Dual-Wavelength Photosensitive Nano-in-Micro Scaffold Regulates Innate and Adaptive Immune Responses for Osteogenesis

Abstract

The immune response of a biomaterial determines its osteoinductive effect. Although the mechanisms by which some immune cells promote regeneration have been revealed, the biomaterial-induced immune response is a dynamic process involving multiple cells. Currently, it is challenging to accurately regulate the innate and adaptive immune responses to promote osteoinduction in biomaterials. Herein, we investigated the roles of macrophages and dendritic cells (DCs) during the osteoinduction of biphasic calcium phosphate (BCP) scaffolds. We found that osteoinductive BCP directed M2 macrophage polarization and inhibited DC maturation, resulting in low T cell response and efficient osteogenesis. Accordingly, a dual-targeting nano-in-micro scaffold (BCP loaded with gold nanocage, BCP-GNC) was designed to regulate the immune responses of macrophages and DCs. Through a dual-wavelength photosensitive switch, BCP-GNC releases interleukin-4 in the early stage of osteoinduction to target M2 macrophages and then releases dexamethasone in the later stage to target immature DCs, creating a desirable inflammatory environment for osteogenesis. This study demonstrates that biomaterials developed to have specific regulatory capacities for immune cells can be used to control the early inflammatory responses of implanted materials and induce osteogenesis.

High proportion strontium-doped micro-arc oxidation coatings enhance early osseointegration of titanium in osteoporosis by anti-oxidative stress pathway

“…, BMP2, TGFβ, etc. ) [ 58 , 59 ]. In angiogenesis, factors secreted from M2 macrophage, especially platelet-derived growth factor-BB (PDGF-BB), could effectively promote the formation of new blood vessels, thus accelerating the process of bone repair [ 60 ].…”

CD301b+ macrophages mediate angiogenesis of calcium phosphate bioceramics by CaN/NFATc1/VEGF axis

“…Immune cells are critical for bone regeneration induced by osteoinductive biomaterials, especially macrophages. It is reported that loss of macrophages impairs tissue regeneration [ 34 ]. Macrophages were highly heterogeneous and plastic, which are responsive to diverse cues and environments.…”

Enhanced bone regenerative properties of calcium phosphate ceramic granules in rabbit posterolateral spinal fusion through a reduction of grain size

“…9 ). Recently, more and more researchers realize that immune responds also play an essential role in bone regeneration [ [55] , [56] , [57] ]. Osteoinductive BCP ceramics might regulate macrophage to secrete related chemokines via ERK signaling pathway, which would accelerate MSCs homing to facilitate bone formation [ 50 ].…”

“…In addition, the immune response of a biomaterial also determines its osteoinductive effect. Zhao Q et al investigated the roles of macrophages and dendritic cells (DCs) during the osteoinduction of BCP scaffolds, and found that osteoinductive BCP directed M2 macrophage polarization and inhibited DC maturation, resulting in low T cell response and efficient osteogenesis [ 58 ]. Our previous work had been proved that HA bioceramics with nanotopography also had a significant influence on osteoclastogenesis, nanotopography markedly impaired osteoclastic formation and function compared to the ones with the submicron topography, which was further related to its osteoinductive capacity [ 25 ].…”