*2.2. Measurement Procedure*

The cylindrical Li-ion battery cell is subjected to the same measurement procedure at each position around the circumference. An ACT0550 battery tester from PEC Corp. (Leuven, Belgium) is used to cycle the battery cell. The battery cell tester can provide currents up to 50 A per channel and apply a voltage of 5 V maximum. All measurements are performed in a climatic chamber of Memmert GmbH & Co. KG (Schwabach, Germany) at a temperature of *T* = 25 ◦C. To investigate the effect of temperature, a temperature sensor PT100 is attached to the outside of the cell and connected to the battery tester.

The cell is always clamped in the cell holder with the position to be examined facing upwards. The battery cell is first fully charged with a current of *I* = 1C (1C ≡ 2.85 A) and also fully discharged again with *I* = 1C in the voltage range of 2.5 V ≤ *U* ≤ 4.2 V. Charge and discharge period consist of a CC phase and a CV phase as listed in Table 2. The termination criterion for the CV phase is when the current drops below 1/100 C, which corresponds to a current of *I*lim = 28.5 mA. For the following investigations, only this one current rate is used. Willenberg et al. [9] showed that expansions also occur at lower current strengths. The influence of the current strength on the uniformity of the expansion has yet to be shown in subsequent work.

The cell is rotated manually by α = 10◦ after each charge and discharge cycle and measured again. During the measurement, voltage, current, and temperature are logged with one data point per second, averaged from the last 1000 recorded values at a frequency of *f* = 1000 Hz. After a total of 36 cycles, the individual positions can be compared with each other.

**Table 2.** Consistent measurement procedure for each measured position around the circumference of the battery cell.


**1. Introduction**

After a decade of rapid technological developments, 3D NAND flash memory has been widely utilized in various kinds of storage applications, especially in file memoryrelated products such as laptops and data centers. Due to the fact of its ultra-high bit density, lower bit cost, and better performances as well as reliabilities, 3D NAND flash is substituting its 2D counterpart step by step. For charge-trap (CT) 3D NAND flash memory, the endurance can largely be improved because the effects of the tunneling layer degradations are weak, and the program time can be faster because the effects of intercell interference (ICI) are well suppressed with larger cell-to-cell space. Recently, a 3D NAND with more than 170 layers was announced by the NAND flash makers [1,2]; more impressively, quadruple-level-cell (QLC, 4 bits/cell), penta-level-cell (PLC, 5 bits/cell), and even hexa-level-cell (HLC, 6 bits/cell) operation modes have been demonstrated [3,4]. All these fundamental developments as well as design-technology co-optimizations (DTCO) will drive 3D NAND flash to the mainstream non-volatile memories in the near future [5].

In NAND flash-based memory systems, a major issue that affects both the performance and reliability is the temperature. In conventional 2D NAND flash with a floating gate (FG) structure, as operation temperature increases, the raw bit error rate (RBER) will increase, and the degradation will become more serious. Therefore, on the one hand, the temperature monitor and controller are necessary in NAND flash-based memory systems with robust reliabilities, and on the other hand, the temperature dependence can be utilized

**Citation:** Chen, F.; Chen, B.; Lin, H.; Kong, Y.; Liu, X.; Zhan, X.; Chen, J. Temperature Impacts on Endurance and Read Disturbs in Charge-Trap 3D NAND Flash Memories. *Micromachines* **2021**, *12*, 1152. https:// doi.org/10.3390/mi12101152

Academic Editors: Cristian Zambelli and Rino Micheloni

Received: 30 August 2021 Accepted: 22 September 2021 Published: 25 September 2021

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

**Copyright:** © 2021 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/).

as an accelerator to build a lifetime prediction model in a short-time using the Arrhenius model [6], which shows high accuracy in 2D FG NAND flash. However, due to the special structures of cells and the arrays in CT 3D NAND flash, the failure mechanisms are much more complex, and the temperature effects are quite different. This can explain why the conventional lifetime prediction model loses accuracy when it is applied to 3D NAND flashes [7]. Accordingly, comprehensive understandings of the temperature impacts on a 3D NAND flash are strongly required.

In this paper, systematic characterizations of the temperature dependences have been conducted on CT-type 3D TLC NAND flash memories from −30~70 ◦C, with focus on the RBER modulations in P/E degradations and read disturbs. By using the FPGA-based raw NAND chip tester, it was experimentally observed that the program/erase time and the RBER in the P/E cycling and read disturbs were highly dependent on the temperature. However, temperature had negligible impacts on the cells' degradation, indicating that the CT 3D NAND is suitable for work at high temperatures with no need to worry about accelerated degradations.

The main contributions of this paper are as follows:

The rest of the paper is organized as follows: Section 2 introduces the background and related work; Section 3 presents the evaluation setup; Section 4 describes the measured results of P/E cycling; Section 5 shows the temperature-dependent read disturbs; finally, Section 6 concludes this work.

#### **2. Background and Related Work**

In 2D NAND flash memory, memory cells use FG to store electrons. However, as scaling the cell size to sub-1X nm, serious issues occur from the large cell-to-cell interference and variations in stored charges in FG. It turns out to be extremely difficult to increase the bit density while also guaranteeing the reliability. Different from 2D NAND flash, 3D NAND flash utilizes stacked storage layers to increase the bit density, which settles the problem of flat area scaling and, thus, the key issue turns to be how many layers can be stacked. The comparisons between the two different NAND flash structures are shown in Figure 1a. In a 3D CT NAND flash cell, besides the core oxide and poly-Si channel, the gate stack contains an oxide tunneling layer, silicon–nitride CT layer, oxide blocking layer, and a control gate (CG).

In NAND flash operations, there includes single-level-cell (SLC, 1 bit/cell), multiplelevel-cell (MLC, 2 bits/cell), triple-level-cell (TLC, 3 bits/cell), QLC, PLC, and HLC. For 2D NAND flash, SLC and MLC modes are adopted in accordance with the products' requirements; while for a 3D NAND flash, TLC mode has been widely used because of the well-tuned reliability and high cost–performance ratio. A typical threshold voltage (V*th*) distribution of TLC in a 3D CT NAND flash is shown in Figure 1b, wherein seven program states from A to G levels can be well distinguished. Only a part of the erase state (ER) can be observed due to the negative V*th* values. Each word-line (WL) consists of three pages, the most significant bit (MSB) page, the central significant bit (CSB) page, and the least significant bit page (LSB). When reading the data from the chip, error bits occur at the overlapping regions between the neighbor states, such as A(B) to B(A) error bits when reading the CSB page at V2 level. Thus, suppressing overlapping regions or optimizing reading voltages are challenges to designing highly reliable NAND flash memory. In

addition, for a 3D CT NAND flash, one special concern is the shared common CT layer between neighboring cells.

**Figure 1.** (**a**) A schematic of a 2D NAND string and a 3D NAND string, wherein a 3D NAND cell unit contains core oxide, poly-Si channel, tunneling layer, CT layer, blocking layer, a and control gate; (**b**) TLC operations by storing 3 bits in each cell at three pages: MSB, CSB, and LSB; V1~V7 denote read voltages with the definitions of V*th* down-shift and up-shift errors.

This makes the reliability mechanisms more complex because the spatial redistributions of stored charges will seriously affect the data retention and read disturbs [8]. It was also reported that the P/E cycling stress affects the charge redistributions more seriously [9]. In other words, in a 2D FG NAND flash, the failure mechanism is simple, and the temperature effects can be monitored, while for a 3D CT NAND flash, the special cell structure makes the failure mechanisms complex and previous temperature-related models are no longer suitable. In the following, several related works are briefly described.

The 3D NAND flash was developed more than ten years ago in 2007 [10], and the first TLC 3D BiCS flash memory with 32 stacked layers was demonstrated by Toshiba in 2015 [11]. Currently, 174 staking storage layers [1,2] as well as HLC operation mode [4] have been realized and demonstrated. So far, 3D NAND flash has been utilized in many kinds of storage products, especially in smartphones, personal computers, and data centers. To assure the robust reliability and high performance of those products, environmental temperature effects should be well considered, and the effects should be included in the system design. Cai et al. studied MLC NAND flash memory and noticed that the error bits from read disturb were much more likely to take place in cells with lower V*th* values [12]. Zambelli et al. studied cross-temperature effects in 2D and 3D NAND flash memories and found that there was a large number of fail-bits when the memory was read at a temperature different from that exercised during the program [13]. Wu et al. found that cell V*th* values had various offset and velocities for different temperate operations, and it can be reduced by shortening the interval time from erase to program during crosstemperature write–read stages [14]. Kong et al. studied the read disturbs in a 3D CT NAND flash memory, and observed that read disturbs were strongly correlated to retention time and temperatures, and proposed the schemes of precharge-the-storage-layer (PCSL) and thermally-stabilize-the-storage-layer (TSSL) to suppress read disturbs [8]. Luo et al. observed that the temperature effects increase retention loss speed at a super-linear rate and increases program variations and concluded that prior models for planer 2D NAND flash were not suitable for 3D NAND flash [15]. Resnati et al. investigated the temperature dependence of cell V*th*, string currents, and random telegraph noise (RTN) distributions in 3D NAND, showing that V*th* distributions will be tight at high temperatures but widened at low temperatures [16]. In order to minimize the V*th* distribution widening at low temperature and cross-temperature operations, Venkatesan et al. reviewed the 3D NAND

technologies and pointed out that polysilicon channel engineering was necessary [17]. H. Shin et al. investigated the dominant failure mechanisms in 3D NAND after cycling [18] and drew their conclusions that failure mechanisms in 3D NAND are complex; it is not reliable to use temperature as an accelerator for burn-in tests on the basis of the Arrhenius model [7].

As a key factor impacting on NAND flash performance and reliability, temperature effects should be well understood. Thus far, in previous reports, temperature effects have been discussed from material-to-device viewpoints or system-level viewpoints, and most of them focused on data retention. It is necessary to have a comprehensive understanding of the temperature effects to conduct device-to-technology co-optimizations (DTCO) and to provide fundamental information for NAND-based applications in a wide temperature range. In this paper, using a high-performance raw NAND chip tester, temperaturedependent characterizations were performed from −30 to 70 ◦C by focusing on the RBER in P/E cycling, read disturbs, and cross-temperature degradations.

#### **3. Evaluation Setup**

Raw NAND chips were characterized using an FPGA-based raw NAND chip tester with eight parallel sockets and high-speed PCIE interfaces with a maximum data transfer speed up to 200 MHz. The tester was specially designed with a capability to withstand wide temperature operations from −40 to 100 ◦C, and a customized software was used as the interface to carry out data program/erase/read scripts and detailed data analysis. Moreover, a high–low temperature test chamber with precise controllability to the temperature and humidity was used to perform cross-temperature tests. In our experiments, we chose the 3D CT TLC NAND flash memory chip with 64 stacking storage layers, 5912 valid blocks, with block containing 768 logical pages with 18,336 bytes per page [19]. As shown in Algorithm 1, experiment processes were divided into the following:

#### **4. P/E Cycling**

The NAND flash memory tested in this experiment was a 3D CT TLC NAND flash chip, and the stored data were divided into eight states according to the V*th* of the storage cell. Ideally, the V*th* between adjacent states has a wide read margin, but the V*th* of adjacent states had overlapping regions in practice, and these overlapping regions were the source of error bits. It should be noted, due to the limited memory window for programming in a high-bit density NAND flash, such as TLC mode, overlapping regions do exist as shown in Figure 1b. The experimental procedure was as follows: firstly, we raised the temperature to the set value; then, we performed 3000 P/E cycles in randomly selected blocks in the chip, and several blocks were characterized to make sure that our results were reliable and stable; finally, the program/erase times of each P/E cycle was recorded in real-time, and the data were exported for analysis.

**Algorithm 1. The process of experiment.**

Figure 2 shows the program time (*tprog*) and the erase time (*terase*) when performing P/E cycling at various temperatures. In the case of *terase*, it had a strong dependence on the temperature, but the effects of P/E cycles were negligible. The higher the temperature, the shorter *terase*. However, *tprog* depended on both P/E cycles and the temperature as shown in Figure 2b. For blocks after a certain number of P/E cycles, the higher ambient temperature of the NAND flash memory, the less time it took to execute the program operation. While at the same ambient temperature, *tprog* decreased with P/E cycles. Thereby, we propose a temperature-dependent cycling program time (TCPT) model on the basis of following equation:

$$t\_{\rm prog} = \kappa(T) \cdot n\_{\rm pc} + \beta(T) \tag{1}$$

$$
\mathfrak{a}(T) = k\_1 \cdot T + k\_2 \cdot \mathfrak{z}(T) \,= k\_3 \cdot T + k\_4 \tag{2}
$$

*T*, *npe*, and *tprog* are the temperature, P/E cycles, and program time, respectively. *α*(*T*) and *β*(*T*) are the temperature-related functions with fitting parameters *kn* (*n* = 1~4). As shown in Figure 2b, for blocks with higher than 100 P/E cycles, simulation curves agreed well with the experimental data, indicating that the model was effective at predicting the program latency in a wide temperature range. The values of the fitting parameters are listed in Table 1.

**Figure 2.** Measured operation times during P/E cycling at different temperatures: (**a**) erase time (*terase*) and (**b**) program time (*tprog*). *terase* depends on the temperature, while *tprog* depends on both the temperature and P/E cycles, which agreed well with the simulation curves in the blocks with higher than 100 P/E cycles.

**Table 1.** The values of fitting parameters in *α*(*T*) and *β*(*T*).

Figure 3 shows the measured RBER when the P/E cycling was performed at different temperatures. No matter what the temperature we choose, RBER has an initially higher value at the fresh state with a decreasing trend in sub-200 P/E cycles, and then it increases during subsequent P/E cycling. Initial higher RBER could possibly come from the unstable initial stage after factory, and the gradually increased RBER can be explained by P/E cycling stress caused cell degradation. During the P/E cycling, defects generated in both the tunneling layer and CT layer and the stability of the NAND cells became worse. The most important thing was that RBER could be suppressed at high temperatures, while it degraded at cold temperatures. These results can be explained by the V*th* distributions' changes that depended on the temperature. According to the simulated results by Resnati et al. [16], V*th* distributions are tight at high temperatures (narrower overlap regions cause fewer error bits) but widened at cold temperatures (wider overlap regions cause more error bits). Furthermore, by normalizing the RBER, it was observed that, although RBER increasing at a rate of 70 ◦C was greater than that at 0 ◦C, the degradation tendencies did not show a clear temperature dependence in the whole temperature range as shown in Figure 3b. Considering that different V*th* distributions had different sensitivities to the cells' degradations, it was necessary to use a unified criterion to study the cells' degradations by cycling stress at different temperatures.

Next, for further evidence, cross-temperature characterizations were conducted to study the temperature effects on P/E cycling stress-related cell degradations. As shown in Figure 4, we designed the following experiment: firstly, we selected three groups of blocks, and all groups performed 1000 P/E cycles at 25 ◦C (Stage-1); secondly, 1000 P/E cycles were executed in three groups, −30, 25, and 70 ◦C (Stage-2); then, the temperatures were lowered to 25 ◦C, and 1000 P/E cycles were subsequently performed on all groups (Stage-3). Finally, each group operated 3000 read cycles at 25 ◦C. It can be observed that, no matter

what the temperature we chose in stage-2, the RBER degradation tendency trends were almost the same in stage-3 and read cycles after cross-temperature P/E cycles. On the one hand, it can be concluded that thermal experiences (up to 70 ◦C) have negligible impacts on RBER degradation; on the other hand, the 3D NAND is suitable for high-temperature operations because the RBER is lower and the effects of P/E cycling caused damage will not be accelerated at higher temperatures. It should be noted that no matter what the operation mode we adopted, operations at higher temperatures did cause larger degradations to memory cells such as enhanced interface trap generation. Fortunately, these damages do not cause worse error bits degradation using the same criteria (Stage-3) as shown in Figure 4.

**Figure 3.** (**a**) Measured RBER with P/E cycling at different temperatures; (**b**) normalized RBER to study RBER degradation.

**Figure 4.** Cross-temperature characterizations to study degradation at various temperatures. The first and third stages were fixed to 25 ◦C, while the second stage selected three different temperatures, −30, 25, and 70 ◦C. The RBER was normalized by the first point of the RBER to compare the degradation trends of each condition.


**6. Concluding remarks**

The Ca-Cu looping process is an emerging CO2 capture process that points out an improved efficiency and reduced cost for H2 production compared to wellestablished technologies. The functional materials needed for running the process are not a barrier for the progress of the technology, being already available with the proper Cu and Ca contents. Further research in long-term stability of these materials would be needed in order to elucidate any problem related with activity loss or agglomeration problems. The key reaction stages of the process have been already tested at a sufficient scale under conditions relevant for the operation at a large scale, but investigation in multiple reactor system at a larger scale is needed for corroborating the promising results found at lab-scale.


**4. New BNT-based ceramics for pyroelectric applications**

At present, the most widely used intrinsic pyroelectric materials are perovskite-type lead-containing materials, such as Pb(Zr, Ti)O3 (PZT), PbTiO3 doped with Ca (PCT), xPb(Mg1/3Nb2/3)O3-(1-x)PbTiO3 (PMN-PT) [35–40]. Over the last few decades, continuous efforts have been devoted to the development of lead-free pyroelectric ceramics. Many lead-free ceramics such as Sr0.3Ba0.7Nb2O6 based, (Ba, Ca)TiO3-based, CaBi4Ti4O15-based bismuth layer-structured and Bi0.5Na0.5TiO3-based ceramics have been investigated [41–44]. Among them, BNT-based ceramics have been regarded as one of most promising alternative lead-free ceramics due to its high pyroelectric coefficient (p), high remnant polarization Pr (around 38μC/cm2 ), high Curie temperature Tc (around 320°C), low-cost, and simple synthesis process. In recent decades, pyroelectric properties of BNT-based materials, including pyroelectric coefficient and detection rate, have been greatly improved. The pyroelectric coefficient of BNT-based lead-free pyroelectric materials has been comparable to commercial PZT [45–47]. However, the enhanced pyroelectric property is usually at the cost of degraded depolarization temperature (<150°C) and thermal stability, which are the hurdles to application. The BNT-based pyroelectric ceramics with low Td will depolarize partially or completely during the heat treatment (typically >100°C) processes, causing degradation of pyroelectric performance. Therefore, from the viewpoint of practical application, it is urgent for BNT-based materials to optimize their depolarization temperature, thermal stability and pyroelectric performance, thus further to promote their applications in infrared detection [48, 49].

### **4.1 BNT- BNN pyroelectric ceramics**

(1-x)(Bi0.5Na0.5)TiO3-xBa(Ni0.5Nb0.5)O3 lead-free pyroelectric ceramics (abbreviated as (1-x)BNT-xBNN) were synthesized by a conventional solid-state reaction method [50], and the thermal stability and depolarization temperature is enhanced at the same time as the excellent pyroelectric performance is maintained. BNN is a compound with a mixed valence state at the b position, which can be solidsolved with BNT and expand a wide range of composition adjustment. The (1-x) BNT-xBNN take into account the advantages of b-position acceptor substitution and donor substitution. The effect of BNN content on phase structure, electrical properties and thermal stability was systematically studied. After the solid-state reaction of BNN, (1-x)BNT-xBNN exhibits enhanced pyroelectric performance with a high depolarization temperature. In addition, it can be exposed to temperature up to ~145°C with negligible deterioration of pyroelectric properties, showing excellent thermal stability.

**Figure 10.**

*Temperature dependence of dielectric constant (*ε*r) and dielectric loss (tan* δ*) for poled (1-x)BNT-xBNN (a) x = 0, (b) x = 0.02, (c) x = 0.03, (d) x = 0.04 in frequency range between 10 kHz and 1 MHz; (e) Pyroelectric coefficient (p) of poled (1-x)BNT-xBNN ceramics as a function of temperature; (f) d33RT/d33T at room temperature after annealing at Ta [50].*

The temperature-dependent properties of poled (1 − x)BNT-xBNN ceramics are displayed in **Figure 10a**–**d**. With the increasing BNN content, the Curie temperature Tc indicated by the maximum dielectric constant decreases and dielectric constant and dielectric loss of BNN decrease first and then increase. The minimum value of dielectric constant and dielectric loss occurs when the BNN content is 2%, which further improve the pyroelectric detection rate figure of merit. The depolarization temperature Td can be characterized by the first anomal point of temperature dependent dielectric properties, and the content of 2% has the highest depolarization temperature. As shown in **Figure 10e**, after the increase of BNN, the room temperature p values rise from 3.01 × 10−8C/cm2 K of pure BNT to 5.94 × 10−8C/cm2 K of 0.96BNT-0.04BNN with the increasing addition of BNN, which gains advantage compared with many other lead-free ceramics. The *p* value of (1-x)BNT-xBNN ceramics increases sharply, which indicates that the (1-x)BNT-xBNN sample is sensitive to ambient temperature. In addition, it can be seen that the p value increases with the increasing temperature, which indicates that the (1 − x)BNT-xBNN samples are sensitive to the surrounding temperature. Besides, 0.98BNT-0.02BNN ceramics have the best thermal stability and it can withstand heat treatment at 145°C without depolarization (**Figure 10f**), which is attributed to the domain switching and phase transition.

### **4.2 BNT-BT pyroelectric ceramics**

BNT-BT possesses a rich phase structure, which can be easily adjusted by varying the BT content. Because of the low tripartite-tetragonal transition barrier, the

### *New Bismuth Sodium Titanate Based Ceramics and Their Applications DOI: http://dx.doi.org/10.5772/intechopen.93921*

morphotropic phase boundary (MPB) of BNT-BT, located at where the BT content is approximately 6%, exhibits the best pyroelectric properties and has received much attention. But it is not advisable to blindly pursue a high pyroelectric coefficient. The improvement of pyroelectric performance is often at the cost of low depolarization temperature, which is not helpful to practical applications. However, it is found that the sample with high BT content is in the tetragonal phase, which brings a higher Td than that of the tripartite, but there is no relevant report on the pyroelectric performance of high BT content.

Based on the above ideas, the tetragonal phase 0.8BNT-0.2BT lead-free pyroelectric material with high BT content was successfully prepared, and the microstructure, dielectric properties, pyroelectric properties, and thermal stability were studied [51]. Owing to its high Td, this composition can endure high-temperature environment (180°C) for half hour with the value of p at room temperature remains ~90% of its initial value, demonstrating that the 0.8BNT-0.2BT samples show excellent thermal stability. Moreover, the Td of the samples is up to ~209°C, which is far higher than that of the reported BNT-based, pyroelectric materials, and it is also comparable to the commercial PZT materials.

The pyroelectric properties of 0.8BNT-0.2BT pyroelectric ceramics between 25 and 70°C are investigated. With the increase of temperature, the pyroelectric performance shows an increasing trend, indicating that the material has good pyroelectric performance in a wide temperature range. Meanwhile, because the 0.8BNT-0.2BT sample has a low dielectric constant and dielectric loss, it will show a larger detection merit (**Figure 11a**). In order to study the depolarization temperature of the material, the dielectric thermo diagram of the sample was shown in **Figure 11b**. When the temperature rises to about 209°C, the dielectric constant of the sample suddenly increases with a dielectric loss peak appearing, indicating that this temperature is the

### **Figure 11.**

*(a) Pyroelectric coefficient (p) and figures of merit (Fi, Fv, Fd) as a function of temperature on heating during the range of RT to 70°C. The figures of merit are determined based on the values of p, CV,* ε*r, and tan*δ*; (b) temperature-dependent dielectric constant (*ε*r) and dielectric loss (tan*δ*) of poled 0.8BNT–0.2BT ceramics; (c) pyroelectric coefficient at room temperature after annealing at Ta. The inset shows the temperaturedependent pyroelectric coefficient on heating after annealing at Ta [51].*

depolarization temperature Td. Notably, the depolarization temperature of reported BNT-based pyroelectric materials is generally lower than 180°C. The materials with high Td (209°C) and high pyroelectric coefficient discovered lay the foundation for the further development of lead-free pyroelectric materials. Moreover, it can be observed from **Figure 11c** that the room temperature pyroelectric coefficient of 0.8BNT-0.2BT maintains about 90% of the original data after being treated at 180°C, indicating that the material has good temperature stability and can withstand high temperature treatment up to180°C without pyroelectric performance loss.

### **4.3 BNT-BA***-***NN pyroelectric ceramics**

A new ternary system 0.98BNT-0.02BA-xNN ceramic was obtained by solid solution of NaNbO3 (NN) in the BNT-BA system and Mn element substitution

### **Figure 12.**

*(a) Temperature dependent dielectric constant (*ε*r) and tangent loss (tan*δ*) of 0.98BNT-0.02BA-xNN ceramics; (b) temperature-dependent pyroelectric coefficient of 0.98BNT-0.02BA-xNN ceramics; (c) the temperature-dependent pyroelectric coefficient p of 0.98BNT-0.02BA-xNN ceramics in the temperature range from 10–80°C; merit (d) Fi, (e) Fv and (f) Fd of 0.98BNT-0.02BA-xNN ceramics measured at 1 kHz over the range of 20–80°C [52].*

*New Bismuth Sodium Titanate Based Ceramics and Their Applications DOI: http://dx.doi.org/10.5772/intechopen.93921*

modification [52]. The NN solution significantly affect the microstructure, phase transition and pyroelectric properties of 0.98BNT-0.02BA-*x*NN ceramics. It was found that NN addition tends to reduce the rhombohedral phase while favoring the formation of the tetragonal phase. The compositions exhibit excellent pyroelectric performance. All components exhibit excellent ferroelectric properties at room temperature, and the Pr values are all higher than 35 μC/cm2 , of which the Pr of the x = 0.03 component is the largest, reaching 45 μC/cm2 .

Furthermore, the influence of NN solid solution on the relaxation characteristics and phase transition of BNT-BA-based ceramics was analyzed by testing the temperature-changing dielectric properties in **Figure 12a**. **Figure 12b** shows the change curve of the pyroelectric coefficient of 0.98BNT-0.02BA-xNN after polarization with temperature changing. The FE-RE phase transition occurs at Td, corresponding to the sudden drop in the polarization intensity Pr. the largest peak appears at the composition x = 0.03, reaching 441.0 × 10−8 C/cm2 K, which is much larger than other BNT-based ceramics reported. As the NN content increases, the Td continuously decreases. Notably, t the Td of the x = 0.02 component is still as high as 155°C. It can be observed from **Figure 12c** that the introduction of NN significantly improves the room temperature pyroelectric coefficient. With the increase of NN content, the p under room temperature (25°C) first increases and then decreases, and the maximum value is obtained at x = 0.03 (p = 8.45 × 10−8 C/cm2 K), which improved about 54% compared to the matrix (x = 0, *p* = 3.87 × 10−8 C/cm2 K). Moreover, the optimal figure of merit (FOMs) at room temperature were obtained at *x* = 0.02 with *F*i = 2.66 × 10−10 m/V, *F*v = 8.07 × 10−2 m2 /C, and *F*d = 4.22 × 10−5 Pa−1/2 (**Figure 12d**–**f**). Furthermore, the compositions with *x* ≤ 0.02 possess relatively high depolarization temperature (≥155°C). Those results unveil the potential of 0.98BNT-0.02BA-*x*NN ceramics for infrared detector applications.

### **5. Conclusion**

Due to its strong ferroelectric properties, BNT-based ceramics exhibit great potential in the fields of energy storage, pulsed power supply and pyroelectric applications. In this chapter, new bismuth sodium titanate ceramics were synthesized and characterized via composition modifications, the ferroelectric properties, phase transition behaviors under external fields and related applications were proposed in this chapter. To detail, BNT-BT-KNN, BNT-BA-KNN, and BNT-SBT-NN ceramics for energy storage application, BNT, BNT-BA-KNN, and BNT-BA-NN ceramics for pulsed power supply, as well as BNT-BNN, BNT-BT, and BNT-BA-NN for pyroelectric detection application were presented.

### **Acknowledgements**

The authors would like to thank the financial support by Youth Innovation Promotion Association, CAS (Grant No. 2017296), National Natural Science Foundation of China (NSFC) (Grant No. 51872312), and Natural Science Foundation of Shanghai (Grant NO.18ZR1444900).

### **Conflict of interest**

The authors declare no conflict of interest.

*Advanced Ceramic Materials*


**5. Examples of application of the method for a step change in temperature of the fluid**

The first example demonstrates the use of the described method of transient fluid temperature measurement in the case of thin sheathed thermocouple application. During the experiment, the thermocouple with outer diameter 1.5 mm at the ambient temperature was suddenly immersed into hot water at saturation temperature. The results are presented in **Figure 2**. The time step Δ*t* of the measured temperature was 1.162 s. The measured history of the temperature was approximated by Eq. (7) in order to determine the time constant *τ* of the thermocouple. In the calculations, TableCurve 2D code [18] was used. The calculations of the time constant and the uncertainty at the confidence level of 95% gave the following results: *τ* = 1.54 ± 0.09 s.

**Figure 2.** Fluid and thermometer temperature changes determined from the first-order equation (1) for the sheathed thermocouple with outer diameter 1.5 mm.

Next, the transient fluid temperature *Tf* was determined using Eq. (1) together with Eqs. (26) and (27). The first-order time derivative d*T*/d*t* in Eq. (1) was also calculated using the central difference quotient of Eq. (29). The results obtained show that the use of a first-order model for thin thermometers is sufficient (**Figure 2**). The results also indicate that the central difference approximation of the time derivative in Eq. (1) leads to less accurate results, since it is more sensitive to random errors in the experimental data.

Another example shows the application of the method for measuring transient fluid temperature with an industrial thermometer with massive thermowell and its complex construction (**Figure 3**). As in the previous example, the thermometer at the ambient temperature was suddenly immersed into hot water at a temperature of about 100°C. To compare the two methods of determining the unknown fluid temperature (using the first-and second-order model) for this thermometer, Eqs. (7) and (23) were used as the functions approximating the transient response of the thermometer. The following values with the 95% confidence uncertainty were obtained: *τ* = 14.07 ± 0.39 s, *τ*1 = 3.0 ± 0.165 s and *τ*2 = 10.90 ± 0.2 s.

Next, the fluid temperature changes were determined from Eq. (1) for the first-order model and from Eq. (20) for the second-order model (**Figure 4**).

The analysis of the results presented in **Figure 4** indicates that the second-order model delivers more accurate results than the first-order model.

Measurement of Transient Fluid Temperature in the Heat Exchangers http://dx.doi.org/10.5772/65686 185

**Figure 3.** Industrial thermometer and its dimensions: *D* = 18 mm, *l* = 65 mm and *L* = 140 mm.

**Figure 2.** Fluid and thermometer temperature changes determined from the first-order equation (1) for the sheathed

and (27). The first-order time derivative d*T*/d*t* in Eq. (1) was also calculated using the central difference quotient of Eq. (29). The results obtained show that the use of a first-order model for thin thermometers is sufficient (**Figure 2**). The results also indicate that the central difference approximation of the time derivative in Eq. (1) leads to less accurate results, since

Another example shows the application of the method for measuring transient fluid temperature with an industrial thermometer with massive thermowell and its complex construction (**Figure 3**). As in the previous example, the thermometer at the ambient temperature was suddenly immersed into hot water at a temperature of about 100°C. To compare the two methods of determining the unknown fluid temperature (using the first-and second-order model) for this thermometer, Eqs. (7) and (23) were used as the functions approximating the transient response of the thermometer. The following values with the 95% confidence uncer-

Next, the fluid temperature changes were determined from Eq. (1) for the first-order model

The analysis of the results presented in **Figure 4** indicates that the second-order model delivers

tainty were obtained: *τ* = 14.07 ± 0.39 s, *τ*1 = 3.0 ± 0.165 s and *τ*2 = 10.90 ± 0.2 s.

was determined using Eq. (1) together with Eqs. (26)

thermocouple with outer diameter 1.5 mm.

184 Heat Exchangers– Design, Experiment and Simulation

Next, the transient fluid temperature *Tf*

it is more sensitive to random errors in the experimental data.

and from Eq. (20) for the second-order model (**Figure 4**).

more accurate results than the first-order model.

**Figure 4.** Fluid and industrial thermometer temperature changes determined from the first-order equation (1) and the second-order equation (20).


**4. Associated symptoms**

Symptoms of corneal neovascularization often include the following:

cause a variety of symptoms, including eye pain and excessive tearing, light sensitivity,

Corneal neovascularization remains a significant risk factor for corneal graft rejection and subsequent graft failure after penetrating keratoplasty. The collaborative corneal transplantation study1 identified, in addition to several other factors, the extent of stromal vessels (quadrants) as a serious risk factor for corneal graft failure. During corneal neovascularization, an upregulation of angiogenic factors is seen in association with down regulation of antiangiogenic molecules. Studies in human and rat models have found vascular endothelial growth factor (VEGF) to be up regulated in inflamed and vascularized cornea .2 In a mouse model, it was observed that corneal avascularity during development is redundantly regulated. Lack of the antiangiogenic factors thrombospondin (TSP)-1 and/or - 2 resulted in no spontaneous corneal angiogenesis. By contrast, TSP-1, more than TSP-2, helped to suppress inflammation-induced corneal angiogenesis postnatally, implying that angiogenic privilege in the cornea is actively maintained .3 Bachmann et al4 in a mouse model found that neutralization of VEGF-A after high-risk corneal transplantation effectively inhibited postoperative hemangiogenesis, lymphangiogenesis, and recruitment

Vascular endothelial growth factor promotes several steps of angiogenesis, including proteolytic activities, endothelial cell proliferation, migration, and capillary tube formation . 5 Topical or systemic application of bevacizumab inhibited both inflammation-induced angiogenesis and lymphangiogenesis in the cornea. This finding suggestes an important role of VEGF-A in corneal lymphangiogenesis and bevacizumab may be useful in preventing

**Superficial**: In superificial corneal vascularization, vessels arrange in arborizing pattern in subepithelial layer and can be traced with conjunctival vessels. This type of vascularization

**Deep**: In deep corneal vascularization, vessels are derived from anterior ciliary artery and lie in corneal stroma. Vessels are usually straight and not anastomosing. This type of vascularization may be observed in graft rejection, interstitial keratitis, deep corneal ulcer,

**Pannus**: In pannus, extensive superficial vascularization occurs with cellular infiltration. It

redness, intolerance to contact lenses, and decreased vision. **Role of Corneal Neovascularization in Corneal Graft Rejection**

of antigen-presenting cells, thereby improving corneal graft survival.

may be observed in trachoma, and phlyctenular conjunctivitis.

 Progressive: Infiltration is ahead of vascularization Regressive: Infiltration is behind the vascular leash.

Symptoms of corneal neovascularization often include the following:

immune rejections after penetrating keratoplasty.

**3. Types of corneal vascularization**

and chemical burn.

**4. Associated symptoms**

Tearing and photophobia

is of two types:

 Eye pain Redness

### **4.1 Advantages of neovascularization**


**1.4. Collaborative learning**

In the 1970s, Sir James Britton and others in England [6] created an active learning procedure known as Collaborative Learning based on the theorizing of Vygotsky [7]. Britton believed that a student's learning is derived from the community of learners made up of other students. Britton was opposed to providing specific definitions of the teacher's and students' roles, which he considered to be *training* (the application of explanations, instructions, or recipes for action). Instead, he recommended placing students in groups and letting them generate their own culture, community, and procedures for learning, which he considered to be *natural learning* (learning by making intuitive responses to whatever one's efforts produce). Britton believed the source of learning is dialogs and interactions with other students (and sometimes the teacher resulting from the positive interdependence among students' learning goals. The heart of collaborative learning, therefore, is the cooperative foundation of students working together to maximize their own and each other's learning.


Author details

Luigi Montano1 \*, Paolo Bergamo2 , Maria Grazia Andreassi3 and Stefano Lorenzetti4

\*Address all correspondence to<EMAIL_ADDRESS>
1 Andrology Unit of the "San Francesco d'Assisi" Hospital, ASL Salerno, Oliveto Citra, Salerno, Italy

4 Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità (ISS), Rome, Italy


**2. New bronchodilators for asthma**

#### **2.1 Anticholinergics**

Maintenance treatment to achieve asthma control currently includes inhaled or systemic glucocorticoids (ICS), leukotriene antagonists, LABAs, theophylline, monoclonal antibodies (mAbs) anti-IgE (omalizumab), and recently, newly included in the latest clinical practice guidelines, tiotropium bromide [1, 2]. The parasympathetic or cholinergic system is the most important bronchoconstrictor and hypersecretory neurological mechanism of the airways [11], and blocking specific muscarinic receptors is a therapeutic alternative to reduce the increase in parasympathetic activity that characterizes the main pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Therefore, the natural alkaloids from the Solanaceae family plants (*Atropa belladonna* and *Datura stramonium*) represent one of the traditional remedies against bronchospasm. Atropine, the prototype nonselective muscar‐ inic receptor antagonist, with "tertiary ammonium" structure, was widely used from the late nineteenth century in oral, parenteral, and inhaled forms for the treatment of asthma; however, its use is constrained by the cardiovascular side effects. Following the introduction of ephe‐ drine and adrenaline, in the early twentieth century, atropine fell into disuse. Later, anticho‐ linergic therapy has returned to the forefront in the treatment of COPD, with the introduction of synthetic quaternary derivatives of atropine, short acting (ipratropium bromide) and long acting (tiotropium, aclidinium, umeclidinium, and glycopyrronium), the latter known under the acronym LAMA (long-acting muscarinic antagonists). The "quaternary ammonium" structure [12] makes them soluble in water and insoluble in lipids, therefore preventing the passage through biological barriers that are easily crossed by "tertiary ammonium" compo‐ nents, such as atropine, hence their lack of central nervous system effects; also they are poorly absorbed from the lung and gastrointestinal tract and do not inhibit the mucociliary clearance [13].

#### *2.1.1 Tiotropium*

of the existence of uniform treatment guidelines, as well as of quite accessible and effective treatments, achieving asthma control often remains a constant challenge. Recent studies indicate that over 50% of patients with asthma are not controlled [3, 4], not even when receiving a combination of inhaled corticosteroids (ICSs) and a long-acting beta-2-agonist (LABA) [5] as controller treatment. These data suggest that the search for alternative treatments is required, particularly for patients with severe uncontrolled a-wrap id="tab1" position="anchor"> sthma.

When searching for new treatment options in asthma, it is important to remember that different drugs, particularly biological agents, act on different pathogenic pathways. So, the individual profile of physiopathological alterations of each patient should be determined to prescribe the

Asthma management, from both a current as well as a future risk perspective, must compre‐ hend the stratification of patients into the recently defined phenotypes (such as clinical, inflammatory, and molecular) [7] and endotypes (such as allergic asthma, aspirin-sensitive asthma, late-onset hypereosinophilic asthma) [8], in the attempt to find a more personalized treatment for each patient. Moreover, in the last 10 years, significant efforts have been made to identify the characteristics that differentiate severe asthma from mild to moderate asthma,

The main goal of the treatment is to achieve and maintain the control of the disease as soon as possible, to prevent chronic airflow obstruction, and to reduce mortality. The goals of the treatment, both in its current control domain and in preventing exacerbations and accelerated loss of lung function (future risk), could be achieved in most of the patients with appropriate

Maintenance treatment to achieve asthma control currently includes inhaled or systemic glucocorticoids (ICS), leukotriene antagonists, LABAs, theophylline, monoclonal antibodies (mAbs) anti-IgE (omalizumab), and recently, newly included in the latest clinical practice guidelines, tiotropium bromide [1, 2]. The parasympathetic or cholinergic system is the most important bronchoconstrictor and hypersecretory neurological mechanism of the airways [11], and blocking specific muscarinic receptors is a therapeutic alternative to reduce the increase in parasympathetic activity that characterizes the main pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Therefore, the natural alkaloids from the Solanaceae family plants (*Atropa belladonna* and *Datura stramonium*) represent one of the traditional remedies against bronchospasm. Atropine, the prototype nonselective muscar‐ inic receptor antagonist, with "tertiary ammonium" structure, was widely used from the late nineteenth century in oral, parenteral, and inhaled forms for the treatment of asthma; however, its use is constrained by the cardiovascular side effects. Following the introduction of ephe‐ drine and adrenaline, in the early twentieth century, atropine fell into disuse. Later, anticho‐

preparing the ground for the development of new selective treatments.

most appropriate treatment in each case [6].

116 Asthma - From Childhood Asthma to ACOS Phenotypes

**2. New bronchodilators for asthma**

treatment [9, 10].

**2.1 Anticholinergics**

Tiotropium bromide is the first long-acting anticholinergic agent (24 hours action), widely used for treatment of COPD. At the end of 2014, it was also approved by the FDA as an additional treatment of asthma in patients >12 years in the United States and in adult patients with asthma not controlled by the ICS in the European Union (Spiriva® Respimat). Such approval has been obtained based on sound scientific evidence on the effectiveness and safety of treatment with tiotropium in patients with mild-to-moderate and severe asthma. The major evidence is discussed below and is summarized in Table **1** [14].

**Table 1.** Summary of studies that demonstrate the efficiency of tiotropium bromide in asthma [14].

A study published in 2009 [15] showed additional improvement in lung function in patients with severe asthma when tiotropium was added to conventional treatment, according to the guidelines (LABA/ICS, theophylline, antagonists of leukotriene receptor, and oral steroids). A total of 138 severe asthmatics with decreased lung function were recruited. Tiotropium 18 μg (via HandiHaler) was added once a day, and lung function was assessed every 4 weeks. Responders were defined as those with an improvement of ≥15% (or 200 mL) in FEV1 that was maintained for at least 8 successive weeks. Of the 138 people with asthma, 46 (33.3%) respond‐ ed to tiotropium.

Peters et al. [16] conducted an independent three-way, double-blind, crossover study in 210 patients with asthma to evaluate the effect of the addition of tiotropium to ICS, when compared with doubling the dose of ICS (primary superiority comparison) or adding salmeterol (secondary comparison of non-inferiority). Use of tiotropium was superior when compared with doubling the dose of ICS; it also demonstrated superiority in the secondary endpoints, including evening PEF, the proportion of asthma control days, prebronchodilator FEV1, and daily symptom scores. The addition of tiotropium was not inferior to the addition of salmeterol on all evaluated results and increased FEV1 prebronchodilator more than salmeterol. In summary, when added to an ICS, tiotropium improved symptoms and lung function in poorly controlled patients with asthma, and its effects appear to be equivalent to those obtained with the addition of salmeterol.

Bateman et al. [17] carried out a double-blind, double-dummy, placebo-controlled trial to compare the efficacy and safety profile of tiotropium (Respimat 5 μg, administered daily in the evening with the Respimat device) with that of salmeterol and placebo added to an ICS, in 16-Arg/Arg patients with asthma that was not controlled by ICS alone. The study population comprised patients aged 18–67 years, with reversibility to bronchodilators and symptoms that were not controlled by regular therapy with ICS (400–1000 μg of budesonide or equivalent maintained throughout the trial). Changes in weekly primary endpoint (PEF) from the last week of the run-in period to the last week of treatment showed that tiotropium was not inferior to salmeterol.

It has been also assessed whether tiotropium could be an effective bronchodilator in patients with severe asthma who remain symptomatic and obstructed despite maximum recommend‐ ed treatment with the combination of ICS and LABA. Kerstjens et al. [18] compared the efficacy and safety profile of two doses of tiotropium (Respimat, 5 and 10 μg daily) with placebo as an add-on therapy in 100 patients with uncontrolled severe asthma despite maintenance treat‐ ment with at least a high dose ICS combined with a LABA, in a randomized, double-blind, crossover study with three treatment periods of 8 weeks each. The PEF was peak FEV1 at the end of each treatment period. Peak FEV1 was significantly higher with 5 μg and 10 μg of tiotropium than placebo, whereas there was no significant difference between the two active doses. Domiciliary PEF values were higher with both tiotropium doses. Adverse events were balanced across groups, except for dry mouth, which was more common in patients taking tiotropium 10 μg. This study shows that the addition of once-daily tiotropium for asthma treatment, including a high-dose ICS combined with a LABA, significantly improves lung function over 24 hours in patients with uncontrolled severe asthma.

**Study Patients' characteristics Main results and Conclusions**

**Table 1.** Summary of studies that demonstrate the efficiency of tiotropium bromide in asthma [14].

A study published in 2009 [15] showed additional improvement in lung function in patients with severe asthma when tiotropium was added to conventional treatment, according to the guidelines (LABA/ICS, theophylline, antagonists of leukotriene receptor, and oral steroids). A total of 138 severe asthmatics with decreased lung function were recruited. Tiotropium 18 μg (via HandiHaler) was added once a day, and lung function was assessed every 4 weeks. Responders were defined as those with an improvement of ≥15% (or 200 mL) in FEV1 that was maintained for at least 8 successive weeks. Of the 138 people with asthma, 46 (33.3%) respond‐

Peters et al. [16] conducted an independent three-way, double-blind, crossover study in 210 patients with asthma to evaluate the effect of the addition of tiotropium to ICS, when compared with doubling the dose of ICS (primary superiority comparison) or adding salmeterol (secondary comparison of non-inferiority). Use of tiotropium was superior when compared with doubling the dose of ICS; it also demonstrated superiority in the secondary endpoints, including evening PEF, the proportion of asthma control days, prebronchodilator FEV1, and daily symptom scores. The addition of tiotropium was not inferior to the addition of salmeterol on all evaluated results and increased FEV1 prebronchodilator more than salmeterol. In summary, when added to an ICS, tiotropium improved symptoms and lung function in poorly controlled patients with asthma, and its effects appear to be equivalent to those obtained with

Bateman et al. [17] carried out a double-blind, double-dummy, placebo-controlled trial to compare the efficacy and safety profile of tiotropium (Respimat 5 μg, administered daily in the evening with the Respimat device) with that of salmeterol and placebo added to an ICS, in 16-Arg/Arg patients with asthma that was not controlled by ICS alone. The study population comprised patients aged 18–67 years, with reversibility to bronchodilators and symptoms that were not controlled by regular therapy with ICS (400–1000 μg of budesonide or equivalent maintained throughout the trial). Changes in weekly primary endpoint (PEF) from the last week of the run-in period to the last week of treatment showed that tiotropium was not inferior

It has been also assessed whether tiotropium could be an effective bronchodilator in patients with severe asthma who remain symptomatic and obstructed despite maximum recommend‐ ed treatment with the combination of ICS and LABA. Kerstjens et al. [18] compared the efficacy and safety profile of two doses of tiotropium (Respimat, 5 and 10 μg daily) with placebo as an

– The addition of tiotropium (409 patients) compared with placebo (405 patients) significantly increased the time to the first severe exacerbation and provided a modest but

sustained bronchodilation.

Nine hundred and twelve patients (814 finished the study) with uncontrolled asthma in spite of ICS/LABA (studies

PrimoTinAsthma 1 and 2).

118 Asthma - From Childhood Asthma to ACOS Phenotypes

*ICS = inhaled corticosteroids; LABA = long-acting beta-2-agonists.*

Kerstjens et al. 2012 [19]

ed to tiotropium.

the addition of salmeterol.

to salmeterol.

Subsequently, Kerstjens et al. [19] have evaluated the influence of add-on treatment with tiotropium on exacerbations, an important marker, as is well known, of asthma control. Two parallel, randomized, double-blind placebo-controlled trials (PrimoTinAsthma 1 and Primo‐ TinAsthma 2) were conducted between October 2008 and July 2011 in 15 countries, involving 912 patients with severe asthma and fixed airflow obstruction, who were randomized for tiotropium (Respimat, 5 μg) or placebo once daily for 48 weeks.

It was concluded that in patients with poorly controlled severe asthma despite the use of ICS and LABA, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided a modest but sustained bronchodilation.

As mentioned in the introduction, we once more insist on the importance of determining the asthma phenotype: a small study (17 patients) showed that tiotropium is more effective in asthmatic smokers or non-smokers treated with medium-to-high doses of ICS if the inflam‐ matory phenotype according to induced sputum is non-eosinophilic [20]. This suggests that perhaps early phenotyping poorly controlled asthmatic patients with high doses of ICS and even systemic corticosteroids (SC) could give tiotropium a corticosteroid-sparing effect in patients who turn out to have steroid-resistant asthma phenotypes. In fact, given its mecha‐ nism of action, the bronchodilator additive effect of tiotropium makes most sense in the following circumstances [21]: patients with asthma–COPD overlap syndrome (ACOS) [12], asthma of psychogenic origin, bronchospasm triggered by beta blockers, asthma with chronic airflow limitation, and severe asthmatics with Arg/Gly variation in codon 16 of the ADRB2 gene [15].

However, it seems that the effect of tiotropium goes beyond the bronchodilation because it has significant anti-inflammatory and antiproliferative capacities, such as reduction of hyperplasia of bronchial smooth muscle and inhibition of proliferation of fibroblasts and myofibroblasts [22]. Furthermore, in vitro studies using experimental models of asthma (ovalbumin-sensi‐ tized guinea pigs) have shown that tiotropium inhibits airway remodeling induced by allergens in a similar way to budesonide [23, 24], so its role in the management of allergic asthma may be more important than it seems at first glance.

Regarding adverse effects, tiotropium is a safe drug and is generally well tolerated, the most common side effect being dry mouth. The heart rhythm disturbances are rare (atrial fibrillation, atrial sinus, or supraventricular tachycardia). The TIOSPIR [25] study concluded that tiotropi‐ um Respimat was safe in COPD patients with ischemic heart disease and/or stable arrhyth‐ mias. The study excluded patients with myocardial infarction in the past 6 months, class III– IV NYHA heart failure, potentially fatal arrhythmias, and chronic renal failure.

#### **2.2. New combinations: ICS/LABA, LABA/LAMA, and triple therapy LABA/LAMA/ICS**

Because combination therapy with ICS and LABA is the usual therapeutic option for the treatment of asthma, there is great interest in developing combinations of administration once a day, in an attempt to simplify treatment and improve treatment compliance [26], a currently achievable challenge with the new ICSs (such as ciclesonide, mometasone, and fluticasone furoate) and the emergence of new ultra-LABAs (such as indacaterol, vilanterol, and oloda‐ terol), which can be administered in a single-daily dose. Currently, new combination therapies of ultra-LABA/ICS have been developed, are in clinical trial phases II–III, or have even recently marketed (vilanterol/fluticasone furoate), like several other LAMA–LABA combinations for the treatment of COPD: tiotropium/ olodaterol, aclidinium/ formoterol, umeclidinium / indacaterol, vilanterol / umeclidinium, and so on [27]. However, the use of some of these drugs in asthma is still being investigated (see also Table **2** ).

#### **Long-acting muscarinic antagonists (LAMA):**

**•** Aclidinium bromide (approved for treatment of COPD)

#### **Ultra-long-acting muscarinic antagonists (ultra-LAMA):**

#### **Ultra–long-acting beta-2-agonists (ultra-LABA):**

#### **New combinations of ultra–long-acting beta-2-agonists (ultra-LABA) and inhaled corticosteroids (ICS):**

#### **New combinations of LAMA or ultra-LAMA and LABA or ultra-LABA:**

**Triple therapy of ultra-long-acting beta-2-agonists (ultra-LABA), inhaled corticosteroids (ICS), and ultra–longacting muscarinic antagonists (ultra-LAMA):**

**•** Vilanterol trifenatate/fluticasone furoate/umeclidinium bromide

um Respimat was safe in COPD patients with ischemic heart disease and/or stable arrhyth‐ mias. The study excluded patients with myocardial infarction in the past 6 months, class III–

**2.2. New combinations: ICS/LABA, LABA/LAMA, and triple therapy LABA/LAMA/ICS**

Because combination therapy with ICS and LABA is the usual therapeutic option for the treatment of asthma, there is great interest in developing combinations of administration once a day, in an attempt to simplify treatment and improve treatment compliance [26], a currently achievable challenge with the new ICSs (such as ciclesonide, mometasone, and fluticasone furoate) and the emergence of new ultra-LABAs (such as indacaterol, vilanterol, and oloda‐ terol), which can be administered in a single-daily dose. Currently, new combination therapies of ultra-LABA/ICS have been developed, are in clinical trial phases II–III, or have even recently marketed (vilanterol/fluticasone furoate), like several other LAMA–LABA combinations for the treatment of COPD: tiotropium/ olodaterol, aclidinium/ formoterol, umeclidinium / indacaterol, vilanterol / umeclidinium, and so on [27]. However, the use of some of these drugs

IV NYHA heart failure, potentially fatal arrhythmias, and chronic renal failure.

in asthma is still being investigated (see also Table **2** ).

**•** Tiotropium bromide (approved for treatment of asthma and COPD)

**•** Carmoterol hydrochloride, milveterol hydrochloride, olodaterol hydrochloride

**New combinations of LAMA or ultra-LAMA and LABA or ultra-LABA:**

**•** Umeclidinium bromide / vilanterol trifenatate (approved for COPD)

**•** Vilanterol trifenatate / fluticasone furoate (approved for treatment of asthma and COPD)

**New combinations of ultra–long-acting beta-2-agonists (ultra-LABA) and inhaled corticosteroids (ICS):**

**•** Glycopyrronium bromide (approved for treatment of COPD)

**•** Indacaterol maleate (approved for treatment of COPD)

**Long-acting muscarinic antagonists (LAMA):**

120 Asthma - From Childhood Asthma to ACOS Phenotypes

**Ultra–long-acting beta-2-agonists (ultra-LABA):**

**•** Indacaterol maleate / mometasone (MGC-149)

**•** Tiotropium bromide / olodaterol hydrochloride

**•** Formoterol/ aclidinium (approved for COPD)

**•** Indacaterol maleate / glycopyrronium bromide (QVA149)

**•** Indacaterol maleate / QAE 397

**•** Aclidinium bromide (approved for treatment of COPD) **Ultra-long-acting muscarinic antagonists (ultra-LAMA):**

*COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; LABA = long-acting beta-2-agonists; LAMA = long-acting muscarinic antagonists.*

**Table 2.** New bronchodilators, either available or under clinical development, with probable upcoming indication for asthma (monotherapy and combinations).

When talking about the triple combination, it refers to ICSs, such as beta-2-agonist and inhaled anticholinergics, but mainly to long-acting drugs (LAMA–LABA–ICS). The possibility of associating these three drugs can contribute to better compliance, better control of the symp‐ toms, and improved quality of life, as well as to a decrease in exacerbations. There are several clinical studies in development: fluticasone/salmeterol/tiotropium and budesonide/formoter‐ ol/tiotropium [28]. The first triple combination formoterol/tiotropium/ciclesonide (Triohale®, Cipla) is now available in India [29], and its probable effectiveness in asthma is yet to be proven in future clinical trials.


**2. Patients and methods**

From 1996 to 2005, 36 patients who had esophageal SCC with submucosal invasion underwent multimodal treatment. Esophagectomy was not performed because of associated complications in 19 cases and due to patient refusal in 17 cases.

In all patients, EMR/ESD was performed before any other treatment. Then chemotherapy, radiotherapy, or chemoradiotherapy was added, depending on the histopathological findings, which were classified according to the Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus4). Submucosal invasion was classified into the following three grades: sm1: ≤200 μm, sm2: >200 μm, and sm2 EM (+): residual cancer cells at the resected margin.

In principle, radiotherapy or chemoradiotherapy was added if the resected margin was suspected to contain residual cancer cells, while chemotherapy was performed if lymphatic invasion was found in the resected specimen (Fig 1). Argon plasma coagulation was added without radiation if the residual tumor was limited to a small area.

#### **2.1 Method of EMR**

EMR was performed by the EEMR or EMRC method1)2). EMRC was done by using a singlechannel endoscope (GIF Q260; Olympus) with a cap (Olympus, Tokyo, Japan). After chromoendoscopy with iodine solution, saline was injected into the submucosal layer.

Combination Therapy After EMR/ESD for

CDDP (80mg/m2) 5FU (800mg/m2)

CDDP (70mg/m2) 5FU (700mg/m2)

**Chemotherapy**

**Chemoradiotherapy**

Fig. 2. Chemotherapy and chemoradiotherapy

Fig. 3. The radiation field was limited to local area

+ radiotherapy, and 10 had EMR + chemoradiotherapy.

**3. Results**

Esophageal Squamous Cell Carcinoma with Submucosal Invasion 93

Day1-5 Day29-33

Day1-4 Day29-32

RT(1.8-2.0Gy/day)

There were no complications of EMR/ESD. On histopathological examination, the depth of tumor invasion was sm1 in 22 cases, sm2 in 9, and sm2 EM (+) in 5. Lymphatic invasion (ly)

Sixteen patients were treated with EMR alone, 8 received EMR + chemotherapy, 2 had EMR

was found in 18 cases (50%), and there was 1 case (3%) of vascular invasion (v).

Next, a snare (SD-7P, Olympus) was opened inside the cap, the tumor was aspirated into the cap, and the snare was closed. The forced coagulation mode was used to perform resection. EMMR was done by using a single-channel endoscope (GIF Q260; Olympus) fitted with an EEMR-tube. The method was same as that for EMRC until the injection of saline. Then a snare (SD-7P, Olympus) was passed through a side channel of the tube and was opened over the tumor. The tumor was aspirated into the tube using the suction of the endoscope and the snare was tightened. Resection was done in the forced coagulation mode.

Fig. 1. Fundamental clinical course

#### **2.2 Method of ESD**

A hook knife from Olympus (Tokyo, Japan) was used for the hook knife method of ESD3)5) along with a single-channel endoscope (GIF Q260; Olympus) and an attachment. The electrical generator was a VIO (ERBE, Tübingen, Germany). Before marking, chromoendoscopy with iodine solution was done to identify the lateral margins of the lesion. Then marking was undertaken in the hook knife using the forced coagulation mode. After 10% glycerin was injected into the submucosal, mucosal incision was performed in the endo cut mode. Before performing submucosal dissection, hyaluronic acid solution was injected into the submucosal lesion. Then the clip with thread was attached to the oral border of the specimen and the thread was pulled in the oral direction to exert traction on the submucosal layer. Next, the submucosal lesion was dissected off the muscle layer by using the hook knife in the endo cut mode. Bleeding was controlled with hemostatic forceps (FD-411QR; Olympus) in the soft coagulation mode or with the hook knife in the spray mode. ESD was performed with the patient under sedation by intravenous administration of diazepam and pentazocine as required plus continuous infusion of propofol.

#### **2.3 Chemotherapy and radiotherapy**

Chemotherapy was performed for 2 courses if lymphatic invasion was found in the resected specimen. Patients were principally given a combination of cisplatin/5-fluorouracil or nedaplatin/5-fluorouracil (Fig. 2). Radiotherapy was given to a total dose of 50-60 Gy, with the radiation field being limited to the local tumor area (Fig. 3).

Next, a snare (SD-7P, Olympus) was opened inside the cap, the tumor was aspirated into the cap, and the snare was closed. The forced coagulation mode was used to perform resection. EMMR was done by using a single-channel endoscope (GIF Q260; Olympus) fitted with an EEMR-tube. The method was same as that for EMRC until the injection of saline. Then a snare (SD-7P, Olympus) was passed through a side channel of the tube and was opened over the tumor. The tumor was aspirated into the tube using the suction of the endoscope and the snare was tightened. Resection was done in the forced coagulation

**ly(-)**

 **Follow up (EMR alone)**

**Chemotherapy**

**Chemoradiotherapy**

**Coagulation (APC)**

**Radiotherapy (RT)**

 **(CRT)**

**ly(+)**

**ly(-)**

A hook knife from Olympus (Tokyo, Japan) was used for the hook knife method of ESD3)5) along with a single-channel endoscope (GIF Q260; Olympus) and an attachment. The electrical generator was a VIO (ERBE, Tübingen, Germany). Before marking, chromoendoscopy with iodine solution was done to identify the lateral margins of the lesion. Then marking was undertaken in the hook knife using the forced coagulation mode. After 10% glycerin was injected into the submucosal, mucosal incision was performed in the endo cut mode. Before performing submucosal dissection, hyaluronic acid solution was injected into the submucosal lesion. Then the clip with thread was attached to the oral border of the specimen and the thread was pulled in the oral direction to exert traction on the submucosal layer. Next, the submucosal lesion was dissected off the muscle layer by using the hook knife in the endo cut mode. Bleeding was controlled with hemostatic forceps (FD-411QR; Olympus) in the soft coagulation mode or with the hook knife in the spray mode. ESD was performed with the patient under sedation by intravenous administration of

Chemotherapy was performed for 2 courses if lymphatic invasion was found in the resected specimen. Patients were principally given a combination of cisplatin/5-fluorouracil or nedaplatin/5-fluorouracil (Fig. 2). Radiotherapy was given to a total dose of 50-60 Gy, with

diazepam and pentazocine as required plus continuous infusion of propofol.

the radiation field being limited to the local tumor area (Fig. 3).

**ly(+)**

mode.

**Complete**

**EMR/ESD**

Fig. 1. Fundamental clinical course

**2.3 Chemotherapy and radiotherapy**

**2.2 Method of ESD**

**Incomplete**

Fig. 2. Chemotherapy and chemoradiotherapy

Fig. 3. The radiation field was limited to local area