Remotely Temporal Scheduled Macrophage Phenotypic Transition Enables Optimized Immunomodulatory Bone Regeneration

Abstract

Precise timing of macrophage polarization plays a pivotal role in immunomodulation of tissue regeneration, yet most studies mainly focus on M2 macrophages for their anti‐inflammatory and regenerative effects while the essential proinflammatory role of the M1 phenotype on the early inflammation stage is largely underestimated. Herein, a superparamagnetic hydrogel capable of timely controlling macrophage polarization is constructed by grafting superparamagnetic nanoparticles on collagen nanofibers. The magnetic responsive hydrogel network enables efficient polarization of encapsulated macrophage to the M2 phenotype through the podosome/Rho/ROCK mechanical pathway in response to static magnetic field (MF) as needed. Taking advantage of remote accessibility of magnetic field together with the superparamagnetic hydrogels, a temporal engineered M1 to M2 transition course preserving the essential role of M1 at the early stage of tissue healing, as well as enhancing the prohealing effect of M2 at the middle/late stages is established via delayed MF switch. Such precise timing of macrophage polarization matching the regenerative process of injured tissue eventually leads to optimized immunomodulatory bone healing in vivo. Overall, this study offers a remotely time‐scheduled approach for macrophage polarization, which enables precise manipulation of inflammation progression during tissue healing.

Bioinspired Piezoelectric Periosteum to Augment Bone Regeneration via Synergistic Immunomodulation and Osteogenesis

“…As is known, the macrophage-mediated inflammatory response plays a vital role in facilitating osteogenesis; the timely cessation of the proinflammatory reaction by optimizing the M1-to-M2 transition enhances the recruitment of BMSCs within the defect area and their osteoblastic differentiation. 65 For osteogenesis evaluation, in this study, immunohistochemical staining was conducted to evaluate the in vivo expression levels of osteogenesis-related markers (i.e., Col-1, Runx2, OPN, and OCN) at 8 weeks, with brown areas indicating positive protein expression. In general, these specific markers mirror the level of osteogenic activity.…”

Remote Activation of M2 Macrophage Polarization via Magneto-Mechanical Stimulation To Promote Osteointegration

“…Methodologically, the study innovatively employed an effective mechanical strategy to modulate macrophage M2 polarization, which overcame the disadvantages of biochemical methods, such as toxic side effects, limited half-life, and susceptivity to environmental interference. Furthermore, the osteointegration of implant might require complex spatiotemporal regulation of macrophages . Magneto-mechanical stimulation was readily applicable with macrophage phenotype transition through alternating the intensity and intervention time of magnetic field, thereby allowing for more flexible clinical application in future.…”

“…Due to the advantages of spatial–temporal controllability, high tissue penetrability, and non-invasiveness, magnetic field stands out as an effective way to elicit a remotely controllable mechanical stimulation. − Recently, we successfully synthesized the magnetic-responsive mineralized collagen (MC) coating by integrating MC coating with superparamagnetic iron oxide nanoparticles (IOPs) . MC endows the coating with an excellent biochemical property, as well as the immunomodulatory capacity to promote macrophage M2 polarization .…”

Smart Hydrogels for Bone Reconstruction via Modulating the Microenvironment

“…It would be ideal to modulate the macrophage polarization to M2 and alleviate inflammation. Huang et al [ 129 ] prepared MF-responsive hydrogels to enhance bone repair by modulating the immune microenvironment (Fig. 8 A and B).…”