Stability constant values obtained for Ni, Mg and Co complexes having different metal to ligand ratio.
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The stability of metal complex generally means that it exists under favorable conditions without undergoing decomposition and has a considerable shelf life period [1]. The term stability of metal complex cannot be generalized since the complex may be stable to one reagent/condition and may decompose in presence of another reagent/condition. The stability of metal complexes can be explained with the help of two different aspects, namely, thermodynamic stability and kinetic stability [2]. Nevertheless, a metal complex is said to be stable if it does not react with water, which would lead to a decrease in the free energy of the system, i.e., thermodynamic stability. On the other hand, the complex is said to possess kinetic stability if it reacts with water to form a stable product and there is a known mechanism through which the reaction can proceed. For example, the system may not have sufficient energy available to break a strong bond, although once the existing bond is broken it could be replaced by new bond which is stronger than the older one [1]. Stability of complex compound is assigned to be its existence in aqueous solution with respect to its bond dissociation energy, Gibbs free energy, standard electrode potential, pH of the solution, and rate constant or activation energy for substitution reactions.
Thermodynamic stability of a complex refers to its tendency to exist under equilibrium conditions. It determines the extent to which the complex will be formed or be converted into another complex at the point of equilibrium. In other words, thermodynamic stability of complexes is the measure of tendency of a metal ion to selectively form a specific metal complex and is directly related to the metal-ligand bond energies. The thermodynamic stability of complexes is represented by formation constant. The formation constant is also known as stability constant, which is the equilibrium constant obtained for the formation metal complex [1, 2].
In general, the metal complexes are not prepared from their corresponding starting materials in gaseous phase but are prepared in aqueous solution. In aqueous solution, a metal cation gets hydrated to give aqua complex of the type [M(H2O)x]n+. When a ligand replaces water molecule from aqua complex ion, a new metal complex is formed and equilibrium is established as shown:
where x is the number of water molecules, n is the oxidation number of the metal cation, and L is the neutral and monodentate ligand. For simplicity, the above reaction can be written in generalized form as given:
The equilibrium constant K
In the above equation, the concentration of water is not included. Since the solution is dilute, the water molecules which enter the bulk solution do not have much influence on the equilibrium constant. It is observed from Eq. (3) that the higher the value of K
The steady decrease in the value of stepwise formation constants from K1 to Kn is due to:
Increase in the number of ligands in coordination sphere that causes to decrease the number of H2O molecules to be replaced and thus the probability of replacement of water molecules decreased
Electrostatic factor
Steric hindrance with increase in number of ligands
Statistical factors (number of replaceable positions)
However, in some cases, it is found that Kn+1 > Kn because of unusual structural changes and changes in electronic configuration of the metal ion. The change in electronic structure of the metal ion causes the variation in the crystal field stabilization energy (CFSE). The complex with higher CFSE value will be stable, and the equilibrium constant for that complex formation will be high. One such example is the formation of [CdBr4]2− complex in aqueous solution. The reaction of aqua complex [Cd(H2O)6]2+ with Br− ligand exhibits four stepwise equilibrium or stepwise formation constants K1, K2, K3, and K4. The order of stepwise formation constants is observed as follows, K1 > K2 > K3 < K4, which is not in agreement with the common trend of K1 > K2 > K3 > K4. Aqua complex of most of the M2+ ions including Cd2+ are octahedral, whereas the halo complexes of Cd2+ ion are tetrahedral. The reaction sequence for the formation of [CdBr4]2− is given as follows:
In the final step, there is an unusual structural change from six coordinated octahedral [Cd(H2O)3Br3]− complex to four coordinated tetrahedral [CdBr4]2− complex in addition to change in the electronic configuration which lead to K4 > K3.
The formation constant (K
Since ∆G° is a thermodynamic property, the formation constant is the measure of thermodynamic stability. From Eqs. (4) to (6), it can be interpreted that the thermodynamic stability of a complex can be measured in terms of formation constant, Gibbs free energy change, and standard electrode potential. A high negative value of ∆G° indicates that the position of equilibrium favors the product (complex); hence the complex formed will be more stable.
The formation constant describes the formation of a complex from metal cation and ligands. Bjerrum (1941) defined that the formation of a metal complex in aqueous solution takes place by replacing the water molecule by another ligand (L) [5, 6]. It is assumed that this reaction does not occur in a single step but occurs in several steps, and each step is characterized by its individual equilibrium constant called as stepwise formation constant (K). For example, consider the formation of a complex [MLn] formed by the following reactions:
By assuming the value of activity coefficients as unity, the equilibrium constant K1 for the complex (ML) having one ligand (L) will be given as
When the metal complex ML reacts with one more ligand L,
and the equilibrium constant K2 will be
Similarly, for the formation of the complex MLn from MLn−1 and L, the equilibrium constant is represented as follows,
The equilibrium constants K1, K2, …, Kn are known as stepwise formation constants. On the other hand, the equilibrium constant for the overall reaction may be considered as
where β1, β2, β3, …, βn are the equilibrium constants called as overall formation constants and K1, K2, K3, …, Kn are stepwise stability or formation constants. The products of stepwise constants are Ks and βs are related one another. For example, consider the product of stepwise formation constants K1, K2, K3, …, Kn.
Above equation indicates that the overall formation constant (β) is equal to the product of the stepwise formation constant K1, K2, K3, …, Kn.
Kinetic stability is related to the reactivity of the metal complexes in solution and deals with the rate of the reaction, its activation energy, etc. Kinetic stability is also related to how fast a compound reacts rather than how stable it is. It aids in determining the rate at which the reaction occurs to establish the equilibrium [7].
The term kinetic stability of complexes is classified into labile and inert by Taube on the basis of rate of the reactions. When the rate of substitution of ligands is high, the complex is said to be labile. For example, the copper complex of the formula [Cu(NH3)4(H2O)2]2+ is labile. In aqueous solution the complex is blue in color, and when concentrated hydrochloric acid is added to this solution, the solution turns green giving rise to complex [CuCl4]2+. On the other hand, in inert complexes the rate of ligand exchange is very slow, and the ligands are very exchanged with difficulty. For example, the cobalt complex [Co(NH3)6]3+ reacts slowly, and no reaction takes place at room temperature when conc. HCl was added to the aqueous solution. However, only one NH3 ligand was found to be substituted by Cl ligand, when the aqueous solution of the complex was heated with 6M hydrochloric acid.
For metal complexes, the stability and reactivity are described in thermodynamic and kinetic terms, respectively. In particular, the terms stable and unstable are related to thermodynamic aspects, whereas labile and inert terms are related to kinetic aspects. As a rule of thumb, a metal complex is said to be labile if it reacts within 1 min at 25°C, and if it takes longer time, it is considered to be inert.
Thermodynamic stability refers to the energy change that occurs while starting materials are converted to products, that is, ∆G, for the reaction. The change in free energy is given by the equation ∆G = ∆H−T∆S = −RTlnK, where ∆S is the entropy, ∆H is the enthalpy, and K is the equilibrium constant for the reaction. Kinetic stability refers to reactivity or the ability of the metal complex to undergo ligand substitution reactions. Complexes which undergo extremely rapid ligand substitution reaction are referred to as labile complexes, and complexes that undergo extremely slow ligand substitution reaction are referred to as inert complexes. Sometimes the thermodynamic and kinetic stabilities of complexes are parallel to one another, but often they do not. One of the suitable examples for thermodynamically stable and kinetically inert complex is [Ni(CN)4]2− as it undergoes ligand substitution reaction very rapidly. On the other hand, the cobalt complex [Co(NH3)6]3+ is thermodynamically unstable but kinetically inert. The complex [Co(NH3)6]3+ is thermodynamically unstable since the complex was observed to decompose very rapidly with rate in the order of 1025 in acidic solution. However, no ligand substitution reaction is found when the complex is kept in acidic solution for several days; hence the complex is kinetically inert. From the above two examples, it can be interpreted that the stability of a complex mainly depends upon the conditions, and it is always recommended to specify the conditions such as pH, temperature, etc. while mentioning the stability of the complex. In brief, it is not necessary for a stable complex to be inert and an unstable complex to be labile.
Consider the three complexes [Ni(CN)4]2−, [Mn(CN)6]3−, and [Cr(CN)6]3−. All the complexes are thermodynamically stable, but kinetically they behave in a different manner. The rate of exchange can be measured when carbon-14-labelled cyanide ions are reacted with metal complexes in solution. It indicates that [Ni(CN)4]2− is labile, [Mn(CN)6]3− is less labile, and [Cr(CN)6]3− is inert and proves that not all stable complexes are inert and vice versa.
There are several factors that can affect the stability of the metal complexes [2, 5, 8, 9], which include:
Nature of the central metal ion
Nature of the ligand
Chelating effect
Macrocyclic effect
Resonance effect
Steric effect or steric hindrance
In metal cations, higher oxidation state forms more stable complex than lower oxidation states with ligands such as NH3, H2O, etc. Even few exceptions are there like CO, PMe3, o-phenanthroline, bipyridyl, CN−, which form more stable complex with lower oxidation state metals.
The stability of metal complex increases with decrease in size of the metal cations. For M2+ ions, the general trend in stability for complexes is
This trend in stability is known as Irving-Williams series.
This order of stability is also in good agreement with the charge to radius ratio concept because the radii decrease from Ba2+ to Cu2+ and then increased to Zn2+. The order of size of dipositive ions is
Basic character of ligands: The greater is the basic character of ligand, the more easily it can donate its lone pair of electrons to the central metal ion and hence greater is the complex stability. In 3D-series metal ion, order of stability of complex with NH3, H2O, and F− is:
The nature of metal-ligand bond also affects the stability of metal complexes. The higher the covalent character, the greater will be the complex stability. For example, the stabilities of silver complexes have different halide ligands which are in the following order:
Ligands having vacant p- or d-orbital tend to form π bond and hence form stable complexes with metals. Ligands that are capable of forming such π bond are CO, CN−, alkene, phenanthroline, etc.
The chelate effect is that the complexes resulting from coordination of metal ions with the chelating ligand are thermodynamically much more stable than the complexes with non-chelating ligands [10, 11]. Chelating ligands are molecules which can bind to single metal ion through several bonds and are also called as multidentate ligands. Simple (and common) examples include ethylenediamine and oxalate. Non-chelating ligands are ligands that bond to just one site, such as chloride, cyanide, and water.
The chelate effect can be understood by comparing the reaction of a metal ion, respectively, with a chelating ligand and with a monodentate ligand having similar/comparable donating groups. During the comparison study, the number of coordination should be maintained equal in both the cases, for example, the value obtained while adding a bidentate ligand is compared with the value obtained for two monodentate ligands. For example, coordination of metal ion with chelating ligand 2,2′-bipyridine can be compared with that of monodentate pyridine ligand. Another such comparison can be made between coordination behavior of chelating 1,2-diaminoethane (ethylenediamine = en) and monodentate ammonia. Such comparison studies revealed that the metal complex formed from chelating ligands are thermodynamically more stable than the complex formed from monodentate ligand. For example, formation of complexes from hydrated cadmium ion, [Cd(H2O)4]2+ with methylamine (CH3NH2), ethylenediamine (en) and triethylenetetramine (trien), and their stability is in the following order:
A macrocyclic ligand is a cyclic molecule that contains nine or more atoms in the cyclic structure and has three or more potential donor atoms which can coordinate to the metal ion. It has been observed that the stability of metal complexes in the presence of macrocyclic ligand of appropriate size is higher than the stability of complexes coordinated to open-ended multidentate chelating ligands. Some notable examples of macrocyclic ligands include cyclic crown polyether, heme, etc. [12].
Resonance increases the stability of the complexes. For example, acetylacetonate anion ligand shows resonance, and as a result it forms stable complexes upon reacting with metal ion (Figure 1). The ligand-metal π bonding increases the delocalization of electrons compared to free enolate as shown below and leads to increased stability (Figure 2).
Resonance structure of acetonylacetonate ligand.
Acetonylacetonate-metal complex.
The presence of bulky substituents in the ligands can affect the stability of the metal complex, and this type of destabilization of metal complex due to bulkiness of the substituent is called as steric effect [13]. For example, consider the ligand 8-hydroxy quinoline and its methyl substituted derivative 2-methyl-8-hydroxy quinolone. Both are bidentate ligands and form chelated complexes with Ni2+ ion as shown in Figure 3.
Chelating complexes of Ni(II) ion showing steric effect.
The complex (II) is less stable than complex (I) because of bulky group attached to an atom adjacent to donor atom which cause a steric hindrance and lower the stability of the complex.
The crystal field stabilization energy (CFSE) is one of the most important factors that decides the stability of the metal complexes. CFSE is the stability that arises when a metal ion coordinates to a set of ligands, which is due to the generation of a crystal field by the ligands. Thus, a higher value of CFSE means that the complex is thermodynamically stable and kinetically inert. Some of the notable examples of complexes that have high CFSE are low spin 5d6 complexes of Pt4+ and Ir3+ and square planar 5d8 complexes of Pt2+. All these complexes are thermodynamically stable and kinetically inert, which undergo ligand substitution reactions extremely slowly [3, 4].
The determination of metal complexes involves several methods including spectroscopic and potentiometric methods. The determination of stability constant is very significant to understand the role and behavior of ligand(s) in stabilizing the metal complexes and found applications in the fields of biology, environmental study, metallurgy, food chemistry, and many other industrial processes. Some of the methods that are used for the determination of stability constants are given as follows.
UV-Vis spectroscopic technique has been used to determine the stability constant and composition of a complex [14]. The formation of metal complex is indicated by the change in absorbance in the UV-Vis spectroscopy. The relationship between absorbance (A) and concentration is given by Beer’s law as shown.
where ԑ = molar extinction coefficient, l = path length of the absorption cell, c = concentration of the complex.
From the above equation, the concentration (c) of the metal complex can be calculated by measuring absorbance (A) using spectrophotometer and knowing the molar extinction coefficient (ԑ) at that wavelength (λ) and path length (l). For example, consider the formation constant (K
By knowing the values of [MLn+], [M], and [L], Kf can be calculated. [MLn+], [M], and [L] can be calculated as follows:
where CL and CM are the total concentrations of the ligand and metal ion, respectively.
From Beer’s law
On rearranging
On substituting Eq. (11) in (8), we get
Similarly, from Eqs. (9) and (11), we get
By introducing the values of [MLn+], [Mn+], and [L] from Eqs. (11) to (13) in the formation constant Eq. (7), we can determine the value of K
Job’s method of continuous variations (MCV) is used to determine the complex formation as well as stability constants [14, 15]. Job’s method is basically used to determine the composition of metal complexes, and this is the modified version of spectroscopic method. This method is applicable in the case of solutions, where the formation of one metal complex takes place.
This method includes the following steps:
Make a volume of 10 mL solutions of metal complex containing different proportions of metal ion as well as ligand. The number of solutions should be 10.
Sr. no. of solution: | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
Volume of metal ion (mL) | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
Volume of ligand (mL) | 9 | 8 | 7 | 6 | 5 | 4 | 3 | 2 | 1 | 0 |
Here the total concentration of the solution is constant, i.e., sum of concentration of the metal, CM, and the ligand, CL, is fixed. Therefore:
In the next step, optical densities of the solutions prepared in the previous step are to be determined spectrophotometrically at the wavelength of light which is strongly absorbed by metal complex but does not get absorbed by metal ion and ligand.
A plot between mole fraction (
On the extrapolation of the curve, the legs of the curve intersect each other at a point which is the point of maximum absorbance.
Suppose MLn is the formula of the complex, then
Determination of the composition of metal complex Job’s method of continuous variation.
Eq. (14) can be rewritten as:
From this equation, namely,
On reducing Eq. (16), we get.
By dividing (17) by (18), we get.
The composition of the complex, MLn, can be determined by the value of n as obtained from Eq. (19). There are some drawbacks of this method. One of the drawbacks is that this method is applicable where, under experimental conditions, only one complex is formed. Also, the total volume of the solutions which contain metal ion and ligand should not be changed. The method of continuous variations has also found tremendous application in the field of organometallic chemistry [16].
The type and extent of interaction existing between the metal ion and ligand can be investigated by various experimental methods [17, 18, 19, 20, 21], and each method requires different experimental conditions and resulted in differences in the interpretation of reaction mechanism and stability constants. Bjerrum’s method to determine the stability constant is also known as potentiometric method. This method is based on the competition between hydrogen ion and metal ion for ligand which is a weak base. Consider a metal ion and an acid such as nitric acid are added to a ligand in aqueous solution; the following equations are obtained:
When acid reacts with ligand
where Ka is acid association constant of the ligand
When metal ion reacts with ligand
where K
Let us consider CH, CM, and CL are the total concentrations of acid, metal ion, and ligand, respectively. Then
By solving above three equations and using the acid association constant Ka, we get
The concentration terms of [ML+], [M+], and [L] can be calculated potentiometrically by using a pH meter and by substituting the values of [ML+], [M+], and [L] in the formation constant (K
In the potentiometric or pH-metric determination of stability constant, a ligand and an acid such as nitric acid are titrated against standard NaOH during which period the pH of the solution has to be measured after each addition. Throughout the experimental studies, several conditions must be maintained such as
For electrical neutrality
The total concentration of the ligand is given as follows:
The protonation of the ligand can be represented as
The equilibrium constant Ka is given as
By combining Eqs. (21)–(23), we get
[OH−] and [H+] are negligible as compared to [Na+] at near neutral solution. Hence Eq. (24) becomes
The above equation is used to calculate the value of pKa of ligand.
When a ligand is titrated with a solution containing Mn+ ion and an equivalent amount of H+, the resulting solution will have an equilibrium mixture of H+, OH−, HL, L−, Mn+, M(n−1)+L, M(n−2)+L2, etc. By measuring the pH values with the help of pH meter and knowing the concentrations of Mn+, H+, HL, etc., one can calculate the stepwise stability constants K1, K2, K3, etc. During the evaluation of equilibrium constants, the concentrations of Mn+ and L− are varied, and such variations in the concentration will lead to changes in the ionic strength of the solutions. In order to maintain the constant ionic strength, a large excess of an ionic salt is added to the reaction mixture. The presence of large excess of ionic salt will compensate any changes in the ionic strength of the solution. The ionic salts that are added for such purpose should not react with M2+ or L−, and commonly used salts include KNO3 and NaClO4, due the low affinity of NO3− and ClO4− ions for most of the M2+ ions. For example, KNO3 was added in excess during the binding study of the ligand p-aminobenzoic acid with Ni, Mg, and Co metal ions. The p-aminobenzoic acid has two coordination sites such as amino and carboxylate groups and has a pKa value of 5.9153. The stability constant values obtained for Ni, Mg, and Co complexes are depicted in Table 1.
Metal | M:L ratio | |||
---|---|---|---|---|
1:1 | 1:2 | 1:5 | 2:3 | |
Ni | 8.492 | 14.8593 | 8.3598 | 3.4649 |
Mg | 8.4664 | 8.3392 | 7.0794 | 11.1943 |
Co | 8.590 | 5.3186 | 8.6337 | 6.2330 |
Stability constant values obtained for Ni, Mg and Co complexes having different metal to ligand ratio.
The stability constant values for Ni shows the trend 2:3 < 1:5 < 1:1 < 1:2, while the trend for Co is 1:2 < 2:3 < 1:1 < 1:5 and for Mg it is 1:5 < 1:2 < 1:1 < 2:3. The values obtained from the above study indicates that 1:2 complex of Ni complex is more stable, whereas Co complex is stable in 1:5 ratio and that of Mg is more stable in the ratio of 2:3.
The Irving and Rossotti method for the determination of stability constant is also based on the principle of potentiometric method [21]. Using this method, the formation curve of metal complex can directly be calculated with the help of pH meter. Another major advantage of this method over the Bjerrum’s method is that the calculation is simple and does not require hydrogen ion concentration. Moreover, this method can be used for types of ligands that are conjugate to weak acids. The calculation of stability constant using this method involves the following steps.
Step 1: The following solutions were titrated separately against base solution
Titration with free acid (A)
Titration with free acid + ligand (A + L)
Titration with free acid + ligand + metal (A + L + M)
Step 2: Calculation of formation functions n, nA, and PL using the values used/obtained from above three titrations
The term formation function “n,” also called as ligand number, is defined as the average number of ligands attached per metal center and is calculated using the following equation
The term nA is similar to n and is defined as the average number of protons bound to the ligand which are not coordinated to the metal center. PL gives the free ligand exponent. All the three terms n, nA, and PL can be calculated with the help of following equations
where N is the normality of base used; V0 is the initial volume of the solution; V1, V2, and V3 are the volume of base consumed during the (A), (A + L), and (A + L + M) titrations, respectively, at same pH value; T0L is the initial concentration of ligand; ℇ0 is the initial concentration of acid; γ is the number of titrable or replaceable protons.
Step 3: Determination of formation curves: by plotting formation function (n) against PL and nA against pH for a HL (protonated ligand) system.
The value formation constants corresponding to formation of protonated ligand are obtained by plotting nA against pH. Similarly, the stepwise stability constants for the formation of metal complexes are obtained from the formation curve resulted by plotting n against PL.
The thermodynamic and kinetic stability of coordination compounds along with the various factors affecting the stability of metal complexes have been discussed in this chapter. Stability constant and its determination have also been listed.
Authors acknowledge National Institute of Technology Kurukshetra, Haryana, India, for its support.
There is no conflict of interest.
Clinical benign prostate hyperplasia is an aging disease, with a high prevalence after 40 years of age, from 8 to 60% at 90 years. The interventional treatments include open adenoma removal, transurethral resection of the prostate, HOLMIUM, and THULIUMenucleation, laser vaporization, steam ablation, microwavethermotherapy, etcetera. Prostate cancer has a high incidence in men over 60 years and is considered the second cause of death. Early detection assisted by PSA (prostate-specific antigen), MR imaging, and in some centers PSMA PET SCAN, and targeted biopsies, let us offer less invasive techniques, compared with radical prostatectomy or external beam radiation, with a decrease of morbidity, achieving what has been called “TRIFECTA”: disease control, urinary continence and erectile function.
High intensity focused ultrasound, a relatively new technique, uses a sound beam directed to a specific spot inside the prostate parenchyma, causing thermal ablation with customized planning, including whole gland, the benign enlargement of localized lesions, defined as focal therapies. More than 50,000 treatments have been performed worldwide, with growing improvement in the outcomes, mainly caused by a good selection of cases and technical improvements of imaging and emission of sound beams. By 2010, Sonablate and Ablatherm devices were used widely in some countries of Latin America (Mexico, Brazil, Ecuador, and Argentina), Europe and Japan, in 2015 FDA cleared the usage of HIFU with both machines. Some countries still consider HIFU as experimental therapy [1, 2].
Sound has been for several centuries a subject of interest for the different branches of science, been the development of its understanding as a physical phenomenon and its use in the different fields of science and technology the main topics. The medical sciences have not been the exception in this search. Ultrasound, a technology derived from sound, has had a significant boom in medicine due to its implementation as a diagnostic or therapeutic instrument. It has been widely disseminated as a diagnostic instrument due to its various advantages ranging from cost–benefit to high sensitivity and specificity for diagnosing pathologies [3]. As a therapeutic option, ultrasound has been used for the development of technologies such as extracorporeal lithotripsy, HIFU, sonophoresis, sonodynamic therapy, sonothrombolysis or histotripsy, among others, which base their efficacy on the induction of sonic bio-effects, both thermal and non-thermal (cavitation, radiation, etcetera) to induce tissue changes [4, 5].
The difference between ultrasound as a diagnostic or therapeutic technology is based on inducing a certain amount of bioeffect at the tissue level [4]. Ultrasound as a diagnostic tool seeks to induce the least possible bioeffect [4, 6]. In contrast, ultrasound as a therapy seeks certain technologies to achieve tissue ablation through inducing thermal or non-thermal bioeffects, such as the HIFU [4, 5, 6].
HIFU had its first antecedents in 1942 when the first destruction of tissue was recorded through an extracorporeal ultrasound energy source [5]; later, in the 1990s, its technology was refined by integrating real-time imaging methods for monitoring the procedure [5]. The use of real-time imaging has improved the efficacy of this treatment, reducing morbidity and mortality at making the treatment more accurate [5, 7]. Its clinical implementation increased significantly after the clinical case report of a patient treating a malignant bone neoplasm in Chongqing, China, in 1997 [5]. During the following 15 years, the use of HIFU clinically reported more than 30,000 cases of kidney, pancreas, bone, liver, or uterine fibroids, showing its great utility as a minimally invasive technology [5, 8]. Currently, HIFU technology can be divided according to the radiological technique used to guide the procedure (Magnetic Resonance or Diagnostic Ultrasound) or according to the system used to deliver the energetic (transrectal for the treatment of prostate pathologies, interstitial for the treatment of biliary or esophageal tumors, extracorporeal for the treatment of organs accessible to sound through the skin) [5, 7, 9].
For this chapter, and to delve into HIFU therapy and its biophysical effects, it is necessary to understand some basic concepts of the physics of sound.
Once a pulse is generated, the energy will oscillate the particles closest to the origin of the pulse, and these particles will, in turn, oscillate with those immediately adjacent so that this energy will be transmitted from proximal to distal. Each pulse generates positive pressure and negative pressure in one wave, together are wave cycles [5, 7].
The HIFU as a therapeutic ultrasound system generates an intensity of approximately 1000–20,000 W/cm2, generating an elevation of between 60 and 100° C in 1 second in that unit area while using a frequency around 0.8−5 MegaHertz (each MegaHertz = 106 Hertz) (Figure 1) [4, 6, 8].
Sound properties. Schematic representation of sound properties. Created with
Multiple bio-effects have been described (thermal and non-thermal) related to the exposure of a sound field by a tissue. Different authors have classified these as thermal and non-thermal bio-effects [4, 5]. For its part, the HIFU system predominantly generates thermal bio-effects; however, these are not pure, since the presence of other non-thermal bio-effects such as cavitation has been described in the same tissue [4].
The main bio-effect caused by HIFU has been compared to the use of a magnifying glass to focus the sun’s rays on a point [6] because it generates a frequency of 0.8−5 MegaHertz with a wavelength of 2−0.3 mm, this is translated into a small area subjected to great ultrasonic power [6, 7]. As we previously mentioned, when this power crosses a specific point can be translated into intensity, being in the case of HIFU between 1000−20,000 watts/cm2 [5, 6]. It is considered that it is necessary to raise the temperature of the tissue to 56–60° C or more for about a second to produce an irreversible cytotoxic lesion with protein denaturation and heat-induced coagulative necrosis; using this concept of the irreversible lesion induced by heat, the result can be inferred from raising the temperature to around 60–100° C at a focal point as occurs with HIFU therapy (Figure 2) [4, 5, 6].
Temperature changes are produced at the focal point, and near the transducer. (Courtesy of HIFUMx).
In different in vivo studies, it has been observed that the main effect caused by HIFU as a thermal injury is the induction of coagulative necrosis through protein denaturation and induction of apoptosis via nuclear lysis by endonucleases [5]. Specific characteristics have been described that differentiate this coagulative necrosis derived from thermal injury from coagulative necrosis of ischemic origin. The difference is mainly due to the predominance in the interaction of giant cells with chronic inflammation, unlike the tissue regeneration process via granulation tissue seen in coagulative necrosis due to ischemia [5].
Associated with coagulative necrosis, the ability of HIFU to injure small-caliber vessels (<2 mm) has been described as an endothelial lesion, and thrombosis of these vessels with these characteristics has been found in various studies. However, the ability of larger vessels to dissipate temperature has been described, thus suffering minor injury (heat sink) (Figure 3) [5].
Thermal ablation. Schematic representation of thermal ablation mechanism and specificity.
The second most crucial mechanism described during the HIFU treatment is the non-thermal bio-effect of a mechanical type induced through cavitation [5, 9]. Cavitation can be defined as gas or vapor cavities forming within a liquid medium and their subsequent dynamics in this medium [5]. Cavitation formation can occur under different conditions (hydrodynamic, thermal, or acoustic energy changes); its importance lies in the possibility of generating a lesion adjacent to the formation of these cavities through micro-boiling, increased temperature, and shear stress [4, 5]. Cavitation, unlike temperature-induced injury, is more unstable in nature and less predictable (Figure 4) [5].
Mechanical destruction. Schematic representation of mechanical destruction mechanism and specificity.
Two types of cavitation have been described by their nature, stable (non-inertial) cavitation and transient (inertial) cavitation [4]. Transient cavitation involves a significant change in bubble size in a period of few acoustic cycles [4], resulting in a more aggressive collapse [4, 5]. In contrast, stable cavitation maintains a more stable range in terms of growth of its diameter without significant growth and remains stable during many acoustic cycles [4, 5].
The appearance of these cavities depends on the different properties of both the source of acoustic energy and the medium where this energy will be exerted. Generally, it is known that to a greater extent, the temperature and pressure exerted on the medium are essential determinants for the formation of cavities. The temperature is inversely proportional to the cavitation threshold (the possibility of a said event happening) [4, 5].
Its importance lies in the possibility of causing more significant tissue damage, currently a field of study for the development of therapies such as histotripsy, which base their efficacy on this principle (Figure 5).
Massive controlled cavitation formed in the posterior aspect of the prostate adenoma (Urovallarta Urology Center).
The first HIFU technology used for the treatment of prostate cancer to become available was Ablatherm® (Edap-Technomed, Lyon, France), with initial clinical results published in 1996 [10].
The Ablatherm system uses separate crystals to produce an image (7.5 MHz) and to deliver treatment (3 MHz), and since 2005, the two types of transducers have been integrated into the same probe, which has a focal point of 45 mm from the crystal. The 3 MHz treatment crystal creates an ablation zone with a volume that can range from 29 mm3 to 36 mm3. The Ablatherm has 3 different types of treatment algorithms, each designed for a specific application: HIFU as primary treatment, HIFU as secondary treatment after failed Radiation Therapy, and HIFU re-treatment [11].
The Ablatherm has a mechanism to detect patient movement based on an internal automatic A-mode ultrasound detection system, which together with the external ultrasound used during the treatment planning phase, measures the distance from the rectal wall, and ensures that the patient has not moved [12].
Treatment with the Ablatherm is performed with the patient in a lateral decubitus position, on their right side. This is done as a precautionary measure, since if there were any bubbles in the liquid around the transducer used for the treatment, these would rise out of the treatment field, with the patient on their side, and the bubbles would not remain between the transducer crystal and the prostate [13].
Focal One® (Edap-Technomed, Lyon, France) is the first HIFU device, specifically designed to perform focal therapy and was introduced for the focal treatment of prostate cancer. With this device, the procedure is performed on a conventional surgical table with the patient in a lateral position to avoid air bubbles in between the crystal and the rectal wall.
The transducer that uses focal one is a dynamic focus transducer, made with 16 isocentric rings, each ring is moved by a dedicated electronic system, composed of 16 lines, this allows the user to move the focal point of the transducer to a maximum of 8 different points that are between 32 and 67 mm from the transducer. The dynamic approach treatment involves unitary HIFU lesions, stacked in the prostate, within the axis of the ultrasound. Each lesion measures approximately 5 mm and by stacking 2 to 8 lesions it is possible to extend the necrotic area by 5 to 40 mm [14].
Focus Surgery (Indianapolis, IN, USA) introduced the Sonablate500® system and preliminary results of its use for the treatment of prostate cancer were published in 2002 [15]. The Sonablate uses a single crystal to obtain the images and to deliver HIFU treatment, to achieve this, the Sonablate uses a transducer that has two crystals placed back-to-back.
At frequencies of 6/4 MHz, it can provide good image quality and effective treatment, respectively. The 6 MHz frequency probe provides good resolution of the anterior prostate but has a lower resolution of the posterior prostate margin and rectal wall, compared to higher frequency transducers. Originally, the operator could choose between different crystals depending on the size of the prostate, with a focal length of between 30 and 40 mm.
The Sonablate does not have a real-time imaging system while the treatment is given, but instead alternates between the treatment mode and image acquisition to create an image overlay that is used to detect patient movement; this is achieved by placing images of treatment planning along with images taken during treatment, if both images are aligned, it is indicative that there has been no movement of the patient (Figure 6) [16].
Schematics of the HIFU transducer used in the Sonablate system and the focal point within the tissue.
Insightec, a company located at Tirat Carmel, Israel, developed a system called EXABLATE 2100, which produces high-intensity focused ultrasound real-time guided by MRI. The focused ultrasound is delivered through an endorectal probe, with a 990-element phased-array transducer.
Once the probe is placed inside the rectum, it is filled with degassed water, producing an interface between the prostate and rectal wall. The MRI imaging includes T1-weighted dynamic contrast-enhanced, T2-weighted, and diffusion-weighted sequences, to accurately localize the lesion to be treated; with these images the EXABLATE software lets the user plan, manually contouring the area, including 5 mm tumor-free margins. The system then produces a specific treatment protocol, calculating the energy required and the number of shots to be delivered, avoiding damage to peripheral tissue. A pretreatment low energy targeting is delivered, checked with MRI thermometry. This information is overlapped on the anatomic images. Once confirmed, full power sonications are produced, monitorization is done with real-time MRI thermometry. A successful therapy is considered when the temperature in sonicated tissue achieves a threshold of 65°. A complete treatment is considered when non-perfused areas on MRI are found [17]. During the 2021 AUA meeting, the FDA 510 k clearance was informed.
The prostate therapy system is called TULSA, which stands for Transurethral Ultrasound Ablation. The device is designed to perform prostate tissue ablation in a transurethral approach. The probe is placed through the urethra, once in place, MRI guidance in real-time is used, so the treatment must be done in MRI suites.
In the main module, using high-definition MRI images, the prostate is contoured, during the planning step, the area to be treated is defined, preserving the urethra, and a 3 mm margin of apical prostate immediately above the sphincter [18, 19]. As described by the company [18], it is possible to treat bigger prostates compared with the ultrasound-guided devices.
The TULSA system uses a robotically-driven directional thermal ultrasound; the probe has 10 independent transducers, each of them delivering therapeutic ultrasound, so it is totally customizable, the user can select the number of elements to be used, depending on the length of the prostate. The probe includes a water pump cooling system, and an endorectal cooling device keeps 1 to 2 mm periurethral and rectal protected from thermal damage.
The therapy is done using an intraurethral rotational movement of the probe, creating a “sweeping heating pattern,” directional energy, with in-and-out sonication into the prostate parenchyma. The probe is fixed by an MRI robotic system, controlling the linear and rotational movements. The real-time MRI guidance, shows the thermal changes inside the treated volumes, every 6 seconds, allowing the users to modify the treatment parameters if needed. At the end of the ablation, a complete MRI revision is done, showing with the thermometric measures, all the missing areas that did not receive adequate energy, reassuring a safe and complete treatment [20].
The use of HIFU for the treatment of BPH has been described since 1992. The physical principle for treating an adenoma is not different from whole gland treatment. Tissue temperatures in the range of 80–90° C can produce thermoablation of the treated tissue, and it is possible to induce intra-prostatic cavities comparable to post-TURP effects.
In a series of 50 cases of prostatectomies after treatment with HIFU, it was possible to study the extent of coagulative necrosis caused by HIFU. Madersbacher reports that the prostate volume that can be destroyed during BPH treatment, with a probe with a focal length of 3−5 cm, is 8 cm3, and 14 cm3 with a focal length of 4 cm, so he calculates that approximately 25−30% of the total prostate could be destroyed during the procedure in these patients while keeping the tissue damage on the adjacent tissues minimal [21].
These results encouraged the search for new, less invasive treatment techniques to alleviate lower tract symptoms while reducing possible adverse effects. The main difference in the treatment of BPH against the whole gland lies in the possibility of delimiting the treatment area only to the prostatic adenoma, leaving the rest of the prostate intact.
In order to decrease the rate of complications due to TURP, Ebert et al. reported the use of HIFU for the treatment of prostate enlargement in 50 patients using a Focus Surgery HIFU generator. The short-term results were interesting, with a mean increase in Qmax from 5.7 to 11.6 ml/s at 6 weeks post-treatment, while the incidence of complications seems to be in favor of HIFU versus TURP [22].
In another report by Madersbacher et al., where 98 patients underwent HIFU for BPH, the author obtained similar results of improvement in urodynamic parameters at 12 months post-treatment, however, in the long-term follow-up, they observed that 43.8% of the treated patients had to undergo re-treatment with TURP due to unsatisfactory clinical results [23].
Both authors concluded that this method is promising, and although the long-term results were not satisfactory, they noted that there was a lot of variability in the results due to the heterogeneity of patients with inclusion criteria (prostate size, detrusor activity, middle lobe, etc.) So more protocols are needed to identify the ideal patient for this technique.
Currently, the authors of this chapter are working on the development of a novel technique for the treatment of BPH using a Sonablate HIFU device, with an up-to-date HIFU system and improved protocols: using higher energies, looking to modify the cavitation threshold, to achieve more cavitation than thermal lesions, with promising results in the time of treatment, catheterization and reduction volume of adenoma.
In the last 20 years, the indications for HIFU have expanded, from its original indication for prostate ablation in localized prostate cancer in patients who were not the candidates for radical prostatectomy to hemi ablation or focal therapy for localized disease or as salvage therapy after failed radiation therapy [24].
Whole gland prostate ablation with HIFU as primary treatment is indicated in patients with localized prostate cancer (T1 - T2, Nx, M0) without high-risk factors. They must not have any anorectal pathology that prevents the correct placement of the endorectal transducer.
The physician must be mindful of the anteroposterior diameter of the prostate and the focal point of the HIFU device he or she is using, since the prostatic tissue that is beyond the focal point will remain outside the ablation zone. If the dimensions of the prostate exceed the capabilities of the transducer in the longitudinal or transverse planes, it is possible to reposition the probe and perform the ablation in two or more phases, but it is not possible to reach tissue beyond the focal point.
It is also important to ensure that there are no significant prostatic calcifications, especially if they project posterior acoustic shadow, since the ultrasound beam could bounce off these calcifications, potentially compromising the oncological outcome of the procedure or the integrity of the rectal wall. It is a common practice to perform a TURP prior to HIFU treatment to remove large calcifications or reduce prostate size, and the procedure can be safely performed 6 weeks after TURP.
The HIFU procedure in the prostate is performed using a HIFU generator connected to an endorectal transducer, which contains piezoelectric crystals capable of generating ultrasound waves; this can alternate between high energy for ablation and low energy for image visualization [25].
The endorectal tube is usually connected to a cooling system that maintains the rectal wall at a temperature between 14 and 16°C. The procedure begins with the introduction of the probe and the visualization of the field to be treated. While Ablatherm requires a special surgical table, and the patient is placed in the lateral position, with Sonablate the patient is in a dorsal position and is performed on a standard surgical table.
Treatment planning is a bit different between devices, with the Ablatherm, the prostate is divided into 4 to 6 volumes, and is treated apex to base, slice by slice in an automated process. With Sonablate, the treatment is carried out in 2 to 3 coronal layers, starting with the anterior area and moving towards the posterior zone, in contact with the rectal wall [26].
The prostate normally must be divided into regions or lines of ablation, which correspond to the focal length of the transducer. The transducer can be moved longitudinally and rotated 180° around the axis of the transducer so that the system can plan an ablation line in the longitudinal or transverse plane as long as it is at the same focal length. Although the focal length is fixed, it is possible to move the transducer, which is attached to a mechanical arm, in an antero-posterior direction to achieve the stacking of several treatment planes, making ablation of the entire gland possible.
Once the treatment is finished, the prostate tissue does not undergo immediate necrosis, but rather through a process of progressive ischemia that ends with coagulation necrosis several days after treatment. The thermal damage suffered by the tissue leads to edema and inflammation of the prostate, with an increase in the volume of up to 30% of its base value, this causes an incidence of acute urine retention between 1 and 20% of patients [27].
During this post-surgical period, it is necessary to perform a urinary diversion through a suprapubic or transurethral Foley catheter to ensure urinary drainage, during this time, it takes the prostate tissue to complete the sloughing phase, which is the elimination of necrotic tissue through the urethra, which happens between the first and fourth weeks after surgery; during this time the patient may complain of dysuria and urgency, in addition to obstructive symptoms.
In 2012, Blana et al., analyzed data from 9 European centers, where 1975 patients received whole gland ablation with HIFU (Ablatherm device): clinical stages T1/T2, 356 (18%) were classified as “complete HIFU patients”; 160 (44.9%) had low-risk cancer, 141 patients (39.6%) intermediate, 52 (14.6%) high risk and 3 (0.8%) were unclassified. 205 had a preHIFU TURP. The median PSA Nadir was 0.11 ng/mL (0.78–3.6 ng/mL), obtained at a mean of 14.4 weeks (3.2 months PO-HIFU). Negative biopsies were reported in 182 patients (80.5%): low risk group 86 (86%), intermediate risk 73 (78.5%), and high risk 23 (78.2%). The biochemical disease-free survival rates (DFSR) at 5 years were: low risk 49 cases (88%), intermediate 82 (40%), and high risk 11 (78%). At 7 years: low-risk group 22 (80%), intermediated 14 (82%), and high-risk 3 (64%) [28].
Crouzet reported in 2013: in 1002 patients treated in a single center the following: a median follow-up of 6.4 years. 392 patients received androgen deprivation therapy prior to HIFU, during a median duration of 4.3 months, to shrink the prostate, and it was stopped after HIFU in all cases.
PO-HIFU biopsies were done in 774 patients (77%), being negative in 485 (63%) and positive in 289 (37%). PSA Nadir was at ≤6 months PO-HIFU in all patients, with a median nadir of 0.14 ng/mL.
Biochemical recurrence (Phoenix definition) in 205 cases (21.2%). The biochemical free-survival rates at 5 and 8 years was: low risk 86−76%, intermediate risk 78−63%, and high-risk group 68–57%, respectively (
The adverse effects reported in this series were: urinary incontinence grade 2/3 from 6.4 to 3.1%, mostly managed conservatively and with physiotherapy (94.5%), requiring artificial sphincter in 3.4%, and suburethral sling in 2.1%. Bladder neck or urethral strictures, from 34.9 to 5.9%, resolved with cold knife incision or TURP. 3 patients required a urethral stent. Erections were preserved in 42.3% of patients with a baseline IIEF score ≥ 17 (<70 years: 55.6%; ≥ 70 years: 25.6% (
Dickinson et al. reported medium-term results of 569 patients, in a multicenter study, where they received total gland ablation with HIFU as a treatment for localized prostate cancer, using the Sonablate 500 system.
They found that prostate ablation with HIFU is a treatment effective in cancer control in the medium term, with a 5-year relapse-free rate of 70%, with 87%, 63%, and 58% for low, intermediate, and high-risk groups, respectively. 29% required re-treatment with HIFU.
The adverse events reported were unique urinary tract infection in 58 of 754 (7.7%); repeated infection with epididymo-orchitis 22/754 (2.9%); rectourethral fistula 1/754 (0.13%); 183/754 (88%) continent; and form 236 patients with good erection prior to HIFU, 91 (39%) remained with good erections after HIFU. In the study, they concluded that HIFU is a repeatable outpatient treatment with good oncological control in localized cancer, with a low complication rate [30].
“Focal therapy” and “partial gland ablation” are therapeutic options more frequently considered as good alternatives to treat localized prostate cancer, decreasing morbidity, seen more frequently after radical prostatectomy and external beam radiation.
According to an International Multidisciplinary Consensus on standardized nomenclature and surveillance methodologies, the definition of “focal therapy” describes “a guided ablation of an image-defined, biopsy-confirmed, cancerous lesion with a safety margin surrounding the targeted lesion” [31]. The therapeutic guided term “partial gland ablation” as stated by the consensus, is regional image-guided ablation based on biopsy location. This alternative therapy does not use the identification of lesions by imaging, but anatomical limits, trying to preserve functionality, with a complete tumor treatment. Included in the partial ablations are quadrant therapy, hemiablation, hockey stick, and subtotal ablation.
The main goal of focal therapies is to ablate the prostate cancer focus, with an adequate margin, considered 8 to 10 mm, to have a good oncological control, with preservation of the surrounding tissue, in order to decrease secondary morbidity common in more extensive treatments, maintaining a good quality of life, continence and erectile function.
The frequency of detection of localized prostate cancer has increased importantly with the routinary usage of PSA; since the refinement of the mpMRI of the prostate, and the updated PI RADS, the possibility of defining suspicious lesions is more reliable. Using this high definition T2-weighted MRI images in the fusion systems (Koelis, Artemis, etc.), have improved the precision in targeting smaller and localized cancers.
The description of the “index lesion”, is defined as the tumor lesion responsible for the biological behavior of prostate cancer. The panelist in the consensus, to standardize nomenclature, considered that all MRI-visible lesions with clinically significant cancer should be used as a target for Focal therapies [31, 32, 33]. All these parameters are suggested to be considered as decision-making guides to select patients for focal therapies or partial gland ablation.
It must be remarked, that focal therapy and partial gland ablation are not included in the AUA or EAU guidelines for the prostate cancer treatment, as a consequence we will base on the recommendations suggested in the expert consensus [31] to indicate them.
The clinically significant prostate cancer (CsPC) has been defined as prostate cancers with a volume more than 0.5 cc, or a T3 stage or major in a whole-mount specimen, and at least one core with Gleason score of 3 + 4 or 6, with core length more than 4 mm [34].
The detection of clinically significant prostate cancer (CsPC) has been facilitated with MRI-TRUS, in-bore MRI-targeted biopsy, and cognitive biopsy techniques. In systematic reviews, MRI-targeted biopsies demonstrated that CsPC detection was significatively more frequent than TRUS-guided biopsy, with the relative sensitivity of 1.16 (95% CI 1.02–1.32) compared with TRUS-guided biopsy [34, 35].
In a meta-analysis that included 16 studies with an accumulated number of 1926 patients, the rate of general detection of prostate cancer was similar between MRI-targeted biopsy (sensitivity, 0.85; 95% CI 0.80−0.89) and TRUS-guided biopsy (sensitivity, 0.81; 95% CI 0.70−0.88); in contrast to detection of CsPC by MRI-targeted biopsy, greater than TRUS-target biopsy (sensitivity 0.91; 95% CI 0.87−0.94 vs. 0.76; 95% CI 0.64−0.84), and a lower detection rate of insignificant cancer (sensitivity 0.44; 95% CI 0.26−0.64 vs. 0.83; 95% confidence interval 0.77−0.87, respectively) [36].
Patient selection is a mandatory step to indicate a focal therapy or a partial gland ablation. As mentioned before, a precise image location of a lesion (PI RADS/LIKERT systems) and a pathology report of an index lesion; the agreement about index lesion (that of greater volume and pathology grade) capable of inducing the risk of prostate cancer progression.
The goal to treat the index lesion is to produce an acceptable oncologic control, decreasing morbidity preserving surrounding structures [32, 33]. The proposed selection criteria included: prostate-specific antigen (PSA) level < 10 ng/mL, no Gleason 4 or 5, the maximum length of cancer in each core of 7 mm, and less than 33% of positive cores [37]. In a multicenter study, reporting safety outcomes and complications, the selection criteria included: Gleason score ≤ 4 + 3 = 7b, if unilaterality, clinical stage T1 or T2, PSA levels - < 15 ng/mL, and life expectancy ≥10 years [38].
The definition to perform focal therapy or partial gland ablation depends on a good visualization of tumoral lesion, corroborated by pathology test, within limits of tumor volume that allows safe oncologic margins; in those cases, with multiple cancer lesions in the same parenchymal topography, the recommended treatment is a templated organ-preserving partial gland ablation, which in general uses urethra as anatomic landmark. Figure 7 defines focal and partial ablations [31].
Differences between focal therapy and templated partial gland ablation. Focal therapy: Focused ablation of image-visible, biopsy-confirmed lesion(s) plus a safety margin. Quadrant ablation: Inclusion of all tissue within a quadrant of the prostate. Hemiablation: Inclusion of all tissue within a lateralized hemisphere of the prostate or the anterior half of the prostate. Hockey stick: Destruction of tissue within a lateralized hemisphere and anterior contralateral zone. Subtotal ablation: Inclusion of most of the parenchyma preserving the posterior lateral zone(s). The intention is to preserve at least one neurovascular bundle.
Treatment is accomplished using any of the two available commercial softwares: Focal-one or Sonablate, both systems can import standard DICOM MRI, to fuse and define the treatment zone, or as cognitive guidance.
Using high definition T2-weighted images as a guide, the prostate contour is done and the ROI section is marked, to be used in the HIFU system, the software allows through elastic fusion to match both MR and ultrasound images, to localize the suspicious lesion, and proceed with the therapy, customizing the number of zones, margins, and power to be used; limits and number of shots are defined automatically by the equipment, starting the treatment [15].
The validation of the treatment is done, in the FOCAL ONE system, once the therapy is finished, doing a CEUS volume, injecting microbubbles. The acquired volume shows very clearly the devascularized area. All sectors treated not showing enhancement after microbubbles injection are considered as entirely destroyed; when prostate sectors show enhancement, this tissue can be considered as living tissue (benign and malignant). The images obtained after CEUS can be fused in the initial planning sequence, showing the treated areas, and if needed new areas can be added to complete the ablation [15].
In the Sonablate system, two seconds immediately after sonication, the equipment scans, updating the prostate images in sagittal and axial, and a proprietary system measures the quality of RF caused in the treated tissue, giving a colorimetric scale: orange adequate energy delivered, yellow energy enough to destroy the tissue, green suboptimal energy delivered, and gray not measured.
This TCM system lets the physician replan those suboptimal or not measured spots and retreat, adjusting the energy to achieve the correct lesion. The second and more reliable procedure to validate the effectiveness of each shot, is the presence of cavitation, called “pop corn”, because the change of echogenicity, same as with TCM, 2 seconds after the sonication, the updated scan, shows in real-time the presence of a hyperechoic lesion, that must be evaluated, to control the power delivered, keeping it inside of the treatment box, as mentioned previously, the main goal is to cause extensive controlled cavitation in the treated tissue [39].
The suggested way to evaluate the treated zone, and the peripheral tissues, is Gadolinium-enhanced (non-dynamic) MRI. The immediate images reveal a central zone without enhancement that explains devascularization secondary to the coagulative necrosis, surrounded by an enhanced rim. After six months post-HIFU, a shrinkage of prostate volume is noticed (61% of median volume reduction), with a decrease of the signal intensity on T2-weighted images [15, 40].
In 2018, Guillaumier S. et al., reported a 5-year outcomes study after focal therapy with HIFU. It was a prospective study including 625 patients with localized clinically significant prostate cancer. The study took place from January 1, 2006, to December 31, 2015, the inclusion criteria were: Gleason score 6−9, clinical-stage T1c-3bN0M0, prostate-specific antigen of ≤30 ng/mL.
All patients were followed for 3−6 months PSA, with mpMRI done at 1 year and 1−2 years the following years. All rises in PSA after nadir were evaluated with prostate biopsy or mpMRI, when suspicious with MRI-targeted biopsy. When clinically significant prostate cancer was found on biopsies, in field or out field, a repeat HIFU was offered. 599 patients completed at least 6 months follow-up, and 505 (84%) presented as intermediate of high-risk prostate cancer (D’Amico classification).
The Failure-free survival was: 1 year 99% (95% CI 98−100%), at 2 years 92% (95% CI 90−95%), and at 5 years88% (95% CI 85−91%). Kaplan–Meier estimated at 5 years for low risk 96% (95% CI 91−100%), intermediate risk 88% (95% CI 84–93%), and high risk group 84% (95% CI 78−90%). 8 patients opted for salvage radical prostatectomy, 36 salvage radiotherapy, and 1 androgen deprivation therapy. 10 patients progressed with metastases: Kaplan–Meier estimated for metastases-free survival: 1 year 99.7% (95% CI 99−100%), 3 years 99% (95% CI 98−100%), and 5 years 99% (95% CI 97−100%). Repeat focal HIFU: one done in 112, and two repeat HIFU in 9.56 patients out of 222, required biopsy after HIFU, secondary to PSA rise or mp MRI suspicion; 29 had in-field recurrence, 16 histological evidence of out-field cancer; and 11 patients both in and out-field cancer [41].
As described by Schmid, Schindele et al., in his multicenter study, included 98 men with localized low to intermediate risk prostate cancer, the parameters were median-PSA before HIFU of 6.5 ng/mL (1.03−14.9 ng/mL); clinical T stage ≥2 with cT1 in 76.5% (n = 75), cT2 in 23.5% (n = 23); Gleason score 3 + 3 = 6 in 17.3% (n = 17), 3 + 4 = 7a in 65.4% (n = 64), and 4 + 3 = 7b in 17.3% (n = 17); median prostate volume of 39.6 cc (21.6−135.2 cc); the treated index lesion volume of 10.5 cc (3.9−28.2 cc).
Their evaluation showed the following complications after HIFU therapy: 35 patients (35.7%) had adverse effects during the following 30 days after HIFU treatment with Clavien-Dindo grade ≥ II: 15 points (15.3%) with urinary tract infection and 26 patients (26.5%) with urinary retention. 4 patients (4.1%) needed another procedure (Clavien-Dindo grade IIIa/b). Late post HIFU complications, happening during days 30 to 90 was 2.0%. Considering the cancer location, the most common complications were those located at the anterior base in 50% of cases. When the urethra was ablated, the complications were present in 48.8% of cases (20 of 41), considered as a significant risk factor during the 30 days post-HIFU (odd ratio = 2.53; 95% confidence interval: 1.08−5.96; P = 0.033) [38].
Recurrence of prostate cancer after EBRT is a common condition, reported in up to 46% of patients treated with radiation. The therapeutic options used to control the progression are salvage prostatectomy, usually indicated in selected cases, because of technical difficulties, and higher morbidity; salvage cryotherapy, hormone blockage, and salvage HIFU. Biochemical recurrence (using PSA levels) in relation to the ASTRO-AUA-EAU guidelines, is a safe parameter to detect local recurrences, between 10−30% of cases. Extension studies must be included in the staging process, mpMRI and PET SCAN PSMA have shown excellent options to discard metastatic involvement.
Ideal patients considered as candidates for salvage HIFU must have PSA levels up to 2 ng/mL according to the ASTRO-Phoenix guidelines, correlated with extension studies as mpMRI or PET SCAN PSMA that will show suspicious tumors in the prostate, biopsy should be used as a confirmatory method; patients with metastatic involvement should be offered another type of procedure but HIFU. Additionally, candidates should have a Gleason score ≤ 8, and clinical-stage ≤T1-T3aNoMo.
Fulfillment of the guidelines can assure a better prognosis among prostate cancer patients treated with HIFU, since case selection is a determinant factor for a successful result, as described in a 2011 evaluation that was performed on a group of 84 men with biochemical failure after EBRT and a whole-gland salvage HIFU. Results have demonstrated that 93% of them were discharged within 23 hours following treatment, and only 20% (17 of 84 patients) needed an intervention for bladder obstruction. Within a follow-up of 19.8 months, 25% (21 of 84 patients) of the cohort presented a residual cancer detected on biopsy after salvage HIFU [42]. It is noteworthy that repeated HIFU procedures are a high-risk factor for rectal fistula development.
In a 2017 prospective study at University College London Hospitals and NHS Basingstoke Trust, in 150 men who received salvage HIFU between 2006 and 2015, the Kaplan–Meier overall survival at 60 months was 92% and among complications, UTI was 11.3% (17 of 150 patients) and bladder neck strictures of 8%. In addition, 87.5% remained pad-free at 2 years among those pad-free at baseline [43].
High-Intensity Focused Ultrasound or Focused Ultrasound Surgery is an emerging image-guided therapy for obstructive benign prostatic hyperplasia and prostate cancer.
With the advent of new methodologies in MRI, specifically multiparametric MRI; the possibility of fusioning the MR images in real-time ultrasound scans, changed the accuracy of targeting biopsies, and recently the therapy targeting to improve control of focalized lesions.
Recently, the usage of MRI guidance with EXABLATE and TULSA-PRO, taking advantage of thermometric scanning, allowed more accurate treatments, limited by the need for MRI facilities. In the case of whole gland ablation, it is compared in outcomes with radical prostatectomy and EBRT, with less adverse effects.
The most common consideration of less aggressive treatments for clinically significant prostate cancer made the focal therapy a growing alternative, only limited at this time for the availability of good technical mpMR images, necessary to assess accurately the parenchymal lesions. The general results in different centers make HIFU a highly promising therapeutic option.
Our deepest thanks to:
Prof. Narendra Sanghvi, Focus-Surgery and Sonablate Corp.
Alex Gonzalez, Sonablate Corp.
Rodrigo Chaluisan, Sonablate Corp. In memoriam.
The authors declare to use a Sonablate device for BPH and prostate cancer treatments, since 2005, participate in the proctoring teaching system of Sonablate Company and participate in a BPH protocol with Sonablate Company.
All video materials referenced in this chapter are available to download here: https://bit.ly/33T5UxZ.
PSA | prostate-specific antigen |
HIFU | high intensity focused ultrasound |
TURP | transurethral resection of prostate |
BPH | benign prostate hyperplasia |
mpMRI | multiparametric magnetic resonance image |
EBRT | external beam radiotherapy |
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Medicinal plants are a rich source of producing secondary metabolites which showed broad-spectrum enzyme inhibitory potential. The position of enzyme inhibitors as new drugs is vast since these compounds have been used for the treatment of various physiological disorders. Bioactive secondary metabolites can deliver excellent pharmacophore patterns for drugs related to numerous illnesses. This book chapter is planned to document the enzyme inhibitory potential of natural compounds, medicinal plant extract, and its isolated compounds.",book:{id:"5540",slug:"enzyme-inhibitors-and-activators",title:"Enzyme Inhibitors and Activators",fullTitle:"Enzyme Inhibitors and Activators"},signatures:"Abdur Rauf and Noor Jehan",authors:[{id:"192295",title:"Dr.",name:"Abdur",middleName:null,surname:"Rauf",slug:"abdur-rauf",fullName:"Abdur Rauf"}]},{id:"39560",doi:"10.5772/50782",title:"Assay Guided Comparison for Enzymatic and Non-Enzymatic Antioxidant Activities with Special Reference to Medicinal Plants",slug:"assay-guided-comparison-for-enzymatic-and-non-enzymatic-antioxidant-activities-with-special-referenc",totalDownloads:8805,totalCrossrefCites:8,totalDimensionsCites:32,abstract:null,book:{id:"2516",slug:"antioxidant-enzyme",title:"Antioxidant Enzyme",fullTitle:"Antioxidant Enzyme"},signatures:"Sujogya Kumar Panda",authors:[{id:"154335",title:"Dr.",name:"Sujogya",middleName:null,surname:"Panda",slug:"sujogya-panda",fullName:"Sujogya Panda"}]}],mostDownloadedChaptersLast30Days:[{id:"54390",title:"Enzyme Inhibitors and Activators",slug:"enzyme-inhibitors-and-activators",totalDownloads:6200,totalCrossrefCites:14,totalDimensionsCites:18,abstract:"Enzymes are very effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Enzyme inhibitors and activators that modulate the velocity of enzymatic reactions play an important role in the regulation of metabolism. Enzyme inhibitors are also useful tool for study of enzymatic reaction as well as for design of new medicine drugs. In this chapter, we focused on the properties of enzyme inhibitors and activators. Here we present canonical inhibitor classification based on their kinetic behavior and mechanism of action. We also considered enzyme inhibitors that were used for design of various types of pharmacological drugs and natural inhibitors as a plausible source for design of future drugs. Mechanisms of action of enzyme activators and some features of allosteric modulators are considered.",book:{id:"5540",slug:"enzyme-inhibitors-and-activators",title:"Enzyme Inhibitors and Activators",fullTitle:"Enzyme Inhibitors and Activators"},signatures:"Olga D. Lopina",authors:[{id:"193286",title:"Prof.",name:"Olga",middleName:null,surname:"Lopina",slug:"olga-lopina",fullName:"Olga Lopina"}]},{id:"54515",title:"Kinetic Modelling of Enzyme Catalyzed Biotransformation Involving Activations and Inhibitions",slug:"kinetic-modelling-of-enzyme-catalyzed-biotransformation-involving-activations-and-inhibitions",totalDownloads:4400,totalCrossrefCites:1,totalDimensionsCites:6,abstract:"To achieve transition from lab scale enzyme studies to industrial applications, understanding of enzyme kinetics plays a critical role. The widely applied Michaelis Menten equation of the single substrate kinetics, sequential and double replacement mechanism of bisubstrate reaction and the relevant kinetics, inhibition and activation of enzyme are all integral parts of this discussion. In this chapter, we have discussed different types of inhibition and kinetic modelling. Systematic approach to generate data and its interpretation as well as designing of inhibitors is also explained.",book:{id:"5540",slug:"enzyme-inhibitors-and-activators",title:"Enzyme Inhibitors and Activators",fullTitle:"Enzyme Inhibitors and Activators"},signatures:"Ganapati D. Yadav and Deepali B. Magadum",authors:[{id:"49324",title:"Prof.",name:"Ganapati",middleName:"D",surname:"Yadav",slug:"ganapati-yadav",fullName:"Ganapati Yadav"},{id:"193953",title:"Ms.",name:"Deepali",middleName:null,surname:"Magadum",slug:"deepali-magadum",fullName:"Deepali Magadum"}]},{id:"52877",title:"Inhibitors and Activators of SOD, GSH‐Px, and CAT",slug:"inhibitors-and-activators-of-sod-gsh-px-and-cat",totalDownloads:3755,totalCrossrefCites:19,totalDimensionsCites:48,abstract:"Reactive oxygen species (ROS) is harmful to our health, and SOD, CAT, and GPX are the major antioxidant enzymes that defend us from effects of ROS. In medicine, food, and dairy industries, antioxidant enzymes often surround complex environments. For better utilization of these enzymes, the inhibitors (including competitive inhibitors and noncompetitive inhibitors) and activators of SOD, CAT, and GPX are descripted in detail in this chapter. Also, the structure and catalytic mechanism of these antioxidants are summarized.",book:{id:"5540",slug:"enzyme-inhibitors-and-activators",title:"Enzyme Inhibitors and Activators",fullTitle:"Enzyme Inhibitors and Activators"},signatures:"Xianyong Ma, Dun Deng and Weidong Chen",authors:[{id:"193346",title:"Prof.",name:"Xianyong",middleName:null,surname:"Ma",slug:"xianyong-ma",fullName:"Xianyong Ma"},{id:"193352",title:"Dr.",name:"Dun",middleName:null,surname:"Deng",slug:"dun-deng",fullName:"Dun Deng"}]},{id:"55893",title:"Lysosomal Degradation of Junctional Proteins",slug:"lysosomal-degradation-of-junctional-proteins",totalDownloads:2196,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"Epithelial cells develop tight junctions (TJs) and cell polarity. Both properties are sensitive to environmental signals such as the epidermal growth factor (EGF) and the cardiotonic steroid ouabain. EGF is regarded as the main protector against injuries in epithelia, and ouabain is a hormone that regulates blood pressure, natriuresis, cell survival, and cell adhesion. After treatment with epidermal growth factor or ouabain, epithelial dog kidney MDCK cells undergo a drastic remodeling that includes changes in the transcription, translation, localization, and degradation of cell junction proteins. Degradation of these proteins involves selective and nonselective autophagy as well as endocytic lysosomal and proteasomal routes. The remodeling mechanism of tight junction’s proteins includes the activation of Src and ERK1/ERK2 kinases, the phosphorylation and translocation into the nucleus of the transcription factor STAT3, the activation of PKC to induce the endocytosis of claudin-2, and the delivery of this protein to the lysosomes. Whole communicating junctions and desmosomes are internalized by one cell and sent to degradation by nonselective autophagy. Nonselective and selective autophagies in epithelial cells are very context dependent; nevertheless, it is clear that, together with endocytic lysosomal and proteasomal degradation, they play a key role in the remodeling and functioning of cell junctions.",book:{id:"5771",slug:"lysosomes-associated-diseases-and-methods-to-study-their-function",title:"Lysosomes",fullTitle:"Lysosomes - Associated Diseases and Methods to Study Their Function"},signatures:"Catalina Flores-Maldonado, Odette Verdejo-Torres, Jessica Campos-\nBlázquez, Agustín Ruiz Cabrera, Vicky García-Hernández, Ruth\nRincón-Heredia and Rubén G. Contreras",authors:[{id:"197919",title:"Dr.",name:"Rubén G.",middleName:null,surname:"Contreras",slug:"ruben-g.-contreras",fullName:"Rubén G. Contreras"},{id:"197921",title:"Dr.",name:"Catalina",middleName:null,surname:"Flores-Maldonado",slug:"catalina-flores-maldonado",fullName:"Catalina Flores-Maldonado"},{id:"197923",title:"M.Sc.",name:"Jessica",middleName:"Paulina",surname:"Campos-Blázquez",slug:"jessica-campos-blazquez",fullName:"Jessica Campos-Blázquez"},{id:"205467",title:"Dr.",name:"Ruth",middleName:null,surname:"Rincón-Heredia",slug:"ruth-rincon-heredia",fullName:"Ruth Rincón-Heredia"},{id:"205468",title:"Dr.",name:"Vicky",middleName:null,surname:"García Hernández",slug:"vicky-garcia-hernandez",fullName:"Vicky García Hernández"},{id:"205470",title:"Mrs.",name:"Odette",middleName:null,surname:"Verdejo-Torres",slug:"odette-verdejo-torres",fullName:"Odette Verdejo-Torres"},{id:"212801",title:"Dr.",name:"Agustin",middleName:null,surname:"Ruiz-Cabrera",slug:"agustin-ruiz-cabrera",fullName:"Agustin Ruiz-Cabrera"}]},{id:"52721",title:"Telomerase Inhibitors and Activators: Pharmaceutical Importance",slug:"telomerase-inhibitors-and-activators-pharmaceutical-importance",totalDownloads:2896,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Telomeres are specialized functional complexes that protect the ends of eukaryotic chromosomes. The telomeric DNA sequences are tandem repeats of a short hexameric sequence unit. The inability to DNA polymerase to replicate the end of the chromosome during lagging strand synthesis results in the loss of telomeric repeats when cell divides. Telomere shortening provides a barrier to cancer progression and the majority of the cancer cells depend on the activation of telomerase to gain proliferative immortality. Thus, telomerase is a molecular target for diseases since its discovery. Telomerase inhibition enables more specific ground for cancer therapy because the telomerase is not detected in most normal tissues. Some of the synthetic and natural telomerase inhibitors were tried on various cancer cells and there was a decrease in the number of cancer cells. But on the other hand, telomere shortening correlates with cellular aging. Some evidence suggests that the progressive loss of telomeric repeats of chromosomes may function as a molecular clock that triggers senescence. Telomerase-related gene mutations also result in some diseases. Because of this, telomerase activators are important for antiaging and telomerase-dependent disease treatments. This chapter summarizes the pharmaceutical importance of telomeres, telomerase structure, telomerase activators, and inhibitors.",book:{id:"5540",slug:"enzyme-inhibitors-and-activators",title:"Enzyme Inhibitors and Activators",fullTitle:"Enzyme Inhibitors and Activators"},signatures:"Ayse Gul Mutlu",authors:[{id:"115828",title:"Dr.",name:"Ayse Gul",middleName:null,surname:"Mutlu",slug:"ayse-gul-mutlu",fullName:"Ayse Gul Mutlu"}]}],onlineFirstChaptersFilter:{topicId:"393",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:126,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:13,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"August 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",slug:"taufiq-choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Rosa María Martínez-Espinosa is a Full Professor of Biochemistry and Molecular Biology at the University of Alicante, Spain, and has been the vice president of International Relations and Development Cooperation at this university since 2010. She created the research group in applied biochemistry in 2017 (https://web.ua.es/en/appbiochem/), and from 1999 to the present has made more than 200 contributions to Spanish and international conferences. Furthermore, she has around seventy-five scientific publications in indexed journals, eighty book chapters, and one patent to her credit. Her research work focuses on microbial metabolism (particularly on extremophile microorganisms), purification and characterization of enzymes with potential industrial and biotechnological applications, protocol optimization for genetically manipulating microorganisms, gene regulation characterization, carotenoid (pigment) production, and design and development of contaminated water and soil bioremediation processes by means of microorganisms. This research has received competitive public grants from the European Commission, the Spanish Ministry of Economy and Competitiveness, the Valencia Region Government, and the University of Alicante.",institutionString:"University of Alicante",institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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He previously worked as a post-doctoral fellow at the Ben-Gurion University of Negev, Israel; University of the Free State, South Africa; and Central University of Technology Bloemfontein, South Africa. He obtained his Ph.D. in Organic Chemistry from Nagaoka University of Technology, Japan. He has published more than seventy-four journal articles and attended several national and international conferences as speaker and chair. Dr. Kendrekar has received many international awards. He has several funded projects, namely, anti-malaria drug development, MRSA, and SARS-CoV-2 activity of curcumin and its formulations. He has filed four patents in collaboration with the University of Central Lancashire and Mayo Clinic Infectious Diseases. His present research includes organic synthesis, drug discovery and development, biochemistry, nanoscience, and nanotechnology.",institutionString:"Visiting Scientist at Lipid Nanostructures Laboratory, Centre for Smart Materials, School of Natural Sciences, University of Central Lancashire",institution:null},{id:"428125",title:"Dr.",name:"Vinayak",middleName:null,surname:"Adimule",slug:"vinayak-adimule",fullName:"Vinayak Adimule",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428125/images/system/428125.jpg",biography:"Dr. Vinayak Adimule, MSc, Ph.D., is a professor and dean of R&D, Angadi Institute of Technology and Management, India. He has 15 years of research experience as a senior research scientist and associate research scientist in R&D organizations. He has published more than fifty research articles as well as several book chapters. He has two Indian patents and two international patents to his credit. Dr. Adimule has attended, chaired, and presented papers at national and international conferences. He is a guest editor for Topics in Catalysis and other journals. He is also an editorial board member, life member, and associate member for many international societies and research institutions. His research interests include nanoelectronics, material chemistry, artificial intelligence, sensors and actuators, bio-nanomaterials, and medicinal chemistry.",institutionString:"Angadi Institute of Technology and Management",institution:null},{id:"284317",title:"Prof.",name:"Kantharaju",middleName:null,surname:"Kamanna",slug:"kantharaju-kamanna",fullName:"Kantharaju Kamanna",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284317/images/21050_n.jpg",biography:"Prof. K. Kantharaju has received Bachelor of science (PCM), master of science (Organic Chemistry) and Doctor of Philosophy in Chemistry from Bangalore University. He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. 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