Application of Carrageenan Hydrogel in Biomedical Field

Hydrogel is a three-dimensional network of hydrophilic polymers that swells in water without dissolving. Because the polymer contains a large number of hydrophilic groups, the hydrogel can absorb and lock a large amount of water. After absorbing water, the hydrogel network can maintain its original shape without being destroyed. Hydrogels are widely used in tissue engineering, drug delivery, biosensing, etc. due to their simple preparation, strong tunability of mechanical properties, good biocompatibility, and elasticity and softness that are very similar to most tissues and extracellular matrices of the human body. The field is developing rapidly. Depending on the source from which the hydrogel is prepared, hydrogels can be divided into natural hydrogels and synthetic hydrogels. Due to society’s demand for sustainable products, hydrogels derived from natural materials, especially those from renewable resources, have attracted attention. Among renewable resources, polysaccharides have become the most promising hydrogel precursors due to their inherent hydrophilicity and biodegradability. Carrageenan is a sulfated polysaccharide extracted from red algae. It is composed of alternating units of D-galactose and 3,6-anhydrogalactose linked by α-1,3 and β-1,4-glycosidic bonds. Carrageenan is divided into 6 basic forms according to its sulfate content, extraction source and solubility, namely: k-carrageenan, t-carrageenan, λ-carrageenan, μ-carrageenan, ν-carrageenan and θ-carrageenan. K-carrageenan, t-carrageenan and λ-carrageenan have important commercial value due to their gelling and viscoelastic properties. t-carrageenan and k-carrageenan have the ability to form hydrogels and form a three-dimensional double helix network through cross-linking of adjacent sulfate groups. However, the sulfate groups of λ-carrageenan do not cross-link and therefore do not form a gel. The presence of hydroxyl/sulfate groups on carrageenan makes it easy to undergo physical or chemical cross-linking, giving carrageenan better physical and chemical properties, new special functions and characteristics. Carrageenan hydrogel has been widely used in biomedicine and tissue engineering fields, such as drug delivery, wound dressings, tissue engineering scaffold materials, etc. This article reviews several types of carrageenan hydrogels and their application progress in the biomedical field.

Figure 1. Recent advances in chemically-modified and hybrid carrageenan-based platforms for drug delivery, wound healing, and tissue engineering.

Several Types of Carrageenan Hydrogels

Traditionally, k-carrageenan and t-carrageenan form brittle hydrogels through ionic cross-linking in the presence of K+ and Ca2+ respectively. In order to improve the performance of carrageenan, one of the measures is to change the cross-linking method. Physical cross-linking is cross-linking through non-chemical bonds such as hydrogen bonding van der Waals forces or mutual entanglement. Chemical cross-linking is the connection between chains through chemical bonds. By compounding carrageenan with polymer materials such as polyvinyl alcohol, gelatin, cellulose, and silk fibroin, a hydrogel with excellent performance can be obtained through a certain cross-linking method (physical cross-linking, chemical cross-linking based on cross-linking agents). On this basis, researchers have studied different types of carrageenan hydrogels, including photo-crosslinked hydrogels, interpenetrating polymer network hydrogels, hydrogel scaffolds, nanogels and 3D bioprinting bioinks etc.

Photo-crosslinked Hydrogel

Photo-crosslinking usually introduces methacrylic acid groups into the carrageenan structure, then adds a photoinitiator to make it photosensitive, and finally cures and cross-links it through ultraviolet or visible light irradiation.

Interpenetrating Polymer Network

Interpenetrating polymer networks (IPNs) are “alloys” of cross-linked polymers in which at least one polymer is synthesized and/or cross-linked in the direct presence of another polymer without any covalent connection between them. polymers cannot be separated unless the chemical bond is broken. One network structure in the interpenetrating polymer network is rigid and brittle, and the other is soft and tough. When stressed, the rigid and brittle network mainly bears the force, while the soft and tough network mainly prevents the gel from breaking.

Hydrogel Scaffold

The gel scaffold has excellent surface adhesion, promoting cell adhesion, proliferation and differentiation; it also has a highly porous structure, which can provide sufficient space for cell adhesion and stimulate new tissue growth. Researchers have used various physical and chemical methods to develop carrageenan gel scaffolds that can simulate the natural extracellular matrix (ECM) in the body.

Nanogel

“Nanogel” refers to a nanohydrogel with a size range of 1 to 1000 nm formed by a physical or chemical cross-linked network. The carrageenan nanogel network can encapsulate drugs, proteins, DNA, etc., providing a large surface area for multivalent biological binding. Bioink for 3D bioprinting

3D bioprinting is a versatile layer-by-layer manufacturing technology that directly guides the gradual addition of materials (bioink) through a predefined digital model to create 3D objects. It can use living cells to create complex tissue structures. Carrageenan has the properties of biocompatibility, biodegradability, shear dilution and ionic gelation, but its gelation properties are difficult to control and is not suitable for use in 3D bioprinting. Researchers have made it suitable for 3D bioprinting by introducing methacrylates, cationic polymers (such as gelatin) and other substances into the carrageenan structure.

Application of Carrageenan in Biomedical Field

Wound Dressing

An ideal wound dressing is nontoxic, antibacterial, keeps the skin surface moist, has a good effect on absorbing wound toxins and accelerates wound healing, and does not cause any trauma to the healing skin when removed. In addition to its biodegradability, biocompatibility and significant swelling properties, carrageenan also exhibits high ductility and can better contact with the skin, making it an ideal wound dressing.

Drug Delivery

Drug delivery plays a key role in continuously delivering medications or key ingredients, including antimicrobials, to wounds. Drug delivery systems can deliver therapeutic drugs to target sites in organs and tissues in a better way. Carrageenan has good biocompatibility, adjustable viscoelasticity, simple gel mechanism and thermally reversible gelation, and has good drug release ability. Therefore, carrageenan-based hydrogels are promising materials for drug delivery systems.

Tissue Engineering

Three-dimensional cell culture plays an important role in tissue repair, replacement or regeneration. Extracellular matrix (ECM) is an important component that produces different types of cells and is the basis of special tissues. To be used in 3D cell culture, biomaterials must imitate the characteristics of the extracellular matrix. Carrageenan is a natural polysaccharide with a similar structure to natural glycosaminoglycans and is one of the important components of tissue extracellular matrix.

Bio-intelligent Sensing

Biosensing is usually the detection of biomolecules with the help of biosensors (analytical devices). These biosensors combine biological components such as sweat, saliva or other vital body fluids with a physicochemical detector. Sensors have received increasing attention due to their portability, extremely short diagnostic time, and reduced sample preparation requirements. In recent years, carrageenan hydrogel has made breakthrough progress in health monitoring as an intelligent wearable sensing device.

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