Mechanical Properties of Human Hepatic Tissues To Develop Liver Mimicking Phantoms For Medical Applications

Biomechanics and Modeling in Mechanobiology (2024) 23:373–396
https://doi.org/10.1007/s10237-023-01785-4
REVIEW PAPER
Mechanical properties of human hepatic tissues to develop

liver‑mimicking phantoms for medical applications
Aicha S. Lemine1,2 · Zubair Ahmad2,3 · Noora J. Al‑Thani2 · Anwarul Hasan1 · Jolly Bhadra2,3
Received: 8 May 2023 / Accepted: 17 October 2023 / Published online: 10 December 2023
© The Author(s) 2023
Abstract
Using liver phantoms for mimicking human tissue in clinical training, disease diagnosis, and treatment planning is a com-
mon practice. The fabrication material of the liver phantom should exhibit mechanical properties similar to those of the real
liver organ in the human body. This tissue-equivalent material is essential for qualitative and quantitative investigation of the
liver mechanisms in producing nutrients, excretion of waste metabolites, and tissue deformity at mechanical stimulus. This
paper reviews the mechanical properties of human hepatic tissues to develop liver-mimicking phantoms. These properties
include viscosity, elasticity, acoustic impedance, sound speed, and attenuation. The advantages and disadvantages of the
most common fabrication materials for developing liver tissue-mimicking phantoms are also highlighted. Such phantoms
will give a better insight into the real tissue damage during the disease progression and preservation for transplantation.
The liver tissue-mimicking phantom will raise the quality assurance of patient diagnostic and treatment precision and offer
a definitive clinical trial data collection.
Keywords Liver · Phantoms · Mechanical properties · Tissue-mimicking · Viscosity · Elasticity
Abbreviations MRE Magnetic resonance elastography

TMMs Tissue-mimicking materials AMUSE Attenuation measuring ultrasound shear wave
HCC Hepatocellular carcinoma elastography
MRI Magnetic resonance imaging KVFD Kelvin–Voigt fractional derivative model
4D CT Four-dimensional computed tomography SLS Standard linear solid model
PVC Polyvinyl chloride KV Kelvin–Voigt model
PVA Polyvinyl alcohol DMA Dynamic mechanical analysis
PAA Polyacrylamide SWE Shear wave elastography
SEBS Styrene-ethylene-butylene-styrene copolymer PVE Poro-visco-elasticity theory
E Young’s modulus FE Finite element method
E′ Viscoelastic storage modulus SSI Supersonic shear imaging
E″ Viscoelastic loss modulus SWS Shear wave speed
ASTM American Society for Testing and Materials NAFLD Non-alcoholic fatty liver disease
G′ Shear storage modulus ELF Enhanced liver fibrosis
G′′ Shear loss modulus ECM Extracellular matrix
USWE Ultrasonic shear wave elastography
* Jolly Bhadra 1 Introduction

[email protected]
The liver is the largest gland/organ inside the human body,
1
Department of Mechanical and Industrial Engineering, with an average dimension of 8 cm by 16 cm by 28 cm
College of Engineering, Qatar University, 2713, Doha, Qatar
(Ahmad et al. 2020a, b). It is located under the rib cage
2
Qatar University Young Scientists Center (QUYSC), Qatar on the right side of the abdomen within the human body
University, 2713, Doha, Qatar
(Ahmad et al. 2020a, b). It acts as the metabolism center
3
Center for Advanced Materials (CAM), Qatar University, PO for vitamins and nutrient production, as well as excretion
Box 2713, Doha, Qatar
13
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374 A. S. Lemine et al.
of waste metabolites. It also functions as the body’s energy Additional studies have adopted dynamic magnetic reso-
reservoir by storing glycogen (Casciaro et al. 2009). In addi- nance elastography in detecting liver fibrosis (Ahmad et al.
tion, it is responsible for numerous vital functions such as 2020a, b; Basdogan 2012; Saraf et al. 2007). For example,
detoxifying substances, assisting digestion, storing iron, Nava et al. utilized an aspiration device to measure the static
making immune factors, maintaining the hormonal bal- mechanical properties of diseased liver invasively and found
ance, regulating blood clotting, and filtering venous blood that the stiffness of fibrotic tissue is three times that of nor-
(Pellicer-Valero et al. 2020; Umale et al. 2013). However, mal tissues (Nava et al. 2004). In addition, Maccabi et al.
its functions are affected by a number of pathologies such used an impact hammer to examine the dynamic properties
as hepatitis, liver fibrosis, hepatocellular carcinoma (HCC), associated with liver tissues affected by liver fibrosis (Mac-
liver cirrhosis, and fatty liver disease (Hosseini et al. 2019). cabi et al. 2018). They detected a rise in human liver elastic
These pathologies could result in the total loss of liver func- storage modulus (E′) when subjected to growth in fibrosis
tions leading to human death within a matter of minutes to level, which is recognizable via histological scoring. In
days (McGarry et al. 2020). addition, the influence of collagen alignment on both struc-
During the past decade, global attention has increased tural and mechanical behaviors of liver tissues in response
toward enhancing clinical ethics and adopting simulation to compression was examined (Maccabi et al. 2018). The
stages, particularly in clinical training for interventional and study concluded a significant variance between collagen
diagnostic trials (Tan et al. 2021), which in return facilitates alignments and stress relaxation responses.
an adequate training experience for clinical trainees toward Herein, this paper will review the qualitative and quan-
improving and promoting medical practices (Bienstock and titative methods used in examining the correlation between
Heuer 2022). Nowadays, using phantoms as simulators has the liver tissues’ histological and mechanical properties
enhanced the learning experience and clinical ethics (Fu toward understanding the mechanisms of tissue-damaging
et al. 2013). The phantoms comprise human tissue-mimick- throughout the evolution of liver diseases. In this regard, the
ing materials (TMMs) fabricated following a typical work- present paper addresses the following:
flow to be equivalent to actual human tissues (Opik et al.
2012). Figure 1I shows the standard workflow for fabricating (a) Standard protocols and tailored guidelines for sample
liver phantom using 3D printing. A recent study has adopted preparation, mechanical testing, and data analysis of
this workflow for developing a durable liver phantom based liver tissues.
on a hybrid simulator consisting of silicone polymer mixed (b) Monitoring, detecting, and measuring tools for the
with additives (Tan et al. 2021). The resulting phantom has liver’s mechanical properties.
an external morphology matching that of the human livers, (c) Most commonly used mechanical properties to design
as illustrated in Fig. 1II (Marchesseau et al. 2017). It has liver tissue-mimicking phantoms.
been used to simulate biopsies and exhibit an anatomically (d) Impact of liver diseases on its mechanical properties.
realistic ultrasound liver phantom mimicking the natural (e) Constitutive models for human hepatic tissues.
liver anatomy, as shown in Fig. 1III (Pacioni et al. 2015). In (f) Most common materials used to fabricate liver phan-
addition, the phantom material showed self-healing prop- toms and their advantages and disadvantages.
erties after biopsy needle removal from parenchyma. Such (g) Factors affecting the measurements of liver mechanical
phantom is required for novices’ training on liver ultrasound properties.
in interventional and diagnostic procedures (Pacioni et al.
2015).
Realistic mechanical properties can help to advance 2 Mechanical testing of liver tissues
radiation therapy techniques, for example, using magnetic to develop mimicking phantoms
resonance imaging (MRI) or four-dimensional computed
tomography (4D CT) to assess an organ displacement dur- The mechanical properties of biological tissues are affected
ing the response to the respiratory motion (Pi et al. 2021). by sample conditions and testing protocols (Kassner et al.
In addition, the prior knowledge of the liver’s mechanical 2009). The target liver tissue and engineered tissue mimetic
behavior will enhance the predictive abilities of algorithms materials characterization must follow the same testing and
for tumor localization (Tian et al. 2015). For instance, liver analysis methods for maintaining testing variables. In vivo
palpation is a standard screening procedure for identifying or imaging-based methods are preferable to direct ex vivo
hepatic diseases (Leitão et al. 2017). It combines with intra- tests. Still, their drawback in being difficult and expensive, as
operative ultrasonography for detecting liver tumors (Leitão well technology, is not available to measure some properties
et al. 2017). Elastography provides data on stiffness changes in vivo. In ex vivo trials, the isolated tissue blocks undergo
among tissues in the liver, which is vital in controlling pri- direct measurements of mechanical properties in tension,
mary liver tumors (Yin et al. 2011). compression, or shear (Kassner et al. 2009). The mechanical
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Mechanical properties of human hepatic tissues to develop liver‑mimicking phantoms for medical… 375
Fig. 1 I Typical fabrication stages of liver phantom: (a) inner mold liver phantom: (b) Front and (c) back surfaces; III The Liver biopsy
printed in 3D by soft material, (b) outer liver shape printed in 3D simulation on liver phantom through the (a) needle’s insertion, (b)
with a rigid material, (c) negative outer mold consisting of inlet visible perfectly on ultrasound (US) scan plane, and (c) reaching the
injection point of polymer and outlet of the bile duct, (d) assembly target quickly. No track of the biopsy needle in the parenchyma after
of outer and inner molds through pouring a liquid polymer into the its removal due to the self-healing properties of phantom liver mate-
mold, (e) extracted inner mold from outer mold, and (f) liver phantom rial (Pacioni et al. 2015), with permission of Springer Nature, copy-
is molded (Tan et al. 2021), with permission of Springer Nature, cop- right 2015
yright 2021. II The (a) Liver anatomy and external morphology of
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testing of the liver is difficult due to the need to maintain or dynamic. For static testing, the applied deformations can
specific homogeneity. be tensile, compressive, shear, or torsion (Fig. 2II, (Guima-
Figure 2I shows the typical preparation stages for a rec- rães et al. 2020)). The slope in the elastic (linear) area of
tangular tensile testing specimen based on a human liver the stress–strain curve corresponds to Young’s modulus (E)
sample (Estermann et al. 2021). The Glisson capsule is (Lemine et al. 2022). The plastic domain of the curve occurs
removed before the sample preparation to get consistent at higher levels of strain, where the material undergoes irre-
specimens with a high proportion of parenchyma tissues versible and permanent deformations until fracturing.
(Karimi and Shojaei 2018). In addition, avoiding the bile In dynamic analysis, the dynamic loading test is a preva-
ducts and large blood vessels ensures relatively homogenous lent method for identifying the viscoelastic properties of
samples. The standard biomechanical testing is either static soft tissues dependent on frequency (MacManus et al. 2019;
Fig. 2 I Typical sample preparation through cutting out the (a) 75 × 20 × 5 mm (Estermann et al. 2021), with permission of Elsevier
whole human liver organ into (b) block of hepatic tissue for placing Ltd., copyright 2021. II Standard mechanical analysis deformations
onto the 3D-printed cutting guide to extract (c) thin liver tissue layer include (a) tensile, (b) compressive, (c) shear, and (d) torsion. (e) The
from the block. Then (d) placing a rectangular stencil onto the tissue typical static and dynamic deformations (Guimarães et al. 2020), with
layer to (e) cutting a sample from the tissue layer in dimensions of permission of Springer Nature, copyright 2020
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Saraf et al. 2007). This test applies minor episodic strains (Evans et al. 2013). It regulates cell behavior and changes
at variable frequencies onto the tissue sample to record the during tissue fibrosis in response to different pathologies
stress response and produce the loss (E″) and storage (E′) like non-alcoholic fatty liver disease and fibrosis (Boursier
moduli, as shown in Fig. 2 (II, e) (Guimarães et al. 2020). et al. 2016; Ijima et al. 2018). These pathologies affect the
The loss modulus reflects the dissipated energy through the stiffness of the hepatic tissues at cellular levels, regional, or
internal structural rearrangements, and the storage modu- whole organs (Boursier et al. 2016).
lus is associated with the material's ability to store energy Liver cirrhosis is a diffuse nodular regeneration enclosed
through material elastic deformation (Mulabecirovic et al. by dense fibrotic septa besides successive extinctions of
2018a). Relaxation studies have also been used in biome- parenchyma and collapses of liver structures (Mueller 2010).
chanics literature to test the soft tissues’ viscoelastic prop- It results from fibrogenesis and necroinflammation (Muel-
erties depending on time (Morr et al. 2021a; Wang and Shi ler 2010). It might develop to hepatocellular carcinoma
2020). In relaxation studies, a strain is applied and held con- (HCC) cancer, which is the most severe adult death as it
stant, resulting in the stress decaying exponentially until the is responsible for the death of over 12,000 adults within a
steady-state value is attained. It is also recognized with a year in the United States (US) (Makhamrah et al. 2019).
time-dependent relaxation modulus (Mattei and Ahluwalia Figure 3 shows the changes in the liver’s nanomechanical
2016). properties throughout cancer progression at typical liver
Significant efforts have introduced standardized methods cirrhosis, HCC, to recurrent HCC (Tian et al. 2015). 1–3%
for examining tissue-engineered products (Sorrentino et al. of diagnosed patients with liver cirrhosis have developed
2020). The American Society for Testing and Materials HCC annually (Tian et al. 2015). The liver tissues could alter
(ASTM) has developed ASTM testing standards to enhance their nanomechanical properties during different stages of
these products’ consistency, safety, and quality (Johnson HCC. The bimodal elasticity distribution indicates that there
et al. 2021; Sorrentino et al. 2020). These standards are is a health and a diseased group. In healthy liver tissues,
explicitly not designed to conduct mechanical tests on bio- the elasticity distribution is characterized with the lowest
logical tissues like human tissues, but they could still guide elasticity peak (LEP) ranging from 0.91kPa to 1.55kPa, as
appropriate testing (McGarry et al. 2020). Specific standards demonstrated in Figs. 3A, B (Tian et al. 2015). The LEP is
for acoustic properties characterization of liver clinical trials frequently reported as the mechanical fingerprint to evaluate
and some mechanical properties as Young’s modulus are the malignancy in living cells (Tian et al. 2015).
provided by the American Institute of Ultrasound in Medi- The hematoxylin stains purplish-blue the cell nuclei,
cine (AIUM) (Greenbaum et al. 2007). Table 1 summarizes while the eosin stains pink the cytoplasm and ECM
living tissues’ standard mechanical characterization tech- (Hoodeshenas et al. 2019). The Masson’s trichrome (Tri.
niques to investigate different mechanical properties based Masson) is used to distinguish between collagen and smooth
on the proper ASTM protocols for ex vivo or in vivo sam- muscle in tumors, as well as the increase of collagen in dis-
ples. Section 3 will discuss the effect of these properties in eases like cirrhosis (Cabibi et al. 2015). In Fig. 3 (C, regu-
the diagnosis and treatment of hepatic tissues. lar column), Tri. Masson and HE staining illustrate that the
liver tissues have organized well with less fibroconnective
tissue and packed hepatocytes. The heterogeneous distribu-
3 Mechanical properties of liver tissues tion in elasticity values can show up to five peaks centering
to develop mimicking phantoms in the range of 4.65–11.50 kPa. It could be attributed to the
in hepatic diseases diagnosis nanomechanical properties associated with the blood ves-
and treatment sels in the portal area (Tian et al. 2015). These values are
comparable to benign fibroadenomas of 3.68 ± 1.92 kPa (Yin
3.1 Elasticity et al. 2011).
In liver cirrhosis tissues, two or more elasticity peaks
Elasticity indicates the material’s ability to recover its origi- might be caused by intrahepatic scaffold turbulence
nal shape and size when subjected to stress or deformation (Fig. 3B). However, there are no significant differences in
(Kim et al. 2013). The mechano-sensitivity of parenchymal LEPs compared to normal liver tissues. The higher elasticity
and non-parenchymal cells shows altering their behavior peak (HEP) increased, and the elasticity distribution broad-
with changes in liver stiffness (Hoodeshenas et al. 2019). ened as the local fibrogenesis became severe, as shown in
Mechanical stiffness also contributes to driving the myofi- Fig. 3 (A and B, liver cirrhosis column). Many tissues have
broblastic differentiation of hepatic stellate cells (HSCs) a stiffness reaching a maximum of 16 kPa, indicating the
(Yin et al. 2011) and portal fibroblast (Cafarelli et al. 2017). occurrence of abundant ECM within the paraneoplastic tis-
In the cellular micro-environment, the principal biome- sue (Ijima et al. 2018). The staining in Tri. Masson images,
chanical cue is the extracellular matrix (ECM) stiffness as shown in Fig. 3C, illustrates the proliferation of ECM
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378
Table 1 Common mechanical characterization techniques of living tissues to estimate Young’s modulus (E), viscoelastic gain (E′) and loss (E′′) moduli, shear loss (G′′), and storage (G′) moduli
based on the ASTM standard testing methods
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Technique Working principle Modulus Sample ASTM Ref
Tensile deformation A standard stress–strain analysis E (elastic) Ex vivo tissue D3039M, D3039, D1708, Karimi and Shojaei (2018)
uses uniaxial stress to stretch D1623, D882, D638,
the sample and establish a rela- D412
tionship with the yield strain
Compressive deformation It is a standard stress–strain anal- E (elastic) Ex vivo tissue D1621, D695 Karimi and Shojaei (2018), Mac-
ysis through the application of cabi et al. (2018)
uniaxial stress to compress the
sample and establish a relation-
ship with the yield strain. The
size of the compressor is similar
to or larger than the sample
Shear rheometry The resulting strain quantifies G′′, G′ (viscoelastic, shear) Ex vivo tissue D5279 Mulabecirovic et al. (2018b), Zhu
through the application of et al. (2016)
low-amplitude oscillatory shear
stress
Dynamic mechanical analysis The deformation of the sample E′′, E′(viscoelastic) Ex vivo tissue D5026, D5024 Zhang et al. (2017)
(DMA) is through cycles of tensile and
compressive
Indentation The tissue sample is indented E (elastic) Ex vivo tissue E2546-15 Maccabi et al. (2018)
with a smaller probe than the
sample and has a defined geom-
etry to calculate the relationship
between the probe load and
indentation depth
Atomic force microscopy (AFM) The AFM relies on shear rheol- G′, G′′ (shear), E (indentation) Dry/wet ex vivo tissue – Tian et al. (2015)
ogy or nanoindentation
Micropipette aspiration The technique forms a relation- E (elastic) Ex vivo tissue – Mazza et al. (2008)
ship between the sample aspira-
tion volume and the aspiration
pressure
Ultrasonic shear wave elastogra- Shear waves generate across the E (elastic) In vivo tissue – Imajo et al. (2021), Yeh et al.
phy (USWE) tissue through ultrasonic pulses, (2002)
and the velocity of the waves
is measured to derive Young’s
modulus of tissues
Magnetic resonance elastography Visualizing tissue deformation G′′, G′ (viscoelastic, shear) In vivo tissue – Cournane et al. (2012), Garczyńska
(MRE) through magnetic resonance et al. (2020)
occurs from the shear waves
introduced into the tissue gener-
ated from external vibrations
A. S. Lemine et al.
Fig. 3 Nanomechanical properties changes during liver cancer pro- sis, HCC, to (right) recurrent HCC, respectively. The SEM and Tri.
gression. A Elasticity maps in 10μmx10μmx100pixels, B elasticity Masson images are in scale bars of 50 μm (Tian et al. 2015), with
distributions, C Tri. Masson staining images and D SEM images of permission of the Royal Society of Chemistry, copyright 2015
liver cancer tissues at various stages from (left) normal, liver cirrho-
distributed around the hepatocytes across the tissue. The 2010). Nanomechanics of recurrent cancer has displayed a
subsequent SEM analysis has confirmed these cues, as pre- unimodal peak centered at 0.45kPa within its elasticity his-
sented at the bottom of the liver cirrhosis column in Fig. 3D. togram, similar to LEP of HCC, as shown in Fig. 3 (A and
Furthermore, it reported that liver cancer’s driving force is B, recurrent HCC column). In addition, the SEM images in
chronic hepatic fibrosis (Yin et al. 2011). Consequently, the Fig. 3 (D, recurrent HCC column) illustrate large numbers
mechanical microenvironment undergoing disordered home- of plentiful microvillus-like protrusions on the surface of
ostasis could lead to malignant transformation, raising the recurrent cancer cells requiring curative resection (Kassner
need to investigate further the correlation between carcino- et al. 2009).
genesis and ECM’s mechanical properties (Yin et al. 2011). The elastography imaging technique also inspects the
The HCC cancer tissue showed an elasticity distribution mechanical properties of natural liver tissues (Pasyar et al.
in the form of two distinct peaks centering at 0.6 kPa and 2020). The magnetic resonance elastography (MRE) imag-
2.1 kPa, as shown in Fig. 3 (A and B, HCC column). A ing technique utilizes the changes of shear wave wavelengths
decrease in LEP characterizes the progression to a malignant passing through the liver in measuring the tissue viscoelas-
state compared to normal and cirrhotic liver tissues. The ticity (Akkaya et al. 2018). The average liver stiffness values
SEM and Tri. Masson staining, as shown in Fig. 3 (C and from MRE measurements in a healthy human body range
D, HCC column), have revealed the origin of such mechani- from 2.05 kPa to 2.12 kPa, with minor variations for age
cal features. The HCC becomes softer compared to other or gender (Zhang et al. 2017). Thus, the stiffness values of
malignant epithelial neoplasms due to decreased tumor normal livers are commonly lower than 2.5 kPa, as shown
stroma and cell variations in mechanical phenotype (Mueller in Fig. 4 (Akkaya et al. 2018). The stiffness values more
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Fig. 4 Effect of different hepatic fibrosis stages on the MRE-meas- color) to 8 kPa (hardest with red color) (Akkaya et al. 2018), with
ured liver stiffness. The relative tissue stiffness is shown in the color- permission of PMC Publications, copyright 2018
coded elastography on a color scale from 0 kPa (softest with purple
than 2.5 kPa are utilized in MRE measurements to diagnose close to the portal vein, stage 3 (F3) is a further extension of
hepatic fibrosis with high specificity and sensitivity (Akkaya fibrosis outside the areas of the portal vein, and stage 4 (F4)
et al. 2018). The stiffness values undergo proportional incre- is evolving of fibrosis into cirrhosis (Cournane et al. 2010).
mentations with different histologic fibrosis grades differen- The F4 is the advanced pathological stage leading to the
tiated in MRE elastography, as shown in Fig. 4. The early distortion of hepatic architecture and vasculature (Mueller
stages of hepatic fibrosis are not detectable using routine 2010). Table 2 shows the liver viscosity at stage F4 might
imaging techniques, while the liver fibrosis grades are all reach 3.7Pa.s comparable to 6.7Pa.s at the healthy state (Def-
detected in high sensitivity, exceeding 95% using MRE fieux et al. 2015; Garczyńska et al. 2020; Zhu et al. 2016).
measurements (Leitão et al. 2017). Furthermore, liver viscoelasticity plays a crucial role
when elastography contrast is insufficient (Gidener et al.
2021). A proposed approach utilizes liver viscoelasticity to
4 Viscoelasticity separate the severely rejected transplanted livers from the
non-rejected ones (Ijima et al. 2018). Zhang et al. character-
The liver is highly viscoelastic, which can provide a means ized the viscoelastic parameters of the liver without using
for clinical diagnostics (Yeh et al. 2015). Liver viscoelas- rheological models but computed through the attenuation
ticity depends on the fibrosis stage and other factors like of shear wave elastography (AMUSE) (Zhang et al. 2017).
inflammation, congestion, extrahepatic cholestasis, and The attenuation and shear wave velocity for fifteen trans-
edema (Sugiura et al. 2019). Different clinical protocols are planted livers have diagnosed patients with severe rejection
available to evaluate fibrosis and cirrhosis extent (Crescenzi and revealed a high agreement with biopsy results (Deffieux
et al. 2019). The Scheuer classification and METAVIR scale et al. 2015). Recently, the viscosity biomarker has facili-
categorize fibrosis into five stages (Cournane et al. 2010). tated supersonic shear imaging (SSI) to release its latest and
Stage 0 (F0) indicates no fibrosis, stage 1 (F1) is minor advanced characterizing device with novel liver features
fibrosis, stage 2 (F2) is the extension of fibrosis into areas like the viscosity imaging feature (Glińska-Suchocka et al.
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Table 2 Viscoelastic Hepatic tissue state Viscosity (Pa.s) Testing method Ref.
biomarkers of human liver
tissues in a healthy state and Healthy 7.3 ± 2.3 MRE Idilman et al. (2020)
different fibrosis states using
Healthy 6.7 ± 1.3 Deffieux et al. (2015)
shear wave spectroscopy
(SWS) and magnetic resonance Fibrosis (F0) 2.0 ± 0.8 SWS Lin et al. (2017)
elastography (MRE) Fibrosis (F1) 2.3 ± 0.7 Lin et al. (2017)
Fibrosis (F2) 2.6 ± 0.5 Pasyar et al. (2020)
Fibrosis (F3) 2.7 ± 1.9 Mazza et al. (2007)
Fibrosis (F4) 3.7 ± 2.5 Seyedpour et al. (2021)
2017). Furthermore, utilizing SSI provided more accuracy et al. 2021). A study has inspected the enhanced liver
than from shear wave imaging using transient elastography fibrosis (ELF) index’s performance features compared
(TE) from FibroScan (Glińska-Suchocka et al. 2017). Fig- to MRE and concluded that the ELF index had shown
ure 5 displays the imaging of healthy and cirrhotic liver with specific markers and high sensitivity to cirrhosis com-
real-time viscosity values (Rus et al. 2020). pared to MRE (Suh et al. 2014). A posterior study on a
The lack of practical guidance and agreement among cohort of 102 patients undergone both liver biopsy and
the elastography specialist or clinical community on the MRE (Crescenzi et al. 2019). The study aims to assess
most suitable rheological model to characterize the soft tis- the association between fibrosis progression in NAFLD
sue has put an additional focus on dispersion slope meas- and increased liver stiffness on MRE. It is concluded that
urements (Idilman et al. 2020). The dispersion slope is a the 15% of liver stiffness increase on MRE probably cor-
viscosity-related parameter measured through shear wave related to the histological fibrosis progression. Therefore,
speed (SWS) imaging to delimit the degree of fibrosis and viscosity imaging is a noninvasive and essential biomarker
diagnose necroinflammation and steatosis in non-alcoholic for further information on liver pathology (Crescenzi et al.
fatty liver disease (NAFLD) (Imajo et al. 2021). NAFLD 2019). However, a precise viscosity quantification is still a
severe cases might lead to cirrhosis and a vital liver trans- challenging inquiry, and the viscoelastic model selection
plant requirement (Hosseini et al. 2019). A set of prelimi- determines the accuracy of the outcomes.
nary studies based on ex vivo and in vivo liver samples from
goose, porcine, mouse, and duck have utilized viscoelasticity
as a potential biomarker in characterizing fatty liver (Wang
and Shi 2020).
Many current publications have emphasized MRE as a
technique for detecting and staging liver fibrosis (Gidener
Fig. 5 Real-time viscosity measurements via supersonic shear imaging (SSI) AIXPLORER MACH30® on a healthy volunteer (left) and patient
volunteer (right) with cirrhotic liver (Rus et al. 2020), with permission of MDPI Publications, copyright 2020
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5 Acoustic impedance and attenuation as the infusion of the hepatic artery with chemotherapeutic
agents (Boursier et al. 2016).
The acoustic impedance is the resistance to the ultrasound The differences in the mechanical properties of silicone-
waves’ propagation through the tissues (Zell et al. 2007). based phantoms mimicking the real liver organ are due to
It results from the speed of sound across the tissue and the amount of graphite used to improve the scattering agent
its density, which varies from one tissue type to another, (Makhamrah et al. 2019; Opik et al. 2012; Rafiq et al. 2018).
giving the unique fingerprint of acoustic impedance (Zell Thus, adding slacker and thinner decreases the viscosity and
et al. 2007). In medical ultrasound, the acoustic impedance enhances the homogeneity to overcome the mechanical and
becomes evident at the interfaces between dissimilar tissue acoustic problems arising from the use of graphite (Zell
types (Cournane et al. 2010). Transferring ultrasound waves et al. 2007). In addition, the thinner Vaseline oil allows bet-
from one tissue type to another varies depending on the vari- ter signal transmission (Zell et al. 2007). Figure 6 shows
ation in impedance of the two tissues (Cournane et al. 2010). natural liver and liver phantom’s anechoic, hyperechoic,
The significant variations in impedance will cause reflection and hypoechoic lesions (Pacioni et al. 2015). The anechoic
of sound. For instance, the passing of an ultrasound beam mass is ascribable to a cyst (Fig. 6, first row), a hyperechoic
through the muscle tissue coming across the bone causes lesion simulates the angioma (Fig. 6, second row), and the
it to reflect off of it due to the differences in tissue density. hypoechoic lesion mimics the real HCC (Fig. 6, last row).
The impedance increases with tissue densities and shows Silicone-based mixtures develop the patient-specific liver
less sensitivity to increased speed of sound (Cafarelli et al. phantom for ultrasound and biopsy hybrid simulators based
2017). Therefore, the high acoustic impedance is better as it on harmless, low-cost, and high-stability materials (Karimi
will produce superior sound quality for professional medical and Shojaei 2018). In addition, such mixtures are the better
diagnostics. 3D models to mimic the liver’s different lesions, vessels, and
In the literature, the acoustic impedance of liver tis- parenchyma, as demonstrated in Fig. 6 (Pacioni et al. 2015).
sues in the human body is around 1.65*106Rayls (Deffieux
et al. 2015). It is similar to blood and kidney, lower than
bone with 7.8*106Rayls, and higher than lung and fat with 6 Failure properties
0.18*106Rayls and 1.34*106Rayls, respectively (Nava et al.
2004). Recently reported that liver phantom-mimicking Many studies have investigated liver failure properties
materials based on silicone exhibit a close acoustic imped- resulting from direct cellular damage, particularly in car
ance to the real human liver, as displayed in Table 3 (Afiqah accidents (Karimi and Shojaei 2018). The data show that
Bakri et al. 2019; Cafarelli et al. 2017). This table also shows vehicle crashes led to severe injuries across different liver
other acoustic properties of the liver and its phantoms as segments requiring considerations in the protection assess-
sound speed, density, and attenuation. The density of liver ments of vehicle passengers, as presented in Fig. 7 (Chenel
organs and phantoms is 1060–1080 kg/m3, while the sound 2018). This organ could undergo three types of injuries like,
speed is 1540–1000 m/s, respectively. The attenuation of vascular, hematoma, and laceration failures, affecting the
liver phantoms varies widely from the real human liver. The dense vascular network, capsule, and parenchyma, respec-
hepatic attenuation is influenced mainly by the accumulation tively (Chenel 2018; Mannelli et al. 2012). Severe injuries
of intracellular vacuoles of triglycerides as hepatic steatosis occur mainly due to the surface of the parenchyma during
(Casciaro et al. 2009). Thus, the increased attenuation values the accident (Mannelli et al. 2012).
are associated with cardiac and alcoholic cirrhosis, as well The mechanical properties used to analyze failure involve
the ultimate tensile strain, true stress, and ultimate load
per width (Brunon et al. 2010). During the tensile test, the
mechanical failure mechanism emerged first on the capsule
Table 3 Comparison of mechanical properties of real human liver and then on the parenchyma, as displayed in Fig. 8I. The
and silicone-based liver phantoms (Afiqah Bakri et al. 2019; Cafarelli resultant load–displacement curve until the end of the cap-
et al. 2017)
sule and parenchyma failures is shown in Fig. 8II. The cap-
Sample Density (kg/ Acoustic Attenuation Sound sule constitutive law is determined through the bi-material
m3) impedance (dB/cm/ speed
model of two parallel springs, as presented in Fig. 8III. The
(MRayl) MHz) (m/s)
model splits the load measurements into capsule load (Fc)
Human liver 1060 1.6 0.7 1540 and parenchyma load (FP) to investigate the sustaining load
Silicone and 1080 1.1 2.2 1080 of each separately.
graphite The liver capsule failure parameters are the ultimate load
mixture
per unit width instead of maximum longitudinal stress due
Ecoflex0010 1063 1 1.5 1000
to its high thickness of 100 µm (Brunon et al. 2010). The
13
Fig. 6 Lesions of anechoic, hyperechoic, and hypoechoic for phan- (first row), angioma (second row), and hypoechoic lesion simulating
tom liver lesions (first column) and real liver organ (second column). real hepatocellular carcinoma (HCC) (last row) (Pacioni et al. 2015),
Compared to the real mass, the anechoic mass ascribable to a cyst with permission of Springer Nature, copyright 2015
normalized load is the slope of the load–displacement curve, et al. 2010; Johnson et al. 2021; Opik et al. 2012). Then,
indicating the load per unit width against the longitudinal we calculate the ultimate true stress and true modulus by
strain (de Jong et al. 2019). The ultimate load is the pro- dividing the ultimate load per width and normalized load,
portion of sustained load via the liver capsule in the exist- respectively, with average liver capsule thickness for porcine
ing width about the localization area, known as true load and humans (Basdogan 2012). The ultimate local strain is
per width unit (Mazza et al. 2008). Table 4 summarizes the more precise than the global strain measurements due to
mechanical failure properties of liver capsules for humans the strain localization (Basdogan 2012). The normalized
and porcine based on fresh and frozen samples (Brunon load in human fresh and frozen capsules is 2.02 ± 1.18 N/
13
Fig. 7 Injury percentage in the liver by segments due to vehicle accidents (Chenel 2018), with permission of Biomechanics Publications, copy-
right 2018
Fig. 8 Mechanical failure analysis of the human liver. I Tensile test the bi-material model consisting of two parallel springs (Brunon et al.
on the liver capsule and parenchyma sample leads to capsule failure 2010), with permission of Elsevier Ltd., copyright 2010
and parenchyma. II The Resultant load–displacement curve and III
mm and 3.27 ± 2.70 N/mm, respectively. In contrast, the tissue state. For instance, the ultimate strain of the porcine
true modulus of the same samples is 16.9 ± 9.9 MPa and capsule is strongly altered by the freezing as it damages
27.5 ± 22.7 MPa, respectively, compared to frozen and its hepatic tissues more than the human capsule, as dis-
fresh porcine capsule samples with 11.6 ± 19.2 MPa and played in Table 4. The conclusions in the literature on the
7.8 ± 10.5 MPa, respectively. influence of freezing on mechanical properties vary for
The principal statistical analysis in the literature of soft biological tissues such as a capsule, parenchyma, liga-
human liver capsules’ failure behavior and properties ments, and muscle (Afiqah Bakri et al. 2019). The cause is
shows a strong dependence on the fresh or frozen hepatic probably the widely different constitutions and mechanical
13
Table 4 Outcomes of the Mann–Whitney statistical test on failure 7 Mechanical modeling and simulation
mechanical properties of the liver capsule in human and porcine tis- of liver tissues to develop mimicking
sues (Brunon et al. 2010; Johnson et al. 2021; Opik et al. 2012)
phantoms
Fresh Frozen
Normalized load (N/mm) The liver constitutive formulation anticipates merging the
Human 2.02 ± 1.18 3.27 ± 2.70 polynomial and logarithmic strain energy in modeling united
Porcine 1.44 ± 1.76 1.53 ± 2.08 elongation and compression experiments on the hepatic tis-
True modulus (MPa) sue (Rethy et al. 2018). The heterogeneous structure of liver
Human 16.9 ± 9.9 27.5 ± 22.7 tissues has caused most of its published mechanical models
Porcine 11.6 ± 19.2 7.8 ± 10.5 in the literature to be nonlinear tissue constitutive equa-
Ultimate load per width (N/mm) tions (Capilnasiu et al. 2020; Chatelin et al. 2011). Instead,
Human 0.22 ± 0.14 0.33 ± 0.32 the models attempt to compute the bulk tissue mechanical
Porcine 0.40 ± 0.48 0.24 ± 0.22 properties and time constants (Yarpuzlu et al. 2014). The
Ultimate true stress (MPa) published data highlight the differences in tissue conditions
Human 1.85 ± 1.18 2.77 ± 2.69 like aging or pathophysiological state (Yarpuzlu et al. 2014).
Porcine 2.03 ± 2.44 1.22 ± 1.12 Therefore, it is only meaningful to compare parameters from
Ultimate strain (%) the same constitutive model.
Human 32.6 ± 13.8 43.9 ± 24.2 The choice of tissue model representing the liver’s
Porcine 43.3 ± 25.4 62.9 ± 35.4 mechanical behavior still varies among scientists (Lin et al.
2017). However, due to the prominent viscoelastic behav-
ior, the three standard models are the generalized Maxwell
(GM), the Kelvin–Voigt fractional derivative (KVFD), and
loadings (Afiqah Bakri et al. 2019). Considering the fresh the porous visco-hyperelastic models, as illustrated in Fig. 9
or frozen liver status is significant in developing liver (Mattei and Ahluwalia 2016). The following sections will
phantoms investigating the severely rejected transplanted detail each model separately to better visualize their princi-
livers from the non-rejected ones, which might be frozen ple in fitting the liver mechanical data in comparison with
before being transported. other common models, namely standard linear solid (SLS).
Fig. 9 Basic models describing the mechanical properties of the liver: a generalized Maxwell, b Kelvin–Voigt fractional derivative (KVFD), and
c porous visco-hyperelastic (Mattei and Ahluwalia 2016), with permission of Elsevier Ltd., copyright 2016
13
8 Generalized Maxwell model model of order 1 and differential equation (Klatt et al.
2010):
By using viscous (dashpots, ηi) and elastic (springs, Ei)
𝜂1 𝜕𝜎(t) 𝜕𝜀(t) 𝜂 E 𝜕𝜀(t)
parts for the most general form utilized in modeling the 𝜎(t) + =𝜂 + E∞ 𝜀(t) + 1 ∞ (4)
E1 𝜕t 𝜕t E1 𝜕t
linear viscoelastic behavior of soft tissues like the liver
based on Maxwell’s arms (n), a spring and dashpot in The SLS model is used to predict the strain curve and the
series, in parallel connections with a spring are demon- behavior for instantaneous loads and, long time, the model
strated in Fig. 9a (Mattei and Ahluwalia 2016). The dash- deficiencies in accurately modeling material systems numer-
pot is the energy dissipative element, and the spring is the ically (Zhu et al. 2014).
energy storage element. The springs represent the flex-
ible component of the model’s response and obey Hook’s
law and generate stress (σspring) proportional to strain (ε) 9 Kelvin–Voigt fractional derivative (KVFD)
using Eq. (1) (Evans and Gentleman 2014), while dash- model
pots represent the viscous component of the viscoelastic
hepatic tissues, with stress (σdashpot) being proportional to It models the quasi-linear or nonlinear behavior of biologi-
the strain rate ( 𝜀̇ ), as shown in Eq. (2) (Zhu et al. 2016). cal tissues, which have a nonlinear stress–strain relation-
ship, as displayed in Fig. 9b (Mattei and Ahluwalia 2016).
𝜎spring = E𝜀 (1)
Such nonlinearity could inhibit assessments of various
studies on living tissue mechanics (Kassner et al. 2009).
𝜎dashpot = 𝜂 (2) Kelvin–Voigt (KV) model is a two-parameter model involv-
E and η are Young’s modulus and the viscosity of the ing a spring with Young’s modulus (E1) and a dashpot ele-
liver, respectively (Zhu et al. 2016). The total strain of the ment with viscosity (η) connected in parallel, as shown in
Maxwell model is the sum of the strains in the dashpot and Fig. 11a (Poul et al. 2022). The generalization of the KV
spring components. Equation (3) shows the constitutive model is the KVFD model, with the stress (σ) in the dash-
relation of the Maxwell model expressed as a linear first- pot being equivalent to the fractional derivative of order α
order differential equation in a function of the two struc- for the strain (ε) (Mattei and Ahluwalia 2016). A fractional
tural constituent parameters (E and η) (Pasyar et al. 2020): derivative approximates the derivative of a function to a real
number order α,
𝜂 𝜕𝜎(t) 𝜕𝜀(t)
𝜎(t) + =𝜂 (3) 𝜕 𝛼 𝜀(t)
E 𝜕t 𝜕t 𝜎(t) = η (5)
𝜕t𝛼
A simpler linear form, known as the standard linear
solid (SLS) or Zener model, simplifies the generalized It is represented by a spring-pot (fractional dashpot), as
Maxwell model but with only one spring–dashpot branch, illustrated in Fig. 11b (Poul et al. 2022). When α = 1, the
as illustrated in Fig. 10 (Ganser et al. 2017). The order spring-pot behaves as a dashpot element; for α = 0, it acts as
(n) of the generalized Maxwell model indicates the order a spring (Hafsah et al. 2014).
of the resulting differential equation for strain and stress. The KVFD model is:
Consequently, the SLS model is a generalized Maxwell
Fig. 10 Comparison between the a standard linear solid (SLS) with Fig. 11 Comparison between the a Kelvin–Voigt (KV) model with
three parameters and b generalized Maxwell with 2n + 1 parameters two-parameter and b Kelvin–Voigt fractional derivative (KVFD)
and order n for modeling the mechanical properties of the liver (Gan- model with three parameters for modeling the mechanical properties
ser et al. 2017), with permission of the Royal Society of Chemistry, of the liver (Poul et al. 2022), with permission of Elsevier Ltd., copy-
copyright 2018 right 2022
13
𝜕 𝛼 𝜀(t) their mechanical behavior at various steatosis stages

𝜎(t) = E0 𝜀(t) + η (6) (Yilmaz 2020). Zener, Maxwell, and Kelvin–Voigt mod-
𝜕t𝛼
els have been used to analyze mechanical properties. The
where α ranges between 0 and 1; the E0 and η are the spring model has to satisfy both the ex vivo dynamic mechanical
elastic constant and viscosity coefficient of the dashpot, analysis (DMA) experiment at low frequency (1–41 Hz)
respectively (Mattei and Ahluwalia 2016). The relaxation and the in vivo shear wave elastography (SWE) experi-
time constant (τ) is used instead of η by letting η= E0τα, ment at high frequency (160–380 Hz) (Pellot-Barakat
resulting in Eq. (7) (Mattei and Ahluwalia 2016). The form et al. 2016). Table 5 summarizes the fitness profile for
of this equation has three constants characterizing the mate- each of the three models to the shear wave velocity (Lin
rials’ mechanical behavior (i.e., E0, τ, and α) (Marchesseau et al. 2017; Pi et al. 2021). The tabulated results reveal
et al. 2017). that the best model characterizing the rats’ mechanical
( 𝛼
) properties at every steatosis stage is the Voigt model with
𝛼 𝜕 𝜀(t)
𝜎(t) = E0 𝜀(t) + 𝜏
𝜕t𝛼
(7) a determination coefficient (R2) near 1.
The KVFD has the following significant differences

(Poul et al. 2022; Zhu et al. 2016): 10 Porous visco‑hyperelastic model
i. KVFD has a continuous and gradual response in creep The liver tissues are modeled frequently as a fluid-filled
compliance, whereas the SLS has a discontinuous and porous matrix. This liver model includes viscosity, poros-
instantaneous response at time zero. ity, and hyperelasticity, modeled by the Prony series (Payan
ii. Stress relaxation varies at t−α for the KVFD model but and Ohayon 2017). At the same time, the linear Darcy law
decays exponentially in the SLS model. signifies the mechanical impact of liver perfusion based on
iii. In the KVFD model, the frequency response of the the porosity model working parallel to visco-hyperelastic
complex Young’s modulus is dependent on ωα instead components, as demonstrated in Fig. 9c (Mattei and Ahlu-
of only ω (where ω is the angular frequency). walia 2016). The poro-visco-elasticity (PVE) model extends
the biphasic theory and describes tissues into two phases of
The frequency response in the KVFD model under- immiscible mixtures containing incompressible phases of
goes a monotonically increase dissimilar to that in the the inviscid fluid and solid elastic phases (Chmarra et al.
SLS model, attaining a plateau (Glińska-Suchocka et al. 2013). The solid phase has intrinsic viscoelasticity, con-
2017; Pi et al. 2021). In addition, the measured velocity sidered in the flow-independent viscoelastic behavior. In
during the propagation of shear waves across the liver at contrast, its solid phase has been modeled as a viscoelas-
distinct values ranging from 40 Hz to 14 MHz indicates tic material using a Prony series with n = 3 Maxwell arms
the monotonical increase of shear velocity with frequency (spring–dashpot) parallel to a single spring (Mattei and
(Glińska-Suchocka et al. 2017; Pi et al. 2021). Concluding Ahluwalia 2016). The testing of ex vivo porcine liver speci-
from the dynamic testing on tissues of the canine liver, the mens at different ramp strain rates ranging from 0.001 s−1 to
KVFD model exhibited a good fit with the experimental 0.1 s−1 has shown that the use of the viscoelastic (VE) model
data compared to other models, such as the KV model resulted in an underestimating of the peak force values in
(Yeh et al. 2015). contrast to the PVE model, which is due to the absence of a
The KVFD model has been used frequently for assess- fluid phase (Chen and Shih 2013).
ing liver viscoelasticity, as reported in most studies (Evans Investigating the influence of the viscous component
et al. 2013; Untaroiu et al. 2015). A recent study has con- by adding viscosity to hyperelasticity will increase the
ducted rheological experiments on rat livers to quantify liver's amplitude as the material's stiffness increases (Rus
et al. 2020). The final state shows the difference in the final
Table 5 Fitting effect of Model The determination coefficient (R2)

the three common models
in dynamic mechanical SWE DMA
analysis (DMA) and shear
wave elastography (SWE) Normal (n = 3) Steatosis (n = 3) Normal (n = 6) Steatosis (n = 6)
experiments on normal and
Generalized 0.35 0.35 0.52 0.53
steatosis liver tissues, with
Maxwell
n being the number of rat
samples. (Lin et al. 2017; Pi KVFD 0.80 0.84 0.89 0.88
et al. 2021) Zener 0.54 0.44 0.94 0.92
13
Fig. 12 (Top) Pressure field of the liver porous component at the ison of the initial/final states and maximum amplitude (Marchesseau
action of gravity (dotted lines highlight the highest-pressure areas). et al. 2017), with permission of Elsevier Ltd., copyright 2017
(Bottom) The Counting of viscosity to hyperelasticity with a compar-
state with respect to the visco-hyperelastic compared to to enhance patient-specific modeling, which could be uti-
hyperelastic models, as demonstrated in Fig. 12 (bottom) lized in surgical environments (Chanthasopeephan et al.
(Marchesseau et al. 2017). Under the action of gravity, the 2007).
liver deforms to overpass the linearity bound of the material Additionally, simulating hyperelastic models is signifi-
as a large amount of compression and extension can occur cantly cheaper than most viscoelastic models (Hashemi et al.
due to the liver’s porous component controlling the viscos- 2020). The constitutive models of soft tissues rely mainly on
ity quantity (Idilman et al. 2020). The implicit integration the homogenized, anisotropic, and hyperelastic model mim-
scheme enables more significant time steps like 0.3s, mak- icking the response of the actual hepatic tissues (Hashemi
ing the real-time interaction probable (Marchesseau et al. et al. 2020). The heterogeneity of the liver tissue impacts the
2017). Figure 12 (top) is a color map of the fluid pressure real-time biomechanical response in augmented reality sur-
field simulated throughout the deformation, which ranges gery (Kumar 2015). Figure 13a shows the mesh geometry of
from the initial pressure (dark blue) to the highest pressure the liver and its vascularization based on its dissimilar seg-
(red) (Marchesseau et al. 2017). A comprehensive model mentations, which demand merging for a complete 3D aniso-
combining porosity and visco-hyperelasticity prevents the tropic structure (Kugler 2018). Michael Kugler et al. applied
liver from undergoing unrealistic deformations (Nava et al. more complex liver meshes and counted their vasculariza-
2008). Consequently, the deformation is not homogenous tion, as shown in Fig. 13b (Michael Kugler et al. 2018a,
any longer and varies with time. b). The generated geometries and overlapping meshes are
from medical images such as CT scan and MRI (Chi et al.
2011). The vascularization is integrated into a single mesh
11 Computational simulation to perform the mechanical simulation (Lauzeral et al. 2019).
Chi et al. considered 20 patient livers and vascularization
Finite element (FE) is a method for numerically solving dif- extracted from the IRCAD open database in FE modeling
ferential equations on a structured mesh representing physi- (Chi et al. 2011). The complexity of the vascularization
cal geometries (Brock et al. 2002). The FE modeling has geometries shows significant variations in the mesh preci-
been used to aid surgical decisions by providing simulated sion compared to the patient livers and in the vascularization
outcomes in real time through augmented reality (Michaël density varying from 0.8% to 3.3%, with an average of 1.4%
Kugler et al. 2018a, b). The real-time organ simulation of the total liver volume (Chi et al. 2011). Thus, there is a
through FE modeling requires precision and time efficiency need for an intelligent homogenized model considering the
13
Fig. 13 a The FE modeling of liver geometry and its vasculariza- mesh corresponding to the liver and other brown, blue-green, and
tion with each cube representing a heterogeneous segment (Kugler green dense meshes corresponding to the vascularization (Michael
2018), with permission of HAL archives-ouvertes.fr, copyright 2018. Kugler et al. 2018a, b), with permission of Elsevier Ltd., copyright
b Example of liver and vascularization surface meshes obtained 2018.
through segmentation of CT scan images from IRCAD with light
anisotropic and nonlinear behavior of the liver to integrate obtain an ideal liver phantom with long-term stability for
it within real-time computations (Untaroiu and Lu 2013). liver procedures (Ahmad et al. 2020a, b). The fabrication
The combination of medical imaging techniques and precise materials of the liver's phantom should be safe to prepare
quantification of the liver's mechanical properties enables and handle, stable under different environmental condi-
accurate patient liver simulations, consideration of the inner tions, facile and reproducible in preparation, easy to store
vascular distributions, and probable tumors utilizing nonin- and transport, and demand low-cost ingredients (Mattei
vasive in vivo characterization (Cheng and Hannaford 2015). et al. 2022). Table 6 displays the mechanical properties
of the commonly utilized fabrication materials of liver
phantoms, including styrene-ethylene-butylene-styrene
12 Fabrication materials to develop (SEBS) copolymer, gelatin, polyvinyl alcohol (PVA), sili-
liver‑tissue‑mimicking phantoms cone, polyvinyl chloride (PVC), and agar. The mechanical
properties per material are compared with the hepatic tis-
The fabrication material of the liver phantom seeks to sues and scored on their closeness. The durability property
mimic the structure and morphology of the actual liver includes shelf life, resistance to deformation/cracking, and
in the human body. Different materials are developed to storage requirements.
Table 6 Mechanical properties of common fabrication materials for phantoms mimicking the human liver
Fabrication material Speed of sound (m/s) Attenuation (dB/cm/MHz) Young’s modulus (kPa) Durability Refs.
Styrene-ethylene-butyl- ++(1423–1502) +(0.25–0.42) +(26–70) +++ Ahmad et al. (2021),

ene-styrene (SEBS) Cabrelli et al. (2017)
copolymer
Gelatin +++(1510–1590) +++(0.12–1.53) +++(35–58) + Anugrah et al. (2020),
Kandala et al. (2021)
Polyvinyl alcohol (PVA) +++(1520–1610) +(0.07–0.35) ++(60–125) + Cournane et al. (2010), In
et al. (2012)
Silicone +(1000–1150) +(1.25–2.63) ++(25–82) +++ Chen and Shih (2013),
Lamouche et al. (2012)
Polyvinyl chloride (PVC) ++(1400–1420) ++(0.44–0.65) +++(24–123) +++ Chatelin et al. (2020b),
Rethy et al. (2018)
Agar +++(1540–1600) +++(0.04–1.42) +(105–115) + Ahmad et al. (2022), In
et al. (2014)
+ = worst;++ = suitable;+++ = best
13
The most frequently reported property is the speed of measurement of attenuation and speed of sound (Chen et al.
sound owing to its significance for ultrasound phantoms 2022). If storage requirements and tedious fabrication meth-
in calibrating clinical transducers to be close to the typical ods can be overcome, PVA is the best option due to its excel-
value of hepatic tissues (1540 m/s). Varying the concentra- lent tunability for all demanded properties. Future phantoms
tion of backscatter agents can increase the attenuation coef- might mimic the complex structure of human hepatic tissues
ficient with negligible effect on the speed of sound (Ahmad by combining existing tissue-mimicking materials or fabri-
et al. 2020a, b). Considering both attenuation and speed of cating multiple tissue layers to investigate spatial control
sound, gelatin and agar closely mimic biological tissue and of acoustic and mechanical properties (Stengl et al. 2022).
produce realistic ultrasound images for building anatomical Additive manufacturing can assist in anatomical landmarks
structures of varying compositions. The ultrasound scans and raise the fidelity of phantoms mimicking human hepatic
of PVA are reported with pixel intensity close to human tissues (Stengl et al. 2022). For example, 3D-printed phan-
tissues (Cournane et al. 2010). The fabrication method of toms based on silicone with additive materials, such as water
PVA is long and complex (Cournane et al. 2010). Still, vary- glucose solution and tertbutyl, have been utilized to mimic
ing material composition and the number of freeze–thaw specific tissues like fatty liver tissues (Morr et al. 2021b).
cycles (FTCs) might tune its acoustic and mechanical prop-
erties to mimic hepatic tissues (de Jong et al. 2019). On
the other hand, silicone is anechoic on ultrasound due to 13 Challenges and outlook
its high attenuation and low speed of sound compared to
biological tissues (Ansar et al. 2019). PVC also has a speed Precisely characterizing the liver’s mechanical behavior is
of sound below that of hepatic tissues, which can be notably pertinent in in vitro applications, diagnostic purposes, and
improved with appropriate plasticizer selection and concen- tissue engineering (Chatelin et al. 2011). The modeling and
tration (Chatelin et al. 2020a). quantifying of materials’ mechanical properties are neces-
Considering the tactile feedback resulting from a suitable sary to understand, monitor, and predict their responses and
mechanical response of the phantom, fabrication materials performance under certain loading conditions. The mechani-
such as PVC, PVA, and gelatin revealed tunability mim- cal characterization through constitutive modeling demands
icking the soft tissues' elasticity (Ahmad et al. 2020a, b). identifying and controlling environmental and geometric
Advanced shear wave speed technologies accurately repre- testing boundary conditions. For decades, characterizing
sent tissue elasticity compared to the longitudinal measure- structural materials have been done through different test-
ment of Young's modulus, which is limited by tissue anisot- ing approaches. However, reliable data for degradable and
ropy (Nikolaev and Cotin 2020). An additional advantage hydrated soft materials are still deficient, particularly the
of silicone, SEBS, and PVC materials is being insoluble non-load-bearing biological tissues, including the kidney,
in water (Mattei et al. 2022). As a result, phantoms fabri- brain, and liver (Afiqah Bakri et al. 2019). The primary rea-
cated from these materials show more stability and dura- son is their softness, shape, and labile nature (Afiqah Bakri
bility throughout aging (Mattei et al. 2022). In contrast to et al. 2019). In addition, such materials are biphasic, involv-
phantoms fabricated from hydrated materials, including ing a solid network being completely swollen and bounded
gelatin and agar, which dehydrate or foster bacterial growth with liquid media (Huerta-López and Alegre-Cebollada
(Łabowska et al. 2021). The less traditional tissue-mim- 2021).
icking materials such as zerdine, urethane, polyacrylamide The mechanical behavior of biological tissues is char-
(PAA), household items (e.g., hair gel, condensed milk, acterized in vivo or ex vivo through numerous models and
wire-pulling lubricant), and foodstuffs (e.g., chicken breast, methods depending on direct tissue specimen measurements
mixed-meat rolls, and tofu) are reported as low-cost vascular or image techniques (Mattei and Ahluwalia 2016). The test-
access phantoms but with limited re-usability, short shelf- ing of tissue in vivo preserves its status, but it has several
life, and absence of studies onto their mechanical properties constraints, including accessibility, subjecting humans to
(McGarry et al. 2020). potential risks, and ethical issues regarding using animals
Eventually, there might be a need for a compromise (Alshipli et al. 2018; Makhamrah et al. 2019). Nevertheless,
between the phantom’s requirements in terms of fabrica- systematic studies have described and characterized the tis-
tion, storage, mechanical feedback, and acoustic properties. sue mechanical behavior in vivo with datasets frequently
In phantoms’ fabrication, the selection of the tissue-mim- restricted to minor deformations (Mazza et al. 2007). Fur-
icking material should be based on carefully considering thermore, the in vivo data interpretation is also tricky due
its fabrication purpose. For instance, PVC exhibits good to the incapability to regulate the internal condition of the
shelf-life and mechanical properties suitable for prolonged organ and challenges in finding a suitable arrangement for
use (Chatelin et al. 2020b). Alternatively, gelatin and agar positioning the tested specimen and instrument (Crescenzi
have tissue-like ultrasound compatibility for quantitative et al. 2019; Glińska-Suchocka et al. 2017).
13
Alternatively, the ex vivo trials are desirable in advancing Additionally, considering liver tissue’s mechanical prop-
novel testing tools, tissue models, and procedures to permit erties is an ultimate goal in manufacturing liver phantoms,
more direct and accessible testing trials fitting regulation with mechanics recapitulating the qualities of living tissue
of boundary conditions and have less ethically problematic (Afiqah Bakri et al. 2019). Initially, mimicking the stiffness
compared to in vivo measurements (Gerhard et al. 2012; or/and softness of native liver structures requires considering
Johnson et al. 2021). Though the numerous published meth- their static mechanical properties (Rethy et al. 2018). How-
ods and studies in the literature, there still needs to be uncon- ever, the biological tissues have a dynamic nature leading
ditional mechanical properties of the liver. The published to a necessity to integrate the mechanics’ changes in time/
results depend strongly on variations in testing protocols and rate dependent and heterogeneity (Guimarães et al. 2020).
techniques, as well as the differences in sample source, type, Considering the time-varying mechanics by adopting mate-
and status, which rely on the different objectives and needs rials from stress-relaxation or stress-stiffening responses
of the researchers. Furthermore, implementing other tissue mimicking the real hepatic tissue response is possible (Rafiq
models as purely elastic models instead of poro-viscoelastic et al. 2018). Thus, the material will respond to the increased
or viscoelastic models could influence the assessed hepatic stress or continued duration through relaxation or stiffness,
tissue properties. respectively (Makhamrah et al. 2019). The lacking mate-
Moreover, stress relaxation and creep tests are the wide- rial for such dynamicity could be overcome through the
spread measuring techniques for viscoelastic materials’ direct application of mechanical deformation on constructs
time-dependent behavior of liver tissues (Cai et al. 2017). to duplicate these properties. The heterogeneity-changing
Such tests have been utilized in combination or separately, mechanics occurs in the tissue interfaces as in areas with
enabling complete and precise data on the time-dependent cartilage turning progressively into bone (Khogalia et al.
behavior of viscoelastic samples (Bartolini et al. 2018). 2020). Mimicking these gradually varying structures is via
However, these tests demand the formation of initial con- gradients of mechanical properties, composition, and design
tact between the testing apparatus and the sample allowing (Khogalia et al. 2020).
the initiation of the measurements (Bartolini et al. 2018).
Consequently, it could lead to noteworthy pre-loading on
the highly soft hepatic specimen and then changing its sta-
tus. For instance, in crash simulation, the mechanical out- 14 Conclusions
comes from impact tests have high strain rates (Untaroiu
et al. 2015). Therefore, establishing standard protocols and The liver phantoms are artificial structures designed to
tailored guidelines for data analysis, mechanical testing, mimic the natural hepatic tissue properties, including their
and sample preparation for each application is necessary to mechanical properties. Considering patient safety, these
facilitate comparative studies (Labonte et al. 2017; Mattei phantoms are utilized to fill the gap between theory and
and Ahluwalia 2016). clinical practice for medical training and simulation. The
Furthermore, there is a need for biomarker assessments in fabrication materials of the liver's phantom should be safe
the safe and non-invasive characterization to replace the his- to prepare and handle, stable under different environmental
tological analysis relying on liver biopsy in quantifying and conditions, facile and reproducible in preparation, easy to
staging liver diseases and their progression from ongoing store and transport, and demand low-cost ingredients. The
inflammation to consequent fibrosis. The liver disease stages constitutive models of mechanical properties for the viscoe-
correlate to their mechanical properties, which are sensi- lastic hepatic tissues are generalized Maxwell (GM), stand-
tive to tissue alterations. Then, their assessment could be ard linear solid (SLS), Kelvin–Voigt (KV), Kelvin–Voigt
utilized as an alternative biomarker to the information from fractional derivative (KVFD), and porous visco-hyperelastic
the liver biopsy test (Wells and Liang 2011). For instance, models. The finite element (FE) method is used in computa-
the fibrosis stages are correlated to liver stiffness, while the tional simulation to aid surgical decisions by providing sim-
inflammation level is related to liver viscosity (Leitão et al. ulated outcomes in real time through augmented reality. The
2017). In addition, the diagnosis performance of liver stea- mechanical properties, including elasticity, viscoelasticity,
tosis staging improves by correlating the staging steatosis to acoustic impedance, and attenuation, are further considered
the liver sound speed and attenuation (Casciaro et al. 2009). critical biomarkers for diagnosing different histopathologic
Thus, the stages of liver inflammation, liver steatosis, and scores of hepatic fibrosis, inflammation, and fat content in
liver fibrosis are of significant importance from a clinical a patient without invasive biopsies. Future phantoms might
perspective to monitor the NASH, antiviral, and antifibrotic mimic the complex structure of human hepatic tissues by
treatments (Gidener et al. 2021), in addition, to follow up combining existing tissue-mimicking materials or fabricat-
on the evolution of chronic liver diseases and assess their ing multiple tissue layers to investigate spatial control of
prognosis (Yin et al. 2011). acoustic and mechanical properties. Additive manufacturing
13
can assist in anatomical landmarks and raise the fidelity of applications in the liver. Diagnostic Interv Radiol 24:328–335.
phantoms mimicking human hepatic tissues. https://doi.org/10.5152/dir.2018.18186
Alshipli, M., Kabir, N.A., Tajuddin, A.A., Hashim, R., Kabir1, N.A.,
Acknowledgements This work was supported by Qatar University Tajuddin1, A., H ashim2, R., M arashdeh1’3, M.W., 2018. Evaluat-
Grant no. GTRA-17722. The statements made herein are solely the ing the Physical Properties of Epoxy Resin as a Phantom Mate-
responsibility of the authors. Open Access funding is provided by the rial to Mimic the Human Liver in Computed Tomography Appli-
Qatar National Library. This study was made possible by NPRP grants cations. https://doi.org/10.15242/IJACEBS.ER12172013
NPRP11S-1211-170083 from the Qatar National Research Fund (a Ansar A, Tahir D, Abdullah B, Nurhasmi F, Jusmawang S (2019)
member of Qatar Foundation). Physical characteristics of soft tissue phantom from silicone rub-
ber based vulcanization system. Mater Sci Forum 966:194–199.
Authors’ contribution ASL did conceptualization and writing—origi- https://doi.org/10.4028/www.scientific.net/MSF.966.194
nal draft. JB done writing—review and editing. ZA, AH and NJA-T Anugrah MA, Suryani S, Ilyas S, Mutmainna I, Fahri AN, Jusmawang
contributed to writing—review and editing. All authors have read and T, D., (2020) Composite gelatin/Rhizophora SPP particleboards/
agreed to the published version of the manuscript. PVA for soft tissue phantom applications. Radiat Phys Chem
173:108878. https://d oi.o rg/1 0.1 016/j.r adphy schem.2 020.1 08878
Funding Open Access funding provided by the Qatar National Library. Bartolini L, Iannuzzi D, Mattei G (2018) Comparison of frequency and
strain-rate domain mechanical characterization. Sci Rep. https://
doi.org/10.1038/s41598-018-31737-3
Declarations Basdogan C (2012) Dynamic material properties of human and animal
livers. Soft Tissue Biomech Model Comput Assist Surg 11:229–
Conflict of interest The authors declare that they have no known com- 241. https://doi.org/10.1007/8415_2012_122
peting financial interests or personal relationships that could have ap- Bienstock J, Heuer A (2022) A review on the evolution of simula-
peared to influence the work reported in this paper. tion-based training to help build a safer future. Med (baltimore)
101:e29503. https://doi.org/10.1097/MD.0000000000029503
Open Access This article is licensed under a Creative Commons Attri- Boursier J, Vergniol J, Guillet A, Hiriart JB, Lannes A, Le Bail B,
bution 4.0 International License, which permits use, sharing, adapta- Michalak S, Chermak F, Bertrais S, Foucher J, Oberti F, Char-
tion, distribution and reproduction in any medium or format, as long bonnier M, Fouchard-Hubert I, Rousselet MC, Calès P, de
as you give appropriate credit to the original author(s) and the source, Lédinghen V (2016) Diagnostic accuracy and prognostic sig-
provide a link to the Creative Commons licence, and indicate if changes nificance of blood fibrosis tests and liver stiffness measurement
were made. The images or other third party material in this article are by FibroScan in non-alcoholic fatty liver disease. J Hepatol
included in the article's Creative Commons licence, unless indicated 65:570–578. https://doi.org/10.1016/j.jhep.2016.04.023
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Biomechanics and Modeling in Mechanobiology (2024) 23:373–396