**7. Algal alginate in pharmaceutical and biomedical applications**

Although the biocompatibility of alginate has a debate, it is still one of the mostly studied polymeric biomaterials in pharmaceutical and biomedical applications for tissue engineering and regenerative medicine (TERM) purposes [100]. Alginate can be fabricated in various shapes and forms (**Figure 4**) for an extensively wide application (**Figure 5**). Alginate provides a biocompatible, cost-effective, low toxicity, and also easy gelation. Currently due to high viscosity and rheological properties with respect to increasing concentration, alginate is utilized as stabilizer and thickeners in pharmaceutical formulations. However, due to increased utilization of hydrogels in TERM, alginate-based formulations are extensively investigated as controlled drug-release platforms and tissue-engineering constructs [104–106].

Kinetic release of pharmaceutical compounds such as drug molecules, proteins, peptides, and nucleic acids is a novel advanced therapeutic approach [107]. Although alginate is a polar biopolymer, amphiphilic design of the alginate, or blending with other polymers can alter the hydrophilicity, thereby enabling the release of hypophobic/amphibic molecules [73, 103]. Alginate also creates a mild environment for proteins and other molecules, which can be affected by heat or alkali conditions resulting due to denaturation. Also, enzymes can be encapsulated with algae to have a controlled biocatalytic conversion. Alginate is usually ionically cross-linked with bivalent cations which is a low-cost and rapid method of gelation. However, when alginate is in an aqueous environment, bivalent cations are released into the environment, which makes a faster release of entrapped drug molecules based on their hydrophilicity, size, and interaction with alginate. In order to increase the control over the alginate, chemical modifications are done to chemically functionalize alginate for thermo-responsive, pH-responsive, or lightresponsive matrices [108].

Wound healing is a complex phenomenon starting from inflammation, cell migration to the wound site, and eventually remodeling of the wound healing area [109]. Recently hydrogel-based wound dressings are gaining attention, and alginate

#### **Figure 4.**

*Alginate in shape (a) fabrication forms of alginate for various application [61, 62, 100–102]; (b) classical immobilization method for alginate crosslinking.*

**Figure 5.**

*Application areas of alginate in pharmaceutical and biomedical purposes [64, 100, 102, 103].*

is one of the most studied and also commercially available wound dressing patches [103, 107]. Due to high water content and immobilization of bioactive molecules inside the patches to create antibacterial, anti-inflammatory and growth factors to promote cell growth and healing alginate are considered a gold standard in these types of applications.

3D cell culture is gaining interest because 2D cell culture does not correspond to the signals of cells in their nature. 3D environment creates a biomimetic

*Algal Alginate in Biotechnology: Biosynthesis and Applications DOI: http://dx.doi.org/10.5772/intechopen.101407*

environment to understand cell behavior, drug response, and 3D tissue culture [64, 102, 110]. Alginate creates a good environment resembling the extracellular matrix (ECM) structure where cells can proliferate and differentiate. Also, alginate can be covalently linked to cellular attachment sequences (mostly utilized RGD) to increase cell-cell interactions and cell-surface interactions [101, 111]. Encapsulation of growth factors in these 3D gels can increase the cell differentiation [104], neotissue formation, and blood vessel development [102, 112].

Alginate can also be a base hydrogel for 3D biofabrication purposes [111, 113]. Due to the availability of advanced imaging methods, these constructs can be customized as a personalized medicine tool [114]. However, due to the low mechanical properties of alginate, the bioprinting is usually done with blends with other hydrogels such as collagen [112], gelatin [111], chitosan [115] or self-assembling peptide hydrogels [104, 106].

Although alginate is a biocompatible and a plant-based biomaterial, the biodegradation of alginate can be troublesome. Alginate does not degrade in the body; however, due to the release of ions form the network, it decomposes into small pieces. Thus, chemical modification such as oxidation of alginate chains may help to achieve a proper biodegradation for clinical applications [116]. Moreover, low mechanical properties and stiffness may hinder the utilization of alginate, especially for hard tissue engineering. Chemical modification may elevate the material properties. However, it may add toxicity to the compound too. Nevertheless, as in vitro drug testing [117] and 3D cell culture platforms [111], even for topical applications [103], alginate is a safe natural biomaterial. It is also highly promising for tissue engineering applications, especially as injectable formulations [104].

## **8. Algal alginate in green nanotechnologies**

Nanotechnology aims to have structures that have a size in a nanometer scale (less than 100 nm) to be produced and applied to provide purposeful design. Nanomaterials, which are a product of nanotechnology, have exceptional surface activity and other physical properties that occur due to their shapes at nanoscale sizes. In the last decade, nanotechnology has gained popularity and it has been used in different fields such as medicine, pharmaceuticals, cosmetics, food, and clothing industries. Production of synthetic nanomaterials is expensive and not an environmentally friendly process, even though they have many applications and benefits today. It is not safe to use them in medicinal applications due to their risks and side effects and the difficulty to form gels in situ. Hence, green routes to synthesize nanomaterials, which is called green nanotechnology has gained attention. The aim of green nanotechnology is to reduce the risks and to solve environmental problems related to nanotechnology [118, 119].

Natural polymers such as alginate, chitosan, agarose, collagen, cellulose, and so on have been used as nanoparticles (NPs) due to the concerns about synthetic ones [118]. Characteristics of these NPs such as small surface area to volume ratio, structural surfaces, agglomeration, and enhanced reactivity make them to be applied in various areas such as cancer therapy, drug targeting, nano-pharmacology, nanomedicine, and agrochemical delivery [120]. In recent times, the most widely used polymer is alginate, since it is considered safe especially for human applications. Alginate is considered to be safe owing to the fact that it has been studied extensively, even though other biomaterials can be good alternatives in the future, However, alginate has properties that offer advantages to the system and make it a perfect fit for biotechnology and drug delivery systems via cell microencapsulation [118]. Temperature and pH changes, signaling molecules, and enzymes stimulate

a drastic chemical and physical change in alginate, which results in making them a potential candidate for drug delivery vehicles [121]. Biocompatible and nontoxic polyionic complex NPs are formed through ionic gelation of alginate and chitosan. These polyionic complexes are used in drug delivery and wound healing purposes because they are non-toxic and biocompatible as well as have effective protection of biomolecules [122]. Natural nano carrier systems can be easily integrated with antiviral, antifungal, antituberculosis drugs, and so on. For antituberculosis drugs, lipid-based formulations and polymer-based formulations are used. Lipid-based formulations have drawbacks with successful targeting, since it is dependent on the parenteral/inhalable route, whereas alginate is already FDA approved for human use and it is successful with the oral treatment of reflux esophagitis as well as being a popular pharmaceutical excipient. Hence, alginate-based carriers have gained popularity in drug targeting. The recent studies prove that if alginate NPs are used, the outcome could be further improved in the sense of encapsulation of drug, pharmacokinetics, bioavailability, and therapeutic efficacy [123]. Alginate NPs can also be used as a carrier for adjuvants and vaccine immunogenicity is increased, since alginate nanocarriers can prolong the release. Agglomeration has not occurred in major organs through the use of alginate NPs. Mucoadhesive properties enhance the permeability of alginate NPs and therefore it is being used in nasal and oral administrations; degradation is reduced in acidic environment [124].

NPs of alginate can be used in agriculture as a nanopesticide, nanoinsecticide, nanoherbicide, nanofertilizer, growth stimulants, pesticide carriers, antimicrobial agents, and nanoformulations [125]. Targeting and systemic delivery of herbicides can be provided by using nanocapsules with alginate/chitosan NPs [126]. Chitosan and alginate as carriers of herbicide and insecticide do not only improve the release of the herbicide but also improves its interaction with the soil [126, 127]. Chitosan/ alginate NPs can also be used as nano carriers for pesticides, herbicides, and fungicides. Slow release of the molecule can be provided and NPs can protect them from UV radiation and it offers a better antifungal activity [120].
