Rapid prototyping of a multicompartment liver-on-chip for dynamic administration of tumour derived vesicles within an electrospun scaffold

Abstract

A novel multicompartment liver-on-chip (LoC) platform has been developed combining laser-micromachined poly(methyl methacrylate) (PMMA) layers with an electrospun poly-lactic acid (PLA) scaffold to emulate the liver's extracellular matrix (ECM) for advanced in vitro modeling. The platform supports the dynamic, chronic delivery of colorectal cancer-derived extracellular vesicles (CRC-EVs) under physiologically relevant conditions. The use of thermoplastic materials such as PMMA provides advantages including low absorption, high optical clarity, and reproducibility, while the biomimetic architecture of the PLA scaffold enhances structural and functional fidelity. The LoC platform demonstrates significant advancements over conventional 2D cultures and static systems. Proteomic analyses revealed enhanced hepatocyte differentiation and activation of liver-specific pathways when cells were cultured on the PLA scaffold under both static and dynamic conditions. Dynamic CRC-EV administration induced the upregulation of the mesenchymal marker vimentin in the hepatocytes, as previously described in a 2D system. This study establishes the LoC as a groundbreaking tool for investigating tumor–liver interactions and pre-metastatic niche formation. By addressing critical limitations of existing platforms, this system advances organ-on-chip technology for cancer research and therapeutic development.