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Changes resulting from the publishing process, such as peer review, editing, corrections,
structural formatting, and other quality control mechanisms may not be reflected in this
document. Changes may have been made to this work since it was submitted for
publication. A definitive version was subsequently published in Journal of Medical
Ultrasound, Volume 21, Issue 2 , Pages 81-91, (June 2013) doi:10.1016/j.jmu.2013.04.004
TITLE PAGE
Original Article
MSI-UniKL Kedah, 09000 Kulim, Kedah & Dept. of Medical Physics, Faculty of Physical
Sciences, Universiti Sains Malaysia, 11800 USM, Pulau Pinang, Malaysia.
(Mail add: 449, Tmn Perdana, Jln Toh Kee Kah, 71000 P.Dickson, N. Sembilan, Malaysia.)
(e-mail: jojab77@yahoo.com) (Tel: +60174194717)
Dept. of Medical Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia. (e-mail:
msj@usm.my).
MAIN TEXT
1. Introduction
1.1 The Ultrasound Induced Lung Haemorrhage
The ultrasound (US) induced lung damage has been observed in animal experimentations at
the exposure levels of diagnostic US imaging. The first reported US induced lung
haemorrhage occurred in adult mouse at exposure values of; pressure threshold, P = 1 MPa,
frequency, f = 2 MHz, pulse duration, PD = 10 s, pulse repetition frequency, PRF = 100 Hz
and exposure duration, ED = 3 min [1]. Since then, the US induced lung haemorrhage has
been observed in other animals such as rats, rabbits, monkeys and pigs at similar exposure
conditions [2-5].
There are no mathematical calculations or theoretical models that support or disprove the
hypothetical alveolar resonance mechanism in producing the US induced lung haemorrhage
[6]. A thorough survey of literature gave no indication that the alveolar resonance mechanism
hypothesis has been experimentally tested or studied in any way.
The elastic tension of the alveolar wall depends on the strain caused by normal tidal
breathing. During recruitment and de-recruitment of the alveolus, the Total Lung Capacity
(TLC) varies from 0% to 20%. However the linear strain is about zero, because the alveolar
walls are not stretched but are unfolded. The normal tidal breathing is from 20% TLC
onwards (after recruitment) and the alveolus is stretched slightly, resulting in linear strain of 0
0.05 [13].
Belete [14] states that cell wounding in parenchyma tissues occurs significantly when linear
strain is 0.08. Vlahakis & Hubmayr [15] also summarized that an excess linear strain
percentage of 2% to 3% (above the linear strain of tidal breath) forms fractures in the plasma
membrane of the alveolar epithelial cells. Thus, this total linear strain of 0.08 that will damage
elements within the alveolar wall and probably cause haemorrhage, will be called here as the
yield linear strain.
ii.
To validate the developed vibration model of the alveolar structure for studying
the US induced lung haemorrhage and to further provide predictions and
precautionary recommendation.
ii) The linear theory of vibration is assumed to be applicable to the alveolar wall.
The alveolar wall is a continuous material governed by partial differential equations (PDE),
which depend on time and spatial coordinates. If an alveolar wall facet vibrates transversely
with small amplitudes (compared to its dimension) and the elasticity of the alveolar wall
provides linear restoring force while damping is also linear, then the vibration is considered as
linear [18].
(1)
The transverse wave velocity in membrane is denoted as cT. The equation of resonant
frequency of the circular membrane model is obtained when the wave equation is solved,
using the separation of variables method together with boundary condition specifications.
The resonant frequency at n-th mode of the clamped circular membrane model is [20];
f n = c T r o -1 ( n )
(2)
The frequency mode is denoted as n and ro is radius of membrane model. Meanwhile, the
transverse wave velocity on the membrane with tension (T) is;
c T = (T / )
with area density () being related to density () and thickness (d) by, = d
(3)
(4)
= E bd
(5)
By inserting E.4 & E.5 into E.3, the transverse wave velocity of the membrane model is;
c T = (T / )
= [( E b d ) /( d )]
cT = ( E b / )
(6)
An indirect calculation was conducted to obtain the equation of Youngs modulus for the
membrane model. The longitudinal speed (cL) of sound waves is dependent on the bulk
modulus (K) and density () of the material of propagation.
cL = ( K / )
(7)
(8)
The equation of Youngs modulus can then be determined by utilizing its relationship with the
bulk modulus. The Poisson ratio of material is denoted as u.
E = 3 K (1 2 u )
E = 3( c L2 )( 1 2 u )
(9)
(10)
A relationship between transverse wave velocity and the areal strains of tidal breath for the
circular membrane model of the alveolar wall facet was derived by applying E.10 into E.6;
cT = ( E b / )
= ([ 3 ( c L2 )( 1 2 u )] b / )
c T = ( 3 6 u ) c L b
(11)
Z =
( F 0 / m eq )
[( o w / Q ) 2 + ( o 2 w 2 ) 2 ]
(12)
with F0 as peak force and w as the angular frequency of the applied driving wave. The
fundamental angular frequency of the membrane model is denoted as o while its equivalent
mass is meq. The equivalent mass depends on the shape of the membrane vibration at
fundamental mode. The quality (Q) factor of the vibrating system is denoted as Q.
Here in this study, the applied driving waves represent the US waves incident on the alveolar
wall surface. If the US wavelength is larger than the dimension of alveolar wall surface area,
it can be considered that the force imparted to the surface is uniformly distributed. Thus, the
peak rarefaction pressure (Po) of US waves applied to a membrane surface area (A) is related
to the peak rarefaction force (Fo) by; P o = F o / A .
( P 0 / eq )
[( o w / Q ) 2 + ( o 2 w 2 ) 2 ]
(13)
(14)
Maximum amplitude, Zmax is the resonant amplitude and it occurs when the frequency of
driving waves approaches the fundamental frequency of membrane model. Thus when w ~
o, the E.13 becomes;
Z max =
P0
o eq
2
(15)
i) The Q-factor
The dominant Q-factors of high frequency micro-resonators existing in non-vacuum medium
are Q-factor of surrounding medium damping (Qmedium) and Q-factor of membranes support
loss (Qsupport) [23]. Hence the total Q-factor (Q) is;
1 / Q = 1 / Q medium + 1 / Q support
(16)
However, the Qmedium factor value is negligible when it is much larger than Qsupport (Appendix
C). Thus, the Q-factor total can be approximated to be equal to Qsupport. The Q-factor of the
vibrating circular membrane is (Appendix D),
Q = Q support = 0 . 64 ( r o / d )
(17)
(18)
The density is denoted as while d is thickness and A is surface area. Thus by using E.14 the
equivalent area density for the vibrating circular membrane at fundamental frequency is,
eq = m eq / A = 0 . 613 dA / A
eq = 0 . 613 d
(19)
= ( A1 A 0 ) / A 0
(20)
The membranes shape while at rest is a flat circular disc. Thus, the initial area is,
A0 = ro 2
(21)
The circular membranes shape while vibrating at fundamental frequency mode is a circular
based dome. If the height, Z is smaller than the dimension of the membrane, then the shape
can be simplified into a spherical cap as an approximation (Fig. 1). Thus the deformed area is;
A1 = ( r o 2 + Z 2 )
(22)
The areal strain at resonance (r) for deformed circular membrane at resonant amplitude (Zmax)
in the fundamental vibration mode is calculated by applying E.21 & E.22 into E.20.
= ( A1 A 0 ) / A 0
r =
( ( r o 2 + Z max 2 )) ( r o 2 )
( r o 2 )
(23)
(24)
The minimum peak pressure of driving waves which will result in enough resonant amplitude
to achieve the yield areal strain and damage the circular membrane model of alveolar wall
facet, will be called here as the threshold pressure. This represents the threshold pressure of
US waves that experimentally produce detectable lesions of US induced lung haemorrhage in
animals.
Meanwhile the alveolar wall (soft tissue) density is 1026 1068 kg / m3 [25]. This range can
be denoted in interval notation as {1026, 1068} kg / m3, to be used in calculations.
The threshold pressure equation for producing damage in the circular membrane model of the
alveolar wall facet is derived by substituting E.17, 19, 23 & 24 and alveolar density () range
into E.15;
Z max =
P0
o eq
2
P0 = o 2eqQ 1 Z max
= ( 2f 1 ) 2 ( 0.613 d )( 0.64 ro / d ) 1 [ ror ]
= {38796.058 , 40384.201} f 1 2 d 2 [r ]
P0 = 38796 .058( f 1 d ) 2 [( 0.1664 b )]
(25)
Only the lower limit is retained as the threshold pressure equation should be concerning the
minimum pressure possible in inducing damage. The threshold pressure formulas for specific
mammals are obtained by inserting alveolar dimension values (Table 1) into E.25.
2 =
(Oi Si ) 2
Si
i =1
p
(26)
where p is number of sets of data, O is the observed empirical data and S is the simulated
theoretical data [27].
The calculated chi-square value is then compared with the critical chi-square value at
significance of 0.05. If it is lower, then this implies that the differences of values are
attributed to chance fluctuations. Therefore the null hypothesis is retained and not rejected.
The experimental data is consistent with the theory (hypothesis) and the theory is acceptable
with 95% probability or confidence. Secondly, experiments that can test and prove the theory
incorrect should be constructed. This is to provide a method of disproving the theory. Finally,
the theory must give predictions of the real world phenomena that can be confirmed in future.
Confirmed predictions will provide support concerning the validity of the theory.
3. Results
3.1 Determination of Transverse Wave Velocity
The Poissons ratio for the alveolar wall (soft tissues) ranges from 0.35 0.45 [37]. This
range can be denoted in interval notation as {0.35, 0.45} to be used in calculations. The
longitudinal speed of sound wave (cL) in alveolar wall (soft tissues) ranges from {1490, 1610}
m/s at 37oC body temperature [25]. Whenever calculations involve ranges, the interval
arithmetic should be used (Appendix F). The substituting of alveolar walls characteristic
interval values into E.11 results in;
c T = ( 3 6 u ) c L b
= ( 3 6{0.35, 0.45} ) {1490, 1610} b
cT = {816.11, 1527.38}b
(27)
The areal strain of tidal breath can range from 0 0.1025 (Appendix F). Thus, the transverse
wave velocity is determined to range from 0 m/s at 0.00 areal strain to 489.00 m/s at 0.1025
areal strain during normal tidal breath.
f1 = {306.04, 572.77} b r o -1 Hz
(28)
The fundamental frequency formulas for specific mammals are obtained by inserting alveolar
dimension values from Table 1 into E.28 (Table 2). The other higher modes that can also
cause resonances are ignored. This is because the vibration analysis at fundamental frequency
and its effects provide the benchmark for structural integrity and failure [38].
4. Discussion
The thickness and size of the alveolar wall varies in species. According to this study, the
threshold pressure for US induced lung haemorrhage depends primarily on the alveolar wall
thickness while the resonant frequency of alveolar structure depends primarily on the length
dimension of the alveolar wall (Table 2). ECMUS [6] supports these findings by stating that
US induced lung haemorrhage depends on the species of animal.
This study shows that the varying tidal breath changes the resonant frequency of the alveolar
wall, which then affects the US induced lung haemorrhage. This agrees with the experimental
result of OBrien [40], where the breathing pattern in mice is seen to alter the results of US
induced lung haemorrhage. This study also demonstrates that the resonance frequencies of the
alveolar wall are within the range of diagnostic US. Thus the alveolus structure is not too
large to oscillate in regard of the diagnostic US frequency range as stated by ter Haar [11].
The resonant frequency of the alveolar wall (as according to the circular membrane model)
depends indirectly to the areal strain of tidal breath. When areal strain of tidal breath is 0.00
(at < 20% TLC); the resonant frequency will be non-existent and the alveolar wall will not
resonate or be affected by US waves. Thus, this theoretical study predicts that it is possible to
avoid the US induced lung haemorrhage by keeping the TLC < 20%. Nonetheless, the 20%
TLC is actually the residual volume (RV) of the end of maximal expiration [41], and so
maintaining it during US exposure will not be an easy task.
This study also predicts that if diagnostic US imaging for humans is kept above 1.55 MHz,
the US induced lung haemorrhage will not occur when MI < 1.9 (Fig. 4). As the US
frequencies for diagnostic imaging of abdominal and thoracic regions are > 2.5 MHz while
for pneumothorax evaluation is > 2 MHz [42, 43], the risk of US induced lung haemorrhage
should be non-existent for human during medical US imaging. There is no evidence of US
induced lung haemorrhage occurring in human, mainly due to the lack of experimental studies
on humans. Only a single study reports that US induced lung haemorrhage do not occur in
humans at 3.5 MHz minimum frequency while maximum pressure is 2.4 MPa [44].
The comparison tests show that the circular membrane model of the alveolar resonance to be
acceptable with 95% probability. The model is found to be valid and it describes the US
induced lung haemorrhage adequately. Therefore, the alveolar resonance should be seriously
considered as a mechanism of the US induced lung haemorrhage based on the theoretical
validation of this circular membrane model.
Experiments that can test the invalidity of this theoretical study should be conducted in future.
If invalidation test results are negative, then it will strengthen the theory of alveolar resonance
as the mechanism of US induced lung haemorrhage and that the circular membrane model of
alveolar wall facet adequately describes it. If the invalidation test results are positive, then the
circular membrane model is to be deemed not suitable to study the alveolar resonance
mechanism or the alveolar resonance is an unlikely mechanism of the US induced lung
haemorrhage.
Several assumptions and approximations are made during modelling process; hence their
usefulness and limitations should be discussed. The accuracy of this study and its results are
limited by those assumptions and approximations. The assumption of the alveolar wall being
linearly elastic had simplified the derivations of the equations in this study. Nonlinear
elasticity treatment would have been highly accurate but very complex. Nevertheless, at small
deformations, the linear elasticity is applicable with certain reduced accuracy. The alveolar
wall is assumed isotropic; however it is too small for direct stress-strain measurement to be
verified [17].
The assumption of the alveolar wall facet undergoing linear vibration has also simplified the
derivations of the equations in this study. Throughout the study, the deflections can be seen
smaller than the alveolar dimension (radius) by analyzing the E.23. Thus it is acceptable to
apply linear vibration for simplicity. The alveolar wall is further assumed as membranes
instead as plates. As membranes, it is allowed to have deflection larger than its thickness
which will produce enough yield areal strain for alveolar wall damage. This do not occur in
thin plates as deflections must be smaller than its thickness.
The assumption of the alveolar facet having fixed boundary narrows down the scope of this
study by ignoring other vibrating states such as un-clamped or simply-supported. The facet of
the alveolar wall is also assumed as circular. The simplification of the geometrical shape
allows simplified derivation of equations throughout this study. The alveolar wall facets are
actually shaped as irregular pentagon, hence the calculations and results in this study should
differ slightly from reality.
APPENDICES
Appendix A: Stiffness calculation for human alveolar wall
The
calculation
utilizes
this
equation
of
membrane/plate
stiffness;
De = Ed 3 / 12(1 u 2 )
The stiffness of the membrane or plate depends on the Youngs modulus (E),
thickness (d) and Poisson ratio (u). The human alveolar wall minimum thickness is 10
x 10-6 m (Table 1).
The Youngs modulus value of the alveolar wall can be determined from its density,
= {1026, 1068} kg / m3 [25]; its longitudinal wave speed, cL = {1490, 1610}[25]; and
its Poissons ratio, u = {0.35, 0.45}[37].
E = 3( c L 2 )(1 2u )
= 3({1026, 1068}{1490 , 1610} 2 )(1 2{0.35, 0.45} )
= {0.68, 2.49} x 10 9 Pa
= {6.46, 26.01}x10 - 6 Nm
U stretch = k stretch ( A1 A0 ) 2 / A0 ,
where the modulus, kstretch is the proportionality constant between a quadratic
deviation of the area from its unstressed state and the respective energy. The
additional A0-1 is a physics convention [45].
The tension, under which the membrane is subjected to, is the derivative of energy
with respect to area:
T = U stretch / A1
= k stretch ( A1 A0 ) / A0
= k stretch
= Ed
kstretch.
with as the acoustic impendence of air = 420 Pa. s. m [23]. The density of the
alveolar wall is {1026, 1068} kg / m3 [25] while the human alveolar wall minimum
thickness is 10 x 10-6 m (Table 1).
Thus at 1 MHz frequency, the Q-factor of air medium damping for human alveolar
wall is;
Q medium = o / = 2 (1 x 10 6 )({1026, 1068})(10 x 10 6 ) / 420 = {1527, 1663}
In a loss factor study of eccentric loading of circular plate, Gupta & Nigam [46] gives
a loss factor value of 50.91 x 105 when loading is near the circular edge (0.96r) at
fundamental mode for a circular plate which radius and thickness is 0.6 m and 0.003
m respectively. This loading about the edge is assumed to deter the edge from
moving, hence representing the clamped resonator state. Thus;
Qsupport = J (r / d )3
50.91 x 105 = J (0.6 / 0.003)3
J = 0.64
When the support is as thin as the resonator, the cubic term degenerates to linearity
[47]. This is because the support is not rigid and isolated anymore against in-plane
bending of the resonator [48]. Thus;
Q support = J ( r / d ) = 0 .64 ( r / d )
= ( L1 L 0 ) / L 0
= ( A1 A 0 ) / A 0
The initial length and area are L0 and A0 respectively while the length and area after
deformation are L1 and A1 respectively. The relation between areal strain and linear
strain can be obtained starting with the stretch ratio equation. The stretch ratio is [17];
= ( L 1 / L 0 ) = ( A1 / A 0 )
Thus the relationship between linear strain and areal strain can be derived as;
= ( A1 / A 0 )
= ( + 1)
1 = ( + 1) 1
= ( + 1) 1
During normal tidal breathing, the linear strain changes [13] between 0 < < 0.05
and so the areal strain changes;
0 0.05
0 [( + 1) 1] 0.05
0 0.1025
The wounding and breaks in cells in the plasma membrane of the alveolar epithelial
cells occurs at about a linear strain of = 0.08 [14, 15]. Thus;
= 0.08
[( + 1) 1] = 0.08
= 0.1664
d, then [49];
x + y = {a + c, b + d }
x + y = {a d , b c}
x + y = {min( ac , ad , bc , bd ), max( ac , ad , bc , bd )}
x + y = {min( a / c, a / d , b / c, b / d ), max( a / c, a / d , b / c, b / d )}
DECLARATIONS
Competing interests: None declared.
Funding: This work was supported in part by the USM PGRS Grant and the UniKL
search, theoretical modeling and analysis, manuscript preparation and editing. MSJ
played the supervisory role in this study
Acknowledgements:. D. John Jabaraj give praises to his Lord and Redeemer, the One
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Table 1: The alveolar dimensions for various adult mammals and humans.
Alveolar
Property
Adult
Mouse
Adult
Rat
Adult
Rabbit
Adult
Dog
Adult
Pig
Adult
Cat
Adult
Monkey
Adult
Human
Ratio of mean
alveolar
diameter[28]
2.3
2.5
2.5
Alveolar radius
range
(m)[29]
{20, 40}
{20, 40}
{40, 80}
{40, 80}
{46, 92}
{50, 100}
{50, 100}
{100, 200}
4.5
10
Minimum
alveolar wall
thickness
(m)[30-36]
Table 2: The formulas of fundamental frequency and threshold pressure of the circular
membrane model of alveolar resonance for various adult mammals and human.
Mammalian
species
Fundamental frequency
(MHz)
Threshold pressure
(MPa)
Adult Mouse
{7.651, 28.639} b
0.349 x 10 12 f 1 2 (0.1664 b )
Adult Rat
{7.651, 28.639} b
0.621 x 10 12 f 1 2 (0.1664 b )
Adult Rabbit
{3.826, 14.319} b
0.621 x 10 12 f 1 2 (0.1664 b )
Adult Dog
{3.826, 14.319} b
0.621 x 10 12 f 1 2 (0.1664 b )
Adult Pig
{3.327, 12.452} b
0.786 x 10 12 f 1 2 ( 0.1664 b )
Adult Cat
{3.060, 11.455} b
0.621 x 10 12 f 1 2 (0.1664 b )
Adult Monkey
{3.060, 11.455} b
0.970 x 10 12 f 1 2 ( 0.1664 b )
Adult Human
{1.530, 5.728} b
3.880 x 10 12 f 1 2 ( 0.1664 b )
Adult Rat
Frequency (MHz)
2.8
5.6
3.7
1.1
1.2
2.3
3.5
3.7
1.2
2.3
2.3
2.3
2.8
3.5
3.4
2.0
2.0
Figure Legends
Fig. 1: a) circular membrane under deformation at fundamental frequency mode.
b) spherical cap as an approximation.
Fig. 2: The threshold pressure vs. fundamental frequency curves of the circular
membrane model of adult mouse alveolar wall together with the plotted past
experimental data of ultrasound induced lung haemorrhage in the adult mouse. An
experimental data point (2.8, 3.6) is clearly an outlier and hence is omitted in the chisquare calculation. Chi-square (2) of data vs. circular membrane model is calculated
as 7.89, while the critical 2 (0.05 sig.) is 16.919.
Fig. 3: The threshold pressure vs. fundamental frequency curves of the circular
membrane model of adult rat alveolar wall together with the plotted past experimental
data of ultrasound induced lung haemorrhage in the adult rat. Chi-square (2) of data
vs. circular membrane models is calculated as 7.09, while the critical 2 (0.05 sig.) is
11.070.
Fig. 4: The threshold pressure vs. fundamental frequency curve of the circular
membrane model of adult human alveolar wall together with the plotted MI = 1.9
limit line.