**2. Epidemiology**

The reported prevalence of CDH varies among studies [2–5]. The European Surveillance of Congenital Anomalies (EUROCAT) registry data analysis (1980- 2009) has described the prevalence to be 2.3 per 10,000 births for all-inclusive and 1.6 per 10,000 for isolated cases [6]. Balayla *et al*. reported an incidence of 1.93 per 10,000 births in the United States [7]. The variability in the reported prevalence is due to differences in the studied geographical population, data collection methodologies, inclusion and exclusion criteria, case ascertainment and hidden mortality [8]. A decreasing trend in the live births with CDH has been reported, most likely due to an increasing number of termination of pregnancies with antenatal diagnosis of fetuses with CDH [5, 6]. Overall, the survival rate in CDH, although variable among centers, is >70% and has consistently improved over time [9, 10]. A nonsignificant improvement in the survival of CDH cases which are complicated with major cardiovascular or chromosomal anomalies has been recently reported [10]. The implementation of the standardized management protocols has improved the survival rate from 67% to 88% [11]. Overall, the evaluation of epidemiology and risk factors for CDH is arduous due to the heterogeneity among the studies.

CDH is more common in males [7]. The reports regarding the association of high maternal age with increased risk of CDH are conflicting [5–7, 12]. Pre gestational hypertension [5, 13] and alcohol abuse are other proposed maternal risk factors [7, 13, 14]. The impacts of ethnicity, race, maternal tobacco use and pre gestational diabetes on the risk for CDH are unclear and need further research, although a slightly lower occurrence in blacks has been documented. The identification of modifiable antenatal risk factors help in deciding the direction of prenatal screening and thus the prevention of CDH.


*4.4. Formula Verification*

In this paper, the data from the tests and extended parameter analyses, as well as the data used for comparison with [9] and [20], were used to verify Formula (9). The verification results are shown in Table 9, whereby the symbol YZSS(YZFS) represents the specimens strengthened by the PCSAM corresponding to [9], while the symbol ZMR(ZRW) represents the specimens from Tang's test corresponding to [20]. It can be observed in the table that the difference between the bearing capacity calculated by Formula (9) and the

**Name BCT(S) \*1 (kN) ACSC of Column** *f* **co (MPa) Filled Concrete Strength** *f* **sc (MPa) Concrete Strength of LCSS** *f* **gc (MPa) Self-Stress** *q* **(MPa) Confinement Coefficient** *θ* **Self-Stress Level** *η* **BCC \*2 (kN) Difference** S1-A 2147 20.1 19.8 20.9 0 0.176 0 2035 −5.20% S1-S 2621 20.1 21.7 20.9 0.99 0.177 0.046 2565 −2.12% S1-SS 2153 20.1 21.7 13.4 0.83 0.147 0.038 2243 4.19% S2-S 1926 20.1 21.7 20.9 0.63 0.250 0.031 2116 9.89% M-1 2578 20.1 21.7 20.9 0.8 0.177 0.037 2507 −2.77% M-2 2695 20.1 21.7 20.9 1 0.177 0.046 2568 −4.71% M-3 2802 20.1 21.7 20.9 1 0.177 0.055 2615 −6.67% M-4 2810 20.1 21.7 23.4 1 0.182 0.046 2648 −5.78% M-5 2876 20.1 21.7 26.8 1 0.192 0.046 2769 −3.71% M-6 2992 20.1 21.7 32.4 1 0.204 0.046 2960 −1.06% M-7 2771 20.1 23.4 20.9 1 0.180 0.043 2633 −4.99% M-8 2859 20.1 26.8 20.9 1 0.187 0.037 2774 −2.96% M-9 2955 20.1 32.4 20.9 1 0.196 0.031 3004 1.66% YZSS1 \*3 3578 39.8 17.9 44.2 0 0.075 0 3470 −3.03% YZSS2 \*3 3220 39.8 17.9 44.2 0 0.075 0 3470 7.76% YZSS3 \*3 3984 39.8 17.9 44.2 0 0.075 0 3470 −12.90% YZFS1 \*3 4640 39.8 17.9 44.2 0 0.125 0 4060 −12.51% YZFS3 \*3 4524 39.8 17.9 44.2 0 0.125 0 4060 −10.26% ZMW1 \*4 1120 20.1 32.8 0 0 0.155 0 991 5.87% ZMW2 \*4 936 20.1 32.8 0 0 0.155 0 991 −11.52% ZRW1 \*4 1027 20.1 45.5 0 0 0.128 0 1153 12.25% ZRW2 \*4 1071 20.1 45.5 0 0 0.128 0 1153 7.66% ZRW3 \*4 1113 20.1 45.5 0 0 0.128 0 1153 3.59%

bearing capacity of the tested and simulated specimens is less than 13%, which shows good applicability.

**Table 9.** Verification results of the fitting formula.

\*1: BCT(S) = Bearing capacity of specimens tested (or simulated). \*2: BCC = Bearing capacity calculated by Formula (4). \*3: The symbol YZSS(YZFS) represents the data from [9]. \*4: The symbol of ZMW(ZRW) represents the data from [20].


**1. Introduction**

Today, about 50% of electrical energy produced is used in electric drives. Electrical motors consume around 40% of total consumed electrical energy (Almeida et al., 2007) and of that thereof, induction motors account for 96% of energy consumption. Around 67% of this energy is used in induction motors with a rating below 75 kW and it can be shown that 85% of the energy losses are dissipated in these rating motors. Efficiency improvements of constant-speed drives, both constant-torque and variable-torque drives, is very important. It is usual that techniques for efficiency improvements of variable-torque drives are different from those of constant-speed and constant-torque applications. The latter is dealt with through optimization; it is very difficult to design and build a motor with high rating efficiency and rating power factor - it has been shown (Fei et al., 1989) that higher efficiencies are associated with lower power factor. It is especially difficult to design and build a drive operating at high efficiency and power factor over an entire range of loads, say from 25 - 100% of rated load (*PN*), i.e. at partial load.

Electrical energy savings in the drive could be realized by improvements of power quality in the consumer network. Term power quality (Linders, 1972; Bonnett, 2000) mostly means quality of supply voltage that should meet the following requirements:

Power losses and reactive loads depend from on voltage magnitude and they are further increased due to unbalanced voltage and (or) the presence of harmonics in supply voltage.

Unbalance voltage can occur due to the presence of larger single-phase consumers or asymmetrical capacitor banks with damage or capacitors that are switched off due to the fuse burning only in one phase. Nowadays, the presence of higher harmonics in the supply voltage is ever more frequent due to the growth of consumers who are supplied through the rectifiers and inverters: regulated actuators, electrothermical consumers and consumers alike.

Effects of Voltage Quality on Induction Motors' Efficient Energy Usage 129

and reactive loads on voltage value will be presented, as well as proceedings for calculation

**Figure 1.** Efficiency versus load for various applied voltages in percent of its 460 V rating for a standard

In order to determine total dependence of power losses on voltage, for the load range from no-load to full load, it is necessary to determine no-load power - voltage dependency, *P0(u)* :

Load losses component (PLL) depend on relative load (*pL=PL/PN*) and relative voltage values

, / *P LL N P P pu*

2 2

0 0 () () () *Cu Fe fw Pu P u P u P* (1)

(2)

**2.1. Dependency of power losses and reactive loads on voltage value**

efficiency motor (10 HP and 50 HP)

*PCu0* copper losses in no-load, *PFe* core losses in no-load,

*PfW* friction and windage losses in no-load.

Where are

(*u=U/UN*):

and analysis of power losses and reactive loads on voltage value.

The effect of a variation in supply voltage, wave-form or frequency on the motor's efficiency and power factor characteristics depends on the individual motor design. Typical variations of current, speed, power factor and efficiency with voltage for constant output power are given in Fink (1983). The usual characteristics of induction motors within the ±10% voltage band (*Un*±10%) are well known. These are included in corresponding table for typical 30- 100 kW, 1500 or 1800 1/min motors (Linders, 1972; Fink, 1983), but the effect of saturation has been largely neglected in these tables. However, it is the author's intent to show a correlation between motor characteristics and voltage level.

This proposed has three parts:


3.2.6. Synthesis of Cu[CH3C(CH2OH)3]2{CuMo6O16(OH)2[CH3C(CH2O)3]2}·6H2O (**6**)

To a stirred solution of CuCl2·2H2O (0.34 g, 2.00 mmol) and CH3C(CH2OH)3 (0.48 g, 4.00 mmol) in water (20 mL), MoO3 (0.86 g, 12.00 mmol) was added. The pH of the resulting solution was adjusted to 3~4 by the concentrated HCl. After heating the mixture to 80 ◦C for 2 h, a blue solution was obtained using hot filtration, which generates blue crystals in several days. Elemental analysis calcd. (%) for Cu[CH3C(CH2OH)3]2{CuMo6O16(OH)2[CH3C(CH2O)3]2}·6H2O (Mw = 1575.36 g mol<sup>−</sup>1): C 15.25%, H 3.58%, Cu 8.07%, and Mo 36.54%; found C 15.58%, H 3.65%, Cu 8.14%, and Mo 36.55%.


**Author details**

Maria Teresa Mascellino\*, Massimiliano De Angelis, Dania Al Ismail and Alessandra Oliva Sapienza University of Rome, Rome, Italy

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


*Article* **Fast Evaluation and Comparison of the Energy Performances of Elastomers from Relative Energy Stored Identification under Mechanical Loadings**

**Jean-Benoît Le Cam**

Institut de Physique UMR 6251 CNRS de Rennes 1, Campus de Beaulieu, Université de Rennes 1, Bât. 10B, CEDEX, 35042 Rennes, France<EMAIL_ADDRESS>
**Abstract:** The way in which elastomers use mechanical energy to deform provides information about their mechanical performance in situations that require substantial characterization in terms of test time and cost. This is especially true since it is usually necessary to explore many chemical compositions to obtain the most relevant one. This paper presents a simple and fast approach to characterizing the mechanical and energy behavior of elastomers, that is, how they use the mechanical energy brought to them. The methodology consists of performing one uniaxial cyclic tensile test with a simultaneous temperature measurement. The temperature measurement at the specimen surface is processed with the heat diffusion equation to reconstruct the heat source fields, which in fact amounts to surface calorimetry. Then, the part of the energy involved in the mechanical hysteresis loop that is not converted into heat can be identified and a quantity *γse* is introduced for evaluating the energy performance of the materials. This quantity is defined as an energy ratio and assesses the ability of the material to store and release a certain amount of mechanical energy through reversible microstructure changes. Therefore, it quantifies the relative energy that is not used to damage the material, for example to propagate cracks, and that is not dissipated as heat. In this paper, different crystallizable materials have been considered, filled and unfilled. This approach opens many perspectives to discriminate, in an accelerated way, the factors affecting these energetic performances of elastomers, at the first order are obviously the formulation, the aging and the mechanical loading. In addition, such an approach is well adapted to better characterize the elastocaloric effects in elastomeric materials.

**Keywords:** elastomer; fast characterization; energy stored and released; heat source reconstruction; intrinsic dissipation; infrared thermography

## **1. Introduction**

Elastomers are widely used in many industries, such as automotive, nuclear or civil engineering, for their high deformability, high damping and, for some of them, their high fatigue resistance. As for most of the engineering materials, their design requires substantial characterization time and cost, typically for fatigue [1–7], crack propagation [8–10], aging [11–13] and damping [14], non-exhaustively. At a time when many sectors that use elastomeric materials are undergoing deep technological changes, such as health with implantable medical devices or mobility with the desire to decarbonize transportation, it is necessary to develop new materials and new technological solutions that must be evaluated in an increasingly limited time and at a low cost. In addition, crystallizing elastomers are increasingly studied for their elastocaloric properties [15–17] and criteria are needed to compare their energy performance. This is why the development of fast characterization methods for rubbers, allowing a classification of the desired performances, however basic, is today a major challenge in most industries.

What makes elastomers attractive for many applications is that their mechanical response exhibits a hysteresis loop. The mechanical hysteresis is generally obtained by

**Citation:** Le Cam, J.-B. Fast Evaluation and Comparison of the Energy Performances of Elastomers from Relative Energy Stored Identification under Mechanical Loadings. *Polymers* **2022**, *14*, 412. https://doi.org/10.3390/ polym14030412

Academic Editors: Radek Stoˇcek, Gert Heinrich and Reinhold Kipscholl

Received: 30 November 2021 Accepted: 17 January 2022 Published: 20 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

adding fillers in the rubber matrix and/or strain-induced crystallization (SIC) and melting. Classically, the mechanical energy involved in the hysteresis loop is assumed to be mainly dissipated into heat. Nevertheless, several observations question this assumption:

One can therefore wonder about the nature and the time dependency of the phenomena involved in the formation of the hysteresis loop and about the real contribution of the intrinsic dissipation to it. To go further in the discussion, it is necessary to recall that in addition to the intrinsic dissipation two other factors can affect to the mechanical hysteresis:

Thus, of the many phenomena that can contribute to the hysteresis loop, some do not appear to dissipate energy as heat. This is in fact what is assessed with self-heating tests for evaluating the fatigue properties [28]. Therefore, the level of self-heating or more precisely intrinsic dissipation must be put into perspective in relation to the energy rate involved in the hysteresis loop. Even more interesting is the part of the mechanical energy brought that is stored and released by reversible microstructure changes, which is not dissipated as heat or used to damage the material, for example to propagate cracks. In the extreme, the mechanical response of an unfilled natural rubber exhibits a hysteresis loop as soon as it is crystallizing, while no (or minimally) energy is converted as heat [22].

Considering that contributions to the hysteresis loop change when one chemical formulation is substituted to another one (see for example [29]), or when one or more ingredients of a chemical formulation is changed to improve a given property (see, for example, [30–33]), the present study assumes that identifying the energy contributions and associated phenomena involved in the mechanical hysteresis is a reliable indicator of the material's performances.

Such analysis echoes the pioneering work by [34,35] who measured the latent energy remaining after cold working in a metal under quasi-static monotonous loadings. Today, the fraction of the anelastic deformation energy rate irreversibly converted into heat is studied through the Taylor–Quinney ratio [36–40]. Polymers have then benefited from this approach in the Rittel's group [41,42] and the Chrysochoos's group [43,44]. Concerning elastomers, only four recent studies investigate the energetic behavior and the energy storage during deformation [22,45–47]. From these studies, the energy storage in different types of elastomers, filled and unfilled, crystallizing or not, can be discussed. The main difference with the pre-mentioned materials is that the energy stored elastically with a given kinetics is

released within the same mechanical cycle, but with a different kinetics. This energy serves for reversible changes in microstructure, typically when the crystallization—crystallite melting process occurs in natural rubbers [20,48]. Section 2 presents the thermodynamics framework for calorimetry under stretch from surface temperature measurements, the methodology for energy balances and the definition of the characteristic quantity giving the energy performance. Section 3 presents a typical experimental setup. Section 4 provides illustrations with different materials, inspired from three recent studies carried out in our group [22,45,47], which provides the first comparison of elastomers according to their energy performances. Concluding remarks close the paper.

#### **2. Thermodynamic Framework**

Identifying the phenomena involved in the mechanical hysteresis requires the calculation of several continuum quantities that are recalled in this section. The calculations are carried out in the case of the uniaxial tension.

#### *2.1. Total Strain Energy Density and Energy Rate Involved in the Hysteresis Loop*

The strain energy density *Wstrain* (in J/m3 ) is the energy brought mechanically to deform the material. It corresponds to the area under the load (unload) strain–stress curve and is calculated as follows:

$$\mathcal{W}\_{\text{strain}}^{load} = \int\_{load} \pi \, d\lambda \, \text{and } \mathcal{W}\_{\text{strain}}^{unload} = \int\_{unload} \pi \, d\lambda,\tag{1}$$

where *λ* is the stretch defined as the ratio between current and initial lengths. *π* is the nominal stress, defined as the force per unit of initial (undeformed) surface. If the material's behavior is purely elastic and if the test is carried out under adiabatic loading conditions, then the mechanical response obtained during a load-unload cycle is such that no hysteresis loop forms (*Wload strain* = *Wunload strain* ). If a hysteresis loop forms, the mechanical energy dissipated over one cycle *W cycle hyst* is defined as follows:

$$\mathcal{W}\_{hyst}^{cycle} = \mathcal{W}\_{strain}^{load} - \mathcal{W}\_{strain}^{unload}.\tag{2}$$

From this energy, a quantity *P cycle hyst* is calculated in W/m3 . It is obtained by dividing *W cycle hyst* by the cycle duration. It is therefore an energy density per time unit or an energy rate. It should be noted that when the mechanical cycle is also a thermodynamic cycle, the energy contained in the hysteresis loops is only due to intrinsic dissipation and thermomechanical coupling effects as long as the specific heat is assumed to be constant (further details are provided in [49,50]). This will be used in the following for carrying out the energy balances and to identify the intrinsic dissipation.

#### *2.2. Heat Sources*

During the mechanical cycle, the material produces and absorbs heat. Under non adiabatic conditions, corresponding temperature variations are influenced by heat diffusion effects. Therefore, temperature is not the relevant quantity to investigate the thermomechanical behavior of materials under non-adiabatic conditions, as most of classical mechanical tests are. This is the reason why the heat source (or the heat power density) is calculated from the heat diffusion equation and the temperature measurement (see [51,52] for further details). The heat source does not depend on the heat diffusion effects and is thus intrinsic to the thermomechanical behavior of materials. Considering the heat source field as homogeneous during uniaxial tensile loading, the formulation of the heat diffusion equation can be simplified as follows:

$$
\rho \mathbb{C} \left( \dot{\theta} + \frac{\theta}{\tau} \right) = \mathbb{S},
\tag{3}
$$

where *ρ* is the initial density, *C* is the specific heat, *θ* is the temperature variation with respect to the equilibrium temperature *T re f* in the reference state, corresponding here to the undeformed state. The heat sources *S* can be divided into two terms that differ in nature:

Equation (3) is formulated in the case where the ambient temperature *Tamb* is constant during the test. In case where changes in ambient temperature occur, the term *θ τ* has to be corrected accordingly as *T*−*Tamb τ* . *τ* is a parameter characterizing the heat exchanges between the specimen and its surroundings. It can be easily identified from a natural return to room temperature after a heating (or a cooling) for each testing configuration (machine used, environment, stretch level, etc). For instance, in cases where the material is beforehand heated, the exponential formulation of the temperature variation *θ*(*t*) = *θ*0*e* −(*t*−*t*0 ) *τ* is used to determine *τ*, where *t* is the time in *s* and *θ*0 = *θ*(*t* = *t*0). Further details are provided in [18]. It should be noted that under uniaxial tension, *τ* depends on the stretch only (*τ* = *τ*(*λ*)) (It should be noted that in the case of heterogeneous strain fields, *τ* spatially varies according to the heterogeneous change in the thickness, that is, to the stretch and to the biaxiality ratio *B* (*τ* = *τ*(*λ*, *B*). Further information on the identification of a *τ* field is provided in [53]). Several strategies can be applied for determining *τ*(*λ*). Either it is evaluated for different stretch levels or by considering the material to be incompressible and the thickness changes to be proportional to *λ* − 1 2 , so that *τ* = *τ*(*λ*) = *τ*0*λ* − 1 2 . It should be noted that when the material is crystallizing, the second strategy is preferred. Indeed, a change in temperature of the material (heating or cooling) changes the crystallinity. Therefore, an additional heat production or absorption is obtained during the return at the initial crystallinity, which affects the temperature variation during the return at ambient temperature and, consequently, the identification of *τ*.

#### *2.3. Identifying the Mean Intrinsic Dissipation*

Integrating the heat source, that is, the left member of Equation (3), with respect to time over one thermodynamical cycle gives the energy density due to intrinsic dissipation, the integration of the thermomechanical couplings being null. This energy is then divided by the cycle duration to obtain the mean intrinsic dissipation D˜ *int*. This amounts to applying the following formula:

$$\mathcal{D}\_{\rm int} = \frac{1}{t\_{\rm cycle}} \int\_{cycle} \mathcal{S} \, dt = \frac{1}{t\_{\rm cycle}} \int\_{cycle} (\mathcal{D}\_{\rm int} + \mathcal{S}\_{\rm lim}) \, dt = \frac{1}{t\_{\rm cycle}} \int\_{cycle} D\_{\rm int} \, dt. \tag{4}$$

#### *2.4. Energy Balance*

Energy balance is carried out from both the mechanical and the calorific responses. The mechanical response provides the strain energy density and its rate *P cycle hyst* involved in the hysteresis loop. The difference between *P cycle hyst* and D˜ *int* gives the rate of the energy stored and released due to microstructure changes at each cycle:

$$P\_{\text{stored}}^{\text{cycle}} = P\_{\text{hyt}}^{\text{cycle}} - \mathcal{D}\_{\text{int}}.\tag{5}$$

To further discuss on the relative contribution of the energy stored in the hysteresis loop of rubbers, a ratio *γse* has been proposed in our group [45,46]. It is written in terms of energy as follows:

$$\gamma\_{s\varepsilon} = \frac{\mathcal{W}\_{stored}^{cycle}}{\mathcal{W}\_{lyst}^{cycle}} \tag{6}$$

#### **3. Overview of the Experimental Setups**

Three different materials have been considered:

**Table 1.** Chemical composition in parts per hundred rubber (phr).

The experimental setups are briefly recalled in Table 2. It should be noted that the loading conditions differ from one study to another, depending on the considered application, but lead to thermodynamical cycles from which energy balance can be carried out. Generally, the stretch is calculated from the initial length of the virgin specimens and is not corrected while a permanent deformation can appear and grow as the cycles follow each other. The temperature was measured with infrared cameras, which were switched on several hours before testing in order to ensure their internal temperature to be stabilized. The calibration of camera detectors was performed with a black body using a Non-Uniformity Correction (NUC) procedure. A typical experiment setup is given in Figure 1, which enabled us to stretch the specimens symmetrically. All the specimens tested had cylindrical ends that avoid any slippage with the grips and makes accurate the determination of the initial length.

**Figure 1.** Typical experimental setup: the specimen is stretched symmetrically with a home-made biaxial testing machine, the temperature field is measured with an infrared camera.

**Table 2.** Summary of the experiments performed.

#### *Remark on the Temperature Measurement*

If the specimen is stretched by the displacement of only one jaw, which means that the initial temperature measurement area is shifted in the tensile direction, the temperature field must be initially homogeneous in order to calculate the heat sources. However, most of the testing machines and in particular the hydraulic ones lead to a thermal gradient in the specimen because the jaws are not at the same temperature. Therefore, a thermal camera has to be used in order to track the measurement area in the thermal images (see for instance [21]). If the specimen is stretched by moving the two jaws symmetrically, the initial temperature measurement area does not move and only one spot measurement with, for example, a pyrometer is possible, which reduces drastically the thermal measurement cost.

#### **4. Results and Discussion**

Figure 2 presents the mechanical responses of the unfilled NR obtained at ±0.17 s −1 (on the left hand side) and ±0.51 s −1 (on the right hand side) in terms of the nominal stress versus the stretch. They are extracted from [21]. For the two loading rates, no stress softening is observed between cycles and the loading rate has no effect on the stiffness expect for the highest stretch at *λ*4 = 7.5 that induces the highest crystallinity. In this case, the highest loading rate leads to the highest stiffness. For cycles at *λ*1 = 2 and *λ*2 = 5, no hysteresis loop is observed. For cycles at *λ*3 = 6, a hysteresis loop forms, which closes at a stretch equal to 3, which is close to the stretch at which crystallite melting is assumed to be complete. It should be noted that the crystallization onset is about 4, meaning that the crystallinity is not high enough to form a hysteresis loop. For cycles at *λ*4 = 7.5, a plateau is observed from *λ* = 6 on, followed by a stress increase that is higher at the highest loading rate, as previously observed and explained in [55,56]. As for the previous cycles at *λ*3 = 6, the hysteresis loop closes at around *λ* = 3.

**Figure 2.** Mechanical responses of the unfilled NR obtained at ±0.17 s−1 (on the left hand side) and ±0.51 s−1 (on the right hand side), extracted from [21].

Figure 3 presents the mechanical responses of the TPU obtained at ±0.08 s −1 (on the left hand side) and ±0.25 s −1 (on the right hand side), extracted from [45]. The mechanical responses exhibit softening, residual stretch and hysteresis, which was widely investigated in the literature by [57–60] and is similar to that observed in filled rubbers. It should be noted that the loading rate does not affect significantly the stiffness, which is a less intuitive result when considering that a hysteresis loop is mainly due to viscosity. This is further discussed in [45].

**Figure 3.** Mechanical responses of the TPU obtained at ±0.08 s −1 (on the left hand side) and ±0.25 s −1 (on the right hand side), extracted from [45].

Figure 4 presents the mechanical response of the F-NR obtained at ±0.21 s −1 , extracted from [47]. As expected, adding fillers to a natural rubber induces a hysteresis loop, this is the reason why it is observed in the mechanical response even at a stretch inferior to the crystallization onset. Furthermore, a stress softening is observed as well as a permanent set. In the case of a filled crystallizing rubber, a typical point is to define what is the part of the energy converted into heat and the one stored reversibly in one thermodynamical cycle. Obviously, this has a consequence on the self-heating and on the energy available for damaging the material, typically discussed in studies dealing with fatigue and fracture mechanics in elastomers.

**Figure 4.** Mechanical response of the F-NR obtained at ±0.21 s−1 , extracted from [47].

The hysteresis loop observed in the mechanical responses of these three materials is due to the different possible contributions recalled in the introduction section. The aim of the following is to identify these contributions. For that purpose, the methodology described in Section 2 has been applied to each material:

• First, the heat source *S* has been calculated from Equation (3) for each stabilized cycle at different maximum stretches (these cycles are considered as thermodynamical ones),

In the following, *γse* is first plotted versus stretch for the unfilled NR and the TPU in Figure 5, which provides the first comparison of rubber compounds with respect to their energy behavior. We recall here that the higher the value of *γse*, the higher the energy storage capacity of the material. If *γse* = 1, then no intrinsic dissipation is involved in the hysteresis loop, that is, no mechanical energy is converted into heat and 100% of the normalized area of the hysteresis loop is energy stored and released during the cycle. The *γse*—stretch relationship for the unfilled NR is given by the green curve in the diagram and was found close to 1, whatever the loading rate and the stretch level once the material is crystallizing (*λ* > *λc* ≈ 4). For stretches inferior to the crystallization onset, no hysteresis loop forms. This illustrates, as demonstrated in [22], that all the energy involved in the hysteresis loop is stored by the crystallization processes and fully released during the crystallite melting. It can be therefore seen as a "cold energy". For the TPU material at the strain rate of ±0.25 s −1 , *γse* is about 0.8 at a stretch of 1.5 and increases with stretch. It is close to 1 for stretches from 2.5 on. The energy involved in the hysteresis loop is therefore almost not converted into heat and the higher the stretch level the higher the relative energy stored in the material. This strong similitude with the unfilled natural rubber is explained by the fact that the TPU considered here crystallizes under tension, but also by the fact that the multi-phase nature of TPU induces strong self-organization as suggested in [27] and regardless of whether it crystallizes or not as shown in [61]. It should be noted that for a strain rate of four times lower, the ratio is close to 1 whatever the stretch applied.

**Figure 5.** Energy characterization in terms of *γse* versus stretch for the U-NR at 0.17 and 0.51 s−1 (in green) and the TPU (in black).

Figure 6 gives *γse* versus stretch for the filled NR stretched at the rate of the same order of magnitude as the lowest rate applied to the unfilled NR. It was observed that about 80% of the energy involved in the hysteresis loop is dissipated as heat at the lowest stretches applied (maximum 4, which induces a very low crystallinity). This means that adding fillers does not only induce viscosity but enables the material to store a part of the mechanical energy without converting it into heat, mechanical energy that is not used to damage and self-heat the material (this energy storage effect of the filler network was also highlighted in the case of carbon black filled acrylonitrile rubber (see [46] for further information)). When the material is crystallizing (when stretch at *λ* = 6), the relative energy

stored strongly increases from 20% of the hysteresis loop area at *λ* = 4 to 50% (*γse* = 0.5) at *λ* = 6. As industrial natural rubbers are filled, comparing their energy behavior amounts to comparing the area under the red curve in the diagram. Typically, the lower this area in the deformation domain defined by the industrial application, the higher the self-heating and energy used to damage the material and the lower the elastic energy stored reversibly. From an elastocaloric point of view, identifying the relative contribution of the intrinsic dissipation during one cycle is of paramount importance as it opposes the heat absorption during the unloading and consequently it reduces the cooling. and energy used to damage the material and the lower the elastic energy stored reversibly. From an elastocaloric point of view, identifying the relative contribution of the intrinsic dissipation during one cycle is of paramount importance as it opposes the heat absorption during the unloading and consequently it reduces the cooling.

the deformation domain defined by the industrial application, the higher the self-heating

*Polymers* **2022**, *1*, 0 10 of 13

**Figure 6.** Energy characterization in terms of *γse* versus stretch for the F-NR at 0.21 s−1 .

#### **Figure 6.** Energy characterization in terms of *γse* versus stretch for the F-NR at 0.21 s−1 **5. Conclusions**

**Funding:** This research received no external funding.

**5. Conclusions** This paper presents a simple and fast approach to determining the energy behavior of elastomers from cyclic uniaxial tensile loadings and temperature measurements. The temperature measurement is used to reconstruct the heat source, that is, the calorimetric response, from the 0D formulation of the heat diffusion equation. Based on the mechanical and calorimetric responses, a ratio *γse* is calculated to relativise the energy stored and released at each cycle. Results show that viscosity is not systematically the preponderant contribution to the hysteresis loop, whatever the elastomer considered, filled and unfilled, crystallizing or not: the mechanical energy brought to the material is not entirely dissipated into heat and can be mainly used by the material to change its microstructure. Therefore, This paper presents a simple and fast approach to determining the energy behavior of elastomers from cyclic uniaxial tensile loadings and temperature measurements. The temperature measurement is used to reconstruct the heat source, that is, the calorimetric response, from the 0D formulation of the heat diffusion equation. Based on the mechanical and calorimetric responses, a ratio *γse* is calculated to relativise the energy stored and released at each cycle. Results show that viscosity is not systematically the preponderant contribution to the hysteresis loop, whatever the elastomer considered, filled and unfilled, crystallizing or not: the mechanical energy brought to the material is not entirely dissipated into heat and can be mainly used by the material to change its microstructure. Therefore, *γse* assesses the ability of the material to store mechanical energy through reversible microstructure changes, energy that is not dissipated as heat and used to damage the material, for example, to propagate cracks. The results obtained enable us to characterize and to compare different materials according to their energetic performance. This study thus proposes an approach well adapted to the design of elastomer parts and opens many perspectives to

.

*γse* assesses the ability of the material to store mechanical energy through reversible microstructure changes, energy that is not dissipated as heat and used to damage the

and to compare different materials according to their energetic performance. This study thus proposes an approach well adapted to the design of elastomer parts and opens many perspectives to discriminate, in an accelerated way, the factors affecting these energetic performances, at the first order are obviously the formulation, the aging and the mechanical loading. This makes it a very promising tool for further investigating the thermomechanical behavior of rubbers and for validating and enriching physical thermodynamical models.

discriminate, in an accelerated way, the factors affecting these energetic performances, at the first order are obviously the formulation, the aging and the mechanical loading. This makes it a very promising tool for further investigating the thermomechanical behavior of rubbers and for validating and enriching physical thermodynamical models.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data can be found in [21,45,47].

**Acknowledgments:** We renew the acknowledgements in [21,45,47] to our industrial and academic partners for their financial support and the fruitful discussions. The National Center for Scientific Research (MRCT-CNRS and MI-CNRS), Rennes Metropole and Region Bretagne are also thank for their financial support.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

The following abbreviations are used in this manuscript:

#### **References**


**Magdalena Palacz \*, Arkadiusz Zak and Marek Krawczuk ˙**

Department of Mechatronics and High Voltage Engineering, Faculty of Electrical and Control Engineering, Gda ´nsk University of Technology, Narutowicza 11/12, 80-233 Gda ´nsk, Poland<EMAIL_ADDRESS>(A.Z.); ˙<EMAIL_ADDRESS>(M.K.)

**\*** Correspondence<EMAIL_ADDRESS>Tel.: +48-58-347-25-08

Received: 2 April 2020; Accepted: 24 April 2020; Published: 28 April 2020

**Abstract:** The numerical modelling of structural elements is an important aspect of modern diagnostic systems. However, the process of numerical implementation requires advanced levels of consideration of multiple aspects. Important issues of that process are the positive and negative aspects of the methods applied. Therefore the aim of this article is to familiarise the reader with the most important aspects related to the process of numerical modelling of one-dimensional problems related to the phenomena of the propagation of elastic waves and their application for damage detection purposes.

**Keywords:** wave propagation; damage detection; numerical modelling


Preface

Semiconductor materials have a long design and manufacturing chain before their use in all types of electronic products, which also need to incorporate various aspects of circuit logic to adapt to current and future needs. Revolutions in the automotive, media and Internet markets depend on this technological synergy, as do other sectors such as banking and financial markets, telemedicine, e-commerce, industrial automation, smart homes, and agriculture, all of which are expected to benefit from these advances.

New power-generation processes and the development of more energy-efficient devices and equipment directly or indirectly involve new advances in semiconductors. Quality of life has greatly improved with the mass production of more affordable devices for individual communication, which directly depends on the reduction of semiconductor costs. Therefore, more efficient and cheaper semiconductor materials can partially solve the problem of the imbalance between energy generation and consumption by individuals and communities.

Semiconductor materials are the basis of photovoltaic cells for on-site electricity generation. They are also used in water purification processes and hydrogen fuel generation. Thus, the field of semiconductor research is interdisciplinary, including chemistry, physics, engineering, and medicine, offering technological solutions in various fields.

New Advances in Semiconductors offers an updated review of semiconductors, including strategies in the field of circuit logic and experiments on some semiconductor materials. It discusses important aspects of the performance of semiconductors, such as environmental parameters of operation optimization, namely, the influence of operating temperature, light incidence, electric current, magnetic field, and even radioactivity. Many devices are influenced by variations of these experimental parameters, from simple diodes and transistors to complex integrated circuits and solar cells.

This book contains six chapters, divided into two sections. Section 1, "Calculations and Simulations in Semiconductors," includes four chapters that discuss several aspects of the mechanisms of action in systems and devices based on semiconductors. They present proposals to obtain greater energy savings in an operational environment and examine how the interfacial mechanisms between semiconductors and electrolytes can be better understood for the continuous improvement of devices in future projects.

Chapter 1 shows how considerations about individual particles introduce additional difficulties in quasi-macroscopic dielectric function calculations and proposes the exclusion of the single-particle effective field model in this type of calculation based on dielectric relaxation matrices. The author proposes that the use of a polyelectronic wave function, as a sufficient condition for the calculations, has the advantage of allowing considerations about the interactions of the electron-hole pair to be disregarded, greatly facilitating the calculations.

Chapter 2 presents a new analytical model for calculating performance in amplitudemodulated systems, which can be very useful for semiconductor optical amplifiers, considering the lower and upper limits of performance. These calculations can be useful for the development of integrated photonic circuit designs that use amplitudemodulated systems, such as optical amplifiers and interconnects. The model is validated through numerical and experimental simulations, including examples of photonic integrated circuit sizing, and shows how the parameters associated with amplitude modulation can be adjusted for application in semiconductor optical amplifiers.

Chapter 3 discusses how the use of a new circuit design based on Tri-State Buffer connection technology can lead to greater efficiency in electronic circuits. The project shows that there are energy savings if a submodule with two logic routines based on ASIC design and Verilog HDL language is inserted into the logic circuit diagram. Thus, the circuit presents greater energy savings due to the reduction of dynamic and total power. These are relevant mathematical approaches, as they demonstrate how energy savings are verified as a function of dissipation reduction. A performance evaluation is also provided for validation in terms of energy dissipated in connections with Tri-State Buffer technology.

Chapter 4 provides an introduction to charge transport at the interphase junction between solid semiconductors and liquid electrolytes. It demonstrates how the changes occur whether the system is illuminated or not, with basic considerations on the use of semiclassical charge transport equations in the semiconductor used as an electrode. The chapter also presents the behavior of the ideal interface between the semiconductor and the electrolyte at a broad level, describing the interactions as a function of the redox reactions in the electrolyte and the energy relations of charge transfer. The proposed system is also interpreted from the point of view of the kinetics of the electron-hole pair recombination during irradiation. Propositions are also made on how the semiconductor surface can be occupied to explain the behavior of the photocurrent-voltage curves.

Section 2, "Semiconductor Materials," contains two chapters. These chapters discuss two important environmental parameters in semiconductor operation. Chapter 5 describes the dependence of electrical resistivity as a function of temperature for dilute magnetic semiconductors. It also presents a specific case of electrical resistivity reduction for a manganese-doped gallium arsenide p-type semiconductor and examines how the behavior of the curves changes as a function of temperature from 0K to 300K. It is shown that, in addition to the temperature dependence, the electrical resistivity of this type of magnetic material also strongly depends on the concentration of dopants in the structure. Considerations on mechanisms of how electrical resistivity considerably affects state density and energy gap are also made.

Chapter 6 discusses the properties and consequences of the response in electronic components and circuits based on semiconductor materials exposed to neutron radiation. It presents the behavior of several semiconductors based on chemical

elements of Group IV and Groups III and V of the periodic table regarding two types of neutron radiation produced by reactions involving deuterium as well as deuterium and tritium. Reaction rates and classification of neutron-induced byproducts are presented, according to their nature and energy.

Please note that this book can be read in or out of sequential order, as there is no progression of basic knowledge level between chapters or sections. We thank each of the chapter authors for bringing us the most current issues in this field of knowledge. This book is a useful resource for students, researchers, and other interested readers.

## **Alberto Adriano Cavalheiro**

Interdisciplinary Laboratory of Advanced Materials of Navirai (LIMAN), State University of Mato Grosso do Sul (UEMS), Navirai-MS, Brazil

Section 1


**FLAVONOIDS - FROM BIOSYNTHESIS TO HUMAN HEALTH**

Edited by **Gonçalo C. Justino**

#### **Flavonoids - From Biosynthesis to Human Health**

http://dx.doi.org/10.5772/65575 Edited by Goncalo C. Justino

#### **Contributors**

Ana Rodrigues, Duraipandiyan Veeramuthu, William Raja T, Naif Abdullah Al-Dhabi, Ignacimuthu Savarimuthu, Beatriz Ramos Solano, Enrique Gutierrez, Ana García-Villaraco Velasco, Jose A. Lucas, F.Javier Gutierrez-Mañero, Weisheng Feng, Zhiyou Hao, Meng Li, Corina Danciu, Diana Antal, Florina Ardelean, Aimée Rodica Chis, Codruta Soica, Florina Andrica, Cristina Dehelean, Valentina Uivarosi, Alexandra Cristina Munteanu, Agustín G. Asuero, Julia Martín, Mª José Navas, Eugenia Marta Kuskoski, Maged Saad Abdel-Kader, Ahmed Foudah, Marisi Soares, João Luiz Baldim, Mário Ferreira Conceição Santos, Daniela Aparecida Chagas-Paula, João Henrique Ghilardi Lago, Welton Rosa, Maurice Ducret Awouafack, Marcos Soto-Hernandez, Graham Johnston, Jane Hanrahan, Tina Hinton, Raul Zamora-Ros, Romina Escobar-Cévoli, Carlota Castro-Espín, Virginie Béraud, Genevieve Buckland, Jose Luis Chavez-Servia, Araceli M. Vera-Guzmán, Elia N. Aquino-Bolaños, Elena Heredia-García, José C. Carrillo-Rodríguez, Sanjuana Hernández-Delgado, Hakan Cetinkaya, Muhammet Karaman, Halide Sedef Karaman, Ferudun Kocer, Muhittin Kulak, Chin Fei Chee, Noorsaadah Abd. Rahman, Ti Tee, Saul Ruiz-Cruz, Sarai Chaparro-Hernandez, Karen Lilian Hernández-Ruiz, Marco Antonio Lopez-Mata, Jesus Ornelas-Paz, Luis A. Cira-Chávez, María Isabel Estrada-Alvarado, Laura Elisa Gassos-Ortega, Rosa Isela Guzmán-Gerónimo, Mónica Herrera-Sotero, Francisco González-Cortés, Hugo García-Galindo, Enrique Juárez-Aguilar, Jose Chavez-Servia, Mauricio Rodríguez-Dorantes, Rosamaria Oliart, Erica Santos, Beatriz Helena Sales Maia, Aurea Ferriani, Sirlei Teixeira, Latifa Chebil, Manel Slimane, Mohamed Ghoul, Aude Cordin

#### **© The Editor(s) and the Author(s) 2017**

The moral rights of the and the author(s) have been asserted.

All rights to the book as a whole are reserved by INTECH. The book as a whole (compilation) cannot be reproduced, distributed or used for commercial or non-commercial purposes without INTECH's written permission. Enquiries concerning the use of the book should be directed to INTECH rights and permissions department (permissions@intechopen.com).

Violations are liable to prosecution under the governing Copyright Law.

Individual chapters of this publication are distributed under the terms of the Creative Commons Attribution 3.0 Unported License which permits commercial use, distribution and reproduction of the individual chapters, provided the original author(s) and source publication are appropriately acknowledged. If so indicated, certain images may not be included under the Creative Commons license. In such cases users will need to obtain permission from the license holder to reproduce the material. More details and guidelines concerning content reuse and adaptation can be foundat http://www.intechopen.com/copyright-policy.html.

#### **Notice**

Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book.

First published in Croatia, 2017 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia

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Additional hard and PDF copies can be obtained from<EMAIL_ADDRESS>
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**8. Analysis and interpretation**

Data from the experiment was gathered and interpreted to clarify the communicating effects of instructions, mainly from two aspects of task performance: efficiency and accuracy. Results from different user groups were compared and examined to find out which type of instructions were more effective and inclusive in terms of communication.

## **8.1 Task analysis**

In the test, all components of the product were given to the participant and product instructions were provided on either a printed sheet or a laptop computer. By using Hierarchical task analysis (HTA), the main goal and sub-goals of the tasks were expressed as below (Figure 9).

As shown in figure9, tasks 1 and 2 were skill-based tasks. Users were asked to follow clear and simple instructions to carry out actions and they did not have to make judgements on the aim and plan of their actions. Task 3 was more complicated, it contained 12 steps and these 12 little tasks were grouped into different sections: 3-A, 3-B, 3-C and 3-D, depending on their goals. Many parts of task 3 required users to recall or understand some rules then make their own decisions on what action they should carry out, in order to achieve the required results.

The choices of the participants had to be carefully planned in order to ensure that their human performance characteristics were checked prior to the beginning of the tests. This was done using a method traditionally used by work-study officers to establish what a hundred percent effort or rating looks like. A full pack of cards is dealt into four hands in a period of 52 seconds. It was ensured that the participants could all carry out this task in periods between 50 and 56 seconds. Thus their human performance characteristics could all

They were asked to follow either the printed instructions for the product or the multimedia ones to complete the same set of given tasks. The tasks included 1) using instructions to find information, 2) checking components of the product and 3) assembling. Their actions were monitored; timing was recorded; errors were observed

Data from the experiment was gathered and interpreted to clarify the communicating effects of instructions, mainly from two aspects of task performance: efficiency and accuracy. Results from different user groups were compared and examined to find out which type of

In the test, all components of the product were given to the participant and product instructions were provided on either a printed sheet or a laptop computer. By using Hierarchical task analysis (HTA), the main goal and sub-goals of the tasks were expressed as

As shown in figure9, tasks 1 and 2 were skill-based tasks. Users were asked to follow clear and simple instructions to carry out actions and they did not have to make judgements on the aim and plan of their actions. Task 3 was more complicated, it contained 12 steps and these 12 little tasks were grouped into different sections: 3-A, 3-B, 3-C and 3-D, depending on their goals. Many parts of task 3 required users to recall or understand some rules then make their own decisions on what action they should carry out, in order to achieve the

instructions were more effective and inclusive in terms of communication.

Fig. 8. Screen examples for the multimedia version of product instructions.

be considered similar.

**8.1 Task analysis**

below (Figure 9).

required results.

and feedback was collected at the end.

**8. Analysis and interpretation**

Fig. 9. The main goal and sub-goals of the refined tasks.

### **8.2 Performance on efficiency**

To examine efficiency of different types of instructions, the following indices were used:

Overall, Data suggested that all participants, who used multimedia instructions, used on average 1379 seconds (22minutes 59 seconds), with a standard deviation of 220 seconds, which seemed to be slightly shorter to those of printed instruction users, who spent 1390 seconds (23 minutes 10 seconds), with a standard deviation of 213 seconds (Table 1). The difference was small therefore the authors were keen to find out if there was statistically significant difference between the total time consumption of different instruction.

Null hypothesis: T1 = T2

There is no significant difference between the average total time of users using either printed or multimedia instructions.

Alternative hypothesis: T1 ≠ T2

There is a significant difference between the average total time of users using either printed or multimedia instructions.

The authors assumed that there was no statistically significant difference between the groups. A t-test was then carried out. to find out the confidence level of this hypothesis. The 2-tailed t- test returned a P-value of 0.89. Since the P-value (0.89) was greater than the significance level (0.05), the null hypothesis was accepted. This indicated that there was no significant difference between the efficiency of two versions of product instructions.

Product Instructions in the Digital Age 49

Similarly, Figure 10 potentially suggested that the Digital Natives performed better, when using either the printed or multimedia instructions, than the digital immigrants. On the other hand, the Digital Natives seemed to perform better using print instructions than multimedia and the opposite happened with the Digital Immigrants. Again, t- tests were

After another 3 sets of 2-tailed t-tests, the results showed that the amount of time Digital Natives and Digital Immigrants used to complete all tasks was not much different. Also, different types of instructions did not have a huge impact in terms of the overall efficiency. This suggested that multimedia product instructions were as efficient as printed ones for

carried out to find out the confidence level of the significant differences.

Fig. 11. Average time to achieve all task sections in each user group.

of their efficiency in general, especially for Digital Immigrants.

**8.3 Performance on accuracy**

By looking at the time, which has been spent on each task section in detail (Figure 11), it was discovered that multimedia product instructions generally have a positive impact on Digital Immigrants in terms of their efficiency. Yet, this does not apply when a spatial judgement is involved in knowledge- based tasks. For Digital Natives, different types of instructions have different effects on time consumption; depending on the nature of each task. Printed instructions were more efficient to be scanned when skill-based tasks were simple enough to be completed intuitively. When instructions are necessary to follow for skill- based tasks, the time difference between the use of multimedia instructions and printed instructions was very little. Although it also took longer for the Digital Natives to use multimedia instructions to fulfil a complicated job when a spatial judgement was needed; multimedia instructions were significantly more efficient to use for a transferable process (rule-based tasks). Therefore the authors believe that multimedia instructions are not always efficient as expected, for example for particular types of tasks; but they are still more effective in terms

The accuracy of users' performance was evaluated through error analysis in this investigation and it was achieved by observations. Every time a user failed to achieve the planned goal, a

both Digital Natives and Digital Immigrants.

Table 1. Average time for all tasks

Fig. 10. Time to achieve all tasks in each user group.

Multimedia

All DN

Printed product instructions

Multimedia product instructions Average duration (s):

Average duration (s):

Fig. 10. Time to achieve all tasks in each user group.

Table 1. Average time for all tasks

1375

1390

Digital Natives (DN) Digital Immigrants (DI) Average Duration (s) Average Duration (s)

Printed (DN) 1284 Printed(DI) 1497

(DI)

1425

Average(s) 1461

(DN) 1332 Multimedia

Average(s) 1308 All DI

Similarly, Figure 10 potentially suggested that the Digital Natives performed better, when using either the printed or multimedia instructions, than the digital immigrants. On the other hand, the Digital Natives seemed to perform better using print instructions than multimedia and the opposite happened with the Digital Immigrants. Again, t- tests were carried out to find out the confidence level of the significant differences.

After another 3 sets of 2-tailed t-tests, the results showed that the amount of time Digital Natives and Digital Immigrants used to complete all tasks was not much different. Also, different types of instructions did not have a huge impact in terms of the overall efficiency. This suggested that multimedia product instructions were as efficient as printed ones for both Digital Natives and Digital Immigrants.

Fig. 11. Average time to achieve all task sections in each user group.

By looking at the time, which has been spent on each task section in detail (Figure 11), it was discovered that multimedia product instructions generally have a positive impact on Digital Immigrants in terms of their efficiency. Yet, this does not apply when a spatial judgement is involved in knowledge- based tasks. For Digital Natives, different types of instructions have different effects on time consumption; depending on the nature of each task. Printed instructions were more efficient to be scanned when skill-based tasks were simple enough to be completed intuitively. When instructions are necessary to follow for skill- based tasks, the time difference between the use of multimedia instructions and printed instructions was very little. Although it also took longer for the Digital Natives to use multimedia instructions to fulfil a complicated job when a spatial judgement was needed; multimedia instructions were significantly more efficient to use for a transferable process (rule-based tasks). Therefore the authors believe that multimedia instructions are not always efficient as expected, for example for particular types of tasks; but they are still more effective in terms of their efficiency in general, especially for Digital Immigrants.

#### **8.3 Performance on accuracy**

The accuracy of users' performance was evaluated through error analysis in this investigation and it was achieved by observations. Every time a user failed to achieve the planned goal, a

Product Instructions in the Digital Age 51

During the tests, by referring to given instructions, users observed and corrected their own errors in the performing progress. When errors were not detected or corrected by the participants, they were recorded and evaluated (Table 2). In this experiment, Digital Natives and Digital Immigrants have both made errors. The numbers of slips and lapses were similar in two user groups. They were caused by each individual's failures of action or failures of memory. Unfortunately, they cannot be perfectly solved by improving product instructions. When looking at the number of mistakes made by the participants, data revealed that multimedia instructions are better for avoiding mistakes, for both Digital

> **Multimedia (DN)**

When each task section was examined (Table 3), it was more evident that multimedia instructions can help users to avoid mistakes, especially in some complicated tasks for example task section 3-B. This section contained the most time consuming jobs in the whole experiment. It was a combination of many small knowledge-based tasks and some tasks required users to make critical decisions. Both Digital Natives and Digital Immigrants have made a few mistakes in this job section when traditional instructions were provided. However, when multimedia instructions with equivalent contents were presented, all users either avoided mistakes or realised errors on their own. Thus it is not difficult to conclude that multimedia instructions are better than traditional instructions (with only images and

Although multimedia instructions are not always more efficient than traditional ones, the authors believe that they are quicker to use for many types of tasks. They allow more flexibility in action and more importantly can help to reduce human errors significantly in the working process. They are effortless to access, can be transferred between different digital platforms and easy to update or replace. It is also proved that they can be used easily

by people who have grown up with or without ubiquitous of digital media.

1 Finding information 0 0 0 0 2 Unpacking- check parts 0 0 0 0 Section 3-A: Make the frame base 1 0 0 0 Section 3-B: Finish the frame 0 3 0 2 Section 3-C: Fix the top sheet 0 1 0 0 Section 3-D: Attach the accessory 0 0 0 0

**Print (DN)**  **Multimedia**

**Print (DI)**

**(DI)**

Slips 2 1 1 2 Lapses 0 1 0 0 Mistakes 4 2 1 0

Natives and Digital Immigrants compare to the traditional instructions.

Table 2. Error analysis

**Tasks**

**9. Conclusion**

Table 3. Mistakes in each task section.

text) in terms of ensuring accuracy of actions.

Print DN Print DI Multimedia DN Multimedia DI

human error was found and recorded. The failures mainly appeared in two different ways (Hollnagel, 1993): the user's plan was adequate but the actions were deficient; or actions were carried out as planned but the intention was wrong according to the given tasks.

To define and classify human error in the tasks, three questions were referenced (Reason, 1990), and they all closely related to intentions:

The questions then were used to categorize discovered errors into three main kinds: slips, lapses and mistakes (Figure 12).

Fig. 12. Generic Error Modelling System (GEMS) (Reason, 1990)

#### **8.3.1 Slips and lapses**

Both slips and lapses were errors that happened in the execution process so that users failed to achieve the desired goals. The intentions were proper, but results were not right. A slip mainly involved actions that were not happening as planned, while lapses were the errors that were caused by failures of memory.

#### **8.3.2 Mistakes**

Mistakes referred to failures in the planning and/or judgemental processes; they are errors in users' intentions (Norman, 1983). They might involve the selection of objectives, or the decisions of means, even actions for achieving the objectives. They are normally caused by either a failure of expertise or lack of expertise(Reason, 1990). They could be effectively avoided or reduced by communicating sufficient information, in this case, using product instructions. Therefore, the number of mistakes left by users after each test was the main criteria to evaluate the accuracy performance of the product instructions.

Table 2. Error analysis

human error was found and recorded. The failures mainly appeared in two different ways (Hollnagel, 1993): the user's plan was adequate but the actions were deficient; or actions were

To define and classify human error in the tasks, three questions were referenced (Reason,

The questions then were used to categorize discovered errors into three main kinds: slips,

Both slips and lapses were errors that happened in the execution process so that users failed to achieve the desired goals. The intentions were proper, but results were not right. A slip mainly involved actions that were not happening as planned, while lapses were the errors

Mistakes referred to failures in the planning and/or judgemental processes; they are errors in users' intentions (Norman, 1983). They might involve the selection of objectives, or the decisions of means, even actions for achieving the objectives. They are normally caused by either a failure of expertise or lack of expertise(Reason, 1990). They could be effectively avoided or reduced by communicating sufficient information, in this case, using product instructions. Therefore, the number of mistakes left by users after each test was the main

criteria to evaluate the accuracy performance of the product instructions.

carried out as planned but the intention was wrong according to the given tasks.

1990), and they all closely related to intentions: 1. Were actions guided by prior goals? 2. Have actions been proceed as planned?

Fig. 12. Generic Error Modelling System (GEMS) (Reason, 1990)

3. Was the desired end achieved?

lapses and mistakes (Figure 12).

**8.3.1 Slips and lapses**

**8.3.2 Mistakes**

that were caused by failures of memory.

During the tests, by referring to given instructions, users observed and corrected their own errors in the performing progress. When errors were not detected or corrected by the participants, they were recorded and evaluated (Table 2). In this experiment, Digital Natives and Digital Immigrants have both made errors. The numbers of slips and lapses were similar in two user groups. They were caused by each individual's failures of action or failures of memory. Unfortunately, they cannot be perfectly solved by improving product instructions. When looking at the number of mistakes made by the participants, data revealed that multimedia instructions are better for avoiding mistakes, for both Digital Natives and Digital Immigrants compare to the traditional instructions.

Table 3. Mistakes in each task section.

When each task section was examined (Table 3), it was more evident that multimedia instructions can help users to avoid mistakes, especially in some complicated tasks for example task section 3-B. This section contained the most time consuming jobs in the whole experiment. It was a combination of many small knowledge-based tasks and some tasks required users to make critical decisions. Both Digital Natives and Digital Immigrants have made a few mistakes in this job section when traditional instructions were provided. However, when multimedia instructions with equivalent contents were presented, all users either avoided mistakes or realised errors on their own. Thus it is not difficult to conclude that multimedia instructions are better than traditional instructions (with only images and text) in terms of ensuring accuracy of actions.


**3. Classification of exclusion criteria (constraints).**

The exclusion criteria are constraints having for objective to limit research of suitable sites which do not tolerate any competition [10].

The classification consists in selecting various areas that represents a new plan of information for a required condition. Maps were classified into two categories: 1 was ranked to zones verifying the condition and 0 was ranked to the other zones. The resulting image is a Boolean image.

The last step consisted in combining, by superposition, the information contained in Boolean layers relative to the exclusion criteria mentioned above. The logical operator "AND" has been used in this part; it translates the intersection between conditions that must be absolutely satisfied.


**4. Toxicity of nanoparticles to the lung**

Epidemiological studies have confirmed a positive correlation between levels of particulate pollution and increased morbidity and mortality rates among general populations (Gwinn & Vallyathan, 2006; Stone et al., 2007).

The adverse health effects seem to be dominated by pulmonary symptoms. For instance, many reports have addressed that occupational exposure of inhaled rigid nanoparticles (NPs) can lead to respiratory diseases such as pneumoconiosis (pulmonary fibrosis) and bronchitis (Byrne & Baugh, 2008; Lkhasuren et al., 2007).

Increasing inhalation of ambient ultrafine particles has been linked with exacerbation of respiratory symptoms and mortality among COPD sufferers (Xia et al., 2009). It has also been documented that NPs can instigate oxidative stress and cellular toxicity in various types of cells (Huang et al., 2009).

It was also reported that chronic exposure to NPs can potentially predispose humans to lung inflammation and increase the risk of COPD.

A concentration range of NPs within the level found in ambience and in nanotechnology industries (Klaine et al., 2008) can promote mucin aggregation.

The second safety aspect of deep lung deposition is the interaction of nanoparticles with the alveolar environment. The alveolar space is covered with a thin surfactant film. This film has important physiological functions e.g. to accelerate gas exchange and to lower the surface tension in the alveolar space. Compromising these functions by inhalable nanoparticles might cause life threatening consequences. Therefore, the compatibility of a delivery system with the alveolar environment must be considered (Azarmi et al., 2008).

For these reasons vesicular nanocarriers, composed of lung surfactants and/or synthetic amphiphiles, provide an efficient delivery system for the treatment of pulmonary disorders due to their biocompatibility, biodegradability and non-toxic nature (Taylor & Newton, 2004).

whether the local inflammation is sufficient to induce systemic effects, or whether a second

Over the years it was evidenced that mucus hypersecretion is an important manifestation of COPD. In the classical phenotype of chronic bronchitis, mucus hypersecretion is the key presenting symptom that appears independent of airflow obstruction. A more recent work demonstrated that obstruction of the small airways by inflammatory exudates containing mucus is predictive of early death after volume reduction surgery in patients with advanced COPD (Hogg et al., 2007). It was suggested that such occlusion enhanced the probability of infection in the lower respiratory tract. In addition, several epidemiological studies showed an association between mucus hypersecretion and outcomes in patients with COPD. Mucus hypersecretion is not an innocent disorder. However, despite these observations, until now few studies have focused on the effects of mucolytic drugs in patients with COPD, even though some of these mucolytic drugs also appear to have antioxidant properties (Dekhuijzen, 2004; Rahman et al., 1997; Rahman &

Histopathological findings from surgical specimens clearly show that increased goblet cell numbers and increased MUC5AC and MUC5B production and secretion are found in the lumen of small airways in COPD patients (Caramori et al., 2004). These findings are inversely associated with pre-surgical Forced Expiratory Volume in the 1st second (FEV1). Thus, patients with higher FEV1 have less goblet cell metaplasia than patients with lower FEV1, suggesting that the presence of mucin-producing cells in the airways is related to increased airflow obstruction. The presence of a prominent goblet cell phenotype also negatively correlates with FEV1 improvement following lung volume reduction surgery (Kim et al., 2005). Collectively, these results show that mucus secretion may be significant enough to result in physiologically and clinically measurable mechanical obstruction of small airways, and it may significantly impact disease pathogenesis and prognosis. The main cause of COPD in humans is cigarette smoking. In mice, chronic cigarette smoke exposure causes strain dependent mucous metaplasia. Cigarette smoke itself has also been shown to promote mucin synthesis directly in vitro by activation of the EGFR cascade (Shao et al., 2004). Inhalation, of one of the many potential toxicants present in cigarette smoke, acrolein (acrylic aldehyde), induces mucous metaplasia and MUC5AC production in animals. Acrolein also induces MUC5AC production in human airway epithelial cell lines, and it is found at significantly elevated levels in the induced sputum and exhaled breath

It has been suggested that mucus can also serve as a suitable medium for adherence and growth of some bacterial pathogens, such as non-typeable H. influenzae. Gram positive and gram negative bacteria products up-regulate MUC5AC and MUC2 gene expression and mucin secretion in human respiratory epithelial cell lines in vitro, and the same effect can be seen in some animal models in vivo. Viral infections are also closely associated with COPD exacerbations in humans (Wedzicha & Donaldson, 2003; Beckham et al., 2005). Surgical specimens from smokers with COPD show increased goblet cell numbers in the epithelium of peripheral airways compared to non-smokers. This is accompanied by increased macrophages and CD8 positive T-lymphocytes, both of which are indicative of viral. Roles for IL-6 and virus-induced mucin overproduction have been suggested. In vivo, IL-6 production is enhanced during the early phase of bacterial or viral-induced inflammation.

pathogenetic event is required (Evans & Koo, 2009; Huertas & Palange 2011).

Kilty 2006; Decramer & Janssens, 2010).

condensates of COPD patients, (Deshmukh et al., 2008).


*Article* **Comparable Outcomes in Early Hepatocellular Carcinomas Treated with Trans-Arterial Chemoembolization and Radiofrequency Ablation**

**Benjamin Wei Rong Tay 1,† , Daniel Q. Huang 1,2,†, Muthiah Mark 1 , Neo Wee Thong 3 , Lee Guan Huei 1,2 , Lim Seng Gee 1,2, Low How Cheng 1 , Lee Yin Mei 1 , Prem Thurairajah 1 , Lim Jia Chen 1 , Cheng Han Ng 2 , Wen Hui Lim 2 , Darren Jun Hao Tan 2 , Da Costa Maureen 4 , Kow Wei Chieh Alfred 4 , Iyer Shridar Ganpathi 4 , Tan Poh Seng 1 and Dan Yock Young 1,2,\***

**Abstract:** The guidelines recommend radiofrequency ablation (RFA) for early hepatocellular carcinomas that are less than 3 cm and trans-arterial chemoembolization (TACE) for intermediate-stage tumors. Real-world patient and tumor factors commonly limit strict adherence to the guidelines. We aimed to compare the clinical outcomes for TACE and RFA in early HCC. All consecutive patients from 2010 to 2014 that were treated with locoregional therapy at our institution were enrolled. The decision for TACE or RFA was based on tumor location, stage and technical accessibility for ablation. A subgroup analysis was performed for patients with tumors less than 3 cm. A total of 168 patients underwent TACE while 56 patients underwent RFA. Patients treated with TACE and RFA had 1- and 5-year survival rates of 84.7% and 39.8% versus 91.5% and 51.5%, respectively (*p* = 0.28). In tumors less than 3 cm, there was no significant difference in overall survival (*p* = 0.69), time to progression (*p* = 0.55), or number of treatment sessions required (*p* = 0.12). Radiofrequency ablation had a significantly higher chance of a complete response (*p* = 0.004). In conclusion, TACE may be selectively considered for early-stage hepatocellular carcinoma in patients unsuitable for other modalities.

**Keywords:** transarterial chemoembolization; radiofrequency ablation; hepatocellular carcinoma

## **1. Introduction**

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1,2]. The optimal treatment for HCC is oncologic resection or liver transplant [3–6]. Unfortunately, this is often limited by poor liver function precluding a safe resection and a shortage of donor livers. In situations when a resection or transplant is not possible and the disease is confined to the liver, locoregional therapies for HCC are recommended, including radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) [7,8].

RFA delivers a high-frequency alternating current via a catheter tip, producing thermalenergy-induced area necrosis to tissue within a 1.5 cm radius. RFA is best used in tumors with a diameter of less than 3 cm and can provide sustained recurrence-free survival in these patients. In major society guidelines, RFA is recommended for small HCCs less than 3 cm in size, especially if resection is not feasible [7–9]. RFA is generally avoided in tumors that are near the dome of the diaphragm or next to bowel lumen, for fear of diaphragmatic injury or bowel perforation [10,11].

**Citation:** Tay, B.W.R.; Huang, D.Q.; Mark, M.; Thong, N.W.; Guan Huei, L.; Gee, L.S.; Cheng, L.H.; Mei, L.Y.; Thurairajah, P.; Chen, L.J.; et al. Comparable Outcomes in Early Hepatocellular Carcinomas Treated with Trans-Arterial Chemoembolization and Radiofrequency Ablation. *Biomedicines* **2022**, *10*, 2361. https://doi.org/10.3390/ biomedicines10102361

Academic Editor: Jinghua Wang

Received: 1 August 2022 Accepted: 18 September 2022 Published: 22 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

TACE delivers chemotherapy-infused particles via the hepatic artery, inducing ischemia in the tumor and delivering the local chemotherapeutic agent. Previously, a Taiwanese study showed that TACE and RFA resulted in similar overall survival for HCC patients within the Milan criteria, although RFA still showed significantly better survival in small tumors with a total tumor volume < 11 cm3 [12]. However, Kim et al. compared TACE and RFA for small tumors less than 2 cm and showed a similar overall survival in both groups, and another study comparing single small tumors less than 3 cm showed a similar tumor response and recurrence [13,14]. The current practice guidelines recommend ablation in HCCs less than 3 cm. Considering the conflicting literature with regards to the use of TACE in small tumors, and the current clinical practice guidelines recommending ablation in HCCs less than 3 cm, we aimed to compare the outcomes of TACE and RFA in patients with HCCs less than 3 cm.

#### **2. Materials and Methods**

#### *2.1. Patients*

This was a single-center retrospective cohort study. We enrolled all consecutive patients between 1 January 2010 to 31 December 2014 treated with either TACE or RFA as the first line monotherapy for Barcelona Clinic Liver Cancer (BCLC) stage 0, A or B HCC. Patients with evidence of vascular invasion or metastatic disease were excluded. This study was approved by the Investigation and Ethics Committee of the National University Hospital (Singapore), according to the standards of the Declaration of Helsinki. Written informed consent was obtained from each patient before treatment.

#### *2.2. Selection of Primary Treatment Modality*

The diagnosis of HCC was in accordance with major society guidelines [7,8,15]. The selection of the locoregional modality was made by a multidisciplinary hepatobiliary tumor board consisting of hepatobiliary surgeons, hepatologists, interventional radiologists, medical/radiation oncologists and pathologists. Locoregional therapy was offered to patients who were not surgical candidates due to a combination of poor liver function, poor functional status and/or multiple comorbidities. The decision between RFA and TACE depended on factors such as tumor location, size, number of nodules and technical feasibility.

#### *2.3. Trans-Arterial Chemoembolization*

Dynamic multiphasic cross-sectional imaging of the liver via magnetic resonance imaging (MRI) or computed tomography (CT) was performed prior to the procedure to guide the approach to the tumor. Catheterization of the hepatic artery and identification of the tumor feeding vessel was performed, followed by administration of Cisplatin, Doxorubicin or Adriamycin.

#### *2.4. Radiofrequency Ablation*

A triphasic CT scan was performed prior to the procedure to guide the approach to the tumor. An ultrasound-guided percutaneous approach was used for the placement of a 14-gauge needle electrode into the target area. Radiofrequency current was then emitted for 12 to 15 min by a 200 W generator.

#### *2.5. Patient Follow-Up*

A CT or MRI scan was obtained from all patients one month following the procedure to document treatment response. Treatment response was assessed using the modified RECIST criteria [16]. Clinical evaluation, surveillance liver scans, and laboratory investigations were subsequently performed every 3–6 months to monitor for progressive disease or recurrence. Repeat treatment was performed for patients with an inadequate response to the initial therapy and for those with recurrence or a progressive disease.

#### *2.6. Evaluation of Data*

The primary outcome evaluated was overall survival, which was defined as the time between HCC diagnosis and death. Secondary endpoints included treatment response in accordance with the modified RECIST criteria, recurrence, and time to progression (TTP). Recurrence was defined as any new onset lesion or progression of lesions originally considered suspicious or metastasis in patients who had demonstrated a complete response at any time during the follow-up. TTP was defined as the time between primary treatment and the first evidence of radiological progression as defined by the modified RECIST criteria. Outcome measures were evaluated for the whole study population followed by subgroup analysis on tumors less than 3 cm. Adverse effects of treatment were monitored throughout the period of admission and recorded.

#### *2.7. Statistical Analysis*

All statistical analysis was performed using the Statistical Packages for Social Sciences version 25.0 (SPSS Inc., Chicago, IL, USA). A two-sided *p*-value of <0.05 was considered to be statistically significant. The chi-squared test was used for categorical data comparison and the Mann–Whitney test was used for continuous data. The Kaplan–Meier method with log-rank testing was used for the analysis of survival and time to progression.

#### **3. Results**

#### *3.1. Baseline Charateristics*

Between March 1989 and September 2013, 224 patients met the inclusion criteria and were entered in the study. TACE was performed for 168 patients while RFA was performed for 56 patients. Patients were predominantly male and Chinese, with a median age of 65 years at the point of diagnosis. About 86% of patients were cirrhotic with the majority being Child-Pugh A. The main etiology of the underlying liver disease was hepatitis B for both groups. Multiple etiologies of chronic liver disease were noted in 11 patients. No significant differences were noted in the background hepatic function or alpha-fetoprotein levels between both cohorts.

The size of tumor was significantly larger (*p* < 0.001) in the cases treated with TACE compared to RFA. The median size of the primary tumor nodule in the cases treated with TACE was 3.8 cm (interquartile range (IQR) 2.2–6.2 cm) while the median size of the primary nodule in cases treated with RFA was 2.1 cm (IQR 1.5–2.7 cm). The baseline characteristics of all the patients treated with TACE and RFA are shown in Table 1.

There were significant differences between the TACE and RFA subpopulations with regard to ethnicity ("Chinese" and "Others") and primary diagnosis ("Non-Alcoholic Fatty Liver Disease (NAFLD)"). All differences in sociodemographics and baseline hepatic and clinical factors were resolved by the stratification to a tumor size less than 3 cm, as shown in Table 2.

**Table 1.** Baseline characteristics of all 224 study subjects.

**Table 1.** *Cont.*

Continuous variables are presented as median (IQR) and categorical variables as n (%).

**Table 2.** Baseline characteristics of patients with primary HCC tumor <3 cm.

Continuous variables are presented as median (IQR) and categorical variables as n (% of total population).

#### *3.2. Survival*

Overall survival rates at 1, 3 and 5 years in the RFA and TACE groups were 91.5%, 72.8%, 51.5% and 84.7%, 57.6%, 39.8%, respectively. There was no statistical significance between the two groups (Figure 1, *p* = 0.28). When overall survival was stratified by a size of the HCC of less than 3 cm, the median survival for TACE and RFA groups was 48.0 (IQR 21.0–75.0) and 54.0 (IQR 42.0–67.0) months, respectively, with no significant difference between the groups (Figure 2, *p* = 0.69). The main cause of death was due to hepatic failure from the progression of hepatocellular carcinoma. FIGURE 1 FIGURE 1

**Figure 1.** Overall survival in unstratified cohort. Fig. 1 Overall survival in unstratified cohort

P = 0.693 **Figure 2.** Survival duration stratified for HCC < 3 cm.

#### Fig. 2 Survival duration stratified for HCC < 3cm *3.3. Time to Progression*

Cumulative Survival

Fig. 2 Survival duration stratified for HCC < 3cm Patients treated with RFA had a significantly longer TTP than those treated with TACE, with a median TTP of 9.0 months (IQR 4.0–19.0) and 13.0 months (IQR 8.0–29.0) (*p* = 0.02),

Survival Duration (Years)

1

1

respectively (Figure 3). However, in a subgroup of patients with HCCs less than 3 cm, there was no significant difference in TTP between the TACE (median TTP 13.0 months; IQR 4.0–28.0 months) and RFA groups (median TTP 13.0 months; IQR 9.0–22.0 months) (*p* = 0.55, Figure 4).

**Figure 3.** Time to progression in unstratified cohort. Fig. 3 Overall Time to Progression in unstratified cohort

Fig. 3 Overall Time to Progression in unstratified cohort

Time to Progression (Years) **Figure 4.** Time to progression stratified for HCC < 3 cm.

#### Fig. 4 Time to Progression stratified for HCC < 3cm *3.4. Chance of Complete Response*

Fig. 4 Time to Progression stratified for HCC < 3cm HCC treated with RFA was associated with a significantly higher chance of complete response (CR) compared to TACE (83.9% vs. 32.7%, *p* < 0.001). When stratified by size, RFA-treated HCCs again had a significantly higher CR rate for lesions less than 3 cm compared to TACE (82.2% vs. 55.7%, *p* = 0.004).

2

2

#### *3.5. Recurrence*

Recurrence rates were similar between the TACE- and RFA-treated cases in the overall cohort including both large and small hepatomas (40.3% vs. 58.2%, *p* = 0.21). When stratified to HCCs less than 3 cm, there was a significantly lower recurrence rate in patients that were treated by TACE compared to RFA (39.7% vs. 61.3%, *p* = 0.03).

#### *3.6. Number of Treatments*

The total number of treatment sessions did not differ significantly (*p* = 0.22) between TACE (median = 2.0, IQR 1.0–3.0) and RFA (median = 2.0, IQR 1.0–3.0). Among hepatomas less than 3 cm, the total number of treatment sessions likewise did not differ significantly (*p* = 0.12), with a median of 2 sessions for TACE (IQR 1.0–2.0) and RFA (IQR 1.0–2.0).

#### *3.7. Adverse Events*

TACE resulted in an adverse event rate of 37% with 7.4% of TACE patients having a greater number of multiple complications. RFA resulted in single adverse events in 16.1% of patients. Of these, the majority were minor adverse events such as pyrexia, nausea, vomiting, abdominal discomfort and elevated transaminases. For tumors <3 cm, adverse events occurred in 17.7% of TACE patients while RFA patients had adverse events 13.3% of the time. Three episodes of major adverse events were associated with TACE of tumors >3 cm, namely one case of hepatorenal syndrome and two cases tumor rupture. RFA resulted in one major adverse event of pneumothorax in a patient with an HCC <3 cm. Three patients died soon after receiving TACE (1.6%), while no patients died after receiving RFA.

#### **4. Discussion**

A substantial proportion of HCC patients presenting to tertiary hospitals require loco-regional therapy. Our study shows that treatment with either TACE or RFA for tumors less than 3 cm did not result in a significant difference in overall survival. This is despite a significantly favorable chance of a complete response following RFA therapy.

In accordance with guidelines, patients in our center with larger tumors and a more advanced BCLC stage tend to be treated with chemoembolization while the smaller tumors are primarily managed with RFA. Even so, there exist factors limiting the use of RFA in these patients: central tumors close to the hepatic hilum are at an increased risk of damage to major biliary structures while those peripherally situated adjacent to extrahepatic organs are liable to heat injuries, such as pleural effusion and intestinal perforation [17]. Incomplete ablation may occur in tumors contiguous to large vessels due to tissue cooling caused by increased circulation [18]. Needle-track seeding is a further consideration that has yet to be addressed convincingly [19]. In these cases, patients were treated with TACE. This trend is especially relevant in Asia where TACE has traditionally been favored as the primary anticancer therapy, and hence is even utilized in treating lesions outside the current guidelines [19].

The outcomes at our center were comparable to published studies [20,21]. Our 3-year overall survival rate of 72.8% for RFA and 57.6% for TACE is in line with the pooled 3-year survival rate of 50.8% described in a systematic review by Singal et al. [20]. TACE was used for patients with a larger tumor load, which could explain the difference in overall survival between TACE and RFA. After stratification for smaller tumors less than 3 cm there was resolution of the survival disparity, with no significant difference seen in median survival between patients treated with TACE and RFA.

The examination of secondary clinical outcomes in the subgroup analysis of hepatomas less than 3 cm provides a possible explanation for the comparable survival between RFA and TACE in small tumors. RFA in small tumors has a higher chance of a complete response compared to TACE, though patients who respond to TACE benefit from a lower recurrence. RFA offers a high chance of a complete response in small tumors due to the ability to completely ablate liver tissue and all tumoral residues in the area of the burn. There are, however, risks of tumor seeding, which may increase recurrence [19]. In contrast, the

efficacy of TACE depends on arterial supply, and incomplete response may occur if there is more than a single supply and incomplete embolization. This effect is higher in larger and multinodular tumors. There have been concerns that the hypoxia induced by TACE induces vascular endothelial growth factor (VEGF) expression, promoting neovascularization and tumor recurrence in patients incompletely treated by TACE [22]. However, in patients who do respond to TACE, the lower recurrence rates in patients could be due to several reasons: (1) Early recurrence would primarily come from microsatellite and microvascular invasion before treatment [23,24]. Many of these are too small to be identified even with high-resolution imaging and may extend past the safety margin of ablation [25,26]. In such a setting, TACE is able to control these micro-metastases missed by radiofrequency ablation; (2) De novo tumors do arise in cirrhotic livers and may occur in the vicinity of previously treated areas, reflecting a milieu that is favorable for carcinogenesis [24,27–29]. The inadvertent spill-over treatment of these high-risk regions with a field change effect downstream of the intended TACE-targeted area may decrease the chance of de novo tumorigenesis and thus explain the longer TTP.

In the era of individualized HCC therapy, there are implications for our results on the treatment of early-stage HCC. The current guidelines advocate for RFA over TACE for the management of HCCs smaller than 3 cm [7,8]. Our study showed that for HCCs less than 3 cm, TACE could lead to a comparable overall survival and TTP compared to RFA. There have been three other retrospective comparative studies of RFA and TACE in small tumors <3 cm or within the Milan criteria, which showed similar overall survival in both groups [12–14]. However, the study by Hsu et al. reported a poorer long-term survival in the subgroup undergoing TACE with a total tumor volume <11 cm3 [12]. In this study, the patients who underwent TACE had a very high mean AFP of 3175 (ng/mL) compared to 320 in the RFA group. Therefore, the TACE group in the study by Hu et al. may have included tumors with a more aggressive biology.

We acknowledge that limitations exist in this study. All the patients in our study had low AFP, which may suggest favorable biology and impact tumor response. This could also explain the differing findings from Hsu et al. and our results have to be cautiously applied to patients with significantly elevated AFP [12]. Due to its retrospective nature and lack of randomization, our study is unable to provide as strong a conclusion as a randomized controlled trial. Our study is also limited by the small numbers in the subgroup analysis. Even so, a direct comparison between TACE and RFA through a randomized trial has been difficult due to the ethical implications imposed by the present treatment guidelines. We hence hope that our study adds to the body of literature supporting the feasibility of TACE in small HCCs less than 3 cm, especially when other options are unfeasible.

#### **5. Conclusions**

In summary, we found that in patients with early-stage HCC, both TACE and RFA led to similar overall survival and recurrence rates. This suggests that TACE may be considered as an alternative treatment option in patients unsuitable for surgery and/or RFA.

**Author Contributions:** Conceptualization, B.W.R.T., D.Q.H., L.J.C. and D.Y.Y.; methodology, B.W.R.T., D.Q.H., L.J.C. and D.Y.Y.; software, B.W.R.T., D.Q.H., L.J.C. and D.Y.Y.; validation, K.W.C.A., I.S.G., T.P.S., D.Y.Y., L.G.H., N.W.T., L.H.C. and M.M.; formal analysis, B.W.R.T., D.Q.H., L.J.C. and D.Y.Y.; investigation, K.W.C.A., I.S.G., T.P.S., D.Y.Y., L.G.H., L.Y.M., P.T., L.S.G., D.C.M., N.W.T., L.H.C. and M.M.; resources, K.W.C.A., I.S.G., T.P.S., D.Y.Y., L.G.H., M.M., L.H.C., L.Y.M., P.T., L.S.G., D.C.M., N.W.T. and M.M.; data curation, B.W.R.T. and L.J.C.; writing—original draft preparation, B.W.R.T., D.Q.H. and L.J.C.; writing—review and editing, B.W.R.T., D.Q.H., L.J.C., P.T., W.H.L., C.H.N., D.J.H.T. and D.Y.Y.; visualization, B.W.R.T. and D.Q.H.; supervision, D.Y.Y.; project administration, D.C.M. and B.W.R.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** This study was approved by the Investigation and Ethics Committee of the National University Hospital (Singapore), according to the standards of the Declaration of Helsinki. 2016/00086-AMD0001.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** Kindly contact corresponding author for information requests.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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**Appendix A**

**Table A1.** Initial compositions of the sample used in the high temperature experiments.

**Table A2.** Experimental Results in the System CaO-MgO-Al2O3 -SiO2 system with Al2O3/SiO2 weight ratio of 0.4.

\* Experimental data from previous work [15–18,23].

**Table A3.** Experimental Results in the System CaO-MgO-Al2O3 -SiO2 system with Al2O3/SiO2 weight ratio of 0.4.

\* Experimental data from previous work [15–18,23].


*<IP_ADDRESS> Wealth index*

Wealth index of women and family often affects contraceptive use due to access to finance and education of the benefits of contraception. The poorer the women, the less likely they will use contraceptives, and those from affluent backgrounds tend to use contraceptives more [18].


**Novel Strategies for the Development of Healthier Meat and Meat Products and Determination of Their Quality Characteristics**

Editors **Claudia Ruiz-Capillas Ana Herrero Herranz**

MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin

*Editors* Claudia Ruiz-Capillas Spanish National Research Council, CSIC, Department of Products Spain

Ana Herrero Herranz Spanish National Research Council, CSIC, Department of Products Spain

*Editorial Office* MDPI St. Alban-Anlage 66 4052 Basel, Switzerland

This is a reprint of articles from the Special Issue published online in the open access journal *Foods* (ISSN 2304-8158) (available at: https://www.mdpi.com/journal/foods/special issues/Novel Strategies Development Healthier Meat Meat Products Determination Quality Characteristics).

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