Bio-based Stimuli-responsive Hydrogels with Biomedical Applications


In recent years, materials from renewable resources have received special attention in a multitude of fields as a w'ay to achieve sustainable development (Alvarez-Lorenzo et al.

2013). The concept ‘sustainable development’ refers to ‘development that meets the needs of the present, without compromising the ability of future generations to meet

their own needs’ (Emas 2015). Transition to the use of renewable resources (biomass) eliminates the dependence on limited resources and, at the same time, reduces the contribution to the greenhouse effect and allows preserving mineral resources for future generations (Voevodina and Krian 2013). Biomass feedstock can be converted into raw materials called ‘bio-materials’ (Nakajima et al. 2017), and this new generation of "bio-materials’ (bio-based, bio-compatible, bio-degradable) offers the possibilities to reduce the dependence on fossil fuels, as well as environmental impacts (Kimura 2009; Babu et al. 2013; Salerno and Pascual 2015; Gicquel 2017). Bio-based materials are obtained through biological, chemical, and physical methods from renewable biomass including crops, trees, or other plants. They have special characteristics such as environmental-friendly, renewable, biodegradable, and other properties that traditional polymers do not have (Gao et al. 2019).

Recently, much research has been focused on obtaining hydrogels from biopolymers due to their unique properties, such as biocompatibility and biodegradability, less toxicity, and an acceptable mechanical strength (Mohite et al. 2018). Biodegradation is an extremely interesting feature when talking about hydrogels with biomedical applications, especially in tissue engineering and drug delivery applications, mainly because of their biological interaction with the body components (Jayaramudu et al. 2013).

Among biopolymers, polysaccharides have received special attention in forming hydrogels because they are abundant and readily available from renewable sources, such as plants, algae, or various microbial organisms, and also have a large variety of compositional and structural properties, making them facile to produce and versatile for gel formation as compared with synthetic polymers (Karoyo and Wilson 2017). Moreover, polysaccharides possess multiple functional groups, including acid, amine, hydroxyl, and aldehyde, which make them suitable for chemical conjugation of therapeutic agents (Thambi et al. 2016). Given this multitude of positive features, along with their structural and functional similarities with the extracellular matrix, it is quite easy to understand why polysaccharides have benefitted from a growing interest in the biomedical field, in recent decades (Tchobanian et al. 2019)

This chapter aims to provide an overview of the recent use of polysaccharides in obtaining stimuli-sensitive hydrogels and their applications, especially in the field of controlled drug delivery and tissue engineering. In addition, the main available sources of polysaccharides in nature, along with their structure and properties, important factors in subsequent biomedical applications, are presented.

Polysaccharides Sources and Properties

Polysaccharides are high-molecular-weight carbohydrate polymers with sugar residues linked by glycosidic bonds. The most common constituent of polysaccharides is D-glucose, but D-fructose, D- or L-galactose, D-mannose, L-arabinose, and D-xylose are also frequent. The main functions played by polysaccharides in nature are either storage or structural functions, the properties of those two classes being dramatically different, although the compositions are quite similar (d’Ayala et al. 2008; Ozcan and Oner 2015).

Chemical structures of naturally occurring polysaccharides. (Reprinted with permission from Oh et al. 2009)

FIGURE 9.1 Chemical structures of naturally occurring polysaccharides. (Reprinted with permission from Oh et al. 2009).

Figure 9.1 shows the chemical structures of the most common polysaccharides in nature (Oh et al. 2009), and their sources of origin and the main structural features and functional groups are presented in Table 9.1.

Polysaccharides from Higher Plants

Cellulose is the most abundant biodegradable polymer, being the main constituent of plants and natural fibres (Sezer et al. 2018; Barman and Das 2018; Kayra and Aytekin 2018) and considered an almost inexhaustible source of raw material for the increasing demand of environmental-friendly and biocompatible products (Huq et al. 2012; Efthimiadou et al. 2014; Ciolacu 2018). Cellulose has properties that make it very promising and attractive material in many applications due to its low cost, biocompatibility, high mechanical and thermal stability. Its only limitation is low solubility, which restricts its use especially in biomedical and pharmaceutical domains, but this drawback is overcome by obtaining cellulose derivatives through various chemical modification procedures, such as esterification, etherification, or oxidation (Jeong et al. 2012; Marques-Marinho and Vianna-Soares 2013; Onofrei and Filimon 2016; Sezer et al. 2018). Cellulose hydrogels can be easily prepared either by physical interactions (chain entanglements, van der Waals forces, hydrogen bonds, hydrophobic, or electronic associations) or by chemical cross-linking (with cross-linking agents) (Ciolacu and Suflet 2018). Cellulose-based hydrogels have sustainable and biodegradable properties which have aroused interest in various biomedical applications (Fu et al. 2018), such as targeted drug delivery and smart sensors, or multi- responsive, injectable, and self-healing hydrogels with enhanced mechanical properties (Liu et al. 2017).


The Source and Main Structural Features of Polysaccharides



Structural Features

Functional Groups


Plant cell walls

Anhydro-D-glucopyranose units linked by p-1,4 linkages

Three hydroxyl groups per each glucose unit


Plant cell walls

Glucose molecules joined together with a-D-( 1,4-) and(or a-D-( 1,6-) linkages

Hydroxyl groups




(1,4) linked p-D-mannuronic and a-L-guluronic acids

Hydroxyl and carboxyl groups


Seaweed (marine algae)

Linear, p(1.3)-sulfated-D- galactose and a( 1,4)-3,6- anhydro-D-galactose (3-cross-linked-).

One (k-), two (i-), or three (1-) sulfate groups per disaccharide unit




Linear, D-glucuronic acid and N-acetyl-D-glucosamine linked by a p-1,3 linkage

Carboxylic functional groups and alcohols




Linear, two repeating units of

  • (1.4) -2-acetamido-2-deoxy- P-D-glucan (N-acetyl D-glucosamine) and
  • (1.4) -2-amino-2-deoxy-p-D- glucan (N-acetyl D-glucosamine)

Amino and hydroxyl groups




Branched, D-glucopyranose residues with 1.6- and some 1,3-glucosidic linkages

Hydroxyl groups





Anhydro-D-glucopyranose units linked by p-1,4 linkages

Three hydroxyl groups per each glucose unit

Starch is the most abundant storage polysaccharide in plants being considered a promising candidate for developing sustainable materials with various applications (Kunal et al. 2006; Lu et al. 2009; Ismail et al. 2013). The properties which make starch a suitable material, especially for biomedical applications, are its biodegradability, biocompatibility, non-toxic degradation products, high swelling capacity in water, and proper mechanical properties (Lu et al. 2009; Zhang 2015). One of its drawbacks is low surface area, but by chemical derivatization (e.g., grafting or etherification), its sorption capacities are improved (Kunal et al. 2006; Ismail et al. 2013; Zhang 2015). With a large number of hydroxyl groups, starch can be used to easily prepare hydrogels. It turns into a gel in a few thermally assisted steps: (i) the swelling occurs by water adsorption in the hydrophilic granules, (ii) the gelatinization takes place after starch is dissolved by heating, resulting in irreversible physical changes, (iii) the destruction of the granule structure (Ismail et al. 2013). Starch-based materials have received much attention in drug delivery and other biomedical applications.

such as wound healing or tissue engineering, because of their extensive availability, low cost, and total compostability, without generating any hazardous residues (Waghmare et al. 2018).

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