*3.8. Antimicrobial E*ffi*cacy*

It is essential to perform microbiological efficacy studies to demonstrate the activity of the drug in the nanoemulsion against the commonly susceptible microorganisms [32]. The optimized formulation (MM3) showed microbicidal activity, when microbiological testing was performed by the cup plate technique. Visible zones of inhibition were noticed in case of MM3 and control formulation. The diameter of the zone of inhibitions generated by MM3 against both test organisms (*Pseudomonas aeruginosa* and *Staphylococcus aureus*) were either similar or more than that produced by commercial ophthalmic drops (Table 4). The broad-spectrum antibacterial activity of moxifloxacin in the nanoemulsion against the susceptible pathogens was similar to the reference formulation in terms of antimicrobial efficacy. This clearly indicates that the prepared formulation did not change the inherent bactericidal effect of the incorporated moxifloxacin.

**Table 4.** Antimicrobial efficacy of the optimized formulation (MM3).

 \* Control: Commercial eye drops of moxifloxacin.


Preface

The ever-increasing global population makes an increasing demand on energy. Fossil fuels are at the forefront of energy sources that we still need. However, due to the limited resour‐ ces of these fuels and global climate change, the availability of alternative sources and ener‐ gy carriers has gained importance. For this reason, studies have been accelerated to obtain blue energy (water) and green energy (wind, solar, etc.) from new technologies to meet the increasing energy demand of human society. Among energy sources, hydrogen gas is clean and renewable and has the potential to solve the growing energy crisis in today's society because of its high-energy density and noncarbon fuel properties. It is also used for many potential applications in nonpolluting vehicles, fuel cells, home heating systems, and air‐ craft. In addition, using hydrogen as an energy carrier is a long-term option to reduce car‐ bon dioxide emissions worldwide by obtaining high-value hydrocarbons through the hydrogenation of carbon dioxide. Water is considered as an ideal hydrogen source because it is clean, abundant, and renewable. Hydrogen production from water is achieved by water splitting using several methods such as thermal decomposition, electrolysis, photolysis, and photoelectrochemical methods.

This book presents the recent progresses and developments in water-splitting processes as well as other hydrogen generation technologies with challenges and future perspectives from the point of energy sustainability. In the first two chapters, the electrolysis of water, which attracts great attention due to its sustainability and renewability, is presented with the theoretical foundations of the operating principles of different types of electrolyzers. The most important technologies, such as alkaline electrolysis, proton exchange membrane elec‐ trolysis, and solid oxide high-temperature electrolysis, are addressed. In Chapter 3, the re‐ cent technological progress in light hydrocarbons regarding the sustainable hydrogen production is highligted, while the following two chapters evaluate the hydrogen produc‐ tion from ethanol by steam and use of hydrogen in a proton exchange membrane fuel cell. In the last chapter, a detailed performance model and optimization strategy is proposed for standalone operation of a concentrated photovoltaic system, with hydrogen production as an energy storage.

> **Asst. Prof. Murat Eyvaz** Co-Head of Department Department of Environmental Engineering Deputy Director Science and Technology Application and Research Center Gebze Technical University

Turkey

**Chapter 1**

Provisional chapter

**Hydrogen Generation by Water Electrolysis**

Hydrogen is a promising energy vector for the future. Among the different methods of its production, the electrolysis of water has attracted great attention because it is a sustainable and renewable chemical technology. Thus, hydrogen represents a suitable energy vector for the storage of intermittent energies. This chapter is devoted to the hydrogen generation by water electrolysis as an important part of both existing and emerging industrial electrochemical processes. It aims to give an insight into the theoretical foundations of the operating principles of different types of electrolyzers. Also, it is developed in this chapter, the thermodynamic and kinetic aspects of the reactions taking place at the electrodes of water electrolysis. The evolution reaction of hydrogen has a rapid kinetics, and thus, the polarization of the cathode is not critical. On the other hand, the evolution reaction of oxygen is characterized by a very slow kinetics and is thus responsible for most of the overvoltage in the electrolysis of water. The most important technologies of water electrolysis are addressed: alkaline electrolysis, proton exchange membrane electrolysis,

DOI: 10.5772/intechopen.76814

Keywords: hydrogen, oxygen, water electrolysis, catalyst, electrolyte, alkaline, polymer,

The United Nations (UN) published The Sustainable Development Program in 2015, which is an action plan for humanity, the planet, and prosperity. A total of 17 sustainable development goals and 169 targets are announced, which will stimulate action over the next 15 years in areas of critical importance for humanity and the planet (People, Planet, Prosperity, Peace, Partnership). The seventh goal is to ensure access to affordable, reliable, sustainable, and modern energy for all [1]. The hydrogen economy is seen as an instrument for the transformation of the energy system [2]. Hydrogen is the fuel most often used in fuel cells. It can have

> © 2016 The Author(s). Licensee InTech. 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 eproduction in any medium, provided the original work is properly cited.

© 2018 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.

Hydrogen Generation by Water Electrolysis

Youssef Naimi and Amal Antar

Youssef Naimi and Amal Antar

http://dx.doi.org/10.5772/intechopen.76814

Abstract

solid oxide

1. Introduction

Additional information is available at the end of the chapter

and solid oxide high-temperature electrolysis.

Additional information is available at the end of the chapter

#### **Chapter 1** Provisional chapter

#### **Hydrogen Generation by Water Electrolysis** Hydrogen Generation by Water Electrolysis

DOI: 10.5772/intechopen.76814

#### Youssef Naimi and Amal Antar Youssef Naimi and Amal Antar

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76814

#### Abstract

Hydrogen is a promising energy vector for the future. Among the different methods of its production, the electrolysis of water has attracted great attention because it is a sustainable and renewable chemical technology. Thus, hydrogen represents a suitable energy vector for the storage of intermittent energies. This chapter is devoted to the hydrogen generation by water electrolysis as an important part of both existing and emerging industrial electrochemical processes. It aims to give an insight into the theoretical foundations of the operating principles of different types of electrolyzers. Also, it is developed in this chapter, the thermodynamic and kinetic aspects of the reactions taking place at the electrodes of water electrolysis. The evolution reaction of hydrogen has a rapid kinetics, and thus, the polarization of the cathode is not critical. On the other hand, the evolution reaction of oxygen is characterized by a very slow kinetics and is thus responsible for most of the overvoltage in the electrolysis of water. The most important technologies of water electrolysis are addressed: alkaline electrolysis, proton exchange membrane electrolysis, and solid oxide high-temperature electrolysis.

Keywords: hydrogen, oxygen, water electrolysis, catalyst, electrolyte, alkaline, polymer, solid oxide

### 1. Introduction

The United Nations (UN) published The Sustainable Development Program in 2015, which is an action plan for humanity, the planet, and prosperity. A total of 17 sustainable development goals and 169 targets are announced, which will stimulate action over the next 15 years in areas of critical importance for humanity and the planet (People, Planet, Prosperity, Peace, Partnership). The seventh goal is to ensure access to affordable, reliable, sustainable, and modern energy for all [1]. The hydrogen economy is seen as an instrument for the transformation of the energy system [2]. Hydrogen is the fuel most often used in fuel cells. It can have

© 2016 The Author(s). Licensee InTech. 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 eproduction in any medium, provided the original work is properly cited. © 2018 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.

several provenances (electrolysis of water, cracking or reforming of petroleum products), with obvious implications on its degree of purity and consequently on the choice of catalyst, electrolyte, and operating conditions. The production of hydrogen by the electrolysis technique is very interesting because it can use a non-greenhouse gas energy source (renewable or nuclear energy). In addition, it remains the basic technique for providing applications that require small volumes of high purity hydrogen, including the semiconductor and food industry.

2. Principle of water electrolysis

positive terminal of the DC source.

H2O ! 1 2

2OH� ! 1

The global reaction for the two cases is:

H2O ! H2 þ

reaction can be written as:

3. Thermodynamic

2

1 2

ing in a chemical reaction (aA þ bB þ … ! mM þ nN þ …):

Water electrolysis is the process whereby water is split into hydrogen and oxygen through the application of electrical energy, as in Eq. (6). Typically, a water electrolysis unit consists of an anode, a cathode separated with an electrolyte, and a power supply. The electrolyte can be made of an aqueous solution containing ions, a proton exchange membrane (PEM) or an oxygen ion exchange ceramic membrane. A direct current (DC) is applied from the negative terminal of the DC source to the cathode (seat of the reduction reaction), where the hydrogen is produced. At the anode, the electrons produced by the electrochemical reaction return to the

For the case of water electrolysis in an acid aqueous electrolyte, the processes that occur at the

� E0

� E0

Electrolysis of water is not a spontaneous phenomenon because the standard global reaction potential is negative. Therefore, it needs an external intervention (power source) and the global

H2O þ electricity ! H2 þ

The equation of the German chemist Walther Nernst can be obtained from thermodynamics. The variation of Gibbs free energy is a function of the concentrations of the species participat-

ΔG ¼ ΔG0 þ RT∙ln am

H2O=O2

Hþ =H2

H2O=H2

OH� =O2

> � E0 OH� =O2

1 2

M∙an N∙…

!

aa A∙ab B∙…

H2O=H2

¼ 1:23V=ENH (1)

Hydrogen Generation by Water Electrolysis http://dx.doi.org/10.5772/intechopen.76814 3

¼ 0:00V=ENH (2)

¼ �0:83V=ENH (3)

¼ 0:4 V=ENH (4)

¼ �1:23 V (5)

(7)

O2 (6)

anode and the cathode are described, respectively, by Eqs. 1 and 2:

O2 þ 2Hþ þ 2e

2Hþ þ 2e� ! H2 E0

2H2O þ 2e� ! H2 þ 2OH� E0

O2 þ H2O þ 2e

The half reactions occurring on the cathode and anode, respectively, can be written as:

O2 ΔE0 ¼ E0

Hydrogen is the lightest chemical element. Its molecules contain two hydrogen atoms. If this gas does not exist in its natural state, it is found in many molecules: water, sugar, proteins, hydrocarbons, and so on.

Hydrogen is a very light gas, colorless, odorless, and extremely flammable and reacts very easily in the presence of other chemicals. The properties of this gas are summarized in Table 1 [3].

The advantages of using hydrogen as a fuel in fuel cells are:

Its low density under normal conditions, the difficulty of storage, and the risk of explosion can summarize the major drawbacks of the use of pure hydrogen in fuel cells.

Notwithstanding the increasing interest in hydrogen as an energy carrier, its main uses continue to be in petroleum refining, ammonia production, metal refining, and electronics fabrication, with an average worldwide consumption of about 40 million tons [4–8]. This large-scale hydrogen consumption consequently requires large-scale hydrogen production. Presently, the technologies that dominate hydrogen production include reforming of natural gas [9], gasification of coal and petroleum coke [10–12], as well as gasification and reforming of heavy oil [13, 14]. Although water electrolysis has been known for around 200 years [15, 16], it still contributes only a minor fraction of the total hydrogen production (4% of the worldwide hydrogen production) [17, 18]. When compared to other available methods, water electrolysis has the advantage of producing extremely pure hydrogen (>99.9%), ideal for some high valueadded processes such as the manufacture of electronic components [4].

Table 1. Characteristics of hydrogen [3].

### 2. Principle of water electrolysis

several provenances (electrolysis of water, cracking or reforming of petroleum products), with obvious implications on its degree of purity and consequently on the choice of catalyst, electrolyte, and operating conditions. The production of hydrogen by the electrolysis technique is very interesting because it can use a non-greenhouse gas energy source (renewable or nuclear energy). In addition, it remains the basic technique for providing applications that require small volumes

Hydrogen is the lightest chemical element. Its molecules contain two hydrogen atoms. If this gas does not exist in its natural state, it is found in many molecules: water, sugar, proteins,

Hydrogen is a very light gas, colorless, odorless, and extremely flammable and reacts very easily in the presence of other chemicals. The properties of this gas are summarized in Table 1 [3].

Its low density under normal conditions, the difficulty of storage, and the risk of explosion can

Notwithstanding the increasing interest in hydrogen as an energy carrier, its main uses continue to be in petroleum refining, ammonia production, metal refining, and electronics fabrication, with an average worldwide consumption of about 40 million tons [4–8]. This large-scale hydrogen consumption consequently requires large-scale hydrogen production. Presently, the technologies that dominate hydrogen production include reforming of natural gas [9], gasification of coal and petroleum coke [10–12], as well as gasification and reforming of heavy oil [13, 14]. Although water electrolysis has been known for around 200 years [15, 16], it still contributes only a minor fraction of the total hydrogen production (4% of the worldwide hydrogen production) [17, 18]. When compared to other available methods, water electrolysis has the advantage of producing extremely pure hydrogen (>99.9%), ideal for some high value-

Molecular weight 2016 g/mol Melting point 259C Boiling point (1.013 bar) 252.8C Evaporation heat (1.013 bar at boiling point) 454.3 kJ/mol Density in the gas phase (1.013 and at 21C) 0.0696 kg/m3 Solubility in water (1.013 bar and 0C) 0.0214 vol/vol

of high purity hydrogen, including the semiconductor and food industry.

The advantages of using hydrogen as a fuel in fuel cells are:

• unlimited availability (as long as you can break down the water),

summarize the major drawbacks of the use of pure hydrogen in fuel cells.

added processes such as the manufacture of electronic components [4].

• its harmless combustion product (H2O) for the environment.

hydrocarbons, and so on.

2 Advances In Hydrogen Generation Technologies

• its high electrochemical reactivity, • its high theoretical energy density,

Table 1. Characteristics of hydrogen [3].

Water electrolysis is the process whereby water is split into hydrogen and oxygen through the application of electrical energy, as in Eq. (6). Typically, a water electrolysis unit consists of an anode, a cathode separated with an electrolyte, and a power supply. The electrolyte can be made of an aqueous solution containing ions, a proton exchange membrane (PEM) or an oxygen ion exchange ceramic membrane. A direct current (DC) is applied from the negative terminal of the DC source to the cathode (seat of the reduction reaction), where the hydrogen is produced. At the anode, the electrons produced by the electrochemical reaction return to the positive terminal of the DC source.

For the case of water electrolysis in an acid aqueous electrolyte, the processes that occur at the anode and the cathode are described, respectively, by Eqs. 1 and 2:

$$\text{H}\_2\text{O} \rightarrow \frac{1}{2}\text{O}\_2 + 2\text{H}^+ + 2\text{e}^- \qquad\qquad \text{E}^0\_{\text{H}\_2\text{O}/\_{\text{O}\_2}} = 1.23\text{V/ENH} \tag{1}$$

$$2H^{+} + 2e^{-} \rightarrow H\_{2} \qquad\qquad\qquad \qquad \begin{aligned} &E\_{H^{+}}^{0}{}\_{/H\_{2}} = 0.00V/\text{ENH} \end{aligned} \tag{2}$$

The half reactions occurring on the cathode and anode, respectively, can be written as:

$$2\text{H}\_2\text{O} + 2\text{e}^- \rightarrow \text{H}\_2 + 2\text{OH}^-\qquad\qquad\qquad \qquad \qquad E\_{\text{H}\_2\text{O}}^0 \!\!/\_{\text{H}\_2} = -0.83\text{V}/\text{ENH}\tag{3}$$

$$2\text{OH}^- \rightarrow \frac{1}{2}\text{O}\_2 + \text{H}\_2\text{O} + 2\text{e}^- \qquad\qquad\qquad \qquad \qquad \qquad \qquad \qquad \text{E}\_{\text{OH}^-}^0 \text{ }\_{\text{O}\_2} = 0.4\text{ V/ENH} \tag{4}$$

The global reaction for the two cases is:

$$\mathrm{H\_2O} \rightarrow \mathrm{H\_2} + \frac{1}{2} \mathrm{O\_2} \qquad \qquad \Delta \mathrm{E^0} = \mathrm{E\_{H\_2O}^0}\_{\mathrm{H\_2O}} \, - \, \mathrm{E\_{OH^-}^0}\_{\mathrm{O\_2}} \, = -1.23 \,\mathrm{V} \tag{5}$$

Electrolysis of water is not a spontaneous phenomenon because the standard global reaction potential is negative. Therefore, it needs an external intervention (power source) and the global reaction can be written as:

$$\text{H}\_2\text{O} + \text{electricity} \rightarrow \text{H}\_2 + \frac{1}{2}\text{O}\_2\tag{6}$$

#### 3. Thermodynamic

The equation of the German chemist Walther Nernst can be obtained from thermodynamics. The variation of Gibbs free energy is a function of the concentrations of the species participating in a chemical reaction (aA þ bB þ … ! mM þ nN þ …):

$$
\Delta G = \Delta G^0 + RT \cdot \ln \left( \frac{a\_M^m \cdot a\_N^n \cdot \dots}{a\_A^a \cdot a\_B^b \cdot \dots} \right) \tag{7}
$$

where aa A, ab B, …, am M, an N, …, are the activities of the species.

Some species involved in the electrode reaction are solids or pure liquids. For these pure substances, the activity is constant and its value is considered unitary. The activity of the gases is usually taken to be the partial pressure of the gases expressed in the atmosphere, and the activity of the ions in dilute solution is generally considered to be their molar concentration. By substituting in Eq. (7) the reactions, and dividing each member of the equation by -nF, we obtain the Nernst equation. Nernst's equation expresses the relationship between the potential of an electrochemical cell and the concentrations of its constituents at equilibrium. In the specific case of an electrochemical cell, it is written:

$$
\Delta E\_{\text{myle}} = \left( E\_{\text{Caathode}}^0 - E\_{\text{Anode}}^0 \right) - \frac{RT}{nF} \ln \left( \frac{a\_M^m \cdot a\_N^u \dots}{a\_A^a \cdot a\_B^b \dots} \right) \tag{8}
$$

#### 3.1. Faraday's law

In 1832, Michael Faraday stated his two laws of electrolysis:

The quantity of material (m) produced is:

$$\mathbf{m} = \mathbf{k} \cdot \int\_0^t \mathbf{I} \cdot \mathbf{d}t \tag{9}$$

ΔE ¼ ΔEthe þ ηa þ ηc þ R∙I (11)

with: ηa ð Þ V is the anodic overvoltage; ηc ð Þ V is the cathodic overvoltage; R (Ω) is the global

Figure 1 shows the relationship between the electrolyzer cell potential and operating temperature [19–22]. The cell potential-temperature plane is divided into three zones by the so-called equilibrium voltage line and thermo-neutral voltage line. The equilibrium voltage is the theoretical minimum potential required to dissociate water by electrolysis, below which the electrolysis of water cannot proceed. The equilibrium voltage decreases with increasing temperature. The thermo-neutral voltage is the actual minimum voltage that has to be applied to the electrolysis cell, below which the electrolysis is endothermic and above which, exothermic. The thermoneutral voltage naturally includes the overpotentials of the electrodes, which are only weakly dependent on temperature. Thus, the thermo-neutral voltage only exhibits a slight increase with temperature. If water electrolysis takes place in the shaded area in Figure 4, the reaction will be

As these electrochemical reactions are heterogeneous surface processes, it is convenient to

A ∙ dm dt .

A∙dt ¼ I

A∙n∙F. Therefore, the expression for

Hydrogen Generation by Water Electrolysis http://dx.doi.org/10.5772/intechopen.76814 5

O þ ne� ⇄ R (12)

resistance and I (A) is the current.

endothermic.

3.3. Electrodes polarizations

For a general electrochemical reaction:

current density, j ¼ I

relate the reaction rate to the electrode area, A, as dm

A, may be rewritten asj ¼ nF

Figure 1. Cell potential for hydrogen production by water electrolysis as a function of temperature [19].

where k is a proportionality constant and I is the instantaneous current flowing through the cell. In a cell in which a continuous current circulates, the majority of this current is connected to chemical reactions (faradic current) and a small part, often negligible can be used for other purposes (non-Faradic current). Thus, the amount of material that forms or disappears at the electrodes is proportional to the intensity of the current and the duration of the electrolysis t. Knowing the number of moles is ð Þ m=M , which corresponds to a quantity of electricity Q ¼ m M ∙N∙F ¼ I∙t � �. Hence, Faraday's law:

$$m = \frac{I \cdot t \cdot M}{nF} \tag{10}$$

With: m is the mass of substances formed (g); M is the molar mass of substances formed (g/mol.); n is number of exchanged electrons, I is the current in amperes (A), Q ¼ I∙t is the quantity of electricity in coulomb (C), t is the time (s).

#### 3.2. Cell voltage (difference of potential)

The potential difference for a cell of an electrolyzer, which is always ΔE ¼ 1:8˜2:0 V at the current density of j ¼ 1000 � 300 Am2 in industry water electrolysis [17], is an addition of four terms:

$$
\Delta E = \Delta \mathbf{E}\_{\text{the}} + \mathfrak{n}\_{\text{a}} + \mathfrak{n}\_{\text{c}} + \mathbf{R} \cdot \mathbf{I} \tag{11}
$$

with: ηa ð Þ V is the anodic overvoltage; ηc ð Þ V is the cathodic overvoltage; R (Ω) is the global resistance and I (A) is the current.

Figure 1 shows the relationship between the electrolyzer cell potential and operating temperature [19–22]. The cell potential-temperature plane is divided into three zones by the so-called equilibrium voltage line and thermo-neutral voltage line. The equilibrium voltage is the theoretical minimum potential required to dissociate water by electrolysis, below which the electrolysis of water cannot proceed. The equilibrium voltage decreases with increasing temperature. The thermo-neutral voltage is the actual minimum voltage that has to be applied to the electrolysis cell, below which the electrolysis is endothermic and above which, exothermic. The thermoneutral voltage naturally includes the overpotentials of the electrodes, which are only weakly dependent on temperature. Thus, the thermo-neutral voltage only exhibits a slight increase with temperature. If water electrolysis takes place in the shaded area in Figure 4, the reaction will be endothermic.

#### 3.3. Electrodes polarizations

where aa

A, ab

3.1. Faraday's law

Q ¼ m

B, …, am M, an

4 Advances In Hydrogen Generation Technologies

specific case of an electrochemical cell, it is written:

The quantity of material (m) produced is:

M ∙N∙F ¼ I∙t � �. Hence, Faraday's law:

3.2. Cell voltage (difference of potential)

quantity of electricity in coulomb (C), t is the time (s).

ΔEnpile ¼ E0

In 1832, Michael Faraday stated his two laws of electrolysis:

N, …, are the activities of the species.

Cathode � E0

tional to the quantity of electricity that passes through the electrolyte.

ity are proportional to the equivalent weight of each substance.

Some species involved in the electrode reaction are solids or pure liquids. For these pure substances, the activity is constant and its value is considered unitary. The activity of the gases is usually taken to be the partial pressure of the gases expressed in the atmosphere, and the activity of the ions in dilute solution is generally considered to be their molar concentration. By substituting in Eq. (7) the reactions, and dividing each member of the equation by -nF, we obtain the Nernst equation. Nernst's equation expresses the relationship between the potential of an electrochemical cell and the concentrations of its constituents at equilibrium. In the

> Anode � � � RT

1. The weights of substances formed at an electrode during electrolysis are directly propor-

2. The weights of different substances formed by the passage of the same quantity of electric-

ðt 0

where k is a proportionality constant and I is the instantaneous current flowing through the cell. In a cell in which a continuous current circulates, the majority of this current is connected to chemical reactions (faradic current) and a small part, often negligible can be used for other purposes (non-Faradic current). Thus, the amount of material that forms or disappears at the electrodes is proportional to the intensity of the current and the duration of the electrolysis t. Knowing the number of moles is ð Þ m=M , which corresponds to a quantity of electricity

m ¼ I∙t∙M

With: m is the mass of substances formed (g); M is the molar mass of substances formed (g/mol.); n is number of exchanged electrons, I is the current in amperes (A), Q ¼ I∙t is the

The potential difference for a cell of an electrolyzer, which is always ΔE ¼ 1:8˜2:0 V at the current density of j ¼ 1000 � 300 Am2 in industry water electrolysis [17], is an addition of four terms:

m ¼ k∙

nF ln am

M:an N…

!

I∙dt (9)

nF (10)

(8)

aa A:ab B…

> As these electrochemical reactions are heterogeneous surface processes, it is convenient to relate the reaction rate to the electrode area, A, as dm A∙dt ¼ I A∙n∙F. Therefore, the expression for current density, j ¼ I A, may be rewritten asj ¼ nF A ∙ dm dt .

For a general electrochemical reaction:

$$O + ne^- \rightleftharpoons R\tag{12}$$

Figure 1. Cell potential for hydrogen production by water electrolysis as a function of temperature [19].

#### 6 Advances In Hydrogen Generation Technologies

Under nonequilibrium potential conditions, the equation that best describes the current density versus potential is the Butler-Volmer expression:

$$\overrightarrow{j}\_{a} = \overrightarrow{j}\_{a} + \overrightarrow{j}\_{c} = nF\overrightarrow{k}\_{0}\mathsf{C}\_{R}(0, t)e^{\left(\frac{a\_{a}nI\left(\frac{\varepsilon}{kT}\right)}{kT}\right)} - nF\overrightarrow{k}\_{0}\mathsf{C}\_{O}(0, t)e^{\left(\frac{a\_{a}nI\left(\frac{\varepsilon}{kT}\right)}{kT}\right)}\tag{13}$$

where j a ! and j c are, respectively, the anodic and cathodic current density; k0 and k0 ! are, respectively, the rates constants of the anodic and cathodic reaction; αa and αc are, respectively, the anodic and cathodic exchanges coefficients; E0 is the standard potential.

Under the control of electron transfer rate, (the concentration of the electrodes' surface is equal to the concentration in the bulk), this equation can be expressed as current density versus overpotential (η ¼ E � Éeq):

$$j = j\_0 j \left( e^{\left(\frac{a\_d n \mathbb{F} \eta}{kT}\right)} - e^{\left(\frac{a\_c n \mathbb{F} \eta}{kT}\right)} \right) \tag{14}$$

(ΔHads,Pd,298ð Þ¼ H2 83:kJ mol:

the rate-determining step.

Cappadonia et al. [29]:

and Pt at the apex of the volcano curve [27].

mol:

�1); for Ni, the heat of adsorption is ΔHads,Ni, 298ð Þ¼ H2 105 kJ

Hydrogen Generation by Water Electrolysis http://dx.doi.org/10.5772/intechopen.76814 7

�1 [25]. Electrode properties, type and concentration of the electrolyte, and temperature are parameters that also influence hydrogen formation. If hydrogen adsorption is the ratedetermining step, electrode materials with more edges and cavities in their surface structure will favor electron transfer and create more centers for hydrogen adsorption. If hydrogen desorption is the rate-determining step, physical properties such as surface roughness or perforation will prevent bubbles from growing and increase electron transfer by adding reaction area, consequently increasing the rate of electrolysis [26]. When the overpotential is low, electron transfer is not as fast as desorption and hydrogen adsorption will be the ratedetermining step. In contrast, when the potential is high enough, hydrogen desorption will be

The hydrogen adsorption energy is a good parameter to identify the most promising materials for the HER. If the activities for the HER of the coinage metals (IB metals: Au, Cu, Ag), the platinum group (Pt, Ir, Ru) metals and the valve metal (Ti) in 0.1 M HClO4, are plotted as a function of the M–Hads binding energy, a volcano relationship is established (Figure 2) with Ir

Further analysis of Figure 2 reveals that the IB group elements are positioned on the ascending slope of the volcano with the order activity increasing from Au < Cu < Ag. Figure 1 also shows that the elements that interact strongly with Hads (such as Ru and Ti) are positioned on the descending slope of the volcano, supporting previous suggestions that the M–Hads binding energy can be used as a descriptor for the HER. Not in passing, given that recent analysis has demonstrated that neither Ru nor Ti are bare metals in the HER region, it is suggested that, in fact, experimentally it is very difficult (impossible) to determine unambiguously solely based on the M–Hads energetics what would be the correct position of these two elements in the observed volcano relationship. This is most likely also true for the HER in alkaline solutions,

The HER exchange current of Pt in acid media is at least two orders of magnitude higher than that in alkaline electrolytes, including KOH. This is due to the shorter Pt � Hads distance in alkaline media, as suggested by theoretical estimates. It has been claimed that Ni(OH)2 nanoclusters on Pt surface enhance HER rates in 0.1 M KOH by one order of magnitude [26], although no theoretical explanation for this synergistic effect has been attempted. The long-term stability of Ni(OH)2 in

The mechanism of the oxygen evolution reaction (OER) is more complex than that suggested for HER. The most generally accepted mechanism for the OER is that described by

OH� ⇄ OHads þ e

OH� þ OHads ⇄ Oads þ H2O þ e

� (20)

Oads þ Oads ⇄ O2 (22)

� (21)

when the rates of the reaction are much slower than in acidic environments [22].

the strongly reducing environment occurring at the cathode is also not discussed.

The anodic and cathodic exchanges coefficients (αa, and αc) are related (αa þ αc ¼ 1), and generally, α ≈ αa ≈ αc ≈ 1 2. For a given single-step reaction at a constant temperature, the j versus η characteristics will depend on j 0, αa, and αc.

For large η values, the Butler-Volmer equations can be simplified to give the Tafel equation ð Þ j j η ¼ a∙ log j jj þ b :

$$\text{For } \eta \ll 0: \log\left(j\right) = -\log\left(j\_0\right) - \frac{\alpha\_\epsilon nF}{2.3RT} \cdot \eta \tag{15}$$

$$\text{For } \eta \gg 0: \log \left( j \right) = -\log \left( j\_0 \right) + \frac{\alpha\_d nF}{2.3RT} \cdot \eta \tag{16}$$

For the hydrogen evolution reaction (HER), the Volmer-Tafel and Volmer-Heyrovský mechanisms are often proposed and well known [16, 23, 24]. The first step (Eq. 17) involves the formation of adsorbed hydrogen, which is then followed by either chemical desorption (Eq. 18) or electrochemical desorption (Eq. 19), where Hads is an adsorbed hydrogen atom.

$$H\_2O + e^- \rightleftharpoons H\_{ads} + OH^- \qquad\qquad\text{Volmer step}\tag{17}$$

$$\text{2H}\_{\text{ads}} \rightleftharpoons \text{H}\_{\text{2}} \tag{18}$$

$$\rm H\_{ads} + H\_2O + e^- \rightleftharpoons H\_2 + OH^- \qquad \quad \text{Heyrovsky} \\ \rm step \tag{19}$$

For the hydrogen evolution reaction (HER), the overpotential, ηH2 , is generally calculated by the Tafel equation. Hydrogen formation is intrinsically determined by the strength of the bond between hydrogen and the electrode surface. Pd has the lowest heat of adsorption of hydrogen (ΔHads,Pd,298ð Þ¼ H2 83:kJ mol: �1); for Ni, the heat of adsorption is ΔHads,Ni, 298ð Þ¼ H2 105 kJ mol: �1 [25]. Electrode properties, type and concentration of the electrolyte, and temperature are parameters that also influence hydrogen formation. If hydrogen adsorption is the ratedetermining step, electrode materials with more edges and cavities in their surface structure will favor electron transfer and create more centers for hydrogen adsorption. If hydrogen desorption is the rate-determining step, physical properties such as surface roughness or perforation will prevent bubbles from growing and increase electron transfer by adding reaction area, consequently increasing the rate of electrolysis [26]. When the overpotential is low, electron transfer is not as fast as desorption and hydrogen adsorption will be the ratedetermining step. In contrast, when the potential is high enough, hydrogen desorption will be the rate-determining step.

Under nonequilibrium potential conditions, the equation that best describes the current den-

αanF E�E0 ð Þ RT

respectively, the rates constants of the anodic and cathodic reaction; αa and αc are, respectively,

Under the control of electron transfer rate, (the concentration of the electrodes' surface is equal to the concentration in the bulk), this equation can be expressed as current density versus

0j e αanFη ð Þ RT � e

The anodic and cathodic exchanges coefficients (αa, and αc) are related (αa þ αc ¼ 1), and

For large η values, the Butler-Volmer equations can be simplified to give the Tafel equation

For the hydrogen evolution reaction (HER), the Volmer-Tafel and Volmer-Heyrovský mechanisms are often proposed and well known [16, 23, 24]. The first step (Eq. 17) involves the formation of adsorbed hydrogen, which is then followed by either chemical desorption (Eq. 18)

the Tafel equation. Hydrogen formation is intrinsically determined by the strength of the bond between hydrogen and the electrode surface. Pd has the lowest heat of adsorption of hydrogen

are, respectively, the anodic and cathodic current density; k0

� nFk0 !

αcnFη ð Þ RT

> 0 � αcnF

0 þ αanF

� ⇄ Hads þ OH� Volmer step (17)

� ⇄ H2 þ OH� Heyrovsḱy step (19)

2Hads ⇄ H2 Tafel step (18)

2. For a given single-step reaction at a constant temperature, the j versus

COð Þ 0; t e

αcnF E�E0 ð Þ RT

2:3RT ∙η (15)

2:3RT ∙η (16)

, is generally calculated by

and k0 ! are,

(13)

(14)

sity versus potential is the Butler-Volmer expression:

¼ nFk0

CRð Þ 0; t e

the anodic and cathodic exchanges coefficients; E0 is the standard potential.

j ¼ j

0, αa, and αc.

For η ≪ 0 : log ðÞ¼� j log j

For η ≫ 0 : log ðÞ¼� j log j

or electrochemical desorption (Eq. 19), where Hads is an adsorbed hydrogen atom.

H2O þ e

Hads þ H2O þ e

For the hydrogen evolution reaction (HER), the overpotential, ηH2

j ¼ j a ! þ j c

6 Advances In Hydrogen Generation Technologies

overpotential (η ¼ E � Éeq):

generally, α ≈ αa ≈ αc ≈ 1

ð Þ j j η ¼ a∙ log j jj þ b :

η characteristics will depend on j

where j a ! and j c

> The hydrogen adsorption energy is a good parameter to identify the most promising materials for the HER. If the activities for the HER of the coinage metals (IB metals: Au, Cu, Ag), the platinum group (Pt, Ir, Ru) metals and the valve metal (Ti) in 0.1 M HClO4, are plotted as a function of the M–Hads binding energy, a volcano relationship is established (Figure 2) with Ir and Pt at the apex of the volcano curve [27].

> Further analysis of Figure 2 reveals that the IB group elements are positioned on the ascending slope of the volcano with the order activity increasing from Au < Cu < Ag. Figure 1 also shows that the elements that interact strongly with Hads (such as Ru and Ti) are positioned on the descending slope of the volcano, supporting previous suggestions that the M–Hads binding energy can be used as a descriptor for the HER. Not in passing, given that recent analysis has demonstrated that neither Ru nor Ti are bare metals in the HER region, it is suggested that, in fact, experimentally it is very difficult (impossible) to determine unambiguously solely based on the M–Hads energetics what would be the correct position of these two elements in the observed volcano relationship. This is most likely also true for the HER in alkaline solutions, when the rates of the reaction are much slower than in acidic environments [22].

> The HER exchange current of Pt in acid media is at least two orders of magnitude higher than that in alkaline electrolytes, including KOH. This is due to the shorter Pt � Hads distance in alkaline media, as suggested by theoretical estimates. It has been claimed that Ni(OH)2 nanoclusters on Pt surface enhance HER rates in 0.1 M KOH by one order of magnitude [26], although no theoretical explanation for this synergistic effect has been attempted. The long-term stability of Ni(OH)2 in the strongly reducing environment occurring at the cathode is also not discussed.

> The mechanism of the oxygen evolution reaction (OER) is more complex than that suggested for HER. The most generally accepted mechanism for the OER is that described by Cappadonia et al. [29]:

$$\text{OH}^- \rightleftharpoons \text{OH}\_{\text{ads}} + e^- \tag{20}$$

$$2\text{ }OH^- + \text{ }OH\_{\text{ads}} \rightleftharpoons \text{O}\_{\text{ads}} + \text{H}\_2\text{O} + e^- \tag{21}$$

$$O\_{ads} + O\_{ads} \rightleftharpoons O\_2 \tag{22}$$

R ¼ X i

wires, connectors, and electrodes. This part of the resistance can be reduced by reducing the length of the wire, increasing the cross-section area and adopting more conductive wire

The ionic solution conductivity χ is a function of concentration and temperature. For an ionic solution containing ions (i), charged þzi or �zi and at the concentration Ci in mol:∙m�3, the

The presence of bubbles in the electrolyte solution and on the electrode surfaces causes additional resistances to the ionic transfer and surface electrochemical reactions. One of the accepted

where κ is the specific conductivity of the gas-free electrolyte solution; f is the volume fraction

Convective mass transfer plays an important role in the ionic transfer, heat dissipation and distribution, and gas bubble behavior in the electrolyte. The viscosity and flow field of the electrolyte determines the mass (ionic) transfer, temperature distribution and bubble sizes, bubble detachment and rising velocity, and in turn influence the current and potential distributions in the electrolysis cell. As the water electrolysis progresses the concentration of the electrolyte increases, resulting in an increase in the viscosity. Water is usually continuously added to the system to maintain a constant electrolyte concentration and thus the viscosity.

The conductivity of the solution is enhanced by the use of strong electrolytes that deliver ions with high mobility [43], such as sodium, potassium for positive ions, and hydroxide or chlorides as negative ions. During electrolysis, the water molecules move to the cathode by diffusion as they are consumed, and the hydroxide ions move to the anode by migration because they have an opposite charge and diffusion because they are consumed. A diaphragm

m�1 � �, is:

χ ¼ X i

theoretical equations to study the bubble effect in the electrolyte is given as follows [41]:

with: λi is the equivalent conductivity of the ion (i) in, S∙m2∙mol:

where χi Ω�1

conductivity of the solution, noted χ Ω�1

of gas in the solution [42].

3.5. Transport resistances

4. Alkaline electrolysis

material.

li Ai∙χi

m�1 � � is the electrical conductivity for each component of the circuit, including

λi∙zi∙Ci (24)

Hydrogen Generation by Water Electrolysis http://dx.doi.org/10.5772/intechopen.76814

�1 .

κg ¼ κð Þ 1 � 1:5∙f (25)

(23)

9

Figure 2. HER activity, overpotential (η) at 5 mA cm2, measured in 0.1 M HClO4 (pH = 1) as a function of calculated M–H binding energy for several metals (volcano plot) [20].

The mechanism is controlled by the charge transfer (step 20 or 21) at low temperatures. On the other hand, at high temperatures, the recombination step (Eq. 22) controls the reaction on Ni electrode [22–30].

Generally, acid solutions or PEMs are used as electrolytes in water electrolyzers because acidic media show high ionic conductivity and are free from carbonate formation, as compared with alkaline electrolytes. Consequently, noble metals are used as electrocatalysts for OER in acidic media. Ruthenium and iridium have shown strong activity for OER, but they were passivated at very high anode potentials [31–36]. Bifunctional electrocatalysts, which can work for both oxygen evolution and oxygen reduction, have also been proposed for water electrolysis. A typical bifunctional electrocatalyst is composed of a noble metal oxide such as IrO2. For unsupported bifunctional electrocatalysts, Pt-MOx (M = Ru, Ir, Na), bimetallic (e.g., Pt-Ir), and trimetallic (e.g., Pt4.5Ru4Ir0.5) materials have been developed [37–40].

At high current densities, are added to the polarization of the electrodes other resistances: ohmic losses in the electrolyte, resistances from bubbles, diaphragm, and ion transfer.

#### 3.4. Electrical resistance

The electrical resistance in a water electrolysis system has three main components: (1) the resistance in the system circuits; (2) the mass transport phenomena including ions transfer in the electrolyte; (3) the gas bubbles covering the electrode surfaces and the diaphragm [15].

The nature and the dimensions of the materials used in the electrodes and the connections and the electric circuit, the methods of their preparations are responsible for the electrical resistance of the system. It can be expressed as follows:

Hydrogen Generation by Water Electrolysis http://dx.doi.org/10.5772/intechopen.76814 9

$$R = \sum\_{i} \frac{l\_i}{A\_{i^\*} \chi\_i} \tag{23}$$

where χi Ω�1 m�1 � � is the electrical conductivity for each component of the circuit, including wires, connectors, and electrodes. This part of the resistance can be reduced by reducing the length of the wire, increasing the cross-section area and adopting more conductive wire material.

The ionic solution conductivity χ is a function of concentration and temperature. For an ionic solution containing ions (i), charged þzi or �zi and at the concentration Ci in mol:∙m�3, the conductivity of the solution, noted χ Ω�1 m�1 � �, is:

$$\chi = \sum\_{i} \lambda\_{i} \mathbf{z}\_{i} \cdot \mathbf{C}\_{i} \tag{24}$$

with: λi is the equivalent conductivity of the ion (i) in, S∙m2∙mol: �1 .

The presence of bubbles in the electrolyte solution and on the electrode surfaces causes additional resistances to the ionic transfer and surface electrochemical reactions. One of the accepted theoretical equations to study the bubble effect in the electrolyte is given as follows [41]:

$$
\kappa\_{\mathcal{S}} = \kappa (1 - 1.5\mathcal{f}) \tag{25}
$$

where κ is the specific conductivity of the gas-free electrolyte solution; f is the volume fraction of gas in the solution [42].

#### 3.5. Transport resistances

The mechanism is controlled by the charge transfer (step 20 or 21) at low temperatures. On the other hand, at high temperatures, the recombination step (Eq. 22) controls the reaction on Ni

Figure 2. HER activity, overpotential (η) at 5 mA cm2, measured in 0.1 M HClO4 (pH = 1) as a function of calculated

Generally, acid solutions or PEMs are used as electrolytes in water electrolyzers because acidic media show high ionic conductivity and are free from carbonate formation, as compared with alkaline electrolytes. Consequently, noble metals are used as electrocatalysts for OER in acidic media. Ruthenium and iridium have shown strong activity for OER, but they were passivated at very high anode potentials [31–36]. Bifunctional electrocatalysts, which can work for both oxygen evolution and oxygen reduction, have also been proposed for water electrolysis. A typical bifunctional electrocatalyst is composed of a noble metal oxide such as IrO2. For unsupported bifunctional electrocatalysts, Pt-MOx (M = Ru, Ir, Na), bimetallic (e.g., Pt-Ir),

At high current densities, are added to the polarization of the electrodes other resistances:

The electrical resistance in a water electrolysis system has three main components: (1) the resistance in the system circuits; (2) the mass transport phenomena including ions transfer in the electrolyte; (3) the gas bubbles covering the electrode surfaces and the diaphragm [15].

The nature and the dimensions of the materials used in the electrodes and the connections and the electric circuit, the methods of their preparations are responsible for the electrical resistance

ohmic losses in the electrolyte, resistances from bubbles, diaphragm, and ion transfer.

and trimetallic (e.g., Pt4.5Ru4Ir0.5) materials have been developed [37–40].

electrode [22–30].

3.4. Electrical resistance

of the system. It can be expressed as follows:

M–H binding energy for several metals (volcano plot) [20].

8 Advances In Hydrogen Generation Technologies

Convective mass transfer plays an important role in the ionic transfer, heat dissipation and distribution, and gas bubble behavior in the electrolyte. The viscosity and flow field of the electrolyte determines the mass (ionic) transfer, temperature distribution and bubble sizes, bubble detachment and rising velocity, and in turn influence the current and potential distributions in the electrolysis cell. As the water electrolysis progresses the concentration of the electrolyte increases, resulting in an increase in the viscosity. Water is usually continuously added to the system to maintain a constant electrolyte concentration and thus the viscosity.

#### 4. Alkaline electrolysis

The conductivity of the solution is enhanced by the use of strong electrolytes that deliver ions with high mobility [43], such as sodium, potassium for positive ions, and hydroxide or chlorides as negative ions. During electrolysis, the water molecules move to the cathode by diffusion as they are consumed, and the hydroxide ions move to the anode by migration because they have an opposite charge and diffusion because they are consumed. A diaphragm separates the two anode and cathode compartments and the gases formed are thus collected: hydrogen at the cathode and oxygen at the anode as shown in Figure 3.

Concentrated solutions of potassium hydroxide are generally used as the electrolytic solution because they have very high conductivities and fewer corrosion problems compared with other alkaline electrolytes. The electrode materials often used are based on nickel because of its low cost, high activity [44].

Electrolysis cells can be of two types of configurations: monopolar and bipolar [14]. Figure 4(a) gives a schematic of the monopolar configuration. The electrodes are altered in the electrolyzer and are all directly connected to the terminals of the DC power supply: the anodes at the positive terminal and the cathodes at the negative terminal. The total voltage applied to the entire electrolysis cell is essentially the same as that applied to the individual pairs of the electrodes in the cell (Utot ¼ Ui), but the current is subdivided between the different unit cells (Itot ¼ n � IiÞ. Figure 4(b) depicts conflation in bipolar mode. Only the two end electrodes are connected directly to the DC power source. The other inner electrodes have a dual role: one side acts as the cathode for a unit cell and the other side acts as the anode for the adjacent unit cell. These cells are electrically linked thanks to their electrodes which are bipolar and ionically via the electrolytic solution. The total voltage of the cell is the sum of the individual voltages of

the unit cells (Utot ¼ n � Ui), but the current for each unit cell is equal to the output current of the generator (Itot ¼ IiÞ. The electrical energy consumed is the same in the two configurations. The wide range of flammability limits of the mixture of hydrogen and oxygen requires a careful design of the electrolyzer system. The separator diaphragm (or membrane) must avoid the mixing of the two gases inside the cell. Furthermore, the corrosive nature of the electrolyte does not allow leaks that are often likely to take place at the connections and seals of the electrolyzer. The bipolar configuration is more risky in mixing oxygen and hydrogen because of their simultaneous productions on the same bipolar electrode (on each side) and also

Hydrogen Generation by Water Electrolysis http://dx.doi.org/10.5772/intechopen.76814 11

Figure 4. Schematics of cell configurations of monopolar (a) and bipolar (b) electrolyzers [14].

Obviously, the life of the system is an important criterion. It is extremely linked to the quality of the materials used. Indeed, these materials must be resistant to high concentrations of the alkaline electrolyte and operating conditions of the electrolyzer (pressure and temperature). In particular, connections and seals are subject to corrosion, which is why it is recommended to

electrolyte leakage as the monopolar design.

use sealing materials that are also stable in this environment [14].

Figure 3. Principle of an alkaline water electrolysis.

Figure 4. Schematics of cell configurations of monopolar (a) and bipolar (b) electrolyzers [14].

separates the two anode and cathode compartments and the gases formed are thus collected:

Concentrated solutions of potassium hydroxide are generally used as the electrolytic solution because they have very high conductivities and fewer corrosion problems compared with other alkaline electrolytes. The electrode materials often used are based on nickel because of

Electrolysis cells can be of two types of configurations: monopolar and bipolar [14]. Figure 4(a) gives a schematic of the monopolar configuration. The electrodes are altered in the electrolyzer and are all directly connected to the terminals of the DC power supply: the anodes at the positive terminal and the cathodes at the negative terminal. The total voltage applied to the entire electrolysis cell is essentially the same as that applied to the individual pairs of the electrodes in the cell (Utot ¼ Ui), but the current is subdivided between the different unit cells (Itot ¼ n � IiÞ. Figure 4(b) depicts conflation in bipolar mode. Only the two end electrodes are connected directly to the DC power source. The other inner electrodes have a dual role: one side acts as the cathode for a unit cell and the other side acts as the anode for the adjacent unit cell. These cells are electrically linked thanks to their electrodes which are bipolar and ionically via the electrolytic solution. The total voltage of the cell is the sum of the individual voltages of

hydrogen at the cathode and oxygen at the anode as shown in Figure 3.

its low cost, high activity [44].

10 Advances In Hydrogen Generation Technologies

Figure 3. Principle of an alkaline water electrolysis.

the unit cells (Utot ¼ n � Ui), but the current for each unit cell is equal to the output current of the generator (Itot ¼ IiÞ. The electrical energy consumed is the same in the two configurations.

The wide range of flammability limits of the mixture of hydrogen and oxygen requires a careful design of the electrolyzer system. The separator diaphragm (or membrane) must avoid the mixing of the two gases inside the cell. Furthermore, the corrosive nature of the electrolyte does not allow leaks that are often likely to take place at the connections and seals of the electrolyzer. The bipolar configuration is more risky in mixing oxygen and hydrogen because of their simultaneous productions on the same bipolar electrode (on each side) and also electrolyte leakage as the monopolar design.

Obviously, the life of the system is an important criterion. It is extremely linked to the quality of the materials used. Indeed, these materials must be resistant to high concentrations of the alkaline electrolyte and operating conditions of the electrolyzer (pressure and temperature). In particular, connections and seals are subject to corrosion, which is why it is recommended to use sealing materials that are also stable in this environment [14].


*2.7. Adhesion Behavior*

Movement and ingestion of sea cucumbers greatly relies on the adhesion of mouth tentacles and tube feet. Adhesion behavior was measured according to Tian et al. [11]. Eighteen sea cucumbers from each group were randomly selected and placed in cubic devices (length × width × height: 180 mm × 140 mm × 45 mm; Figure 1E) with eighteen compartments. Each sea cucumber was placed in one compartment. Seawater was added to the devices until the seawater level reached a height of 2 cm. The devices were slowly turned to 180◦ after 10 min. We recorded the time that sea cucumbers fell from the top of the devices, since their adhesion abilities were disabled to support their body weight. The adhesion time was recorded as 600 s if sea cucumbers still adhered to the top of the box after 10 min. Wet body weight (g) of each sea cucumber was measured by using an electronic balance (G & G Co., San Diego, CA, USA) after the recording (*n* = 6). Data are accurate to one decimal place. Adhesion index (*Ai*) was formulated, as described by Tian et al. [11]:

$$A\_i = \frac{T}{W}$$

where *Ai* is the adhesion index, *T* is the adhesion time (s), and *W* is the wet weight of an individual sea cucumber (g).

#### *2.8. Statistical Analysis*

All data were subjected to the analysis of variance distribution and homogeneity of variance using the Kolmogorov–Smirnov test and the Levene test, respectively. The mortality and morbidity of experiments I and II were non-normally distributed and/or heterogeneity of variance. Thus, the data were compared by using the Mann–Whitney *U* test. Crawling frequency, tentacle activity frequency, and the adhesion index were analyzed by using Kruskal–Wallis *H* in both experiments. All statistical analyses were performed using SPSS 22.0 statistical software. The level of significance was considered as *p* < 0.05.

### **3. Results**

#### *3.1. Experiment I*

#### 3.1.1. Mortality and Morbidity

Mortality was significantly higher in group C (43.06 ± 2.56%) than that in group O (5.56 ± 4.12%; Mann–Whitney *U* = 2.961, *p* = 0.003; Figure 2A). Consistently, group C showed significantly higher morbidity (48.61 ± 1.39%) than group O (6.94 ± 3.98%; Mann– Whitney *U* = 3.017, *p* = 0.003; Figure 2B).

**Figure 2.** Mortality (**A**) and morbidity (**B**) of sea cucumbers between groups C and O. The asterisks \*\* mean *p* < 0.01 (mean ± SE, *n* = 6). Group C: sea cucumbers without artificial reefs; Group O: sea cucumbers with artificial reefs.

#### 3.1.2. Crawling Frequency

There was no significant difference in crawling frequency between sea cucumbers of group C (4.44 ± 0.88 times) and individuals outside the artificial reef of group O (3.22 ± 0.50 times; Kruskal–Wallis *H* = 14.332, *p* = 1.000; Figure 3A). Crawling frequency was significantly higher in sea cucumbers inside the artificial reefs of group O (10.83 ± 1.52 times) than that in sea cucumbers outside the artificial reefs of group O (Kruskal–Wallis *H* = 14.332, *p* = 0.001) and group C (Kruskal–Wallis *H* = 14.332, *p* = 0.008; Figure 3A).

**Figure 3.** Crawling frequency (**A**), tentacles activity frequency (**B**) and adhesion behavior (**C**) of sea cucumbers. The asterisks \*, \*\*, \*\*\* mean *p* < 0.05, *p* < 0.01 and *p* < 0.001, respectively (mean ± SE, *n* = 6). Group C: sea cucumbers without artificial reefs in group C; Group O-Out: sea cucumbers outside the artificial reefs in group O; Group O-In: sea cucumbers inside the artificial reefs in group O.

#### 3.1.3. Feeding Behavior

There was no significant difference in tentacle activity frequency between sea cucumbers of group C (10.44 ± 3.51 times) and individuals outside the artificial reefs of group O (8.50 ± 1.87 times; Kruskal–Wallis *H* = 7.705, *p* = 1.000; Figure 3B). Consistently, tentacle activity frequency was not significantly different between sea cucumbers outside (8.50 ± 1.87 times) and inside (18.72 ± 3.26 times) the artificial reefs (Kruskal–Wallis *H* = 7.705, *p* = 0.067; Figure 3B). Tentacle activity frequency was significantly higher in sea cucumbers inside the artificial reefs in group O than that in individuals of group C (Kruskal–Wallis *H* = 7.705, *p* = 0.036; Figure 3B).

#### 3.1.4. Adhesion Behavior

The adhesion index was not significantly different between sea cucumbers outside the artificial reefs of group O (16.66 ± 5.50) and individuals of group C (9.75 ± 6.28; Kruskal– Wallis *H* = 0.561, *p* = 0.065; Figure 3C). Consistently, the adhesion index was not significantly different in sea cucumbers outside and inside the artificial reefs (283.62 ± 61.4) in group O (Kruskal–Wallis *H* = 0.561, *p* = 0.076; Figure 3C). However, sea cucumbers inside the artificial reefs of group O showed significantly higher adhesion index than individuals of group C (Kruskal–Wallis *H* = 0.561, *p* < 0.001; Figure 3C).


*Edited by Pere M. Pares-Casanova*

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## New Insights into Morphometry Studies

*Edited by Pere M. Pares-Casanova*


*Article* **Elevated Vascular Sympathetic Neurotransmission and Remodelling Is a Common Feature in a Rat Model of Foetal Programming of Hypertension and SHR**

**Maria Sofia Vieira-Rocha 1,2, Joana Beatriz Sousa 1,2,\*, Pilar Rodríguez-Rodríguez 3, Silvia Madaglena Arribas 3 and Carmen Diniz 1,2,\***

**Abstract:** Hypertension is of unknown aetiology, with sympathetic nervous system hyperactivation being one of the possible contributors. Hypertension may have a developmental origin, owing to the exposure to adverse factors during the intrauterine period. Our hypothesis is that sympathetic hyperinnervation may be implicated in hypertension of developmental origins, being this is a common feature with essential hypertension. Two-animal models were used: spontaneously hypertensive rats (SHR-model of essential hypertension) and offspring from dams exposed to undernutrition (MUN-model of developmental hypertension), with their respective controls. In adult males, we assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), sympathetic nerve function (3H-tritium release), sympathetic innervation (immunohistochemistry) and vascular remodelling (histology). MUN showed higher SBP/DBP, but not HR, while SHR exhibited higher SBP/DBP/HR. Regarding the mesenteric arteries, MUN and SHR showed reduced lumen, increased media and adventitial thickness and increased wall/lumen and connective tissue compared to respective controls. Regarding sympathetic nerve activation, MUN and SHR showed higher tritium release compared to controls. Total tritium tissue/tyrosine hydroxylase detection was higher in SHR and MUN adventitia arteries compared to respective controls. In conclusion, sympathetic hyperinnervation may be one of the contributors to vascular remodelling and hypertension in rats exposed to undernutrition during intrauterine life, which is a common feature with spontaneous hypertension.

**Keywords:** foetal programming of hypertension; sympathetic neurotransmission; sympathetic innervation; vascular remodelling; fibrosis; foetal undernutrition


**1. Introduction**

Vertical axis wind turbines (VAWTs) are typically characterized by lower wind energy-conversion efficiency than commonly used horizontal axis wind turbines (HAWTs). However, they are often favored in micro power generation due to their simple design, a possibility to locate a generator near the ground, and to accept the wind blowing from different directions [1,2]. They are quieter and safer than small-scale HAWTs and, thus, suitable for applications in urbanized areas [3–5].

A vertical axis wind turbine, referred to as the Savonius turbine, was invented by S.J. Savonius [6]. In the top view, it resembles the letter "S" with two typically semi-cylindrical blades, often slightly overlapping. Its primary advantage lies in simple and, thus, cheap and robust design [7,8]. Similar to other VAWTs, Savonius turbines are independent of the wind direction. However, contrary to Darrieus wind turbines, they are characterized by a high starting torque for selected rotor positions. They are classified as drag-driven turbines and operate at low rotational speeds, with tip speed ratios not exceeding 2, which makes them safer than HAWTs at strong winds [9]. They perform well at low wind speeds most often encountered close to the ground and they are characterized by a low level of noise emission. Thus, Savonius turbines are suitable for application in urbanized areas [3].

Unfortunately, the primary disadvantage of Savonius turbines is their low efficiency. Typically reported values of the power coefficient for designs with semi-cylindrical blades fall

within the range *Cp* = 0.15–0.20 [7,10,11]. Therefore, this kind of turbine in its basic configuration is not usually a reasonable alternative when compared to other types of wind turbine. Nonetheless, owing to their advantages, Savonius turbines were subject to numerous investigations aimed at increasing their efficiency. Many works were focused on the search for optimal dimensions of geometrical parameters of rotors. The influence of the number of blades, overlap ratio, aspect ratio, end plates and other factors was studied both with experimental and numerical methods. Results of those investigations were presented in numerous papers, which further were summarized in thorough reviews [7,12].

Many studies were focused on modifications of the blade shape or an application of additional elements to direct the air flow towards blades. The replacement of conventional semi-cylindrical blades by more sophisticated shapes allowed one to increase the Savonius turbine performance significantly, with maximal values of the power coefficient up to *Cp* = 0.25–0.30. A substantial part of the research concentrates on two-dimensional (2D) thin blade configurations, i.e.,: Bach, Benesh, elliptical and spline [11,13,14]. Airfoil shape blades were studied in [15,16]. Optimization methods were also applied in order to search for an optimal blade shape in [16–19], taking advantage of 2D simplifications in numerical simulations. Three-dimensional (3D) blade arrangements with twisted or helical blades were tested as well. In this case, it was possible to reduce static and dynamic torque variations for different angular positions of the rotor with respect to the incoming wind, however, no significant improvement was reported as far as the turbine performance is considered [12,14].

Different augmentation systems can be used to change the wind flow path around and in the Savonius rotor. Its power output was increased by 20% up to 50% if the turbine rotor was equipped with flat plate deflectors [18,20,21], v-shaped deflectors [22] or a combination of flat and circular deflectors [23], shielding the returning blade and reducing its negative moment. A similar effect was achieved if the wind was directed towards the advancing blade with a curtain-deflector system [24], self-adjusting conveyor-deflector curtains [15], a system of adjustable shielding plates for twin rotors [9] or even a rectangular guide-box tunnel surrounding the rotor [25]. A comprehensive summary of different augmentation systems with the power coefficient exceeding considerably *Cp* = 0.3 can be found in [11,26]. However, a disadvantage of such approaches consists in larger dimensions of the turbine, an increase in the complexity of its geometry and dependence on the wind direction.

An idea of the Savonius turbine with a variable geometry of blades is proposed in order to enlarge the projected area of the advancing blade (increase the positive moment) and, at the same time, to diminish the area of the returning blade (decrease the negative moment). Elaborate two-dimensional (2D) computational fluid dynamics (CFD) simulations were performed to assess the output power gain for different arrangements of blade deformations.

The deformations of blades in this case were determined with a structural solver and then the geometry was transferred to a fluid solver for the aerodynamic analysis. This approach is referred to as the fluid-structure interaction (FSI). The FSI is a very wide concept of solvers coupling in order to obtain high-fidelity numerical solutions. Solvers can be one-way coupled once the data, i.e., loads from the fluid acting on the wall, are transferred to the structural solver where stress and strains are determined [27,28]. Another example of one-way coupling takes place where the deformation of the structure influences the flow structure and loads determined in the fluid solver. The most advanced method, called the two-way FSI, requires co-simulation between computational fluid dynamics and structural mechanics. Both CFD and structural solvers are coupled and synchronized to attain converged solutions. The two-way FSI is applied to highly dynamical systems as in the case of the aeroelastic response analysis [29] or whenever the structure is flabby [30]. The FSI strategy is typically used in horizontal axis wind turbines (HAWTs). It is also used in the analysis of vertical axis wind turbines (VAWTs), e.g., in the case of an H-rotor [31,32], but no reference reporting an analysis of the Savonius-based turbine is known to the authors. It is due to much lower blade loads than in the case of lift-driven HAWTs or VAWTs.

Idea of the Savonius Rotor with Deformable Blades

An idea of the novel turbine with a variable geometry of blades is shown in Figure 1 for subsequent phases of the rotor revolution [33]. Shapes of the blades made of a flexible material change constantly during its rotation. This is achieved by guiding the outer edges of the blades (tips marked as dots in the color of the blades) along the guide ring (red) placed eccentrically with respect to the rotor shaft. Rods attached to the outer edges of the blades can move linearly with respect to sliders, which are fixed to the shaft. The rode–slider mechanisms, marked by a red dashed line, are applied at the top and bottom of the turbine and they transfer the torque generated by the blades to the shaft. The inner edges of the blades are also attached to the rotor shaft.

**Figure 1.** Principle of the turbine operation.

The phases 90◦ and 270◦ presented in Figure 1 illustrate the maximal deformation of the blades. If the extended, advancing blade is located in such a way that its concave side is exposed to the wind and, simultaneously, the wind blows at the convex side of the contracted, returning blade, one can expect that the turbine will be driven with the wind energy more efficiently than in the case of both blades having the same, fixed shape. This implies that the turbine needs to be properly located with respect to the incoming wind. Therefore, the guide ring needs to change its position by rotation around the axis of the base of the turbine, which is coaxial with the rotor shaft axis, marked as a black X in Figure 1. The guide ring mechanism has to be equipped with an aerodynamic or mechanical system in order to adjust its position with respect to the wind direction. The turbine generator is fixed to the frame and a gear or a transmission has to be applied to transfer the mechanical energy from the turbine blades.

The additional mechanisms make the design of the proposed turbine more complex than the original Savonius. However, they consume a part of the energy generated by the turbine. Thus, all elements need to be carefully designed to be resistant and efficient. The present study focuses on the aerodynamic performance of a novel, efficient design but neither mechanical losses due to friction nor energy losses due to blade deformations are considered. Thus, one must bear in mind that the overall performance of the turbine will depend on the mechanical design and that a portion of energy will be consumed by the system itself.


**4. Conclusions**

In the present work, the electrochemical oxidation of three cytostatic drugs and their mixtures in a recirculating split-flow batch reactor equipped with a BDD anode was investigated. The oxidation of cytostatic drugs was performed in an anodic compartment separated from the cathodic compartment by a cation-exchanged membrane. The values of kapp for the single-drug solution and for mixtures of cytostatic drugs in Na2SO4 as electrolyte were in the following order: kapp 5-FU < kapp CP < kapp

IF. The degradation of drugs in their mixtures showed that the PO43− has no significant effect on the drugs' degradation, while Cl− mainly accelerated this process. Based on the TOC removal and TN conversion to gaseous products, it was found that the degradation pathway of IF was different than that of CP. The organic intermediates found after 6 h of electrolysis were also different for these drugs.

Comparing the results in NaNO3 and Na2SO4 electrolytes, it was suggested that the different oxidising species with different levels of reactiveness participated in cytostatic drugs degradation. In Na2SO4, 5-FU was mainly oxidized by OH• and SO4−• radicals, while chlorine active species simultaneously with OH• and SO4−• entities participated in the CP and IF degradation and nitrogen conversion to gaseous products. Given that Cl− is abundant in natural waters, the involvement of chlorine active species in the electro-oxidation fate of drugs should not be neglected. This was confirmed by the high mineralization and efficiency of drugs removal in the effluent from WWTP, and this is beneficial from the practical point of view. This study is helpful in understanding the fundamental reaction mechanism, as well as the effects of natural water constituents on the kinetics and mechanisms of electrochemical oxidation of cytostatic drugs in their mixtures. Further studies should address the effects of composition of contaminated water (by natural organic matter, carbonates and other anions and cations) on the transformation of cytostatic drugs and the examination of effluents toxicity obtained from AOPs.

**Supplementary Materials:** The following are available online. Figure S1: Cyclic voltammograms of IF, CP and 5-FU (25 mg/L) in 42 mM Na2SO4 (pH = 6.6), BDD as a working electrode, counter electrode (CE)—Pt, scan rate = 100 mV·s−1, T = 20 ± 2 ◦C.

**Author Contributions:** E.M.S. conceptualized and designed the experiments; S.A.O.-C., A.P., A.B.-G. and P.W. performed the experiments and analyzed the data; E.M.S wrote the paper; and polished the paper; E.M.S. and A.P. acquired funding for the research. All authors read and approved the final manuscript.

**Funding:** This research was supported by the Polish Ministry of Research and Higher Education, Poland under the Grant DS530-8626-D596-18 and DS530-8626-D596-19.

**Acknowledgments:** Thank you very much for the help in lab Katarzyna Bachli ´nska and Agnieszka Fiszka Borzyszkowska.

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


PD-L1 remains the most common immune-based biomarker for several malignancies. PD-L1 staining in SCLC is less intense and infrequent compared to NSCLC [130]. In KEYNOTE-158, a combined score >1 for PD-L1 expression by the Dako 22C3 assay appeared to predict increased response to pembrolizumab and improved survival when compared with patients negative for PD-L1 [44]; however, the PD-L1 positivity based on Dako 28-8 assay as in the CheckMate 032 did not replicate those results [131]. The assays differ in that KEYNOTE-158 used a PD-L1 score based on staining of tumor cells, lymphocytes and macrophages, whereas CheckMate 032 used staining of only tumor cells to determine positivity. The ongoing phase II REACTION (NCT02580994) and the phase III KEYNOTE-604 (NCT03066778) trials will require measurement of PD-L1 at baseline to provide insight into the predictive role of PD-L1 expression. Higher tumor mutation burden (TMB) has been recognized as a likely predictor of response to immunotherapy across disease types [132]. In an exome-sequencing analysis of CheckMate 032, patients with high TMB appeared to have a greater improvement in OS when treated with nivolumab. Patients with high-, medium-, and low-TMB had a median OS of 5.4 months, 3.9 months, and 3.1 months, respectively; the one-year OS rates were 35.2%, 26.0%, and 22.1%, respectively [133]. However, in the IMpower-133, a blood-based TMB failed to predict benefit for atezolizumab, thus requiring further prospective randomized validation TMB studies. Circulating tumor cells (CTCs) can be detected in 85% of SCLC patients and can potentially serve as a biomarker [134]. CTCs have been explored in multiple studies as a biomarker to predict response and resistance to therapy; however, additional studies looking into the genomic, epigenetic, and transcriptomic heterogeneity of CTCs at diagnosis and during relapse need to be done before it can be applied in clinics [135,136]. Cell-free DNA (cfDNA) widely used in NSCLC has also been examined in SCLC. A study with 27 patients showed cfDNA was able to mirror treatment response and even identified disease recurrence before radiological progression [137]. Future work based on tumor or blood-based biomarkers will help a long way in understanding treatment resistance in SCLC.

#### *8.2. Combination Therapy*

To overcome treatment resistance, novel combination approaches targeting multiple pathways are being explored in combination with chemotherapy and immunotherapies. Lurbinectedin, a novel cytotoxic drug, is a transcriptional inhibitor that inhibits RNA polymerase II. In a phase II trial for both sensitive and resistant disease, lurbinectedin was active as a single agent in second-line SCLC with an ORR of 35.2% [138]. Based on this study, the FDA has approved lurbinectedin for the treatment of ES-SCLC patients with disease progression after platinum-based chemotherapy. A phase III study (ATLANTIS trial, NCT02566993) of lurbinectedin in combination with doxorubicin vs. chemotherapy has completed recruitment and results are pending. Current trials investigating targeted therapies with or without chemotherapy include WEE1 inhibitor AZD1775 in combination with carboplatin (NCT02937818) and olaparib (NCT02511795), checkpoint kinase 1 (CHK1) inhibitor SRA737 in combination with cisplatin/gemcitabine (NCT027979770), ataxia–telangiectasia and Rad3 related (ATR) inhibitor AZD6738 in combination with olaparib (NCT02937818), another ATR inhibitor VX-970 in combination with topotecan (NCT02487095), Bcl-2 inhibitor navitoclax and mTOR inhibitor vistusertib (NCT03366103), Bcl-2 inhibitor venetoclax and ABBV-075 (NCT02391480), and Aurora B kinase inhibitor (NCT02579226) are all ongoing, which should shed some light on the future of targeted therapy in SCLC. There are numerous early phase trials investigating the combination of immunotherapy and targeted drugs as well. Durvalumab with olaparib (NCT02734004, MENDIOLA), avelumab with utomilumab, which is a humanized monoclonal antibody (mAb) that stimulates signaling through CD137 (NCT02554812), nivolumab plus ipilimumab with dendritic cell-based p53 vaccine 9 (NCT03406715) in relapsed SCLC, atezolizumab with chemotherapy and a CDK 4/6 inhibitor trilaciclib (NCT03041311) in first-line ES-SCLC are some of the novel combinations of immunotherapy with targeted agents.

#### *8.3. Other Modalities*

Other modalities of therapies targeting cell surface antigens expressed on tumor cells by monoclonal antibodies or surface-targeting immunotherapies, such as CAR-T cells and bispecific T-cell engagers (BiTEs), arein early stages of development. CD56is expressedin almost all SCLC tumors, and thus, presents to be an attractive target for treating SCLC [139]. In a preclinical study, promiximab-duocarmycin (DUBA), a CD56 antibody conjugated to a potent DNA alkylating agent with a novel linker, showed promising results. This antibody drug conjugate (ADC) demonstrated high efficacy in SCLC xenograft models [140], suggesting that further clinical evaluation of this compound may be beneficial. Another ADC sacituzumab govitecan is comprised of a humanized mAb targeting Trop-2 (trophoblastic antigen-2), which is highly expressed in several epithelial cancers [141], fused to SN-38 (the active metabolite of irinotecan), which induces double- and single-strand DNA breaks by inhibiting topoisomerase I [142]. Sacituzumab govitecan is currently being investigated in several trials, including a phase I/II trial where it is being evaluated as a single agent in patients with previously treated, advanced SCLC (NCT01631552). CAR-T cells targeting DLL3 have entered a phase I clinical trial (NCT03392064). AMG 757, a BiTE, is also being evaluated in a phase I trial that includes ES-SCLC patients requiring first-line maintenance therapy and those with SCLC recurrence (NCT03319940). In patients with metastatic solid tumors including relapsed SCLC, targeting other immune checkpoints, such as PD-1 and CTLA-4, with immunotherapies, including TIM3 and LAG3, are being evaluated in clinical trials in combination with anti-PD-1 or anti-PD-L1 antibodies (NCT03708328, NCT03365791). Finally, radiation therapy is assumed to modulate immune response, as it can increase tumor antigen production and presentation and also enhance cytotoxic T-lymphocyte activity [143]. Potential synergy of radiotherapy in combination with immunotherapy in patients with ES-SCLC is being evaluated in innovative ongoing trials, and results are expected in the near future. Altogether, advancement in biomarkers, targeting multiple critical pathways, and enhancing immunotherapy efficacy in SCLC will hopefully improve the survival outcomes for SCLC patients, which has been elusive for many years.

#### **9. Community Network-City of Hope Experience**

City of Hope is a National Cancer Institute (NCI)-designated Comprehensive Cancer Center and a member of the National Comprehensive Cancer Network (NCCN). In addition, all clinical sites accept the Via Oncology Pathways (modified by City of Hope) for evaluation, antitumor treatment and surveillance after treatments have concluded. City of Hope is composed of a central academic site in Duarte and several satellite sites within Southern California. At the academic center, preclinical work is performed, and clinical trials on that translational research can be rapidly deployed across the entire enterprise, making bench-to-bedside research feasible and fascicle. The collaboration between basic research done on the main campus and clinical research done at both the main and satellite campuses, furthers the discovery of disease biomarkers and novel drug targets. This results in more rational drug design, improved therapeutic efficacy, and quicker optimization of high priority drugs for clinical use (Figure 2).

**Figure 2.** Collaboration between main academic site and community sites for clinical research.

Clinical trials are initiated at the academic campus in Duarte and at one or more of our 27 affiliated network community cancer center offices that are staffed with 43 medical oncologists, 40 radiation oncologists, seven advanced practice providers (APPs) and a clinical trials coordinator. As directed by the Recalcitrant Cancer Research Congressional Act of 2012 (H.R.733), the National Cancer Institute (NCI) allocates resources for research and treatment of recalcitrant cancers having five-year relative survival rates of <20% and estimated to cause at least 30,000 deaths in the US per year. SCLC is considered a recalcitrant cancer having a dismal five-year survival rate of less than 7%. One of the major limitations to ongoing research in SCLC is tumor tissue availability, as the disease is rarely treated surgically. Another issue is many clinical trials in SCLC cannot be completed due to lack of accrual. Using the academic collaboration model with the academic center along with 27 community sites, enrollment becomes more feasible. The rapid progression of disease in SCLC relapse also places research on an urgent timeline to test new agents with a small window to observe treatment efficacy. Given single Institutional Review Board (IRB) approval in our institution, clinical trials can be opened at multiple sites in a rapid fashion. At the academic site, preclinical investigations are done, and clinical trials based on translational research data can be rapidly designed and disseminated across the entire

enterprise, facilitating bench-to-bedside SCLC research in a more feasible manner. The collective knowledge gained from the interaction between the academic and community sites will provide insight into how to overcome challenges that continuously hinder therapeutic advancements in SCLC.

#### **10. Future Directions**

Traditionally, SCLC has been regarded as a homogenous disease, which led to most SCLC patients being treated with essentially one standard regimen. Recent studies from molecular analysis of patient tissues and genetically defined models indicate that there is notable heterogeneity among SCLCs in terms of histology, growth characteristics, expression of neuroendocrine cell differentiation markers, MYC activation, Notch pathway inactivation, and role of neuronal lineage-specific transcription factors in this disease (ASCL1, achaete-scute homologue 1; NeuroD1, neurogenic differentiation factor 1; POU2F3, POU class 2 homeobox 3; YAP1, yes-associated protein 1) [144–148]. Currently, SCLC is classified into four subtypes based on increased expression of different markers: ASCL1 high (SCLC-A), NEUROD1 high (SCLC-N), POU2F3 high (SCLC-P), and YAP1 high (SCLC-Y) [79]. SCLC-A and SCLC-N are neuroendocrine subtypes, whereas SCLC-P and SCLC-Y are non-neuroendocrine subtypes. These subtypes can be associated with specific biomarkers that are either drug-specific targets or predictors of drug response (e.g., DLL3 in SCLC-A, AURKA in SCLC-N, CDK4/6 in SCLC-Y and IGF1R in SCLC-P). These distinct gene expression profiles will guide us in designing new clinical trials. Recent advances in using patient-derived xenograft (PDX) models based on biopsy/resected tumors, CTCs, genetically engineered mouse models (GEMM), as well as omics profiling will drastically enhance our capacity to identify and test novel drugs and discover biomarkers for treatment and prognostication [93,149].

In conclusion, we recommend: (i) setting up a centralized biobank and repository leading to creation of a database incorporating full genomic, proteomic, and microRNA information; (ii) enrolling a higher proportion of SCLC patients into clinical trials with obligatory biomarker analysis; (iii) creating a master protocol which will help reduce duplicative effort and thus ease the eligibility requirements for clinical trials; (iv) create and incentivize academic and community research partnership centers of excellence, since most SCLC patients are treated in community sites; (v) collaborate with bioengineers, cancer biologists, and biophysicists to gather the genetic aberrations discovered and harness the power of computational modeling of genetic information, which will be a powerful tool in understanding SCLC and developing future therapies. Given the academic and community partnership we have established at City of Hope, this should be achievable and pave way for success in treating this challenging disease.

**Author Contributions:** Conceptualization, S.S., A.N., and R.S.; methodology, S.S., A.N., and N.G.; writing—original draft preparation, S.S. and A.N.; writing—review and editing, S.S., A.N., N.G., A.B., P.K., and R.S.; supervision, R.S.; project administration, P.K.; funding acquisition, R.S. All authors have read and agreed to the published version of the manuscript.

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

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

#### **References**

© 2020 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 (http://creativecommons.org/licenses/by/4.0/).


**3. Clinical difference between EAC and ESCC**

#### **3.1. Location of ESCC and EAC**

In 50–60% of cases, ESCC is located in the middle third thoracic esophagus in Thailand, Iran, and Japan [3, 12, 13, 14]. About 60% of SCCs is also located in the middle third of the esophagus in Iran. Several studies have found that ESCC was most commonly located in the lower third of the esophagus, such as studies conducted in Ghana [15].

In 80% of cases, EAC is located at the gastroesophageal junction (GEJ) and 20% in the lower third thoracic esophagus. This entity is capable of producing EAC directly or, more commonly, through an intermediate pre-neoplastic lesion or Barrett's esophagus (BE). BE is a pre-malignant lesion that develops in 6–14% of patients with Gastroesohageal reflux disease (GERD), of which approximately 0.5–1% will develop EAC [10, 11]. Increased incidence of BE in the past 30 years correlates with an increased incidence of EAC during the same period.