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- 1. Respiratory Deposition and Different Modeling Approaches Hussain Majid Ph.D Scholar
- 2. Contents <ul><li>Types of aerosol </li></ul><ul><li>Importance and structure of the lung </li></ul><ul><li>Deposition mechanism </li></ul><ul><li>Factors effecting deposition </li></ul><ul><li>Lungs models </li></ul><ul><li>Experimental techniques </li></ul><ul><li>Lung deposition modeling </li></ul><ul><li>Conclusions </li></ul>
- 3. Why is this important? <ul><li>Assessing toxic effects of airborne pollutant depositing in certain region of the lung. </li></ul><ul><li>Evaluating efficiency of dose deliverance i.e. how much and how long particles will remain in the lung. </li></ul><ul><li>Pulmonary drug delivery </li></ul>
- 4. What kind of aerosol do we breath in??? <ul><li>Bioaerosol (virus,pollen,etc.) </li></ul><ul><li>(0.02 to 100μm) </li></ul><ul><li>Smoke (<2μm) </li></ul><ul><li>Smog (<1μm) </li></ul><ul><li>Dust and other particle </li></ul><ul><li>(0.10-30μm) </li></ul><ul><li>Fog and Mist ( 10μm – 100μm) </li></ul><ul><li>Medicine (0.001 to 0.005μm) </li></ul>Pesticides Dust Smoke Fume Mist Clouds
- 5. <ul><li>Lung is a part of the respiratory system. On average, lung contains 1500 miles (2414 km)of airway, with total surface area of 80 m 2 </li></ul><ul><li>A person breaths in 10 - 25m 3 of air per day, depending on the breathing rate. </li></ul><ul><li>Functions of the lung are: </li></ul><ul><li>O 2 in CO 2 out </li></ul><ul><li>Shock absorber for the heart </li></ul><ul><li>Filter out gas micro bubble and blood clot in the blood stream </li></ul>Healthy Lung Importance of Lungs
- 6. Head airway (HA) Air and aerosol enter from HA Use to remove dust and other particles from entering the respiratory Humidify the air before entering the lung Separate out food to digestive system Tracheaobronchial (TB) Trachea direct air into the lung Bronchial tree is the first part of the lung. This part directs air in the lung Each branch in the tree split into 2 part Lung Regions Mouth Pharynx Larynx Nose Bronchial Tree Trachea Parent Branch Major daughter Minor daughter Bifurcation
- 7. Alveolar or Pulmonary (AV) Alveoli are located at the end of the bronchial tree Gas exchange occur at the Alveoli If particle deposit in this region it can directly enter the blood stream alveoli Alveolar duct Alveolar entrance rings 100µm Alveoli
- 8. Airway Generation <ul><li>Lung is made up of airway call generation. Trachea is generation 0 (G0), this is a straight duct with ring structure </li></ul><ul><li>The upper bronchial consist of generations 1 to 16. This is a series of branching “smooth” tube. High flow in this region with large airway. </li></ul><ul><li>Alveoli start appearing at generation 17. Airways are much smaller and the wall with alveoli is no longer smooth. This is a region of low flow and high residence time </li></ul>ICRP66 Respiratory Tracts Compartment dosimetry Model Average no of terminal bronchioles=34856
- 9. Deposition Mechanisms Involved Major: Minor: Diffusion Sedimentation Impaction Interception Electrostatic Naso-pharyngeal: impaction, sedimentation, electrostatic (particles > 1 μm) Tracheo-bronchial: impaction, sedimentation, diffusion (particles < 1 μm) Pulmonary: sedimentation, diffusion (particles < 0.1 μm)
- 10. Diffusion Cause by Brownian motion Diffusion is the deposition mechanism for small particles. Diffusion depends increases with decreasing particle size and flow rate. More deposition occurs in the alveoli region because longer residence time and smaller airway.
- 11. Sedimentation <ul><li>When gravitational force act on the particle </li></ul><ul><li>Particles will settle to the lower surface of the airway. This occur more in the lower generation where the velocity is much lower and the airway is smaller </li></ul><ul><li>Lung airways have different orientation so deposition of particle will be different depending on the direction of the particle flow and direction of gravitational force </li></ul>Force Force
- 12. Impaction Particle cannot follow the trajectory due to its inertia and hit the wall called impaction. Impaction increases with particle size and flow rate. This type of deposition occur through out the lung. This is important, especially in the head airway where most of the large particles are screened out Impaction occurs mostly in the upper generation airways due to high velocity
- 13. Factors that Effect Deposition <ul><li>Aerosol property </li></ul><ul><li>Air Flow property </li></ul><ul><li>Respiratory tract </li></ul>Size distribution (MMD, AMD. Etc) Concentration Particle hygroscopicity Gas particle interaction Chemical reaction Particle surface charge Lung structure and morphology Model uses: Weibel, Raabe, and Horsfield Lung capacity Breathing frequency
- 14. Aerosol Properties <ul><li>Size and density of the aerosol will determine where the aerosol will deposit. Each of the major mechanisms are depended on particle size and mass. </li></ul><ul><li>Retention rate of aerosol is depended on the type of aerosol (wet/dry) and on the chemical composition of aerosol. </li></ul><ul><li>Particle interaction are important because it can lead to changes in size and concentration via condensation and nucleation. </li></ul>
- 15. Air flow property <ul><li>Parameter used to characterize the lung volumes </li></ul>Lung parameter depend on age,height and gender, etc. Source: ICRP66 Respiratory Tracts Model Breathing frequency determines the rate which air enter the lung and exit. Breathing frequency is either controlled during respiratory study or the patient breaths at normal breathing rate. Controlled breathing 2 conditions are generally observe: rest and exercise Average adult male Condition TV (mL) Breathing Frequency (bpm) Rest age 10 450 12 Rest age 30 850 12 Exer age 10 550 20 Exer age 30 1250 20 Lung Volumes Volume (mL) Total Lung Capacity (TLC) 6700 Tidal Volume (TV) 500 Vital Capacity (VC) 5500 Residual Volume (RV) 1700 Functional Residual Capacity (FRC) 3300
- 16. Respiratory tract <ul><li>Deposition varies depending the respiratory tract uses. </li></ul><ul><li>This can be different type of lung, species, or different model. </li></ul><ul><li>Model can range from a very simple idealized lung to a very complicated airway arrangement. </li></ul>
- 17. Weibel’s Lung model <ul><li>Developed in 1963 by Weibel’s et al. as a symmetrical tree lung model for adult with 35 branching angle </li></ul><ul><li>Feature a symmetry in all tubes of the same generation with identical geometric parameter (diameters, lengths, branching and gravity angle) </li></ul><ul><li>Same number of tubes along each pathway </li></ul><ul><li>Simplest model of human lung and is widely used </li></ul><ul><li>Used Bronchogram to develop the model </li></ul>Weibel,1963 plastic cast
- 18. Raabe Lung Model Made in 1976 by the Lovelace foundation The lung’s airways are asymmetric making the model more realistic but difficult to model Lung is divided into 5 area: Right Upper Right Middle Right Lower Left Upper Left Lower Structure of the lung was taken from replica of human lung casts.
- 19. Physical Lung Model <ul><li>CT 1 /PET 2 scan to take image of solid lung cast </li></ul><ul><li>A contrast media injected lung cast can also be used </li></ul>Hollow human lung cast can be used for deposition study 1 Computed Tomography 2 Positron emission tomography Top & Left: Experimental and Numerical Smoke Carcinogen Deposition in a Multi-Generation Human Replica Tracheobronchial Model Right: http://people.rit.edu/rjreme/research_RatLungReplica.htm Bottom: Acute Rat Lung Injury: Feasibility of Assessment with Micro-CT
- 20. Lung model from existing lung <ul><li>Image is reconstructed using computer algorithm </li></ul>The reconstructed lung can be used for numerical modeling of deposition There are different reconstruction algorithms to choose Source: Experimental and Numerical Smoke Carcinogen Deposition in a Multi-Generation Human Replica Tracheobronchial Model
- 21. Deposition Experiment
- 22. Human Experiment <ul><li>Most human experiments are for clinical trial of experimental drug . </li></ul>Volunteer breaths in a specific amount Use to find Particle size Use to find Specific activity Capture Exhale aerosol The exhale aerosol sample is collected at different time point for retention rate Ultrafine Particle Deposition in Subjects with Asthma
- 23. Human Experiment (contd.) Deposition Fraction Dosage Rate A – Activity V min – 1 Minute Ventilation C – Concentration This experimental method is very common in pulmonary drug studies To see how much drug would be deposit when administrated. Unless the aerosol particle emits radiation, this method does not give any information about where particles are deposited. The radioactive aerosol can be scanned for regional deposition location using PET* scan Ultrafine Particle Deposition in Subjects with Asthma
- 24. Lung Deposition Modeling
- 25. Types of Modeling <ul><li>Empirical –ICRP Model </li></ul><ul><li>Computational Fluid Particle Dynamic (CFPD) also called CFD </li></ul><ul><li>Multi Path Model (MPM) </li></ul><ul><li>Stochastic Lung Model </li></ul>
- 26. Empirical – ICRP Model <ul><li>Developed by International Commission on Radiological Protection (ICRP) to calculate regional deposition </li></ul><ul><li>Based on experimental data and 3 major deposition mechanisms </li></ul><ul><li>Model calculates deposition in each region (Extra thoracic ET; Bronchial BB and bronchiolar bb regions) </li></ul>
- 27. Inhalation Fraction Original aerosol Aerosol inhale Inhaling Inhalation fraction is the ratio on aerosol inhaled to the total aerosol in the airflow. This is affected by the entry point, the orientation of the flow to the entry point, the flow rate and particle size. IF is usually presented as orientation average IF =
- 28. ICRP Model Empirically fitting the 3 deposition equations will give:
- 29. ICRP Prediction
- 30. <ul><li>Micron sized particles deposit at the head airway region because large particles impact at the sharp turn </li></ul><ul><li>High deposition at the head airway for nano-sized </li></ul><ul><li>ultrafine particles because of diffusion, especially </li></ul><ul><li>in the nose. </li></ul><ul><li>Tracheaobronchial had very little deposition fraction relative to other region for all particle sizes </li></ul><ul><li>Micron sized (0.01-0.1µm) particle deposited in the Alveolar region because the airway diameter becomes so small. Particle deposited in this area due to diffusion </li></ul><ul><li>Very little deposition for submicron particles </li></ul><ul><li>ICRP model is measured with monodisperse spheres of standard density unity </li></ul><ul><li>Model only valid up to 100 µm particle sizes </li></ul>
- 31. Empirical Model Limitations <ul><li>Empirical models are quick and simple to use but they are not as robust, there are limitations to the model. </li></ul><ul><li>ICRP uses symmetrical morphometric lung model with 16 airway generations </li></ul><ul><li>Bronchial region is divided simplified in two compartments regions i.e. bronchial (BB) 0 to 8 and bronchiolar(bb) 9 to15 </li></ul><ul><li>Simple empirical deposition equations are used in the ICRP model </li></ul><ul><li>Aritmetic mean (average) procedure is used in two compartments inspite of generation specific data for deposition,clearance and cellular doses. </li></ul>Empirical Modeling of Particle Deposition in the Alveolar Region of the Lungs: A Basis for Interspecies Extrapolation
- 32. Computational Fluid Particle Dynamics (CFPD) <ul><li>CFPD model takes all the transport equation and solves them simultaneously. </li></ul><ul><li>Assumes that flow is symmetric so only one flow is needed for all the passages in lung. </li></ul>
- 33. Air flow governing equations: Continuity equation Momentum equation Turbulence kinetic energy equation CFPD Pseudo-vorticity equation Particle transport equations: Slip collection factor Reynolds number Particle trajectory equation
- 34. CFPD The equations are solved using commercially available program CFX4.4 is used by Zhang et. al Need to set up algorithm and other parameters before the program can be run Outputs: Time, position, velocity of each particles at the end of each iteration Run simulation Time it take to run will depend on processing power and the simulation parameter Air Flow Equations Particle Equations Lung Model
- 35. CFPD Micro-particle transport and deposition in a human oral airway model
- 36. <ul><li>Developed by Anjilvel and Asgharian </li></ul><ul><li>Method is very similar to the CFPD, but MPM include the asymmetry airway and the calculation is done for individual airway </li></ul><ul><li>Due to the large amount of airway, MPM only calculate the concentration amount deposited in each airway </li></ul><ul><li>MPM is used for calculating deposition at a specific site in lung </li></ul>MPM
- 37. Stochastic Lung Model <ul><li>Develped by W.Hofmann & Koblinger in 1990 </li></ul><ul><li>Particle inhalled follow random path in the lung </li></ul><ul><ul><li>Random selection of actual path out of millions of possible pathway by tracing histories of large number of smiulated particles </li></ul></ul><ul><ul><li>Physical nature of the walk of a particle </li></ul></ul><ul><li>Deposition fraction and distribution within airways generations are found by stochastice lung model </li></ul><ul><li>Weibel (1963) symmetric branching of ariways is used </li></ul>
- 38. Stochastic Lung Model (cont...) <ul><li>Intra-subject variability of particle deposition is modeled by Raabe (1976) stochastic lung mdel </li></ul><ul><li>(variability of lenghts and diameter of airways are described by log-normal frequency distribution) </li></ul><ul><li>Analytical (deterministic) formulas are used for computing deposition by diffusion, sedimentation and impaction </li></ul><ul><li>Monte Carlo process continues even after depsition of particle within airway by decreasing statistical weights of particles </li></ul>
- 39. Inspiratory spatial deposition patterns of 1 nm particles, representing unattached radon progeny in a symmetric idealized bronchial airway bifurcation (generations 3-4) for 10 3 randomly selected particle trajectories. The inspiratory flow rate of 4 L/min corresponds to a respiratory minute volume of 30 L/min.
- 40. Bronchial deposition fraction under resting breathing conditions (V T = 1000 mL, t = 4s) as a function of particle diameter using different scaling procedures
- 41. Deposition patterns of 10 nm particles under sedentary breathing conditions (V T = 500 mL, t = 4s) for five sets of diffusion deposition equations. Deposition is normalized to the number of particles entering the trachea.
- 42. Particle Clearance <ul><li>Getting rid of deposited particles from the lung is called clearance </li></ul><ul><li>The muco-ciliary escalator operates in the tracheobronchial region for clearance predominantly up to generation 12 and fading out at generation 16 </li></ul>Particle Clearance mechanisms : The Naso-pharyngeal Compartment: • mucociliary clearance (transport back to nasopharynx ) • mechanical clearance (sneezing, coughing, swallowing) • absorption into circulation (soluble particles). The Tracheo-bronchial Compartment: • mucociliary clearance (transport to oropharynx) • endocytosis into peribronchial region (insoluble particles) • absorption into circulation (soluble particles) The Pulmonary Compartment: • alveolar macrophage mediated clearance • endocytosis by lung epithelial cells into interstitum • absorption into circulation (soluble particles)
- 44. Conclusions <ul><li>Estimation of aerosle deposition patteren in the lung play key role for dose assesment </li></ul><ul><li>Some of the alternative modeling assumption leads to an increased while other to a decreased deposition fraction in different generations of the lung due to differences in model structures and computational methods </li></ul><ul><li>The critical paramenters in lungs dosimetry i.e. intersubject variability of lung morphometry, breathing patterens, local inhomogeneties of particle deposition and muco-ciliary clearance need further investgation for improvement </li></ul>

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