Zinc oxide nanoparticles in cartilage tissue engineering: a comprehensive mapping of the literature

Abstract

Introduction: Osteoarthritis and focal osteochondral defects represent a major clinical challenge due to the avascular nature and limited regenerative capacity of articular cartilage. While mesenchymal stem cell (MSC)-based therapies offer immense potential, directing their specific chondrogenic lineage remains a bottleneck. Zinc oxide nanoparticles (ZnO-NPs) have emerged as promising bioactive agents providing structural reinforcement and osteochondrogenic signaling cues. Material and Methods: A comprehensive mapping of the literature was conducted, analyzing extensive pre-clinical data (~300 citations) to evaluate the therapeutic efficacy, physicochemical properties, and cytotoxicity profiles of ZnO-NPs in cartilage tissue engineering. Data were systematically clustered based on nanoparticle morphology, concentration, signaling pathways, and scaffold integration. Results: The therapeutic window of ZnO-NPs is strictly dose- and morphology-dependent. Concentrations below 10–15 µg/mL demonstrate excellent biocompatibility and promote MSC chondrogenesis without inducing apoptosis. However, smaller (<30 nm) and spherical NPs accelerate Zn²⁺ burst release, increasing the risk of acute reactive oxygen species (ROS) generation and cytotoxicity. Conversely, anisotropic and streamlined ZnO-NPs exhibit a gradual ion release, offering sustained biological effects and enhanced rheological properties in hydrogels. Molecularly, ZnO-NPs effectively upregulate key chondrogenic markers (SOX9, COL2A1) and modulate critical pathways (TGF-β, Wnt/β-catenin). Furthermore, integrating ZnO-NPs into synthetic, natural, or 3D-printed scaffolds significantly improves biomechanical stability and cellular integration in various in vivo models. Conclusions: ZnO-NPs represent a highly versatile platform for cartilage regeneration, actively driving chondrogenic differentiation while suppressing hypertrophic degeneration. Standardizing their physicochemical parameters (size, shape, dose) is essential to maximize therapeutic efficacy, avoid nanotoxicity, and accelerate successful clinical translation.