Regulation of extracellular bioactive cations in bone tissue microenvironment induces favorable osteoimmune conditions to accelerate in situ bone regeneration

The design of orthopedic biomaterials has gradually shifted from“immune-friendly”to“immunomodulatory,”in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration.Despite the well-known effects of bioactive metallic ions on osteogenesis,how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied.Herein,we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation(Mg^(2+))in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid(PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions.The results suggest that the Mg^(2+)-controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory(IL-10)and pro-osteogenic(BMP-2 and TGF-β1)cytokines production.It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.The in vivo results further verify that a large amount of bony tissue,with comparable bone mineral density and mechanical properties,has been generated at an early post-surgical stage in rat intramedullary bone defect models.This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment.

M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator

Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing.Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes,which respectively exhibit pro-inflammatory or anti-inflammatory functions.Therefore,modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing.Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity.In this study,we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures.The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages,thereby accelerating diabetic fracture healing.We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway.Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing.

Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration

Biomaterials as bone substitutes are always considered as foreign bodies that can trigger host immune responses.Traditional designing principles have been always aimed at minimizing the immune reactions by fabricating inert biomaterials.However,clinical evidence revealed that those methods still have limitations and many of which were only feasible in the laboratory.Currently,osteoimmunology,the very pioneering concept is drawing more and more attention-it does not simply regard the immune response as an obstacle during bone healing but emphasizes the intimate relationship of the immune and skeletal system,which includes diverse cells,cytokines,and signaling pathways.Properties of biomaterials like topography,wettability,surface charge,the release of cytokines,mediators,ions and other bioactive molecules can impose effects on immune responses to interfere with the skeletal system.Based on the bone formation mechanisms,the designing methods of the biomaterials change from immune evasive to immune reprogramming.Here,we discuss the osteoimmunomodulatory effects of the new modification strategies—adjusting properties of bone biomaterials to induce a favorable osteoimmune environment.Such strategies showed potential to benefit the development of bone materials and lay a solid foundation for the future clinical application.

Calcium silicate bioactive ceramics induce osteogenesis through oncostatin M

Immune reactions are a key factor in determining the destiny of bone substitute materials after implantation.Macrophages,the most vital factor in the immune response affecting implants,are critical in bone formation,as well as bone biomaterial-mediated bone repair.Therefore,it is critical to design materials with osteoimmunomodulatory properties to reduce host-to-material inflammatory responses by inducing macrophage polarization.Our previous study showed that calcium silicate(CS)bioceramics could significantly promote osteogenesis.Herein,we further investigated the effects of CS on the behavior of macrophages and how macrophages regulated osteogenesis.Under CS extract stimulation,the macrophage phenotype was converted to the M2 extreme.Stimulation by a macrophage-conditioned medium that was pretreated by CS extracts resulted in a significant enhancement of osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs),indicating the important role of macrophage polarization in biomaterial-induced osteogenesis.Mechanistically,oncostatin M(OSM)in the macrophage-conditioned medium promoted osteogenic differentiation of BMSCs through the ERK1/2 and JAK3 pathways.This in vivo study further demonstrated that CS bioceramics could stimulate osteogenesis better thanβ-TCP implants by accelerating new bone formation at defective sites in the femur.These findings improve our understanding of immune modulation of CS bioactive ceramics and facilitate strategies to improve the in vitro osteogenesis capability of bone substitute materials.