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Oxidized alginate based hydrogels for tissue engineering applications: A review Supachai Reakasame, and Aldo R. Boccaccini Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.7b01331 • Publication Date (Web): 27 Nov 2017 Downloaded from http://pubs.acs.org on November 28, 2017
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Biomacromolecules
Oxidized alginate based hydrogels for tissue engineering applications: A review Supachai Reakasame and Aldo R. Boccaccini* Institute of Biomaterials, University of Erlangen-Nuremberg, Cauerstr.6, 91058 Erlangen, Germany KEYWORDS: oxidized alginate; alginate dialdehyde; tissue engineering; hydrogels
ABSTRACT
Oxidized alginate (OA) based hydrogels have drawn considerable attention as biodegradable materials for tissue engineering applications. OA possesses a faster degradation rate and contains more reactive groups compared to native alginate. This review summarizes the research publications reporting the development of OA based hydrogels for tissue engineering applications including bone, cartilage, blood vessel, cornea and other soft tissues and highlighting OA key properties and processing approaches.
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1. Introduction Tissue engineering (TE) aims to induce tissue regeneration and repair employing the combination of life science and materials science methods.1, 2 Three main factors required in TE are tissue specific cells, scaffold materials, and signals to guide cell phenotype.1, 3 Scaffolds are key for the success of the TE approach. Scaffolds act as temporary support allowing cells to attach, grow, proliferate and regenerate new tissue for the recovery of their functionality.3, 4 An important group of scaffold materials are hydrogels. Hydrogels are hydrophilic, polymeric networks capable of retaining large amount of water and biological fluids. Because of their soft and rubbery consistence which is similar to living tissue, hydrogels have drawn attention for TE applications as an injectable scaffold allowing to deliver cells into the body with a minimal invasion5,
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or for the development of matrices for cell encapsulation and for
biofabricating 3D scaffolds.7 Natural polymer based hydrogels are ideal scaffolds for TE because of their biocompatibility and biodegradability.8 They have potential to support cell attachment, proliferation, and differentiation in their native state.9 Alginate based hydrogels have been widely used in TE because they possess many features similar to the extra cellular matrix of human tissues.10, 11 Alginates are anionic linear polysaccharides derived from algae and bacteria. They are block copolymers comprising of 1,4linked β-D-mannuronic acid (M) with 4C1 ring conformation and α-L-guluronic acid (G) with 4C1 conformation12-15, as illustrated in Figure 1. Alginate has been studied in many biomedical applications due to its biocompatibility.11 Alginate can form a physical hydrogel in the presence of divalent cations such as Ca2+ and Ba2+.13 This is because of the interaction between divalent ions and G block monomers in the polymer chains leading to ionic bridge formation between 2 ACS Paragon Plus Environment
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Biomacromolecules
adjacent polymer chains. A gentle gelation process makes alginate a potential material for cell encapsulation. 3, 16, 17
Figure 1. Chemical structure of alginate.15 However, an important limitation of physical alginate hydrogels is their rather low in vivo degradability. Normally, such hydrogels degrade very slowly in an unpredictable manner through dissociation of the ionic crosslinking following by releasing of high and low molecular weight alginate strands. Only relatively low molecular weight strands (having molecular weight lower than 50 kDa) can be removed from the body through the kidney. On the other hand, high molecular weight alginate may be difficult to clear from the body because mammals lack alginate degrading enzymes.11,
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Moreover, alginate exhibits poor cell adhesion and
infiltration because of its lack of specific molecular interaction capability with mammalian cells.21,
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It is now well established that the oxidation of alginate can enhance its
biodegradability,23 and the number of investigations focusing on oxidized alginate (OA) for numerous biomedical application is continuously increasing. Given the interesting opportunities offered by oxidized alginate (OA) for broadening biomedical applications of alginate, the review will cover comprehensively previous research on OA with focus on TE applications.
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2. Synthesis of oxidized alginate Oxidized alginate (OA) also known as alginate dialdehyde (ADA) is a derivative of alginate which can be synthesized via oxidation of sodium alginate. Oxidation of alginate to form OA was first introduced by Malaprade in 1928.13 In recent years, OA has been widely studied in TE because it contains more reactive groups and degrades faster than alginate,24 which makes it more attractive for cell encapsulation and for TE scaffolds. Periodate has been used as oxidizing agent in most previous studies reviewed in this article. Periodate can oxidize both M and G subunits in the alginate structure.25 Gomez et al.26 reported that G units preferentially react with sodium periodate than M units. Sodium periodate can oxidize the hydroxyl group at the second and third carbon positions (C-2 and C-3) of the repetitive unit in the alginate chain. This results in the cracking of the carbon-carbon bond leading to the formation of two aldehyde functional groups at the oxidized carbon of the monomeric unit. The resulting aldehyde groups react simultaneously with hydroxyl groups of the adjacent unoxidized uronic residues in the polymer chain and form cyclic hemiacetals, as shown in Figure 2. The presence of aldehyde groups in OA is in equilibrium with hemiacetals.3, 13, 25 Alginate oxidation in aqueous solution was used for the production of OA in many studies. In general, alginate powder has been dissolved in water before mixing with either sodium periodate powder or aqueous solution of sodium periodate in the desired amount.1, 5, 27-32 The limitation of alginate oxidation in aqueous solution is that the reaction can be carried out only at low concentration of alginate (
