The Effect And Mechanisms Of Polyphenol Modified HAP Delivery System For The Alleviation Of Intervertebral Disk Degeneration

Intervertebral Disk Degeneration(IVDD)is a degenerative disease that reduces the antiload capacity of the IVD due to the reduction of the water content and the loss of elasticity of the IVD.Its main characteristics are the formation of IVD cracks,structural relaxation and height reduction.The main cause of IVDD is the combination of aging,mechanical stimulation and inflammation,which is the primary cause of low back pain(LBP).Nucleus pulposus(NP)cell(NPC)degeneration is one of the important manifestations of IVDD,which is characterized by the imbalance of extracellular matrix(ECM)anabolism and catabolism.The disturbance of inflammatory microenvironment is an important reason for the imbalance of ECM anabolism and catabolism.The tissue regeneration process begins with early inflammatory response after tissue injury.It is generally accepted that during the regenerative repair phase,an anti-inflammatory state is necessary in vivo to maximize the regenerative repair capacity of stem/progenitor cells and minimize the damaging effects of inflammation over a long period.The transitional nature of the inflammatory state has been largely attributed to the transition of macrophages from a classic "M1-phenotype" to an "M2-phenotype"(which promotes ECM synthesis,angiogenesis,and osteogenesis).Current therapies for IVDD include conservative and invasive treatments.However,these treatments are characteristic with slow onset,long treatment time and accelerating the degeneration of adjacent IVD.Treatment based on biomaterials to regulate immune microenvironment of tissue regeneration has become a research hotspot.Hydroxyapatite(HAP)shows functional similarity to the mineral composition of organisms.HAP nanostructure have exceptional biocompatibility,appropriate biodegradability,and can promote chondrocyte differentiation,which play a crucial role in promoting the production of ECM synthesis.Epigallocatechin-3-gallate(EGCG)is a kind of plant polyphenol with high biological activity and low toxicity,which can regulate the immune microenvironment by promoting M2 polarization.Previous studies have mostly focused on the application effect of anti-inflammatory factors.However,few studies have been conducted on naturally derived compounds and nanorods that regulate macrophage polarization,which further affect the regeneration and repair of IVD.In conclusion,we prepared an injectable and biodegradable nanocomposite hydrogel by cross-linking CMCS and HA loaded with HAP-EGCG nanorods(HAP-EGCG@CS-HA)to achieve a better and persistent ability to treat the IVD.The simultaneous effects of HAP-EGCG nanorods effectively repaired NP,which were attributed to the promotion of ECM anabolism(ACAN,SOX9 and COL2)and the decrease in ECM catabolism(MMPs)due to M2 polarization.We demonstrated for the first time that the HAP-EGCG@CS-HA can regulate the anabolism/catabolism balance of the ECM in the NP through IL17 signaling pathway and regenerating the IVD.Finally,the nanocomposite hydrogel HAP-EGCG@CS-HA has self-healing ability to withstand forces and energy from any direction as well as biodegradable property to release HAP-EGCG nanorods in IVD.Via the injection of HAP-EGCG@CS-HA,a preferable ECM anabolism/catabolism environment was established in vivo and vitro,which provides new insights for treating IVDD.