Components of biocompatibility
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During the past few years, the biocompatibility of biomaterials (non-vital material intended to interact with biological systems within or on the human body) has evolved into a comprehensive, complex, and independent discipline of biomaterials science. Consequently, a number of terms have been developed or were adopted from toxicology. Some of these terms may be familiar to patients and clinicians from daily life – for example, the term “safety”. Safetyin relation to the evaluation of biomaterials means freedom from unacceptable risks. Thus, safety does not stand for a complete lack of risks.
Biocompatibility is a word that is extensively used within biomaterials science, but there still exists a great deal of uncertainty about what it actually means and about the mechanisms that are subsumed within the phenomena that collectively constitute biocompatibility. During the 2nd Consensus Conference in Liverpool, biocompatibility was defined as “the ability of a material to perform with an appropriate host response in a specific application” (Gatti & Knowles, 2002, as cited in 2nd Consensus Conference, 1991). A biocompatible material may not be completely “inert”; in fact, the appropriateness of the host response is decisive. Previously, the selection criteria for implantable biomaterials evolved as a list of events that had to be avoided, most of these originating from those events associated with the release of some products of corrosion or degradation, or additives to or contaminants of the main constituents of the biomaterial, and their subsequent biological activity, either locally or systemically. Materials were therefore selected, or occasionally developed, on the basis that they would be non-toxic, non-immunogenic, non-thrombogenic, non-carcinogenic, non-irritant and so on, such a list of negatives becoming, by default, the definition of biocompatibility. A re-evaluation of this position was initiated by two important factors. Firstly, an increasing number of applications required that the material should specifically react with the tissues rather than be ignored by them, as required in the case of an inert material. Secondly, and in a similar context, some applications required that the material should degrade over time in the body rather than remain indefinitely. It was therefore considered that the very basic edict that biocompatibility, which was equated with biological safety, meant that the material should do no harm to the patient, was no longer a sufficient pre-requisite. Accordingly, biocompatibility was redefined in 2008 as “the ability of a material to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient or beneficiary of that therapy, but generating the most appropriate beneficial cellular or tissue response in that specific situation, and optimizing the clinically relevant performance of that therapy” (Williams, 2008).
In addition to the beneficial tissue response and the clinically relevant performance of a biomaterial, cytotoxicity, genotoxicity, mutagenicity, carcinogenicity and immunogenicity are considered to be the components which constitute “biocompatibility” (Table 1).
Beneficial tissue response and the clinically relevant performance |
Cytotoxicity (systemic and local) |
Genotoxicity |
Mutagenicity |
Carcinogenicity |
Immunogenicity |
Components of biocompatibility
Toxicityof a material describes the ability to damage a biological system by chemical means. In higher organisms (animals, human beings), local toxicity – that is, adverse reactions emerging at the application site – is differentiated from systemic toxicity, in which adverse reaction appear in an area distant from the application site.Cytotoxicityrefers to damage to individual cells, for example in cell cultures. Cells can die because of necrosis or apoptosis (programmed cell death).
Immunogenicity is referred to the ability of a substance to provoke an immune response or the degree to which it provokes a response. An allergic reaction to a substance can be triggered if the organism was previously sensitized to this substance. The concentrations that elicit a reaction in a previously sensitized person vary between subjects. The dose levels causing allergic reactions are generally significantly lower than those causing toxic reactions.
Genotoxicity describes an alteration of the basepair sequence of the genome DNA. Cells possess numerous mechanisms to repair genotoxic damages. Alternatively, a transfer of these genetic damages to subsequent generations of cells can be avoided by programmed cell death (apoptosis). Nonetheless, if theses genetic damages are passed on to the next generation, this effect is called mutagenicity. Mutagenicity and carcinogenicity are not the same. Carcinogenicity means that alterations in the DNA have caused a cell to grow and divide inappropriately; in other words, alterations of DNA promoted the generation of malignant tumors. Carcinogenicity results from several mutations. It is important to understand that not all mutagenic events lead to carcinogenesis. However, mutagenicity can be assessed as an indicator of “possible” carcinogenicity of substances that directly attack DNA.
The components of biocompatibility will be discussed in relation to bioceramics later in the current chapter.
In practical sense, the term bioceramics can be referred to a group of ceramics, which are used in the field of biomedicine. These biomaterials are ceramics, which are manufactured or processed to be suitable for use in or as a medical device that comes into intimate contact with proteins, cells, tissues, organs, and organ systems.
Bioceramics are used to restore normal activity of diseased or damaged parts of the body. As people age, progressive deterioration of tissues requires replacements in many critical applications. After successful researches, various bioceramic products are now commercially available in the medical market as substitutes for the original damaged body parts and for many other critical applications (Table 2).
Dentistry | Dental restorations |
Prosthodontic devices | |
Orthodontic brackets | |
Repair of periodontal disease | |
Maxillofacial reconstruction | |
Orthopedics | Joint replacements |
Cardiology | Prosthetic heart valves |
Neurosurgery | Cranioplasty repair |
Otolaryngology | Middle ear implants, Vocal cord paralysis |
Miscellaneous | Magnetic treatment of bone tumors |
Drug delivery systems |
Benefits of ceramics in biomedicine.
Traditionally, ceramics have seen widescale use as restorative materials in dentistry. Dental ceramics are rigid materials that are shaped by sintering, casting, pressing, milling, or sonoerosion. Dental ceramics are also available as prefabricated inlays (inserts). Dental ceramic restorations include materials for denture teeth, fixed partial dentures, full crowns, veneers, inlays, onlays, and post - cores to restore missing tooth part, a tooth, or teeth. Restorative dental ceramics could be bonded to metal (Metal-Ceramics) or be metal free ceramics (All-Ceramics). High-performance ceramics yield excellent technical properties, which make them suitable to be used as copings or frameworks for crowns and bridges. To improve their aesthetics, they have to be veneered with other, mainly silicium oxide ceramics. Dental ceramics are further applied as implant materials, for example as coating for titanium implants, or as full ceramic implants. The most recent use for ceramics in dentistry is orthodontic brackets.The development and demand for these items has been driven solely by aesthetics. Also, ceramics are used for repair for periodontal diseases. They are also useful for maxillofacial reconstruction, augmentation and stabilization of the jaw bone because bioceramics may develop the clinical applications of bone substitutes. The physical, chemical and biological properties of bioceramics can be used for preparing advanced bone substitutes. Bioactive glass ceramics and calcium phosphate ceramics are the two ceramic types used as bone substitute or for bone healing process. Bioactive glass ceramics bonds to bone without an intervening fibrous connective tissue interface (Schepers et al., 1991). When granules of bioactive glass ceramics are inserted into bone defects, ions are released in body fluids and precipitate into a bone-like apatite on the surface, promoting the adhesion and proliferation of osteogenic cells (Neo et al., 1993). After long-term implantation, this biological apatite layer is partially replaced by bone (Neo et al., 1994). Bioactive glass with a macroporous structure has the properties of large surface areas, which are favorable for bone integration. The porosity provides a scaffold on which newly-formed bone can be deposited after vascular ingrowth and osteoblast differentiation. The porosity of bioactive glass ceramics is also beneficial for resorption and bioactivity (De Aza et al., 2003). Calcium phosphate polycrystalline ceramic materials can be produced by precipitation from aqueous solutions and by solid-state reactions. The rationale for using hydroxyapatite as a biomaterial is the advantage of using a material having similar composition and crystalline structure as natural calcified tissues. Hydroxyapatite and other calcium-based ceramic materials can actively encourage bone regeneration at the surface of an implant. It has been postulated that the use of calcium phosphate ceramic biomaterials might replace the use of bone grafts. The chemistry of these materials is reasonably well established (Nascimento et al., 2007) and significant animal experiments have shown these materials to be both biocompatible and bioactive.
However, bioceramics use in other fields of biomedicine has not been as extensive, compared to metals and polymers. For example, in orthopedics, ceramics such as alumina (aluminum oxide ceramics) and zirconia (zirconium oxide ceramics) are used for wear applications in joint replacements. Bioceramics can now be used for hips, knees, tendons and ligaments replacements. In cardiovascular or circulatory system (the heart and blood vessels involved in circulating blood throughout the body), problems can arise with heart valves and arteries. The heart valves suffer from structural changes that prevent the valve from either fully opening or fully closing, and the diseased valve can be replaced with a variety of substitutes. As with dental implants, ceramics may be used as pyrolytic carbon coatings for prosthetic heart valves (Sarkar & Banerjee, 2010). Less obvious examples of the use of ceramics as biomaterials are in neurosurgical cranioplasty repair of the skull bone defects, in hand arthroplasty of the metacarpophalangeal joint, in otolaryngology as implants in the middle ear, or the use of bioactive glass ceramics in the treatment of vocal cord paralysis. Bioactive glass ceramics containing magnetite can be used to kill bone tumors when a magnetic field is applied. Ceramics implants can also be used as drug delivery systems (Nascimento et al., 2007).
Based on their chemical reactivity with the physiological environment, bioceramics can be broadly categorized in three types (Fig. 1):
They are such as alumina, result in little or no physiological reaction in the human body and tend to exhibit inherently low levels of reactivity which peak in the order of hundreds of years. They are attached by compact morphological fixation.
Theyare such as bioactive glass ceramics (bioglass), react in a positive way with local cells, i.e. they directly attach by chemical bonds and have a substantially higher level of reactivity, peaking in the order of 100 days.
They are porous or nonporous structures which are slowly and gradually replaced by bone such as tricalcium phosphate, have even higher levels of reactivity, peaking in the order of 10 days (Shackelford, 2005).
Classification of bioceramics according to biocompatibility
Biocompatibility of ceramics is a critical issue because of three different reasons. The first is that these materials are in intimate contact with human tissues for long terms and cannot be removed by the patient. Secondly, biocompatibility is an ongoing process and not a static one. For example, it is possible that a dental implant that is osseointegrated today may or may not be osseointegrated in the future. Thirdly, it has to be stressed that biocompatibility of fixed prosthodontic materials like ceramics is often overlooked because many practitioners assume that, if the material is on the market, its biocompatibility does not need to be questioned. For example, two systems are currently responsible for standards that can be used to document dental products quality: the American National Standard Institute / American Dental Association (ANSI/ADA) document No. 41 (1997) and addendum No. 41A (1982) and the International Standards Organization (ISO) 10993 document (1993). The ANSI/ADA and ISO do not require specific biologic tests to approve the quality of a new dental material. Rather, they place the responsibility on the manufacturer to present evidence for a compelling case for approval. So, it is up to the manufacturer to defend the substantial equivalence argument. The evidences used for approval of quality of a dental material consist of in vitro tests (cell-culture), in vivo tests (animal experiments), and clinical tests (clinical trials of the material). However, it is becoming increasingly impractical to test all new materials through all of these stages. The problems of time, expense, and ethics have limited the usefulness of this traditional biologic testing scheme. Therefore, companies market materials with little clinical experience, and may rely heavily on in vitro and animal experiments (Wataha, 2001).
Although most ceramic materials are generally regarded as being more or less inert, their possible effects of degradation products on biological systems must not be overlooked. The composition and physical properties of ceramic materials can affect the inertness. Safety cannot be inferred from measurements of one ceramic formulation to other compositions or conditions. Since bioceramics have been mainly used in dentistry, biocompatibility and its relevant properties for ceramics will be mainly discussed in relation to oral health.
It is believed that biologic reactions in general are mainly based on the interaction of a substance eluted from a material with a biologically relevant molecule. Thus, the composition of a material is of importance for its biocompatibility (Schmalz & Garhammer, 2002). Different elements in the periodic table of elements can be used in ceramics. The diversity of these ceramics makes understanding their biocompatibility difficult, because any element in a material may be released and may influence the body.
Ceramics are commonly described by their composition. However, composition can be generally expressed in two ways; either as weight percentage (wt %) of elements or percentage of the number of atoms of each element in the material (atomic percentage = at %). Weight percentage is the most common way of describing a material\'s composition, and is used by material manufacturers and by standard organizations. However, biologic properties are best understood by knowing the atomic percentage composition. Atomic percentage better predicts the number of atoms available to be released and affect the body. The wt% and at% of a material or an alloy may be substantially different from each another.
Ceramics could be oxide or non-oxide ceramics. Oxide ceramics in dentistry are primarily based on silicon oxide (SiO2), aluminum oxide (Al2O3), and zirconium oxide (ZrO2). Non-oxides, such as silicon carbide, silicon nitrite, and aluminum nitrite, are of minor importance in dentistry due to their black color. Some dental ceramics can be combined, such as an Al2O3-ceramic framework veneered with SiO2 ceramic. Lanthanum glass is used as a coupling agent, which infiltrates the aluminum oxide framework. Lanthanum glass consists of 39% lithium oxide. Additives (such as leucite) are intended to improve the mechanical properties of the ceramics, in particular to limit crack propagation. Further additives in dental ceramics are fluxing agents and coloring pigments, such as metal oxides, as well as fluorescents such as oxides of cesium and samarium. Some calcium phosphate materials are regarded as ceramics, too. These substances represent a very heterogeneous group of materials, including sintered hydroxyl apatite (HA) with a very low solubility and tricalcium phosphate (TCP) ceramics with varying resorption behaviors. Calcium phosphate ceramics usually consists of 100% of the respective mineral phase (TCP or HA).
Biological systems may have harmful or destructive effects on bio-materials, classified as biodegradation. In the oral environment, this includes not only the process of destruction and dissolution in saliva but also chemical/physical destruction, wear and erosion caused by food, chewing and bacterial activity. Therefore, it is important to evaluate the material reactivity in the oral cavity, which is governed by thermo-dynamic principles and electro-chemical reaction kinetics. This means that when a material is placed in the oral cavity, the material-saliva system will be driven toward a state of thermo-dynamic equilibrium. At equilibrium, the material either will remain stable in its elemental form or oxidize into its ionic form (corrosion). Thus, the initially uncharged elements inside the material lose electrons and become positively charged ions as they are released into solution. Corrosion is a chemical property that has consequences on other material properties, such as esthetics, strength, and biocompatibility. From a biocompatibility standpoint, the corrosion of a material indicates that some of the elements are available to affect the tissues around it.
The chemical durability of dental ceramics is basically good. They are commonly regarded as insoluble or only very slightly soluble at best. However, the degradation of dental ceramics can generally occur because of mechanical forces (wear) or chemical attack (solubility in an acidic, neutral, or alkaline environment), or a combination of the two. Some calcium phosphate ceramics are internationally engineered for a gradual resorption (TCP). The release of substances can generate unwanted effects (biological and mechanical) on one hand, or it may promote biocompatibility on the other hand, such as in terms of improved bone apposition (bioactivity). The multiphase microstructure of many dental ceramic materials results in complicated corrosion modes, as each phase is likely to react individually to the corrosive medium. Besides, chemical durability of ceramic materials may be influenced by many other factors, such as the chemical character of the corrosive medium, the exposure time, and the temperature. For glass ceramics, the initial surface reaction is mainly an acid-base reaction in which leaching ions are replaced by H+ ions, the result of which will be an alkali-ion-depleted leach layer overlying a permeable gel layer. Beneath the alkali-depleted layer, the corrosion process will produce a silica-rich layer, offering some protection to the bulk material. However, because of differences in composition, microstructure, and local corrosion conditions, the corrosion process is far more complicated and may also lead to the partial breakdown of the silicate structure at the surface. In addition, glasses high in K2O have been less chemically durable than glasses made with soda (Na2O) as an added flux material, whereas the presence of zirconia and alumina has shown to improve the chemical durability of glasses. When exposed to hydrolysis testing, ultra-low-temperature sintering ceramics displayed higher solubility than traditional high-temperature sintering ceramics. However, in repeated hydrolysis tests, high- and low-sintering ceramic materials did not react in the predicted manner. Alumina, which is regarded as a very stable material, may also undergo compositional changes when exposed to a corrosive environment (Milleding et al., 2002).
Corrosion, as mentioned before, is always accompanied by a release of elements and a flow of current. The release of substances from dental materials is considered to be gradual and to occur in small amounts. Evaluation of mass release from dental ceramics is not common in the literature, although there are some studies that have demonstrated such mass release. The leakage of inorganic ions from ceramics has been found to take place in aqueous media and vary with the glass composition and environmental conditions. Under more severe conditions (as the concentration of alkali ions increases), the Si-O-Si bonds may be broken, and the entire glass structure may be impaired. The reduction in chemical durability is of importance, since an increased susceptibility to chemical attack may release ions of the elements (K2O.Al2O3.4SiO2), which in certain circumstances, could be considered undesirable from a biocompatibility perspective (Milleding et al., 2002).
Two dominant mechanisms could be responsible for the aqueous corrosion of alkali-silicate glasses: (1) the selective leaching of alkali ions and (2) the dissolution of the glass network. At a pH of 9 or less, selective leaching of alkali ions could be the dominant mechanism. This mechanism can be controlled by the diffusion of H+ or H3O+ ions from an aqueous solution into the glass and the loss of alkali ions from the glass surface. In general, alkali metal ions from glass are much less stable in the glass phase than in the crystalline phase and thus could be leached more rapidly.
In contact with saliva or other organic fluids, biomaterials are instantly covered with organic films, the composition and properties of which undoubtedly influence the surface corrosion process and subsequent bio-reactions. It has been assumed that organic films on ceramic surfaces reduce the surface degradation by building up concentration gradients and reducing the diffusion of ionic elements through the surface films. In addition, it has been found that leaching of inorganic ions can be influenced by pH of the corrosion solutions and the ions potential for the complex binding of dissolved glass constituents, resulting in more extensive corrosion than indicated by the pH value alone (Milleding et al., 2002).
Sjögren et al. (2000) tested the release of elements from different dental ceramics (low-fusing, conventional veneering, press-casting ceramics) into a cell culture medium by inductively coupled plasma optical emission spectrophotometry. They found multiple released elements such as aluminum (Al), silicon (Si), sodium (Na), potassium (K), magnesium (Mg), and calcium (Ca). Also, Milleding et al. (2002) studied the in vitro ion dissolution from glass-phase ceramics, with or without crystalline inclusions, and from all-crystalline ceramics using the inductively coupled plasma optical emission spectroscopy. A large number of inorganic elements leached out from the previous dental ceramics. The major leaching elements were sodium and potassium. There were also magnesium, silicon, and aluminum. The various glass-phase ceramics displayed significant differences in ion release and significantly higher release values than all-crystalline alumina and zirconia ceramics. No significant difference in dissolution was found between high and low-sintering glass-phase ceramics or between glass-phase ceramics with high volume fractions of crystallites in the glass phase in comparison with those with lower crystalline content.
Logically, it has to be noted that the type of released elements depends on the composition of ceramic material itself. From silicon oxide ceramics, silicon, sodium, potassium, boron, and aluminum are released into various diluents at different pH values; silicon, sodium, and potassium are leached in higher amounts than are aluminum and boron. Aluminum oxide ceramics leach only minimal amounts of ions under physiological conditions. Calcium phosphate ceramics release calcium and phosphate into adjacent tissues. Overall, hydroxyapatite and fluorine apatite ceramics are less soluble than tricalcium phosphate ceramics (Lacefield, 1999).
Biomaterials are developed in order to evaluate, treat, augment or replace human tissue, organ or function. Biocompatibility is the main prerequisite for their safe use as medical devices. In order to assess the biocompatibility of a material, it is necessary to do a battery of tests, depending on the intended use, location and duration the material is to come in contact with the tissues. The evaluation of biocompatibility is dependent not only on the tested biomaterial but also on the test method used. So clinicians need to be familiar with these methods. Biocompatibility is measured with 3 types of biologic tests: in vitrotests, animal experiments and clinical tests (Fig. 2).
Plan of biocompatibility tests in order.
The common approach when testing the biological behavior of materials is to start with simple in vitro tests. If these experiments and investigations of a material’s efficiency deliver promising findings, then more comprehensive studies on experimental animals (in vivo evaluation) will be performed. Clinical trials (usage tests) are the final step of this evaluation process.
In vitrobiocompatibility tests are less expensive ways to survey newly developed materials. They simulate biological reactions to materials when they are placed on or into tissues of the body. These tests are performed in a test tube, cell-culture dish, or otherwise outside of a living organism in which cells or bacteria are generally placed in contact with a material. For example, a strain of bacteria may be used to assess the ability of a material to cause mutations (the Ames test). The advantages of in vitrobiocompatibility tests are, being experimentally controllable, repeatable, fast, relatively inexpensive and relatively simple. Another major advantage is that these tests generally avoid the ethical and legal issues that surround the use of animals and humans for testing. The primary disadvantage of in vitrobiocompatibility tests is their questionable clinical relevance.
In animal experiments, the material is placed into an animal, usually a mammal. For example, the material may be implanted into a mouse or placed into the tooth of a rat, dog, cat, sheep, goat or monkey. Animal models allow the evaluation of materials over long time durations and in different tissue qualities (e.g. normal healthy or osteopenic bone) and ages. Not only can the tissues in the immediate vicinity be assessed, but, tissues in remote locations of the implanted material can also be studied, which is particularly relevant to the study of wear particle debris. However, questions arise about the appropriateness of an animal species to represent the human response and that they are time-consuming and expensive. In animal experiments, ethical concerns and animal welfare issues are very important.
The clinical test is, by definition, the most relevant biocompatibility test. These tests are essentially clinical trials of a material in which the material is placed into a human volunteer in its final intended use.In a controlled clinical study, test and control materials are examined at the same time. Controlled clinical studies possess a higher level of significance/evidence compared with studies in which only one material is investigated. Biocompatibility data from clinical studies are naturally of special interest for the clinician, since the examination was done on the target group of this material (patients). But this should not conceal the fact that clinical studies reveal limitations, too. An uncritical transfer of such results to patients in daily practice may result in problems, for instance, if data are not based on a blinded study. Therefore, at least treatment and subsequent assessment should be done by different persons. Many unwanted reactions appear only after chronic exposure. But clinical studies – in particular those with new materials – are frequently limited to comparatively short periods of time (some are only 6 months). In addition, only a small and often strictly selected group of patients is included in the study, for instance in a university hospital. The clinical studies are also expensive, time-consuming, extraordinarily difficult to control its variables, difficult to interpret and may be legally and ethically complex. Clinical tests are done only if satisfactory results are obtained in the in vitroand animal experiments.
Experimental animals are usually used to determine systemic toxicity. Previously, the acute lethal dose 50% (acute LD50) was determined as routine. Acute LD50 isthe dose required to kill half the members of a tested population after specified test duration. Today, other methods that are more sparing of animals are used, such as the so-called limit test (administration of a fixed dose, e.g., 2,000 mg/kg body weight). The chronic systemic toxicity will be determined by administering the material or extract over several months. Tests are sometimes extended over the lifetimes of the experimental animals. At the end of these studies, survival rates of the animals and patho-histological alterations of the main organs will be determined. Further information regarding chronic toxicity is obtained from accidents (high exposure level) and based on observations of occupationally exposed subjects (e.g., dental personnel) who are often in contact with the “active” unset material.
One fundamental concern about the safety of ceramics used as fixed prosthodontic materials is their ability to cause systemic toxicity in the body. A stress must be applied on several key concepts that affect this concern. For example, in dentistry, the following should be concerned (Wataha, 2000):
Elements released from a dental fixed prosthodontic material into the oral cavity are not inside the body because these elements may gain access to the inside of the body through absorption in the gastrointestinal tract, in the oral mucosa, from the skin, or in the respiratory system. The mechanism for this absorption depends on the nature of the chemical properties of the released elements - whether they exist as ions, as hydrophilic and lipophilic compounds, as volatile substances, or as particles. In contrast, elements that are released from dental implants into the bony tissues around the implant are, by definition, inside the body. Therefore, elemental release from ceramic implants is thought to be more critical systemically than elemental release from dental ceramics used for prosthetic restorations.
The route by which an element gains access inside the body is critical to its biological effect. Some elements become more toxic when administered intravenously into mice than when administered orally.
Any biomaterial, once inside the body, can release ions which can be distributed to many tissues by diffusion through tissues, the lymphatic system, or the blood stream. Released metallic particles (0.5 to 10.0 um) may also be ingested by cells such as macrophages. Almost all dental materials release substances into the oral cavity, from where they may enter the human body through different routes, including swallowing of saliva and inhalation, with subsequent passage of the epithelial barriers in the gastrointestinal tract or the lungs. These substances may, via the blood circulation, be transported to different organs. The oxidation state and chemical form of the metallic ions will significantly influence its absorption, distribution, retention half-life, and excretion. Ultimately, the body generally eliminates the released ions through the urine, feces, or lungs. The application site may thus be in a different location from the effect. At the location of the effect, there may be interference with the function of the specific organ if the concentration is sufficiently high (systemic toxicity). According to the time frame, acute (up to an exposure period of 24 h), subacute (up to 3 months), and chronic toxicity are differentiated.
In general, the systemic toxicity of ceramics is considered to be extremely low (Aldini et al., 2002). In dentistry, only dental laboratory technicians might be exposed to an inhalation of ceramic dust due to processing and finishing of dental ceramics that may cause silicosis (fibrotic pneumoconiosis). These lung diseases have been observed in workers in the ceramic industry who were exposed to ceramic dust for an extended period of time. The risk to a dental laboratory technician of developing silicosis due to ceramic dust is currently unknown. The patient’s silicosis risk is considered “very minimal” (Mackert, 1992) if commonly accepted safety measures, such as dust removal, are followed. On the other hand, there is evidence that released metallic ions from fixed prosthodontic materials can and do gain access to the body, and these metallic ions may be widely distributed (Wataha, 2000). Person-Sjögren & Sjögren (2002) found a statistically significant increase in levels of insulin release from the Langerhans cells after exposure to lithium-containing ceramic (Empress ceramics). The danger lies in overseeing the possibility that minimal amounts of ions eluted due to chemical or mechanical wear might adversely affect the pancreas, or other organs or tissues.
Current knowledge about biomaterials-tissue interactions has been gained through bioassays in vitro and in vivo. Taking into account biocompatibility tests available in the general field, cytotoxicity assays are of special concern. In vitro studies are mainly performed to evaluate the cytotoxicity. A vast number of different in vitro test methods exists which include both quantitative and qualitative methods of cytotoxic effect, i.e. cell damage or lysis caused by membrane leakage. However, each test method basically consists of three components: (a) the biological system, (b) the cell/material contact, and (c) the biological endpoint and corresponding recording system. The biological system used in in vitro cytotoxicity tests may be (i) organ cultures, (ii) cells in culture or (iii) cell organelles. The cell-material contact may be direct; the cells grow next to, or even on the test material. In in vitro tests, direct cell/material contact methods simulate the in vivo situation in certain instances. In indirect contact, materials and cells are separated by a barrier. Eluates derived from a dental material by storing it for a specific period of time in a liquid, such as the nutrient medium, may be used for toxicity testing instead of the material itself. Besides the description of cell morphology, different biological endpoints can be used as indicators for cell damage: membrane effects, cell activity and proliferation rate. The cell reaction can be described morphologically as is done with the lysis index in the agar overlay test. However, this method is considered to be only qualitative, or at most, semi-quantitative in nature. Furthermore, some dental filling materials contain or produce considerable amounts of ingredients, which if applied to cells in culture; the morphology of the cells will appear to be normal, indicating no cell damage even though the cells are no longer vital (Schmalz & Netuschil, 1985). The use of membrane effects, cell activity and proliferation rate have no such drawbacks. Membrane effects can be demonstrated by dye exclusion (trypan blue). The trypan blue exclusion assay can be used to indicate cytotoxicity, where the dead cells take up the blue stain of trypan blue, and the live cells have yellow nuclei. Direct cell counting is easy to perform and can be combined with a vital stain in order to exclude dead cells.
Different researches have been performed to study local cytotoxicity of dental ceramics. Cobb et al. (1988) investigated the in vitro biocompatibility of porous air-fired opaque porcelain with human gingival fibroblasts. Their results indicated that porous air-fired opaque porcelain is biocompatible. Then, Josset et al. (1999) studied the reaction of human osteoblasts cultured with zirconia and alumina by investigating cellular functions, and found that no cytotoxic effect was observed because neither material altered cell growth rate in accordance with the absence of any inducing effect on DNA synthesis or proliferation. Also, Sjögren et al. (2000) evaluated the cytotoxicity of different types of feldspathic porcelain ceramics by using cells from a mouse fibroblast cell line and the agar overlay test, Millipore filter test, and MTT(3-(4, 5-dimethylthiazol-2-y1)2, 5-diphenyltetrazolium bromide)-based calorimetric assay. All the ceramics studied were rated “non-cytotoxic”. Consistent with the former study, Uo et al. (2003) tested the cytotoxicity of different feldspathic, leucite-reinforced glass, and lithium-containing ceramics against human gingival fibroblasts that were cultured using extraction solutions of ceramics, with the aid of almar blue assay. They found that no ceramic extractions showed any evidence of significant cytotoxicity.
Different implantation studies have been also performed for different types of ceramics in different tissues. Silicon oxide ceramic did not cause inflammation after implantation in muscle (G. Schmalz & C. Schmalz, 1981). Bioglasses based on silicon oxide were osteoconductive and osteoinductive when implanted in bone (Chan et al., 2002). Aluminum oxide ceramic, before and after infiltration with lanthanum glass, was found to cause a significantly thicker connective tissue encapsulation and an increased number of inflammatory cells 12 weeks after subcutaneous implantation, compared with Teflon and titanium (Limberger & Lenz, 1991). On the other hand, aluminum oxide ceramic resulted in osseointegration in other studies and thus revealed a good compatibility with surrounding bone (Piatelli et al., 1996). There are obviously differences between the compatibility of various ceramics, and these may be correlated to different indications and applications and different contact with tissue (for example, core ceramic versus implant ceramics). Zirconium oxide ceramic showed good osseointegration when implanted in guinea pigs (Aldini et al., 2002). Calcium phosphate ceramics have been implanted in various animal models. Results were heterogeneous according to the materials tested and depended mainly on the following parameters: calcium (Ca)/phosphate (P) ratio, chemical purity, removal of organic compounds from raw materials, sintering technique, crystal structure (monophase or polyphase), and size and type of pores. Numerous macrophages and foreign body giant cells were observed histologically during the first weeks after implantation of absorbable TCP ceramics. The integration of non-soluble hydroxyl-apatite ceramic in bone without any cellular interface (osseointegration) indicates good biocompatibility (Lacefield, 1999).
Various degrees of ceramic toxicity have been stated. Messer et al. (2003) studied the cytotoxicity of feldspathic porcelains, lithium-disilicate ceramics, and leucite-based glass ceramics by testing their ability to alter cellular mitochondrial dehydrogenase activity (SDH activity) using tetrazolium assay. Their results revealed that dental ceramics are not equivalent in their in vitro biologic effect, even with the same class of material and most ceramics caused only mild in vitro suppression of cell function to levels that would be acceptable on the basis of standards used to evaluate alloys and composites (< 25% suppression of SDH activity). However, the lithium-containing ceramics exhibited cytotoxicity that would not be deemed biologically acceptable on the basis of prevailing empirical standards for dental alloys. Additionally, Pera et al. (2005) investigated the in vitro cytotoxicity of different ceramic materials (lithium-containing, aluminous, zirconium, and feldspathic ceramics) with the use of MTT testing on mouse fibroblasts. Their results revealed that not all tested materials were free from cytotoxicity. Other confirmatory studies have been reported by Elias et al. (2002); Yamamoto et al. (2004) who revealed a varying ability to induce inhibition of cell proliferation, cytotoxicity (as measured by colony forming efficiency) of silica, and alumina components in ceramic materials used for orthopedic prostheses.
It has to be noted that the biocompatibility has been mainly studied for traditional feldspathic porcelains. Most newer ceramic materials, such as those for computer aided design – computer aided manufacture (CAD-CAM) all-ceramic systems, have not been tested for biologic response with the same scrutiny as has been applied to dental casting alloys or even traditional ceramics. In vitro studies have reported different mass loss and cytotoxicity of some newer formulations of all-ceramic materials. An in vitro study done by theauthor of the current chapter (Elshahawy et al., 2009a) investigated the ion release from CAD-CAM leucite-reinforced glass ceramic material into both sodium chloride and lactic acid immersing solutions using inductively coupled plasma mass spectroscopy and showed that transient exposure of tested material to an acidic environment for one week is likely to significantly increase elemental release from it (e.g. aluminum and potassium ions). However, the amounts of these released elements (ions) were shown by the author of the current chapter to be not enough to show high evidence of toxicity against cultured fibroblasts using the trypan blue assay (Elshahawy et al., 2009b).
Whatever is the dental material used for fixed prosthodontic appliance, it is nevertheless difficult to predict the clinical behavior of a material from in vitro studies, since oral factors such as changes in the quantity and quality of saliva, diet, oral hygiene, polishing of the material surface, amount and distribution of occlusal forces, or brushing with toothpaste, can all influence corrosion to varying degrees. From a biocompatibility standpoint, the corrosion of a material indicates that some of the elements are available to affect the tissues around it. Therefore, a study was performed by the author of the current chapter (Elshahawy et al., 2010) which quantitatively assess the element release from CAD-CAM fabricated leucite-reinforced glass ceramic crowns into saliva of fixed prosthodontic patients. They revealed the release of silicon and aluminum ions from them after three months in service. These released amounts were not enough to produce pronounced cytotoxic effects against fibroblasts.
The Ames assay is used worldwide as an initial screen to determine the mutagenic potential of new chemicals and drugs. It is perhaps the most rapid, simple, sensitive and economical screening test for mutagenicity and has an extensive database and good correlation with carcinogenicity.
The comet assay is a quick, simple, sensitive, reliable and fairly inexpensive genotoxicity test which is widely used to evaluate the genotoxic potential of chemical and physical substances. Ostling & Johanson (1984) first demonstrated “comets” and described the tails in terms of DNA with relaxed supercoiling through a process of electrophoresis (pH 9.5) of cells embedded and lysed in agarose on a microscope slide. Later, Singh et al. (1988) used alkaline electrophoresis to analyze DNA damage from treatments with X-rays or hydrogen peroxide (H2O2). Since then, the worldwide acceptance of Comet assay makes it a good assay for detecting DNA damage.
The mutagenicity (genotoxicity) of dental ceramics is not clear due to the lack of research focusing on this aspect. Takami et al. (1997) tested the mutagenicity of aluminous(Al2O3) ceramic by using Ames assay and tester Salmonella typhimurium strains TA98, TA100 and TA1535. Mutagenicity was not induced by extracted samples of the Al2O3 ceramic with and without metabolic activation in Salmonella typhimurium strains TA98 and TA1535. Another study by Covacci et al. (1999) in which zirconia ceramic stabilized by yttria (Y-TZP) was evaluated for mutagenic and carcinogenic potential in the form of discs did not show any mutagenic or oncogenic effects in vitro. A study by Noushad et al. (2009) found that dental ceramics did not induce any DNA damage after using tester Salmonella strains TA98 and TA1537 to detect frameshift mutations whereas using tester strains TA100 and TA1535 to detect base-pair substitution mutations. From previous studies, it is noted that some biomaterials are mutagenic to one tester strain while it is not mutagenic to another. Even though many investigators have sometimes used just 2 strains to determine the mutagenic potential of biomaterials, it is felt that the use of at least four tester strains as recommended by Mortelmans & Zeiger (2000) gives a more definite result.
Other studies tested the mutagenicity and carcinogenicity of the different components of ceramics separately. For example, lithium is a component of certain ceramics. Leonard et al. (1995) reviewed the information available on the mutagenicity, carcinogenicity and teratogenicity of lithium. It was concluded that lithium is unlikely to be carcinogenic. Weiner et al. (1990) studied the effects of lithium hypochlorite in a series of tests including five strains of Salmonella. Lithium was not found to be genotoxic in any of the test systems with the exception of an equivocal response in the Chinese hamster ovary/hypoxanthine-guanine phosphor-ribosyl transferase assay, which was not replicable in a subsequent experiment.
Silica and alumina are main components of ceramics on which genotoxic studies have been reported. In one Comet assay, Zhong et al. (1997) indicated that silica and glass fibers can induce DNA damage in mammalian cells and that crystalline silica has a higher DNA-damaging activity than amorphous silica. Simon et al. (2007) assessed the genotoxicity of alumina and titanium oxide (TiO2) using the Comet assay and showed that DNA damage was limited to single-strand breaks and/or alkali-labile sites and that genotoxicity was weak. From previous studies, the genotoxicity of some of the components of dental ceramics remains controversial.
Three decades ago, uranium salts were previously added at a concentration of 1,000 ppm to dental ceramics for simulating the natural luminescence of teeth. Because of the radioactivity of uranium salts, alternatives are now applied, such as oxides of rare earths. Today, radiation of dental ceramics is only due to natural radionuclides (mainly α and γ emitters) and much below the materials dated back to the times, when uranium salts had been added. Feldspathic ceramic specimens showed an activity concentration (Uranium/Thorium chains) that is in the same order of magnitude as for the human body. No radiation related adverse effects of dental ceramics have been documented in the literature (Veronese et al., 2006). Raw materials used for zirconium oxide ceramics (e.g., Zirkon, ZrSiO4) may contain contaminants such as thorium and uranium. These contaminants generate α-, β-, and γ-radiation. However, the effective activity of zirconium oxide ceramic was far below the mean value of the annual exposure to natural radiation (Piconi & Macauro, 1999).
So far, no clinical reports have been published that document a carcinogenic effect of certain dental ceramic materials in the oral cavity. The long exposure time that is necessary for the emergence of a malignant tumor is a very aggravating factor for clinical assessment of potential carcinogenic properties. Therefore, it is only possible to draw indirect conclusions from other areas (e.g., occupational exposure to chemicals) to a possible carcinogenic effect.
As mentioned before, the term immunogenicity is referred to the ability of a substance to provoke an immune response or the degree to which it provokes a response. Sun et al. (2009) studied the clinical effects and security of nanometer ceramics artificial bone transplantation to treat the bone defect. After follow-up period for 24 months, the artificial bone has no immunogenicity, no rejection, does not affect the blood calcium and phosphorus content, and has higher osteogenic activity. According to our knowledge, there is no documentation about sensitivity to ceramics.
Ceramics are rigid materials and therefore generally need to be luted to human hard tissues like teeth. There can be allergies/sensitivities to the cements/bonding agents that are necessary for the attachment of ceramic fixed prosthodontic restorations. Postoperative sensitivities have been observed in a few cases after the (adhesive) luting of ceramics (inlays, crowns) (Pallesen & Dijken, 2000; Studer et al., 1996). Also, one thing that may be an issue is that if the ceramic fixed prosthodontic restoration is impinging on a vital tissue, e.g. if margins of dental ceramic veneers are impinging on what is called the biologic width of gingiva (the amount of space under the gum where nothing can be placed) then a chronic state of inflammation will ensue.
Substances are released from ceramics into the surrounding tissues; mainly silicon, aluminum, potassium.
Systemic toxicity of ceramics is unlikely to occur due to the relatively low amounts of released elements such as lithium and lead.
Few ceramics have shown to be cytotoxic in vitro. The clinical relevance of these findings remains unclear.
Generally, local toxicity of ceramics is considered as low. However, more cytotoxicity researches are needed due to possible exceptions.
Overall, there is no evidence that ceramics cause or contribute to neoplasia in the body.
Ceramics are generally considered as biocompatible materials, although relatively little data are available.
Future biocompatibility studies should be performed to study more measurements dealing with cells functions such as protein fabrication (e.g. collagen synthesis), respiratory and digestive cell functions in a response to elements released from ceramics.
Future biocompatibility studies should be also performed to test the combinations of the elemental salts released from ceramic materials for the detection of synergistic, antagonistic, or additive effects caused by different mixtures of cations.
Pectin is the major constituent of all plants and makes up approximately two-third of the dry mass of plant primary cell walls. It provides structural integrity, strength, and flexibility to the cell wall and acts as barrier to the external environment [1]. Pectin is also a natural component of all omnivorous diet and is an important source of dietary fiber. Due to the resistant in digestive system and lack of pectin digestive enzymes, human beings are not able to digest pectin directly but microorganism present in large intestine can easily assimilate the pectin and convert it into soluble fibers. These oligosaccharides promote beneficial microbiota in gut and also help in lipid and fat metabolism, glycemic regulation, etc. [2]. Being complex and highly diverse in structure, role of pectin is not only limited to the biological and physiological functions, but it has tremendous potential and contributes substantially in other applications ranging from food processing to pharmaceuticals. Pectin is a water-soluble fiber and used in various food as emulsifier, stabilizer, gelling, and thickening agent.
\nCommercial pectins are extracted from citrus and apple fruit. On the basis of dry mass, apple pomace contains 10–15% pectin, whereas citrus peel possesses 20–30% pectin. However, pectin has also been extracted in higher amount from several other fruits and their by-products, such as sunflower head, mango peal, soybean hull [3], passion fruit peel [4], sugar beet pulp [5], Akebia trifoliata peel [6], peach pomace [7], banana peel [8], chickpea husk [9], and many more [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]. Table 1 summarizes the different types of pectin extracted from various horticultural crops. But detection and extraction of pectin in higher concentration is not sufficient to qualify that fruit as a source of commercial pectin because of the structural variation and modification in side-chain sugars, and also that pectin from different sources has different gelling properties.
\nS. No | \nSource | \nParts used | \nExtraction method used | \nPectin yield (%) | \nType of pectin (HMP/LMP) | \nRef | \n
---|---|---|---|---|---|---|
1 | \nPassion fruit | \nPeel | \nAPP | \n14.8% | \nHMP | \n[4] | \n
2 | \nBanana | \nPeel | \nAPP | \n5–21% | \nHMP (DE, 50–80%) | \n[8] | \n
3 | \nChick pea | \nHusk | \nAcid extraction, APP, and freeze dried | \n8% | \nLMP (DE, 10%) | \n[9] | \n
4 | \nKrueo Ma Noy | \nLeaves | \nAPP, DPP | \n21–28% | \nLMP (DE, 34–42%) | \n[11] | \n
5 | \nYellow Passion | \nFruit rind | \nAPP, DPP, MPP | \n3–16% | \nHMP (DE, 54–59%) | \n[12] | \n
6 | \nDurian | \nRind | \nAPP | \n2–10.25% | \nHMP (DE, 50–64%) | \n[13] | \n
7 | \nMulberry | \nMulberry bark with epidermis (MBE) and without epidermis (MB) | \nExtracted using 60–100% isopropanol | \n11.88% | \nHMP (MB–DE, 71.13%); LMP (MBE–DE, 24.27%) | \n[14] | \n
8 | \nYuzu, citrus family | \nPomace | \nExtracted with APP and enzyme (Viscozyme® L with 1.2 × 10−4 fungal β-glucanase | \nDPP, APP (7.3–8%) | \nLMP (APP–DE, 41%; DPP–DE, 46.3%) | \n[16] | \n
9 | \nCacao pods | \nHusk | \nExtracted with 1 N HNO3 at different pH and precipitated by ethanol and acetone | \n3.7–8.6% | \nLMP (DE 36.7% @ pH 1, DE 44.3% @ pH 3); HMP (DE 52.4% @ pH 2) | \n[17] | \n
10 | \nCashew apple | \nPomace | \nAOP at different pH (1.0, 1.5, and 2.0) | \n10.7–25.3% | \nLMP (DE, 28–46%) | \n[18] | \n
11 | \nCyclea barbata Miers (CBM) | \nLeaves | \nExtracted with acid and alkali, precipitated the pectin by ethanol | \n4–8% | \nHMP (acid treated: 65–75% DE) LMP (Alkali treated: 36% DE) | \n[19] | \n
12 | \nDragon fruit | \nPeel | \nExtracted using HCl, precipitated and purified with 70 and 99.6% isopropanol. | \n18.59% | \nLMP (DE, 46.95%) | \n[20] | \n
13 | \nJackfruit | \nPeel | \nUltrasonic-microwave-assisted extracted (UMAE) pectin | \n21.5% | \nHMP (DE, 62.5%) | \n[22] | \n
14 | \nPotato | \nPulp | \nExtracted with different acids and precipitated by ethanol | \n4.08–14.34% | \nLMP (DE, 21.51–37.45%) | \n[23] | \n
High methoxyl pectins (HMP) and low methoxyl pectins (LMP) from various horticultural crops.
APP, alcohol-precipitated pectin; MPP, metal ion-precipitated pectin; DPP, dialyzed precipitated pectin.
Pectin is a highly complex plant cell wall polysaccharide that plays a significant role in plant growth and development. It is predominantly present in fruits and vegetables and constitutes approximately 35–40% of the primary cell wall in all the dicot plants [24]. The composition and structure of pectin is influenced by the developmental stages of plants [25, 26]. Structural analysis of pectin revealed that it is a polymer comprised of chain-like configuration of approximately 100–1000 saccharide units; therefore, it does not possess a defined structure. In general, pectin is illustrated as a heteropolysaccharide of three components namely, homogalacturonan (HG), rhamnogalacturonan-I (RGI), and rhamnogalacturonan-II (RGII) [28, 29]. The Backbone structure may branch with other neutral sugar chains such as arabinan, xylogalacturonan (XGA), arabinogalactan I (AG-I), and arabinogalactan II (AG-II).
\nHomogalacturonan (HG) is a polymer of galacturonic acid (GalA), in which Gal A residues are linked together by α-1-4 glycosidic bond and the number of GalA residues in HG may vary from 72 to 100% depending on the source of pectin [30]. For instance, the HG backbone of cashew apple pectin, C. maxima pectin, sunflower pectin, citrus pectin, comprises of 69.9–85%, 71–75%, 77–85%, 80–95%, GalA residues, respectively. Amaranth pectin contains more than 80% GalA residues in HG backbone structure. Furthermore, it was also observed that HG may be methoxy-esterified at C-6 and/or O-acetylated at the O-2 and/or O-3. Some exception has also been reported in the detailed structural analysis of HG region of pectin such as C-3 substitution of the galacturonic acids of HG with xylose in pea, apple, carrot, duck weed, etc. [31], and C-2 or C-3 with apiose in duck weeds (Lemna minor) [32]. HG is susceptible to both mechanical and enzymatic deesterification and degradation.
\nRhamnogalacturonan I represents approximately 20–35% of the pectin polysaccharides. It is the highly branched and heterogeneous polysaccharide which is characterized as repeating units of α-(1 → 2)-linked rhamnose and α-(1 → 4)-linked GalA residues. It can be O-acetylated at O-2 and/or O-3 positions of GalA residues [33, 34]. Pectin from citrus peels, mung bean, kidney bean, apple fruit, and flax hypocotyls has been reported 100% methyl esterified in the RGI region [35, 36]. The composition of RGI varies in pectin extracted from different sources. In sugar beet pectin, 80 repeating units of [→2] –α-L-Rha-(1–4)- α-D-GalA-(1→) comprised the backbone of rhamnogalacturonan I (RG-I), whereas citrus pectin contains only 15–40 repeating units [37]. The polymeric side chains of galactans and arabinans are substituted at the O-4 position of RG-I backbone. Arabinogalactan I (AG-I) and arabinogalactan II (AG-II) are also reported to be present as polymeric side chains [38, 39, 40]. The side chains are often referred to as “hairs” and believed to play an important role in pectin functionality. The loss of side chains may increase the solubility of the pectin [41]. PGI is prone to enzymatic depolymerization. However, protease and acid-catalyzed cleavage of RGI has also been reported [28, 42, 43].
\nThe highly conserved polysaccharide of pectin is rhamnogalacturonan II which constitutes about 10% of the pectin polymer [44]. This polysaccharide is made up of (1 → 4)-linked-α-D-GalA units containing 12 monosaccharide such as apiose, acetic acid, 3-deoxy-manno-2-octulosonic acid (KDO), and 3-deoxy-lyxo-2-heptulosaric acid (DHA) as side chains [30, 39]. GalA present in backbone of rhamnogalacturonan II (RG-II) may be methyl esterified at the C-6 position. The percentage of esterified GalA and acetylated groups in HG chain is termed as the DE and DAc, respectively. It is proposed that in the early developmental stages of plants, highly esterified pectin is formed that undergoes some deesterification in the cell wall or middle lamella. In general, tissue pectin ranges from 60 to 90% DE [45]. Both the DE and the DAc of pectin may vary depending on the method of extraction and plant origin [30, 46]. The functional properties of the pectin are determined by the amount and the distribution of esterified GalA residues in the linear backbone. Presence and distribution of esterified and nonmethylated GalA in pectin define the charge on pectin molecules. Based on their degree of esterification (DE), pectins are classified as high methoxy pectins (HMP) or low methoxy pectins (LMP). DE values of HM pectin range from 60 to 75%, whereas pectin with 20–40% of DE is referred as LM pectin. It was also observed that solubility, viscosity, and gelation properties of pectin are correlated and highly dependent on structural features [47, 48]. Pectin and monovalent salts of pectins are generally soluble in water but di- and trivalent ions are insoluble. The solubility of pectin in water increases with decrease in polymer size and increase in methoxy contents. Pectin powder gets hydrated very fast in water and forms clumps. The solubility of these clumps is very slow. As the pectin molecules come in contact with water, deesterification and depolymerization of pectins start spontaneously. The rate of decomposition of pectin depends on pH and temperature of the solution. As the pH of the solution decreased, with elevated temperature, ionization of carboxylate groups also reduced, which suppresses the hydration and repulsion between the polysaccharide molecules and results in the association of molecules in the form of gels. During thermal processing, solubilization of pectin is affected by β-elimination which depolymerized the pectin molecule and reduced its chain length. Small polymers have poor affinity with cell wall framework and solubilize easily. However, preheating, as well as reduced moisture contents in thermal processing, adversely affects the solubility of pectin in water [49, 50].
\nFood additives that are used in food processing to blend two immiscible liquids to produce a desirable product are known as food emulsifier or emulgent. These additives act as surface-active agents on the border of immiscible layers and reduce oil crystallization and prevent water separation. Emulsifiers are used in large number of food products such as ice creams, low-fat spreads, yoghurts, margarine, salad dressings, salty spreads, bakery products, and many other creamy sauces, to keep them in stable emulsion [27]. Emulsifiers increase the whip-ability of batters, enhance mouthfeel of the products, and improve texture and shape of the dough. Moreover, emulsions also help to encapsulate the bioactives [51]. Based on the disperse phase, there are two types of emulsion: oil in water (O/W) and water in oil (W/O). Milk, mayonnaise, dressings, and various beverages are some examples of O/W emulsion, whereas butter and margarine are the typical examples of W/O emulsion. Progress in hydrocolloid chemistry has resulted in the development of multitype emulsion such as O/W/O and O/W/O type emulsion (Figure 1). These emulsions are very important for fat reduction or encapsulation of bioactives and are used in preparation and stabilization of various low-fat creams, seasoning, and flavoring of sauces [52].
\nTypes of emulsions.
Commonly used emulsifiers in food processing are (i) small-molecular surfactant such as lectithins, derivatives of mono- and diglycerides prepared by mixing edible oils with glycerin or ethylene oxide, fatty acid derivatives such as glycol esters, sorbitan esters, polysorbates and (ii) macromolecular emulsifiers that include proteins and plant-based polymers such as soy polysaccharide, guar gum, modified starch, pectin, etc. [53]. As far as the properties of food emulsifier are concern, a good emulsifier should be low in molecular weight, capable to reduce the surface tension rapidly at interface, and should be soluble in continuous phase [54]. Research on food additives revealed the adverse effect of synthetic food additives on human being. Chassaing et al. found that polysorbate 80(P80) or carboxy methyl cellulose (CMC) had adverse effects on gut microbiota and their continuous use triggered the weight gain and metabolic syndrome after 12 weeks of administration in mouse [55]. A recent research carried out on mice shows that regular use of P80 and CMC triggers low-grade intestinal inflammation which may ultimately lead to the development of colon cancer [56]. Therefore, safety issues with the synthetic food additives and consumer’s demand for all natural food ingredients have necessitated the use of plant-based emulsifiers and stabilizers in food.
\nPectin is a natural hydrocolloid which exhibits wide spectrum of functional properties. Because of the gelling ability of pectin, it is used as viscosity enhancer. During emulsification process, pectin molecules adsorb at the fine oil droplets from at O/W interface and protect the droplet from coalescing with adjacent drops (short-term stability). The quality of emulsifier is defined by its ability to provide long-term stability against flocculation and coalescence [27]. Figure 2 depicts the stages in long-term emulsion formation using pectin as emulgent. When the viscosity of the continuous phase is increased, the movements of oil droplets become restricted which improves the shelf life of emulsion [57]. In the past decade, some pectin has also been reported to exhibit surface active behavior in oil-water interface and thereby stabilizing the fine oil droplets in emulsion [42, 58]. These functions of pectin are determined by its source, structural modification during processing, distribution of functional groups in pectin backbone, and also by various extrinsic factors such as pH, temperature, ionic strength, cosolute concentration, etc. The emulsification or surface active properties of pectin, i.e., formation of fine oil droplets, are mainly contributed due to the high hydrophobicity of protein residue present in pectin [46, 59] and also by hydrophobic nature of acetyl, methyl, and feruloyl esters [42, 60], whereas emulsion-stabilizing ability is attributed to the carbohydrate moieties and their conformational features [61].
\nEmulsion formation and stabilization using polymer as emulgent.
The mechanism of emulsion formation is shown in Figure 3. Different models explain the emulsion formation as covalently bound protein moieties in pectin are adsorbed onto the oil-water interface [46], form anchor points at the interface, and reduce the interfacial tension while the charged carbohydrate units extend into the aqueous phase [62] and stabilize by steric and viscosity effects in the aqueous phase(Figure 3a). Now, it is a well-established fact that pectin from different source shows variability in structure and protein contents. Leroux et al. identified many anchor points in sugar beet pectin (SBP) molecules [46], and proposed a loop-and-tail model (Figure 3b). According to the authors, only a limited amount of protein is adsorbed at the oil surface and acts as main moiety in the stabilization of the emulsion. This model was further confirmed by Siew and others [62]. The study was carried out to measure the thickness of the adsorbed SBP on oil-water interface layer, proposed a multilayer adsorption model (Figure 3c). Electrostatic interactions between the positively charged protein moiety and the negatively charged carbohydrate moiety were also reported.
\nDifferent models showing pectin adsorption at oil/water interface during emulsion formation.
Pectin O/W emulsion is generally stabilized through steric and electrostatic interaction. The carbohydrate moieties and neutral sugar side chains of RG I region of pectin confer the stability to the pectin emulsions through steric properties of the adsorbed polymers, when pectin is used as monoemulsifiers. In addition, pectin reversible association with galactan/arabinogalactan prior to emulsification also improves the emulsion stability [42, 63]. Electrostatic stabilization of emulsion is ascribed to sugar moieties and structural features of the HG units of pectin. If the pH of dispersion medium is above 3.5, nonmethylated carboxylic group of HG region gets ionized and confers charge on the pectin surface. Interaction of an ionic surfactant with oil droplets results in electrostatic stabilization [64]. Pectin viscosity also plays an important role in controlling the emulsion stability. HG region-rich pectin shows higher intrinsic viscosity ([η]); therefore, HG and RG ratio of pectin and molecular interactions that improve the intrinsic viscosity ([η]) of pectin solution also contributes in shelf life of emulsion [65, 66]. It has also observed that structural features of pectin such as pectin protein content, molecular mass, and presence of ferulic acid, and acetyl group in carbohydrate moieties of pectin also affect pectin’s emulsifying and emulsion stabilization properties [15]. Williams et al. showed that ferulic acid-rich pectin did not show significant difference in emulsifying ability of pectin when compared with pectin poor in ferulic acid [67]. Digestion of sugar beet pectin(SBP) with acidic proteases resulted in formation of larger size of oil droplet, lower creaming stability, and loss of emulsifying activity of SBP which confirms that protein contents of SBP play an important role in emulsifying ability of the polymer [42]. Nevertheless, in other research, it was also found that protein-rich fractions of SBP did not necessarily displayed better emulsifying ability; therefore, it was concluded that both protein with carbohydrate moiety together help in controlling emulsifying ability of SBP. Castellani et al. further suggest that both the carbohydrate and protein moieties function together as unit and affect the hydrophilic-hydrophobic equilibrium of the SBP molecule [68]. Therefore, when SBP is digested with proteases or other enzyme, a single moiety may function differently. Furthermore, it was also proposed that protein folding may also mask the hydrophobic effect of protein and thus affect the overall properties of the polymers [69].
\nMolecular weight of pectin has also been reported to affect the emulsifying capacity of pectin. Pectin with low molecular weight was more efficient in stabilizing small emulsion droplets than high-molecular weight pectin. However, very small size of citrus pectin had negative effect on emulsion-stabilizing ability of pectin. It could be due to the poor steric stabilization of depolymerized polymer [59].
\nEmulsion-based food products can be defined as a network of pectin-protein molecules entrapping the oil droplet in between. Nowadays, a large number of pectin- and polysaccharide-based emulsified low-fat dairy products, meat products, spreads or desserts, bakery products, sauces, etc., are available in market. Low-fat and low-cholesterol mayonnaise, low-fat cottage cheese, low-fat drinking yogurt, and flavored oil-containing acidified milk drinks are the few examples of pectin-based emulsified products. These products are prepared by replacing full-fat milk from skimmed milk, emulsified oil, and whey proteins [70, 71]. A low-fat cheese was prepared using skimmed milk and water-in-oil-in-water (W1/O/W2) emulsified canola oil. Different emulsifiers such as amidated low-methoxyl pectins (LMP), gum arabic (GA), carboxymethylcellulose (CMC), and combinations of GA-CMC or GA-LMP were used to stabilize the emulsion. Textural characteristics and sensory evaluation of low-fat cheese show that polymers used to stabilize the emulsion affected both microcrystalline structure and organoleptic properties. The cheese prepared using GA and LMP was almost similar in textural characteristics to the full-fat milk cheese [72]. In another study, Liu et al. compared the textural and structural features and sensory quality of full-fat and low-fat cheese analogs prepared with or without the incorporation of pectin [71]. Microstructure analysis using scanning electron microscopy revealed that full-fat cheese was denser and contained higher concentration of fat globules than low-fat cheese made with or without pectin. Comparison within the low-fat cheese analogs showed clear difference in their hardness, gumminess, chewiness, and adhesiveness. Addition of pectin had positive effect on textural and sensory attribute and scored better in mouthfeel also.
\nLow-fat (Lf) mayonnaise was prepared by partial replacement of egg yolk and incorporation of pectin as emulsifier [73, 74]. Pectin weak gel, pectin microencapsulation, and whey protein isolate were used in preparation of low-fat (Lf) mayonnaise. Physicochemical and sensory properties of Lf mayonnaise were compared with full-fat (Ff) mayonnaise; Lf mayonnaise had low energy and more water contents than Ff. Textural features and rheological properties of the Lf and Ff mayonnaise were similar and both displayed thixotropic shear thinning behavior and categorized as weak gels. Moreover, Lf mayonnaise prepared using pectin had better acceptability than whey protein incorporation [75]. Emulsified oil is used as an effective delivery system of active compound in functional foods, and also serves as milk fat replacer in fat-free dairy products. To improve the nutritional value of food, low-fat dairy products are produced, whereas saturated milk fat is generally replaced with emulsified-unsaturated vegetable oils [76].
\nIn recent year, pectin in combination with inulin has been reported to prepare low-fat meat batter. Méndez-Zamora et al. studied the effect of substitution of animal fat with different formulations of pectin and inulin on chemical composition, textural, and sensory properties of frankfurter sausages [77]. Finding of the research showed that fracturability, gumminess, and chewiness of the low-fat sauces were slightly lower than those of the control. However, addition of 15% inulin improves the sensory properties. In a similar work, replacement of pork back fat with 15% pectin and 15% inulin was found effective in maintaining the physicochemical properties and emulsion stability of the low-fat meat batter [78].
\nThe use of pectin in food products as a gelling agent is a long tradition. Later on, it was discovered that pectin forms different types of viscoelastic solution under suitable conditions. This property of pectin is commercially exploited in preparation of jams, jellies, and marmalades. Rheological behaviors of pectin depend on pectin source, its degree of methylation, distribution of nonmethylated GalA unit on pectin backbone, and degree of acetylation, and also on various extrinsic factors such as temperature, pH, concentration, and presence of divalent ions. At a constant pH, the setting time of pectin increases with decreasing DM and degree of blockiness (DB) in the absence of bivalent ions [79]. Therefore, on the basis of gelling process, pectin is classified as rapid, medium, and slow set pectin [80].
\nGelling process of pectin and its stabilization follows different mechanisms for different types of pectin. HMP form gels in a narrow pH range (2.0–3.5) in the presence of sucrose at a concentration higher than 55% w/v in medium. During the gelatin process of HMP, junction zones are formed due to the cross-linking of two or more pectin molecules. These junctions are stabilized by weak molecular interaction such as hydrogen and hydrophobic bonds between polar and nonpolar methyl-esterified groups and require high sugar concentration and low pH [81]. These gels are thermally reversible. LMP can form gel over a wide pH range (2.0–6.0) independent of sucrose, but requires divalent ion, such as calcium [82, 83]. LMP follow the eggbox model for its gelation, where positively charged calcium ions (Ca2+) are entrapped in between the negatively charged carboxylic group of pectin. The zigzag network of Ca2+ ion and GalA molecules looks like eggbox, and therefore, model is named as eggbox model [80]. These gels are stabilized by electrostatic bonds. In the presence of Ca2+, calcium bridges are formed with pectin molecules that make the solution more viscous. At the higher pH, the ionic strength of the solution is increased and thus more Ca2+ is needed for gelation. In case of highly acetylated pectin such as sugar beet, acetyl groups cause steric hindrances and interfere with the Ca2+ ion and GalA bond formation, thus preventing gel formation. Kuuva et al. [84] reported that enzymatic modification in pectin structure, i.e., removal of acetyl groups using α-arabinofuranosidase (α-Afases) and acetyl esterase enzymes, can improve the gelling property of acetylated pectin.
\nHMP are generally used in preparation of standard jams where sugar contents are above 55%, high-quality, tender confectionary jellies, fruit pastes, etc. LMP do not require sugar for its gelatin and therefore preferred choice for the production of low-calorie food products such as milk desserts, jams, jellies, and preserves, [28, 85]. LM pectins are more stable in low pH and high temperature conditions as compare to HM pectins and can be stored for more than a year.
\nFood packaging is one of the fastest growing segments of food industry. Traditionally, packaging system was limited to the containers and packaging material to transport the food items from manufacturer to the retail market and then to the consumers. Such type of packaging was unable to contribute in the extension of the shelf life and maintenance of the quality of the products. Due to the globalization of food market and increasing demand of shelf-stable processed food that retains the natural properties of food, the need of functional/active packaging material is increasing. To meet the industrial demand, a number of polymers are being synthesized and used in food packaging because of their flexibility, versatility, and cost effectiveness. Although, synthetic materials are able to fulfill all the industrial needs and keep food fresh and safe by protecting them from abiotic factors such as moisture, heat, oxygen, unpleasant odor, and biotic components such as micro- and macroorganisms. But, disposal of nonbiodegradable packaging material is a serious problem which poses a threat to the environment. Therefore, more research has been focused on the development of biodegradable packaging for food packaging applications using poly(lactic acid) (PLA), poly(hydroxyalkanoates) (PHAs), starch, etc. [86]. Among all the natural polymers, polysaccharides are gaining more attention as they are versatile in nature and easily available in relatively low cost.
\nA variety of natural polysaccharides, such as pectin, chitosan derivatives, alginate, cellulose, seaweed extract, and starch are usually used in the preparation of edible films and coatings [87]. Pectin is one of the most significant renewable natural polymers which are the main component of all the biomass and ubiquitous in nature. Being flexible in nature, pectin and its derivatives are used in many biodegradable packaging materials that serve as moisture, oil, and aroma barrier, reduce respiration rate and oxidation of food [88]. Pectin along with food grade emulsifiers is also used in the preparation of edible films. These films are used in fresh and minimally processed, fruits and vegetables, foods and food products as pectin is the main component of the omnivorous diet and can be metabolized. Edible coating protects the nutritional properties of the food and also saves highly perishable food from the enzymatic browning, off-flavor development, aroma loss, retards lipid migration, and reduces pathogen attack during storage.
\nAt low pH, LM pectins are cross-linked with calcium cations and form hard gels. These gels have highly stable structure and act as water barriers. Because of these properties, LM pectin films are used as edible coatings [88, 89]. Extension of shelf life of avocado fruits was also reported to over a month at 10°C by using edible pectin films. It was found that when avocados were coated with edible pectin films and stored at 10°C, rate of oxygen absorption and rate of respiration decreased which results in delaying of texture and color change of fruits [90]. Oms-Oliu et al. used calcium chloride and sunflower oil cross-linked with LM pectin films onto fresh-cut melon to see the effect on extension of shelf life of cut fruits [91]. It was observed that edible pectin films maintained the initial firmness, decrease the wounding stress of fresh-cut fruits, and prevent the dehydration during storage up to 15 days at 4°C but could not reduce the microbial growth onto the fresh melon. It has been observed that to reduce the respiration rate and to prevent the off-flavor development, different pectin and emulsifier formations are required for different fruits. Edible coating film formulation consisted on pectin, sorbitol, and bee wax was successfully used by Moalemiyan et al. to keep the fresh-cut mangoes in original state for over 2 weeks [92]. Whereas in a similar study, pectin coating containing sucrose and calcium lactate was able to prevent the fruits’ respiration rate and maintain sensory properties in fresh melon fruits for up to 14 days storage at 5°C. In a similar study [93], pectin edible coating solution containing pectin (3%), glycerol (2.5%), polyvinyl alcohol (1.25%), and citric acid (1%) was prepared and applied on sapota fruits by dipping method and uncoated sapota fruits were used as control. Both the treated and control fruits were stored at 30 ± 3°C. Physicochemical parameters namely, weight, color, firmness, acidity, TSS, pH, and ascorbic acid contents of both the coated and control fruits were measured at regular interval up to 11th day of the storage at 30 ± 3°C. Reduced rate of change in weight loss and other parameters were reported in pectin-coated sapota as compared to control fruits and it was observed that pectin film formulation was able to maintain good quality attributes and extend the shelf life of pectin-coated sapota fruits up to 11 days of storage at room temperature, whereas control fruits were edible up to 6 days. Furthermore, it was also observed that sapota fruits dipped in sodium alginate containing 2% pectin solution for 2 min were more effective in maintaining the organoleptic properties up to 30 days of refrigerated storage as compared to sapota fruits dipped for 4 min and untreated sapota fruits [94]. Bayarri et al. developed antimicrobial films using lysozyme and LM pectin complex. The main purpose of the study was to control the release of lysozyme in packaged food and to target lysozyme-sensitive bacteria such as Bacillus and Clostridium. It was observed that in the presence of fungal pectinase, due to the dissociation of pectin linkage, lysozyme activity of films increased remarkably. Many food-contaminating bacteria are pectinase producing and such type of films may be used to control food contaminants. These results have opened new avenues for custom-made biodegradable film [95].
\nIn last few years, some researchers have focused on pectin-based coating containing edible essential to improve the antimicrobial properties and to enhance the efficiency of the pectin films. Edible coating formulation containing sodium alginate and pectin (PE) enriched with eugenol (Eug) and citral (Cit) essential oil at different concentrations was used to increase the shelf life of strawberries. Physical and organoleptic parameters of coated fruits stored at 10°C for 14 days show that formulation containing PE 2% + Eug 0.1%; PE 2% + Cit 0.15% was more suitable than sodium alginate-based formulations [96]. Pectin coating containing lemon and orange peel essential oils was reported to increase the shelf life and quality attributes of the strawberry fruits up to 12 days when stored at 5°C. It was also observed that fruits coated with pectin + 1% orange essence showed less weight loss and soluble solids as compare to their control during the storage [97]. Sanchís et al. studied the combined effect of edible pectin coating with active modified atmospheric packaging on fresh-cut “Rojo Brillante” persimmon. Persimmon fruit slices were coated by dipping in the pectin-based emulsion or in water as control. Both the treated and control slices were packed under 5 kPa O2 (MAP) or under ambient atmosphere for up to 9 days at 5°C. Various parameters, such as package gas composition, color and firmness of slice, polyphenol oxidase activity, were measured during storage. It was observed that edible coating along with MAP significantly reduced the CO2 emission and O2 consumption in the packaged fruits. Furthermore, coating was also effective in controlling microbial growth and reducing enzymatic browning and maintains good sensory parameters up to 10 days on storage [98].
\nDrying is the traditional and oldest method of fruit and vegetable preservation. It decreases the enzymatic activity, reduces the moisture contents, and protects the food from microbial attack. However, drying results in loss of nutrients, vitamins, heat-labile enzymes, modifies the texture, color, and organoleptic quality of dried fruits and vegetables and therefore diminishes the market value also. Pretreatment of food products with pectin coatings containing other bioactive compound such as ascorbic acid, CaCl2, edible gum, etc., before drying or blanching has been proposed as an effective method to preserve the nutritional as well as organoleptic quality of dried food [99]. Recent researches have shown that application of pectin coating could protect the moisture and vitamin C loss in pretreated papaya slice and osmotic dehydrated pineapple. In one of the research [100], pineapple slice was pretreated with pectin coating formulation containing (50%)/calcium lactate (4%)/ascorbic acid (2%) solutions and then dried by hot-air-drying method. Physicochemical analysis of dried product showed less reduction in vitamin C contents as compared to untreated pineapple slice. In a similar work, pectin coating supplement with vitamin C (1%) was used for precoating of papaya slice. It was found that incorporation of vitamin C did not affect the drying process. However, significant increase in vitamin C content was observed in final product [101].
\nFrying is a method of cooking that causes changes in chemical and physical parameters of food and enhances the taste. However, high temperature vaporizes the water of food and affects the nutritional properties due to protein denaturation and starch gelatinization. The oil uptake during frying is affected by various parameters such as type of oil used, frying temperature and duration, product moisture content, shape, porosity, prefrying treatment, etc. [102]. Surface area and pretreatment of products are the major factors that determine the oil absorbed. Edible coating has also been used successfully, to reduce the oil uptake during frying in various deep-fried products. Reduction in oil uptake and improvement of texture and quality of potato slices was reported by Daraei Garmakhany et al. in 2008. Authors found that coating of potato slices with pectin, guar, and CMC solutions can reduce the oil uptake when compared with nontreated potato chips [103]. Similar results were also obtained by Khalil, where a combination of pectin or sodium alginate with calcium chlorides significantly reduces the oil uptake of French fries. Coating formulation of 0.5% calcium chloride and 5% pectin was most effective in reducing the oil uptake [104]. Kizito et al. used different edible coatings (pectin, carboxy methyl cellulose, agar, and chitosan) at a concentration of 1–2% for pretreatment of potato chips, followed by deep frying of chips. Fried chips were analyzed biochemically and organoleptically to investigate the quality attributes of the products. It was revealed that all the coating polymers were successful in reducing the oil uptake but pectin was most effective and reduced oil uptake up to 12.93%, followed by CMC (11.71%), chitosan (8.28%), and agar (5.25%) and significantly improved moisture retention of strips (p < 0.05) [105].
\nThe application of natural polymers in food industry is increasing day by day. Researchers are focusing more and more toward the pectin because of the ease-of-availability, structural flexibility, and versatile composition. Pectin can be sourced from a number of easily available horticulture crops (Table 1). Pectin is a hydrocolloid which is used as a food emulsifier, gelling agent, thickener, and stabilizer. It is the preferred choice of most of the food processors as fat or sugar replacer in low-calorie foods. In the recent years, increasing demand of ready-to-serve foods, fresh-cut fruits, and vegetable has opened a new market for edible films. Being biodegradable and recyclable, a lot of research is being done on pectin-based edible film formulations. These films reduce the exchange of moisture, gases, lipids, and volatiles between food and environment, and also serve as protective barrier for microorganisms.
\nEven though a lot of information is available regarding pectin structure and many pectin-based products are available in market, role of many carbohydrate moieties and their effect on various function of pectin are not yet well defined. Therefore, it is necessary to understand the structural-function relationship of pectin and its interactions for developing functional food products.
\nThe authors thank Director, CSIR-CFTRI for the encouragement.
\nThe authors declare no conflict of interest.
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. 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