| BackgroundKidney disease has high morbidity,high mortality and heavy disease burden,which is a thorny public health problem in the world.Regenerative medicine and in situ tissue engineering provide new ideas for kidney repair and regeneration and treatment of kidney diseases.GelMA hydrogel can promote the adhesion,internalization and remodeling of host cells,and has good biocompatibility and degradability.Deferoxamine mesylate(DFO),as a FDA-approved safe drug,could not only exerts anti-ROS capacity and inhibits ferroptosis,but also upregulates HIF1α,VEGF and other key downstream effectors under normoxia.Angiogenic factors play a role in promoting angiogenesis and potentially promoting renal injury repair and regeneration,and also have antioxidant capacity independent of iron chelation properties and participate in the regulation of oxidative stress in inflammatory responses.According to the pathology and physiological mechanism of renal disease,we believe that GelMA hydrogel loaded with DFO(DFO-gel)may be of great significance to the repair of renal injury and regeneration of kidney.ObjectiveDesign and construct DFO-gel scaffold material with optimal mechanical properties and optimal biological correspondence,and study the effect and related mechanism of modified tissue engineering scaffold on kidney injury repair and regeneration.Method1.DFO-gels with different DFO graft concentrations were prepared,and the microscopic morphology observation,mechanical properties characterization,degradation and sustained release measurement were carried out.2.In vitro,to evaluate the cytocompatibility of DFO-gel,HIF-1α and VEGF levels,capatcity of promoting angiogenesis and anti-oxidative stress effect and the correlation between the above biological effects and DFO loading concentration.3.In vivo,construct a 4/6 nephrectomy rat model,implant DFO-gel in situ,then evaluate the renal function level and histological repair and regeneration effect in the early(2 weeks)and late(12 weeks)stages were analyzed to evaluate the late biocompatibility and safety of DFO-gel.Results1.DFO-gel exhibits a pore size that is more suitable for cell internalization,proliferation,migration and blood vessel formation,more suitable water absorption and water retention properties,and presents elastic modulus that is closer to a soft environment under physiological conditions,also embodies good thermal stability,biodegradability and sustained release of DFO.The above characteristics can be adjusted according to the loading amount of DFO,among which 4mg/mL DFO hydrogel(4-DFO-gel)hydrogel shows the most prominent among the above advantages.2.DFO-gel exhibites good biocompatibility,can promote cell proliferation and upregulates HIF-1α and VEGF under normoxia.Its ability to promote angiogenesis has a dose-effect relationship with the amount of DFO grafted.DFO-gel shows excellent repair ability of oxidative stress injury,and can reverse or even completely repair oxidative stress injury to a certain extent.3.The 4-DFO-gel group shows better renal injury repair effect in the early and late postoperative period,manifested as more obvious renal function protection(lower serum creatinine level,close to normal blood urea nitrogen level),histopathological level of Renal injury repair and regeneration(lesser inflammatory infiltration,degree of fibrosis and appearance of kidney-like structures in areas of material degradation).Long-term biocompatibility and safety are good.ConclusionDFO-gel has optimized mechanical properties and biological responsiveness.It can improve the damaged microenvironment through anti-oxidative stress,antiinflammatory and promoting angiogenesis.DFO-gel may also play a role in proregenerative effect by upregulating HIF-1α.In animal experiments,the kidney structural and functional repair are verified.The nephron-like units around the degradation zone of scaffold material are speculated to be formation of new tissues.In conclusion,our study may provide new strategies for the treatment of kidney diseases. |
PDF Full Text Request