**Acknowledgements**

core-shell nanofibers were prepared by the seed-mediated growth Au shell on electrospun SiO2 nanofibers [240]. Then horseradish peroxidase (HRP) was immobilized on the SiO2@Au nanofibers modified electrode via physical adsorption to construct an amperometric H2O2 biosensor. This biosensor exhibited high biological affinity to H2O2 and the HRP enzyme on

**Figure 14.** (A) Typical SEM images of Hb microbelts at low (scale bar=10 μm) and high (inset, scale bar=1 μm) magnifi‐ cation; (B) CVs of the bare GC electrode (a) and Hb microbelts modified GC electrode (b) in 0.1 M pH 7.0 phosphate

In past few years, numerous studies have demonstrated that elctrospinning is a simple and versatile method for fabricating nanofibers of organic or inorganic materials. Various func‐ tional components, such as nanoparticles, CNTs, proteins, DNA and so on, have been incor‐ porated into the electrospun nanofibers. These composite nanofibers exhibited excellent properties and extended the applications of electrospun nanomaterials. With the profound understanding the electrospinning process and the development of setup for electrospinning,

the gold shell kept its activity with a low-diffusion barrier.

62 Advances in Nanofibers

buffer solution. Scan rate, 100 mV s-1 [237].

**5. Conclusions and remarks**

This work was financially supported by the National Nature Science Foundation of China (NO. 21155002, 21105098, 21222505).


3.2.2. Surface Morphology and Lipid Distribution

images of SLH prepared with PG8 are shown.

3.2.2. Surface Morphology and Lipid Distribution Surface morphology, internal structure, and lipid distribution within fabricated SLH formulations were examined using SEM and confocal laser scanning micriscopy (Figures 3 and 4). Blank FS particles formed semi-spherical shapes of varying particle sizes with distinct concave-like structures (Figure 3A). No difference in appearance was observed between blank FS and 80% FS PG8 (Figure 3B). However, at 200% saturation level, regardless of the lipid used, FS particles appeared to form clusters and large aggregates (Figure 3C). In contrast, MPS appeared as angular structures and formed aggregates irrespective of the lipid used or FEN saturation level (Figure 3E,F). No difference in appearance was observed between SLH prepared with either lipid types; therefore, only SEM Surface morphology, internal structure, and lipid distribution within fabricated SLH formulations were examined using SEM and confocal laser scanning micriscopy (Figures 3 and 4). Blank FS particles formed semi-spherical shapes of varying particle sizes with distinct concave-like structures (Figure 3A). No difference in appearance was observed between blank FS and 80% FS PG8 (Figure 3B). However, at 200% saturation level, regardless of the lipid used, FS particles appeared to form clusters and large aggregates (Figure 3C). In contrast, MPS appeared as angular structures and formed aggregates irrespective of the lipid used or FEN saturation level (Figure 3E,F). No difference in appearance was observed between SLH prepared with either lipid types; therefore, only SEM images of SLH prepared with PG8 are shown.

*Pharmaceutics* **2020**, *12*, x FOR PEER REVIEW 10 of 22

**Figure 3.** SEM images of (**A**) blank FS, (**B**) 80% FS PG8, (**C**) 200% FS PG8, (**D**) blank MPS, (**E**) 80% MPS PG8, and (**F**) 200% MPS PG8. **Figure 3.** SEM images of (**A**) blank FS, (**B**) 80% FS PG8, (**C**) 200% FS PG8, (**D**) blank MPS, (**E**) 80% MPS PG8, and (**F**) 200% MPS PG8.

Confocal imaging revealed that the lipid distribution within the silica microparticles was dependent on the type of silica and lipid used. More lipid was observed within the internal structure of FS particles than MPS, evidenced by the intensity of the fluorescently labeled lipid within the pores of the silica microparticles (Figure 4). However, it was evident that PG8 was less prone to imbibe into the porous matrix compared to C300, with lipid droplets tending to reside between inter-particle cavities, irrespective of the silica type. In contrast, C300 homogeneously distributed throughout the internal structure, with the presence of additional lipid droplets between the particles. Confocal imaging revealed that the lipid distribution within the silica microparticles was dependent on the type of silica and lipid used. More lipid was observed within the internal structure of FS particles than MPS, evidenced by the intensity of the fluorescently labeled lipid within the pores of the silica microparticles (Figure 4). However, it was evident that PG8 was less prone to imbibe into the porous matrix compared to C300, with lipid droplets tending to reside between inter-particle cavities, irrespective of the silica type. In contrast, C300 homogeneously distributed throughout the internal structure, with the presence of additional lipid droplets between the particles.

*Pharmaceutics* **2020**, *12*, x FOR PEER REVIEW 11 of 22

**Figure 4.** Confocal images of: (**A**) SLH prepared with FS and (**B**) SLH prepared with MPS. Rhodamine B (red) was used to label silica, and coumarin 6 (green) was used to label lipid. **Figure 4.** Confocal images of: (**A**) SLH prepared with FS and (**B**) SLH prepared with MPS. Rhodamine B (red) was used to label silica, and coumarin 6 (green) was used to label lipid.

### *3.3. In Vitro Dissolution 3.3. In Vitro Dissolution*

The dissolution performance of various SLH prepared with FS and MPS, APO-fenofibrate, and crystalline FEN is reported in Figure 5. The equilibrium solubility of FEN in 0.0125 M SLS (0.36%) was 128 ± 0.01 µg/mL; thus, the study was performed under sink conditions. Crystalline FEN and APO-fenofibrate displayed 7.8% and 25.1% solubilization after 90 min, respectively. At 80% saturation level, all SLH formulations, irrespective of type of silica or lipid, exhibited significantly enhanced FEN dissolution, with FS formulations achieving 70.9–98.1% after 90 min and displaying slightly improved performance compared to MPS formulations (*p* > 0.05). FEN dissolution from FS formulations at 80% Seq corresponded to 8- to 10-fold and 2.6- to 3.2-fold increase in dissolution compared to crystalline FEN and APO-fenofibrate, respectively (*p* < 0.05). However, FEN dissolution from supersaturated SLH formulations was dependent on type of lipid and silica utilized. FS PG8 formulations at all saturation levels (80%, 200%, 400%, 600% Seq) achieved a comparable extent of The dissolution performance of various SLH prepared with FS and MPS, APO-fenofibrate, and crystalline FEN is reported in Figure 5. The equilibrium solubility of FEN in 0.0125 M SLS (0.36%) was 128 ± 0.01 µg/mL; thus, the study was performed under sink conditions. Crystalline FEN and APO-fenofibrate displayed 7.8% and 25.1% solubilization after 90 min, respectively. At 80% saturation level, all SLH formulations, irrespective of type of silica or lipid, exhibited significantly enhanced FEN dissolution, with FS formulations achieving 70.9–98.1% after 90 min and displaying slightly improved performance compared to MPS formulations (*p* > 0.05). FEN dissolution from FS formulations at 80% Seq corresponded to 8- to 10-fold and 2.6- to 3.2-fold increase in dissolution compared to crystalline FEN and APO-fenofibrate, respectively (*p* < 0.05). However, FEN dissolution from supersaturated SLH formulations was dependent on type of lipid and silica utilized. FS PG8 formulations at all saturation levels (80%, 200%, 400%, 600% Seq) achieved a comparable extent of FEN dissolution of ~80% after

FEN dissolution of ~ 80% after 90 min, despite 600% FS PG8 displaying slower release kinetics (*p* >

90 min, despite 600% FS PG8 displaying slower release kinetics (*p* > 0.05) (Figure 5B). In contrast, FEN dissolution was significantly hindered in supersaturated MPS PG8 formulations, with 200% MPS PG8 achieving 43.9% FEN dissolution after 90 min, and was further reduced for 400% and 600% Seq with no significant difference compared to crystalline FEN and APO-fenofibrate (*p* > 0.05). *Pharmaceutics* **2020**, *12*, x FOR PEER REVIEW 12 of 22 formulations, with 200% MPS PG8 achieving 43.9% FEN dissolution after 90 min, and was further reduced for 400% and 600% Seq with no significant difference compared to crystalline FEN and APOfenofibrate (*p* > 0.05).

**Figure 5.** The in vitro dissolution profiles of crystalline FEN, APO-fenofibrate and FEN-loaded SLH formulations (at different saturation levels) in 0.0125 M SLS, dosed at 10 mg of FEN over 90 min at sink conditions. (mean ± SD, *n* = 3). (**A**) SLH C300 formulations, (**B**) SLH PG8 formulations, and (**C**) FEN % dissolution at 90 min vs % Seq. **Figure 5.** The in vitro dissolution profiles of crystalline FEN, APO-fenofibrate and FEN-loaded SLH formulations (at different saturation levels) in 0.0125 M SLS, dosed at 10 mg of FEN over 90 min at sink conditions. (mean ± SD, *n* = 3). (**A**) SLH C300 formulations, (**B**) SLH PG8 formulations, and (**C**) FEN % dissolution at 90 min vs % Seq.

The 200% FS C300 formulation achieved the highest FEN dissolution of 98.1%, which corresponds to approximately 4- and 14-fold increased dissolution compared to APO-fenofibrate and crystalline FEN, respectively (*p* < 0.05). However, this was not statistically significant when compared to 200% FS PG8 (*p* > 0.05). Only 66.8% and 64.6% FEN dissolution was observed from 400% and 600% Seq for FS C300 formulations, respectively. When MPS was utilized to solidify supersaturated C300 LBFs, a similar pattern was observed to supersaturated MPS PG8 formulations (Figure 5C), where the dissolution was significantly reduced with increased supersaturation. 200% MPS C300 achieved 55.2% FEN dissolution, whereas FEN dissolution of only 35.4% and 23.5% was attained from 400% and 600% MPS C300 formulations, respectively, with no significant difference compared to crystalline FEN and APO-fenofibrate (*p* > 0.05). The influence of silica type and saturation level on The 200% FS C300 formulation achieved the highest FEN dissolution of 98.1%, which corresponds to approximately 4- and 14-fold increased dissolution compared to APO-fenofibrate and crystalline FEN, respectively (*p* < 0.05). However, this was not statistically significant when compared to 200% FS PG8 (*p* > 0.05). Only 66.8% and 64.6% FEN dissolution was observed from 400% and 600% Seq for FS C300 formulations, respectively. When MPS was utilized to solidify supersaturated C300 LBFs, a similar pattern was observed to supersaturated MPS PG8 formulations (Figure 5C), where the dissolution was significantly reduced with increased supersaturation. 200% MPS C300 achieved 55.2% FEN dissolution, whereas FEN dissolution of only 35.4% and 23.5% was attained from 400% and 600% MPS C300 formulations, respectively, with no significant difference compared to crystalline FEN and APO-fenofibrate (*p* > 0.05). The influence of silica type and saturation level on FEN dissolution

was evident when FEN dissolution at 90 min was plotted against saturation level (Seq). As displayed in Figure 5C, SLH prepared with FS, irrespective of type of lipid or % Seq, achieved similar extent of dissolution (*p* > 0.05). In contrast, MPS stabilized SLH formulations displayed significant linear reduction in FEN dissolution with an increase in % Seq. The decrease in performance was more profound for MPS PG8 formulations (R2 = 0.86) than MPS C300 formulations (R2 = 0.80); however, it was not statistically significant (*p* > 0.05).


3. Data-level approach

Throughout this section, we show several approaches used in the literature to pre-process time series by re-framing them into new representations for a further CNN implementation. Indeed, a raw time series needs to be converted into a set of fixed-length vector or matrix inputs before being fed into the CNN. Then, we discuss our data-level approach (of previous works [3, 4]) based on the Stockwell transform method.


*2.2.1 Classification of wettability*

The most common measurements involving the static CA and the dynamic CA are utilized to know the surface property. The materials with specific wettability attain excessive attention owing to their outstanding performances for practical applications [9–11].


**2. Laser – assisted materials surface treatment requirements**

Figure 2 shows general regimes of various laser surface treating parameters for both pulsed and continuous wave lasers. Short pulses (ns to fs) with high peak power densities are desirable for laser shock processing and ablation applications. In general, longer pulses (μs to ms) or continuous wave lasers are preferred for melting and heating processes (Nagarathnam & Taminger, 2001).

Laser chemical vapor deposition and laser surface transformation hardening require lower densities and interaction times as compared to processes involving meting and vaporization.

Laser Surface Treatments of Aluminum Alloys 117

interdiffuse into the substrate. As soon as the laser pulse is finished the resolidification

Laser surface alloying may induce an extreme heating/cooling rate of 104-1011k/s, thermal gradient of 105-108 k/m and solidification velocity as high as 30m/s (Draper & Poate, 1985). Due to the high cooling rates, solid state diffusion can be neglected and homogeneous and fine solidification microstructures can be achieved with a wide variety of surface compositions without the limitations of conventional processes, for instance, to extend solid solutions and to obtain metastable structures or even metallic glasses (Damborenea, 1998). Laser surface alloying of Al- alloys by different alloying elements and different techniques was investigated by several researchers. In most of their reports, it was shown that the structure of the zones of laser alloyed depends on the properties of the treated and alloying materials and on the dispersity of the alloying particles, the power of the laser radiation, and the duration of the irradiation (Aleksandrov, 2002). Figure 3 shows the structure of Al-alloy D16 saturated with NiO2 and NbSi2 particles. The saturation with NiO2 is provided by convective mass transfer, which is confirmed by the vortex-like appearance of the structure of the molten zone (figure 3a). The well–manifested heterophase (figure 3b) in the surface layer is provided by the mechanism of penetration of particles of NbSi2 into the molten pool.

NiO2

Fig. 3. Structure of the molten zone after laser alloying of Al-alloy D16 with NiO2 (a) and

NbSi2 (b). x200. (Aleksandrov, 2002)

NbSi2

process begins from the liguid/solid interface towards the surface.

Fig. 1. Various laser surface treatment methods

Fig. 2. Laser power density, specific energy and interaction times for various laser processing regimes (Nagarathnam & Taminger, 2001)

### **3. Laser surface alloying of aluminium alloys**

Laser surface alloying (LSA) involves tailoring the surface microstructure and composition by rapid melting, intermixing and solidification of a pre/co deposited surface layer with apart of the underlying substrate (Majumdar & Manna, 2002 ). Also in this treatment, a shallow layer at the surface of the material is melted by the laser beam which becomes efficiently coupled to the surface, while alloying elements are added simultaneously to give a local composition having the desired surface properties on solidification (Renk et al., 1998). When alloying elements are added to the melted pool then they will start to

Laser Surface Treatment

Solid state processing Ageing

10 10 10 10 10 -8 -6 -4 -2 Log(Interaction Time), D/V

Fig. 2. Laser power density, specific energy and interaction times for various laser processing

Laser surface alloying (LSA) involves tailoring the surface microstructure and composition by rapid melting, intermixing and solidification of a pre/co deposited surface layer with apart of the underlying substrate (Majumdar & Manna, 2002 ). Also in this treatment, a shallow layer at the surface of the material is melted by the laser beam which becomes efficiently coupled to the surface, while alloying elements are added simultaneously to give a local composition having the desired surface properties on solidification (Renk et al., 1998). When alloying elements are added to the melted pool then they will start to

LCVD

● ●

●

Cutting Glazing VAPORIZATION

Welding

Stereolithography

● ●

Melting

●

Cladding

●

LPVD

MELTING

●

Remelting

Alloying Hardfacing

Shock

Glazing

Transformation hardening

VAPORISING

MELTING

Liquid state processing

HEATING

HEATING

Shock hardening

●

Transformation hardening

Drilling

Fig. 1. Various laser surface treatment methods

●

●

10

8

10

Log(Power Density), P/D , W/mm

2

4

10

regimes (Nagarathnam & Taminger, 2001)

**3. Laser surface alloying of aluminium alloys**

interdiffuse into the substrate. As soon as the laser pulse is finished the resolidification process begins from the liguid/solid interface towards the surface.

Laser surface alloying may induce an extreme heating/cooling rate of 104-1011k/s, thermal gradient of 105-108 k/m and solidification velocity as high as 30m/s (Draper & Poate, 1985). Due to the high cooling rates, solid state diffusion can be neglected and homogeneous and fine solidification microstructures can be achieved with a wide variety of surface compositions without the limitations of conventional processes, for instance, to extend solid solutions and to obtain metastable structures or even metallic glasses (Damborenea, 1998).

Laser surface alloying of Al- alloys by different alloying elements and different techniques was investigated by several researchers. In most of their reports, it was shown that the structure of the zones of laser alloyed depends on the properties of the treated and alloying materials and on the dispersity of the alloying particles, the power of the laser radiation, and the duration of the irradiation (Aleksandrov, 2002). Figure 3 shows the structure of Al-alloy D16 saturated with NiO2 and NbSi2 particles. The saturation with NiO2 is provided by convective mass transfer, which is confirmed by the vortex-like appearance of the structure of the molten zone (figure 3a). The well–manifested heterophase (figure 3b) in the surface layer is provided by the mechanism of penetration of particles of NbSi2 into the molten pool.

Fig. 3. Structure of the molten zone after laser alloying of Al-alloy D16 with NiO2 (a) and NbSi2 (b). x200. (Aleksandrov, 2002)

Laser Surface Treatments of Aluminum Alloys 119

They suggested that the influence of convection in liquid homogenization could be characterized by the surface tension number, S, which relates thermocapillarity-induced

( )

*d qd dT s u k*

μ

Where (dσ/dT) is the temperature coefficient of the surface tension, q is the net heat flow from the laser beam, d is diameter of the laser beam, μ is the viscosity, u0 is the scanning speed of the laser beam, and k is the thermal conductivity. When S is low (S≤45000), convection is negligible. Due to the short lifetime of the melt pool, mass transport will be insufficient for melt homogenization. When S is high, convection plays a dominant role in transport phenomena in the melt pool. In general for metals, the convection speed is several orders of magnitude higher than the scanning speed, leading to rapid homogenization. However, for liquid Al the temperature coefficient of the surface tension (dσ/dT) is relatively low (-0.155×10-3 Nm-1k-1), and therefore S will be low. Consequently, in some cases insufficient homogenization of the melt pool is to be expected for laser surface alloying of Al-alloys. For example, this was happened for recently mentioned Almeida's research that is shown in figure 4 (Almeida et al., 2001). A further difficulty arises when the alloying elements react with the melt pool material to form insoluble high melting temperature phases, such as intermetallic compounds. In the matter the diffusion phenomena is

The dissolution kinetics was theoretically analysed by Costa and Vilar (Costa & Vilar, 1996) using a spherical geometry and dropping the quasi-steady–state approximation. Figure 5 shows the results of evaluation of intermetallic layer thickness of Al3Nb as a function of time. This result is reported by Almeida and co-workers (Almeida et al., 2001). They calculated the dissolution time of Nb particles with a diameter of 100μm. These particles takes about 22s to transform to Al3Nb, a time much longer than the interaction time used

Fig. 5. Thickness of intermetallic layer and size of particle for any laser interaction time

σ

0

= (1)

convection velocity and laser beam scanning speed, and is give by:

responsible to control of dissolution kinetics.

(0.24s) in their research.

(Almeida et al., 2001)

The structure of the laser surface alloyed of Al with Nb is shown in figure 4 (Almeida et al., 2001). A strong segregation of Nb in structure leading to the formation of a zone of resolidified Al solid solution and a zone with a high Nb concentration, consists of dendrites of Nb-free α-Al solid solution and undissolved particles of Nb (figure 4a), that some of these particles can be surrounded by a layer consisting of Al3Nb dendrites in an α- Al matrix (figure 4b) showing incipient dissolution and partial redistribution of Nb due to convective flow. It is necessary to mentioned that the temperature and convective mass transport must be sufficient to allow for the complete homogenization of the alloyed layers. This, it can be seen in figure 4 that the temperature and convective mass transport were not sufficient to allow for the complete homogenization of the material (Almeida et al., 2001).

Mazumder (Majumdar & Manna, 2002) studied mass transport in melt pools using a numerical model and concluded that the extremely fast homogenization frequently observed in laser surface alloying can only be explained by the intense Marangoni convection caused by the high temperature gradients within the melt pool (Almeida et al., 2001), with diffusion having only a minor role.

Fig. 4. (a) Structure of the bottom layer (A). (b) Undissolved Nb particle surrounded by a layer of Al3Nb dendrites and α-Al (Almeida et al., 2001)

The structure of the laser surface alloyed of Al with Nb is shown in figure 4 (Almeida et al., 2001). A strong segregation of Nb in structure leading to the formation of a zone of resolidified Al solid solution and a zone with a high Nb concentration, consists of dendrites of Nb-free α-Al solid solution and undissolved particles of Nb (figure 4a), that some of these particles can be surrounded by a layer consisting of Al3Nb dendrites in an α- Al matrix (figure 4b) showing incipient dissolution and partial redistribution of Nb due to convective flow. It is necessary to mentioned that the temperature and convective mass transport must be sufficient to allow for the complete homogenization of the alloyed layers. This, it can be seen in figure 4 that the temperature and convective mass transport were not sufficient to

Mazumder (Majumdar & Manna, 2002) studied mass transport in melt pools using a numerical model and concluded that the extremely fast homogenization frequently observed in laser surface alloying can only be explained by the intense Marangoni convection caused by the high temperature gradients within the melt pool (Almeida et al.,

Fig. 4. (a) Structure of the bottom layer (A). (b) Undissolved Nb particle surrounded by a

layer of Al3Nb dendrites and α-Al (Almeida et al., 2001)

allow for the complete homogenization of the material (Almeida et al., 2001).

2001), with diffusion having only a minor role.

They suggested that the influence of convection in liquid homogenization could be characterized by the surface tension number, S, which relates thermocapillarity-induced convection velocity and laser beam scanning speed, and is give by:

$$s = \frac{\left(d\sigma \Big/\_{dT}\right)\eta d}{\mu u\_0 k} \tag{1}$$

Where (dσ/dT) is the temperature coefficient of the surface tension, q is the net heat flow from the laser beam, d is diameter of the laser beam, μ is the viscosity, u0 is the scanning speed of the laser beam, and k is the thermal conductivity. When S is low (S≤45000), convection is negligible. Due to the short lifetime of the melt pool, mass transport will be insufficient for melt homogenization. When S is high, convection plays a dominant role in transport phenomena in the melt pool. In general for metals, the convection speed is several orders of magnitude higher than the scanning speed, leading to rapid homogenization. However, for liquid Al the temperature coefficient of the surface tension (dσ/dT) is relatively low (-0.155×10-3 Nm-1k-1), and therefore S will be low. Consequently, in some cases insufficient homogenization of the melt pool is to be expected for laser surface alloying of Al-alloys. For example, this was happened for recently mentioned Almeida's research that is shown in figure 4 (Almeida et al., 2001). A further difficulty arises when the alloying elements react with the melt pool material to form insoluble high melting temperature phases, such as intermetallic compounds. In the matter the diffusion phenomena is responsible to control of dissolution kinetics.

The dissolution kinetics was theoretically analysed by Costa and Vilar (Costa & Vilar, 1996) using a spherical geometry and dropping the quasi-steady–state approximation. Figure 5 shows the results of evaluation of intermetallic layer thickness of Al3Nb as a function of time. This result is reported by Almeida and co-workers (Almeida et al., 2001). They calculated the dissolution time of Nb particles with a diameter of 100μm. These particles takes about 22s to transform to Al3Nb, a time much longer than the interaction time used (0.24s) in their research.

Fig. 5. Thickness of intermetallic layer and size of particle for any laser interaction time (Almeida et al., 2001)

Laser Surface Treatments of Aluminum Alloys 121

Fig. 6. The micro structural aspects of the laser alloyed layer (Gingu et al., 1999)

Fig. 7. The adherence aspect of the layer at the material support (Gingu et al., 1999)

 and *T Z* ∂

*X* ∂ ∂

temperature gradient *T*

pool. In the case of low gradients *T*

the form (Aleksandrov, 2002):

*X* ∂

A mathematical modeling of laser surface alloying with solid particles is established by Aleksandrov (Aleksandrov, 2002). According to this model, the presence of a transverse

effective force of gravity (with allowance for the buoyancy force). The higher the difference in the densities of the alloying and Al alloys, the more effective the immersion of the particles. The equations of the motion of a single particle in Cartesian coordinates X, Z have

∂ makes the particles move to the peripheral part of the molten

∂ the particles simply drown in the field of the

In order to obtain significant particle dissolution, the temperature of the melt pool must be higher than the melting point of the intermetallic compounds.

Since convection-driven homogenization is negligible, and the melting point of alloying elements is higher than the melting temperature of Al, the latter starts to solidify before the alloying particles dissolve, and a layer consists of the starting material will be formed. In general, this happened in the bottom layers. In the upper layers, due to the higher temperature of the melt, the alloying particles dissolve in the liquid Al.

The microstructure of alloyed layer depends on solidification rate (R) and the temperature gradient at the solid-liquid interface (G) which in turn depend on heat and mass transfer in the system (Almeida et al., 2001). A simple relation exists between the local solidification rate (R) and the scanning speed gives by fallow equation:

$$\mathbf{R} = \mathbf{V}\_{\\$} \cos \theta \tag{2}$$

where θ is the angle between the normal to the solid-liquid interface and the scanning direction. The solidification rate increases with decreasing depth from 0 at the bottom of the melt pool (cosθ=0 at this point) to a value that remains lower that the scanning speed, because cos θ<1. Conversely, the thermal gradient G is higher at the bottom of the melt pool and decreases as depth decreases. Both solidification parameters vary rapidly during the first stages of solidification (near the bottom of the melt pool) to reach a value that remains approximately constant during most of the solidification process. Consequently, the microstructure in most of the re-solidified layer can be characterized by a single set of solidification parameters and should not change significantly.

Sometimes, in laser surface alloying the microstructure of alloyed layer appears as a texture. The texture effect increases with increasing solidification speed. The origin of this texture can be understood by considering the solidification mechanism in laser surface alloying and the variation of the shape of the melt pool as a function of scanning speed.

Gingo and et. al (Gingu et al., 1999) produced Al/SiCp composite by laser surface alloying. Figure 6 presents the microstructural aspect of the alloyed layer produced at the surface of an AA413 alloy. There is an obvious difference between the base microstructure of the Al alloy, which is the classic eutectic AlSi12, characterised by dendrites grains dispose randomly in the eutectic mass (zone 1), and the very fine granulated microstructure of the alloyed layer (zone2).

In this process, depending on the processing parameters, it is possible to use or not use an adhesive layer at the material support. As can be seen in figure 7, in this case there is a perfect adherence of the alloyed layer at the AA413 support; this phenomenon can be explained by the perfect compatibility of the matrix of Al- alloy (Gingu et al., 1999).

In laser surface alloying of Al with Nb as an alloying element, the dendritic structure was observed by Almeida et. al (Almeida et al., 2001), showing that Al3Nb grows with a dendritic solid/liquid interface. In this type of growth, there is a preferential growth direction usually a low index crystallographic direction. During the initial stages of solidification competition between neighboring dendrites with different orientations occurs, and those with the preferential growth direction nearest to the heat flow direction will be favored, leading to preferential orientation, and eventually to a strong texture. When the scanning speed of surface is increased the shape of melt pool increasingly elongated from semi-hemispherical. Also, when the scanning speed is low the heat flow direction changes progressively from the fusion line to the surface, leading to a variety of preferential growth directions of columnar grains (Almeida et al., 2001).

In order to obtain significant particle dissolution, the temperature of the melt pool must be

Since convection-driven homogenization is negligible, and the melting point of alloying elements is higher than the melting temperature of Al, the latter starts to solidify before the alloying particles dissolve, and a layer consists of the starting material will be formed. In general, this happened in the bottom layers. In the upper layers, due to the higher

The microstructure of alloyed layer depends on solidification rate (R) and the temperature gradient at the solid-liquid interface (G) which in turn depend on heat and mass transfer in the system (Almeida et al., 2001). A simple relation exists between the local solidification

 R=VS cos θ (2) where θ is the angle between the normal to the solid-liquid interface and the scanning direction. The solidification rate increases with decreasing depth from 0 at the bottom of the melt pool (cosθ=0 at this point) to a value that remains lower that the scanning speed, because cos θ<1. Conversely, the thermal gradient G is higher at the bottom of the melt pool and decreases as depth decreases. Both solidification parameters vary rapidly during the first stages of solidification (near the bottom of the melt pool) to reach a value that remains approximately constant during most of the solidification process. Consequently, the microstructure in most of the re-solidified layer can be characterized by a single set of

Sometimes, in laser surface alloying the microstructure of alloyed layer appears as a texture. The texture effect increases with increasing solidification speed. The origin of this texture can be understood by considering the solidification mechanism in laser surface alloying and

Gingo and et. al (Gingu et al., 1999) produced Al/SiCp composite by laser surface alloying. Figure 6 presents the microstructural aspect of the alloyed layer produced at the surface of an AA413 alloy. There is an obvious difference between the base microstructure of the Al alloy, which is the classic eutectic AlSi12, characterised by dendrites grains dispose randomly in the eutectic mass (zone 1), and the very fine granulated microstructure of the

In this process, depending on the processing parameters, it is possible to use or not use an adhesive layer at the material support. As can be seen in figure 7, in this case there is a perfect adherence of the alloyed layer at the AA413 support; this phenomenon can be

In laser surface alloying of Al with Nb as an alloying element, the dendritic structure was observed by Almeida et. al (Almeida et al., 2001), showing that Al3Nb grows with a dendritic solid/liquid interface. In this type of growth, there is a preferential growth direction usually a low index crystallographic direction. During the initial stages of solidification competition between neighboring dendrites with different orientations occurs, and those with the preferential growth direction nearest to the heat flow direction will be favored, leading to preferential orientation, and eventually to a strong texture. When the scanning speed of surface is increased the shape of melt pool increasingly elongated from semi-hemispherical. Also, when the scanning speed is low the heat flow direction changes progressively from the fusion line to the surface, leading to a variety of preferential growth

explained by the perfect compatibility of the matrix of Al- alloy (Gingu et al., 1999).

higher than the melting point of the intermetallic compounds.

rate (R) and the scanning speed gives by fallow equation:

solidification parameters and should not change significantly.

directions of columnar grains (Almeida et al., 2001).

alloyed layer (zone2).

the variation of the shape of the melt pool as a function of scanning speed.

temperature of the melt, the alloying particles dissolve in the liquid Al.

Fig. 6. The micro structural aspects of the laser alloyed layer (Gingu et al., 1999)

Fig. 7. The adherence aspect of the layer at the material support (Gingu et al., 1999)

A mathematical modeling of laser surface alloying with solid particles is established by Aleksandrov (Aleksandrov, 2002). According to this model, the presence of a transverse temperature gradient *T X* ∂ ∂ makes the particles move to the peripheral part of the molten pool. In the case of low gradients *T X* ∂ ∂ and *T Z* ∂ ∂ the particles simply drown in the field of the effective force of gravity (with allowance for the buoyancy force). The higher the difference in the densities of the alloying and Al alloys, the more effective the immersion of the particles. The equations of the motion of a single particle in Cartesian coordinates X, Z have the form (Aleksandrov, 2002):

Laser Surface Treatments of Aluminum Alloys 123

conglomerates of high-hardness particles. The use of lubricating materials improves the service properties of various friction pairs (Aleksandrov, 2002). Similar results are reported by Tomlinson and co- workers (Tomlinson & Bransden, 1996). They studied the effect of laser alloying of metallic elements such as Si, Ni, Fe, Cu, Mn, Cr, Co, Mo and Ti on hypoeutectic cast Al-Si alloys using a pre-placed coating method, and found an improvement in the wear resistance of aluminum. Senthile selvan and co-workers (Senthil Selvan et al., 2000), reported that when laser alloying of Al with Ni was carried out at the highest scan speed of 1.1 m min-1, the hardness increased to 800-900 Hv with negligible fluctuations in the hardness behavior. This may be attributed to a uniform LAC with well distributed intermetallic phases. While, at a slightly increased scan speed, the hardness increased from 300 to 800 Hv, but with large fluctuations, which can be attributed to the

Fig. 9. Dependence of the wear intensity of aluminium alloy on the specific load in a wear test laser treatment at P=1kw, ν=12.5 mm/sec, 1)Initial state, 2) after LHT 3,4,5) after alloying

The homogeneous distribution of hard intermetallic phases in Al matrix can prevent adhesion and abrasive wear during fretting. Yongqing Fu (Yongqing et al., 1998), reported that after a large number of fretting cycles, the rate of fretting wear depth decreases, which means that the wear volume loss is probably caused by an increase in fretting area rather by wear along the depth. This phenomenon is probably caused by the formation and compaction of fretting oxide debris, which can reduce the wear along the fretting depth. Laser surface alloying can decreases the fretting wear volume by a factor of three and decreases the coefficient of friction, probably due to the hardening effect of oxide debris which can prevent adhesion and abrasive wear during fretting, therefore, it can offers an

effective means of preventing fretting wear (figure 11). The (Yongqing et al., 1998).

with Ni, NbSi2, Cr, respectively (Aleksandrov, 2002)

homogeneous alloyed layer (figure 10).

$$\frac{4}{3}\pi p R^2 \stackrel{\cdots}{\mathbf{x}} = 2\alpha\_0 \frac{\partial T}{\partial \mathbf{x}} R - 6\pi \eta R \stackrel{\cdots}{\mathbf{x}}\tag{3}$$

$$\frac{4}{3}\pi p R^3 \stackrel{\cdots}{z} = 2\alpha\_0 \frac{\partial T}{\partial z} R + \frac{4}{3}\pi \left(P - P\_1\right) R^3 \mathcal{g} - 6\pi \eta R \stackrel{\cdots}{z} \tag{4}$$

where ρ is the density of the particle, R is the radius of the particle, ρ1 is the density of the Al alloy, η is the viscosity of the Al alloy, . .. *x x*, are the transverse velocity and acceleration of the particle respectively, and . .. *z z*, are the vertical velocity and acceleration of the particles, respectively.

The mechanism of the infusion and velocity of particles in melt pool affects on the formation of heterogeneous or homogenous structure in alloyed layer. The corresponding qualitative dependence ν0(R) is plotted in figure 8.

Fig. 8. Dependence of the initial velocity of the particles ν0 on their radius R at a fixed surface density (ρi) of the energy of laser radiation (P1<P2<P3<P4<P5) (Aleksandrov, 2002)

The order of magnitude of the initial velocity of the particles νo needed for the alloying is determined by the time τ of the action of laser radiation and the depth of the molten region H (νo= *H* τ ). Particles with a size ranging between R2 and R3 may acquire the requisite values νo.

Under actual conditions and fixed energy and time of the laser action, the dependences νo(R) corresponds to a certain domain (hatched in figure 8).

Aleksandrove (Aleksandrov, 2002) also studied the wear resistance of laser surface alloyed layer of Al alloy with Ni, NbSi2 and Cr. The results of wear tests are presented in figure 9.

It can be seen that wear resistance of the hardened surface of aluminum alloy layer is much higher (by factor of 4-5) that the initial one or the one provided by LHT. Also, the friction coefficient tests show that laser surface alloying of Al alloys with Cr, NbSi2 and Ni decreases the friction coefficient of the friction surface by about a factor of 3-4, which makes it possible to vary it by changing the filling factor of the surface and the filling of the alloyed zone with

 α

*T*

∂

*z*

3

πα

alloy, η is the viscosity of the Al alloy, . ..

dependence ν0(R) is plotted in figure 8.

particle respectively, and . ..

respectively.

H (νo= *H* τ

π

3 3

.. . 2 0 4 2 6

( ) .. . 3 3 0 1 4 4 2 6

*pR z R P P R g Rz*

 π

where ρ is the density of the particle, R is the radius of the particle, ρ1 is the density of the Al

The mechanism of the infusion and velocity of particles in melt pool affects on the formation of heterogeneous or homogenous structure in alloyed layer. The corresponding qualitative

Fig. 8. Dependence of the initial velocity of the particles ν0 on their radius R at a fixed surface density (ρi) of the energy of laser radiation (P1<P2<P3<P4<P5) (Aleksandrov, 2002)

The order of magnitude of the initial velocity of the particles νo needed for the alloying is determined by the time τ of the action of laser radiation and the depth of the molten region

Under actual conditions and fixed energy and time of the laser action, the dependences

Aleksandrove (Aleksandrov, 2002) also studied the wear resistance of laser surface alloyed layer of Al alloy with Ni, NbSi2 and Cr. The results of wear tests are presented in figure 9. It can be seen that wear resistance of the hardened surface of aluminum alloy layer is much higher (by factor of 4-5) that the initial one or the one provided by LHT. Also, the friction coefficient tests show that laser surface alloying of Al alloys with Cr, NbSi2 and Ni decreases the friction coefficient of the friction surface by about a factor of 3-4, which makes it possible to vary it by changing the filling factor of the surface and the filling of the alloyed zone with

νo(R) corresponds to a certain domain (hatched in figure 8).

). Particles with a size ranging between R2 and R3 may acquire the requisite values νo.

= +− −

 πη

∂ = − ∂ (3)

πη

∂ (4)

*x x*, are the transverse velocity and acceleration of the

*z z*, are the vertical velocity and acceleration of the particles,

*T pR x R Rx x*

conglomerates of high-hardness particles. The use of lubricating materials improves the service properties of various friction pairs (Aleksandrov, 2002). Similar results are reported by Tomlinson and co- workers (Tomlinson & Bransden, 1996). They studied the effect of laser alloying of metallic elements such as Si, Ni, Fe, Cu, Mn, Cr, Co, Mo and Ti on hypoeutectic cast Al-Si alloys using a pre-placed coating method, and found an improvement in the wear resistance of aluminum. Senthile selvan and co-workers (Senthil Selvan et al., 2000), reported that when laser alloying of Al with Ni was carried out at the highest scan speed of 1.1 m min-1, the hardness increased to 800-900 Hv with negligible fluctuations in the hardness behavior. This may be attributed to a uniform LAC with well distributed intermetallic phases. While, at a slightly increased scan speed, the hardness increased from 300 to 800 Hv, but with large fluctuations, which can be attributed to the homogeneous alloyed layer (figure 10).

Fig. 9. Dependence of the wear intensity of aluminium alloy on the specific load in a wear test laser treatment at P=1kw, ν=12.5 mm/sec, 1)Initial state, 2) after LHT 3,4,5) after alloying with Ni, NbSi2, Cr, respectively (Aleksandrov, 2002)

The homogeneous distribution of hard intermetallic phases in Al matrix can prevent adhesion and abrasive wear during fretting. Yongqing Fu (Yongqing et al., 1998), reported that after a large number of fretting cycles, the rate of fretting wear depth decreases, which means that the wear volume loss is probably caused by an increase in fretting area rather by wear along the depth. This phenomenon is probably caused by the formation and compaction of fretting oxide debris, which can reduce the wear along the fretting depth. Laser surface alloying can decreases the fretting wear volume by a factor of three and decreases the coefficient of friction, probably due to the hardening effect of oxide debris which can prevent adhesion and abrasive wear during fretting, therefore, it can offers an effective means of preventing fretting wear (figure 11). The (Yongqing et al., 1998).

Laser Surface Treatments of Aluminum Alloys 125

(c) Fig. 10. Microhardness profiles of laser- alloyed Cp- Al with Ni at powers of a) 1.1, b) 1.3

 (a) The maximum fretting wear depth (b) Fretting wear volume Fig. 11. The maximum fretting wear depth and retting volume for the Al6061 and lasertreated Al- alloy (normal load of 2N, amplitude of 50μm, frequency of 50Hz under

and c) 1.5 kw at different scan speeds (Senthil Selvan et al., 2001)

unlubricated conditions) (Yongqing et al., 1998)

(a)

(b)

Fig. 10. Microhardness profiles of laser- alloyed Cp- Al with Ni at powers of a) 1.1, b) 1.3 and c) 1.5 kw at different scan speeds (Senthil Selvan et al., 2001)

Fig. 11. The maximum fretting wear depth and retting volume for the Al6061 and lasertreated Al- alloy (normal load of 2N, amplitude of 50μm, frequency of 50Hz under unlubricated conditions) (Yongqing et al., 1998)

Laser Surface Treatments of Aluminum Alloys 127

Laser surface alloying of Al with Fe is studied by Tomida and Nakata (Tomida & Nakata, 2003). They reported that the hardness of laser alloyed layer increases with increasing Fe content as shown in (Figure 12). However, cracking occurred in the alloyed layer with higher hardness than Hv600, because the brittle 1ump-like Fe2Al5 compound was produced in these layers. The wear resistance of the alloyed layer improved with increasing the hardness due to the formation of the fine Fe rich intermetallic compounds. This result is

Laser surface melting (LSM) is a well established technology applied to many materials for

LSM is a versatile and promising technique that can be used to modify the surface properties of a material without affecting its bulk property (Yue et al., 2004; Rams et al., 2007). The modifying in the surface properties of the material is due to rapid melting followed by rapid solidification. The intimate contact between the melt and the solid substrate causes a very fast heat extraction during solidification resulting in very high cooling rates of the order of 105 to 108 k/s. The high cooling rates to which this surface layer is submitted result in the formation of different microstructures from bulk metal leading to improved surface properties (Aparecida Pinto et al., 2003). Materials processed via rapid solidification tend to show advantages of refined microstructure, reduced microsegregation, extensive solid solubility and formation of metastable phases (Munitz, 1985; Zimmermann et al., 1989). It is generally accepted that the improvement in corrosion performance is due to refinement/homogenisation of microstructure and dissolusion/redistribution of precipitates or inclusions, which result from rapid solidification (Chong et al., 2003). This was considered to be due to the presence of the compact oxide layers on top of the lasermelted zone. The layers mainly consisted of structures α-Al2O3, which is a homogeneous and chemically stable phase and serves as an effective barrier to protect the matrix against corrosion attacks. In untreated surfaces of Al alloys the microsegregation in relatively thin surface layer plays an important role in initiating pitting in the inhomogeneous structures. The schematic of the laser surface melting process is shown in figure 14 (Aparecida Pinto et

Some industrial laser sources such as CO2, Nd:YAG, excimer and high power diode lasers were applied to surface melting of aluminium alloys. Since aluminum alloy have no solid phase transformation, if the surface of aluminium alloys should not be melted, the surface cannot be strengthened. In view of the basic physical properties of aluminium alloy, such as large specific heat, high heat conductivity and high reflectivity to laser power density than that for ferrous alloy (Wong et al., 1997). The controlling of laser parameters is very

Because the properties of a material depend largely on its microstructure, controlled formation of such microstructures is essential to develop new materials with desired properties (Aparecida Pinto et al., 2003). Laser parameters such as laser power density, interaction time and scan speed affect on solidification behaviour and thus the

The diagram shown in figure 15 associated the microstructural evolution with the

hardening, reducing porosity and increasing wear and corrosion resistance.

shown in figure 13.

al., 2003).

**4. Laser surface remelting of aluminium alloy**

important factor for laser surface melting process.

microstructure of melted zone can be changed.

solid/liquid front velocity (Aparecida Pinto et al., 2003).

Fig. 12. Relation between Fe content and hardness of laser alloyed layer on aluminum (Tomida & Nakata, 2003)

Fig. 13. Relation between surface hardness of laser alloyed layer and abrasive wear behavior. (Tomida & Nakata, 2003)

Fig. 12. Relation between Fe content and hardness of laser alloyed layer on aluminum

Fig. 13. Relation between surface hardness of laser alloyed layer and abrasive wear

(Tomida & Nakata, 2003)

behavior. (Tomida & Nakata, 2003)

Laser surface alloying of Al with Fe is studied by Tomida and Nakata (Tomida & Nakata, 2003). They reported that the hardness of laser alloyed layer increases with increasing Fe content as shown in (Figure 12). However, cracking occurred in the alloyed layer with higher hardness than Hv600, because the brittle 1ump-like Fe2Al5 compound was produced in these layers. The wear resistance of the alloyed layer improved with increasing the hardness due to the formation of the fine Fe rich intermetallic compounds. This result is shown in figure 13.


**3. Results**

150 Technical Problems in Patients on Hemodialysis

nitrogen aborted volume in the saturation point (P/P0 ~ 0.99). The micropores and primary micropores were calculated from the intercept point of the t-plot linear region after the saturation of the micropores and primary micropores respectively. The volume of the mesopores was calculated from the difference between the total volume of the pores and the volume of the micropores, also, the volume of the secondary micropores was calculated by the difference between the volume of the mesopores and the volume of the primary micropores. The distribution of the size of the pores in the micropore and mesopore regions in the ACs was obtained from the methods developed by Horvath-Kawazoe (HK) and

An isotherm study of adsorption equilibrium is important as to describe an interaction between adsorbate and adsorbents, and it is critical in the optimization of these materials for both studies in continuous or in batch process. Information regarding the distribution of the sizes of the AC pores were obtained from comparison of the adsorption characteristic for three different adsorbates: methylene blue and [D-Leucine1]microcystin-LR ([D-Leu1]MCYST-LR). The choice of these molecules is justified by their properties, forms and polarities, being the first commonly used for foretelling the capacity of the activated charcoal in adsorbing micropollutants in industrial effluents (Hsieh & Teng, 2000; Lussier et al., 1994), besides providing an estimate of the volumes in secondary micropores +

The trihydrate methylene blue (99.95%, Merck, EUA) analytical grade was used in the solution preparation as to determine the Methylene Blue Index (MBI). The adsorption experiments were made in accordance with the norm JIS (Japanese Industrial Standard), JIS-K 1474 (1991). The methylene blue concentrations in the liquid phase after the equilibrium were determined indirectly from molecular adsorption spectrophotometry (spectrophotometer GBC UV/VIS – 911 A) in the wave length of 665 nm. The experimental data were adjusted to the Freundlich's model, and the quantity of the methylene blue

> C C 0 q V m

For the foretelling of the capacity and removal de microcystine in water by activated charcoal, an aqueous extract of [D-Leu1]MCYST-LR of concentration around to 6000 g/L, prepared in drinkable water exempt of chloride, was used as adsorbate. This toxin has been already identified in growths in Lagoa dos Patos, Rio Grande do Sul, Brazil, (coordinates 31° 9'56.93"S 51°25'51.45"W) by Matthiensen et al. (2001) and in Lagoa de Jacarepaguá, Rio de Janeiro, Brasil (22°59'10.69"S 43°23'57.95"W) by Oliveira et al. (2004). The preparation of the respective extract, as in the quantification model of the referred toxin by High Performance Liquid Chromatography (HPLC) was fully discussed by Kuroda et al. (2005). The experimental data were adjusted to the Langmuir's model and the quantity of adsorbed

(1)

**]microcystin-**

Barrett-Joyner-Halenda (BJH), respectively (Webb & Orr, 1997).

**LR**

**<IP_ADDRESS> Batch experiments**

**2.1.2 Adsorption in liquid phase: Methylene blue index and [D-Leucine1**

mesopores, as foretold in previous works by Albuquerque Junior et al. (2005).

adsorbed by the charcoals (q) was calculated according to the equation 1.

toxin by the activated charcoals was measured from the equation 1.

#### **3.1 Textual characteristics of activated charcoals**

The activated charcoals are formed by an interconnected net of pores, which according to IUPAC (International Union of Pure and Applied Chemistry) may be classified according to its diameters in different categories: macropores (di > 50 nm), mesopores (2 nm < di < 50 nm), primary micropores (di < 0,8 nm) and secondary micropores(0,8 nm < di < 2nm) (Everett, 1988).

The activated charcoal porosity may be estimated from the form of the isotherm of Nitrogen adsorption according to the Brunauer, Deming, Deming and Teller (BDDT) (Gregg & Sing, 1982) classification. Therefore, from that classification, it was observed that the AC-B-F, AC has presented an isotherm characteristic of the type I, typical of micropores material, with relatively small external surface area. Nevertheless, loops characteristic from hysteresis in partial pressures (P/P0) above 0,4 in other ACs, which indicate that these charcoals must present a small band of pores in the secondary micropore region and mesopores. Thus, these other charcoals have presented a combination between the isotherms I and II, the same observed for charcoals taken as reference (fig. 2).

Specifications of the Quality of Granulated Activated Charcoal

Centers A (HC Campinas) for the removal of contaminants.

REF. BET Micro Meso Primary

Table 2. Activated Charcoals textural properties.

Used in Water Systems Treatment in Hemodialysis Centers in Brazil 153

The adsorption isotherms could also be analyzed from the hysteresis loop format according to the standard classification, which contains 4 types: H1–H4 (Girgis & Hendawy, 2002). The hysteresis loops appear in multilayer regions of isothermal of physiosorption, and are considered as being associated to capillary condensation. The hysteresis loop style found for the analyzed charcoals was of the H4 type, which was originated from the influence, even

The charcoal sample AC-A-D has presented an unusual behavior from the obtained isothermal data of N2 adsorption/desorption, as it has shown a very low Nitrogen adsorpted volume, around 0.27 cm3/g, when compared with those obtained by other sampled charcoals, which then Nitrogen adsorpted volumes were above 248 cm3/g (Figure 2d). By the adsorption behavior of that charcoal, it is assumed that the same is an activated charcoal and, thus, could not be used in the water treatment station in the Hemodialysis

The used ACs in the water treatment station of the Hemodialysis Center A have presented BET area (SBET) between 764.9 m2/g e 1,017.4 m2/g, whereas the ones used in the Hemodialysis Center B have presented SBET between 632.8 m2/g and 789.5 m2/g (Table 2).

\*Secondary

micropore (%) Mesopore (%) Total

Surface area ( m2/g) Pore Volume (cm3/g)

AC-A-A 764.9 756.2 8.7 0.16 (44.7) 0.21 (55.3) 0.01 (2.6) 0.38 AC-A-B 871.2 857.6 13.6 0.12 (31.9) 0.32 (68.1) 0.03 (6.4) 0.47 AC-A-C 1017.4 967.9 49.5 0.08 (31.9) 0.38 (69.1) 0.09 (16.4) 0.55 \*AC-A-D 4.6 4.5 0.015 - - - 0.003 AC-B-E 632.8 610.2 22.6 0.17 (55.9) 0.15 (44.1) 0.02 (5.9) 0.34 AC-B-F 789.5 772.0 17.5 0.14 (37.5) 0.30 (62.5) 0.04 (8.3) 0.48 AC-R-G 1079.5 1014.2 65.3 0.08 (50.0) 0.29 (50.0) 0.20 (34.5) 0.58 AC-R-H 1174.3 1097.3 77.3 0.10 (22.3) 0.35 (77.7) 0.39 (41.8) 0.76

A first observation of these results would imply in the choice of charcoals of any of the two centers, however, according to Quinlivan et al. (2005), the BET area (SBET) is a poor indicator of the adsorption capacity of activated charcoals, hence, the sampled charcoals quality cannot be assessed only by their BET (SBET) area data, so, other effectiveness parameters must be taken into consideration in order to choose a charcoal for a determined aim. Thus, beyond that parameter, the secondary micropores and mesopores volumetric fractions must also be considered in the choice of an activated charcoal for the use in water treatment, as these pores are significantly important in the adsorption of organic micropollutants like the microcystins by the activated charcoals according to Donati et al. (1994) and Pendleton et al. (2001). According to Donati et al. (1994), there is no correlation between the adsorption capacity of activated charcoals by microcystins and the BET area, the micropores volume and the number of Iodine. However, the mesopores presence in these adsorbents may favor the adsorption of the cyanobacterium toxin. Moreover, Pendleton et al. (2001), have shown that besides the mesopores volume, the adsorption capacity of that toxin, was also influenced by the

micropore (%)

\* The very low adsorption capacity has not allowed the calculation of these parameters.

small, of the existing secondary micropores and mesopores in these materials.

Fig. 2. Nitrogen adsorption/desorption Isothermes at -196oC. (a) AC-A-A, (b) AC-A-B, (c) AC-A-C, (d) AC-A-D, (e) AC-B-E, (f) AC-B-F, (g) AC-R-G and (h) AC-R-H

Fig. 2. Nitrogen adsorption/desorption Isothermes at -196oC. (a) AC-A-A, (b) AC-A-B, (c)

320

300

280

 (cm 2 Adsorbed volume N 3/g)

260

240

Adsorption

Desorption

170

160

220

200

(a) (b) (c) (d)

440

210

200

/g)

190

 (cm 2 Adsorbed volume N 3

180

400

350

/g)

300

 (cm 2 Adsorbed volume N 3

250

Adsorption

Desorption

420

/g)

400

 (cm 2 Adsorbed volume N 3

380

360

Adsorption

Desorption

340

Adsorption

Desorption

200

320

300

(e) (f) (g) (h)

0,2 0,4 0,6 0,8 1,0

> 0,2 0,4 0,6 0,8 1,0

P/P0

0,2 0,4 0,6 0,8 1,0

P/P0

P/P0

0,0 0,2 0,4 0,6 0,8 1,0

P/P0

150

AC-A-C, (d) AC-A-D, (e) AC-B-E, (f) AC-B-F, (g) AC-R-G and (h) AC-R-H

0,2 0,4 0,6 0,8 1,0

P/P0

0,2 0,4 0,6 0,8 1,0

P/P0

0,2

 0,4

 0,6

P/P0

 0,8

 1,0

0,0 0,2 0,4 0,6 0,8 1,0

P/P0

0,00

230

250

310

360

0,30

0,25

/g)

adsorption

0,20

 (cm 2 Adsorbed volume N 3

0,15

340

/g)

320

 (cm 2 Adsorbed volume N 3

300

300

290

/g)

280

 (cm 2 Adsorbed volume N 3

270

240

/g)

 (cm 2 Adsorbed volume N 3

230

220

adsorption

260

Adsorption

280

Adsorption

Desorption

0,10

0,05

260

240

Desorption

250

240

desorption

210

The adsorption isotherms could also be analyzed from the hysteresis loop format according to the standard classification, which contains 4 types: H1–H4 (Girgis & Hendawy, 2002). The hysteresis loops appear in multilayer regions of isothermal of physiosorption, and are considered as being associated to capillary condensation. The hysteresis loop style found for the analyzed charcoals was of the H4 type, which was originated from the influence, even small, of the existing secondary micropores and mesopores in these materials.

The charcoal sample AC-A-D has presented an unusual behavior from the obtained isothermal data of N2 adsorption/desorption, as it has shown a very low Nitrogen adsorpted volume, around 0.27 cm3/g, when compared with those obtained by other sampled charcoals, which then Nitrogen adsorpted volumes were above 248 cm3/g (Figure 2d). By the adsorption behavior of that charcoal, it is assumed that the same is an activated charcoal and, thus, could not be used in the water treatment station in the Hemodialysis Centers A (HC Campinas) for the removal of contaminants.

The used ACs in the water treatment station of the Hemodialysis Center A have presented BET area (SBET) between 764.9 m2/g e 1,017.4 m2/g, whereas the ones used in the Hemodialysis Center B have presented SBET between 632.8 m2/g and 789.5 m2/g (Table 2).

\* The very low adsorption capacity has not allowed the calculation of these parameters.

Table 2. Activated Charcoals textural properties.

A first observation of these results would imply in the choice of charcoals of any of the two centers, however, according to Quinlivan et al. (2005), the BET area (SBET) is a poor indicator of the adsorption capacity of activated charcoals, hence, the sampled charcoals quality cannot be assessed only by their BET (SBET) area data, so, other effectiveness parameters must be taken into consideration in order to choose a charcoal for a determined aim. Thus, beyond that parameter, the secondary micropores and mesopores volumetric fractions must also be considered in the choice of an activated charcoal for the use in water treatment, as these pores are significantly important in the adsorption of organic micropollutants like the microcystins by the activated charcoals according to Donati et al. (1994) and Pendleton et al. (2001). According to Donati et al. (1994), there is no correlation between the adsorption capacity of activated charcoals by microcystins and the BET area, the micropores volume and the number of Iodine. However, the mesopores presence in these adsorbents may favor the adsorption of the cyanobacterium toxin. Moreover, Pendleton et al. (2001), have shown that besides the mesopores volume, the adsorption capacity of that toxin, was also influenced by the

Specifications of the Quality of Granulated Activated Charcoal

with an internal diameter close to 2-3 nm.

**3.2 Adsorption on liquid phase 3.2.1 Batch experiments**

from adsorption data in gaseous phase.

Reference

impossible to calculate the MBI.

Table 3. Freundlich's model adsorption parameters.

charcoals' Methylene Blue Index (MBI), are displayed on Table 3.

Freundlich's model parameters

AC-A-A 9.2 0.13 0.91 7.6 AC-A-B 40.7 0.07 0.98 36.6 AC-A-C 43.4 0.02 0.95 42.1 \* AC-A-D - - - - AC-A-E 35.4 0.1 0.97 32.5 AC-A-F 85.6 0.05 0.99 79.2 AC-A-G 104.5 0.08 0.94 92.6 AC-A-H 271.4 0.16 0.99 217.5 \*This charcoal has a very low adsorption capacity (close to zero) for methylene blue, which makes it

Used in Water Systems Treatment in Hemodialysis Centers in Brazil 155

be taken as referential of the latter. Thus, taken the approximate dimensions of the MCYST-LR it is presumed that the [D-Leu1]MCYST-LR is adsorbed in the activated charcoal pores

The distribution of the pores size (Figure 3) estimated from the HK/BJK has allowed to observe that the sampled charcoals have a pores average diameter between 2.5-4 nm, which would make these charcoals potential adsorbents for their use in the removal of the water microcystin, but the low volume of the pores observed in this 2.5-4 nm band is smaller than 0.07 cm3/g, which makes these charcoals adsorbents of low adsorption capacity for such aim.

Knowing the adsorption equilibrium represents the first step in investigating the possibilities for using an adsorbent in a determined separation process. Besides, additional information regarding the distribution of the sizes of the activated charcoal pores can be obtained by comparing the adsorption characteristics of adsorbate by taking those obtained

Methylene blue (MB) has been widely used as an adsorbate to estimate the adsorption capacity of CA from continuous in fixed bed or batch experiments (Kumar & Sivanesan, 2006; Macedo et al., 2006; Zhang et al., 2006). Studies on MB adsorption equilibrium in activated charcoal can provide important information about the selectivity of these adsorbents regarding this molecule, given that the MB is accessible to the charcoal pores with an inner diameter greater than 1.5 nm, being important for the characterization of the secondary micropores (0.8 <di <2.0 nm) and mesopores (2 nm < di < 50 nm) mainly, besides being a model compost used for predicting the adsorption of organic contaminants found in industrial effluents such as textile dye and microcystines (Barton, 1987; Baçaoui et al., 2001). According to the JIS norm (1994), the Methylene Blue Index is operationally defined as the adsorbed amount of that molecule when its residual concentration in liquid phase after equilibrium is of 0.24 mg/L. This adsorption capacity was obtained from an equilibrium isotherm where the experimental data were adjusted to Freundlich's adsorption model. The correlation coefficients for linear regression from the adjustment of the experimental data to the respective linearized model along with its empirical parameters, K and 1/n, besides the

> Methylene Blue Index K (L/mg) 1/n r2 MBI (mg/g)

volumetric fraction correspondent to the secondary micropores. In these charcoals, the secondary micropores and mesopores volumetric fractions have exceeded 37% e 28%, respectively, favoring the adsorption of microcystin in 200.0 g/mg.

The activated charcoals of the water treatment in the hemodialysis Center (A and B) have presented secondary micropores and mesopores volumetric portions of 0.15 to 0.38 cm3/g (44.1 to 69.1%) and of 0.01 to 0.09 cm3/g (2.6 to 16.4%), respectively. These charcoals have presented secondary micropores portions higher than those found by Pendleton et al. (2001), however, they have also presented very low mesopores volumetric fractions, around 8% in average, which characterizes microporous charcoals. Nevertheless, those commercial activated charcoals obtained as reference by the authors, have presented secondary micropores volumetric fractions and mesopores of 59.2 to 63.6% and of 34.5 to 41.8%, respectively, which can be characterized as a good indicator for the AC for the treatment water use.

A visualization of the pores size distribution can be obtained from the distribution function calculated by the HK and BJH (Figure 3) methods. The (A), (B) and (C) charcoals have shown a distribution function HK/BJH, with dW/dLo of 0.04; 0.07 and 0.06 cm3/nm/g consisting of pores average diameters of 3.81, 3.80 and 3.28 nm, respectively. Due to the low adsorption capacity of the D charcoal, it was not possible to obtain its distribution of the pores sizes. For the E charcoal, the distribution function dW/dLo has presented two peaks with 0.02 and 0.01 cm3/nm/g a 2.53 and 4.15 nm in pores average diameter; while the AC-B-F has presented dW/dLo ≈ 0.06 cm3/nm/g to an average pore diameter of 2.7 nm. In contrast with these results, the standards AC-R-G and AC-R-H have shown a distribution function a little higher: (AC-R-G) dW/dLo ≈ 0.3 cm3/nm/g with 1.61 nm of pore average diameter, and AC-R-H has presented two peaks with dW/dLo ≈ 0.17 and 0.08 cm3/nm/g with pore average diameter of approximately 1.71 and 3.00 nm, respectively.

Fig. 3. Function distribution HK/BJH: (■) AC-A-A; (□) AC-A-B; (∆) AC-A-C; () AC-B-E; () AC-B-F; (Ө) AC-R-G; (О) AC-R-H.

According to Lanaras et al. (1991) the MCYST-LR when dissolved in water, has a solvated volume of 2.63 nm, length of 1.9nm, height of 1.5nm, thickness of 1.1nm, and solvated area of 1.8 nm2. The [D-Leu1]MCYST-LR has an amino acid residue, D-Leucine, which has replaced the amino acid residue, D-Alanine, of MCYST-LR, that confers the [D-Leu1]MCYST-LR more hydrophobicity than the MCYST-LR. But, these differences between their chemical structures are not so significant regarding their heights, solvated volume and transversal section area, enabling that approximate dimensions of the first MCYST-LR might be taken as referential of the latter. Thus, taken the approximate dimensions of the MCYST-LR it is presumed that the [D-Leu1]MCYST-LR is adsorbed in the activated charcoal pores with an internal diameter close to 2-3 nm.

The distribution of the pores size (Figure 3) estimated from the HK/BJK has allowed to observe that the sampled charcoals have a pores average diameter between 2.5-4 nm, which would make these charcoals potential adsorbents for their use in the removal of the water microcystin, but the low volume of the pores observed in this 2.5-4 nm band is smaller than 0.07 cm3/g, which makes these charcoals adsorbents of low adsorption capacity for such aim.


*2.4. Step 3: Validation of the Objectives, Criteria, and Metrics of the RAF*

In this step, the RAF was submitted to stakeholders to identify knowledge gaps and improvement opportunities. The RAF validation includes the involvement and participation of stakeholders with different contexts, in a different resilience development level and with diverse NBS in the city, as water utilities or municipalities. The proposed dimensions, resilience objectives, criteria, and metrics were analysed with the stakeholders during working sessions. Metrics determination for participating cites and case studies is also carried in this step, taking into consideration the available information. In addition, a survey was conducted to determine the RAF metrics' relevance and the feasibility of application to their own cities.

The validation step includes (i) RAF submission to stakeholders to identify improvement opportunities and gaps, (ii) RAF application to participating cities, (iii) determination of metrics relevance and feasibility of application to cities, and (iv) complete RAF application to case studies.

Seven participating cities have contributed to the RAF validation steps—namely, Almada (Portugal), Coimbra (Portugal), Lisbon (Portugal), Porto (Portugal), Barcelona (Spain), Bristol (the United Kingdom), and Vancouver (Canada). The participating cities present different challenges regarding urban resilience and NBS. The participation of cities allows to validate the RAF taking into consideration different international and urban context, city dimension and management, NBS management (e.g., private, public), social involvement, and awareness, among other factors. Stakeholders from water utilities, municipal council and private organisation participated in the working sessions. A total of eight organizations validated the RAF.

#### *2.5. Step 4: Definition of Reference Values for Each Metric*

Reference values for each metric were defined to assess the NBS contribution to urban resilience on a normalized scale. The definition of reference values was based on existing literature review, regulations, standards and available assessment frameworks. An overall assessment will be proposed to measure the NBS contribution to urban resilience.

Reference values allow metric´s classifications by means of a judgment (e.g., satisfactory or unsatisfactory performance). Comparing the results of a metric with its reference values allow to pinpoint the existing problems and to monitor the implemented solutions.


**4. First neuroprotective pharmacological and non-pharmacological treatments**

In the search to find new alternatives of neuroprotective agents, a great variety of molecules have been explored that affect one or several strategic points of the pathophysiology, and that promise good results; some are mentioned below.

During the onset of AIS, glucose and oxygen concentrations decrease, and this promotes the activation of adenosine monophosphate-activated protein kinase (AMPK). This process upregulates cellular pathways that control energy metabolism through catabolic pathways such as glycolysis and lipid oxidation to increase adenosine triphosphate (ATP) production and decrease its consumption through the inhibition of gluconeogenesis. Observations have been made regarding the fact that the activation of this enzyme for short periods increases neural survival, but its activation for extended periods will lead to cell death through apoptosis, necrosis, and autophagy [53], which is why several drugs that modulate AMPK activation have been tested recently in search for beneficial effects.

To mention some, metformin has been widely studied for cerebral ischemia since it possesses pleiotropic activity and modulates AMPK activation [54]. In 2016, Zhang et al. administered 7 mg/kg of metformin intraperitoneally to C57BL/6 mice for 7 days, before middle cerebral artery occlusion (MCAO). After MCAO, the authors observed that it induced neuroprotection by reducing infarct size, through lower AMPK, results that were not observed if administered for short periods of 1–3 days before MCAO, or after the occlusion; also, these benefits were not found in the case of reperfusion [55]. Also, the neuroprotective effect of metformin was observed in a global ischemia model in rats; after administration, apoptosis decreased, and mitochondrial biogenesis was induced [56]. Other experiments have demonstrated that metformin has the potential to improve memory and learning through the increase in brain-derived neurotrophic factor (BDNF) and p7056k protein [57]. On the other hand, it has also been implicated in the reduction of IL-6, IL-1β, TNF-α, and adhesion molecule levels, as well as a decrease in neutrophil infiltration [58]. Considering these results, it is crucial to clarify how this modulation is carried out since there is some controversy about the mechanism (**Table 1**).

**Drug Mechanism Observed effect Authors**

*Available Therapeutics after a Stroke: Current and Promising Options*

Infarct size Neurological deficit

Infarct size Neurological deficit

Memory Learning

barrier

Protection of blood-brain

Neurological deficit

CA1 neurons of the

Edema

hippocampus

Infarct size Neural survival

Infarct size Edema

Infarct size Neurological deficit

Neurological deficit

barrier

Neurogenesis Infarct size

Protection of blood-brain

Deng et al. [55]

Ashabi et al. [56]

Liu et al. [58]

Cheng et al. [60]

Shao et al. [61]

Xu et al. [68]

Chang et al. [70]

Cai et al. [71]

Belayev et al. [72]

Neural survival Bazzigaluppi et al. [69]

Ghadernezhad et al. [57]

Metformin AMPK

Apoptosis

*DOI: http://dx.doi.org/10.5772/intechopen.91282*

AMPK Apoptosis

AMPK BDNF P70S6K

AMPK NFkβ IL-6 IL-1β TNF-α ICAM Neutrophils

pJNK3 Caspase 3

AMPK pAKT

ROS Astrogliosis

TNF-α IL-6 IL-1β

Macrophages Neutrophils T lymphocytes B lymphocytes Infiltration Polarization of macrophages to M2

Microglia Leukocyte infiltration

DHA Macrophages

Ketosis HIF-α

**285**

Atorvastatin Aquaporin AQP4 Infarct size

Atorvastatin is a statin that has pleiotropic effects, since it allows angiogenesis and synaptogenesis, increases blood flow, blunts atherosclerotic plaque formation, and provides neuroprotection in cerebral ischemia model [59] by reducing aquaporin 4 expression (AQP4) [60], thus, preventing cerebral edema and the increase of infarct size. This statin has also been reported to attenuate cognitive deficit [61] through caspase 3 inhibition and avoiding neural death in the CA1 region of the hippocampus.

There is also a great variety of neuroprotective drugs or molecules that act closer by modulating inflammation, through the promotion of an anti-inflammatory microglial phenotype activation; only the most representative will be mentioned below.

DRα1 recombinant protein linked to the MOG peptide has demonstrated the ability to decrease macrophage migration and monocyte activation through its binding to CD74, which translates to a reduction in infarct size [62]. It has also been shown that it reduces proinflammatory cytokine expression, such as IL-1β, I-17, TNF-α, and INF-ϒ, as well as lowers T lymphocyte infiltration and promotes a polarization toward an M2 phenotype macrophage activation [63].

Cop-1 or glatiramer acetate is a copolymer formed by four amino acids (L-alanine, L-lysine, L-glutamic, and L-tyrosine) that has shown to exert neuroprotective effects by being able to reduce infarct size and improve neurological deficit [64]. Cop-1 increases the expression of IL-10, BDNF, Insulin-like growth factor-1 (IGF-1), and neurotrophin (NT-3) in the choroid plexus [65], and the cortex, which stimulates greater neurogenesis [66]. Mangin et al. and their study group obtained similar results; they reported that Cop-1 is capable of reducing COX-2, CD32, TNF-α, and IL-1β, as well as inducing greater neurogenesis and thus, reducing memory loss in mice with cerebral ischemia [67].

On the other hand, food strategies have also been proposed; for example, dietinduced ketosis has demonstrated its neuroprotective effects. Xu et al. observed, in 2017, that the ketogenic diet induced a reduction in infarct size through the overexpression of transcription factors HIF-1α, pAKT, and AMPK [68]; in 2018 Stefanovic, beneficial effects of administering exogenous β-hydroxybutyrate intraperitoneally were also observed in a model of cerebral ischemia induced by endothelin-1 in rats. He reported that the ischemic penumbra cells had a diminished glucose uptake, which translated into less ROS production, astrogliosis, and neuronal death [69]. Ketone bodies or ketosis is worth further exploration since clinical

*Available Therapeutics after a Stroke: Current and Promising Options DOI: http://dx.doi.org/10.5772/intechopen.91282*

To mention some, metformin has been widely studied for cerebral ischemia since it possesses pleiotropic activity and modulates AMPK activation [54]. In 2016, Zhang et al. administered 7 mg/kg of metformin intraperitoneally to C57BL/6 mice for 7 days, before middle cerebral artery occlusion (MCAO). After MCAO, the authors observed that it induced neuroprotection by reducing infarct size, through lower AMPK, results that were not observed if administered for short periods of 1–3 days before MCAO, or after the occlusion; also, these benefits were not found in the case of reperfusion [55]. Also, the neuroprotective effect of metformin was observed in a global ischemia model in rats; after administration, apoptosis

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

decreased, and mitochondrial biogenesis was induced [56]. Other experiments have demonstrated that metformin has the potential to improve memory and learning through the increase in brain-derived neurotrophic factor (BDNF) and p7056k protein [57]. On the other hand, it has also been implicated in the reduction of IL-6, IL-1β, TNF-α, and adhesion molecule levels, as well as a decrease in neutrophil infiltration [58]. Considering these results, it is crucial to clarify how this modulation is carried out since there is some controversy about the mechanism (**Table 1**). Atorvastatin is a statin that has pleiotropic effects, since it allows angiogenesis and synaptogenesis, increases blood flow, blunts atherosclerotic plaque formation,

and provides neuroprotection in cerebral ischemia model [59] by reducing aquaporin 4 expression (AQP4) [60], thus, preventing cerebral edema and the increase of infarct size. This statin has also been reported to attenuate cognitive deficit [61] through caspase 3 inhibition and avoiding neural death in the CA1

There is also a great variety of neuroprotective drugs or molecules that act closer

DRα1 recombinant protein linked to the MOG peptide has demonstrated the ability to decrease macrophage migration and monocyte activation through its binding to CD74, which translates to a reduction in infarct size [62]. It has also been shown that it reduces proinflammatory cytokine expression, such as IL-1β, I-17, TNF-α, and INF-ϒ, as well as lowers T lymphocyte infiltration and promotes a

by modulating inflammation, through the promotion of an anti-inflammatory microglial phenotype activation; only the most representative will be mentioned

Cop-1 or glatiramer acetate is a copolymer formed by four amino acids (L-alanine, L-lysine, L-glutamic, and L-tyrosine) that has shown to exert

neuroprotective effects by being able to reduce infarct size and improve neurological deficit [64]. Cop-1 increases the expression of IL-10, BDNF, Insulin-like growth factor-1 (IGF-1), and neurotrophin (NT-3) in the choroid plexus [65], and the cortex, which stimulates greater neurogenesis [66]. Mangin et al. and their study group obtained similar results; they reported that Cop-1 is capable of reducing COX-2, CD32, TNF-α, and IL-1β, as well as inducing greater neurogenesis and thus,

On the other hand, food strategies have also been proposed; for example, dietinduced ketosis has demonstrated its neuroprotective effects. Xu et al. observed, in

endothelin-1 in rats. He reported that the ischemic penumbra cells had a diminished glucose uptake, which translated into less ROS production, astrogliosis, and neuronal death [69]. Ketone bodies or ketosis is worth further exploration since clinical

2017, that the ketogenic diet induced a reduction in infarct size through the overexpression of transcription factors HIF-1α, pAKT, and AMPK [68]; in 2018 Stefanovic, beneficial effects of administering exogenous β-hydroxybutyrate intra-

peritoneally were also observed in a model of cerebral ischemia induced by

polarization toward an M2 phenotype macrophage activation [63].

reducing memory loss in mice with cerebral ischemia [67].

region of the hippocampus.

below.

**284**

Neurotrophins are a group of proteins that are involved in the maintenance and survival of the central nervous system [75]; this includes BDNF, NT-3, NT-4, NT-5, nerve growth factor (NGF), and IGF-1. Neurotrophins interact with two types of receptors, Trk (tyrosine kinase receptors) and the p75 receptor that belongs to the

Among the most studied neurotrophins are BDNF and NT-3; BDNF is produced by almost all brain cells and is known to participate in processes of proliferation, survival, and neuronal differentiation. Its receptors are widely distributed [76] and activate critical signaling pathways such as PLCγ, PI3K, and ERK, which ultimately lead to phosphorylation and activation of the transcription factor CREB that mediates the expression of genes that are essential for the survival and differentiation of neurons [77]. NT-3 has also been involved in the processes of cell proliferation and differentiation through the notch pathway [78], as well as participating in processes

Experiments have shown that the increase of neurotrophic factors in the ischemia model is commonly related to a better functional or memory recovery and that it is usually associated with neurogenesis or neuroplasticity—as in the case of metformin, which showed an increase in BDNF expression and that induced a more significant recovery of memory and learning [57]. Also, Cop-1 was able to induce the increase of BDNF, IGF-1, and NT-3; which correlated with the increase in neurogenesis [65]; and the experiments of Luan et al. showed that patients with cerebral ischemia who presented higher levels of NGF obtained a better functional

Stem cell transplantation has also been linked to better neurological recovery; although clinical trials have not reported the expected results [80], basic research using stem cells has shown an increase in neurological rehabilitation and suggested mechanisms include the overexpression of BDNF and IGF-1 [81, 82], as well as immunomodulatory cytokines like IL-10, which together induce a polarization

In recent years, there has been an increase in the interest of studying how the external environment has a direct effect on the structure and neuronal function, that is, on neuroplasticity [84], and that is why researchers keep studying what kind of external characteristics (specifically physical and social activity) can increase

In 2017, Chen et al. explored whether a specific type of environment stimulated the production of BDNF in rats with cerebral ischemia, and what they observed was that physical stimulation increases the expression of neurotrophic factors more than social stimulation and obtains a higher neurological recovery [85]. Mang, on the other hand, observed that the increase in BDNF after an ischemic event is determined by the type of aerobic exercise and the val66met variant of the BDNF gene [86].

The effects on NT-3 have also been evaluated, and the results have been very similar; there is an increase in its levels with physical stimulation after the ischemic event and a more significant functional recovery [87]. Other proteins have also been associated with neuronal plasticity through axonal growth, such as the growthassociated protein 43 (GAP-43), which has been observed to increase when rats

Electrical stimulation directly into the fastigial nucleus (FNS) has proven to be beneficial in a model of MCAO [89]. The mechanism through which FNS has shown to improve walking balance and neurological scores is due to the activation of the PKA/cAMP pathway, suppressing the expression of Rho-Kinase, and through the

In this sense, experiments continue to be designed to establish the efficacy of

TNFR receptor family, implicated in apoptosis processes.

*Available Therapeutics after a Stroke: Current and Promising Options*

*DOI: http://dx.doi.org/10.5772/intechopen.91282*

of memory and learning [76].

recovery at 3 months after the ischemia [79].

toward an anti-inflammatory M2 microglial phenotype [83].

these factors and thereby obtain more significant benefits.

with cerebral ischemia undergo fastigial electrostimulation [88].

training types and times to modulate inflammation, the production of

overexpression of GAP-43 protein [89].

**287**

#### **Table 1.**

*Main neuroprotective agents in ischemia.*

trials in Alzheimer's patients with mild cognitive decline have shown improvements in verbal memory after being treated with a ketogenic diet [73].

Dietary administration with docosahexaenoic acid (DHA) has also proven to have anti-inflammatory and neuroprotective effects in cerebral ischemia through the reduction of proinflammatory cytokine expression, such as TNF-α, IL-1β and IL-6; even, a decrease in macrophage and microglial activation and a decrease in leukocyte infiltration to the lesion site [70]. Similar observations were made by Cai et al. who noted that macrophage, neutrophil, and T and B lymphocyte infiltration was significantly decreased, besides stimulating an anti-inflammatory macrophage (M2) activation [71]; DHA is also capable of inducing neurogenesis and angiogenesis [72], which makes it a promising molecule for future experimental research.

## **5. Neurorestoration**

Many of the cytokines and growth factors that result from immunomodulation processes are directly involved in neurorestoration processes, the latter understood as the set of strategies that seek to reconstruct the affected neural circuits through neuroplasticity or neurogenesis [74].

#### *Available Therapeutics after a Stroke: Current and Promising Options DOI: http://dx.doi.org/10.5772/intechopen.91282*

Neurotrophins are a group of proteins that are involved in the maintenance and survival of the central nervous system [75]; this includes BDNF, NT-3, NT-4, NT-5, nerve growth factor (NGF), and IGF-1. Neurotrophins interact with two types of receptors, Trk (tyrosine kinase receptors) and the p75 receptor that belongs to the TNFR receptor family, implicated in apoptosis processes.

Among the most studied neurotrophins are BDNF and NT-3; BDNF is produced by almost all brain cells and is known to participate in processes of proliferation, survival, and neuronal differentiation. Its receptors are widely distributed [76] and activate critical signaling pathways such as PLCγ, PI3K, and ERK, which ultimately lead to phosphorylation and activation of the transcription factor CREB that mediates the expression of genes that are essential for the survival and differentiation of neurons [77]. NT-3 has also been involved in the processes of cell proliferation and differentiation through the notch pathway [78], as well as participating in processes of memory and learning [76].

Experiments have shown that the increase of neurotrophic factors in the ischemia model is commonly related to a better functional or memory recovery and that it is usually associated with neurogenesis or neuroplasticity—as in the case of metformin, which showed an increase in BDNF expression and that induced a more significant recovery of memory and learning [57]. Also, Cop-1 was able to induce the increase of BDNF, IGF-1, and NT-3; which correlated with the increase in neurogenesis [65]; and the experiments of Luan et al. showed that patients with cerebral ischemia who presented higher levels of NGF obtained a better functional recovery at 3 months after the ischemia [79].

Stem cell transplantation has also been linked to better neurological recovery; although clinical trials have not reported the expected results [80], basic research using stem cells has shown an increase in neurological rehabilitation and suggested mechanisms include the overexpression of BDNF and IGF-1 [81, 82], as well as immunomodulatory cytokines like IL-10, which together induce a polarization toward an anti-inflammatory M2 microglial phenotype [83].

In recent years, there has been an increase in the interest of studying how the external environment has a direct effect on the structure and neuronal function, that is, on neuroplasticity [84], and that is why researchers keep studying what kind of external characteristics (specifically physical and social activity) can increase these factors and thereby obtain more significant benefits.

In 2017, Chen et al. explored whether a specific type of environment stimulated the production of BDNF in rats with cerebral ischemia, and what they observed was that physical stimulation increases the expression of neurotrophic factors more than social stimulation and obtains a higher neurological recovery [85]. Mang, on the other hand, observed that the increase in BDNF after an ischemic event is determined by the type of aerobic exercise and the val66met variant of the BDNF gene [86].

The effects on NT-3 have also been evaluated, and the results have been very similar; there is an increase in its levels with physical stimulation after the ischemic event and a more significant functional recovery [87]. Other proteins have also been associated with neuronal plasticity through axonal growth, such as the growthassociated protein 43 (GAP-43), which has been observed to increase when rats with cerebral ischemia undergo fastigial electrostimulation [88].

Electrical stimulation directly into the fastigial nucleus (FNS) has proven to be beneficial in a model of MCAO [89]. The mechanism through which FNS has shown to improve walking balance and neurological scores is due to the activation of the PKA/cAMP pathway, suppressing the expression of Rho-Kinase, and through the overexpression of GAP-43 protein [89].

In this sense, experiments continue to be designed to establish the efficacy of training types and times to modulate inflammation, the production of

trials in Alzheimer's patients with mild cognitive decline have shown improvements

Dietary administration with docosahexaenoic acid (DHA) has also proven to have anti-inflammatory and neuroprotective effects in cerebral ischemia through the reduction of proinflammatory cytokine expression, such as TNF-α, IL-1β and IL-6; even, a decrease in macrophage and microglial activation and a decrease in leukocyte infiltration to the lesion site [70]. Similar observations were made by Cai et al. who noted that macrophage, neutrophil, and T and B lymphocyte infiltration was significantly decreased, besides stimulating an anti-inflammatory macrophage (M2) activation [71]; DHA is also capable of inducing neurogenesis and angiogenesis [72], which makes it a promising molecule for future experimental research.

Many of the cytokines and growth factors that result from immunomodulation processes are directly involved in neurorestoration processes, the latter understood as the set of strategies that seek to reconstruct the affected neural circuits through

in verbal memory after being treated with a ketogenic diet [73].

**Drug Mechanism Observed effect Authors**

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

Infarct size Motor functions

Neurological deficit

Infarct size Neurological deficit

Edema Memory

Infarct size Benedek et al. [62]

Neurological deficit Cruz et al. [65].

Neurological deficit Cruz et al. [66]

Wang et al. [63]

Ibarra et al. [64]

Mangin et al. [67]

Macrophages migration Monocytes

Cop-1 Immunomodulation Infarct size

TNF-α IL-17 IL-1β INF-ϒ T lymphocytes Infiltration

IL-10 BDNF IGF-1 NT-3

Neurogenesis NT-3

COX2 Cd32 TNF-α IL-1β

*, regulation ; , activation.*

*Main neuroprotective agents in ischemia.*

**Table 1.**

DRα-1MOG35-55

**5. Neurorestoration**

**286**

neuroplasticity or neurogenesis [74].

neurotrophins, and the impact on patient mobility, as in the proposal developed by Scalzo et al. [89] that gives rise to the continued development of a well-founded physical therapy for patients with cerebral ischemia.

Functional electrical therapy has been used alongside other types of electrical stimulation to induce repetitive muscular contraction to mobilize certain joints [6]. Somatosensory stimulation might enhance neurorehabilitation after stroke through the stimulation of corticomotoneuronal excitability [6]. It has been proposed that this type of therapy increases muscle strength, reduces spasticity, and facilitates

Guided self-rehabilitation (GSR) is a method in which the intensity of training can be increased inside the home environment. While combined with conventional rehabilitation, it has proven to be efficacious in engaging the patients in their recovery through a contract between the patient and the therapist, allowing for an increased sense of responsibility and motivation for the patients, who are required to register their progress in a diary [100]. Although not many physical therapists accept such an approach [100], positive changes have been observed after 1 year of GSR and conventional rehabilitation in ultrasound measuring of the soleus' and medial gastrocnemius' thickness and fascicle length, as well as clinical improvement, observed in soleus extensibility and ambulation speed [101] in chronic stroke patients.

Constraint-induced therapy requires constraining the non-affected limb for 90%

Videogame- or virtual reality-based (VRb) therapies have been under study for

In addition to continuing the search for pharmacological agents that allow the neuroprotection and neurorestoration of tissue affected by cerebral ischemia, the development of physical therapy and diet modification offers new horizons that have shown satisfactory results in the clinical setting in short times. However, it has not yet been possible to establish a protocolized treatment that can be added to the health care guidelines; so it is important to continue exploring all possible strategies to improve the quality of life of people who have suffered a cerebral infarction and

of the waking hours, forcing the patient to use the paretic limb, inducing the increase of use-dependent plasticity, although this therapy is not practical for most

upper extremity functional recovery in acute and subacute or chronic patients [91, 96, 99, 102]; the rationale for such approaches is that they promote motor learning and repetitive, intense movements, and in the specific case of virtual reality, the patient is exposed to interactive visual, auditive, and proprioceptive feedback [91, 102]. Different videogame and VRb therapies have reported improvements in fine dexterity, grip strength [96], and grasp force [99] in upper extremities, and, activities of daily living [91] and cognition [102] in young and elderly patients after several weeks of rehabilitation. Better results have been observed when combined with conventional therapy, although it is still not known

voluntary movements, among other motor benefits [6].

*Available Therapeutics after a Stroke: Current and Promising Options*

*DOI: http://dx.doi.org/10.5772/intechopen.91282*

whether it enhances or speeds up recovery [91].

**7. Final remarks and future directions**

of the population [6].

that of their caregivers.

**289**