A Ceria Nanoparticle-incorporated Thermoresponsive Hydrogel Combining Stem Cell Therapy For Spinal Cord Injury Treatment

Mesenchymal stem cell（MSC）-based therapy for spinal cord injury（SCI）has been widely studied.However,the massive inflammatory cell infiltration and intense oxidative stress after SCI lead to reduced survival of transplanted stem cells in vivo,which seriously affects the therapeutic efficacy of stem cell therapy for SCI.Based on this,this study prepared a thermoresponsive hydrogel with antioxidant effect to synergize with MSCs for the treatment of SCI.On the one hand,the hydrogel with thermoresponsive property can form a gel in situ,which provides a biological scaffold for MSCs,and on the other hand,it improves the survival rate of MSCs in vivo by regulating the microenvironment of SCI,which in turn improves the therapeutic effect.In this study,cerium oxide nanoparticles（Ce O₂ NPs）with a hydrated particle size of about 8 nm,ζ-potential of-24.70±1.95 m V,the presence of both Ce³⁺and Ce⁴⁺on its surface,and good crystallization properties were prepared.The Ce O₂ NPs exhibited excellent hydrogen peroxide decomposition ability as well as superoxide anion dismutation ability.Subsequently,Ce O₂-gel was prepared by loading Ce O₂ NPs into chitosan hydrogel,which has a loose three-dimensional pore structure,fast thermoresponsibility,good water absorption,swelling,biodegradation and antioxidant properties.Further,the cytocompatibility of Ce O₂ NPs and Ce O₂-gel was demonstrated at the cellular level,as well as the property of scavenging excess reactive oxygen species（ROS）in the oxidative stress environment,thereby maintaining of redox homeostasis in MSCs and improving cell survival.Subsequently,we established an animal model of spinal cord complete transection injury was established to verify that Ce O₂-gel loaded with MSCs rapidly covered the wound area through in situ gelation and significantly increased the survival of MSCs at the injury site as well as the expression levels of neurotrophic and angiogenesis-related factors in spinal cord tissue by modulating the disease microenvironment,achieving effective neural tissue repair and recovery of motor function in the hindlimbs of rats.In addition,the in vivo safety of this synergistic treatment strategy and the protective effect on the urinary system were demonstrated by serum biochemical assays and hematoxylin-eosin staining of main organs.In conclusion,a Ce O₂-gel was prepared to achieve in situ delivery of MSCs at the site of injury in a simple and minimally invasive manner by using the thermoresponsive ability of hydrogel,while effectively improving the therapeutic effect of MSCs in vivo by modulating the SCI microenvironment,providing an effective theoretical and experimental basis for the study of local delivery of stem cells.