Imaging-guided platform for real-time intervention in complex in vitro models

Complex in vitro models (CIVMs), including organoids, spheroids, and bioprinted constructs, have emerged as powerful platforms for recapitulating human tissue architecture and function. However, their inherent heterogeneity and dynamic nature pose significant challenges for standardization, reproducibility, and real-time manipulation. Here, we present VISIBLE (Versatile Imaging-Guided Sampling and Interactive Bioprinting System), a modular platform that integrates real-time monitoring with automated manipulation and 3D bioprinting that addresses these challenges. VISIBLE employs a unique co-registered dual-axis system, enabling image-guided, closed-loop spatiotemporal interventions within live cultures. We demonstrate its transformative capabilities across diverse applications, including precise morphology- and function-based sampling of organoids and neurospheres, interactive 3D bioprinting with on-the-fly adjustments, and autonomous serial interventions for longitudinal studies. Furthermore, we illustrate its utility in translational pipelines through selective sampling and successful in vivo implantation of barcoded patient-derived cancer organoids for clonal lineage tracing. VISIBLE supports long-term culture within an integrated incubation environment and accommodates interchangeable tool-heads for scalable, high-throughput workflows. By enabling dynamic, feedback-controlled experimentation, VISIBLE addresses critical bottlenecks in current CIVM platforms, offering a versatile and powerful solution for a wide range of biomedical applications. By transforming CIVMs from static cultures into interactive, programmable systems, VISIBLE represents a critical step toward autonomous in vitro experimentation and paves the way for next-generation platforms in tissue engineering, disease modelling, and preclinical research.