Flow-Based Human Tissue Models Reveal Enhanced Immune Responses, while Multi-Organ Tox Plates Advance Drug Testing

Flow-based human tissue models are revealing immune responses missed by static culture, while new multi-organ plates are advancing drug-induced toxicity testing. In a flow-based model, the bispecific T-cell engager (BiTE) blinatumomab induced higher levels of targeted cancer cell death and elevated cytokine release, compared with a static culture. In a separate development, Sartorius (Göttingen, Germany) introduced a 96-well multi-organ tox plate (MOTP) with advanced 3D human tissue models of the liver, kidneys and intestines, designed to improve drug toxicity studies by mimicking in vivo human physiology.

The Mera flow-based platform demonstrated that continuous circulation, which matches physiological flow more closely, enabled enhanced cancer cell–immune interactions. No statistically significant difference was observed between control and treatment in static conditions (~1.1-fold decrease), whereas under Mera flow conditions a highly significant (>2-fold) reduction in B-cell count (p < 0.001) indicated BiTE-induced B-cell killing. Approximately 1.7-fold increase in lactate dehydrogenase (LDH) release was seen under flow compared to no-flow conditions, consistent with enhanced target cell lysis. Cytokine expression (TNF-α, IFN-γ and IL-2) was significantly elevated under Mera flow, with 1.5- to 2-fold increases compared with static conditions; the most pronounced effects were observed for IFN-γ and IL-2 (~2-fold), key indicators of immune-cell activation and effector function.

These findings show that flow conditions promote a more robust and polyfunctional T-cell response, with enhanced cytotoxic activity not observed in static systems. Flow-based, human-relevant platforms such as Mera replicate physiological fluid dynamics and enable continuous immune-cell trafficking, creating conditions that more closely resemble the in vivo immune microenvironment. Dynamic flow enables real-time monitoring of cytokine kinetics, allowing earlier identification of exaggerated immune responses. Cytokine release syndrome (CRS) remains one of the most significant safety challenges associated with T-cell-engaging therapies; static in vitro systems fail to capture dynamic immune interactions, while animal models often lack translational relevance. This approach enables early screening of immunotherapies for CRS liability.

The Sartorius multi-organ tox plate integrates with tools like Incucyte S3 and Cytotox Green Dye, enabling real-time imaging, dose-response analysis and EC50 calculations, offering a predictive and cost-effective alternative to animal testing.

In vitro systems have become indispensable tools for modelling human biology, enabling mechanistic investigation of development, physiology, and disease in experimentally tractable settings. Advances in stem cell biology, tissue engineering, biomaterials, and microfluidics have driven the development of increasingly sophisticated platforms, ranging from 2D cell cultures and 3D spheroids to organoids, organ-on-a-chip technologies, and multi-organ microphysiological systems. These models can capture key features of tissue architecture, cellular interactions, and physiological function while offering opportunities to improve drug discovery, toxicity testing, and translational research. As human cell-based models continue to evolve, they are increasingly being used as new approach methodologies (NAMs) to complement or replace traditional animal models.

Recent developments in the field include an immunocompetent liver-on-a-chip platform that identifies cell-type-specific contributions to drug-induced hepatotoxicity, a gravity-driven organoid perfusion (GDOP) chip for uniform TNBC organoids for three-drug sensitivity testing, a human bone marrow microphysiological system for profiling hematopoietic and immunotoxic effects of biologics, and an engineered human placental organoid microphysiological system that models Zika virus infection in a vascular niche. Additionally, multiple cerebral organoids connected with axon bundles form loop connectoids that show complex and near-critical dynamics, enabling optogenetic entrainment and strengthening in vitro studies of neural networks.