bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2021‒01‒10
five papers selected by
Joram Mooiweer
University of Groningen


  1. Nanotheranostics. 2021 ;5(1): 73-89
    Guo QR, Zhang LL, Liu JF, Li Z, Li JJ, Zhou WM, Wang H, Li JQ, Liu DY, Yu XY, Zhang JY.
      Microfluidic chip is not a chip in the traditional sense. It is technologies that control fluids at the micro level. As a burgeoning biochip, microfluidic chips integrate multiple disciplines, including physiology, pathology, cell biology, biophysics, engineering mechanics, mechanical design, materials science, and so on. The application of microfluidic chip has shown tremendous promise in the field of cancer therapy in the past three decades. Various types of cell and tissue cultures, including 2D cell culture, 3D cell culture and tissue organoid culture could be performed on microfluidic chips. Patient-derived cancer cells and tissues can be cultured on microfluidic chips in a visible, controllable, and high-throughput manner, which greatly advances the process of personalized medicine. Moreover, the functionality of microfluidic chip is greatly expanding due to the customizable nature. In this review, we introduce its application in developing cancer preclinical models, detecting cancer biomarkers, screening anti-cancer drugs, exploring tumor heterogeneity and producing nano-drugs. We highlight the functions and recent development of microfluidic chip to provide references for advancing cancer diagnosis and treatment.
    Keywords:  Biomarker; Cancer; Drug screening; Microfluidic chip; Nanoparticle; Preclinical model
    DOI:  https://doi.org/10.7150/ntno.49614
  2. Micromachines (Basel). 2020 Dec 30. pii: E37. [Epub ahead of print]12(1):
    Tu KH, Yu LS, Sie ZH, Hsu HY, Al-Jamal KT, Wang JT, Chiang YY.
      Three-dimensional (3D) cell cultures and organs-on-a-chip have been developed to construct microenvironments that resemble the environment within the human body and to provide a platform that enables clear observation and accurate assessments of cell behavior. However, direct observation of transendothelial electrical resistance (TEER) has been challenging. To improve the efficiency in monitoring the cell development in organs-on-a-chip, in this study, we designed and integrated commercially available TEER measurement electrodes into an in vitro blood-brain barrier (BBB)-on-chip system to quantify TEER variation. Moreover, a flowing culture medium was added to the monolayered cells to simulate the promotion of continuous shear stress on cerebrovascular cells. Compared with static 3D cell culture, the proposed BBB-on-chip integrated with electrodes could measure TEER in a real-time manner over a long period. It also allowed cell growth angle measurement, providing instant reports of cell growth information online. Overall, the results demonstrated that the developed system can aid in the quantification of the continuous cell-pattern variations for future studies in drug testing.
    Keywords:  3D cell culture; TEER; in-situ monitoring; transendothelial electrical resistance
    DOI:  https://doi.org/10.3390/mi12010037
  3. Front Bioeng Biotechnol. 2020 ;8 612091
    Xu M, Wang Y, Duan W, Xia S, Wei S, Liu W, Wang Q.
      Anti-tumor drugs can effectively shrink the lesions of primary lung cancer; however, it has limited therapeutic effect on patients with brain metastasis (BM). A BM preclinical model based on a multi-organ microfluidic chip has been established proficiently in our previous work. In this study, the BM subpopulation (PC9-Br) derived from the parental PC9 cell line was isolated from the chip model and found to develop obvious resistance to antineoplastic drugs including chemotherapeutic agents (cisplatin, carboplatin, pemetrexed) and tyrosine kinase inhibitors (TKIs) which target epidermal growth factor receptor (EGFR); this suggested that the acquisition of drug-resistance by brain metastatic cells was attributable to the intrinsic changes in PC9-Br. Hence, we performed proteomic and revealed a greatly altered spectrum of BM protein expression compared with primary lung cancer cells. We identified the hyperactive glutathione (GSH) metabolism pathway with the overexpression of various GSH metabolism-related enzymes (GPX4, RRM2, GCLC, GPX1, GSTM4, GSTM1). Aldehyde dehydrogenases (ALDH1A1, ALDH3A1) were also found to be upregulated in BM. What's more, loss of EGFR and phosphorylated EGFR in PC9-Br gave reasons for the TKIs resistance. Collectively, our findings indicated potential mechanisms for the acquirement of drug resistance occurred in BM, providing new strategies to overcome therapeutic resistance in lung cancer BM.
    Keywords:  brain metastasis; drug resistance; lung cancer; microfluidic organ-on-a-chip; proteomic
    DOI:  https://doi.org/10.3389/fbioe.2020.612091
  4. Expert Opin Drug Deliv. 2021 Jan 07.
    Gholizadeh H, Ong HX, Bradbury P, Kourmatzis A, Traini D, Young P, Li M, Cheng S.
      OBJECTIVES: This study demonstrates a human nasal epithelial mucosa (NEM) on-a-chip integrated with a novel carbon nanofibers-modified carbon (CNFs-C) electrode for real-time quantitative monitoring of in vitro nasal drug delivery. The NEM-on-a-chip was also integrated with platinum electrodes for real-time measurement of transepithelial electrical resistance (TEER) to monitor the epithelial barrier function.METHODS: The air-liquid interface culture of nasal epithelial RPMI 2650 cells in the NEM-on-a-chip was optimized to mimic the key functional characteristics of the human nasal mucosa. The epithelial transport of ibuprofen in the NEM-on-a-chip was electrochemically monitored by the CNFs-C electrode in real-time under static and physiologically realistic dynamic flow conditions.
    RESULTS: The proposed NEM-on-a-chip mimics the mucus production and nasal epithelial barrier function comparable to the physiological characteristics of the human nasal mucosa in vivo. The real-time drug quantification by the CNFs-C electrode in the NEM-on-a-chip was similar to measurements produced by the high-performance liquid chromatography method. The drug transport rate monitored in the NEM-on-a-chip was also responsive to the change in the dynamic condition of the fluid in the bottom compartment of the chip, highlighting the importance of emulating the dynamic in vivo condition for nasal drug transport studies.
    CONCLUSION: The proposed novel NEM-on-a-chip with in situ real-time analysis of drug transport and TEER could potentially be used as an in vitro pre-clinical drug screening platform to offer a low-cost and time-efficient alternative to the costly laborious techniques conventionally used for in vitro drug transport assays.
    Keywords:  Nasal drug delivery; Nasal epithelial mucosa-on-a-chip; RPMI 2650; Real-time drug screening; TEER
    DOI:  https://doi.org/10.1080/17425247.2021.1873274
  5. ACS Biomater Sci Eng. 2019 May 13. 5(5): 2417-2429
    Sundarakrishnan A, Zukas H, Coburn J, Bertini BT, Liu Z, Georgakoudi I, Baugh L, Dasgupta Q, Black LD, Kaplan DL.
      Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown etiology with no current curative treatment. Modeling pulmonary fibrotic (PF) tissue has the potential to improve our understanding of IPF disease progression and treatment. Rodent animal models do not replicate human fibroblastic foci (Hum-FF) pathology, and current iterations of in vitro model systems (e.g., collagen hydrogels, polyacrylamide hydrogels, and fibrosis-on-chip systems) are unable to replicate the three-dimensional (3D) complexity and biochemical composition of human PF tissue. Herein, we fabricated a 3D bioengineered pulmonary fibrotic (Eng-PF) tissue utilizing cell laden silk collagen type I dityrosine cross-linked hydrogels and Flexcell bioreactors. We show that silk collagen type I hydrogels have superior stability and mechanical tunability compared to other hydrogel systems. Using customized Flexcell bioreactors, we reproduced Hum-FF-like pathology with airway epithelial and microvascular endothelial cells. Eng-PF tissues can model myofibroblast differentiation and permit evaluation of antifibrotic drug treatments. Further, Eng-PF tissues could be used to model different facets of IPF disease, including epithelial injury with the addition of bleomycin and cellular recruitment by perfusion of cells through the hydrogel microchannel.
    Keywords:  antifibrotic drug testing; fibroblast activation; idiopathic pulmonary fibrosis; in vitro models; pulmonary fibrosis; three-dimensional culture
    DOI:  https://doi.org/10.1021/acsbiomaterials.8b01262