Polydopamine‐Mediated Interfacial Functionalization of Implants for Accelerating Infected Bone Repair through Light‐Activatable Antibiosis and Carbon Monoxide Gas Regulated Macrophage Polarization

Abstract

Current treatments for implant-associated infection remain unsatisfactory due to secondary infection and excessive inflammation, which impairs osseointegration. Herein, an interfacial functionalization strategy is proposed by the integration of a carbon monoxide gas (CO) nanogenerator on titanium implants, followed by covalently grafting arginine-glycine-aspartic acid (RGD) polypeptide. Under near-infrared light (NIR) irradiation, the designed surface displays great light-activatable antibiosis through CO-potentiated mild photothermal therapy. Interestingly, the functionalized surface exerts a CO-mediated anti-inflammatory effect by activating the expression of heme oxygenase (HO-1), and inducing the down-regulation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) (p50/p65). More importantly, the combination of CO delivery and RGD immobilization drives the polarization of lipopolysaccharide (LPS)-stimulated M1-phenotype macrophages towards anti-inflammatory M2-pheno type through a potentialJanus kinase 1/signal transducer and activator of transcription 6 (JAK1/STAT6) pathway, thereby remodeling the damaged microenvironment into a proregenerative microenvironment. In a rat model of implant-associated infection, the designed surface effectively eliminates the residual bacteria, alleviates the accompanying inflammation and mediates macrophagemediated immunomodulation, resulting in good osteogenesis. Together, these findings are a first report on the therapeutic potential of CO signal in the cascade of immunomodulation-osteogenic differentiation. The functionalized implant may serve as a promising candidate in implant replacement surgeries.

Self-Adaptive Antibiofilm Effect and Immune Regulation by Hollow Cu2MoS4 Nanospheres for Treatment of Implant Infections

“…After the implant infection is eliminated, the excessive proinflammatory response of macrophages may also damage the tissues surrounding the implant. , Thus, we further analyzed cytokines associated with macrophages in infected tissues after treatment for four days. CD86-positive cells in H-CMS and H-CMS + US groups were fewer than those in saline and saline + US groups (Figure a,b), suggesting that H-CMS NSs inhibited M1-like macrophages.…”

Local delivery of gaseous signaling molecules for orthopedic disease therapy

“…After the pathogens are eliminated, CO continues to exert a powerful anti-inflammatory effect by inhibiting M1 inflammatory factor expression and promoting M1 macrophage polarization to M2 to rapidly adjust the tissue’s internal environment to a repair and osteogenesis-promoting mode. The conditions for CO release are relatively vague, although this gentler therapy has achieved remarkable results in in vivo experiments [ 180 ]. Postsurgical wound infections are likewise quite problematic and likely to cause systemic diseases, whereby the bacterial pathogen Staphylococcus aureus is the leading cause of skin and soft tissue infections in humans [ 181 ].…”

Metal-Phenolic Networks Assembled on TiO2 Nanospikes for Antimicrobial Peptide Deposition and Osteoconductivity Enhancement in Orthopedic Applications

“…Titanium (Ti) and its alloys account for a significantly large proportion in orthopedic implant applications due to their superior mechanical properties, corrosion resistance, and biocompatibility. − However, the surfaces of Ti and its alloys are prone to be colonized by planktonic bacteria and aggregates of these microorganisms subsequently form biofilm, causing increasing cases of biomaterial-associated infections (BAIs) during or after the implantation. , Additionally, the inherent bio-inertness of Ti inevitably leads to the shortage of osteoconductive activity at the implant interface and impedes the long-term structural fixation. , It was estimated that bacterial infection is responsible for around 20% operation failure, while aseptic loosening of implants accounts for nearly 18% operation failure. , The frequent occurrence of infection and loosening of implants increases the risk of secondary surgery, leaving patients in physical and psychological torment as well as burdening the healthcare system. , To overcome these challenges, it is urgently needed to develop coping strategies to endow them with effective antibacterial capabilities and osteoconductive activities. , …”

“…9,10 The frequent occurrence of infection and loosening of implants increases the risk of secondary surgery, leaving patients in physical and psychological torment as well as burdening the healthcare system. 11,12 To overcome these challenges, it is urgently needed to develop coping strategies to endow them with effective antibacterial capabilities and osteoconductive activities. 13,14 In order to improve the bioactivity of Ti implants, various micro/nanostructures have been constructed on the surface of Ti, like nanotubes, nanorods, nanospikes, nanopores, nanoleaves.…”