In vitro vascularized liver and tumor tissue microenvironments on a chip for dynamic determination of nanoparticle transport and toxicity

Abstract

This paper presents the development of a vascularized breast tumor and healthy or tumorigenic liver microenvironments‐on‐a‐chip connected in series. This is the first description of a vascularized multi tissue‐on‐a‐chip microenvironment for modeling cancerous breast and cancerous/healthy liver microenvironments, to allow for the study of dynamic and spatial transport of particles. This device enables the dynamic determination of vessel permeability, the measurement of drug and nanoparticle transport, and the assessment of the associated efficacy and toxicity to the liver. The platform is utilized to determine the effect of particle size on the spatiotemporal diffusion of particles through each microenvironment, both independently and in response to the circulation of particles in varying sequences of microenvironments. The results show that when breast cancer cells were cultured in the microenvironments they had a 2.62‐fold higher vessel porosity relative to vessels within healthy liver microenvironments. Hence, the permeability of the tumor microenvironment increased by 2.35‐ and 2.77‐fold compared with a healthy liver for small and large particles, respectively. The extracellular matrix accumulation rate of larger particles was 2.57‐fold lower than smaller particles in a healthy liver. However, the accumulation rate was 5.57‐fold greater in the breast tumor microenvironment. These results are in agreement with comparable in vivo studies. Ultimately, the platform could be utilized to determine the impact of the tissue or tumor microenvironment, or drug and nanoparticle properties, on transport, efficacy, selectivity, and toxicity in a dynamic, and high‐throughput manner for use in treatment optimization.

The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors

“…Ozkan et al aimed at a partial recreation of the interplay between healthy or tumorigenic liver and breast tumor niches throughout the development of a simple dual organ-on-chip [55]. The system connected a liver microtissue and a breast cancer tumor module via an endothelialized vascular channel (Figure 7b-i).…”

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

“…Investigation of flow‐associated liver function and clearance has been conducted in vitro in several on‐chip platforms ( Figure ). [ 362,371–374 ] In particular, comparative studies of hepatocyte culture in static versus perfused conditions reveal the important role of flow in albumin and urea secretion, cytochrome P450 metabolism, toxicity modulation of drug compounds, liver zonation, and overall long‐term maintenance of hepatocyte viability. [ 285,375–377 ] One study uncovered the role of vessel perfusion in stretching of LSECs, activating integrin β 1 and vascular endothelial growth factor receptor 3 (VEGFR3), upregulating HGF secretion, and resulting in increased hepatocyte proliferation and survival.…”

“…[ 378 ] In vitro platforms recapitulating the complex hepatic niche offer a roadmap toward testing first‐pass metabolism and toxicity of candidate drugs, and mechanistic insights into liver regeneration. [ 362,371 ] However, decoupling the individual roles of shear stress, cyclic stretch and pressure on different cell types in the liver sinusoid within complex hepatic microenvironments is necessary to develop liver‐specific mechanotherapeutics and warrants further investigation. In addition, the role of the lymphatic vasculature in the hepatic niche is also understudied and could potentially be recapitulated in microphysiological systems.…”

Evaluating Nanoparticles in Preclinical Research Using Microfluidic Systems

“…Compared with 2D and 3D static culture, microfluidic systems exhibit advances in capturing the well-controlled flow pressure in vivo, better spatial and temporal control to the microenvironment, and parallel testing of effects of chemical and oxygen gradient with little cells and chemicals employed (Table 1). Based on its general features, single-cell culture models, complicated 3D tumor cultures and various organs-on-chip models are developed in microfluidic devices [3,69,70,71,72]. They could test NP haemocompatibility, transport, uptake and toxicity, targeted accumulation, and general NP efficacy using different model settings with more physiological relevant testing results.…”