Abstract
While conventional in vitro and in vivo models of orthopaedic conditions have yielded valuable insights into disease mechanisms and drug efficacy, only a few discoveries have been successfully translated to clinical practice. Organoids and organs-on-chips (OoCs) are transforming orthopaedic translation by providing 3D customizable models that aim to faithfully recapitulate musculoskeletal (MSK) (patho)physiology. Using joint-mimicking OoCs and skeletal muscle organoids as examples, we review the evolution of these systems that have been developed to model the pathogenesis, progression, prognosis, and treatment of orthopaedic conditions. We highlight how organoid and OoC models recapitulate multi-tissue crosstalk, drug responses, and disease heterogeneity. Furthermore, we summarize and discuss the global regulatory landscape for organoids and OoCs. Current global regulatory trends support the potential of these human-centric platforms as alternatives, or even future replacements for animal testing. Looking ahead, organoids and OoCs are gaining increasing attention in AI-guided drug development, patient stratification, and regenerative medicine evaluation. The ongoing rapid developments are expected to position organoids and OoCs at the forefront of precision orthopaedics. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This article accelerates the clinical translation of orthopaedic discoveries by demonstrating how OoCs and organoids can be positioned as regulatory-ready alternatives to animal studies. Using joint-on-a-chip systems and skeletal muscle organoid as examples, we review the technological development of these platforms. By connecting recent policy shifts from key global regulators, including the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), China National Medical Products Administration (NMPA), and Pharmaceuticals and Medical Devices Agency (PMDA), to practical model qualification steps, we provide clinicians, industry, and regulators with a clear pathway to adopt OoCs and organoids. This process will facilitate their use as human-centric systems for patient stratification, implant safety evaluation, and disease-modifying drug development within the 3Rs (Replacement, Reduction, and Refinement) framework.