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In vitro vascularized liver and tumor tissue microenvironments on a chip for dynamic determination of nanoparticle transport and toxicity |
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| Authors: | Alican Ozkan Neda Ghousifam Paul Jack Hoopes Thomas Edward Yankeelov Marissa Nichole Rylander |
| Affiliation: | 1. Department of Mechanical 2. Engineering, The University of Texas at Austin, Austin, Texas;3. Department of Biostatistics and Medicine, Dartmouth College, Lebanon, New Hampshire;4. Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas Institute of Computational Engineering and Sciences, The University of Texas at Austin, Austin, Texas Departments of Diagnostic Medicine, The University of Texas at Austin, Austin, Texas Department of Oncology, The University of Texas at Austin, Austin, Texas Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, Texas;5. Engineering, The University of Texas at Austin, Austin, Texas Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas Institute of Computational Engineering and Sciences, The University of Texas at Austin, Austin, Texas |
| 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. |
| Keywords: | EPR effect microfluidics organ-on-a-chip particle transport tissue engineering tumor microenvironment |