Substance deposition assessment in obstructed pulmonary system through numerical characterization of airflow and inhaled particles attributes

Background Chronic obstructive pulmonary disease (COPD) and asthma are considered as the two most widespread obstructive lung diseases, whereas they affect more than 500 million people worldwide. Unfortunately, the requirement for detailed geometric models of the lungs in combination with the increased computational resources needed for the simulation of the breathing did not allow great progress to be made in the past for the better understanding of inflammatory diseases of the airways through detailed modelling approaches. In this context, computational fluid dynamics (CFD) simulations accompanied by fluid particle tracing (FPT) analysis of the inhaled ambient particles are deemed critical for lung function assessment. Also they enable the understanding of particle depositions on the airways of patients, since these accumulations may affect or lead to inflammations. In this direction, the current study conducts an initial investigation for the better comprehension of particle deposition within the lungs. More specifically, accurate models of the airways obstructions that relate to pulmonary disease are developed and a thorough assessment of the airflow behavior together with identification of the effects of inhaled particle properties, such as size and density, is conducted. Our approach presents a first step towards an effective personalization of pulmonary treatment in regards to the geometric characteristics of the lungs and the in depth understanding of airflows within the airways. Methods A geometry processing technique involving contraction algorithms is established and used to employ the different respiratory arrangements associated with lung related diseases that exhibit airways obstructions. Apart from the normal lung case, two categories of obstructed cases are examined, i.e. models with obstructions in both lungs and models with narrowings in the right lung only. Precise assumptions regarding airflow and deposition fraction (DF) over various sections of the lungs are drawn by simulating these distinct incidents through the finite volume method (FVM) and particularly the CFD and FPT algorithms. Moreover, a detailed parametric analysis clarifies the effects of the particles size and density in terms of regional deposition upon several parts of the pulmonary system. In this manner, the deposition pattern of various substances can be assessed. Results For the specific case of the unobstructed lung model most particles are detected on the right lung (48.56% of total, when the air flowrate is 12.6 L/min), a fact that is also true when obstructions arise symmetrically in both lungs (51.45% of total, when the air flowrate is 6.06 L/min and obstructions occur after the second generation). In contrast, when narrowings are developed on the right lung only, most particles are pushed on the left section (68.22% of total, when the air flowrate is 11.2 L/min) indicating that inhaled medication is generally deposited away from the areas of inflammation. This observation is useful when designing medical treatment of lung diseases. Furthermore, particles with diameters from 1 μm to 10 μm are shown to be mainly deposited on the lower airways, whereas particles with diameters of 20 μm and 30 μm are mostly accumulated in the upper airways. As a result, the current analysis indicates increased DF levels in the upper airways when the particle diameter is enlarged. Additionally, when the particles density increases from 1000 Kg/m3 to 2000 Kg/m3, the DF is enhanced on every generation and for all cases investigated herein. The results obtained by our simulations provide an accurate and quantitative estimation of all important parameters involved in lung modeling. Conclusions The treatment of respiratory diseases with inhaled medical substances can be advanced by the clinical use of accurate CFD and FPT simulations and specifically by evaluating the deposition of inhaled particles in a regional oriented perspective in regards to different particle sizes and particle densities. Since a drug with specific characteristics (i.e. particle size and density) exhibits maximum deposition on particular lung areas, the current study provides initial indications to a qualified physician for proper selection of medication

Particle depositions in multi stage liquid impinger as simplified lung model using computational fluid dynamic

Inhaled medication is typically used to treat obstructive pulmonary disease and systemic diseases. The effectiveness of pulmonary drug delivery depends on the amount of drug deposited beyond the oropharyngeal region, the place where the deposition and the uniform distribution occurred. In this study, the performance of multistage liquid impinger (MSLI) simplified model which imitates the physiological lung in delivering the drug was analyzed. In order to achieve this main aim, the airflow patterns and particle depositions efficiency were evaluated in MSLI simplified model using computational fluid dynamic of COMSOL® software. The particle deposition efficiency is studied by varying flowrates (30.0 L/min, 60.0 L/min and 100.0 L/min) and particle sizes (0.1, 1.0, 3.0, 5.0, 10.0 pm) of salbutamol sulphate (density 20.0 kg/m3). The highest particle deposition occurred at flowrate 100.0 L/min and particle size of 1.0 pm as the deposition yield was 15.55% compared to flowrate 60 L/min and 30 L/min which were 10.50% and 3.09% respectively. Previous studies claimed that higher inhalation flowrate generated dispersion forces for sufficient inhalation flowrate thus enhanced higher deposition efficiency. The paired-samples T-test shows there were significant different (t= -15.400, df= 4, p <0.05) in the performance of particle depositions in MSLI simplified model with different flow rates (60.0 L/min and 100.0 L/min). Thus, the efficient fine particle deposition was significantly contributed by higher flowrate. This study also revealed that particle size ranges from 1.0 to 3.0 pm was the most suitable for inhalation treatment. Smaller particle size less than 1.0 pm was not suitable as it tended to exhale before it deposit of while larger particle (more than 5.0 pm) was not suitable for inhaled drug. In conclusion, vigorous air flow pattern promotes higher particle deposition. For efficient fine particle depositions, it is important to consider not only the particle size distribution, but also the flowrate as vital aerosol transportation agent. Statistical analysis, two-way ANOVA indicated that there was a statistically significant interaction between the effect of flowrate and particle size on particle deposition efficiency, F (8, 30)=5.857, p=0.00

Pulmonary delivery of brittle matrix powders produced by thin film freezing

textRecently, the portfolio of compounds approved for inhalation therapy has expanded rapidly for lung disease therapies. The rationale for this delivery approach includes a more targeted and localized delivery to the diseased site with reduced systemic exposure, potentially leading to decreased adverse side effects. We have proposed that brittle matrix powders prepared by thin film freezing (TFF) are a suitable platform for pulmonary drug delivery which can achieve high lung concentrations while limit the corresponding systemic levels associated with toxicity, and enhanced physicochemical and aerodynamic properties can be obtained by varying TFF processing parameters. In Chapter 2, the in vitro and in vivo performance of an amorphous formulation prepared by TFF and a crystalline micronized formulation produced by milling was compared for Tacrolimus (TAC). TFF processed matrix powders was capable of achieving deep lung delivery due to its low density, highly porous and brittle characteristics. When emitted from a Miat® monodose inhaler, TFF processed TAC formulations exhibited a fine particle fraction (FPF) of 83.3% and a mass median aerodynamic diameter (MMAD) of 2.26 µm. Single dose 24-h pharmacokinetic studies in rats demonstrated that the TAC formulation prepared by TFF exhibited higher pulmonary bioavailability with a prolonged retention time in the lung, possibly due to decreased clearance (e.g., macrophage phagocytosis), compared to the micronized TAC formulation. Additionally, TFF formulation generated a lower systemic TAC concentration with smaller variability than the micronized formulation following inhalation, potentially leading to reduced side effects related to the drug in systemic circulation. Chapter 3 investigated the impact of processing parameters in the TFF process on the physicochemical and aerodynamic properties of the resulting formulations. All of these enhanced powder properties resulted from higher freezing rate contributed to a better aerodynamic performance of the obtaining formulations. Moreover, a decreasing trend of FPF was observed for these TFF powders when the initial solid concentrations increased. The variation of the freezing rate and initial solid loading in the TFF process enabled the production of formulations with enhanced physicochemical properties and improved aerodynamic performance.Pharmaceutical Science

Investigation of bipolar charge distribution of pharmaceutical dry powder aerosols using the phase doppler anemometry system

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London.Electrostatic properties of formulation component materials and blends play an important role in dry powder inhalation (DPI) products, and that valid measurement of charge distribution will lead to more precise control of powder behavior in DPI manufacturing processes. Ultra-fine powders are known to be bipolarly charged, have non-spherical shapes and tend to be highly cohesive. Real time, non-invasive techniques need to be developed to obtain a precise and accurate time-history characteristic of electrically charged powders as they aerosolize from a DPI product, and how this measure relates to materials behavior throughout the various steps of a manufacturing process i.e. from drug micronisation, blending with lactose, through to filling dose units. A novel non-invasive technique for simultaneous measurement of size and charge of pharmaceutical powders is considered which employs the Phase Doppler Anemometry (PDA) system. Previous research demonstrated the advantages of this technique in measuring the bipolar charge distribution on a population of particles. These findings led to significant improvements in understanding performance of dry powder formulations, manufacturing processes and development of new platforms for inhaled drug delivery. The main aim of this research is to perform an investigation of electrostatic propertiesof pharmaceutical dry aerosols using the PDA system. The PDA technique was used to track the motion of charged particles in the presence of an electric field. The magnitude as well as the polarity of the particle charge can be obtained by solving the equation of particle motion in DC and AC fields combined with the simultaneous measurement of its size and velocity. The results show the capability of the technique to allow real-time size and charge distribution in the control of dry powder attributes that are critical to fully understanding manufacturing design space. The data obtained from initial investigations of electrical properties of pharmaceutical powders and bipolar charge measurements was used to perform an in-depth study of electrostatic properties of pharmaceutical aerosols dispensed by dry powder inhaler (DPI) devices. The delivery of a drug to the lungs can only be achieved by a combination of inhaler device and drug formulation which is capable of producing an aerosol of an aerodynamic diameter smaller than 5 μm and of appropriate charge. The aerosols generated by these devices are often bipolarly charged and can influence specific site deposition in human lung. By controlling the electrostatic charge generated by tribielectrification, it may be possible to achieve the desired drug deposition in the airways. Bipolary charged dispensed ultrafine particles are inhaled through the extrathoracic and tracheobronchial airways down into the alveolar region. Anatomically realistic respiratory airways and computation fluid dynamics (CFD) models have been created to study airflow structures and predict aerosol deposition within the human respiratory system using visible human data sets, human casts and morphometric data. Many theoretical studies of charged aerosol deposition in human respiratory systems have been developed, however getting real time, non-intrusive data of bipolar charge levels on aerosols dispensed from DPI’s within the human respiratory system represents a challenging issue. This research project presents a simplified human upper airway model which combined with the modified Phase Doppler Anemometry (PDA) system is able to provide real time bipolar charge distributions of aerosols delivered from several commercially available DPI devices. A three dimensional (3D) reconstruction of the upper respiratory system was performed from two dimensional (2D) images obtained from computerized tomography (CT), magnetic resonance imaging (MRI) and cryosectioned images available from Visible Human Server data set (Ecole Polytechnique Fédérale de Lausanne). The resulting dimensions of the model were consistent with morphometric data from the literature from which the simplified upper airway model consisting of two connected segments, i.e., the oral airways from the mouth to trachea (Generation G0), was created. The findings of this study provided a better understanding of the interaction between specific active ingredients and DPI devices. These results may be used in designing future generation DPI devices and a better understanding of aerosol transport and deposition efficiency within the human airways.Engineering and Physical Sciences Research Council. Pfizer team, U

Airborne Transmission of SARS-CoV-2: The Contrast between Indoors and Outdoors

COVID-19 is an airborne disease, with the vast majority of infections occurring indoors. In comparison, little transmission occurs outdoors. Here, we investigate the airborne transmission pathways that differentiate the indoors from outdoors and conclude that profound differences exist, which help to explain why SARS-CoV-2 transmission is much more prevalent indoors. Near- and far-field transmission pathways are discussed along with factors that affect infection risk, with aerosol concentration, air entrainment, thermal plumes, and occupancy duration all identified as being influential. In particular, we present the fundamental equations that underpin the Wells–Riley model and show the mathematical relationship between inhaled virus particles and quanta of infection. A simple model is also presented for assessing infection risk in spaces with incomplete air mixing. Transmission risk is assessed in terms of aerosol concentration using simple 1D equations, followed by a description of thermal plume–ceiling interactions. With respect to this, we present new experimental results using Schlieren visualisation and computational fluid dynamics (CFD) based on the Eulerian–Lagrangian approach. Pathways of airborne infection are discussed, with the key differences identified between indoors and outdoors. In particular, the contribution of thermal and exhalation plumes is evaluated, and the presence of a near-field/far-field feedback loop is postulated, which is absent outdoors

Surgery of the turbinates and “empty nose” syndrome

Surgical therapy of the inferior and/or middle turbinate is indicated when conservative treatment options have failed. The desired goal is a reduction of the soft tissue volume of the turbinates regarding the individual anatomic findings, whilst simultaneously conserving as much mucosa as possible. As the turbinates serve as a functional entity within the nose, they ensure climatisation, humidification and cleaning of the inhaled air. Thus free nasal breathing means a decent quality of life, as well

Technegas easy breather accessory (TEBA: a new concept in lung ventilation scintigraphy

The findings of this thesis represent a novel aspect in lung ventilation imaging involving a series of experiments with a new apparatus known as the Technegas Easy Breather Accessory (TEBA). The investigations were undertaken with both normal and Chronic Airways Limitation (CAL) volunteers and with Intubated Intensive Care patients. The data presented in this research were collected from 144 patients in total. In experiment one there were 25 normal volunteers who underwent conventional ventilation imaging and 25 normal volunteers who underwent TEBA assisted ventilation imaging, while in experiment two, there were 25 volunteers with CAL for conventional ventilation and 25 for TEBA; in experiment three, 25 intubated Intensive Care Patients successfully completed ventilation scintigraphy using TEBA. For experiment four, 20 patients volunteered to complete a Technegas ventilation study prior to their bronchoscopy procedure. Experiments one and two demonstrated that TEBA was effective in distinguishing normal lung ventilation from ventilation defects found in Chronic Airways Limitation (CAL) and Pulmonary Embolism (PE). Experiment three showed TEBA ventilation imaging could be successfully undertaken by intubated and unconscious patients. This has significant implications for the diagnosis and treatment for patients in ICU who formerly could not undergo this procedure. The results of this experiment will have implications for improving the diagnosis and treatment of patients in critical care. The findings of this thesis provide further evidence for the first line role of lung scintigraphy in the diagnosis of Pulmonary Embolism (PE). This is of vital importance to the large number of patients who are at risk from the life-threatening diseases of PE and Deep Venous Thrombosis (DVT). This is because timely lung ventilation imaging in the diagnosis and follow-up phase of these diseases will reduce the clinical uncertainty in directing treatment and consequently lower health care costs

The potential risks of nanomaterials: a review carried out for ECETOC

During the last few years, research on toxicologically relevant properties of engineered nanoparticles has increased tremendously. A number of international research projects and additional activities are ongoing in the EU and the US, nourishing the expectation that more relevant technical and toxicological data will be published. Their widespread use allows for potential exposure to engineered nanoparticles during the whole lifecycle of a variety of products. When looking at possible exposure routes for manufactured Nanoparticles, inhalation, dermal and oral exposure are the most obvious, depending on the type of product in which Nanoparticles are used. This review shows that (1) Nanoparticles can deposit in the respiratory tract after inhalation. For a number of nanoparticles, oxidative stress-related inflammatory reactions have been observed. Tumour-related effects have only been observed in rats, and might be related to overload conditions. There are also a few reports that indicate uptake of nanoparticles in the brain via the olfactory epithelium. Nanoparticle translocation into the systemic circulation may occur after inhalation but conflicting evidence is present on the extent of translocation. These findings urge the need for additional studies to further elucidate these findings and to characterize the physiological impact. (2) There is currently little evidence from skin penetration studies that dermal applications of metal oxide nanoparticles used in sunscreens lead to systemic exposure. However, the question has been raised whether the usual testing with healthy, intact skin will be sufficient. (3) Uptake of nanoparticles in the gastrointestinal tract after oral uptake is a known phenomenon, of which use is intentionally made in the design of food and pharmacological components. Finally, this review indicates that only few specific nanoparticles have been investigated in a limited number of test systems and extrapolation of this data to other materials is not possible. Air pollution studies have generated indirect evidence for the role of combustion derived nanoparticles (CDNP) in driving adverse health effects in susceptible groups. Experimental studies with some bulk nanoparticles (carbon black, titanium dioxide, iron oxides) that have been used for decades suggest various adverse effects. However, engineered nanomaterials with new chemical and physical properties are being produced constantly and the toxicity of these is unknown. Therefore, despite the existing database on nanoparticles, no blanket statements about human toxicity can be given at this time. In addition, limited ecotoxicological data for nanomaterials precludes a systematic assessment of the impact of Nanoparticles on ecosystems