Injectable oligomer-cross-linked chitosan hydrogels for biomedical applications

Abstract

Injectable chitosan hydrogels, designed to emulate the extracellular matrix (ECM) in tissue engineering, are conventionally formed through physical gelation. This study aims to enhance stability and broaden the range of gel properties by adopting a covalent cross-linking approach. To achieve this, a series of hydrophilic oligomeric macromers were synthesized, incorporating acryloyl morpholine (AMo) and reactive maleic anhydride (MA) in varying ratios, both with and without the hydrophobic comonomer pentaerythritol diacrylate monostearate (PEDAS). These oligomers, characterized by low molecular weight (Mn < 5,000 Da) and differing anhydride content, were rheologically assessed for their ability to cross-link chitosan under physiological conditions. The resulting injectable oligomer-cross-linked chitosan hydrogels (iCsgel) exhibited substantial elastic strength (with an estimated E of up to 28 kPa). Furthermore, oligomer-cross-linking facilitated the production of chitosan-based hydrogels with customizable mechanical properties, controllable swelling behavior, and regulated degradation kinetics. Importantly, cell-laden iCsgel demonstrated excellent cytocompatibility and supported cell proliferation. As a proof-of-concept, some macromers were partially modified with a model fluorescent dye before the cross-linking process, resulting in decorated iCsgel. In summary, the established injectable oligomer-cross-linked chitosan hydrogels represent a promising platform with tunable material properties, making them well-suited for applications in tissue engineering and various biomedical fields, including bioprinting.