bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2022‒09‒04
seven papers selected by
Joram Mooiweer
University of Groningen
  1. 3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake.
  2. All-in-One microfluidic design to integrate vascularized tumor spheroid into high-throughput platform.
  3. Intestinal Permeability of Drugs in Caco-2 Cells Cultured in Microfluidic Devices.
  4. Evaluating the reliability of tumor spheroid-on-chip models for replicating intratumoral drug delivery: Considering the role of microfluidic parameters.
  5. 3D Bioprinted Hydrogel Microfluidic Devices for Parallel Drug Screening.
  6. Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction.
  7. Real-Time Measurement of Cell Mechanics as a Clinically Relevant Readout of an In Vitro Lung Fibrosis Model Established on a Bioinspired Basement Membrane.
  1. Sci Rep. 2022 Sep 02. 12(1): 14997
    3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake.
    Jeffrey O Aceves, Szilvia Heja, Kenichi Kobayashi, Sanlin S Robinson, Tomoya Miyoshi, Takuya Matsumoto, Olivier J M Schäffers, Ryuji Morizane, Jennifer A Lewis.
      Three-dimensional, organ-on-chip models that recapitulate kidney tissue are needed for drug screening and disease modeling. Here, we report a method for creating a perfusable 3D proximal tubule model composed of epithelial cells isolated from kidney organoids matured under static conditions. These organoid-derived proximal tubule epithelial cells (OPTECs) are seeded in cylindrical channels fully embedded within an extracellular matrix, where they form a confluent monolayer. A second perfusable channel is placed adjacent to each proximal tubule within these reusable multiplexed chips to mimic basolateral drug transport and uptake. Our 3D OPTEC-on-chip model exhibits significant upregulation of organic cation (OCT2) and organic anion (OAT1/3) transporters, which leads to improved drug uptake, compared to control chips based on immortalized proximal tubule epithelial cells. Hence, OPTEC tubules exhibit a higher normalized lactate dehydrogenase (LDH) release, when exposed to known nephrotoxins, cisplatin and aristolochic acid, which are diminished upon adding OCT2 and OAT1/3 transport inhibitors. Our integrated multifluidic platform paves the way for personalized kidney-on-chip models for drug screening and disease modeling.
    DOI:  https://doi.org/10.1038/s41598-022-19293-3
  2. Biotechnol Bioeng. 2022 Aug 31.
    All-in-One microfluidic design to integrate vascularized tumor spheroid into high-throughput platform.
    Youngtaek Kim, Jihoon Ko, Nari Shin, Seonghyuk Park, Seung-Ryeol Lee, Suryong Kim, Jiyoung Song, Seokjun Lee, Kyung-Sun Kang, Jeeyun Lee, Noo Li Jeon.
      The development of a scalable and highly reproducible in vitro tumor microenvironment (TME) platform still sheds light on new insights into cancer metastasis mechanisms and anticancer therapeutic strategies. Here, we present an all-in-one injection molded plastic array 3D culture platform (All-in-One-IMPACT) that integrates vascularized tumor spheroids for highly reproducible, high-throughput experimentation. This device allows the formation of self-assembled cell spheroids on a chip by applying the hanging drop method to the cell culture channel. Then, when the hydrogel containing endothelial cells and fibroblasts is injected, the spheroid inside the droplet can be patterned together in three dimensions along the culture channel. In just two steps above, we can build a vascularized TME within a defined area. This process does not require specialized user skill and minimizes error-inducing steps, enabling both reproducibility and high-throughput of the experiment. We have successfully demonstrated the process, from spheroid formation to tumor vascularization, using patient-derived cancer cells (PDCs) as well as various cancer cell lines. Furthermore, we performed combination therapies with Taxol (paclitaxel) and Avastin (bevacizumab), which are used in standard care for metastatic cancer. The All-in-One IMPACT is a powerful tool for establishing various anticancer treatment strategies through the development of a complex TME for use in high-throughput experiments. This article is protected by copyright. All rights reserved.
    Keywords:  All-in-one; High-throughput experimentation; Microfluidics; Organ-on-a-chip; Patient-derived cancer cells (PDCs); Tumor microenvironment (TME); Vascularized tumor spheroid
    DOI:  https://doi.org/10.1002/bit.28221
  3. Biol Pharm Bull. 2022 ;45(9): 1246-1253
    Intestinal Permeability of Drugs in Caco-2 Cells Cultured in Microfluidic Devices.
    Yuko Sasaki, Hirotaka Tatsuoka, Masahiro Tsuda, Takumi Sumi, Yuka Eguchi, Kanako So, Yuriko Higuchi, Kazuo Takayama, Yusuke Torisawa, Fumiyoshi Yamashita.
      Microfluidic devices are attracting attention for their ability to provide a biomimetic microenvironment wherein cells are arranged in a particular pattern and provided fluidic and mechanical forces. In this study, we evaluated drug transport across Caco-2 cell layers in microfluidic devices and investigated the effects of fluid flow on drug transport and metabolism. We designed a microfluidic device that comprises two blocks of polydimethylsiloxane and a sandwiched polyethylene terephthalate membrane with pores 3.0 µm in diameter. When cultured in a dynamic fluid environment, Caco-2 cells were multilayered and developed microvilli on the surface as compared with a static environment. Drugs with higher lipophilicity exhibited higher permeability across the Caco-2 layers, as well as in the conventional method using Transwells, and the fluidic conditions had little effect on permeability. In the Caco-2 cell layers cultured in Transwells and microfluidic devices, the basal-to-apical transport of rhodamine 123, a substrate of P-glycoprotein, was greater than the apical-to-basal transport, and the presence of tariquidar, an inhibitor of P-glycoprotein, completely diminished asymmetric transport. Furthermore, fluidic conditions promoted the metabolism of temocapril by carboxylesterases. On the other hand, we showed that fluidic conditions have little effect on gene expression of several transporters and metabolic enzymes. These results provide useful information regarding the application of microfluidic devices in drug transport and metabolism studies.
    Keywords:  Caco-2; drug absorption; gut-on-a-chip; microfluidic device; organ-on-a-chip; polydimethylsiloxane
    DOI:  https://doi.org/10.1248/bpb.b22-00092
  4. J Drug Target. 2022 Aug 28. 1-22
    Evaluating the reliability of tumor spheroid-on-chip models for replicating intratumoral drug delivery: Considering the role of microfluidic parameters.
    Mohsen Besanjideh, Amir Shamloo, Siamak Kazemzadeh Hannani.
      Several tumor spheroid-on-chip models have already been proposed in the literature to conduct high throughput drug screening assays. The microfluidic configurations in these models generally depend on the strategies adopted for spheroid formation and entrapment. However, it is not clear how successful they are to mimic in vivo transport mechanisms. In this study, drug transport in different tumor spheroid-on-chip models is numerically investigated under static and dynamic conditions using porous media theory. Moreover, the treatment of a solid tumor at the initial stage of development is modeled using bolus injection and continuous infusion methods. Then, the results of tumor spheroid-on-chip, including drug concentration, cell viability, as well as pressure and fluid shear stress distributions, are compared with those of the solid tumor, assuming identical transport properties in all models. Finally, a new configuration of the microfluidic device along with the optimal drug concentrations is proposed, which can well imitate a given in vivo situation.
    Keywords:  Concentration; Drug screening; Microfluidics; Porous media; Tumor spheroid
    DOI:  https://doi.org/10.1080/1061186X.2022.2119478
  5. ACS Appl Bio Mater. 2022 Aug 29.
    3D Bioprinted Hydrogel Microfluidic Devices for Parallel Drug Screening.
    Anant Bhusal, Elvan Dogan, Daniel Nieto, Seyed Ali Mousavi Shaegh, Berivan Cecen, Amir K Miri.
      Conventional high-throughput screening (HTS) platforms suffer from the need for large cell volumes, high reagent consumption, significant assembly cost, and handling efforts. The assembly of three-dimensional (3D) bioprinted hydrogel-based microfluidic chips within platforms can address these problems. We present a continuous and seamless manufacturing approach to create a bioprinted microfluidic chips with a circular pattern scalable toward HTS platforms. Digital light processing 3D bioprinting is used to tune the local permeability of our chip, made of polyethylene glycol diacrylate and cell-laden gelatin methacryloyl, for creating predefined gradients of biochemical properties. We measured the flow-induced physical characteristics, the mass transport of drug agents, and the biological features of the proposed chip. We measured reactive oxygen species from the encapsulated cells through an integrated process and showed the capacity of the hydrogel-based chip for creating drug/agent gradients. This work introduces a chip design based on a hydrogel that can be changed and could be used for modern HTS platforms such as in vitro organoids.
    Keywords:  bioprinting; digital light processing; high-throughput screening; hydrogel; microfluidics; organ-on-a-chip
    DOI:  https://doi.org/10.1021/acsabm.2c00578
  6. Biomicrofluidics. 2022 Jul;16(4): 044113
    Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction.
    Jiandong Yang, Satoshi Imamura, Yoshikazu Hirai, Toshiyuki Tsuchiya, Osamu Tabata, Ken-Ichiro Kamei.
      To clarify the physiological and pathological roles of gut-liver-axis (GLA) in the human body, a GLA microphysiological system (GLA-MPS) holds great potential. However, in current GLA-MPSs, the importance of a physiologically relevant flow for gut and liver cells' cultivation is not fully addressed. In addition, the integration of individual organ perfusion, circulation flow, and organ tissue functions in a single device has not been achieved. Here, we introduce a GLA-MPS by integrating two cell-culture chambers with individually applied perfusion flows and a circulation channel with an on-chip pneumatic micropump under cell-culture chambers via a porous membrane for interconnecting them. We analyzed the fluid shear stress (FSS) with computational fluid dynamics simulations and confirmed that the physiologically relevant FSS could be applied to the gut (Caco-2) (8 × 10-3 dyn cm-2) and liver (HepG2) cells (1.2 × 10-7 dyn cm-2). Under the physiologically relevant flow, the Caco-2 and HepG2 cells in the GLA-MPS maintained a cell survival rate of 95% and 92%, respectively. Furthermore, the expression of functional proteins such as zonula occludens 1 (in Caco-2) and albumin (in HepG2) was enhanced. To demonstrate the GLA interaction, the inflammatory bowel disease was recapitulated by applying lipopolysaccharide for only Caco-2 cells. The inflammatory proteins, such as inducible nitric oxide synthase, were induced in Caco-2 and HepG2 cells. The presented GLA-MPS can be adapted as an advanced in vitro model in various applications for disease modeling associated with inter-tissue interactions, such as inflammatory disease.
    DOI:  https://doi.org/10.1063/5.0088232
  7. Adv Mater. 2022 Aug 27. e2205083
    Real-Time Measurement of Cell Mechanics as a Clinically Relevant Readout of an In Vitro Lung Fibrosis Model Established on a Bioinspired Basement Membrane.
    Ali Doryab, Mehmet Berat Taskin, Philipp Stahlhut, Jürgen Groll, Otmar Schmid.
      Lung fibrosis, as one of the major post-COVID complications, is a progressive and ultimately fatal disease without a cure. Here, we introduce an organ- and disease-specific in vitro mini-lung fibrosis model equipped with non-invasive real-time monitoring of cell mechanics as a functional readout. To establish an intricate multi-culture model under physiologic conditions, we developed a biomimetic ultrathin basement (BETA) membrane (<1 μm) with unique properties, including biocompatibility, permeability, and high elasticity (<10 kPa) for cell culturing under air-liquid interface (ALI) and cyclic mechanical stretch conditions. The human-based triple co-culture fibrosis model, which includes epithelial and endothelial cell lines combined with primary fibroblasts from idiopathic pulmonary fibrosis (IPF) patients established on the BETA membrane, is integrated into a millifluidic bioreactor system (CIVIC) with dose-controlled aerosolized drug delivery, mimicking inhalation therapy. We show the real-time measurement of cell/tissue stiffness (and compliance) as a clinical biomarker of the progression/attenuation of fibrosis upon drug treatment, which was confirmed for inhaled Nintedanib -an FDA-approved anti-fibrosis drug. The mini-lung fibrosis model allows the combined longitudinal testing of pharmacodynamics and pharmacokinetics of drugs, which is expected to enhance the predictive capacity of preclinical models and hence facilitate the development of approved therapies for lung fibrosis. This article is protected by copyright. All rights reserved.
    Keywords:  aerosolized drug delivery; biomimetic membrane; cell mechanics; cyclic mechanical stretch; in vitro lung fibrosis model
    DOI:  https://doi.org/10.1002/adma.202205083
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