Design And Application Of Dynamic Microgels Based On Hyaluronic Acid And Carboxymethyl Chitosan

Microgels are colloidal particles with a cross-linked polymer network,ranging in size from 0.1 to 100μm,which can respond to biological signals in vivo and in vitro,thereby fitting wide range of applications in biomedicine field.Chitosan（CS）and hyaluronic acid（HA）,the natural macromolecular polysaccharides from a wide range of sources,possess excellent physical and chemical properties,good biocompatibility and stability.It has been widely used in drug delivery systems and tissue engineering field.In this paper,the two derivatives,carboxymethyl chitosan（CMCS）and aldehyde hyaluronic acid（A-HA）,were used as starting materials to prepare microgel particles by precipitation polymerization method.The physicochemical properties,biocompatibility,and application of the microgels as a pulmonary drug delivery system for sustainable drug delivery were investigated.Using the microgel particles as the basic structure,swellable dry powder aerosol particles,and functionalized alginate hydrogels were prepared.The biomaterials were further explored as sustained pulmonary drug delivery systems and wound dressings for diverse applications.The details of the study are as follows:（1）Microgel affords a porous and swollen microstructure for the establishment of pulmonary delivery system with sustained released properties.Here,we report a microgel（with the diameter around 4μm）prepared with a precipitation method,synthesized by coordinating Zn²⁺to the Schiff base cross-linked carboxymethyl chitosan and glycol split hyaluronate.The microgel has shown well swollen and p H sensitive behaviors,high safety and biocompatibility in vitro.Besides,the biomaterial could escape from macrophage phagocytosis,a key factor contributes to quick drug clearance in the lung after co-incubated with RAW264.7 cells.In consist with this,the bovine serum albumin loaded in the microgel showed sustained release behavior in 24 h in vitro;meanwhile,the drug had a retention time up to 36 h in the lung followed by clearance in ICR mice through pulmonary administration.Thus,our microgel platform provides a promising candidate for pulmonary drug delivery systems with controlled release rate.（2）Dry powder inhalation is a promising alternative for the on-site treatment of chronic pulmonary diseases.Herein,we prepared a swellable dry powder aerosol particles using CMCS and A-HA as starting materials,Zn²⁺as cross-linkers.The particles have high yield,high drug encapsulation efficiency,suitable particle size,and strong drug sustained release properties.The drug carriers were preserved for at least 48 h after entering the lungs.Besides,the theophylline-loaded microspheres can significantly reduce the number of inflammatory cells in bronchoalveolar lavage fluid and alleviate the inflammatory conditions of the lung tissue compared with single drug administration.The spray dried microparticle was a potential alternative of the pulmonary drug delivery systems with sustained release properties.（3）Alginate hydrogel has drawn great attention in tissue engineering.However,the limited tunability of the ironic cross-linking method prevents the delicate management of physical properties in response to diverse wound conditions.We addressed this issue by using microgel particle（fabricated by zinc ions coordinated the complex of carboxymethyl chitosan and aldehyde hyaluronic acid）as a novel cross-linker.Then cation was introduced as a second crosslinker to create a double cross-link network.The crosslinking method leads to precise regulation of the hydrogel characters,including bio-degradation rate and controlled release of the drug.As a result,the optimized hydrogels could serve as physical supports of the NIH 3T3cells in vitro,facilitated the cell infiltration in vivo,and boosted the tissue regeneration of diabetic wound.The results indicated that the addition of microgel as a new crosslinker created flexibility during alginate hydrogel construction for widely application in tissue regeneration.