Polysaccharide based covalently linked multi-membrane hydrogels

Layer-by-layer techniques bear great potential for biomaterials as they allow sequential construction of hierarchical constructs. This especially accounts for hydrogels which can be tuned for biochemically, morphologically and mechanically different microenvironments and find numerous applications for encapsulation and release of drugs and cells. Here we present a novel radiation-free preparation method for multi-membrane hydrogels based on polysaccharides using prepolymer cross-linkers. Isocyanate functional prepolymers were used either alone or for cross-linking unmodified hyaluronic acid to form hydrolytically stable hydrogel membranes, whereas acrylate-bearing prepolymers were used to cross-link thiofunctional hyaluronic acid resulting in fully degradable hydrogel layers. Covalently linked multi-membrane systems can be formed through initial formation of a central hydrogel core followed by sequential embedding of the preformed hydrogel in an aqueous precursor solution for the following membrane. As a proof of principle, sequential drug release from a three layer system is shown in which ampicillin and dexamethasone were embedded in the outer and inner membranes, respectively, with a hydrolytically stable middle membrane as separation layer and diffusion barrier.