Design of chitosan/ gelatin-based hydrogel system, sensitive to extracellular matrix enzymes in the treatment of rheumatic diseases

Abstract

Introduction: Intra-articular (IA) injection of therapeutic agents is an emerging treatment for RA, a chronic autoimmune disease, which provides localized drug accumulation and reduces undesirable side effects. In this regard, injectable hydrogels made from biomaterials such as chitosan have gained more attention for intra-articular injection because of their perfect biocompatibility and biodegradability, which can result in extended drug retention time and their high loading capacity.Aims: The aim of this study was to design enzyme-responsive chitosan/gelatin hydrogel, which could titrate drug release to match the disease activity, resulting in optimal therapeutic efficacy.Materials and methods: Chitosan/gelatin hydrogels were prepared with the addition of β-glycerophosphate as an ionic crosslinker. Gelation time, morphology, and swelling/degradation properties of synthesized hydrogels were characterized. The cytotoxicity studies were conducted on Huvec cell line using MTT assay. Enzyme-responsive release of diclofenac sodium from hydrogels was investigated in PBS buffer (pH 7.4), with or without collagenase I with incubation at 37 °C and 150 rpm for seven consecutive days. In this regard, an aliquot of sink medium was replaced with the same volume of fresh PBS at specific time intervals. Drug release was determined by UV-VIS spectrophotometry at 276 nm. Results: An enzyme-responsive hydrogel was successfully prepared with injectable properties, which had an interconnected porous structure and it exhibited good biocompatibility and biodegradability. Drug release study showed that the amount of released drug was related to the rate of gelatin degradation, which confirmed the sustained and controlled release in the presence of different concentrations of collagenase.Discussion: In this study, we have introduced a novel enzyme-responsive drug delivery system, which has the potential to respond to different concentrations of metalloproteinase enzymes. This system contains enzyme-cleavable sites to facilitate hydrogel disassembly in response to enzymes present in inflammatory environments.