bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2021–10–17
nine papers selected by
Joram Mooiweer, University of Groningen
  1. Development of a Hybrid Polymer-Based Microfluidic Platform for Culturing Hepatocytes towards Liver-on-a-Chip Applications.
  2. Peristaltic on-chip pump for tunable media circulation and whole blood perfusion in PDMS-free organ-on-chip and Organ-Disc systems.
  3. Enabling peristalsis of human colon tumor organoids on microfluidic chips.
  4. Microvessel-on-Chip Fabrication for the In Vitro Modeling of Nanomedicine Transport.
  5. Microfluidic Arrays of Breast Tumor Spheroids for Drug Screening and Personalized Cancer Therapies.
  6. Dynamic flow and shear stress as key parameters for intestinal cells morphology and polarization in an organ-on-a-chip model.
  7. Microfluidic arrays of dermal spheroids: a screening platform for active ingredients of skincare products.
  8. Angiogenic Sprouting Dynamics Mediated by Endothelial-Fibroblast Interactions in Microfluidic Systems.
  9. Adoption of organ-on-chip platforms by the pharmaceutical industry.
  1. Polymers (Basel). 2021 Sep 23. pii: 3215. [Epub ahead of print]13(19):
    Development of a Hybrid Polymer-Based Microfluidic Platform for Culturing Hepatocytes towards Liver-on-a-Chip Applications.
    Gulsim Kulsharova, Akbota Kurmangaliyeva, Elvira Darbayeva, Luis Rojas-Solórzano, Galiya Toxeitova.
      The drug development process can greatly benefit from liver-on-a-chip platforms aiming to recapitulate the physiology, mechanisms, and functionalities of liver cells in an in vitro environment. The liver is the most important organ in drug metabolism investigation. Here, we report the development of a hybrid cyclic olefin copolymer (COC) and polydimethylsiloxane (PDMS) microfluidic (HCP) platform to culture a Huh7 hepatoma cell line in dynamic conditions towards the development of a liver-on-a-chip system. The microfluidic platform is comprised of a COC bottom layer with a microchannel and PDMS-based flat top layer sandwiched together. The HCP device was applied for culturing Huh7 cells grown on a collagen-coated microchannel. A computational fluid dynamics modeling study was conducted for the HCP device design revealing the presence of air volume fraction in the chamber and methods for optimizing experimental handling of the device. The functionality and metabolic activity of perfusion culture were assessed by the secretion rates of albumin, urea, and cell viability visualization. The HCP device hepatic culture remained functional and intact for 24 h, as assessed by resulting levels of biomarkers similar to published studies on other in vitro and 2D cell models. The present results provide a proof-of-concept demonstration of the hybrid COC-PDMS microfluidic chip for successfully culturing a Huh7 hepatoma cell line, thus paving the path towards developing a liver-on-a-chip platform.
    Keywords:  cyclic olefin copolymer; hepatocytes; huh7; hybrid polymer-based liver-on-a-chip; liver-on-a-chip; microfluidic chip; microfluidics; microphysiological platform; polydimethylsiloxane
    DOI:  https://doi.org/10.3390/polym13193215
  2. Lab Chip. 2021 Oct 12. 21(20): 3963-3978
    Peristaltic on-chip pump for tunable media circulation and whole blood perfusion in PDMS-free organ-on-chip and Organ-Disc systems.
    Stefan Schneider, Marvin Bubeck, Julia Rogal, Huub J Weener, Cristhian Rojas, Martin Weiss, Michael Heymann, Andries D van der Meer, Peter Loskill.
      Organ-on-chip (OoC) systems have become a promising tool for personalized medicine and drug development with advantages over conventional animal models and cell assays. However, the utility of OoCs in industrial settings is still limited, as external pumps and tubing for on-chip fluid transport are dependent on error-prone, manual handling. Here, we present an on-chip pump for OoC and Organ-Disc systems, to perfuse media without external pumps or tubing. Peristaltic pumping is implemented through periodic compression of a flexible pump layer. The disc-shaped, microfluidic module contains four independent systems, each lined with endothelial cells cultured under defined, peristaltic perfusion. Both cell viability and functionality were maintained over several days shown by supernatant analysis and immunostaining. Integrated, on-disc perfusion was further used for cytokine-induced cell activation with physiologic cell responses and for whole blood perfusion assays, both demonstrating the versatility of our system for OoC applications.
    DOI:  https://doi.org/10.1039/d1lc00494h
  3. Biofabrication. 2021 Oct 12.
    Enabling peristalsis of human colon tumor organoids on microfluidic chips.
    Guocheng Fang, Hongxu Lu, Russul Al-Nakashli, Robert Chapman, Yingqi Zhang, Lining Arnold Ju, Gungun Lin, Martina H Stenzel, Dayong Jin.
      Peristalsis in the digestive tract is crucial to maintain physiological functions. It remains challenging to mimic the peristaltic microenvironment in gastrointestinal organoid culture. Here, we present a method to model the peristalsis for human colon tumor organoids on a microfluidic chip. The chip contains hundreds of lateral microwells and a surrounding pressure channel. Human colon tumor organoids growing in the microwell were cyclically contracted by pressure channel, mimicking the in vivo mechano-stimulus by intestinal muscles. The chip allows the control of peristalsis amplitude and rhythm and the high throughput culture of organoids simultaneously. By applying 8% amplitude with 8~10 times/min, we observed the enhanced expression of Lgr5 and Ki67. Moreover, ellipticine-loaded polymeric micelles showed reduced uptake in the organoids under peristalsis and resulted in compromised anti-tumor efficacy. The results indicate the importance of mechanical stimuli mimicking the physiological environment when using in vitro models to evaluate nanoparticles. This work provides a method for attaining more reliable and representative organoids models in nanomedicine.
    Keywords:  colon tumor organoids; micelle; microfluidic chip; nano drug carriers; peristalsis
    DOI:  https://doi.org/10.1088/1758-5090/ac2ef9
  4. ACS Omega. 2021 Oct 05. 6(39): 25109-25115
    Microvessel-on-Chip Fabrication for the In Vitro Modeling of Nanomedicine Transport.
    Sergio Dávila, Jean Cacheux, Isabel Rodríguez.
      Tumor-on-chip devices are becoming ideal platforms to recreate in vitro the particular physiological microenvironment of interest for onco-nanomedicine testing and development. This work presents a strategy to produce a round artificial microvessel on-a-chip device for the study of physiologically relevant nanomedicine transport dynamics. The microchannels have a diameter in the range of the tumor capillaries and a semicircular geometry. This geometry is obtained through an intermediate thermal nanoimprint step using a master mold with square-shaped channel structures produced by standard silicon micromachining or by stereolithography three-dimensional (3D) printing. The working microfluidic chip devices are made by casting polydimethylsiloxane on the imprinted intermediate mold. Artificial blood microvessels are created by seeding human endothelial cells into the round-shaped channels acting as the scaffold. The microchip is connected by 3D-printed reservoirs to a pressure controller, allowing for a fine fluidic control. Under physiological flow conditions, the dynamic interaction of nanoparticles (NPs) with the artificial endothelium was assessed by high-magnification fluorescence microscopy. Overtime, internalization of NPs and clustering was observed and the accumulation rate into the endothelial cells could be characterized in real time.
    DOI:  https://doi.org/10.1021/acsomega.1c00735
  5. Adv Healthc Mater. 2021 Oct 11. e2101085
    Microfluidic Arrays of Breast Tumor Spheroids for Drug Screening and Personalized Cancer Therapies.
    Elisabeth Prince, Sina Kheiri, Yihe Wang, Fei Xu, Jennifer Cruikshank, Valentina Topolskaia, Huachen Tao, Edmund W K Young, Alison P McGuigan, David Cescon, Eugenia Kumacheva.
      One of the obstacles limiting progress in the development of effective cancer therapies is the shortage of preclinical models that capture the dynamic nature of tumor microenvironments. Interstitial flow strongly impacts tumor response to chemotherapy; however, conventional in vitro cancer models largely disregard this key feature. Here, we report a proof of principle microfluidic platform for the generation of large arrays of breast tumor spheroids that are grown under close-to-physiological flow in a biomimetic hydrogel. We use this cancer spheroids-on-a-chip model for time- and labor-efficient studies of the effects of drug dose and supply rate on the chemosensitivity of breast tumor spheroids. We show the capability to grow large arrays of tumor spheroids from patient-derived cells of different breast cancer subtypes and demonstrate correlation between in vivo drug efficacy and on-chip spheroid drug response. The proposed platform can serve as an in vitro preclinical model for the development of personalized cancer therapies and effective screening of new anticancer drugs. This article is protected by copyright. All rights reserved.
    Keywords:  Breast cancer; cancer; drug testing; microfluidics; personalized medicine; preclinical models; spheroids
    DOI:  https://doi.org/10.1002/adhm.202101085
  6. Biomed Microdevices. 2021 Oct 16. 23(4): 55
    Dynamic flow and shear stress as key parameters for intestinal cells morphology and polarization in an organ-on-a-chip model.
    Chiara A M Fois, Aaron Schindeler, Peter Valtchev, Fariba Dehghani.
      Gut-on-a-chip microfluidic devices have emerged as versatile and practical systems for modeling the human intestine in vitro. Cells cultured under microfluidic conditions experience the effect of shear stress, used as a biomechanical cue to promote a faster cell polarization in Caco-2 cells when compared with static culture conditions. However, published systems to date have utilized a constant flow rate that fails to account for changes in cell shear stress ([Formula: see text]) resulting from changes in cell elongation that occur with differentiation. In this study, computational fluid dynamics (CFD) simulations predict that cells with villi-like morphology experience a [Formula: see text] higher than bulge-like cells at the initial growth stages. Therefore, we investigated the use of a dynamic flow rate to maintain a constant [Formula: see text] across the experiment. Microscopic assessment of cell morphology and dome formation confirmed the initiation of Caco-2 polarization within three days. Next, adopting our dynamic approach, we evaluated whether the following decreased flow could still contribute to complete cell differentiation if compared with the standard constant flow methodology. Caco-2 cells polarized under both conditions, secreted mucin-2 and villin and formed tight junctions and crypt-villi structures. Gene expression was not impacted using the dynamic flow rate. In conclusion, our dynamic flow approach still facilitates cell differentiation while enabling a reduced consumption of reagents.
    Keywords:  Cell differentiation; Computational fluid dynamics; Intestinal models; Microfluidics; Organ-on-a-chip
    DOI:  https://doi.org/10.1007/s10544-021-00591-y
  7. Lab Chip. 2021 Oct 12. 21(20): 3952-3962
    Microfluidic arrays of dermal spheroids: a screening platform for active ingredients of skincare products.
    Zhengkun Chen, Sina Kheiri, Albert Gevorkian, Edmond W K Young, Valerie Andre, Ted Deisenroth, Eugenia Kumacheva.
      Organotypic micrometre-size 3D aggregates of skin cells (multicellular spheroids) have emerged as a promising in vitro model that can be utilized as an alternative of animal models to test active ingredients (AIs) of skincare products; however, a reliable dermal spheroid-based microfluidic (MF) model with a goal of in vitro AI screening is yet to be developed. Here, we report a MF platform for the growth of massive arrays of dermal fibroblast spheroids (DFSs) in a biomimetic hydrogel under close-to-physiological flow conditions and with the capability of screening AIs for skincare products. The DFSs formed after two days of on-chip culture and, in a case study, were used in a time-efficient manner for screening the effect of vitamin C on the synthesis of collagen type I and fibronectin. The computational simulation showed that the uptake of vitamin C was dominated by the advection flux. The results of screening the benchmark AI, vitamin C, proved that DFSs can serve as a reliable in vitro dermal model. The proposed DFS-based MF platform offers a high screening capacity for AIs of skincare products, as well as drug discovery and development in dermatology.
    DOI:  https://doi.org/10.1039/d1lc00619c
  8. Adv Biol (Weinh). 2021 Oct 15. e2101080
    Angiogenic Sprouting Dynamics Mediated by Endothelial-Fibroblast Interactions in Microfluidic Systems.
    Noosheen Walji, Sina Kheiri, Edmond W K Young.
      Angiogenesis, the development of new blood vessels from existing vasculature, is a key process in normal development and pathophysiology. In vitro models are necessary for investigating mechanisms of angiogenesis and developing antiangiogenic therapies. Microfluidic cell culture models of angiogenesis are favored for their ability to recapitulate 3D tissue structures and control spatiotemporal aspects of the microenvironments. To capture the angiogenesis process, microfluidic models often include endothelial cells and a fibroblast component. However, the influence of fibroblast organization on resulting angiogenic behavior remains unclear. Here a comparative study of angiogenic sprouting on a microfluidic chip induced by fibroblasts in 2D monolayer, 3D dispersed, and 3D spheroid culture formats, is conducted. Vessel morphology and sprout distribution for each configuration are measured, and these observations are correlated with measurements of secreted factors and numerical simulations of diffusion gradients. The results demonstrate that angiogenic sprouting varies in response to fibroblast organization with correlating variations in secretory profile and secreted factor gradients across the microfluidic device. This study is anticipated to shed light on how sprouting dynamics are mediated by fibroblast configuration such that the microfluidic cell culture design process includes the selection of a fibroblast component where the effects are known and leveraged.
    Keywords:  angiogenesis; angiogenic sprouting; fibroblasts; microfluidics; organ-on-a-chip; tumor microenvironment
    DOI:  https://doi.org/10.1002/adbi.202101080
  9. Nat Rev Drug Discov. 2021 Oct 13.
    Adoption of organ-on-chip platforms by the pharmaceutical industry.
    Paul Vulto, Jos Joore.
      
    DOI:  https://doi.org/10.1038/s41573-021-00323-0
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