Role of Mononuclear Phagocytes and Flow Influences on Penetration and Toxicity Behavior of Nanoparticles in a 3D Kidney Model

• Applicants: Professor Dr. Michael Becker; Professorin Dr. Christina Graf
• Subject Area: Toxicology, Laboratory Medicine ; Solid State and Surface Chemistry, Material Synthesis ; Technical Chemistry ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558325171

While nanoparticles (NPs) have demonstrated promise as drug carriers and contrast agents, they often exhibit cytotoxic effects, particularly on renal cells, posing risks to patients with pre-existing kidney damage. These cytotoxic effects are linked to the uptake of NPs into renal cells, an issue that has been studied primarily in static 2D cell cultures. However, such 2D systems fail to account for the complex flow conditions present in vivo, where fluid dynamics, shear stress, and flow-induced forces significantly impact NP uptake and cell interactions. Previous studies have primarily focused on the effects of NP size and rarely shape on cellular uptake, with little attention paid to the influence of fluid shear stress and secondary flow effects on NP-cell interactions. Moreover, while mononuclear phagocytes (MNPs) are known to directly phagocytose NPs, contributing to inflammation and NP-mediated nephrotoxicity, the role of MNPs in the context of different types of NPs and renal cells under dynamic flow conditions remains underexplored. Organ-on-a-chip models, such as the OrganoPlate® (OP®), offer a more physiological platform for analyzing NP interactions with multiple cell types under flow conditions. Although these systems enable the study of the complex interplay of different cell types, including MNPs on NP-mediate nephrotoxicity under flow limitations, persist, particularly in replicating the non-linear and non-uniform fluid dynamics found in biological systems. The laminar, straight-channel flows in these models do not capture the complex flow patterns, such as secondary flows, present in the kidney. Such secondary flows, induced by curvature and obstacles in biological vessels, significantly influence NP transport, binding, and uptake. To overcome these limitations, this work proposes a dual strategy. First, NP interactions with renal cells and MNPs will be analyzed under flow conditions in the OP® format. Second, a novel microfluidic experimental setup will be developed to replicate better the complex, three-dimensional flow fields seen in vivo, allowing for the fine-tuning of secondary flows. This approach will provide deeper insights into how fluid dynamics, MNPs, NP size, shape, and surface roughness influence NP uptake and nephrotoxicity, offering a more comprehensive understanding of the NP behavior in the kidney and their nephrotoxicity.

• DFG Programme: Research Grants
• International Connection: Ireland
• Co-Investigator: Professor Dr. Frank Schael
• Cooperation Partner: Hender Lopez, Ph.D.