<p>Improved Immunoregulation of Ultra-Low-Dose Silver Nanoparticle-Loaded TiO₂ Nanotubes via M2 Macrophage Polarization by Regulating GLUT1 and Autophagy</p>

Abstract

Introduction: The bone regeneration of endosseous implanted biomaterials is often impaired by the host immune response, especially macrophage-related inflammation which plays an important role in the bone healing process. Thus, it is a promising strategy to design an osteo-immunomodulatory biomaterial to take advantage of the macrophage-related immune response and improve the osseointegration performance of the implant. Methods: In this study, we developed an antibacterial silver nanoparticle-loaded TiO 2 nanotubes (Ag@TiO 2-NTs) using an electrochemical anodization method to make the surface modification and investigated the influences of Ag@TiO 2-NTs on the macrophage polarization, osteo-immune microenvironment as well as its potential molecular mechanisms in vitro and in vivo. Results: The results showed that Ag@TiO 2-NTs with controlled releasing of ultra-low-dose Ag + ions had the excellent ability to induce the macrophage polarization towards the M2 phenotype and create a suitable osteo-immune microenvironment in vitro, via inhibiting PI3K/Akt, suppressing the downstream effector GLUT1, and activating autophagy. Moreover, Ag@TiO 2-NTs surface could improve bone formation, suppress inflammation, and promote osteo-immune microenvironment compared to the TiO 2-NTs and polished Ti surfaces in vivo. These findings suggested that Ag@TiO 2-NTs with controlled releasing of ultra-low-dose Ag + ions could not only inhibit the inflammation process but also promote the bone healing by inducing healing-associated M2 polarization. Discussion: Using this surface modification strategy to modulate the macrophage-related immune response, rather than prevent the host response, maybe a promising strategy for implant surgeries in the future.

Modulatory Role of Silver Nanoparticles and Mesenchymal Stem Cell–Derived Exosome-Modified Barrier Membrane on Macrophages and Osteogenesis

“…Additionally, surface immobilization using Ag nanoparticles has been frequently used in various antibacterial implants, such as wound dressings and catheters ( Besinis et al, 2017 ; Choi et al, 2019 ). Recently, the immunoregulatory role of Ag nanoparticle-modified surface on immune cells has also been reported ( Chen et al, 2020 ). PCL, a high-performance bioresorbable and biocompatible polymer, has been approved by the US Food and Drug Administration (FDA) for soft and hard tissue repair ( Mondal et al, 2016 ).…”

Titanium dioxide nanotubes promote M2 polarization by inhibiting macrophage glycolysis and ultimately accelerate endothelialization

“…The relationship between TNTs and macrophage polarization has been described in many studies, both in modified TNTs. Previous studies have reported that nano‐arrays on the surface of titanium plates can regulate macrophage polarization towards M2‐type by activating autophagy 14 . Wang et al 15 have also found that TNTs of different diameters could regulate the polarization of macrophages.…”

“…Previous studies have reported that nano‐arrays on the surface of titanium plates can regulate macrophage polarization towards M2‐type by activating autophagy. 14 Wang et al 15 have also found that TNTs of different diameters could regulate the polarization of macrophages. The results revealed that the TNTs regulated macrophage polarization by influencing cell metabolism.…”

Biomaterial-based immunotherapeutic strategies for rheumatoid arthritis

“…Administration of this NP into CIA mice achieved a reduction of TNF-α, IL-6, and IL-1β within the synovium [123]. On the topic of re-polarization, silver NPs have been shown to increase intracellular Ag + , promoting macrophage polarization towards an M2 phenotype through inhibition of phosphoinositide 3-kinase (PI3K)/ Akt signaling, decreasing expression of glucose transporter expression, and inducing autophagy [124]. In a similar macrophage re-educating strategy, Yang et al [125] functionalized a silver NP with folate and successfully induced the death of inflammatory macrophages, or their polarization towards an M2 phenotype in the CIA murine model [125].…”