Welcome to new respirology by a 4D modeller of the human lung,

alias, “Lung4Cer”

Ver.1.1

Hiroko Kitaoka

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Introduction

This is a free application software which generates various kinds of 4D (= 3D space + time axis)

models of the human broncho-alveoalar system for the purpose of studying anatomy and physiology

of the lung. The name of “CataChiCalaCli-er” comes from Japanese words, Catachi (= form,

structure) and Calacli (= machine, mechanism). The last “er” indicates a doer in English and its

pronunciation also means a doer in Japanese (Ya).

“CataChiCalaCli” is a kind of coinage in which several basic Japanese words are contained.

“Catachi” is a compounded word of “Cata” and “Chi”, meaning space and energy, respectively.

“Calacli” is also compounded of “Cala” and “Cli”, meaning direction (or relation) and cyclic time,

respectively. Furthermore, Japanese word “Chicara, compounded of “Chi” and “Cara”, means

“gradient vector of energy potential field”, exactly the same as the definition of force in physics.

When you separate “CataChiCalaCli” into “Catachi” and “Calacli”, it means geometry and

kinematics, or structure and function. When you separate “CataChiCalaCli” into “Cata”, “Chicala,

and “Cli”, it means dynamics which connects structure and function. Furthermore, when you insert

“by” between “Catachi” and “Caracuri”, it means morphogenesis. Thus, “CataChiCalaCli” is an

appropriate term to comprehensively indicate 4D phenomena in the living body. Since its

translations into other languages seem extremely difficult, the author proposes to use an alphabetical

notation of Japanese original words. The author also proposes an alias of CataChiCalaCli-er , “4Cer”,

identically pronounced to “forcer”, a farmer growing vegetables rapidly. Actually, Lung4Cer makes

lung models in a very short time.

Nowadays, people get information mainly by 2D media such as book, television, and computer

display through their eyes. However, when we wish to know a 3D object in reality, we have to use

not only our visual systems but also our motor systems. If you were at the front of the Mona Lisa in

the Louvre, you could watch her without stirring an inch. However, if you were at the front of the

Venus de Milo, you would move around her, watch details from various directions, and even touch

her if there were nobody except you and the Venus. If she were alive, you would try to dance with

her. Thus, we use our motor systems for understanding a 4D object. “Learn” in Japanese,

“Manabu”, comes from “Manebu” or “Maneru”, which means “mimic”. The original meaning of

“Manabu” is to reproduce the shape and the motion of an object using ones own body.

Nowadays, virtual reality technology provides us a new method for 4D learning. Users intervene in

computer models with a mouse through GUI (graphic user interface). Lung models generated by

Lung4Cer can be moved, cut, and sliced by the use of a visualization application software.

Please let them breathe synchronously with your breath. Eventually you will understand the 4D

structure of the lung in your physical memory. However, it is a great pity that computer models

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cannot be touched in your hands in reality. If you could make a real solid model by yourself, you

would understand more clearly how it would be generated and how it would be moved. Alveolar

Origami models developed by the author are attached in Appendix. Please cut, fold, and construct

Origami models, and use them complementarily with the computer models.

Lung4Cer has been developed by the author with VC++ by Microsoft Inc. Expected personal

computers for executing the application are Windows Xp. Vista, and 7 (either 32 or 64 bits) with

memory beyond 1GB. Free application software, ParaView, easily obtained through internet, is

expected to use for visualizing lung models. ParaView can be easily obtained by internet. Instruction

for ParaView is written in Chapter 2 in this manual..

The basic algorithms for generating lung models have been already published in academic

journals (See references 1-4). Airflow within the lung during breathing can be simulated with a 4D

shape model of the broncho-alveoalar system by the use of Computational Fluid Dynamics (CFD).

However, CFD requires a shape model to be connected without gaps and to be geometrically

consistent during breathing motion. Lung4Cer includes new algorithms for converting geometric

models onto 4D finite element models for CFD. Therefore, generated model has one single

continuous surface from the trachea to alveoli, as the real lung has one single continues surface of

epithelium. Since a high performance computer is required in order to generate finite element

models and to perform airflow simulation, the present version of Lung4Cer makes models only for

visualization so as to be executed by a common PC. In the near future, an extend version for airflow

simulation will be released.

Lung4Cer is under evolution. There may be several programming errors. There may be many

academically questionable points. Please inform the author of your comments so as to evolve

Lung4Cer (hirokokitaoka000@hotmail.com).

Feburary 3, 2011

Hiroko Kitaoka, PhD, MD

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CONTENTS

0. Introduction ・・・・・・・・・・ 1

1. Let’s make an airway tree by Lung4Cer ・・・・・・・・・・ 4

2. Let’s see the airway tree by ParaView ・・・・・・・・・・ 8

(1) Download and start up of ParaView ・・・・・・・・ 8

(2) Read file ・・・・・・・・ 8

(3) Observe the airway tree model ・・・・・・・・ 9

(4) Make image files and movies ・・・・・・・・ 15

3. Parameters for generating lung models ・・・・・・・・・・ 16

4. Airway tree model with air-supplying parenchymal regions ・・・・・・・・・・ 20

(1) Whole lung model ・・・・・・・・ 20

(2) Lung segment model ・・・・・・・・ 22

5. Air pathway model from the trachea to alveoli in a single subacinus ・・・・・・・・・・ 24

6. Alveolar system model ・・・・・・・・・ 29

(1) Straight alveolar duct model ・・・・・・・29

(2) Origami models ・・・・・・・31

(3) Pyramidal subacinar model ・・・・・・・33

7. Estimation of ventilation distribution with various body posture models ・・・・・・・・35

8. References ・・・・・・・・・・・ 38

Appendix: paper sheets for Origami alveolar duct models

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Chapter 1：Let’s make an airway tree by Lung4Cer

１．Double-click on the icon , a white window appears.

2. Click a tab “Model Generation” > “Model Type”, and a dialog-box “Model Generation” opens

in which parameters for model generation are asked.

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3. Here, just click “OK” button in the dialog-box. Immediately, pictures of an airway tree down to

segment bronchi at TLC (total lung capacity) are drawn on the window. There are explanations about

respiratory mode at the right side of the window. If the window does not have enough length, drag

the right edge of the window so as to see the full description.

４．Next, click a tab “File Output” > “File Type”, and a dialog-box “File Type” opens.

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5. Here, click “OK” button in the dialog-box, too. Then, another dialog-box opens for “Save As” in

which file name is asked.

６．Write the file name “smallTree” in “Name box” (N) and click “Save button” (S). A few second

later, the file name and the number of generated branches appear on the window.

In the present case, 67 branches including the trachea have been modeled. The filename on the

window is the full name in your PC. Let‘s make sure what files are generated in “My Documents”.

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There are twenty files named smallTree000.vtk, smallTree001.vtk, smallTree002.vtk, ,,,,, and

smallTree019.vtk. It means that the respiratory cycle is divided into 20 time steps and 3D shape

information of the airway tree at each time step is described in each file. The extension “vtk” is a

standard format of VTK (Visualization Tool Kit), one of the most popular open sources for image

processing. Two periods before “vtk” indicate a set of time serial VTK files. Lung4Cer expects users

to use a free visualization software “ParaView “, which has been developed based on VTK.. Usage

of ParaView will be explained in Chapter 2.

7．If you wish to quit the application, click “File” > “Exit”. Although a dialog-box asks you

something, click the button “No”.

The above is the basic process of model generation by Lung4Cer. You can make plenty of models

with various combinations of bronchi, parenchyma, respiratory modes, and body postures. Details

will be explained in Chapter 3.

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Chapter 2: Observation of the airway tree model by ParaView

ParaView is a free application software for visualization developed in the US. You can easily

download it by internet and visualize various data from a simple graph to complex mechanical

simulation data. In this chapter, basic methods for 4D observation will be explained using the airway

tree model generated in the previous chapter.

１． Download and start “ParaView”

(1) Access the official site of ParaView（http://www.ParaView.org）by internet.

(2) Click ”Download” in the right part in the window, and select an adequate executive file for

your PC.

(3) Save the Installer on the desktop in your PC. Then, start it by clicking the icon. Continue the

process as the guidance.

(4) When the installation is finished, the executive file “ParaView-3.8.0” appears in the Start

Menu. Just click the icon, and the main window of ParaView will open. If there is no icon for

ParaView in Start Menu, you can go to “C¥Program Files¥ParaView3.8.0¥bin”and

double-click the executive file.

２． Open the file (1) Click “File” > “Open”, and a dialog-box for file selection is opened. You will fin d

“smallTree..vtk”, which indicates a set of files for all time steps of smallTree. Double-click

the file name, and the word “smallTree0*” appears in the area “Pipeline Browser” located

in the left upper part of the main window.

(2) A green button “Apply” is seen in the area “Object Inspector” in the left lower part of the

main window. Click it, and the airway tree down to segment bronchial level appears in the

view window.

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Fig.2-1. Visualization of “smallTree”

3. Observation of an object

(1) Transformation： Move the mouse by pressing the left button on the view window,

and the object will be rotated according to the mouse motion. Move the mouse by

pressing the right button, and the object will be change its size. Move the mouse by

pressing the left button in the mouse and pressing Shift key in the keyboard at the

same time, and the object will be shifted parallel. There are several icons on the third

raw in the main window useful for transformation.

The icon on the left end is to reset an object at the center.

Six icons with XYZ axes are rotation at 90 degrees around the axis.

The fourth icon from the right end is to show/hide coordinate axes.

The third icon from the right end is to show/hide the center.

The icon on the right end is to assign a rotative center.

(2) Color of the background： White background is adequate for transparent view.

Open “Edit” > “Settings” > “Colors” > “Background Color”. Choose white on

the pallet, and press “OK” > “Apply”.

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Fig.2-2. Color Selection of background color

(3) Transparent view： Open ”Object Inspector ”> “Display”（red circle in Fig.2-3）, shift

down the scrolling bar on the right edge., and you will find a box named “Opacity” (green

circle in Fig. 2-3). Change the value less than 0.5, and you will see superimposed branches

through transparent airway walls.

Fig.2-3. Transparent view

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If you wish edit the object color, click the icon marked by red circle in Fig.2-4.

Click “Choose Preset”, and select adequate a color scale.

Fig.2-4. Color Edition

(4) Animation：There are several icons related animation in the center of the upmost raw in

the main window, which work in the same way as usual movie software. You can see

breathing motion of “smallTree”. The macroscopic breathing motion of the lung is

computed based on elastic deformation of lung tissue in which gravity effect is taken

account. Thoracic wall motion is given as boundary conditions and the elastic property is

assumed linear and uniform in the whole lung under normal condition (see Reference 4).

(5) Clipping： Click the icon marked by red circle in Fig.2-4, and a red rectangle frame

appears in the view window. At the same time, You will find a new icon “Clip1” in

“Pipeline Browser”. Press “Apply” in “Object Inspector”, and you will see a sectioned

airway tree. Drag the red frame leftwards (rightwards in the body) in order to shift the

location of cross section like Fig.2-4. Drag the normal axis( indicated by a long arrow) in

order to change the direction of cross section.

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Fig.2-4. Clipping

You will notice that the icon on the left side of “smallTree0*” in “Pipeline Browser” has

changed color from black to gray. It indicates that the object of whole “smallTree0*” is hidden

automatically. If you click this icon, hidden “smallTree0*”is shown again. To show/hide the

red frame of cross section is performed by checking “Show Plane”. In addition, to select a side

of cross section is performed by checking “Inside Out” in “Object Inspector”. Fig.2-5 shows a

endo-bronchial view of the right lower lobar bronchus from the sectioned intermediate trunk.

There are five orifices s of segmental bronchi in the right lower lobe (B6, B7, B8, B9, and

B10).

The above images are drawn by emphasized perspective. It has a merit to provide a clear

3D effect but a demerit in size comparison. If you need to compare approximate size

comparison, open “Edit” > “View Settings”, and check “ Use Parallel Projection” ( green

circle in fig.2-6). Fig.2.7 shows the difference in two kinds of perspective. Note that the

tracheal orifices are very different in size.

If you wish to indicate multiple views simultaneously, click the icon at the right upper

corner in the view window (red circle in Fig.2-6). You will see the window is divided. Select

“3D View” to create a new view.

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Fig.2-5. Endo-bronchial view of right lobar bronchus（B6, B7, B8, B9, B10）

Fig.2-6. Percpective（upper: enhanced, lower: parallel projection）

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(6) Slicing： Click the icon marked by red circle in Fig.2-7, and a red frame appears in the

view window. At the same time, You will find a new icon “Slice1” in “Pipeline Browser”.

Press “Apply” in “Object Inspector”, and you will see a thin-sliced airway tree.

Fig.2-7. Slicing

The left view window in Fig.2-7 is a slice image where B6 arises from the lower lobe bronchus.

“Line Width” in “Display” has changed from 1 to 2 so as to see sectioned bronchial walls clearly.

Since it is difficult to recognize orientation of the slice, superimposing with the whole airway tree

image are indicated in the middle and the right view windows.

When you go to animation process under this condition, all views are animated simultaneously.

You can see how bronchial cross sections may change during breathing in relation with the whole

lung motion. There may be cross sections whose areas decrease during inspiration. However, it is not

caused by bronchial volumetric change, but due to positional change of the cross section relative to

the airway tree. This is a very important point for morphometric study using CT images.

4. Saving image files

(1) If you wish to save a view as a static image file, open “File” > “Save Screenshot”. Write a file

name and save it. If you have opened multiple views and wish to save aall views in one

image, check off “Save only selected view” in the dialog box “Save Snapshot resolution”.

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(2) If you wish to save a view as a movie file, open “File” > “Save Animation”. Write a file

name and save it. Note that all opened view windows are recorded for animation.

The above is a minimal but sufficient manual for visualizing 4D lung models by ParaView. You

may feel that smallTree model is easy to be generated but too simple to observe precisely. In chapter

3, how to make complicated complex 4D lung models will be explained.

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Chapter 3：Parameters for model generation

Lung4Cer can generate various types of human lung model by combining several parameters which

assign element, composition, location, breathing mode, and body postures.

(A) Model Type

1: generate an airway tree down to respiratory bronchioles without parenchymal elements.

To which level, and in which region, are assigned by parameters in (B) and (C),

respectively.

2: generate an airway tree with air-supplied parenchymal regions. Terminal branches in the tree

have respective parenchymal regions to which they supply air. Each parenchymal region

is expressed as a set of cubes whose side lengths are equal to the diameter of the terminal

branch. There is an approximate relationship between the diameter of a branch (D) and the

volume of parenchymal region to which the branch supplies air (V): V ≃ 1,000 x D3.

3. generate an air pathway from the trachea to one single subacinus consisting of space-filling

alveolar ducts and sacs. The subacinus is defined as a part of the pulmonary acinus to

which one last respiratory bronchiole supplies air.

４： generate one last bronchiole and its supplying subacinus. Since Model Type 3 is

multi-scale from 10 cm length of the trachea to 10 micron meter thickness of the alveolar

wall, it is impossible to observe the model at a glance. It is necessary to generate only

the subacinar region in order to observe precisely the subacinar structure, to ,

5. generate only the alveolar system with various geometric shape independent from the whole

lung structure.

(B) Branch number in the airway tree

There is an a relationship between the number of the human airway tree and the anatomical

property of the terminal branches such as follows: .

Lobar bronchi ≃ 10 (= 9)

Segmental bronchi ≃ 40

Miller’s lobular bronchi = 1,000 – 5,000

Reid’s lobular bronchioles = 5,000 – 30,000

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Respiratory bronchioles ≃ 20,000 – 500,000

Approximate total number in the airway tree is used in order to assign the anatomical property

of the terminal branches. In this version, at most 3,000 branches can be for Model Type 1.

On the other hand at most 121 branches can be generated for Model Type 2, because it needs a

lot of computational costs for generating parenchymal regions. There is a simple relationship

between the total number of branches in a tree (B) and the number of terminal branches (T) as

follows: B = 2T +1, as long as branching is always dichotomy (trichotomy can be

interpreted as double dichotomies with a very short interval). Therefore, at most 60 regions

can be generated for Model Type 2.

For Model type 3 or 4, it is necessary to assign the number at 60,000 (at least 20,000),

because at least one respiratory bronchiole should be generated. However, when Region of

Interest, which will be explained next, is assigned adequately, the number of really generated

branches is reduced drastically.

Note that the number of branches in a generated model is not the same as the input number.

The real number in the model is written on the window of Lung4Cer.

(C) Region of Interest: ROI

0: the whole lung

1: right upper lobe, 2: right middle lobe, 3: right lower lobe

4. left upper lobe, 5. left lower lobe

Lung segment in the right lung = 100 + segment number

Lung segment in the left lung = 200 + segment number

For Model Types 1-4, the model generation is performed only within the assigned region.

If you wish to make a whole-lobe model, assign Model Type at 2, Branch Number at 10, and

ROI at 0. If you wish to make a whole-segment model, assign Model Type at 2, Branch

Number at 40, and ROI at 0. If you wish to make a one whole-lobular model in one segment,

assign Model Type at 2, Branch Number at 1000, and ROI beyond 100.

If you wish to make a subacinar model, assign Model Type at 3 or 4, Branch Number at

60000, and ROI beyond 100. If you assign a ROI number without corresponding lung

segments, a subacinus in the nearest segment in number is generated.

（D）Composition of the alveolar system

Lung4Cer generates an alveolar system model by connecting a lot of alveolar duct unit so as

to mimic an air pathway in the pulmonary subacinus (See Reference 2 and 3). The alveolar

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duct unit is a basically cubic but bumpy deformed duct with eight alveoli inside. The

following parameters assign how many units are how arranged. If you assign Model Type at

1 or 2, you do not have to consider them.

The present version of Lung4Cer can connect at most 160 units, which realize an average

size of the human pulmonary subacinus. The smaller number is the better for precisely

observing 4D structure of the alveolar duct. Note that the number of units in a generated

model is not always the same as the input number. The real number in the model is written on

the window of Lung4Cer.

Four types of the subacinar shape are provided as follows:

0. space-filling: fills a given space (cubic for Model Type 5 )

1. pyramid: pyramidal subacinus whose apex is the end of its-supplying bronchiole

2. sheet: square sheet in which duct units are arranged in 2D

3. bar: straight duct in which duct units are arranged in 1D

4. For Model Type s 4 and 5, there are many candidate respiratory bronchioles for model

generation. In order to identify those candidates, ID number is allocated to every generated

respiratory bronchiole according to generated order. When the shape is assigned at 0, there

are several respiratory bronchioles which fail to connect to their own air-supplying regions

due to shortcomings of the algorithms. In such a case, try another ID number.

For Model Type 5, it is possible to select whether the last respiratory bronchiole is added

(0) or not (1). The last bronchiole is necessary for airflow simulation but unnecessary for

structural simulation.

（E）Breathing mode

There are four parameters to assign breathing mode, the lung capacities at the beginning and

the end of inspiration, I/E ratio, and the body posture.

In general, the lung capacity (LC) is expressed by an equation as follows:

LC = RV + f‧VC,

where RV is the residual volume、VC is the vital capacity, and f is the volume fraction of VC. LC is

equal to RV when f = 0, , and is equal to the total lung capacity (TLC) when f = 1. In the present

model, the functional residual volume (FRC) is assigned at f = 0.35, and the inspiratory lung

capacity at rest is assigned at f = 0.5. Since the lung parenchymal volume is dependent on the

parenchymal position and body posture, the value of f should be regarded as an approximated

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value. As a default condition, FRC to TLC with I/E ratio of 2 : 3 under upright posture is assigned. If

you wish to make a model for the full vital capacity, lung capacity at the beginning of inspiration

should be changed into 0. Although it is known that there is hysteresis in respiratory cycle, no

hysteresis are included in this version for the sake of simplicity.

Parameters related to file output

In this version, files for only visualization are generated (an extended version will have a file

option for computational fluid dynamics in the near future). One parameter is provided which assign

time steps for the file.

Open “ File Output” > “File type”, and select the time steps. Press OK, and a file dialog box

asking file name is opened. Write an adequate name without any extension and press “Save” (S). File

generation may take several seconds or several minutes according to model type model scale, and

computer resources. Do not use a number at the end of file name so as to avoid confusion with

time series number.

（Attention）

1. When you make Model Type 3 in succession, the respiratory bronchiole may be connected the

former subacinus. In such a case, Lung4Cer is initialized by the following operation:

(1) Assign Model Type at 1 and Branch number at 1, and press OK

(2) File Output１: OK > File Save :Cancel.

2. When you make a big model, Lung4Cer may not continue to generate a new model. In such a case,

you should quit and restart Lung4Cer. When you intend to make a too big model, Lung4Cer may

freeze. In such a case, you should quit Lung4Cer through Task Manager in your PC.

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Chapter 4: Airway tree model with air–supplying parenchymal regions

Lung parenchyma which is supplied air by the trachea is the bilateral whole lung. Parenchymal

regions which are supplied air by five lobar bronchi are respective lung lobes. Even though terminal

branches are assigned arbitrarily in the airway tree, every terminal branch has its own air-supplying

region and the sum of respective regions is the same as the whole lung. This is because that the

airway tree has no loop and one-to-one correspondence between a branch and its air-supplying

region is always true down to acinar and subacinar levels. A classic model of the lung function is a

combination of one single tube and one single balloon. This model is too simple to consider

intra-pulmonary phenomena. During breathing, thoracic shape changes according to respiratory

muscular activities. Change of thoracic shape causes change of shape of the lung parenchyma. The

lung parenchyma mainly consists of alveolar walls. Regional parenchymal deformation generates air

flow within alveoli. Although each alveolar air flow is very tiny, the sum of airflow from several

hundred million alveoli is conveyed through the airway tree. Therefore, instead of the single

tube-balloon model, it is more constructive and practical to model the lung as a tree with multiple

terminal air sacs which fill the whole lung space. Potentially, Lung4Cer can make a tree model with

several hundred million alveoli. However, it costs incredibly huge amount of computer resource.

Lung 4Cer limits data size so as to meet the performance of common PC. In this chapter, a whole

lung model with five lobes and a single lung segment model with about fifty lobules are introduced.

(1) Whole lung model

Fig.4-1 shows a whole lung model at TLC with the airway tree down to five lobar bronchi and

lobes. The method for making this model by Lung4Cer is as follows:

Click “Model Generation” > “Model Type”, and a dialog-box “Model Generation” is opened.

Assign “Model Type” at 2, “Branch Number” at 10, and “ROI” at 0. No attention is necessary for

composition of alveolar system. Breathing mode is default (FRC and TLC, I/E ratio = 2:3,

upright). Press “OK”, and a tree down to lobar bronchi is drawn in the window at once. Then, click

“File Output” > “File Type”, press “OK” in the dialog-box “File Type”, write a filename, and press

“Save”. About two minutes later, the window becomes as shown in Fig. 4-2.

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Fig. 4-1. Five-lobe model

Fig.4-2. Indication of Lung4Cer at the moment of file generation for five-lobe model

The lobar boundaries are very rugged because lobes are expressed as sets of cubes whose side

lengths are equal to diameters of the lobar bronchi. However, the cubic shape has a merit for

estimating regional ventilation as will be mentioned in Chapter 7.

Ends of lobar bronchi are connected continuously with one cube in the lobe so that air can be moved

into inside of lobes. Lung4Cer considers only gravity effect as a cause of physiological ventilation

inhomogeneity. Therefore, sliding or incoherent motions between regions are not reproduced.

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Fig.4-2 shows superimposed views with the transparent lobar model and an airway tree model

composed of 2,921 branches. The airway model is colored by segment numbers (It takes about 10

minutes to make this tree model).

Fig. 4-2. Combination of the lobe model and the airway tree model with 2,921 branches

(2) Lung segment model

Since it needs a lot of computational costs for generating parenchymal regions, at most 60

regions can be generated in the present version of Lung4Cer. In order to make lobular region

model, ROI should be limited to one segment.

Figs.4-3 and 4-4 indicate a lobular region model in right S10. “Approximate branch number” was

assigned at 1600, and “ROI” was assigned at 110. Here, right S10 is divided into 57 regions

corresponding to anatomical “Miller’s lobule”. Miller’s lobule is recognized in CT images as a

polygon bordered by interlobular septa, as indicated in the lower part of Fig. 4-3. An airway tree

model without regions is superimposed in Fig. 4-4 so that spatial relationship between a bronchus

and its air-supplying region may be recognized.

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Fig. 4-3. Fifty seven-lobular model in right S10（TLC）

Fig. 4-4. Fifty seven-lobular model in right S10（FRC）

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Chapter 5: Air pathway model from the trachea to alveoli in a single subacinus

As mentioned before, regional airflow generated by parenchymal deformation is gathered to the

trachea through respective bronchi, and finally expired to the atmosphere. There are many textbooks

in which the alveolus is pictured as a sole balloon attached to the end of a long tube. However, in

reality, the relationship between the alveolus and its air pathway is never one-to-one but multi-to-one

correspondence, and the alveolar wall is always shared with neighboring alveoli. Let me explain by

an analogy of house and street. The alveolar system is not a house located at the dead end of a

mountain path but a cluster of shopping streets along which many shops are opened without gap.

Lateral walls of a shop are shared with neighboring shops. The back wall of a shop is also shared

with another shop which is facing to another street. Customers with money are coming and going

through the street, like the air with oxygen. Shops call in customers through the opened door and

convey their money on the wall in which capillary network is embedded. Absorbed money in the

capillary network is gathered into a back street, a part of the pulmonary vein system. The important

point is that the shop wall is not in possession of a shop owner but shared with neighbors. Shops in

the shopping are not competitors but collaborators for the purpose of realizing the most effective

respiratory motion with the least energy loss. This is a kind of ideal system for the human being.

Since a shopping street is arranged on 2D ground, the alveolar system embedded in 3D space is still

more complicated than this analogy.

The pulmonary acinus is defined as a parenchymal region supplied air by a terminal bronchiole

(TB). The TB branches three times in average and branched bronchioles are called “respiratory

bronchioles (RB)” because there are a few alveolar opening in their inner walls. The last RB still

branches several times, however, branched ducts are no more bronchioles but called “alveolar ducts”

because the duct walls are completely replaced by alveoli. Terminal alveolar ducts with dead ends

are called alveolar sacs. The subacinus, defined as the parenchymal region supplied air by the last

RB, purely consists of the alveolar system without airway components. Therefore,, not the acinus but

the subacinus is used as the minimum respiratory unit in this manual. Since one TB branches three

times in average, there are eight subacini in one acinus in average.

Figs.5-1 and 5-2 indicate two air pathway models from the trachea to alveoli in respective

subacini in right S10. The lower parts in the figures indicate magnified views of a subacinus located

at the dorsal position. Alveoli are colored by path length from the end of the air-supplying

bronchiole. All alveoli are connected to the trachea through branched alveolar duct. How to make an

air pathway within a subacinus is written in reference 2.

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Fig.5-1. Air pathway model from the trachea to one subacinus in rt. S10 (FRC)

Left: dorso-ventral, center: lateral, right: toe-head direction

Fig.5-2. Air pathway model from the trachea to one subacinus in rt. S10 (TLC)

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Comparison between Figs.5-1 (at FRC at upright) and 5-2 (at TLC at upright) indicates gravity

effect to the parenchymal deformation. Size change along gravity direction is much larger than

along other directions. Since the size changes in thoracic diameter is only 6 % in this model,

comparison of inspiratory and expiratory 2D-CT images may underestimate the volumetric change.

Fig.5-3 indicates a slice image of the model with 0.25 mm in thickness like thin-sectioned

high-resolution CT images by the twice use of “Clip”, s ince the module “Slice” has no

thickness. Net-like patterns of the alveolar wall at FRC and TLC are apparently different because

of the alveolar structural change. This change causes the change of tissue density, and hence, the

change of CT value.

In addition, CT value changes not only by lung capacity but also by blood volume. There are

many papers regarding inspiratory and expiratory CT images that low CT value at expiratory CT

indicates trapped air by bronchiolar obstruction. However, low CT value at expiratory CT may occur

when regional blood flow decreases. In order to judge”air-trapping”, one must indicate no volume

change at expiration and airway obstruction only at expiratory phase. .Of course, one can not do only

by CT value comparison.

Fig.5-3. Simulated thin-section CT images of the subacinar model with 0.25 mm in thickness

Upper row: at FRC, lower row: at TLC

Left: the whole view from CT direction, center: magnified image, right: lateral view

27

The method for making the above model by Lung4Cer is as follows: Assign Model Type at 3,

Branch number at 60,000, and ROI at 110. Assign Number of alveolar duct units at 160, Shape at 0

(= space-filling), Registered number at 1. You do not have to consider with or without RB.

Parameters for breathing mode are defaults (Lung volumes at the beginning and the end of

inspiration are FRC and TLC, respectively. I/E ratio is 2:3. Body posture is upright). Then press OK,

and pictures of small branches in right S10 are drawn on the window in two minutes. Next, click

“File Output” > “File Type”, press “OK”, write a filename, and press “Save”. About two minutes

later, the window of Lung4Cer becomes as shown in Fig.5-4. Blaclk closed circles added to the

airway pictures indicate the position of generated subacinus.

Fig.5-4. Indication of Lung4Cer at the moment of file generation for subacinar model

Models for Model Type 3 are multiscale from 10 cm of the tracheal length down to 10 micron

meter of the alveolar wall thickness. Usually such a multiscale object can not be observed by a single

image modality, as well as by human naked eyes. The combination of Lung4Cer and ParaView

enables us to observe such a multiscale model either as a whole or as a set of microscopic details.

However, it is extremely difficult to observe details of a subacinus with global breathing motion.

Therefore, only for Model Type 3, there is an option to relatively convert global breathing motion so

as to fix the endpoint of the last respiratory bronchiole during breathing cycle. Note that this option

causes inconsistency in superimposition with other lung models except the first time step. If you

wish to observe only a subacinar model with its supplying bronchiole, you should assign Model

Type at 4.

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The other subacinar model located ventrally in Fig.5-1 was generated by assigning registered

number at 101. Be careful not to use the same file name for different ID number.

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Chapter 6: Alveolar system model

Lung4Cer provides a 4D structural model of the human alveolar system whose algorithms are

based on lung morphogenesis, anatomy, and physiology. As long as the author knows, the model is

the only model in which morphogenetic deformation during lung development and dynamic

deformation during breathing are taken account. In this chapter, methods to make and observe the

model will be explained. See Reference 3 for details of the algorithm. The present version of

Lung4Cer makes a model in which all alveoli have the same shape, which are unrealistic. Although

another version can make an irregular-shape alveolar model, as shown in Reference 3, however, the

computational cost becomes much higher. The congruent alveolar model is thought to be enough

for the purpose of understanding 4D structure of the alveolar system.. Here, a simplest straight

model and a realistic pyramidal model will be introduced.

(1) Straight duct model

Assign Model Type at 5, Number of alveolar duct units at 3, Shape at 3, RB at 1. You do not have

to consider other parameters. Regarding breathing mode, assign Lung capacity at the beginning and

the end of inspiration at 0 and 1, respectively. Since gravity effect is not taken account for Model

Type 5, you do not have to assign body posture. Perform the same procedure as previous model

generation.

Open the model file by ParaView, and a long straight duct is on the view window. Transparent

view is useful for observing internal structure as shown in Fig.6-1. When you rotate the duct 45

degree around the longitudinal axis, the whole shape of one alveolus is observed (the second and

the fourth rows in Fig.6-1). An animated view indicates that three round hole becomes gradually

large with the expansion of the duct. Those wholes are alveolar mouths (alveolar entrance rings）,

where 80 % of elastic fibers in the alveolar wall is distributed.

Clipped view along the longitudinal axis indicates directly the internal structure of the alveolar

duct model., as shown in Fig. 6-2. There are three points like “X” in the picture at second row. Those

are closed alveolar mouths over which air-contained alveolar spaces exist. There are eight cross

sections of alveolar spaces with closed alveolar mouths, four are at upper side and other four are at

lower side of the duct. Note that closed alveoli are not collapsed. Note again that the inner part of

the alveolar duct is smooth without protrudent alveolar walls. During inspiration, alveolar mouths

gradually open, and alveolar walls which form alveolar mouths gradually protrude toward the central

axis of the duct. According to the motion of alveolar mouths, dihedral angles between the duct walls

become duller, and the volume increases, like accordion motion.

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Fig.6-1. Straight alveolar duct model（upper two rows: min. volume, lower two: max. volume）

Fig.6-2. Straight alveolar duct model（Clipped view under the same condition as in Fig.6-1）

31

After eight clipping operation along various directions, one single alveolus is clipped out as

shown in Fig.6-3.

Fig 6-3. Alveolar shape in a duct model at FRC

(2) Origami models

The author has developed a method to construct an alveolar duct model in reality, because

computer models can not be touched and less convincing than real solid models. Origami, a Japanese

traditional paper craft, is very useful because one can make and operate it by oneself. When you

handle the Origami alveolar duct duct model with your hands, you can feel airflow generated by

Origami motion on the palm. However, it takes a lot of manual labor for large models. In addition, it

is impossible to perform numerical simulation by Origami model. Complementary usage of both

models is desirable.

Fig.6-4 indicates a single alveolar Origami model, almost identical to the computer model shown

in Fig. 6-3. Cut out a part of the second part in Appendix (the same one as in the left end in

Fig.6-4), fold lines, and connect neighboring edges by cellophane tape. Finally, a pink ring,

corresponding to the alveolar mouth, appears. When the alveolar mouth is fold up, the volume of the

alveolus decreases, and finally the alveolar mouth is closed (right end in Fig.6-4). Exactly saying,

Origami should be made of a square sheet without cutting or connecting by tape. However, since the

essence of the Origami model is to express its motion as reversible changes of folding angles, it is

not inadequate to call the real model “Origami model”.

32

Fig.6-4. Origami model for single alveolus

Since it is very complicated to make an Origami alveolar duct model, how to make the fetal duct

model (the left in Fig.6) is explained at fist according to the morphogenetic process of the alveolar

system. The fetal alveolar duct is a rugged duct without alveolar opening. The alveolar formation

begins one month before birth at which new alveolar septa grow from ridges of rugged wall and

form alveolar mouths. Two strings in the first page in Appendix are corresponding to the unwrapped

rugged duct. Two sets of two green squares correspond to convex parts in the s fetal duct, and other

parts of the strings correspond to concave parts in the s fetal duct. The latter is equal to the

subtraction of the sheet by the red part in Fig. 6-4. Connect edges by cellophane tape so as to arrange

convex and concave parts and alternatively and connect ends of strings respectively, then the fetal

duct model is accomplished as shown in the left in Fig.6-5. This is a cubic column with deformed

four walls. There is a void in the center of each wall. The duct volume can be changed by changing

shape of the void. Of course, there are no such voids in the real fetal duct but duct walls are

continues.

Here, you would understand how to make an adult alveolar duct model by Origami; to add

alveolar mouths rings to the concave parts in the fetal duct model. However, it is extremely difficult

to do so in reality. Instead, it is feasible to prepare the concave parts with alveolar mouths as printed

in the second sheet in Appendix. Connect them to the convex parts, the Origami alveolar duct model

is accomplished.

Fig.6-5. Origami model for alveolar duct unit

（left: fetal duct, center: adult normal duct, rt. Alveolar collapse）

33

There are eight alveoli in the alveolar duct unit, however, only four concave parts have the

alveolar mouths. Since the convex parts are surrounded by alveolar mouths belonging to concave

parts, they look like to have their own mouths. Although they look similar to concave parts at TLC,

they become parts of smooth duct wall when the alveolar mouths are closed.

There area few slight differences between the Origami and the computer models: First, the

alveolar mouth in the Origami model is not contracted but folded. However, when fold interval is

very small, it behaves like a elastic membrane. Secondly, although all elements in the Origami model

do not change their shapes, those in the computer model slightly do in order to connect to

neighboring ducts at all directions without gap through respiratory cycle. Thirdly, the alveolar

shape in Fig 6-3 is not symmetric, unlikely to the Origami model or the model in Reference 3. This

is due to technical modification for constructing 4D finite element model.

(3) Pyramidal subacinar model

Fig. 6-7 shows an pyramid-shaped subacinar model by connecting 155 duct units. There are

about 1,200 alveoli. The size, shape, and the alveolar number are nearly the same as an average

human subacinus. Comparison between two conditions at the minimum and maximum volumes

indicates that the macroscopic shape is homothetic without gravity effect although microscopic

appearance is extremely nonhomothetic, as will be mentioned in detail later.

Fig. 6-7. Pyramidal subacinar model

(upper: at minimum volume, lower: at maximum volume)

34

Right two images in each row in Fig. 6-7 are longitudinal slice images at two different directions.

Inside of the subacinus is filled by branched alveolar duct without gap. Even during breathing

motion, no gaps are generated. Slice images at the maximum volume are similar to the histological

image of normal lung tissue fixed by formalin at total lung volume. If you compare a sliced image

with its corresponding clipped image, you would recognize that alveolar septa protruded toward the

center of duct space are cross sections of opened alveolar mouths. There are many small closed

polygons and few protruded alveolar septa in slice images at minimum volume in Fig. 6-7. Those

closed polygons are cross sections of closed alveolar space. Note that alveolar duct space becomes

smooth and never obstructed. These findings are very similar to those recognized in a histologic

section of rapidly-frozen rat lung at very low lung volume (See Reference 4 where the photograph is

reprinted).

Closing volume has been regarded in the textbook as an index of peripheral airway closure.

However, there have been no direct evidences which indicate the obstruction of peripheral airway

(= bronchi and bronchiole less than 2 mm in diameter) during phase four. The hypothesis that

closing volume in healthy subject be caused by alveolar mouth closure can explain consistently

several related phenomena as mentioned in Reference 4. By the way it is worthwhile to mention that

a few closed polygons in the lower right image in Fig.6-7 are cross sections of not closed but open

alveoli. In general, it is impossible to distinguish whether a polyhedron is closed or open by its cross

section. However, if there is a cluster of closed polygons in the cross section, the possibility of

existence of closed polyhedron is very high.

When the alveolar mouth is closed, the alveolar space is completely separated and the surface

tension of liquid film covering the alveolar wall acts so as to pull the wall inside. If the pulmonary

surfactant function is normal the surface tension is tiny and closed alveoli are stable. However, if the

pulmonary surfactant dysfunction occurs by some reason, closed alveoli would collapse due to high

surface tension of the liquid film, as shown in the right image in Fig.6-5. Note that the alveolar duct

itself does not collapse but contain air inside. This is a differential point from atelectasis at which no

air is contained in the lung parenchyma. This is the reason why the CT image of ARDS (acute

respiratory distress syndrome) or DAD (diffuse alveolar damage) indicates ground glass pattern. In

the Origami model, collapsed alveolar walls are irregularly folded up as if one single wall were

thickened. Furthermore, the open alveolar duct looks as if one single alveolus were surrounded by

thickened alveolar wall. However, it is a wrong interpretation from a point of view of 4D structure

of the alveolar system．

The present version of Lung4Cer does not contain models for alveolar collapse, although it

papered in Reference 3. Pathologic models will be added in Lung4Cer in the future.

35

Chapter 7 Estimation of ventilation distribution with various body posture models

Gravity effect to ventilation distribution has been argued for several decades. However, methods

for in vivo measurement of 3D ventilation distribution require special instruments, special drugs,

and/or extremely long time, and hence, those methods have not been in common clinical use.

Recently, high-speed X-ray CT and progress of image processing technique provides 3D ventilation

distribution map（Reference 5）. Here, gravity effect to ventilation distribution is explained by the use

of the five-lobar models under supine and prone postures.

Make these models as described in Chapter 4. Open two files by ParaView, divide the view

window, and simultaneously indicate two models (two more views are not necessary although there

are four views in Fig.7-1 for the sake of explanation. There is a tab “Surface” in the third row in

the main widow of ParaView. Click here, and change it into “Surface with Edges, then, a lot of edge

lines appear on the model surface. Model Type 3 represents shape of a parenchymal region at TLC

by a set of cubes whose side lengths are equal to the diameter of its air-supplying bronchi. The

cubic shape changes according to breathing motion.

Here, let the author explain briefly the algorithm of macroscopic lung deformation during

breathing in Ref.4. Lung deformation is formulated as a superposition of linear displacement

generated by the thoracic deformation and nonlinear gravity effect which acts along only gravity

direction, under the assumption of uniform elasticity of lung tissue. Since ventilation inhomogeneity

is caused by non-linear displacement, the algorithm reproduces only gravitational ventilation

inhomogeneity. The lung tissue is assumed to be expanded uniformly at TLC without gravitational

gradient. As the contraction force of respiratory muscles decreases during expiration from TLC, the

gravity effect becomes gradually obvious and lung tissue in dependent zone is more compressed than

that in nondependent zone. This means that expired air volume, in other words, ventilated air volume,

is larger in dependent zone than in nondependent zone. Thus, regional ventilation is equal to the

regional volume change of the parenchyma. In the lobar model by Lung4Cer, all cubes in the same

lobe have the same size at TLC. Therefore, changes in cube shape indicate regional ventilation

distribution. Other physiological ventilation inhomogeneities which may cause inter-regional

distortion or incoherent motion are not included in Lung4Cer.

36

Fig.7-1. Five-lobar models under supine and prone postures at TLC

Fig.7-2. Five-lobar models under supine and prone postures at FRC

37

References

１．Kitaoka H, Takaki R, and Suki B. A three-dimensional model of the human airway tree. J.

Appl. Physiol. 87: 2207-2217, 1999.

2. Kitaoka H, Tamura S, and Takaki R. A three-dimensional model of the human pulmonary acinus.

J. Appl. Phsiol. 88: 2260-2268, 2000.

3．Kitaoka H, Nieman GF, Fujino Y, Carney D, DiRocco J, Kawase I. A 4-dimensional model of the

alveolar structure. J Physiol. Sci. 57: 175-185, 2007.

4. Kitaoka H, Kawase I. A novel interpretation of closing volume based on single-breath nitrogen

washout curve simulation. J Physiol. Sci. 57: 367-376, 2007.

5. Kitaoka H, Kijima T, Mihara N, Tomiyama N, Jokoh T, Nakamura H, Kawase I. 3D-3pirogram: a

combinatory system of 3D-CT image analysis and computational mechanics for assessing the

pulmonary function. I nternational Journal of Compter-Assisted Radiology and Surgery: 1, 22-24,

2006.