Vol.:(0123456789) 1 3 Biomedical Materials & Devices https://doi.org/10.1007/s44174-023-00118-4 REVIEW Crosslinking Methods in Polysaccharide‑Based Hydrogels for Drug Delivery Systems Mayara T. P. Paiva 1  · João Otávio F. Kishima 1  · Jaquellyne B. M. D. Silva 2  · Janaina Mantovan 1  · Franciely G. Colodi 1  · Suzana Mali 1 Received: 28 May 2023 / Accepted: 11 July 2023 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC 2023 Abstract Polysaccharides are inspiring and valuable molecules to the development of novel drug delivery systems owing to their natural availability, non-toxicity, biocompatibility, good biological performance, and chemical similarity to the physiological environment, besides their noticeable use for tailored-materials assembly. Biodegradable hydrogels based on polysaccharides have been widely studied as potential pharmaceutical forms due to their controlled release properties, which improve drug bioavailability, therapeutic efcacy, and patient compliance. Despite these advantages, polysaccharide materials present insufcient mechanical properties or processability, thus, to overcome these drawbacks, feasible and suitable crosslinking methods are employed to improve polysaccharide hydrogels strength and stability. Therefore, this review presents recent advances in crosslinking methods of polysaccharide hydrogels, including chitosan, cellulose, hyaluronic acid, and alginate, providing examples of manufacturing processes with emphasis in their use as carriers in drug delivery. Polysaccharide-based hydrogels represent a sustainable, biocompatible, and appreciable alternative to obtain novel drug delivery systems. Keywords Polysaccharides modifcation · Three-dimensional polymeric networks · Biodegradable hydrogels Introduction Drug delivery systems may allow an active compound to reach its target site with minimized adverse side efects, in addition to the maintenance of a controlled release rate. These requirements can be accomplished by the entrapment of a drug in polymers hydrogels systems, which are able to release the drug, essentially, as a result of the polymer solu- bility modifcation, biodegradation, deaggregation, confor- mational changes, modifcation of the drug-system afnity, or even cleavage of the drug-system linkages (Fig. 1) [1–3]. The mechanism of drug release is highly afected by the morphology of hydrogels, as porosity and swelling degree [2, 4]. Therefore, the release strategy will depend on the design of the drug delivery system and on the physical and chemical features of the target cells or tissue. Hydrogels are three-dimensional polymeric networks with hydrophilic character, which can absorb large amounts of water or biological fuids without dissolving or losing their morphology [5, 6]. They are assembled from hydro- philic polymers crosslinking, and the swelling is one of the main properties of these materials, very desirable for drug delivery. The presence of hydrophilic groups, such as hydroxyl (–OH), carboxyl (–COOH), amine (–NH 2 ), amide (–CONH 2 ), and sulfonate (–SO 3 H), confers swelling abili- ties to hydrogels, besides reactive capability to produce new chemical features and tailored-materials [7–9]. These three- dimensional networks can be divided according to the origin of the polymer: natural, when employing biopolymers such as alginate, cellulose, and chitosan; synthetic, namely poly- vinyl alcohol, polyacrylamide, poly (sodium acrylate), poly (acrylic acid), and polyvinylpyrrolidone; and semi-synthetic, when composed by mixtures of natural and synthetic poly- mers [10]. Biodegradable hydrogels as drug delivery systems have attracted keen interest considering the limitations of conven- tional delivery systems, namely tablets, capsules, granules, * Suzana Mali smali@uel.br 1 Department of Biochemistry and Biotechnology, State University of Londrina (UEL), Celso Garcia Cid Road, Km 380, Londrina, PR 86051-990, Brazil 2 Department of Food Science and Technology, State University of Londrina (UEL), Celso Garcia Cid Road, Km 380, Londrina, PR 86051-990, Brazil