bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2021–10–10
five papers selected by
Joram Mooiweer, University of Groningen
  1. Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption.
  2. Aspiration-mediated hydrogel micropatterning using rail-based open microfluidic devices for high-throughput 3D cell culture.
  3. Transendothelial migration induces differential migration dynamics of leukocytes in tissue matrix.
  4. Generation of Tetrafluoroethylene-Propylene Elastomer-Based Microfluidic Devices for Drug Toxicity and Metabolism Studies.
  5. Bioinspired Artificial Liver System with hiPSC-derived Hepatocytes for Acute Liver Failure Treatment.
  1. Nat Commun. 2021 Oct 08. 12(1): 5907
    Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption.
    Iosif Pediaditakis, Konstantia R Kodella, Dimitris V Manatakis, Christopher Y Le, Chris D Hinojosa, William Tien-Street, Elias S Manolakos, Kostas Vekrellis, Geraldine A Hamilton, Lorna Ewart, Lee L Rubin, Katia Karalis.
      Parkinson's disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis of the substantia nigra. Although clinical evidence and in vitro studies indicate disruption of the Blood-Brain Barrier in Parkinson's disease, the mechanisms mediating the endothelial dysfunction is not well understood. Here we leveraged the Organs-on-Chips technology to develop a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson's disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model may enable research into the dynamics of cell-cell interactions in human synucleinopathies and serve as a testing platform for target identification and validation of novel therapeutics.
    DOI:  https://doi.org/10.1038/s41467-021-26066-5
  2. Sci Rep. 2021 Oct 07. 11(1): 19986
    Aspiration-mediated hydrogel micropatterning using rail-based open microfluidic devices for high-throughput 3D cell culture.
    Dohyun Park, Jungseub Lee, Younggyun Lee, Kyungmin Son, Jin Woo Choi, William J Jeang, Hyeri Choi, Yunchan Hwang, Ho-Young Kim, Noo Li Jeon.
      Microfluidics offers promising methods for aligning cells in physiologically relevant configurations to recapitulate human organ functionality. Specifically, microstructures within microfluidic devices facilitate 3D cell culture by guiding hydrogel precursors containing cells. Conventional approaches utilize capillary forces of hydrogel precursors to guide fluid flow into desired areas of high wettability. These methods, however, require complicated fabrication processes and subtle loading protocols, thus limiting device throughput and experimental yield. Here, we present a swift and robust hydrogel patterning technique for 3D cell culture, where preloaded hydrogel solution in a microfluidic device is aspirated while only leaving a portion of the solution in desired channels. The device is designed such that differing critical capillary pressure conditions are established over the interfaces of the loaded hydrogel solution, which leads to controlled removal of the solution during aspiration. A proposed theoretical model of capillary pressure conditions provides physical insights to inform generalized design rules for device structures. We demonstrate formation of multiple, discontinuous hollow channels with a single aspiration. Then we test vasculogenic capacity of various cell types using a microfluidic device obtained by our technique to illustrate its capabilities as a viable micro-manufacturing scheme for high-throughput cellular co-culture.
    DOI:  https://doi.org/10.1038/s41598-021-99387-6
  3. J Cell Sci. 2021 Oct 08. pii: jcs.258690. [Epub ahead of print]
    Transendothelial migration induces differential migration dynamics of leukocytes in tissue matrix.
    Abraham C I van Steen, Lanette Kempers, Rouven Schoppmeyer, Max Blokker, David J Beebe, Martijn A Nolte, Jaap D van Buul.
      Leukocyte extravasation into inflamed tissue is a complex process that is difficult to capture as a whole in vitro. We employed a blood-vessel-on-a-chip model in which endothelial cells were cultured in a tube-like lumen in a collagen-1 matrix. The vessels are leak-tight, creating a barrier for molecules and leukocytes. Addition of inflammatory cytokine TNF-α caused vasoconstriction, actin remodelling and upregulation of ICAM-1. Introducing leukocytes into the vessels allowed real-time visualisation of all different steps of the leukocyte transmigration cascade including migration into the extracellular matrix. Individual cell tracking over time distinguished striking differences in migratory behaviour between T-cells and neutrophils. Neutrophils cross the endothelial layer more efficiently than T-cells, but upon entering the matrix, neutrophils display high speed but low persistence, whereas T-cells migrate with low speed and rather linear migration. In conclusion, 3D imaging in real-time of leukocyte extravasation in a vessel-on-a-chip enables detailed qualitative and quantitative analysis of different stages of the full leukocyte extravasation process in a single assay.
    Keywords:  Blood vessels; Blood-vessel-on-a-chip; Endothelial cells; Extracellular matrix; Inflammation; Leukocyte transendothelial migration; Migration dynamics.; Physiological hydrogel; Tissue
    DOI:  https://doi.org/10.1242/jcs.258690
  4. ACS Omega. 2021 Sep 28. 6(38): 24859-24865
    Generation of Tetrafluoroethylene-Propylene Elastomer-Based Microfluidic Devices for Drug Toxicity and Metabolism Studies.
    Emi Sano, Sayaka Deguchi, Naoki Matsuoka, Masahiro Tsuda, Mengyang Wang, Kaori Kosugi, Chihiro Mori, Keisuke Yagi, Aya Wada, Shinsuke Yamasaki, Tsuyoshi Kawai, Masahide Yodogawa, Hiroyuki Mizuguchi, Norihito Nakazawa, Fumiyoshi Yamashita, Yu-Suke Torisawa, Kazuo Takayama.
      Polydimethylsiloxane (PDMS) is widely used to fabricate microfluidic organs-on-chips. Using these devices (PDMS-based devices), the mechanical microenvironment of living tissues, such as pulmonary respiration and intestinal peristalsis, can be reproduced in vitro. However, the use of PDMS-based devices in drug discovery research is limited because of their extensive absorption of drugs. In this study, we investigated the feasibility of the tetrafluoroethylene-propylene (FEPM) elastomer to fabricate a hepatocyte-on-a-chip (FEPM-based hepatocyte chip) with lower drug absorption. The FEPM-based hepatocyte chip expressed drug-metabolizing enzymes, drug-conjugating enzymes, and drug transporters. Also, it could produce human albumin. Although the metabolites of midazolam and bufuralol were hardly detected in the PDMS-based hepatocyte chip, they were detected abundantly in the FEPM-based hepatocyte chip. Finally, coumarin-induced hepatocyte cytotoxicity was less severe in the PDMS-based hepatocyte chip than in the FEPM-based hepatocyte chip, reflecting the different drug absorptions of the two chips. In conclusion, the FEPM-based hepatocyte chip could be a useful tool in drug discovery research, including drug metabolism and toxicity studies.
    DOI:  https://doi.org/10.1021/acsomega.1c03719
  5. Adv Healthc Mater. 2021 Oct 02. e2101580
    Bioinspired Artificial Liver System with hiPSC-derived Hepatocytes for Acute Liver Failure Treatment.
    Jinglin Wang, Haozhen Ren, Yuxiao Liu, Lingyu Sun, Zhuohao Zhang, Yuanjin Zhao, Xiaolei Shi.
      Bioartificial liver (BAL) system has become a promising alternative to traditional liver transplantation in rescuing acute liver failure (ALF) patients. Herein, inspired by natural microstructure of hepatic lobules, we developed a novel biomimetic bioartificial liver system (BBALS) by integrating human induced pluripotent stem cell-derived hepatocytes (hiPSC-Heps) cell-laden microparticles and semipermeable microtubes into a microfluidic platform. As the working units were hepatic lobules-like semipermeable microtubes surrounding with serum-free suspension differentiated hiPSC-Heps microcarriers, the BBALS was endowed with functional cell aggregates and effective circulation system. Thus, the BBALS possessed high cell viability, favorable function regeneration, and effective substances exchange. Based on these features, we created a three-dimensional (3D) liver chip with multiple parallel BBALS units for filtering the plasma of ALF rabbits, which validated the research significance and application potential of the proposed BBALS. Moreover, the novel integrated BBALS was applied to treat ALF rabbits and showed great advantages in increasing survival, generating serum proteins, and decreasing inflammation. These properties point to the broad prospects of BBALS in treating related diseases and improving traditional clinical methods. This article is protected by copyright. All rights reserved.
    Keywords:  acute liver failure; bio-artificial liver; bioinspired; microcarrier; microfluidics; tissue engineering
    DOI:  https://doi.org/10.1002/adhm.202101580
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