**2.3 Biocompatibility**

Alginate biocompatibility varies at the level of its purity and has been extensively evaluated in-vivo as well as in-vitro. Alginate is a naturally occurring anionic polysaccharide typically extracted from brown seaweed and has been extensively investigated and used for many purposes due to its biocompatibility and mild gelation by the addition of divalent cations such as Ca2+ [20]. The composition of Alginate defines the level of purity and degree of biocompatibility of Alginate. Biocompatibility has been reported that Alginate containing a high number of M monomers is more immunogenic in nature and 10 times more strongly promoting cytokine biosynthesis in the comparison of G monomer in alginates but apart from this, reported very less response or no immune response across alginate implants [21]. Impurities of alginates, including heavy metals, endotoxins, proteins, and polyphenolic compounds, can cause a variable reaction at the implantation or injection sites. In contrast, not huge serious tissue injury or inflammatory cases were reported in alginates obtained from branded or reputed companies, commercially available or certified [22].

### **2.4 Alginate derivatives**

Various alginate derivates have been reported to date and are useful in the range of biomedical and pharmaceutical applications. Derivatives of Alginate with amphiphilic nature have been synthesized by introducing non-water-resistant moieties (e.g., alkyl chains, non-water-resistant polymers) to the backbone of Alginate [23]. These derivatives are capable of forming self-organized structures, include particles and gels in aqueous media, and are also useful for drug delivery applications. Sodium alginate amphiphilic derivatives have been made by the conjugation of long alkyl chains to the alginate backbone via ester bond formation [24]. Dodecyl or octadecyl is an example of long-chain alkyl groups that form bonds with the alginates matrix via esterification. Rheology, gelling and crosslinking properties are much needed for bone regeneration and cartilage repair [25]. Drug delivery sustained or controlled vehicles are obtained from Alginate derived from Poly butyl methacrylate. Alginate also has peptides with cell adhesive peptides made by adding peptides as side chains and joints together with carboxylic groups of sugar residues [25, 26]. Derivatives of Alginate containing cell adhesive peptides have been gaining scientific applications in human health. These derivates are synthesized by chemically introducing peptides as side chains. Sodium alginate (NaC6H7O6) is made from the sodium salt of alginic acid, and potassium alginate (KC6H7O6) is the potassium salt of alginic acid [27]. Calcium alginate (CaC12H14O12) is derived from sodium alginate, and during calcium alginate synthesis, sodium ions are replaced with calcium by the ion exchange process.

### **2.5 Alginate gelling properties**

Alginates form gels by reaction with divalent cations, including Ca2+; the exchange of sodium ions from glucuronic acids with divalent cations in solution is the crucial factor for gelation and crosslinking of Alginate [28]. Gelation is an important property of Alginate, and it is induced by Ca2+. The gelation phenomena are well known, reported as an egg-box model, and intensively studied in the last five decades. Alginate gel formation is affected by many factors, including the concentration of reactant, heating temperature, pH, and salts [29]. These factors are decided gel strength and rheological properties, including viscosity, storage, and loss moduli of the gel. Sodium alginate is a gelling and thickening agent in the presence of calcium that forms stable heat gels; calcium ions are chemically reacted with the G monomer present in sodium alginate structure to crosslink with another molecule [30, 31]. EDTA sodium citrate or monovalent ions complex ions (phosphate and citrate) are potent complex-forming agents that have a high chemical affinity to Ca2+, which can disrupt calcium alginate gel in an easy manner. The appearance of non-gelling ions (Na + and Mg2+) in high concentrations also participates to instability [32]. Alginate is only forms gels when chemically reacted with divalent ions (Ca2+, Sr2+, and Ba2+) or trivalent ions (Fe3+ and AI3+) ions. Divalent and trivalent ions have been explored for the fabrication of carriers for the well-controlled and sustained release delivery of drugs [33]. This is happened due to ionic interactions and intramolecular bond formation that are present within carboxylic acid groups on the polymer matrix. Alginate is a combination of two uronic acids; each unit of uronic acid includes a negatively charged carboxyl group of high ionic exchange capacity, these units form chains, which create the polymer structure of Alginate [34–36]. The molecules of Alginate

*Introduction to Alginate: Biocompatible, Biodegradable, Antimicrobial Nature and Various… DOI: http://dx.doi.org/10.5772/intechopen.110650*

in an aqueous solution push away from each other by electrostatic repulsion forming a smooth viscous liquid. When calcium ions are added with negatively charged Alginate, molecules attract positively charged calcium ions forming a salt [36]. When will further add positive charge, calcium ions with negatively charged Alginate make contact with other alginate molecules and become linked by a calcium ion. This phenomenon is known as "egg box junction" After its visual similarity to an egg in an egg carton. This reaction occurs instantly throughout the solution, and alginate gels come in contact with calcium ions [37, 38]. When an aqueous solution of sodium alginate is added dropwise to an aqueous solution of calcium salt and gels instantly, wherever it comes into contact with calcium ions aqueous solution of sodium alginate forms beads as it gels due to surface tension creating a jelly by controlling ionization of calcium [39]. It is possible to gel the entire solution into any desired shape; this process is called the ion control method. According to the ion control method, calcium ions are first sequestered, and Alginate cannot react chemically with them; sequestered calcium does not react chemically with aqueous alginate solution, then it mixes uniformly in the solution [40]. The pH of a solution is gradually reduced sequestered calcium becomes released, reacting with alginate solution gels uniformly. Calcium reacts as a sequestering agent and a pH reduction agent by varying the type and quantity of these two types of agents the time required for gelation can be freely adjusted from as little as a few minutes to an overnight process [41]. Making use of this property, Alginate is used as a gelling agent in a wide range of medical and pharmaceutical applications.

#### **2.6 Effect of pH on alginates**

The Alginate's water solubility is effected by parameters including pH and ionic strength. Alginates have not so much water solubility with further down pH values caused by the deprotonation of carboxylic groups (-COO-) [42]. The alginates viscosity is constant above pH > 5. Although in solutions containing pH < 5, the COO- group in attendance in alginates will get protonated to COOH, and then electrostatic repulsion will decrease between chains [42, 43]. They can proceed together near to make hydrogen bonds, by which measures a decrease in viscosity. It has been pH > 11 reported alginates viscosity is decreased due to de-polymerization. The crosslinking is influenced by the concentration of an ionic solution, which is capable of increasing in viscosity and molecular weight of alginates [44]. Furthermore, the crosslinking depends upon G monomer confirmation and M groups present in the matrix of Alginate. Pawar and Edgar, in 2012, reported the compounds synthesized from sodium alginate and observed it to be stable between pH 5 to 10 [1, 44].

#### **2.7 Sterilization**

The viscosity of Alginate decreases with autoclave sterilization because autoclave heating is responsible for randomly breaking alginate chains. It means autoclave sterilization is not favorable for Alginate [45, 46]. The value to which this loss occurs is measured by the appearance of other kinds of components in the solution. Gamma radiation and ethylene oxide are important for alginate solution sterilization without any disadvantages [46]. Alginate sterilization is important for the removal and overcoming of contamination from alginate solution before use.

#### **2.8 Immunogenicity**

Drug delivery in control or sustained release manner is the latest trend of pharmaceutical dosage forms requirements for proper application in drug vehicles; alginates play a crucial role because of their immunogenicity and biocompatibility [47]. Chemical composition and mitogenic pollutants are two factors responsible for alginate immunogenicity. When Alginate makes contact with blood, it is believed to have decreased hemolysis and mild cytotoxic effects. Alginate is an example of a weak immunogen, but the immune responses produced by Alginate are very effective or strong in killing *pseudomonas bacteria* [47, 48]. SLN is important to increase the alginate immunogenicity; SLN is useful in drug delivery and can prolonged boost effectiveness. The SLN-Alginate conjugate is better at stimulating the immune system to produce a high number of immunoglobulins with effective outcomes compared to Alginate antigen alone; this is proven by the results of ELISA and opsonophagocytosis tests. The challenge experiment also reported that the Alg-SLN-treated mice showed a higher level of immunity in comparison of mice treated with pure Alginate against infections caused by *pseudomonas aeruginosa* [48]. Overall results show the efficacy of the newly synthesized vaccine to induce immunogenicity, and therefore it will be considered a candidate for a strong vaccine against *pseudomonas aeruginosa*.

#### **2.9 Bioadhesion**

Bioadhesion and mucoadhesion is the phenomenon through which natural and synthetic macromolecules stick fast to mucosal surfaces in the body. If these materials are then included into formulations, drug soaking up by mucosal cells may be increase or the drug released at the site for an make larger period of time [49]. The Carboxyl group of Alginates has a mucoadhesive anionic polymeric layer and represents mucoadhesive properties. In the comparison of polycation or nonionic polymers, polyanion polymers have more efficient bioadhesive properties. Alginate contains better mucoadhesive strength in compared to polymers, including Polystyrene, Chitosan, Carboxymethyl cellulose, and Poly (lactic acid) [50]. The mucoadhesive properties of Alginate play a crucial role as a mucosal drug delivery vehicle to the GI tract and nasopharynx by extending drug residence time at the site of, making them more effective. Alginate is widely used as a bioadhesive for its biodegradability and biocompatibility properties and it undergoes electrostatic interactions with positively charged compounds [51, 52]. Alginate bioadhesive systems provide intimate contact between a dosage form and the absorbing tissue, which may result in high concentration in a local area and hence high drug flux through the absorbing tissue.

#### **2.10 Toxicity**

Alginates are reported nontoxic according to plenty of studies and crosslinked with sodium/calcium are nontoxic to cells, even not harmful for eyes and skin. While, Alginate due to its nontoxic nature found various applications in fully controlled and sustained release drug delivery, biomedical, cosmetics, food industry, paper and pulp industries [53]. Sodium alginate is perfectly safe and nontoxic for using as additive in food products. As sodium alginate is widely known as nontoxic, there is no limit on the amount consumed.

*Introduction to Alginate: Biocompatible, Biodegradable, Antimicrobial Nature and Various… DOI: http://dx.doi.org/10.5772/intechopen.110650*
