Osteoimmunomodulation has informed the importance of modulating a favorable osteoimmune environment for successful materials-mediated bone regeneration. Nanotopography is regarded as a valuable strategy for developing advanced bone materials, due to its positive effects on enhancing osteogenic differentiation. In addition to this direct effect on osteoblastic lineage cells, nanotopography also plays a vital role in regulating immune responses, which makes it possible to utilize its immunomodulatory properties to create a favorable osteoimmune environment. Therefore, the aim of this study was to advance the applications of nanotopography with respect to its osteoimmunomodulatory properties, aiming to shed further light on this field. We found that tuning the surface chemistry (amine or acrylic acid) and scale of the nanotopography (16, 38, and 68 nm) significantly modulated the osteoimmune environment, including changes in the expression of inflammatory cytokines, osteoclastic activities, and osteogenic, angiogenic, and fibrogenic factors. The generated osteoimmune environment significantly affected the osteogenic differentiation of bone marrow stromal cells, with carboxyl acid-tailored 68 nm surface nanotopography offering the most promising outcome. This study demonstrated that the osteoimmunomodulation could be manipulated via tuning the chemistry and nanotopography, which implied a valuable strategy to apply a "nanoengineered surface" for the development of advanced bone biomaterials with favorable osteoimmunomodulatory properties.

The osteoimmune environment plays indispensable roles in bone regeneration because the early immune environment that exists during the regenerative process promotes the recruitment and differentiation of osteoblastic lineage cells. The response of immune cells growing on nanotopographic surfaces and the microenvironment they generate should be considered when evaluating nanotopography-mediated osteogenesis, which are topics that are generally neglected in the field. In this study, we investigated the modulatory effects of nanoporous anodic alumina with different sized pores on macrophage responses and their subsequent effects on the osteogenic differentiation of bone marrow stromal cells (BMSCs). The nanopore structure and the pore size were found to be important adhesive cues for macrophages, which affected their spreading and cell shape, subsequently regulated the expression and activation of autophagy pathway components (LC3A/B, Beclin-1, Atg3, Atg7, and P62) and modulated the inflammatory response, osteoclastic activities, and release of osteogenic factors. Subsequently, the osteogenic pathways (Wnt and BMP) of BMSCs were found to be regulated by different nanopore-induced inflammatory environments, which affected the osteogenic differentiation outcomes. This study is the first to emphasize the effects of immune cells on nanotopography-mediated osteogenesis, which could lead to a new strategy for the development of advanced nanobiomaterials for tissue engineering, nanomedicine and immunotherapeutic applications.

No abstract

Immune cells play vital roles in regulating bone dynamics. Successful bone regeneration requires a favourable osteo-immune environment. The high plasticity and diversity of immune cells make it possible to manipulate the osteo-immune response of immune cells, thus modulating the osteoimmune environment and regulating bone regeneration. With the advancement in nanotechnology, nanotopographies with different controlled surface properties can be fabricated. On tuning the surface properties, the osteo-immune response can be precisely modulated. This highly tunable characteristic and immunomodulatory effects make nanotopography a promising strategy to precisely manipulate osteoimmunomdulation for bone tissue engineering applications. This review first summarises the effects of the immune response during bone healing to show the importance of regulating the immune response for the bone response. The plasticity of immune cells is then reviewed to provide rationales for manipulation of the osteoimmune response. Subsequently, we highlight the current types of nanotopographies applied in bone biomaterials and their fabrication techniques, and explain how these nanotopographies modulate the immune response and the possible underlying mechanisms. The effects of immune cells on nanotopography-mediated osteogenesis are emphasized, and we propose the concept of "nano-osteoimmunomodulation" to provide a valuable strategy for the development of nanotopographies with osteoimmunomodulatory properties that can precisely regulate bone dynamics.

Microglia-mediated neuroinflammation is one of the most significant features in a variety of central nervous system (CNS) disorders such as traumatic brain injury, stroke, and many neurodegenerative diseases. Microglia become polarized upon stimulation. The two extremes of the polarization are the neuron-destructive proinflammatory M1-like and the neuron-regenerative M2-like phenotypes. Thus, manipulating microglial polarization toward the M2 phenotype is a promising therapeutic approach for CNS repair and regeneration. It has been reported that nanoparticles are potential tools for regulating microglial polarization. Gold nanoclusters (AuNCs) could penetrate the blood–brain barrier and have neuroprotective effects, suggesting the possibility of utilizing AuNCs to regulate microglial polarization and improve neuronal regeneration in CNS. In the current study, AuNCs functionalized with dihydrolipoic acid (DHLA–AuNCs), an antioxidant with demonstrated neuroprotective roles, were prepared, and their effects on polarization of a microglial cell line (BV2) were examined. DHLA–AuNCs effectively suppressed proinflammatory processes in BV2 cells by inducing polarization toward the M2-like phenotype. This was associated with a decrease in reactive oxygen species and reduced NF-kB signaling and an improvement in cell survival coupled with enhanced autophagy and inhibited apoptosis. Conditioned medium from DHLA–AuNC-treated BV2 cells was able to enhance neurogenesis in both the neuronal cell line N2a and in an ex vivo brain slice stroke model. The direct treatment of brain slices with DHLA–AuNCs also ameliorated stroke-related tissue injury and reduced astrocyte activation (astrogliosis). This study suggests that by regulating neuroinflammation to improve neuronal regeneration, DHLA–AuNCs could be a potential therapeutic agent in CNS disorders.