bims-miftum 2020-09-27 papers

Issue of 2020–09–27
four papers selected by
Nidhi Menon, Virginia Tech

Biomed Microdevices. 2020 Sep 22. 22(4): 70

Microfluidic-enabled self-organized tumor model for in vitro cytotoxicity assessment of doxorubicin.

Yamin Yang, Sijia Liu, Chunxiao Chen, Haipeng Huang, Ling Tao, Zhiyu Qian, Weitao Li.

The advent of microfluidic technologies has enabled a better recapitulation of in vitro tumor model with higher biological relevance over conventional monolayer assays. This work built upon a microfluidic system that supported the spontaneous aggregate formation of tumoral cells under flow-induced dynamic physical forces in a confined microchamber without additional matrix materials. Our findings indicated that fluidic streams significantly modulated the biological and architectural features of human breast adenocarcinoma cell (MCF-7), human hepatocarcinoma cell (HepG2), and human cervix adenocarcinoma cell (HeLa) with cell-type-dependent variation. The microfluidic platform was further integrated with a fluorescence detection and imaging system, allowing for non-invasive monitoring of cellular accumulation and spatial distribution of a chemotherapeutic agent, doxorubicin (DOX). The cytotoxic effects of DOX of various concentrations were determined and compared in MCF-7 cells in conventional two-dimensional (2D) static and microfluidic culture conditions. Dose-dependent response to DOX was noticed in both cultures, whereas tumor micronodules grown in microfluidic devices demonstrated significantly lower sensitivity to DOX at increased concentration. Our platform owns promising potentials as a universal modality for bridging traditional 2D cell cultures and in vivo experimentation for preclinical anticancer drug screening.

Keywords: Doxorubicin; In vitro cytotoxicity assessment; Microfluidics; Tumor-on-chip

DOI: https://doi.org/10.1007/s10544-020-00523-2

Angiogenesis. 2020 Sep 21.

Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes.

Jing Bai, Mehrdad Khajavi, Lufei Sui, Haojie Fu, Subrahmanian Tarakkad Krishnaji, Amy E Birsner, Lauren Bazinet, Roger D Kamm, Robert J D'Amato.

Angiogenesis plays a key role in the pathology of diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. Understanding the driving forces of endothelial cell migration and organization, as well as the time frame of these processes, can elucidate mechanisms of action of important pathological pathways. Herein, we have developed an organ-specific microfluidic platform recapitulating the in vivo angiogenic microenvironment by co-culturing mouse primary brain endothelial cells with brain pericytes in a three-dimensional (3D) collagen scaffold. As a proof of concept, we show that this model can be used for studying the angiogenic process and further comparing the angiogenic properties between two different common inbred mouse strains, C57BL/6J and 129S1/SvlmJ. We further show that the newly discovered angiogenesis-regulating gene Padi2 promotes angiogenesis through Dll4/Notch1 signaling by an on-chip mechanistic study. Analysis of the interplay between primary endothelial cells and pericytes in a 3D microfluidic environment assists in the elucidation of the angiogenic response.

Keywords: 3D cell culture; Angiogenesis; Microfluidic; Pericyte; Primary endothelial cell

DOI: https://doi.org/10.1007/s10456-020-09746-6

Lab Chip. 2020 Sep 21.

Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety.

Alan Chramiec, Diogo Teles, Keith Yeager, Alessandro Marturano-Kruik, Joseph Pak, Timothy Chen, Luke Hao, Miranda Wang, Roberta Lock, Daniel Naveed Tavakol, Marcus Busub Lee, Jinho Kim, Kacey Ronaldson-Bouchard, Gordana Vunjak-Novakovic.

Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease, motivating the development of microfluidic organs-on-a-chip (OOC) platforms that can mimic many aspects of human physiology and in the process alleviate many of the discrepancies between preclinical studies and clinical trials outcomes. Linsitinib, a novel anti-cancer drug, showed promising results in pre-clinical models of Ewing Sarcoma (ES), where it suppressed tumor growth. However, a Phase II clinical trial in several European centers with patients showed relapsed and/or refractory ES. We report an integrated, open setting, imaging and sampling accessible, polysulfone-based platform, featuring minimal hydrophobic compound binding. Two bioengineered human tissues - bone ES tumor and heart muscle - were cultured either in isolation or in the integrated platform and subjected to a clinically used linsitinib dosage. The measured anti-tumor efficacy and cardiotoxicity were compared with the results observed in the clinical trial. Only the engineered tumor tissues, and not monolayers, recapitulated the bone microenvironment pathways targeted by linsitinib, and the clinically-relevant differences in drug responses between non-metastatic and metastatic ES tumors. The responses of non-metastatic ES tumor tissues and heart muscle to linsitinib were much closer to those observed in the clinical trial for tissues cultured in an integrated setting than for tissues cultured in isolation. Drug treatment of isolated tissues resulted in significant decreases in tumor viability and cardiac function. Meanwhile, drug treatment in an integrated setting showed poor tumor response and less cardiotoxicity, which matched the results of the clinical trial. Overall, the integration of engineered human tumor and cardiac tissues in the integrated platform improved the predictive accuracy for both the direct and off-target effects of linsitinib. The proposed approach could be readily extended to other drugs and tissue systems.

DOI: https://doi.org/10.1039/d0lc00424c

Adv Healthc Mater. 2020 Sep 23. e2000880

High-Throughput Tumor-on-a-Chip Platform to Study Tumor-Stroma Interactions and Drug Pharmacokinetics.

Chun-Wei Chi, Yeh-Hsing Lao, A H Rezwanuddin Ahmed, Elizabeth C Benoy, Chenghai Li, Zeynep Dereli-Korkut, Bingmei M Fu, Kam W Leong, Sihong Wang.

Drug screening in oncology, especially for triple-negative breast cancer (TNBC), has high demand but remains unsatisfactory. Currently available models are either nonrepresentative of the complex tumor microenvironment or only suitable for low throughput screening, resulting in a low-yield success for drug development. To tackle these issues, the L-TumorChip system is developed in this study. It is a three-layered microfluidic tumor-on-a-chip platform integrating tumor microvasculature and tumor-stromal microenvironment with high throughput screening capability. Its layered and modular design is readily scalable through simple integration of multiple units. Here, L-TumorChip is validated with a TNBC model. The L-TumorChip system emulates certain tumor-stroma complexities and tumor-endothelium interactions, including TNBC invasion through the leaky microvasculature and angiogenesis. Additionally, with this L-TumorChip, the influence of different stromal cells, including normal fibroblasts, mesenchymal stem cells, and cancer-associated fibroblasts (CAF), on cancer cell growth as well as the stromal effects on drug responses to doxorubicin treatment is investigated. The presence of CAF delays drug pharmacokinetics, while apoptotic responses indicated by caspase-3 activities are higher in coculture with normal fibroblasts. Collectively, the L-TumorChip system represents a translational high-throughput screening toolkit that enables drug screening with a scenario closer to the in vivo conditions. This potential use may therefore facilitate development of new cancer drugs.

Keywords: drug screening; microfluidics; tumor microenvironments; tumor-on-a-chip

DOI: https://doi.org/10.1002/adhm.202000880