In Situ Sustained Macrophage-Targeted Nanomicelle-Hydrogel Microspheres for Inhibiting Osteoarthritis

There are stillchallenges in applying drug nanocarriers for in situ sustained macrophage targeting and regulation,due to the rapid clearance of nanocarriers and burst drug release invivo.Herein,a nanomicellehydrogel microsphere,characterized by its macrophage-targeted nanosized secondary structure that allows it to accurately bind to M1 macrophages through active endocytosis,is employed for in situ sustained macrophage targeting and regulation,and addresses the insufficient osteoarthritis therapeutic efficacy caused by rapid clearance of drug nanocarriers.The 3-dimensional structure of a microsphere can prevent the rapid escape and clearance of a nanomicelle,thus keeping it in joints,while the ligand-guided secondary structure can carry drugs to accurately target and enter M1 macrophages,and release drugs via the transition from hydrophobicity to hydrophilicity of nanomicelles under inflammatory stimulation inside the macrophages.

Biomimetic injectable hydrogel microspheres with enhanced lubrication and controllable drug release for the treatment of osteoarthritis

The occurrence of osteoarthritis(OA)is highly associated with the reduced lubrication property of the joint,where a progressive and irreversible damage of the articular cartilage and consecutive inflammatory response dominate the mechanism.In this study,bioinspired by the super-lubrication property of cartilage and catecholamine chemistry of mussel,we successfully developed injectable hydrogel microspheres with enhanced lubrication and controllable drug release for OA treatment.Particularly,the lubricating microspheres(GelMA@DMA-MPC)were fabricated by dip coating a self-adhesive polymer(DMA-MPC,synthesized by free radical copolymerization)on superficial surface of photo-crosslinked methacrylate gelatin hydrogel microspheres(GelMA,prepared via microfluidic technology),and encapsulated with an anti-inflammatory drug of diclofenac sodium(DS)to achieve the dual-functional performance.The tribological test and drug release test showed the enhanced lubrication and sustained drug release of the GelMA@DMA-MPC microspheres.In addition,the functionalized microspheres were intra-articularly injected into the rat knee joint with an OA model,and the biological tests including qRT-PCR,immunofluorescence staining assay,X-ray radiography and histological staining assay all revealed that the biocompatible microspheres provided significant therapeutic effect against the development of OA.In summary,the injectable hydrogel microspheres developed herein greatly improved lubrication and achieved sustained local drug release,therefore representing a facile and promising technique for the treatment of OA.

Gelatin-based composite hydrogels with biomimetic lubrication and sustained drug release

The occurrence of osteoarthritis is closely related to progressive and irreversible destruction of the articular cartilage,which increases the friction significantly and causes further inflammation of the joint.Thus,a scaffold for articular cartilage defects should be developed via lubrication restoration and drug intervention.In this study,we successfully synthesized gelatin-based composite hydrogels,namely GelMA–PAM–PMPC,with the properties of biomimetic lubrication and sustained drug release by photopolymerization of methacrylic anhydride modified gelatin(GelMA),acrylamide(AM),and 2-methacryloyloxyethyl phosphorylcholine(MPC).Tribological test showed that the composite hydrogels remarkably enhanced lubrication due to the hydration lubrication mechanism,where a tenacious hydration shell was formed around the zwitterionic phosphocholine headgroups.In addition,drug release test indicated that the composite hydrogels efficiently encapsulated an anti-inflammatory drug(diclofenac sodium)and achieved sustained release.Furthermore,the in vitro test revealed that the composite hydrogels were biocompatible,and the mRNA expression of both anabolic and catabolic genes of the articular cartilage was suitably regulated.This indicated that the composite hydrogels could effectively protect chondrocytes from inflammatory cytokine-induced degeneration.In summary,the composite hydrogels that provide biomimetic hydration lubrication and sustained local drug release represent a promising scaffold for cartilage defects in the treatment of osteoarthritis.

Fullerol-hydrogel microfluidic spheres for in situ redox regulation of stem cell fate and refractory bone healing

The balance of redox homeostasis is key to stem cell maintenance and differentiation.However,this balance is disrupted by the overproduced reactive oxygen species(ROS)in pathological conditions,which seriously impair the therapeutic efficacy of stem cells.In the present study,highly dispersed fullerol nanocrystals with enhanced bioreactivity were incorporated into hydrogel microspheres using one-step innovative microfluidic technology to construct fullerol-hydrogel microfluidic spheres(FMSs)for in situ regulating the redox homeostasis of stem cells and promoting refractory bone healing.It was demonstrated that FMSs exhibited excellent antioxidant activity to quench both intracellular and extracellular ROS,sparing stem cells from oxidative stress damage.Furthermore,these could effectively promote the osteogenic differentiation of stem cells with the activation of FoxO1 signaling,indicating the intrinsically osteogenic property of FMSs.By injecting the stem cells-laden FMSs into rat calvarial defects,the formation of new bone was remarkably reinforced,which is a positive synergic effect from modulating the ROS microenvironment and enhancing the osteogenesis of stem cells.Collectively,the antioxidative FMSs,as injectable stem cell carriers,hold enormous promise for refractory bone healing,which can also be expanded to deliver a variety of other cells,targeting diseases that require in situ redox regulation.