Respiratory Depositionand Different Modeling

Approaches

Hussain MajidPh.D Scholar

Contents

• Types of aerosol

• Importance and structure of the lung

• Deposition mechanism

• Factors effecting deposition

• Lungs models

• Experimental techniques

• Lung deposition modeling

• Conclusions

Why is this important?

• Assessing toxic effects of airborne pollutant depositing in certain region of the lung.

• Evaluating efficiency of dose deliverance i.e. how much and how long particles will remain in the lung.

• Pulmonary drug delivery

What kind of aerosol do we breath in???

• Bioaerosol (virus,pollen,etc.)(0.02 to 100μm)

• Smoke (<2μm)

• Smog (<1μm)

• Dust and other particle (0.10-30μm)

• Fog and Mist (10μm – 100μm)

• Medicine (0.001 to 0.005μm)

Dust Smoke

Fume Mist

Clouds Pesticides

Lung is a part of the respiratory system. On average, lung contains 1500 miles (2414 km)of airway, with total surface area of 80 m2

A person breaths in 10 - 25m3 of air per day, depending on the breathing rate.

Functions of the lung are:

• O2 in CO2 out

• Shock absorber for the heart • Filter out gas micro bubble and

blood clot in the blood stream

Healthy Lung

Importance of Lungs

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

Mouth

Pharynx

Larynx

Nose

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

Bronchial Tree

Trachea

Parent Branch

Major daughter Minor daughter

Bifurcation

Lung Regions

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

alveoli Alveolar duct Alveolar entrance rings

100µm

Airway Generation Lung is made up of airway call

generation. Trachea is generation 0 (G0), this is a straight duct with ring structure

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.

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

ICRP66 Respiratory Tracts Compartment dosimetry Model

Average no of terminal bronchioles=34856

Deposition Mechanisms Involved

Major:

Minor:

DiffusionSedimentationImpaction

InterceptionElectrostatic

Naso-pharyngeal: impaction, sedimentation, electrostatic (particles > 1 μm)Tracheo-bronchial: impaction, sedimentation, diffusion (particles < 1 μm)Pulmonary:sedimentation, diffusion (particles < 0.1 μm)

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.

Sedimentation

• When gravitational force act on the particle

• 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

• 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

ForceForce

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

Factors that Effect Deposition

1. Aerosol property

2. Air Flow property

3. Respiratory tract

Size distribution (MMD, AMD. Etc)ConcentrationParticle hygroscopicity

Gas particle interactionChemical reactionParticle surface charge

Lung structure and morphologyModel uses: Weibel, Raabe, and Horsfield

Lung capacityBreathing frequency

Aerosol Properties• 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.

• Retention rate of aerosol is depended on the type of aerosol (wet/dry) and on the chemical composition of aerosol.

• Particle interaction are important because it can lead to changes in size and concentration via condensation and nucleation.

Air flow property

Parameter used to characterize the lung volumes

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

Condition TV (mL) Breathing Frequency (bpm)

Rest age 10 450 12Rest age 30 850 12Exer age 10 550 20Exer age 30 1250 20

2 conditions are generally observe:rest and exercise

Lung Volumes Volume (mL)

Total Lung Capacity (TLC) 6700Tidal Volume (TV) 500Vital Capacity (VC) 5500Residual Volume (RV) 1700Functional Residual Capacity (FRC) 3300

Average adult male

Respiratory tract

• Deposition varies depending the respiratory tract uses.

• This can be different type of lung, species, or different model.

• Model can range from a very simple idealized lung to a very complicated airway arrangement.

Weibel’s Lung model

• Developed in 1963 by Weibel’s et al. as a symmetrical tree lung model for adult with 35 branching angle

• Feature a symmetry in all tubes of the same generation with identical geometric parameter (diameters, lengths, branching and gravity angle)

• Same number of tubes along each pathway

• Simplest model of human lung and is widely used

• Used Bronchogram to develop the model

Weibel,1963 plastic cast

Raabe Lung ModelMade 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 UpperRight MiddleRight LowerLeft UpperLeft Lower

Structure of the lung was taken from replica of human lung casts.

Physical Lung Model

CT1/PET2 scan to take image of solid lung cast

A contrast media injected lung cast can also be used

Hollow human lung cast can be used for deposition study

1 Computed Tomography2 Positron emission tomography

Top & Left: Experimental and Numerical Smoke Carcinogen Deposition in a Multi-Generation Human Replica Tracheobronchial ModelRight: http://people.rit.edu/rjreme/research_RatLungReplica.htmBottom: Acute Rat Lung Injury: Feasibility of Assessment with Micro-CT

Lung model from existing lung

Image is reconstructed using computer algorithm

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

Deposition Experiment

Human ExperimentMost human experiments are for clinical trial of experimental drug.

Volunteer breaths in a specific amount

Use to find Particle size

Use to find Specific activity

CaptureExhale aerosol

The exhale aerosol sample is collected at different time point for retention rate

Ultrafine Particle Deposition in Subjects with Asthma

Human Experiment (contd.)Deposition Fraction

IN

EX

A

ADF 1

CVDFDrate min

Dosage Rate

A – ActivityVmin – 1 Minute VentilationC – Concentration

This experimental method is very common in pulmonary drug studiesTo 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

Lung Deposition Modeling

Types of Modeling

• Empirical –ICRP Model

• Computational Fluid Particle Dynamic (CFPD) also called CFD

• Multi Path Model (MPM)

• Stochastic Lung Model

Empirical – ICRP Model

• Developed by International Commission on Radiological Protection (ICRP) to calculate regional deposition

• Based on experimental data and 3 major deposition mechanisms

• Model calculates deposition in each region (Extra thoracic ET; Bronchial BB and bronchiolar bb regions)

Inhalation Fraction

IF 1 0.5 11

1 0.00076dp2.8

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

Original aerosol Aerosol inhaleIF =

Inhaling

ICRP Model

ppHA dd

IFDFln885.1924.0exp1

1

ln183.184.6exp1

1

22 61.1ln819.0exp9.6340.3ln234.0exp00352.0

dpdp

dDF

pTB

22 362.1ln482.0exp11.1984.2ln416.0exp0155.0

dpdp

dDF

pAL

pptotal dd

IFDFln58.2508.0exp1

943.0

ln485.177.4exp1

911.00587.0

Empirically fitting the 3 deposition equations will give:

ICRP Prediction

Micron sized particles deposit at the head airway region because large particles impact at the sharp turn

• High deposition at the head airway for nano-sized ultrafine particles because of diffusion, especially in the nose.

• Tracheaobronchial had very little deposition fraction relative to other region for all particle sizes

• 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

• Very little deposition for submicron particles

• ICRP model is measured with monodisperse spheres of standard density unity

• Model only valid up to 100 µm particle sizes

Empirical Model Limitations

Empirical models are quick and simple to use but they are not as robust, there are limitations to the model.

• ICRP uses symmetrical morphometric lung model with 16 airway generations

• Bronchial region is divided simplified in two compartments regions i.e. bronchial (BB) 0 to 8 and bronchiolar(bb) 9 to15

• Simple empirical deposition equations are used in the ICRP model

• Aritmetic mean (average) procedure is used in two compartments inspite of generation specific data for deposition,clearance and cellular doses.

Empirical Modeling of Particle Deposition in the Alveolar Region of the Lungs: A Basis for Interspecies Extrapolation

Computational Fluid Particle Dynamics (CFPD)

CFPD model takes all the transport equation and solves them simultaneously.

Assumes that flow is symmetric so only one flow is needed for all the passages in lung.

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

CFPDAir Flow Equations

Particle Equations

Lung ModelThe 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 simulationTime it take to run will depend on processing power and the simulation parameter

CFPD

Micro-particle transport and deposition in a human oral airway model

• Developed by Anjilvel and Asgharian

• Method is very similar to the CFPD, but MPM include the asymmetry airway and the calculation is done for individual airway

• Due to the large amount of airway, MPM only calculate the concentration amount deposited in each airway

• MPM is used for calculating deposition at a specific site in lung

MPM

Stochastic Lung Model

• Develped by W.Hofmann & Koblinger in 1990

• Particle inhalled follow random path in the lung– Random selection of actual path out of millions of possible

pathway by tracing histories of large number of smiulated particles

– Physical nature of the walk of a particle

• Deposition fraction and distribution within airways generations are found by stochastice lung model

• Weibel (1963) symmetric branching of ariways is used

Stochastic Lung Model (cont...)• Intra-subject variability of particle deposition is

modeled by Raabe (1976) stochastic lung mdel (variability of lenghts and diameter of airways are

described by log-normal frequency distribution)• Analytical (deterministic) formulas are used for

computing deposition by diffusion, sedimentation and impaction

• Monte Carlo process continues even after depsition of particle within airway by decreasing statistical weights of particles

Inspiratory spatial deposition patterns of 1 nm particles, representing unattached radon progeny in a symmetric idealized bronchial airway bifurcation (generations 3-4) for 103 randomly selected particle trajectories. The inspiratory flow rate of 4 L/min corresponds to a respiratory minute volume of 30 L/min.

Bronchial deposition fraction under resting breathing conditions (VT = 1000 mL, t = 4s) as a function of particle diameter using different scaling procedures

(O)- the original Raabe et al. (1976) morphometry at total lung capacity( )- linear scaling procedure assuming a constant scaling factor( )- the Habib et al. (1994) scaling proceduresnormalized to the Horsfield et al. (1971) model( )- the Habib et al. (1994) scaling procedures normalized to the Raabe etal. (1976) data( )-Deposition is normalized to the number of particles entering the trachea.

(O)- the original Raabe et al. (1976) morphometry at total lung capacity( )- linear scaling procedure assuming a constant scaling factor( )- the Habib et al. (1994) scaling proceduresnormalized to the Horsfield et al. (1971) model( )- the Habib et al. (1994) scaling procedures normalized to the Raabe etal. (1976) data( )-Deposition is normalized to the number of particles entering the trachea.

(O)- the original Raabe et al. (1976) morphometry at total lung capacity( )- linear scaling procedure assuming a constant scaling factor( )- the Habib et al. (1994) scaling proceduresnormalized to the Horsfield et al. (1971) model( )- the Habib et al. (1994) scaling procedures normalized to the Raabe etal. (1976) data( )-Deposition is normalized to the number of particles entering the trachea.

Deposition patterns of 10 nm particles under sedentary breathing conditions (VT = 500 mL, t = 4s) for five sets of diffusion deposition equations.

Deposition is normalized to the number of particlesentering the trachea.

Particle Clearance• Getting rid of

deposited particles from the lung is called clearance

• The muco-ciliary escalator operates in the tracheobronchial region for clearance predominantly up to generation 12 and fading out at generation 16

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)

Conclusions

• Estimation of aerosle deposition patteren in the lung play key role for dose assesment

• 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

• 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