Daily recommended dose of magnesium for kids, youth and adults [16].
\r\n\tThere are generally two types of masonry: brick and stone masonry. Brick masonry: a type of masonry that uses bricks. However, masonry is further divided into "clay work," which uses clay to fill various joints with bricks to build walls, and "cement masonry," the cheapest type of masonry. Masonry: this is the art of building with bricks or stone. The ability of masonry to support the load imposed by the structural elements above it is called strength. The application of loads to masonry creates internal stresses and deformations. The brand of mortar and brick, the shape and size of masonry materials, and the thickness and density of mortar joints affect the strength of masonry. The ability of masonry to maintain its position under horizontal load is called stability. This property limits the height of masonry depending on its thickness and the magnitude of wind loads. The thermal conductivity of bricks of different types (silicate, ceramic, facing, refractory) is considered. A comparison of bricks in terms of their thermal conductivity is made; the thermal conductivity coefficients of refractory bricks are presented at different temperatures - from 20 to 1700°C. The thermal conductivity depends mainly on the density and the configuration of the voids. Architecture and construction consist of various elements for building works, and masonry is the main element with which these constructions are realized. Masonry is a piece of fired clay with a rectangular shape and is used to build walls and structures. Nowadays, eco-masonry can be made of different materials that offer a variety of advantages, but all of them offer benefits at the level of the environment and sustainability; some of these utensils are plastic bottles, clay, etc. The book addresses the holistic issue of using modern masonry in construction. This book interprets masonry as an essential theme of contemporary architecture and sustainable construction. It is one of the most valuable materials in the history of mankind.
",isbn:"978-1-83768-126-6",printIsbn:"978-1-83768-125-9",pdfIsbn:"978-1-83768-127-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"85ef86d046d15e7d4b1988f1ec5dd750",bookSignature:"Prof. Amjad Almusaed and Prof. Asaad Almssad",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12061.jpg",keywords:"Unreinforced Masonry Buildings, Masonry in Sustainable Building, Energy Saving and Masonry, Eco-Friendly Masonry, Modern Architecture and Masonry, Masonry and Human Behavior, Esthetic and Masonry, History of Advanced Masonry, Structural Masonry, Modeling of Masonry Structures, Modern Masonry Manufacturing, Masonry Walls",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 20th 2022",dateEndSecondStepPublish:"June 17th 2022",dateEndThirdStepPublish:"August 16th 2022",dateEndFourthStepPublish:"November 4th 2022",dateEndFifthStepPublish:"January 3rd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"20 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Prof. Amjad Almusaed, affiliated with Jönköping University has carried out a great deal of research and technical survey work and has performed several studies in these areas. 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It constitutes 2.7% of the earth’s crust and can be found in the form of minerals, such as dolomite, magnesite or kainite [1]. The mechanical properties of pure magnesium are poor, therefore alloying additives are introduced to improve them. Magnesium alloys, in which the major additive is aluminum – typically 6–10% – are the most widely used industrial alloys of magnesium. Zinc or manganese [2, 3] are added to improve corrosion resistance of magnesium alloys. Initially, magnesium alloys were produced mainly for military purposes. Due to the high specific strength and vibration damping capacity, magnesium alloys are mainly used in the automotive industry [3, 4].
Currently, research is carried out mainly on new groups of magnesium alloys, such as Mg-Ca, Mg-Zn and Mg-Zn-Ca, which have not been produced on an industrial scale so far. Studies are carried out on the use of these alloy groups as materials for implants, especially orthopedic ones. Injuries of the osteoarticular system, as well as diseases of the musculoskeletal system, including the continuous increase in the incidence of bone cancer, are the main and the most common threat to the health of modern society. 2,710,000 cases of orthopedic fractures were noted in Poland in 2010. Due to the aging of the population, it is predicted that, in 2025, their number will reach 3,239,564, and 10 years later – over 4 million. In 2017, 85,488 joint arthroplasties (partial or total) were performed in Poland, including 56,688 of the hip and 27,653 of the knee. Surgical joining of broken bones through their correct connection and immobilization is performed with the use of bone plates, wires, clamps and/or screws. The use of these elements results in bone union and obtaining the correct bone structure, which, in turn, allows the patient to move, and thus return to basic life activity [5, 6, 7, 8].
In medical practice, both long-term implants (e.g. joint prostheses) and short-term implants (e.g. plates, bone screws), used to stabilize broken bones, are produced from titanium alloys, cobalt alloys or stainless steel. Implants made of those are classified as neutral, i.e. neutral to the body, as long as protective layers (usually oxide) remain on their surface. Unfortunately, after some time, these layers become corroded and damaged, and implant components – which are usually biologically incompatible (toxic to the body) – pass into the human body, and thus are a threat to health and life. Resorbable biomaterials are an alternative to the metal alloys used so far for short-term orthopedic implants. The resorbable biomaterials used in medical practice so far include oxide glasses (composed of Na, K, Mg, Ca, Si and P oxides), ceramics based on calcium phosphates, e.g. hydroxyapatite [Ca10(PO4)6(OH)2] and polymers, such as polylactide, polyglycolide or copolymers of these materials. Unfortunately, their use in orthopedic implantology is limited. They are mainly used as fillers for bone defects, elements of dentures or coatings for medical implants [9, 10, 11]. This is due to poor mechanical properties of resorbable biomaterials. Mechanical strength of the resorbable materials used in medicine is 30–100 MPa [10, 12]. Consequently, mechanical properties of resorbable polymers and ceramics are a barrier to their use as biomaterial for implants, such as short-term orthopedic implants. Accordingly, resorbable metallic biomaterials that can be used for orthopedic implants are necessary. Resorbable metallic biomaterials are an alternative to the metal alloys previously used for short-term orthopedic implants. Magnesium alloys are appropriate materials for resorbable metallic biomaterials.
This chapter presents the role of magnesium in the human body and its use in medicine. It presents the concept and potential applications of magnesium alloys in medicine, as well as classification of magnesium alloys as potential biomaterials due to the structure (amorphous, crystalline) and alloying elements (rare earth elements, noble metals etc.). The chapter also describes mechanisms and degradation behavior (in vitro) of magnesium alloys due to their structure. The impact of alloy additives (rare earth elements, noble metals) and protective coatings on the degradation process of magnesium alloys for biomedical applications in in vitro conditions has also been assessed.
Magnesium is called an element of life, because it participates in many processes of the human body. It is necessary to maintain proper homeostasis, i.e. the proper functioning of the human body. It is estimated that there are approximately 22–26 g of magnesium in the human body [13]. It should be mentioned, that both the value and the range of the concentration of an element in the human body depends on the age, sex, absorption of the elements or even diet. The World Health Organization (WHO) has issued standards defining the daily demand for the element [14, 15]. Similarly, demand for magnesium is different for a certain age. Table 1 shows the daily magnesium requirement depending on age.
DEMAND FOR MAGNESIUM [mg/24 h] | |||||
---|---|---|---|---|---|
kids < 6 years old | kids 6–9 years old | youth 10–18 years old | adults 19–60 years old | adults < 60 years old | |
Daily recommended dose of magnesium for kids, youth and adults [16].
Magnesium is distributed in the body (in the skeletal system: approx. 60%; in skeletal muscles: approx. 20% and other soft tissues: approx. 19%). Magnesium in acidic form, absorbed from food, in about 30%, can be found predominantly in the small intestine. The daily recommended dose of magnesium depends on the age, gender and current condition of the body. It has been proven, that the average dose for an adult human is about 300–400 mg. Approximately 30% of magnesium is absorbed from the gastrointestinal tract. Absorption of this element is influenced, among others, by the amount of consumed protein, fiber and phosphates. The normal blood magnesium level of a healthy person is 0.75–0.95 mmol/dm3, and its homeostasis is maintained by the kidneys.
Magnesium has a lot of functions in the human body. For example, it:
regulates the activity of about 300 enzymes involved in metabolic changes,
is necessary for proper bone mineralization. It has been confirmed that magnesium deficiency disturbs bone mineralization processes, increasing the incidence of postmenopausal osteoporosis [17],
is involved in nerve conduction and muscle contractility. It is likely that magnesium could be used to treat affective disorders and depression. A positive effect of magnesium on depression symptoms has been demonstrated in patients with low levels of magnesium in erythrocytes [18],
plays a vital role in most hormonal responses. Magnesium has been shown to influence insulin synthesis, catecholamine storage and parathyroid hormone release,
participates in the regulation of blood pressure,
regulates muscle tension,
regulates the thyroid gland and widens the airways, supporting the treatment of asthma and bronchitis.
Magnesium has been used in treatment of various diseases. Figure 1 presents the main uses of magnesium for treatment of diseases.
The most important uses of magnesium in treatment of diseases [
Symptoms of magnesium deficiency influence every system in the human body. The most common symptoms are not very specific – they include fatigue, poor concentration and memory, as well as increased susceptibility to stress. Excessive loss of magnesium can be caused by serious diseases of the gastrointestinal tract (e.g. fistulas, pancreatitis), urinary tract disorders, endocrine disorders (primary hyperparathyroidism, intensive insulin therapy), D3 hypervitaminosis, use of immunosuppressants, increased sympathetic nervous system tension or alcoholism.
The progress of both the medicine and materials engineering results in an intensification of research works on new biomaterials. Nowadays, magnesium alloys are considered potential resorbable metallic biomaterials. Furthermore, it is assumed that a magnesium alloy as a resorbable biomaterial should gradually degrade in the human body until the bone fuses. Degradation products of a resorbable implant would be processed, absorbed or excreted from the patient’s tissues and body fluids. The use of implants designed according to this concept does not require re-operation and it allows the foreign object (implant) to stay in the human body. Apart from good mechanical properties and biocompatibility, magnesium has a number of other advantages, such as [20, 21]:
good strength-to-weight ratio. Pure magnesium has 158 kNm/kg; however, its alloys can reach up to 490 kNm/kg. This is twice as much as the most commonly used titanium alloys (260 kNm/kg), therefore, less material is needed to obtain similar mechanical properties.
ease of processing magnesium and creating complex shapes, which is extremely important in medical applications, because every person is different and, therefore, it is possible to design a custom-made implant for a specific patient.
safe degradation – titanium, stainless steel and Co-Cr alloys do not ensure safe degradation. All surgically implanted alloys are subject to electrochemical degradation, as they are in a corrosive environment. Additionally, they are subject to significant wear. Implant particles can be released into the surrounding tissue, causing discomfort and potential health hazards. Magnesium and its alloys can minimize these problems during the degradation process. It is possible that, after a controlled period of time, the implant completely degrades in the human body.
The main problems and research limitations of this concept are as follows:
production of implants with good mechanical properties, which guarantee the appropriate time (allowing bones to fuse) of the implant’s activity in human bodily fluids,
high degradation of an implant with very intense release of hydrogen, which is harmful to the body. In addition, there is possible exceeding the daily demand for the element (also biocompatible), introducing into the body. Metal alloys used for resorbable biomaterials should only include elements that are already present in the human body in high concentration and are macro- or microelements.
The major problem concerning all metal biomaterials consists in the adjustment of their mechanical properties to those of the reconstructed tissues. The density of steel is approx. 4 times higher than the density of bone tissue. Steel has several times higher yield point and tensile strength, higher elongation and about 10 times higher Young’s modulus. The differences in the mechanical properties of materials and those of the tissues they replace result in inappropriate loading of the tissues surrounding the implant, causing pain and discomfort in patients [22].
The density of magnesium alloys is similar to the density of the human bones, therefore, there is no possibility of stress shielding, as in the case of the previously used implant materials, based on stainless steel and titanium. Stress shielding is a process, in which the bone mass and density decrease near the implant, because it transfers the loads. The density of magnesium alloys is three times lower than that of titanium alloys and five times lower than that of stainless steel and Co-Cr alloys. The modulus of elasticity and fracture resistance are much lower than for the biomaterials used so far [23, 24]. In the 19th and 20th centuries, magnesium alloys were used in medicine (Table 2). They were used in the form of scaffolds and to improve healing of wounds or organs. In addition, magnesium and its alloys have been used in orthopedic surgery for such elements as screws, plates, fasteners or as stents in the cardiovascular system.
Author | Application date | Mg/Mg alloys | Application |
---|---|---|---|
Huse | 1878 | Pure magnesium | Stitches |
Payr | 1892–1905 | Pure magnesium | Nerve’s linkers |
Hopfner | 1903 | Pure magnesium | Vessels’ linkers |
Lambotte | 1906–1932 | Pure magnesium | Bone screws and plates |
Lespinasse | 1910 | Pure magnesium | Bone plates |
Groves | 1913 | Pure magnesium | Bone pits |
Andrews | 1917 | Mg-Al/Zn | Bone wires |
Seelig | 1924 | Pure magnesium | Bone wires |
Verbrugge | 1933–1937 | Mg-Al6-Zn3-Mn | Bone screws and plates |
McBride | 1938 | Mg-Mn | Bone wires and plates |
Maier | 1940 | Pure magnesium | Stitches |
Stone | 1951 | Mg-Al (2 wt.%) | Bone wires |
Wexler | 1980 | Mg-Al (2 wt.%) | Bone wires |
Hussl | 1981 | Pure magnesium | Vascular wires |
Applications of magnesium and its alloys in medicine [25].
At present, magnesium alloys are mainly considered as potential materials for applications in orthopedic implantology, vascular surgery and laryngeal microsurgery [26, 27, 28, 29, 30]. As regards orthopedic implantology, Mg alloys are used as compression screws. MAGNEZIX is the trade name of biodegradable orthopedic screws for human osteosynthesis application [31]. In the literature, there are some reports [32, 33, 34] on resorbable stents made of magnesium alloys (their trade name is Lekton Magic, produced by Biotronik company). This material is composed of zirconium (< 5 wt.%), yttrium (< 5 wt.%) and rare earth elements (< 5 wt.%). The stents degrade in a living body with time, but their location can still be identified. Finally, the stent material completely degrades and the space around it is filled with a calcium-apatite complex with an admixture of phosphate elements. The stents were implanted in 20 people and good flow in the implanted blood vessel was achieved after one month. In 2013, Biotronik, a German company, has obtained the CE mark for biodegradable coronary stents made of Mg alloy. It was the leader in development of biodegradable metal coronary stents. The areas of potential applications of magnesium and its alloys in implantology are presented in Figure 2.
Potential applications of Mg and its alloys in implantology [
In the context of resorbable orthopedic implants, research was initially carried out on technical magnesium alloys, for example AZ31, AZ91, WE43, LAE442. Unfortunately, magnesium alloys containing aluminum (AZ31) and heavy metals have been excluded as biomaterials because these additives have a toxic effect on the human body. The research was limited to alloys containing biocompatible elements and/or small amounts of rare earth elements, that are tolerated by the human body in appropriate concentrations [15].
As regards magnesium alloys for resorbable implants with a crystalline structure, the following groups of alloys has been examined: Mg-Ca, Mg-Zn, Mg-Zn-Ca, Mg-Mn, Mg-Si, Mg-Zr, Mg-Zn-Zr, Mg-Zn-Y, Mg-Zn-Zr-Y, Mg-Zn-Mn.
Rare earth elements (REE) are added in order to improve mechanical properties and creep resistance at elevated temperatures [35, 36]. Gadolin (Gd) and yttrium (Y) increase the strength properties during precipitation hardening. Neodymium (Nd) improves tensile strength at ambient and elevated temperatures. Yttrium and strontium (Sr) reduce the texture, and thus anisotropy, in rolled and extruded semi-finished products [35].
Magnesium alloys with the addition of rare earth elements, such as Mg-Y, Mg-Gd [37] and Mg-Nd, have been designed for use as biomaterials. ZW21 and WZ21 alloys (with the addition of Y and Zn) show promising mechanical and corrosion properties. For example, they are ductile (up to 20% elongation) and their tensile strength ≈ 270 MPa. Alloys such as AE21 and WE43 are used for stents [38, 39].
Noble metals as an additive to magnesium and calcium alloys have been studied mainly by the authors of this chapter [12, 40]. There is no information in the literature on the influence of Au and Pt addition on the degradation rate and mechanical properties of magnesium alloys. There are several sources for adding silver to magnesium alloys [41, 42].
The mechanical and corrosion properties of the alloy can be regulated by the structural and chemical composition of the alloy. Compared to their crystalline counterparts, magnesium-based metallic glasses may be more resistant to corrosion, due to their single-phase structure, which may result in a more uniform alloy corrosion. An example confirming the higher corrosion resistance of the amorphous material in physical fluid compared to the crystalline material with the same chemical composition is shown in Figure 3.
Results of structural tests of Mg36.6Cu36.2Ca27.2 alloy with amorphous structure (a) and crystalline structure (b) and surface images after 1.5 h of immersion in physiological fluid with amorphous structure (c) and crystalline structure (d) [
Magnesium alloys with amorphous structure, such as bulk metallic glasses (e.g. rods, plates) in the following phase systems: Mg-Cu-Y (-Ag, -Pd, -Gd), Mg-Ni-Y (-Nd), Mg-Cu-Gd (-Zn, -Y), Mg-Zn-Ca were obtained. In addition, studies are also carried out on Mg-based metallic glass without rare earth elements. The Laws [44] obtained bulk metallic glasses based on Mg-Cu-Ca, Mg-Ag-Ca, Mg-Cu-Ag-Ca alloy systems. However, for applications in implantology, magnesium alloys should have a biocompatible chemical composition. Therefore, the group of alloys based on the Mg-Zn-Ca phase system is most frequently considered as a new biomaterial for resorbable orthopedic implants [45]. In 2005, Gu et al. were the first to obtain bulk metallic glass in the Mg-Ca-Zn system, which was characterized by good strength properties and high glass transition capacity [46].
In the process of designing new degradable biomaterials, elements with potential toxicological problems should be omitted whenever possible and, if they are absolutely necessary, they should be reduced to the minimum. Calcium and zinc are essential elements in the human body; therefore, these elements should be the first choice for alloying additives in biomedical magnesium alloys. The concentration of calcium should not exceed 2 wt.%, and zinc – 6 wt.%, due to the corrosive properties of these magnesium alloys [47].
The most commonly used chemical elements for magnesium alloys are: Zn, Zr, Ca, Sr., Yb, Al, Li, Mn and rare earth elements (REEs) (Ce, Er, La, Gd, Nd, Y). The following are the additions, the influence of which on the properties of magnesium alloys is described in detail:
addition of zinc (< 5 wt.%) reduces the harmful influence of iron and nickel impurities, increases corrosion resistance [48],
addition of zirconium (< 2 wt.%) increases corrosion resistance [48],
addition of strontium (< 2 wt.%) improves corrosion properties and affects the strength of the alloy, which is similar to the natural bone [48, 49]. Optimal content of Zr and Sr. in Mg-based alloys increases surface energy and the ability to simulate contact osteogenesis. Mg-Zr-Sr alloys (2 wt.% Sr) display the best osseointegration and complete biodegradation [50],
addition of ytterbium (at the level of 2 wt.%) improves bending plasticity, corrosion properties and biocompatibility [49],
addition of calcium (> 1 wt.%) in pure Mg reduces corrosion resistance [48]. Calcium in magnesium alloys, without the addition of strontium, reduces surface energy and bone induction [50],
addition of yttrium (> 2 wt.%) decreases corrosion resistance in Mg-Y alloys [48].
Noble metals, such as gold and silver, were used as alloying additives in pure magnesium to increase its ductility. However, the alloys had low tensile strength [51]. Another source mentions that the addition of silver, as a substitute for calcium, improves the corrosion properties, strength and has an anti-bacterial effect [49].
Figure 4 shows variation in the open-circuit potential with time and polarization curves for pure Mg and Mg65Zn20.1Ca1.7Yb13Sr0.2 alloy in Ringer solution at 37°C.
Variation of the open-circuit potential with time (a) and polarization curves (b) for pure Mg and Mg65Zn20.1Ca1.7Yb13Sr0.2 alloy in Ringer solution at 37°C.
In the OCP plot (Figure 4a), various levels of recorded curves are visible, which results from differences in chemical compositions. The steady-state for pure magnesium is in the range of approx. -1.65 V, while for Mg65Zn20.1Ca1.7Yb13Sr0.2 alloy – slightly above −1.4 V. This shift towards positive values indicates favorable behavior of samples with alloy additions. Potentiodynamic measurements (Figure 4b) also show the differences between the studied alloys. The values of corrosion current density were slightly higher for magnesium alloy, as compared to pure Mg. However, significant differences in Ecorr by approx. 0.25 V are observed, which indicates that it is recommended to use alloying elements to improve corrosion resistance. E. Mostaed et al. [52] showed similar results regarding the differences in electrochemical tests between pure magnesium and the ZK60 alloy.
Designing of magnesium alloys as biomedical materials is a great challenge, due to rapid degradation of Mg in the environment of bodily fluids and insufficient implant-bone connection in orthopedic applications [50]. These disadvantages can be limited due to an appropriate selection of alloying additions. The purpose of optimal chemical composition of a new class of Mg-based biodegradable materials is to obtain optimal strength, ductility, resistance to fatigue and corrosion by modifying the structure and phase distribution [50, 53]. Currently, efforts are being made to select alloying additions that would promote osseointegration, understood as the fusion of the implant with the newly formed bone tissue and biodegradation without adverse effects on the functioning of body organs [50].
In the case of biomedical engineering, corrosion is the main factor determining the usefulness of implant materials. The tendency of biomaterials to corrode in the human body is, in fact, closely connected to their biocompatibility. Before placing in the human body, the material must be examined for the effects on the body and its properties. Ensuring such experimental conditions is difficult, as it is difficult to recreate the environment of the human tissues. Many parameters related to the production of magnesium-based materials and test parameters have an impact on the degradation results (Figure 5).
Parameters influencing the course of magnesium alloy corrosion process (in vitro) divided into subgroups: Research conditions and material factors [
The alloying elements and the processing parameters of Mg have a strong impact on its degradation properties (microstructure of the material described by the grain size, impurity content, type of phases etc.). Calcium as alloying element to Mg alloy is an extremely reactive metal and spontaneously reacts with water generating hydrogen [55].
Moreover, the research methods and conditions can significantly change the corrosion rate, as well as the formation and composition of the degradation layer, and thus determine the corrosion type [56].
Living microorganisms play an important role in the process of implant degradation. Such metabolic activity may directly or indirectly reduce the quality of the implant due to the corrosion process. Cells can act as an electrolyte on the metal surface, thus changing the corrosion resistance of the implant surface or even its composition [6].
Corrosion of magnesium in an aqueous environment occurs as a result of an electrochemical reaction with water, resulting in the formation of magnesium hydroxide, Mg(OH)2 and hydrogen gas, according to reactions (1–3) [54]:
In the initial phase of immersion, the surface of the material is exposed to the electrolyte and the anodic and cathodic reactions begin. Magnesium grains act as an anode and the cathodic reaction takes place in noble regions of alloy, which are grain boundaries, phase separation and precipitation. This leads to the exchange of electrons between the two regions, wherein the magnesium is degraded at the same rate, at which hydrogen is generated as a gas (H2). The cathodic reaction increases the pH by releasing H2 gas, while hydrolysis lowers it [54, 57].
When the concentration of Mg2+ and the increase of pH reach the solubility limit, magnesium hydroxide Mg(OH)2 is precipitated on the surface of alloy Mg [1]. In an environment, such as body fluids, where the concentration of chloride ions is greater than 30 mmol/dm3, the hydroxide formed on the surface of the magnesium alloy converts to highly soluble magnesium chloride. This reduces the level of protection of the surface layer by increasing its activity [58]. The formation of soluble magnesium chloride is described by the reaction (4):
This process accelerates the degradation of the material and increases the pH of the environment [6]. The presence of Cl− ions initiates pitting corrosion.
It should be mentioned that the structure of magnesium alloys mainly affects the course and rate of the degradation process. The analysis of corrosion tests results and studies of degradation products on the surface of the amorphous Mg64Zn32Ca4 alloy allow to distinguish and link the probable stages of the degradation process for the tested alloy in selected micro-areas, which include [59]:
transformation of the oxide layer into hydroxide,
penetration of the hydroxide layer by chlorides,
release of metallic ions and their transfer to solution,
hydrogen evolution,
creating a protective layer.
It should be noted, that the specified steps are not consecutive, but may occur simultaneously during the immersion of the amorphous Mg64Zn32Ca4 alloy. Therefore, the degradation of the amorphous Mg64Zn32Ca4 alloy can be considered as a total result of the following processes: the release of alloy components and the formation of protective layers. When the sample is immersed in a chloride solution, degradation occurs directly at the surface, due to the rapid release of active Mg and Ca. On the other hand, this results in enrichment of the sample’s surface with less active zinc. With the progress of degradation, zinc is oxidized and accumulates in the vicinity of disturbed chlorides, and therefore protects against further progression of degradation [60, 61]. However, the protective layer is not dense enough to completely prevent degradation. Chlorine ions damage the zinc oxide layer. Damage to the protective layer facilitates the transition to the Ca and Mg ion solution. These mechanisms are repeated until the amorphous magnesium alloy has degraded completely [62].
High corrosion rate of magnesium-based alloys in tissue environment may be limited, in addition to modifying the chemical composition, by surface treatment technologies. The degradation process can be controlled by way of coating the surface or changing its structure [53, 60, 61]. There are two methods of coating: conversion and deposition processes. Conversion coatings are the product of complex interaction of metal dissolution and precipitation, usually during treatment in aqueous solutions, while deposition treatments consist of metallic, inorganic and organic coatings [53, 62, 63]. Modifications in the surface of magnesium alloys by mechanical treatment are also used [62]. The classification of the coating technology for magnesium alloys is shown in Figure 6.
General classification of surface treatment technologies applied on magnesium alloys [
Homogeneity of the corrosion process is an important aspect that determines the degradation rate and the physical condition of the implant at a specific treatment stage [63]. Magnesium alloy coatings often have pores and cracks. Corrosion, which begins in these areas, leads to uneven rate of corrosion, accelerates destruction of the coating and premature degradation of the implant [63, 64]. Therefore, it is important to minimize the porosity of the coating by adjusting the parameters of the application process or the appropriate preparation of the substrate’s surface [62, 65]. In addition, protective coatings on biodegradable magnesium alloys should be adapted to specific applications – e.g. vascular stents have different surface requirements than orthopedic implants, where osseointegration with newly formed bone is important [62, 63]. Selected technologies of forming coatings on magnesium alloys are discussed below with regard to their advantages and disadvantages in terms of use, with an aim to reduce the corrosion rate:
Chemical conversion treatment – coatings based on Mg(OH)2 and fluorine are the most commonly used coatings developed with this technique, increasing corrosion resistance, while remaining non-toxic for the surrounding tissues [63, 66]. Their main advantage is good adhesion [67]. Chemical conversion treatment is still considered an economically viable technique [63, 66].
Micro-arc oxidation (MAO) – is considered the most cost-effective technology in the production of protective coatings against corrosion on Mg-based alloys. Surface pores and cracks, which accelerate the corrosion rate, are a significant disadvantage of this technology [60, 63].
Electrochemical deposition (ED) – is one of the most widely used methods. It has the ability to create homogeneous, dense protective layers, preventing further corrosion of the magnesium alloy substrate. Its great advantages, from technological point of view, are reproducibility and low temperatures of deposition [63, 66, 67].
Anodization – the quality of the coating obtained in this technique is strongly dependent on the parameters of the process: electrolytic composition, applied constant voltage or current, quality of the alloy surface and concentration of the alloying elements. The obtained 5–200 μm thick oxide layer creates functional corrosion protection with excellent adhesion [63, 67]. The main disadvantage of anodization is low wear resistance [67]. The technique makes it possible to obtain nano-tubular porous layers. However, this kind of surface structure is not suitable for some applications, e.g. stents [62, 63].
Ion Implantation – thin layers, resulting from the process, do not provide the required corrosion resistance. Despite many advantages of this technique, like modification of physical, chemical and electrical properties, ion implantation is expensive and is not suitable for complex geometries of implant components [62, 63, 67].
Physical/Chemical Vapor Deposition (PVD/CVD) – known, widely used technologies [63]. PVD enables the formation of hard coatings, resistant to tribological wear, but from the perspective of corrosion resistance, the layers are too thin and have pores. CVD is energy-efficient and does not manifest toxicity, but has the disadvantages of complicated layer growth and requires high temperatures [67].
In choice of the coating technology, one should always take into account preservation of the alloy’s biocompatibility, due to the potential toxicity of the elements introduced in coating treatments. In addition to coating, an alternative solution is mechanical treatment (shot peening, machining, burnishing, deep rolling), which solves the toxicity problem. The literature also describes hybrid techniques, which combine mechanical treatment with coating, as a promising solution for controlling the corrosion rate and mechanical properties at individual stages of treatment [63]. Biomimetic coatings are also noteworthy, as they are of biological origin and ensure excellent biocompatibility, but further work is required to improve their low adhesion to the substrate alloy [63, 67].
The types of protection coatings used to delay/reduce the degradation rate of magnesium alloys are shown in Figure 7. Besides phosphate and fluoride, most of the proposed ceramic coatings are non-resorbable. In the case of resorbable materials, considered polymeric coatings include PLA, PLGA and copolymers. Composite coatings increasing the corrosion resistance of magnesium alloys, tested by several researchers, include the following types of coatings: ceramic-metallic and ceramic-polymer.
Types of protective coatings used to delay/reduce the degradation rate of magnesium alloys [
As part of the authors’ own research, tests of phosphate coatings on magnesium alloys were carried out. In this work [78], the chemical method was used for Ca-P coatings preparation. NaOH and ZnSO4 as accelerators were added to phosphatizing baths, with an aim to form a dense and uniform protective phosphate coating. It should be noted, that NaOH and ZnSO4 are used to improve corrosion resistance of Mg alloys. The results of microscopic observations and phase identification of the obtained phosphate coatings (with the use of chemical composition of the phosphating bath) are shown in Figure 8.
X-ray diffraction patterns and SEM images of Ca-P coatings on Mg alloy [
XRD results indicate that obtained protection layers included dicalcium phosphate dihydrate (CaHPO4·2H2O). Both NaOH and ZnSO4 formed the morphology of the produced layers. The coating obtained by immersion in a phosphatizing bath with ZnSO4 addition (ZnAM50 sample) consisted of petals. The coating obtained by immersion in a bath with NaOH addition (NaAM50 sample) showed plate-like morphology.
The degradation tests of magnesium alloys with Ca-P layers were also performed (Figure 9a and b) in Ringer’s solution at 37°C. The results of electrochemical tests indicated that coated samples have more positive value of Ecorr than non-coated AM50 sample (Figure 9a). In addition, the cathodic part of potentiodynamic curve determined for the coated samples is located in a low current range, which indicated a low cathodic activity. It corresponds with the immersion tests results (Figure 9b). The volume of evolved hydrogen (hydrogen is a result of cathodic reactions) in an uncoated sample was higher than its level in coated samples.
Results of degradation tests of Mg alloys with calcium phosphate coatings in Ringer’s solution at 37°C: (a) polarization curves, (b) hydrogen evolution [
The degradation rate of ceramic material determines the occurrence of defects, cracks and flaws in technology. Defected ceramics can be destroyed in contact with water. Inclusions of other phases are equally disadvantageous to ceramic materials, that lead to their degradation. In contact with water, these inclusions accelerate aging and increase volume. These processes also have a direct impact on deterioration of the mechanical properties of ceramic materials [79].
Magnesium is a very important macroelement for the human body and serves a lot of functions. Its deficiency can cause many disorders and health ailments. Accordingly, magnesium is widely used in therapy, primarily for the treatment of heart disease, cardiovascular system or respiratory system. This became a premise for the use of magnesium and its alloys in medicine as a potential biomaterial for medical implants. The concept of using magnesium alloys as resorbable medical implants assumes that it will be non-toxic to the human body. The alloy components will also be elements present in the human body. The resorbable biomaterial of a magnesium alloy would be an alternative to the previously used implants, mainly orthopedic ones. Unfortunately, the high degradation rate of the magnesium alloy and the release of hydrogen gas in the environment of physiological fluids limit the use of these alloys as a biomaterial. Therefore, the research community continues to test different types of surface treatment for magnesium alloys, to protect it from rapid degradation. Taking into account the results of the global research and the authors’ own research, this seems to be the right way to obtain a resorbable biomaterial of magnesium alloy.
The authors declare no conflict of interest.
Prolonged jaundice is defined as a serum bilirubin level higher than 85 μmol/L (5 mg/dl), which persists at postnatal 14 days in term infants and 21 days following the birth in preterm infants. It affects 2–15% of all newborns and 40% of breastfed infants [1].
Although underlying cause can not be found in the majority of prolonged jaundice cases, this may also be the first sign of a serious causative pathology [2]. The most important point is to determine whether prolonged jaundice is of a benign cause or is due to a substantial disease. For this reason, health care providers should not take unnecessary tests in normal infants, but should also recognize infants with a causative pathology. The timing of initial investigations should be between two and four weeks in order to reduce the associated mortality and morbidity. Neonatal jaundice still maintains its importance in neonatal clinical practice, since early diagnosis and treatment is feasible [3, 4, 5, 6].
Although jaundice in early infancy is predominantly caused by indirect hyperbilirubinemia, it can also be seen as direct hyperbilirubinemia. Distinguishing between these types of jaundice is crucial in determining the etiology of prolonged jaundice.
To date, the most common cause of prolonged jaundice of indirect hyperbilirubinemia has been identified as breastmilk jaundice. It is known that breastmilk jaundice is seen at a rate of 1.3% in newborn infants and 2.4–25% in infants fed with breastmilk [7, 8, 9]. Besides, breastmilk jaundice may extend up to the twelfth week of life [10]. However, the diagnosis of breast milk jaundice is made by excluding other causes. Other possible causes of indirect hyperbilirubinemia include dehydration, hemolysis, infection, congenital hypothyroidism, inborn diseases of metabolism, and pyloric stenosis [2, 11]. Delayed diagnosis of these causes may increase morbidity.
Despite the jaundiced appearance, newborns with breast milk jaundice appear healthy, grow up in a normal way, and have no signs of an underlying disease. However, the presence of abnormalities in laboratory tests consistent with hepatobiliary dysfunction, such as elevation of aminotransferases and/or γ-glutamyl transpeptidase (GGT), warrants investigating pathological causes [12].
Direct hyperbilirubinemia is defined as serum direct bilirubin >20 μmol/L (>1.2 mg/dl) or direct bilirubin >20% of total bilirubin. Although rare, it usually indicates an underlying pathological cause and requires immediate investigation and prompt intervention. Direct hyperbilirubinemia (cholestatic jaundice) is never physiological. It affects 1/2500 live births and should be suspected in all jaundiced infants with light coloured stools and/or dark urine [4]. Delayed presentation of cholestatic newborns is still an important issue. For the early diagnosis of cholestasis, it is recommended to measure the serum total bilirubin (STB) and direct bilirubin levels of each newborn with prolonged jaundice [13].
Intrahepatic or extrahepatic biliary obstructions, viral infections, inborn diseases of meatabolism and endocrine disorders can lead to hyperbilirubinemia [13]. Extrahepatic biliary atresia is rare. It has been reported to occur at a rate of 1 per 21,000 live births in the UK and 9 per 14,000 live births in New Zealand [14]. Biliary atresia is the most common cause of neonatal cholestasis, and affected infants may appear healthy for a considerable time [15]. Kasai hepatoportoenterostomy should be performed in the first 45 days of life to restore bile flow and reduce further damage to the liver [16]. Early diagnosis of biliary atresia is the most important predictive factor in operated newborns [17].
Various conditions such as intrauterine infections, bacterial sepsis, galactosemia, aminoacidemias, and congenital hypopituitarism can occur with a mixture of increased direct and indirect bilirubin [18].
When severe jaundice goes untreated for too long, it can cause a condition called kernicterus. Kernicterus, or bilirubin encephalopathy, is bilirubin-induced neurologic damage, typically in infants. It can cause athetoid cerebral palsy and hearing loss. Kernicterus also causes problems with vision and teeth and sometimes can cause intellectual disabilities. Early detection and management of jaundice can prevent kernicterus.
A global protocol for investigating prolonged jaundice is not defined yet. The incidence of conditions that play a role in prolonged jaundice in terms of etiology varies between countries. This difference is the main reason for the various protocols. The cost of the examinations in cases with prolonged jaundice and the differences in healthcare systems between countries also contribute to this situation. The fact that prolonged jaundice can persist up to 3 months in most of the breastfed newborns and that prolonged jaundice in some newborns can be caused by serious underlying pathologies, even which may lead to liver transplantation, makes the current situation more difficult [19, 20].
The cause of prolonged jaundice seen in 15–40% of newborns is breastfeeding [21]. Breast milk jaundice is highly prevalent among the etiologies of prolonged jaundice. However, the diagnosis of breast milk jaundice is a diagnosis of exclusion. In neonatal prolonged jaundice, at the first step, direct hyperbilirubinemia and indirect hyperbilirubinemia should be differentiated, promptly. This requires getting a detailed history of the patient and a meticulous physical examination. Especially in the history, stool color and urine color should be questioned. Whether the urine and stool color is normal, the following initial tests should be performed.
1. Direct and indirect bilirubin level and liver function tests, in case of direct bilirubin level is increased | 4. Glucose 6 phosphate dehydrogenase (G6PD) enzyme level |
2. Complete blood count, peripheral blood smear | 5. TSH, fT4 |
3. Maternal blood group, infant blood group, Direct Coombs test | 6. Urinalysis, urine culture |
If there is no direct bilirubin elevation in the initial tests, these tests are sufficient for the follow-up and treatment of neonatal prolonged jaundice [22]. However, if increased direct bilirubin level is observed, the infant should be examined for cholestasis and specific tests to some cholestatic liver diseases should be done [23].
Tests for cholestatic liver disease | |
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1. ALT, AST, ALP, GGT, PT, APTT | 6. Serology for TORCH-S infections |
2.Abdominal and hepatobiliary ultrasonography | 7. Reducing substance in the urine |
3. Urine organic acids and blood amino acids | 8. Alpha feto protein |
4. Serum bile acids | 9. Sweat test |
5. Alpha-1 antitrypsin level |
Albeit most of the causes of prolonged jaundice other than breast milk are rare, congenital hypothyroidism and direct hyperbilirubinemia, which require urgent diagnosis (recognition) and treatment, should also be excluded [6]. Determining whether jaundice is hemolytic is important in order to identify the initial approach [2]. The causes of indirect hyperbilirubinemia and direct hyperbilirubinemia regarding etiological investigation in neonatal prolonged jaundice are classified as follows:
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The reason for isoimmunization in the mother and the formation of IgG antibodies is the passage of fetal erythrocytes into the maternal circulation. The basis of hemolytic disease in the newborn is the breakdown of fetal erythrocytes by antibodies passing through the placenta [25, 26].
Hemolytic diseases are classified in two groups as immune and nonimmune. Rh, ABO and minor blood group incompatibilities are in the immune group. In the nonimmune hemolytic group, erythrocyte enzyme defects, erythrocyte structural defects, infection, polycythemia and sequestration exist. Rh and ABO incompatibilities are the most common causes of immune hemolytic diseases [27, 28].
Rh incompatibility occurs in 30–35% of cases of prolonged jaundice which goes with hemolysis [29, 30]. Rh is a large protein with many antigenic sites. Common antigens are D, C, c, and E antigens. All antigens cause their specific antibody responses. In fact, 90% of this response is against the D antigen [31]. Therefore, a response to the D antigen is required for the diagnosis of Rh positivity [32]. Since the Rh antigen is only present on the erythrocyte membrane, severe hemolysis can be met in the event of Rh compability [33]. Rh system genes are located in the short arm of chromosome 1. The presence of the Rh gene can be learned in the first trimester by polymerase chain reaction (PCR) method via amniocentesis. Alloimmunization occurs when as little as 0.1 ml of blood from the Rh (D) positive fetus passes through the placenta into the circulation of the Rh negative mother [28, 30, 34]. The level of antibodies developed in the mother determines the degree of hemolytic disease. Hemolysis is caused by IgG type antibodies. The level of these antibodies indicates that the mother is sensitized.
In order to prevent the risk of Rh hemolytic disease and maternal sensitization, Rh (−) women whose spouses are Rh (+) should be routinely administered 300 μg anti-D immunoglobulin (Rhogam), whether the indirect Coombs test result is (−) at 28 weeks of pregnancy. This dose provides a prophylaxis for Rhesus disease in the vast majority of deliveries. The risk increases gradually in pregnancies after maternal sensitization [35]. The increase in serum bilirubin level during follow-up determines the severity of the hemolytic event [36].
Prolonged jaundice can be seen in Rh incompatibility. Rh incompatibility should not be forgotten in patients with prolonged jaundice which goes with hemolysis.
The most common blood group incompatibility is the ABO group incompatibility. It does not cause serious problems generally, although it is the most common reason. Unlike Rh incompatibility, the mother does not need to be sensitized beforehand in this entity [37]. Hemolytic disease due to ABO incompatibility is seen in cases where the mother’s blood type is O and the infant has A or B blood type. Although ABO incompatibility is seen in 20–25% of pregnancies, fetal sensitization findings (direct Coombs positivity) vary between 3 and 4% [38, 39].
Unlike Rh incompatibility, most of the maternal antibodies for ABO incompatibility are in the IgM form. Therefore, those antibodies do not have the ability of crossing the placenta. In addition, A and B antigens are not only found on erythrocytes, they are also found on different tissue cells. Consequently, not all antibodies passed to the fetus are retained by erythrocytes, but by other tissue cell antigens as well. These situations described, are the main reasons why ABO incompatibility does not cause serious problems compared to Rh incompatibility [40].
The clinical course resulting from hemolysis due to ABO incompatibility is generally mild in many cases and jaundice is observed as the only clinical finding. Jaundice usually develops on the first day and is often kept under control with phototherapy [38]. However, severe hemolysis due to ABO incompatibility is considerably rare [41].
Since it is the most common condition in patients with prolonged jaundice with hemolysis, it should definitely be investigated.
Minor blood group incompatibility accounts for as low as 3% of neonatal hemolytic disease cases. Duffy, Kidd and MNS antigens are responsible for this hemolysis. The pathophysiology of hemolysis is similar to Rh and ABO incompatibilities. Minor blood group incompatibilities can usually cause subclinical hemolysis as well as possible severe hemolysis and worsen pictures [30, 34].
Since it usually goes with subclinical hemolysis, it may cause milder manifestations such as prolonged jaundice [42].
The most common enzyme defects are; Glucose 6 phosphate dehydrogenase deficiency is a deficiency of 5′ nucleotidase and pyruvate kinase.
The most common enzyme deficiency is glucose 6 phosphate dehydrogenase deficiency. The G6PD enzyme acts as a catalyst and helps to reduce oxidative products in erythrocytes.
Due to the X-linked recessive inheritance, it is more common in male. Numerous mutations of the G6PD gene have been detected on the X chromosome. Because of having so many variants of the enzyme, hemolysis caused by G6PD can be present in different scenarios [43, 44]. In infants with G6PD in the neonatal period, hemolysis develops in case of exposure to oxidant stress or infection, and jaundice occurs as a result. Jaundice usually develops within 24–72 hours of life. In newborns with G6PD enzyme deficiency, bilirubin conjugation is much lower than in infants with normal G6PD enzyme. In fact, there are newborns with kernicterus caused by G6PD deficiency in the literatüre [45, 46]. The rate of G6PD deficiency in the etiology of prolonged jaundice varies according to populations. Various studies reported the rate of G6PD deficiency between 3.8% and 24% [47, 48].
Since prolonged jaundice may be the first sign of G6PD deficiency, the enzyme level should be checked in newborns diagnosed with prolonged jaundice.
It is inherited autosomal recessively. It is less common than G6PD deficiency. Unlike G6PD deficiency, signs of hyperbilirubinemia, anemia and reticulocytosis are present from the very beginning. Pyruvate kinase enzyme deficiency should be considered in infants with negative Coombs test and hemolytic anemia, in case of prolonged jaundice without erythrocyte membrane defect [49].
Hereditary spherocytosis, eliptocytosis, stomatocytosis and infantile pycnocytosis, which are erythrocyte membrane defects, can elicit hemolysis in the neonatal period. Hereditary spherocytosis is common in this group, while hereditary elliptocytosis and stomatocytosis are the other rare causes of hemolysis in newborn infants.
It has an autosomal dominant inheritance. Transforming spherocytic erythrocytes, which are more fragile than normal ones, under osmotic stress, is the characteristic of hereditary spherocytosis. The diagnosis of hereditary spherocytosis is made by detecting spherocytes in the peripheral smear and by osmotic fragility test. ABO incompability can be confused with hemolytic disease. Because microspherocytes can also be seen in the peripheral blood smear in ABO hemolytic disease. The distinction between these two diseases is made with the direct Coombs test [49].
Kocabay et al. found the rate of hereditary spherocytosis to be 0.1% in neonatal jaundice cases. Hyperbilirubinemia occurs in approximately half of newborn infants with hereditary spherocytosis, but this jaundice is usually considered as physiological, and may be overlooked. It can also be a reason for prolonged jaundice in a minority of the newborn infants [50].
In Gilbert’s syndrome, both hepatocytes’ bilirubin uptake is decreased and UDPGT activity is decreased. It is inherited in autosomal dominant or autosomal recessive. It has a prevalence of 2–6%. Although it can cause neonatal hyperbilirubinemia, the diagnosis is usually made at a later stage [25, 50]. It is thought that hyperbilirubinemia, which is observed in newborns with weight loss after insufficient caloric intake, also has a similar etiologic mechanism to Gilbert’s syndrome. Phenobarbital can be used as treatment in selected cases of Gilbert’s syndrome [51].
Studies have shown that Gilbert syndrome either elicit neonatal prolonged jaundice.
Crigler-Najjar Syndrome type 1 is caused by the complete absence of the hepatic glucuronyl transferase enzyme and is inherited autosomal recessively. It is a chronic non-hemolytic indirect hyperbilirubinemia syndrome and has a severe clinical course. In the homozygous form, severe indirect hyperbilirubinemia, which may progress to kernicterus, develops within the first three days of life, and bilirubin levels increase gradually, whether treatment is delayed. Diagnosis is made by percutaneous liver biopsy. UGT activity is measured in the biopsy sample/specimen. Phenobarbital is not an effective treatment of choice in Crigler-Najjar Syndrome type 1 syndrome [43, 52].
Crigler Najjar Syndrome Type 2 is more common than Type 1. Besides, the clinical course is better. The reason for this is that the activity of the UDPGT enzyme is partially present in Type 2. It has an autosomal dominant inheritance. Although indirect bilirubin levels start to increase in the first days of life, they usually do not go above 20 mg/dl levels. Unlike type 1, Crigler-Najjar Syndrome responds to phenobarbital. Therefore, response to phenobarbital can be used as a distinguishing strategy for type 1 and type 2 disease [25, 53]. Crigler-Najjar syndrome is also an important reason for prolonged jaundice.
In Crigler-Najjar syndrome type II, UDPGT activity is reduced in the same way as is found in infants with prolonged jaundice due to Gilbert’s syndrome [54]. Therefore, it is an etiology that should be kept in mind in newborns with prolonged jaundice.
It is a rare disease of newborn, which goes with high bilirubin levels in the postnatal first two days of life. Bilirubin levels are above 20 mg/dl and may rise to levels that can require exchange transfusion. These high bilirubin levels can persist for longer than 14 days [40]. Most of these infants develop kernicterus, whether exchange transfusion is not performed.
It is one of the substantial causes of neonatal prolonged jaundice. Prolonged jaundice is seen in approximately 10% of infants with congenital hypothyroidism. Decreased UGT activity is blamed for the pathophysiology of hyperbilirubinemia seen in congenital hypothyroidism. In this case, hyperbilirubinemia may persist for several months. Treatment with thyroid hormone leads rapid resolution of jaundice [55, 56].
Galactosemia may present with hyperbilirubinemia in the neonatal period. In the clinical picture of the disease; there are findings such as vomiting, dehydration, hepatomegaly, splenomegaly. Diagnosis is made by detecting the reducing substance in urine, sugar chromatography and enzyme levels [30].
Galactosemia is one of the etiologies of prolonged conjugated hyperbilirubinemia as a hereditary and metabolic disease. In newborns with galactosemia, hyperbilirubinemia becomes evident in the first week of life and can proceed with prolonged jaundice in many patients [57].
In the neonatal period, infections can be accompanied by jaundice. Particularly, urinary tract infections, and sepsis are common causes of jaundice. Indirect hyperbilirubinemia can develop in sepsis due to hemolysis caused by endotoxins [44].
Direct and indirect hyperbilirubinemia is seen in congenital infections such as TORCH-S group infections [30].
The incidence of urinary tract infection in asymptomatic infants, under two months of age with jaundice, but without fever, has been shown to be 7.5%. Therefore, prolonged jaundice may be the unique finding in urinary tract infection [58]. In a study, the most common infection associated with jaundice in the neonatal period was found to be urinary tract infection [59].
Extravasation of blood in the body leads to increased bilirubin production by enhanced heme protein metabolism via destruction of erythrocytes. Accumulation of red blood cells in tissue layers surrounding the brain and skull (cephalo hematoma, subdural hematoma, subgaleal hematoma) or in any part of the body in traumatic deliveries can lead severe hyperbilirubinemia [60].
Cephal hematoma defines a bleeding into the subperiosteal region and occurs in approximately 1–2% of all live births. Rupture of vessels results in a blood collection extending from the bone to the periosteum during labor [61]. Cephal hematoma can be causitive for jaundice due to the increase in bilirubin synthesis in the first 48–72 hours of life because of the destruction of erythrocytes in the extravasous blood collection [41].
The aim of the treatment is to reduce the increased bilirubin levels in order to prevent the damage to the central nervous system by the formation of kernicterus. Timely and prompt treatment is crucial to prevent the permanent effects of bilirubin toxicity such as kernicterus [62].
Whether the underlying cause of hyperbilirubinemia is known, treatment should be arranged according to that etiology. The most commonly used methods in the treatment of jaundice are: Phototherapy, intra venous immunoglobulin (IVIG) administration, exchange transfusion, and phenobarbital. Treatment indications vary according to the gestational week of the infant, postnatal age, bilirubin level, and the presence of hemolysis [63].
Treatment of Neonatal Jaundice | |
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1. Phototherapy | 2. Phenobarbital |
3. Intravenous Immunoglobulin | 4. Metalloporphyrins |
5. Exchange Transfusion |
It is appropriate to use the curves designed by American Academy of Pediatrics, which evaluate either the gestational week, and risk factors for infants whose gestational age is greater than 35 weeks. Instead, the tables include the cut-off bilirubin levels according to birth weight, for the infants whose gestational age is less than 35 weeks [64].
In case of a rapid rise in bilirubin levels within the first 24 hours, newborn infants should be evaluated for hemolysis. The ETCOc measurement directly indicates heme catabolism and bilirubin production [65]. The hourly rate of increase in bilirubin levels is also an important indicator for hemolysis. An increase of 0.2–0.5 mg/dl per hour in the bilirubin level is thought as an indicator of hemolysis. With a positive direct Coombs test (+), higher reticulocyte count, a decrease in hemoglobin and hematocrit levels are laboratory findings supporting hemolysis [66].
Phototherapy is used to reduce increased serum bilirubin level and reach a normal bilirubin level, to reduce the need for exchange transfusion and to prevent the development of kernicterus. Phototherapy lowers bilirubin levels by using certain wavelengths of light energy [67]. Blue light at a wavelength of 440–460 nm is the value at which bilirubin is best absorbed. In order for phototherapy to be effective, the energy must be a maximum of 5u/cm/nm. In order to obtain this energy, ideally, 440–460 nm, which is the best absorbed wavelength, and blue light should be used. The distance of the light should be adjusted to be 30–40 cm away from the infant. It should be given at the ideal wavelength and distance of 40 uw/cm/nm [68, 69]. In the same way, multidirectional administration of one-way phototherapy, from different angles enhances the success of the treatment [70].
In phototherapy, treatment decision was determined by bilirubin level, rate of increase in bilirubin level over time, birth weight, gestational age and postnatal age, and the presence of risk factors such as Rh, ABO and minor blood group incompatibility, G6PD enzyme deficiency, presence of asphyxia, hypothermia, acidosis, sepsis, and lower levels of albumin. Phototherapy is started when the serum bilirubin rises to a level that pose a risk for neurotoxicity. Phototherapy should be started in bilirubin values that exceed the determined limits. Risk factors that should be considered when determining the phototherapy limit are: Rh, ABO and minor blood group incompatibility, G6PD, albumin levels below 3 g/dl, presence of asphyxia, pronounced tendency to sleep, sepsis, hypothermia, presence of acidosis in blood gas analysis. In order for a newborn to be considered risk-free, all risk factors must be excluded, otherwise the newborn is considered as under risk. Decision of phototherapy, depends on the TSB.
Phototherapy is considered as safe. But it can have some undesirable effects. These side effects can be listed as follows: Retinal degeneration without an eye protective cover, fluid loss, bronze baby syndrome, rash, lactose intolerance, hypocalcemia, an increased risk of PDA particularly in preterm infants [40, 68]. There are studies showing that phototherapy increases the risk of conjunctivitis, and it predisposes to asthma and allergic rhinitis in long term [71].
Exchange transfusion is a successful but risky treatment method used in severe neonatal hyperbilirubinemia [72]. When TSB exceeds the cut-off level that is determined for exchange transfusion, the procedure should be performed without a delay.
Whether the expected decrease is not reached in TSB level despite intensive phototherapy or in case of a gradual increase, or when the risk of kernicterus is greater than the risk of exchange transfusion, or whether kernicterus has developed and signs are present, transfusion should be performed quickly [73].
When albumin levels are low, more care should be taken in terms of exchange transfusion. Because the amount of free bilirubin that cannot be bound to albumin will increase and there will be a high amount of free bilirubin which can increase the risk of kernicterus. The bilirubin/albumin ratio does not make a decision for exchange transfusion, but is used to support the treatment decision in conjunction with TSB levels in newborn infants. Albumin infusion is not recommended in patients with either hyperbilirubinemia and hypoalbuminemia [66].
A central catheter is placed before the patient for blood exchange. Then, blood collection from the newborn and replacement of the patient’s own blood with whole blood or erythrocyte suspension mixed with plasma are performed through this catheter. Approximately twice of the blood volume of the infant, which corresponds to 160–170 ml/kg, is exchanged by this way. The volume of blood taken or given once during the exchange transfusion process should not exceed 5 ml/kg. Besides, the volume rate of blood given or taken in the exchange process should not be more than 2 mL/kg/min. The reason for this is that if this rate is exceeded, sudden changes in intracranial pressure can occur due to blood pressure fluctuation [74]. The exchange transfusion process ensures that the majority of the infant’s sensitized erythrocytes are replaced by unsensitized erythrocytes. This change provides a significant decrease in serum bilirubin level.
Serum electrolytes, bilirubin and blood glucose level should be checked at regular intervals during exchange transfusion. Because hypocalcemia and hypoglycemia may occur depending on the content of the blood product used during the procedure.
Exchange transfusion is not an innocent procedure and complications may befall. During the procedure, the newborn can have apnea, blood pressure imbalances can be met, the heart rate can slow down, electrolyte disturbances may be observed, disturbances in blood glucose level can be observed, thrombocytopenia, coagulation disorders, disseminated intravascular coagulation, metabolic acidosis, thromboembolism, malnutrition, necrotizing enterocolitis, sepsis can also be observed. While the risk of death is 1% in healthy infants, it is 12% in infants with risk factors [75].
The use of exchange transfusion has greatly decreased due to the frequent and ideal use of phototherapy. This has also reduced the incidence of possible mortality and morbidity risk arising from the exchange transfusion procedure.
Agents used to treat neonatal jaundice can be classified according to their action of mechanism as follows; Inhibition of bilirubin (Tin protoporphyrin and mesoporphyrin, Zinc protoporphyrin and mesoporphyrin), accelerating bilirubin excretion process (Phenobarbital, Ethanol, Chloroquine, Antihistamines, Clofibrate, Antipyrine), inhibiting the enterohepatic circulation (Agar, Activated charcoal, Cholestyrylpyrron, bilirubin oxidase) and IVIG [75]. IVIG, phenobarbital, and metalloporphyrins are the most preferred ones in the treatment of hyperbilirubinemia.
Phenobarbital is a potent inducer of microsomal enzymes. It makes this strong induction by inducing the enzyme glucuronyl transferase. By this mechanism, it increases bilirubin conjugation, excretion and bile flow, which means that it affects all steps of bilirubin metabolism. In addition, phenobarbital is used in the diagnosis and treatment of Crigler Najjar disease [76]. It is recommended for use only in high-risk conditions.
Intravenous immunoglobulin therapy can be used in Coombs test positive Rh or ABO incompatibility, minor blood group incompatibility, and newborn infants who received intrauterine transfusion/s. IVIG should be given timely at a dose of 0.5–1 g/kg and within 2 hours, without delay, in newborn infants with hyperbilirubinemia that do not decrease despite intense phototherapy, and whose bilirubin level is close to the limits of exchange transfusion [77].
High-dose IVIG therapy in newborn infants, such as a dose of 0.5 g/kg, reduces the need for exchange transfusion. It does this by slowing the rate of bilirubin rise and lowering maximum bilirubin levels. IVIG is thought to prevent hemolysis by its mechanism of blocking reticuloendothelial Fc receptors [78, 79].
As a special case, the management of hemolytic disease due to Rh incompatibility is as follows; Preparation should be made before birth. First of all, preparation of the blood product to be given should be done. Since exchange transfusion can be required as soon as in the delivery room, equipment should be ready for use and IVIG should be kept, if needed. A staff experienced in neonatal resuscitation should be present. As soon as the infant is born; intensive phototherapy treatment is started and IVIG is given to the patient as a pharmacological treatment promptly. Hemoglobin (Hb) and STB levels are checked from the blood sample taken from the umbilical cord. Intensive phototherapy should be started in newborn infants born above 38 weeks, if the bilirubin level is above 6 mg/dL and/or the Hb value is less than 10 g/dL in the blood sample taken from the umbilical cord, as well as the preparation begins for exchange transfusion. In case of the STB increase is more than 0.5 mg/dL per hour despite intensive phototherapy and IVIG therapy, rapid exchange transfusion should be performed [80].
Metalloporphyrins, which competitively inhibit heme oxygenase enzyme, slow down bilirubin synthesis. The most effective metalloporphyrin is Tin (Sn) because it lowers bilirubin [81, 82]. A single dose of 6 μmol/kg is used in the treatment of neonatal jaundice. It has been observed that Sn-mesoporphyrin applied together with phototherapy can elicit transient erythema in some of the newborn infants. Currently, metalloporphyrins are not a part of routine practice of treatment for neonatal jaundice [76].
Prolonged jaundice can become an intensive care problem, if not noticed early. Extreme hyperbilirubinemia (TB of 25 to 30 mg/dL) can cause bilirubin encephalopathy, Kernicterus, which is usually characterized by the deposition of unconjugated bilirubin in brain cells. Neuronal necrosis/damage occurs in the basal ganglia, hippocampus, hypothalamic nuclei as a bilirubin-phosphatidylcholine precipitate, diencephalon, midbrain, neurohumoral and electrolyte control, brainstem nuclei for oculomotor and auditory function, and in the cerebellum. Clinical manifestations include cerebral palsy, deafness, seizures, etc.
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\n\nIntechOpen works with award winning print-houses and we hold to the fact that all of our printed products are of the highest quality.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. 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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:"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. 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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. 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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:"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://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.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.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",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. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"28",type:"subseries",title:"Animal Reproductive Biology and Technology",keywords:"Animal Reproduction, Artificial Insemination, Embryos, Cryopreservation, Conservation, Breeding, Epigenetics",scope:"The advances of knowledge on animal reproductive biology and technologies revolutionized livestock production. Artificial insemination, for example, was the first technology applied on a large scale, initially in dairy cattle and afterward applied to other species. Nowadays, embryo production and transfer are used commercially along with other technologies to modulate epigenetic regulation. 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She has over 25 years of experience working in reproductive biology and biotechnology areas with a special emphasis on embryo and gamete cryopreservation, for research and animal genetic resources conservation, leading research projects with several peer-reviewed papers. Rosa Pereira is member of the ERFP-FAO Ex situ Working Group and of the Management Commission of the Portuguese Animal Germplasm Bank.",institutionString:"The National Institute for Agricultural and Veterinary Research. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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