Osteomyelitis remains a global challenge in the field of orthopedics. Even after standard debridement and antibiotic-assisted treatment, the long-term recurrence rate remains at 20%-30%. Given the dynamic changes in immune responses and defense mechanisms during bone infection, as well as the complex “race for the surface” involving bacterial adhesion and host cells (macrophages and tissue cells) on implant surfaces, biomaterials with immunomodulatory functions have attracted considerable attention. Macrophages, as crucial components of the immune system, participate in the inflammatory regulation and tissue remodeling of bone infections through highly plastic polarization mechanisms after bacterial invasion. The different microenvironmental characteristics and therapeutic needs at different stages of bone infection highlight the promising applications of biomaterials capable of macrophage polarization remodeling and sequential regulation. In this review, we provide a detailed discussion of the complex immune regulatory patterns in the bone infection microenvironment and the critical functions of macrophage polarization. We then explore how implant surface properties influence bacterial adhesion and macrophage function, highlighting the importance of achieving precise and dynamic regulation of macrophage polarization based on the Race for the Surface theory. Furthermore, we focus on recent advances, potential challenges, and opportunities in biomaterial-mediated macrophage polarization remodeling and sequential modulation strategies across different stages of osteomyelitis, aiming to offer insights that may accelerate the clinical translation of novel biomaterial-based macrophage immunotherapies.

The high concentration of antibacterial metal ions may exhibit unavoidable toxicity to cells and normal tissues. The application of antibacterial metal ions to activate the immune response and induce macrophages to attack and phagocytose bacteria is a new antimicrobial strategy. Herein, 3D-printed Ti-6Al-4V implants modified by copper, and strontium ions combined with natural polymers were designed to treat implant-related infections and osseointegration disorders. The polymer-modified scaffolds rapidly released a large amount of copper and strontium ions. During the release process, copper ions were employed to promote the polarization of M1 macrophages, thus inducing a proinflammatory immune response to inhibit infection and achieve the immune antibacterial activity. Meanwhile, copper and strontium ions promoted the secretion of bone-promoting factors by macrophages, induced osteogenesis and showed immunomodulatory osteogenesis. This study proposed immunomodulatory strategies based on the immunological characteristics of target diseases and provided ideas for the design and synthesis of new immunoregulatory biomaterials.

Regeneration of critical-size bone defects hinges on the reconstruction of neurovascular networks. The electrophysiological properties of native bone underscore the pivotal role of endogenous bioelectricity in coordinating nerve-vascular-bone regeneration. However, traditional piezoelectric scaffolds impede regenerative efficiency due to their intrinsic limitations. To tackle this, 3D printed flexible polyvinyl alcohol/whitlockite/barium titanate (PVA/WH/BaTiO₃) composite scaffolds endowed with ultrasonic-driven wireless electrical stimulation capacity were engineered. The PVA/WH composite strategy significantly enhanced the printability, flexibility, shear-thinning behavior, mechanical robustness, and bioactivity of the scaffolds, systematically addressing the intrinsic limitations of traditional piezoelectric scaffolds while fulfilling the multifaceted requirements of orthopedic applications. By adding BaTiO₃, when subjected to noninvasive low-intensity pulsed ultrasound as a stimulus, the scaffolds exhibited controllable wireless electrical stimulation properties with tunable duration and intensity to meet specific therapeutic requirements. In vitro experiments illustrating electrical stimulation can significantly promote neuralization, vascularization and osteogenic differentiation. Furthermore, the 3D printed flexible composite scaffolds with ultrasonic-driven wireless electrical stimulation facilitated neuro-vascularization network reconstruction and osteogenic proteins up-regulation in rat calvarial critical-sized defect models of 7 mm, thereby accelerating the regeneration and repair of critical-size bone defects. It held great potential as a promising material for critical-size bone defects treatment.