Next-Generation Joint-on-a-Chip: Toward Precision Mechanical Control in Multi-Tissue Systems.

Osteoarthritis is among the leading causes of disability worldwide, and no pharmacological therapies currently exist to reverse its progression. This lack of therapies is primarily attributed to the inadequacies of conventional in vitro models of joint physiology and pathology, which significantly hinder advancements in disease mechanism research and drug development. As an emerging in vitro joint model, joint-on-a-chip (JoC) technology allows low-cost, efficient simulation of physiological and pathological joint activities, making it a focal point of current research. Cartilage, subchondral bone, and synovium are among the key tissues required for constructing in vitro joint models, with cartilage playing a central load-bearing role in joint movement. This article provides a detailed overview of the structure and function of these tissues, with an emphasis on the load-bearing mechanisms of cartilage, and identifies the microenvironmental characteristics that JoC should aim to replicate. Subsequently, we review the current types of JoC and highlight their core challenge: the seamless integration of multi-tissue co-culture with specific mechanical stimulation. To address this issue, we propose potential solutions and present a conceptual design for a JoC prototype. Finally, we discuss the challenges and issues related to the outlook for JoC. Our ultimate goal is to develop a JoC capable of replicating the key microenvironments of joints, serving as a high-performance in vitro joint model to advance the study of disease mechanisms and facilitate drug development.