Mucoadhesive hyaluronic acid composites for prolonged gastric retention

The interaction between mucoadhesive materials and the mucin layer is a critical factor in the development of advanced drug delivery systems designed to enhance site-specific targeting and prolong gastrointestinal residence time. Among these materials, hyaluronic acid (HA), a naturally occurring, linear glycosaminoglycan composed of repeating disaccharide units of β(1 → 3)-D-glucuronic acid and β(1 → 4)-N-acetyl-D-glucosamine, has emerged as a promising mucoadhesive agent due to its unique physicochemical properties. Despite the inherent electrostatic repulsion between the anionic carboxylate groups (-COO^-) of HA and the negatively charged sialic acid residues on mucin glycoproteins, HA achieves strong mucoadhesion through a combination of non-electrostatic interactions. These include: (1) hydrogen bonding between the hydroxyl (-OH) and protonated carboxyl (-COOH) groups of HA and functional groups such as hydroxyl, amide, and carboxyl groups on mucin; (2) physical entanglement of HA's flexible polymeric chains within the mucin network; (3) hydration-mediated cohesion driven by HA's high water retention capacity and hydrogel-forming nature; and (4) van der Waals forces at hydrophobic domains within the mucin layer. HA exhibits shear-thinning rheological behavior and molecular weight-dependent viscosity, which are advantageous for mucoadhesion, particularly under the acidic conditions of the gastric environment. Moreover, HA-based composites, including chitosan-HA hybrids, nanoparticles, and hydrogel systems, demonstrate enhanced mucosal adhesion and penetration through mechanisms such as steric stabilization and improved tissue interaction. These effects have been validated by a range of analytical techniques, including rheological measurements, atomic force microscopy (AFM), and in vivo imaging modalities. HA has been successfully utilized in the development of pH-responsive delivery platforms for antibiotics and gastroprotective agents, resulting in improved gastric retention and therapeutic efficacy. To overcome physiological challenges such as rapid mucus turnover (approximately every 4-6 h), current research focuses on engineering stimuli-responsive systems, mucopenetrating nanoparticles, and employing three-dimensional (3D) bioprinted mucosal models to optimize drug delivery. Looking ahead, innovations integrating high-throughput omics technologies and scalable manufacturing approaches hold great promise for the development of next-generation HA-based therapeutics. These advancements position HA as a cornerstone for precision-targeted therapies for gastric ulcers, inflammation, and other gastrointestinal disorders. This review critically examines mucoadhesive mechanisms and compares HA derivatives' gastric-retention and mucoadhesive performance, showing how specific modifications produce measurable improvements.