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Journal of Biomechanics
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Age- and region-related changes in the biomechanical properties

and composition of the human ureter
Dimitrios P. Sokolis a,n, Despoina C. Petsepe b, Stavroula A. Papadodima c,
Stavros K. Kourkoulis b
a
Laboratory of Biomechanics, Center of Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of
Athens, Athens, Greece
b
Department of Mechanics, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Athens, Greece
c
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Athens, Greece

art ic l e i nf o a b s t r a c t

Article history: The ureter has been largely overlooked heretofore in the study of the biomechanics of soft biological tissues,
Accepted 28 November 2016 although there has been significant motivation to use its biomechanical properties as inputs to mathematical
models of ureteral function. Herein, we used histological analysis for quantification of collagen contents and
Keywords: thickness/area of ureteral layers, with concomitant geometrical analysis of zero-stress and no-load states, and
Human ureter inflation/extension testing to biomechanically characterize with the Fung-type model the ureters from
Inflation/extension cadavers. The effects of age and gender on the regional distribution of those properties were examined. Tissue
Fung-type model properties did not differ (p40.05) between the left and right ureter. Regional heterogeneity was established
Collagen that was profoundly age-related but seldom gender-related, based on the following evidence: 1) In younger
Opening angle
subjects, the axial stress-circumferential strain curves of upper ureter were shifted to smaller stresses and
Residual strain distribution
model parameter a2 representing axial stiffness was smallest (po0.05), i.e. upper ureter was the least stiff
Aging
Gender region axially; 2) upper ureter underwent axial stiffening with advanced age, evidenced by the increasing
(po0.05) parameter a2 , and the stress-strain curves were uniformly exhibited along the ureter, evidenced by
the non-varying (p40.05) parameters C; a1 ; a2 ; and a4 ; 3) aging raised (po0.05) the collagen content of
upper ureter to favor a near-uniform regional distribution; 4) wall thickness increased with age, unlike the
opening angle and residual strains, reflecting the thickening of outer (muscular) vs. inner (mucosal) layers in
aged subjects, with significant differences (po0.05) in some regions; and 5) gender affected little (p40.05)
the opening angle and morphometry of no-load and zero-stress states.
& 2016 Elsevier Ltd. All rights reserved.

1. Introduction Additionally, the ureters may become mechanically obstructed by

The ureters are paired tubular structures that propel urine pro-
duced by the kidneys to the urinary bladder. They are about 25–
30 cm long and 2–3 mm in radius in the average adult, with their
upper half located in the abdomen and their lower half located in the
pelvic area. Histologically, they have thick walls consisting of the
mucosa, the fibrous lamina propria, the muscular layer facilitating
peristalsis, and externally of the adventitia (Wein et al., 2016). Sur-
prisingly, the ureters have been largely overlooked in the study of soft
tissue biomechanics, even though their conduit function is clearly
mechanical, and there is clinical motivation to study their bio-
mechanical properties given that they may be subject to iatrogenic or
other types of mechanical trauma, e.g. trauma caused by motor
vehicle accidents (Burks and Santucci, 2014; Morey et al., 2014).
n (Hansen and Gregersen, 1999). Our group (Sokolis, 2012, 2014)
Correspondence to: 35 Lefkados St, Athens 15354, Greece.
Fax: þ30 210 6597365.
E-mail address: DimitrisSokolis@ath.forthnet.gr (D.P. Sokolis).
numerous conditions, e.g. kidney stones, tumors, infection, blood
clots, in which case ureteral stents are inserted to keep them open,
thereby restoring urine flow to the bladder and allowing the kidney
to function normally (Smith et al., 2012).
Existing mathematical simulations of ureteral function in phy-
siologic/pathophysiologic states and after clinical treatments
(Waters et al., 2008; Vahidi et al., 2011; Vahidi and Fatouraee,
2012; Hosseini et al., 2013; Gómez-Blanco et al., 2016) are limited
by oversimplified assumptions regarding the biomechanical
properties and ignore residual strains, assumptions inconsistent
with data from other soft tissues (Gregersen, 2002). Pioneering
studies on animal ureters have been worthwhile to establish basic
principles, i.e. the exponentially-shaped and pseudoelastic defor-
mational response (Yin and Fung, 1971; Knudsen et al., 1994), and
regional differences in that response as well as in residual strains
recently reported inflation/extension data for rabbit ureter with
reference to a properly-determined zero-stress state, fulfilling

http://dx.doi.org/10.1016/j.jbiomech.2016.11.067
0021-9290/& 2016 Elsevier Ltd. All rights reserved.

Please cite this article as: Sokolis, D.P., et al., Age- and region-related changes in the biomechanical properties and composition of the
human ureter. Journal of Biomechanics (2016), http://dx.doi.org/10.1016/j.jbiomech.2016.11.067i
2 D.P. Sokolis et al. / Journal of Biomechanics ∎ (∎∎∎∎) ∎∎∎–∎∎∎

basic requirements for multiaxial characterization (Fung, 1993;
Humphrey, 2002), but it is questionable whether these data may
be extrapolated to the human condition. Because of the relative
scarcity of human data (Boone and Smith, 1955; Rassoli et al.,
2014), we initiated biomechanical studies in cadaveric tissue.
In this article, we report on the geometrical and biomechanical
characterization based on the Fung-type model, using histological
analysis as an adjunct study to assist with the quantification of layer-
specific wall thickness and collagen content. We examined the effects
of aging and gender on the regional distribution of those properties in
an attempt to address physiological implications.
2. Material and methods
2.1. Human ureteral tissue and specimen preparation
Both ureters were harvested within 24 h of death from twelve subjects whose
bodies had been preserved at 4 °C before autopsy at the Department of Forensic
Medicine and Toxicology, Athens University Medical School. Subjects with impor-
tant pathology of the urinary system were excluded; cadaveric data are listed in
Table S1 (Supplementary material). The research protocol was approved by the
Institutional Ethics Committee on Human Research. Informed consent was
obtained from the relatives. All ureters were excised as long tubes, including the
major calyces and a small part of the bladder, and stored in refrigerated saline
within 48 h of harvesting until experimentation. Adherent tissue was trimmed and
the ureters were subsequently divided into upper, middle, and lower regions
(Fig. 1). Two tubular segments from each region, keeping clear of the renal pelvis
cylinder under intraluminal pressure and axial force is presented in standard
textbooks of biomechanics, e.g. (Humphrey, 2002).
First, the diameter-pressure and force-pressure data were regressed with
polynomial functions of 7th–9th order, as deemed appropriate, using MicroCal
s
Origin v8.5 (OriginLab Corp, Northampton, MA, USA), giving the same weight to
the entire pressure range and each axial stretch. Polynomials were fitted to 41000
data points and the regressions accepted when correlation coefficients reached
r40.95. All biomechanical parameter calculations were done on the regressed
data. The internal diameter di during inflation/extension was calculated from:
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
2 4A0
di ¼ de  ; ð1Þ
πλz
where de was the external diameter and A0 the cross-sectional area of the ureteral
wall at the zero-stress state. The circumferential and axial stretch ratios λθ and λz
were calculated relative to the zero-stress state as:
s l
λθ ¼ ; λz ¼ ; ð2Þ
S L
where S was the zero-stress state circumference of the ureter and s that at the no-
load or loaded states, and L and l were the ex situ and in situ lengths. The cir-
cumferential residual strains Eθ were determined at the internal and external wall
boundaries using the Green strain definition:
1 2 
Eθ ¼ λ 1 : ð3Þ
2 θ
Mean strain Eθ was calculated via mid-wall circumference at zero-stress and
loaded states, given by S ¼ ðSe þ Si Þ=2 and s ¼ ðse þ si Þ=2. Mean values of normal
stress components (2nd Piola–Kirchhoff definition) in the circumferential and axial
directions Sθ and Sz were determined using the following equations:
Pdi 4F þ P π di
2

and the bladder by 2 cm, were used in the experiments. Sθ ¼ ; Sz ¼  ; ð4Þ

λ θ ðd e  d i Þ
2
2πλz de  di
2 2 2

2.2. Biomechanical analysis
The biomechanical and histological methods are described elsewhere (Sokolis,
2012, 2014) as well as in Sections §S.2.1–S.2.3 (Supplementary material). Briefly, the
ureters were cannulated at 100–120% of their no-load length while immersed in
oxygenated (5% CO2 in O2) calcium-free Krebs solution (37 °C) with EGTA to abolish
muscle tone. Five (preconditioning) inflation-deflation loops between 0–50 mmHg
were performed on each length to minimize viscoelasticity and the inflating limb
from an additional loop was used for analysis. At completion of the inflation/
extension tests, two rings were removed from the midpoint of the ureteral seg-
ments to determine the zero-stress/no-load states.
The inflation/extension measurements and geometrical characteristics of zero-
stress/no-load states were used to calculate biomechanical parameters, assuming
that ureters are nonlinear, pseudo-elastic, anisotropic, incompressible, and homo-
geneous tubes subjected to finite deformation, whose radially cut-open state is
stress-free. The theoretical formulation for a thick-walled and residually-stressed
where P was intraluminal pressure and F axial force.
To generate model parameters for future computational simulations of the
ureter, the data from each specimen were characterized by the Fung-type model
(Fung et al., 1979):
C
W ¼ ðexp Q  1Þ; Q ¼ a1 E2θ þ a2 E2z þ 2a4 Eθ Ez ; ð5Þ
2
via parameters C (scaling factor) and a1 ; a2 ; and a4 , characterizing respectively tissue
stiffness in the circumferential and axial directions and their interaction, as in (Sokolis,
2012, 2014) for rabbit ureter. Note that this model is applicable to the 3D boundary
conditions of inflation/extension testing by direct enforcement of incompressibility
(Humphrey, 2002). Pressure-diameter-force data ( 4700) from 1–50 mmHg and all
except the 100% axial stretch (to avoid negative axial forces associated with bending)
were simultaneously fitted using a user-defined C-routine in MicroCal Origin and the
least-squares Levenberg–Marquardt algorithm. The parameters were restrained by
inequalities that ensured model convexivity. Optimization was repeated for various

Fig. 1. Left panel: preparation of testing specimens; fresh intact ureters from a 68 y old female after cleaning adherent tissues. The upper, middle, and lower thirds are
demarcated, from which straight tubular segments approximately 3 cm in length were removed for histology, inflation/extension testing, and determination of the no-load
and zero-stress states. Right panel: representative photos of closed and radially-cut rings from the upper, middle, and lower ureter of a younger (25 y old) and an older
subject (65 y old) at the no-load and zero-stress state. To enable calibration of dimensions, the rings were placed over millimeter paper.

Please cite this article as: Sokolis, D.P., et al., Age- and region-related changes in the biomechanical properties and composition of the
human ureter. Journal of Biomechanics (2016), http://dx.doi.org/10.1016/j.jbiomech.2016.11.067i
 D.P. Sokolis et al. / Journal of Biomechanics ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 3

initial parameter values ensuring global extrema. The fitting quality was estimated by
determination coefficient r 2 and root-mean-square error ε.
Results are presented as mean 7standard error (SE) unless otherwise stated.
The two-tailed paired t-test did not reveal significant differences between the left
and right ureters, so that data were pooled together; refer to Figs. S2 and S3, and
Table S4 (Supplementary material). The significance of differences for pooled data
from the left and right ureters was evaluated through analysis of variance (for
repeated measures when needed), considering age, gender, and region as inde-
pendent variables. Post-hoc multiple comparisons were performed with Tukey test.
Pearson's product-moment coefficient was used to detect correlations. A prob-
ability p-value o 0.05 was considered statistically significant. The software package
used was the SPSS v20.0 (SPSS Inc, Chicago, IL, USA).
3. Results
3.1. Geometrical and residual strain data
For each ureteral region, regression lines were fitted to the opening
angle, residual strain, and geometrical data against age (Figs. 2 and 3).
As disclosed by the regression equations in Fig. 2(A–C), the opening
angle decreased with age in the upper (males: r ¼  0:45; p ¼ 0:03;
females: r ¼ 0:36; p ¼ 0:08) and lower (females: r ¼  0:48; p ¼
0:02), but not in the middle ureter; the opening angles for the two
genders were similar throughout the ureter (Fig. 4A). Residual strains at
the internal surface displayed a tendency to be reduced with age, given
their significant correlations with the opening angle (Fig. 2D; males:
r ¼ 0:63; p ¼ 9 10  4 ; Fig. 2E; males: r ¼  0:49; p ¼ 0:02; Fig. 2F;
males: r ¼  0:39; p ¼ 0:05; females: r ¼  0:64; p ¼ 7 10  4 ). In
contrast, external residual strains remained constant with age in all
regions in males, as evidenced by their non-significant correlations
with the opening angle, while increasing in females (Fig. 2H:
r ¼ 0:39; p ¼ 0:05; Fig. 2I: r ¼ 0:46; p ¼ 0:02), so that their difference
decreased with age in all regions, with females again having similar
residual strain difference values as males (data not shown).
Wall thickness rose with age in the middle (Fig. 3B; females:
r ¼ 0:64; p ¼ 8  10  4 ) and lower ureter (Fig. 3C; females: r ¼ 0:41;
p ¼ 0:04), with greater values (p o0.05) in females only in the
middle ureter throughout the entire adult life (Figs. 3B and 4C).
The variation of internal diameter with age was non-significant
(data not shown). Thickness displayed strong tendency towards
reduction with increasing internal diameter in either gender
(Fig. 3D; males: r ¼ 0:58; p ¼ 0:003; Fig. 3E; males:r ¼  0:63; p
¼ 9  10  4 ; females: r ¼  0:68; p ¼ 3  10  4 ; Fig. 3F; males:
r ¼ 0:73; p ¼ 6  10  5 ; females: r ¼  0:40; p ¼ 0:05).
Opening angle exhibited a gradual decline along the ureter (Fig. 4A),
but differences attained significance (po0.05) only in females between

Fig. 2. Opening angle against age (A–C) and against residual strain at the internal (D–F) and external layers (G–I) for males (black line-circles) and females (red line-
triangles). Note that almost all linear regressions in panels A, C, D, and F for the upper and lower ureter were statistically significant unlike the middle ureter. Non-significant
were most regressions in panels G–I for the upper, middle, and lower ureter. (For interpretation of the references to color in this figure legend, the reader is referred to the
web version of this article.)

Please cite this article as: Sokolis, D.P., et al., Age- and region-related changes in the biomechanical properties and composition of the
human ureter. Journal of Biomechanics (2016), http://dx.doi.org/10.1016/j.jbiomech.2016.11.067i
4 D.P. Sokolis et al. / Journal of Biomechanics ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Fig. 3. Wall thickness against age (A–C) and inner diameter (D–F) for male (black line-circles) and female subjects (red line-triangles). The linear regressions against subject
age were always positive, but very weak and non-significant in the upper ureter (A), unlike the middle (B) and lower ureter (C). Negative and of high statistical significance
were most linear regressions against diameter in the upper (D), middle (E), and lower ureter (F).(For interpretation of the references to color in this figure legend, the reader
is referred to the web version of this article.)

Fig. 4. Opening angle at the zero-stress state (A), internal and external residual strains at the no-load state (B), wall thickness (C), as well as internal diameter (D) for the
upper, middle, and lower ureter of male (black fill) and female subjects (red fill). Error bars denote SE. Symbol * denotes p o0.05 against males, while symbols † and # denote
in turn p o 0.05 against upper and middle ureter. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

the upper and lower regions. The regional differences in residual strains (po0.05) compared to the lower ureter. There was also a significant
were minor (Fig. 4B). Wall thickness increased throughout the ureter in increase (po0.05) of internal diameter in the middle compared to the
males only (Fig. 4C); there were no differences between the upper and upper and lower ureter (Fig. 4D), without gender differences despite the
middle ureter, but these segments displayed a significant difference mere physical size being less in females.

Please cite this article as: Sokolis, D.P., et al., Age- and region-related changes in the biomechanical properties and composition of the
human ureter. Journal of Biomechanics (2016), http://dx.doi.org/10.1016/j.jbiomech.2016.11.067i
 D.P. Sokolis et al. / Journal of Biomechanics ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 5

Table 1
Parameters of the Fung-type model fitted to the pressure-diameter-force data of the upper, middle, and lower ureter from young and old subjects.

C (kPa) a1 (-) a2 (-) a4 (-) r 2 (-) ε (-)

YOUNG SUBJECTS Upper Ureter 1.584 7 0.602 0.748 7 0.114 18.7467 2.384 1.257 70.254 0.8007 0.018 0.395 7 0.014
Middle Ureter 0.918 70.378 1.384 7 0.190 32.3447 4.133† 3.3597 0.547† 0.803 7 0.019 0.396 7 0.022
Lower Ureter 1.256 7 0.542 1.239 7 0.217 33.646 7 3.925† 3.064 7 0.642† 0.809 7 0.017 0.371 70.019

OLD SUBJECTS Upper Ureter 1.639 7 0.876 1.4827 0.648 32.539 7 3.388§ 1.746 70.315 0.82470.016 0.363 7 0.018
Middle Ureter 1.2737 0.303 0.7367 0.100§ 29.5137 3.812 1.6247 0.281§ 0.803 7 0.016 0.390 7 0.016
Lower Ureter 1.462 7 0.827 1.3617 0.347 31.52474.213 2.2337 0.516 0.842 7 0.019 0.341 7 0.022

C, a1 , a2 , and a4 are material parameters, r 2 the determination coefficient, and ε the root-mean-square error of fitting. Symbol † denotes p o0.05 against upper ureter and
symbol § denotes p o0.05 against young subjects.

Fig. 5. External diameter (A–C) and axial force (D–F) against intraluminal pressure data at four axial stretch ratios for the upper, middle, and lower ureter of young (dark blue
fill) and old subjects (light blue fill). Error bars denote SE. Data are shown every 2 mmHg for clarity. (For interpretation of the references to color in this figure legend, the
reader is referred to the web version of this article.)

3.2. Inflation/extension data and characterization by Fung-type
model
The Fung-type model provided reasonably accurate fits to the
data with errors ε  0.35; refer to Figs. S4 and S5 (Supplementary
material) showing representative fits for the upper, middle, and
lower ureter from a young and an old subject, respectively. Table 1
lists mean material parameters according to age and region.
Individual parameter values and fitting quality are listed in Tables
S2–S4 (Supplementary material) according to age, gender, and left
vs. right ureter.
For both young and old ureters, there was minimal downward
displacement of the external diameter-intraluminal pressure (de –P)
curves and leftward displacement of the circumferential stress–strain
(Sθ  Eθ ) curves from the upper to lower segment for all axial stretch
ratios λz (Figs. 5 and 6). In young ureters, there was marked upward
displacement of the axial force-intraluminal pressure (F–P) and axial
stress–circumferential strain (Sz  Eθ ) curves along its length, con-
trasting the minor or even reverse variation in old ureters.
It is inferred from the higher values of parameters a2 and a4 in
the middle and lower than the upper ureter (p o0.05; Table 1),
characterizing tissue stiffness in the axial direction and
circumferential-axial stiffness interaction respectively, that young
ureters became stiffer with distance from the kidney mostly in the
axial and less in the circumferential direction. Axial stiffening of
the upper segment, as inferred by the higher a2 -values in old vs.
young ureters (p o0.05), led to non-varying parameters C; a1 ; a2 ;
and a4 (p 40.05) along the length of old ureters and to a uniformly
distributed axial and circumferential stiffness. Minor were the
differences in the Sθ  Eθ and Sz  Eθ curves among genders (data
not shown), substantiated by the non-significant differences in
parameters C, a1 ; a2 ; and a4 (p 4 0.05; Table S3). Note that the
absence of gender differences in the inflation/extension and the
morphometric data of Fig. 4 is valid, given the non-significant age
difference among the female (55 78 y, n¼ 6) and male (54 79 y,
n ¼6) subjects of our study population.
3.3. Histological data
Epithelium thickness decreased significantly (p o0.05) from
the upper to lower ureter in young subjects, while lamina propria,
muscle, and adventitia thickness remained invariant (p 40.05;
Fig. 7). The cross-sectional areas of all layers were similarly dis-
tributed along the ureter. This pattern was not observed in old
subjects, however. The thickness and area of epithelium and
lamina propria in old ureters were indistinguishable from or
smaller than those in young ureters, unlike the thickness and area

Please cite this article as: Sokolis, D.P., et al., Age- and region-related changes in the biomechanical properties and composition of the
human ureter. Journal of Biomechanics (2016), http://dx.doi.org/10.1016/j.jbiomech.2016.11.067i
6 D.P. Sokolis et al. / Journal of Biomechanics ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Fig. 6. Circumferential (A–C) and axial Cauchy stress (D–F) against circumferential strain data at four axial stretch ratios for the upper, middle, and lower ureter of young
(dark blue fill) and old subjects (light blue fill). Error bars denote SE. Data are shown every 2 mmHg for clarity. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)

Fig. 7. Left panel: histological sections of the upper, middle, and lower thirds of ureter from a 65 and a 25 y old male, stained with Sirius red for collagen identification. A
higher magnification (  10) of the rectangular region of interest is shown in the inset, positioned to the right of the low magnification (  2.5) of the upper ureter from the
young subject. Right panel: Thickness, area, and collagen content of the epithelium, lamina propria, muscle layer, and adventitia for the upper, middle, and lower ureter of
young (dark blue fill) and old subjects (light blue fill). Error bars denote SE. Symbol § denotes p o0.05 against young subjects, while symbol † denotes p o 0.05 against upper
ureter. The muscle layer was considerably thicker in old subjects unlike the epithelium and lamina propria. Note also that collagen content was considerably greater in old
subjects. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

of muscle that were significantly greater (p o0.05), identically so
in all regions.
Despite established regional differences in collagen area den-
sity of the lamina propria and muscle layer in young subjects, with
the area densities of middle and lower ureter being significantly
higher than those of the upper ureter (p o0.05; Fig. 7), there was
no demonstrable statistical difference (p 40.05) in old subjects.
Age caused excessive collagen deposition (p o0.05) in the muscle
layer especially of upper ureter and collagen density of the entire
wall became invariant throughout the ureter. The latter was
caused by the non-significant (p4 0.05) regional variations in area
density and cross-sectional area of the different layers in old

Please cite this article as: Sokolis, D.P., et al., Age- and region-related changes in the biomechanical properties and composition of the
human ureter. Journal of Biomechanics (2016), http://dx.doi.org/10.1016/j.jbiomech.2016.11.067i
 D.P. Sokolis et al. / Journal of Biomechanics ∎ (∎∎∎∎) ∎∎∎–∎∎∎
subjects. The small number of histological samples made it diffi-
cult to detect variations according to gender. Moderate-to-strong,
significant (p o0.05) correlations were found between collagen
area density of the entire wall and the Fung-type model para-
meters. Those with parameters a1 ; a2 ; and a4 were direct, unlike
those with parameter C (Fig. S6; Supplementary material).
4. Discussion
Despite the non-significant differences between the left and
right ureters (Figs. S2 and S3, and Table S4; Supplementary
material), regional differences were established by the displace-
ment of the stress–strain curves from the upper to lower ureter
(Fig. 6) and the associated variation of the Fung-type model
parameters (Table 1). The differing distribution of properties may
account for the apparent functional differences. The stiffness
increase distally may constitute an adaptation of the ureter to its
functional demands, namely storage of urine proximally where it
is wider and distensible, and transfer of urine distally where it is
more resistant by being narrower and stiffer. Albeit less striking,
this would be comparable to observations in pigs and rabbits.
Importantly, given that the porcine model is a close analogue to
humans, our data complement earlier studies in youngling pigs
(Knudsen et al., 1994), and we hypothesize that older pigs have
ureteral properties more similar to humans. It would generally be
advantageous that a good animal model be established for the
ureter, because there may be instances when animal studies will
be the only alternative, e.g. when biomedical engineers are inter-
ested in evaluating the efficacy of a medical device.
A study on the alterations in biomechanical properties with age
was made, because we were not aware of prior reports on this issue. It
is generally thought that the structure of ureter does not change
much with age, unlike the bladder and other components of the
urinary tract (Smith, 2010), but this study suggests otherwise. Studies
examining the effects of age on biomechanical properties of soft tis-
sues suggest that the tissue becomes biomechanically less efficient
with age; refer for instance to the review article by Greenwald (2007)
for vascular tissues. Based on the present results, the same can be said
about ureter. Particularly, the upper ureter underwent stiffening with
increasing age, as evidenced by the increased Fung-type model
parameters (Table 1), displaying an impaired capacity for expansion in
response to distending pressure compared to younger subjects and
biomechanical properties were uniformly exhibited throughout the
ureter length (Figs. 5 and 6).
Differences in stiffness with aging and/or region are mirroring
differences in collagen content (Fig. S6; Supplementary material)
or a decrease of its integrity; see for instance our report on vas-
cular tissues (Sokolis et al., 2006). While confirming our assess-
ment on rabbit ureter (Sokolis, 2014), the present collagen data
(Fig. 7) demonstrate strong support for the regional heterogeneity
in biomechanical properties, emphasizing that this is an intrinsic
characteristic of the healthy young ureter. Early studies examined
the structural properties of normal ureter and changes in the
dilated ureter mostly in childhood (Hanna et al., 1976a, 1976b;
Pagano et al., 1976; Lee et al., 1992; Neves et al., 2014), but no
histological evidence has existed as regards the effects of aging.
Not unexpectedly, aging led to increased collagen content proxi-
mally, resulting in a more homogeneous distribution of bio-
mechanical properties. The increased stiffness of aged upper
ureteral segments reflects well the greater amount of collagen but
increase in fiber cross-linking should not be precluded. Note also
that collagen evaluation from histological methods is at best semi-
quantitative and thus debatable. Regardless, there may be
numerous reasons for the increased collagen deposition with
aging in the ureter, e.g. biomechanical, vascular, bacterial injuries,
Please cite this article as: Sokolis, D.P., et al., Age- and region-related changes in the biomechanical properties and composition of the
human ureter. Journal of Biomechanics (2016), http://dx.doi.org/10.1016/j.jbiomech.2016.11.067i
7
but these were outside the scope of this study and most likely
constitute permanent irreversible changes. Unfortunately, the
small specimen number reserved for histology may have not
allowed distinctions among genders. A lack of gender differences
is, however, compatible with the inflation/extension and mor-
phometric data, and the model parameters.
Our geometrical data disclosed that the opening angles of all
ureteral regions were lower in older subjects, which is a reflection
of the reduced amounts of the circumferential residual strains
existing in the ureteral wall (Figs. 1 and 2) and strongly suggest
that old ureters may be in less need to minimize the stress con-
centrations experienced in their inner wall; note also that the
thickness of ureters rose steadily with age (Fig. 3). Gender did not
appear to affect the opening angle and geometrical characteristics
of the no-load and zero-stress states, and how these vary with
aging. Our histological quantifications in Fig. 7 lend support to
Fung's hypothesis of non-uniform remodeling (Fung, 1991), i.e. of
the unequal growth of the different wall layers with aging. Pre-
sumably, the reduced opening angle is associated with the greater
outer (muscle) layer area and thickness as well as with the smaller
inner (mucosa) layer area and thickness in old compared to
younger subjects, and markedly contrasts earlier data for vascular
tissues that exhibit a diverse structure; refer for instance to our
recent study on human aorta, where we described the reverse
trend, i.e. an increasing opening angle with aging, and the studies
cited therein (Sokolis, 2015). To our best knowledge, these are the
first opening angle and residual strain measurements reported for
the human ureter, but recently Zhao and Gregersen (2015a, 2015b)
observed a progressive decline with age in their opening angle
data for the murine esophagus and small intestine that is largely
consistent with our findings, given that tissues from the gastro-
intestinal and urinary tracts share a comparable structure. In the
absence of previous corroboration, the present data provide novel
histological insight into the zero-stress state remodeling of ureter
with aging that may also apply to esophageal and small intestinal
tissues.
Our group (Sokolis, 2014) previously measured opening angles
and morphometric measures of no-load and zero-stress states at
three ureteral positions in rabbits and similarly to this study found
the highest opening angle in the upper ureter (Fig. 4). Hansen and
Gregersen (1999) on the other hand displayed a more complex
distribution, namely 90 deg at the ureteropelvic junction and
30 deg at the most proximal and distal regions of the porcine
ureter, affording a more precise anatomical mapping compared to
our recent and present assessments.
Further studies addressing limitations of our experimental
methods and analysis would be of interest. The present results
were obtained using the intact ureter and we have hypothesized in
our biomechanical analysis that its wall is materially homo-
geneous, despite the varying composition of the mucosa, muscle,
and adventitia. These layers possess distinct biomechanical prop-
erties, as has been shown by our group e.g. for the esophagus
(Stavropoulou et al., 2009, 2012). This limitation emphasizes that a
more detailed (layer-specific) ureter model may be warranted, and
microdissection techniques would be necessary to define the
biomechanical contribution from the different wall layers. It is also
to be noted that understanding of the active properties of the
human ureters is needed to quantitatively analyze ureteral peri-
stalsis. Early studies examined the active length-tension (Yin and
Fung, 1971; Weiss et al., 1972) and force-velocity relationships
(Zupkas and Fung, 1985), but only in the axial direction of the
dog's and cat's ureter. The anisotropic nature of ureter disclosed
herein mandates that the multiaxial properties of tissue be
explored in the active state; still an important issue. Furthermore,
the living ureter is not accessible for testing, so the sole practical
source for whole-length normal ureter was autopsy material. The
8 D.P. Sokolis et al. / Journal of Biomechanics ∎ (∎∎∎∎) ∎∎∎–∎∎∎
effect of time since death and mode/duration of storage are critical
issues, but inconsistencies in storage were avoided by utilizing
similar procedures for all specimens. To address a possibly dete-
riorating effect caused by the time elapsed between death and
experimentation, correlations were sought between this time
period and the opening angle and Fung-type parameters that were
non-significant (Fig. S7; Supplementary material). Consequently,
apart from the first 24 h after death for which any changes could
not be accounted for, no changes occurred during the ensuing 48-
h-period. The cutoff age that divided the study population in
younger and older age groups was fifty years, although it would be
more appropriate to consider young, middle-aged, and older
groups, had we examined a larger number of subjects. None-
theless, the specimen number in all analyses was considerable, so
that the inferences from statistical analyses would likely be
unaffected. Finally, conclusions pertaining to the effects of the
cause of death and risk factors summarized in Table S1 (Supple-
mentary material) on the histomechanical properties would
request a significantly greater number of subjects than those used
herein.
Despite these drawbacks, it is hoped that the presently-reported
biomechanical properties and dimensions may be used as the base-
line to study the effects of disease, e.g. vesicoureteral reflux,
obstruction, severe diuresis, or infection, and as inputs to mathema-
tical models of the human ureter to predict the spatial distribution of
wall stresses in physiologic and disease states, and during clinical
interventions.
Conflict of interest
The authors declare no competing interests.
Appendix A. Supporting information
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.jbiomech.2016.11.067.
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