerosol patterns, also called aerosol fingerprints, provide clues to the health of the lung and can be used to detect disease-modified airway structures. The key is how to decode the exhaled aerosol fingerprints and retrieve the lung structural information for a non-invasive identification of respiratory diseases.

Exhaled aerosol pattern discloses lung structural abnormality: a sensitivity study using computational modeling and fractal analysis.

Although direct nose-to-brain drug delivery has multiple advantages, its application is limited by the extremely low delivery efficiency (<1%) to the olfactory region where drugs can enter the brain. It is crucial to developing new methods that can deliver drug particles more effectively to the olfactory region.

Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers.

Diagnosis and prognosis of tumorigenesis are generally performed with CT, PET, or biopsy. Such methods are accurate, but have the limitations of high cost and posing additional health risks to patients. In this study, we introduce an alternative computer aided diagnostic tool that can locate malignant sites caused by tumorigenesis in a non-invasive and low-cost way. Our hypothesis is that exhaled aerosol distribution is unique to lung structure and is sensitive to airway structure variations. With appropriate approaches, it is possible to locate the disease site, determine the disease severity, and subsequently formulate a targeted drug delivery plan to treat the disease. This study numerically evaluated the feasibility of the proposed breath test in an image-based lung model with varying pathological stages of a bronchial squamous tumor. Large eddy simulations and a Lagrangian tracking approach were used to model respiratory airflows and aerosol dynamics. Respirations of tracer aerosols of 1 µm at a flow rate of 20 L/min were simulated, with the distributions of exhaled aerosols recorded on a filter at the mouth exit. Aerosol patterns were quantified with multiple analytical techniques such as concentration disparity, spatial scanning and fractal analysis. We demonstrated that a growing bronchial tumor induced notable variations in both the airflow and exhaled aerosol distribution. These variations became more apparent with increasing tumor severity. The exhaled aerosols exhibited distinctive pattern parameters such as spatial probability, fractal dimension, and multifractal spectrum. Results of this study show that morphometric measures of the exhaled aerosol pattern can be used to detect and monitor the pathological states of respiratory diseases in the upper airway. The proposed breath test also has the potential to locate the site of the disease, which is critical in developing a personalized, site-specific drug delivery protocol.

CFD modeling and image analysis of exhaled aerosols due to a growing bronchial tumor: towards non-invasive diagnosis and treatment of respiratory obstructive diseases.

Xiuhua A. Si

Department of Mechanical Engineering

California Baptist University

Modeling and Simulations of Olfactory Drug Delivery with Passive and Active Controls of Nasally Inhaled Pharmaceutical Aerosols