bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2021–06–13
seven papers selected by
Joram Mooiweer, University of Groningen
  1. A high-throughput microfluidic bilayer co-culture platform to study endothelial-pericyte interactions.
  2. Human colorectal cancer-on-chip model to study the microenvironmental influence on early metastatic spread.
  3. Biomechanical forces enhance directed migration and activation of bone marrow-derived dendritic cells.
  4. A Microfluidic Multisize Spheroid Array for Multiparametric Screening of Anticancer Drugs and Blood-Brain Barrier Transport Properties.
  5. On-chip determination of tissue-specific metastatic potential of breast cancer cells.
  6. Computational and experimental studies of a cell-imprinted-based integrated microfluidic device for biomedical applications.
  7. Spatiotemporal determination of metabolite activities in the corneal epithelium on a chip.
  1. Sci Rep. 2021 Jun 09. 11(1): 12225
    A high-throughput microfluidic bilayer co-culture platform to study endothelial-pericyte interactions.
    Miles T Rogers, Ashley L Gard, Robert Gaibler, Thomas J Mulhern, Rivka Strelnikov, Hesham Azizgolshani, Brian P Cain, Brett C Isenberg, Nerses J Haroutunian, Nicole E Raustad, Philip M Keegan, Matthew P Lech, Lindsay Tomlinson, Jeffrey T Borenstein, Joseph L Charest, Corin Williams.
      Microphysiological organ-on-chip models offer the potential to improve the prediction of drug safety and efficacy through recapitulation of human physiological responses. The importance of including multiple cell types within tissue models has been well documented. However, the study of cell interactions in vitro can be limited by complexity of the tissue model and throughput of current culture systems. Here, we describe the development of a co-culture microvascular model and relevant assays in a high-throughput thermoplastic organ-on-chip platform, PREDICT96. The system consists of 96 arrayed bilayer microfluidic devices containing retinal microvascular endothelial cells and pericytes cultured on opposing sides of a microporous membrane. Compatibility of the PREDICT96 platform with a variety of quantifiable and scalable assays, including macromolecular permeability, image-based screening, Luminex, and qPCR, is demonstrated. In addition, the bilayer design of the devices allows for channel- or cell type-specific readouts, such as cytokine profiles and gene expression. The microvascular model was responsive to perturbations including barrier disruption, inflammatory stimulation, and fluid shear stress, and our results corroborated the improved robustness of co-culture over endothelial mono-cultures. We anticipate the PREDICT96 platform and adapted assays will be suitable for other complex tissues, including applications to disease models and drug discovery.
    DOI:  https://doi.org/10.1038/s41598-021-90833-z
  2. iScience. 2021 May 21. 24(5): 102509
    Human colorectal cancer-on-chip model to study the microenvironmental influence on early metastatic spread.
    Carly Strelez, Sujatha Chilakala, Kimya Ghaffarian, Roy Lau, Erin Spiller, Nolan Ung, Danielle Hixon, Ah Young Yoon, Ren X Sun, Heinz-Josef Lenz, Jonathan E Katz, Shannon M Mumenthaler.
      Colorectal cancer (CRC) progression is a complex process that is not well understood. We describe an in vitro organ-on-chip model that emulates in vivo tissue structure and the tumor microenvironment (TME) to better understand intravasation, an early step in metastasis. The CRC-on-chip incorporates fluid flow and peristalsis-like cyclic stretching and consists of endothelial and epithelial compartments, separated by a porous membrane. On-chip imaging and effluent analyses are used to interrogate CRC progression and the resulting cellular heterogeneity. Mass spectrometry-based metabolite profiles are indicative of a CRC disease state. Tumor cells intravasate from the epithelial channel to the endothelial channel, revealing differences in invasion between aggressive and non-aggressive tumor cells. Tuning the TME by peristalsis-like mechanical forces, the epithelial:endothelial interface, and the addition of fibroblasts influences the invasive capabilities of tumor cells. The CRC-on-chip is a tunable human-relevant model system and a valuable tool to study early invasive events in cancer.
    Keywords:  Bioengineering; Biomedical materials; Cancer; Classification Description; Tissue engineering
    DOI:  https://doi.org/10.1016/j.isci.2021.102509
  3. Sci Rep. 2021 Jun 08. 11(1): 12106
    Biomechanical forces enhance directed migration and activation of bone marrow-derived dendritic cells.
    Ji-Hun Kang, Hyun Joo Lee, Ok-Hyeon Kim, Yong Ju Yun, Young-Jin Seo, Hyun Jung Lee.
      Mechanical forces are pervasive in the inflammatory site where dendritic cells (DCs) are activated to migrate into draining lymph nodes. For example, fluid shear stress modulates the movement patterns of DCs, including directness and forward migration indices (FMIs), without chemokine effects. However, little is known about the effects of biomechanical forces on the activation of DCs. Accordingly, here we fabricated a microfluidics system to assess how biomechanical forces affect the migration and activity of DCs during inflammation. Based on the structure of edema, we proposed and experimentally analyzed a novel concept for a microchip model that mimicked such vascular architecture. The intensity of shear stress generated in our engineered chip was found as 0.2-0.6 dyne/cm2 by computational simulation; this value corresponded to inflammation in tissues. In this platform, the directness and FMIs of DCs were significantly increased, whereas the migration velocity of DCs was not altered by shear stress, indicating that mechanical stimuli influenced DC migration. Moreover, DCs with shear stress showed increased expression of the DC activation markers MHC class I and CD86 compared with DCs under static conditions. Taken together, these data suggest that the biomechanical forces are important to regulate the migration and activity of DCs.
    DOI:  https://doi.org/10.1038/s41598-021-91117-2
  4. Adv Sci (Weinh). 2021 06;8(11): e2004856
    A Microfluidic Multisize Spheroid Array for Multiparametric Screening of Anticancer Drugs and Blood-Brain Barrier Transport Properties.
    Christoph Eilenberger, Mario Rothbauer, Florian Selinger, Anna Gerhartl, Christian Jordan, Michael Harasek, Barbara Schädl, Johannes Grillari, Julian Weghuber, Winfried Neuhaus, Seta Küpcü, Peter Ertl.
      Physiological-relevant in vitro tissue models with their promise of better predictability have the potential to improve drug screening outcomes in preclinical studies. Despite the advances of spheroid models in pharmaceutical screening applications, variations in spheroid size and consequential altered cell responses often lead to nonreproducible and unpredictable results. Here, a microfluidic multisize spheroid array is established and characterized using liver, lung, colon, and skin cells as well as a triple-culture model of the blood-brain barrier (BBB) to assess the effects of spheroid size on (a) anticancer drug toxicity and (b) compound penetration across an advanced BBB model. The reproducible on-chip generation of 360 spheroids of five dimensions on a well-plate format using an integrated microlens technology is demonstrated. While spheroid size-related IC50 values vary up to 160% using the anticancer drugs cisplatin (CIS) or doxorubicin (DOX), reduced CIS:DOX drug dose combinations eliminate all lung microtumors independent of their sizes. A further application includes optimizing cell seeding ratios and size-dependent compound uptake studies in a perfused BBB model. Generally, smaller BBB-spheroids reveal an 80% higher compound penetration than larger spheroids while verifying the BBB opening effect of mannitol and a spheroid size-related modulation on paracellular transport properties.
    Keywords:  anticancer drugs; blood-brain barrier; in vitro tests; microfluidics; multicellular spheroids
    DOI:  https://doi.org/10.1002/advs.202004856
  5. Biotechnol Bioeng. 2021 Jun 10.
    On-chip determination of tissue-specific metastatic potential of breast cancer cells.
    Burcu Firatligil-Yildirir, Gizem Bati-Ayaz, Ismail Tahmaz, Muge Bilgen, Devrim Pesen-Okvur, Ozden Yalcin-Ozuysal.
      Metastasis is one of the major obstacles for breast cancer patients. Limitations of current models demand the development of custom platforms to predict metastatic potential and homing choices of cancer cells. Here, two organ-on-chip (OoC) platforms, invasion/chemotaxis (IC-chip) and extravasation (EX-chip) were used for the quantitative assessment of invasion and extravasation towards specific tissues. Lung, liver and breast microenvironments were simulated in the chips using tissue specific cells embedded in matrigel. In the IC-chip, invasive MDA-MB-231, but not non-invasive MCF-7 breast cancer cells invaded into lung and liver microenvironments. In the EX-chip, MDA-MB-231 cells extravasated more into the lung compared to the liver and breast microenvironments. In addition, lung-specific MDA-MB-231 clone invaded and extravasated into the lung microenvironment more efficiently than the bone-specific clone. Both invasion/chemotaxis and extravasation results were in agreement with published clinical data. Collectively, our results show that IC-chip and EX-chip, simulating tissue specific microenvironments, can distinguish different in vivo metastatic phenotypes, in vitro. Determination of tissue specific metastatic potential of breast cancer cells is expected to improve diagnosis and help select the ideal therapy. This article is protected by copyright. All rights reserved.
    Keywords:  breast cancer; extravasation; invasion; lab-on-a-chip; metastasis
    DOI:  https://doi.org/10.1002/bit.27855
  6. Sci Rep. 2021 Jun 09. 11(1): 12130
    Computational and experimental studies of a cell-imprinted-based integrated microfluidic device for biomedical applications.
    Sepideh Yazdian Kashani, Mostafa Keshavarz Moraveji, Shahin Bonakdar.
      It has been proved that cell-imprinted substrates molded from template cells can be used for the re-culture of that cell while preserving its normal behavior or to differentiate the cultured stem cells into the template cell. In this study, a microfluidic device was presented to modify the previous irregular cell-imprinted substrate and increase imprinting efficiency by regular and objective cell culture. First, a cell-imprinted substrate from template cells was prepared using a microfluidic chip in a regular pattern. Another microfluidic chip with the same pattern was then aligned on the cell-imprinted substrate to create a chondrocyte-imprinted-based integrated microfluidic device. Computational fluid dynamics (CFD) simulations were used to obtain suitable conditions for injecting cells into the microfluidic chip before performing experimental evaluations. In this simulation, the effect of input flow rate, number per unit volume, and size of injected cells in two different chip sizes were examined on exerted shear stress and cell trajectories. This numerical simulation was first validated with experiments with cell lines. Finally, chondrocyte was used as template cell to evaluate the chondrogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs) in the chondrocyte-imprinted-based integrated microfluidic device. ADSCs were positioned precisely on the chondrocyte patterns, and without using any chemical growth factor, their fibroblast-like morphology was modified to the spherical morphology of chondrocytes after 14 days of culture. Both immunostaining and gene expression analysis showed improvement in chondrogenic differentiation compared to traditional imprinting methods. This study demonstrated the effectiveness of cell-imprinted-based integrated microfluidic devices for biomedical applications.
    DOI:  https://doi.org/10.1038/s41598-021-91616-2
  7. Exp Eye Res. 2021 Jun 05. pii: S0014-4835(21)00212-8. [Epub ahead of print] 108646
    Spatiotemporal determination of metabolite activities in the corneal epithelium on a chip.
    Rodi Abdalkader, Romanas Chaleckis, Craig E Wheelock, Ken-Ichiro Kamei.
      The corneal epithelial barrier maintains the metabolic activities of the ocular surface by regulating membrane transporters and metabolic enzymes responsible for the homeostasis of the eye as well as the pharmacokinetic behavior of drugs. Despite its importance, no established biomimetic in vitro methods are available to perform the spatiotemporal investigation of metabolism and determine the transportation of endogenous and exogenous molecules across the corneal epithelium barrier. This study introduces multiple corneal epitheliums on a chip namely, Corneal Epithelium on a Chip (CEpOC), which enables the spatiotemporal collection as well as analysis of micro-scaled extracellular metabolites from both the apical and basolateral sides of the barriers. Longitudinal samples collected during 48 h period were analyzed using untargeted liquid chromatography-mass spectrometry metabolomics method, and 104 metabolites were annotated. We observed the spatiotemporal secretion of biologically relevant metabolites (i.e., antioxidant, glutathione and uric acid) as well as the depletion of essential nutrients such as amino acids and vitamins mimicking the in vivo molecules trafficking across the human corneal epithelium. Through the shifts of extracellular metabolites and quantitative analysis of mRNA associated with transporters, we were able to investigate the secretion and transportation activities across the polarized barrier in a correlation with the expression of corneal transporters. Thus, CEpOC can provide a non-invasive, simple, yet effectively informative method to determine pharmacokinetics and pharmacodynamics as well as to discover novel biomarkers for drug toxicological and safety tests as advanced experimental model of the human corneal epithelium.
    Keywords:  Corneal epithelial barrier on chip; Metabolism; Transporters; Untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.exer.2021.108646
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