bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2022‒10‒02
six papers selected by
Joram Mooiweer
University of Groningen
  1. Functional microvascularization of human myocardium in vitro.
  2. Modeling mucus physiology and pathophysiology in human organs-on-chips.
  3. Recapitulation of dynamic nanoparticle transport around tumors using a triangular multi-chamber tumor-on-a-chip.
  4. LY6E protein facilitates adeno-associated virus crossing in a biomimetic chip model of the human blood-brain barrier.
  5. Quantifying the transport of biologics across intestinal barrier models in real-time by fluorescent imaging.
  6. High Throughput Omnidirectional Printing of Tubular Microstructures from Elastomeric Polymers.
  1. Cell Rep Methods. 2022 Sep 19. 2(9): 100280
    Functional microvascularization of human myocardium in vitro.
    Oisín King, Daniela Cruz-Moreira, Alaa Sayed, Fatemeh Kermani, Worrapong Kit-Anan, Ilona Sunyovszki, Brian X Wang, Barrett Downing, Jerome Fourre, Daniel Hachim, Anna M Randi, Molly M Stevens, Marco Rasponi, Cesare M Terracciano.
      In this study, we report static and perfused models of human myocardial-microvascular interaction. In static culture, we observe distinct regulation of electrophysiology of human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) in co-culture with human cardiac microvascular endothelial cells (hCMVECs) and human left ventricular fibroblasts (hLVFBs), including modification of beating rate, action potential, calcium handling, and pro-arrhythmic substrate. Within a heart-on-a-chip model, we subject this three-dimensional (3D) co-culture to microfluidic perfusion and vasculogenic growth factors to induce spontaneous assembly of perfusable myocardial microvasculature. Live imaging of red blood cells within myocardial microvasculature reveals pulsatile flow generated by beating hiPSC-CMs. This study therefore demonstrates a functionally vascularized in vitro model of human myocardium with widespread potential applications in basic and translational research.
    Keywords:  E-C coupling; cardiac physiology; cardiomyocyte; electrophysiology; endothelial cell; microphysiological systems; microvasculature; organ-on-chip; stem cell-derived models; tissue engineering
    DOI:  https://doi.org/10.1016/j.crmeth.2022.100280
  2. Adv Drug Deliv Rev. 2022 Sep 27. pii: S0169-409X(22)00432-X. [Epub ahead of print] 114542
    Modeling mucus physiology and pathophysiology in human organs-on-chips.
    Zohreh Izadifar, Alexandra Sontheimer-Phelps, Bob A Lubamba, Haiqing Bai, Cicely Fadel, Anna Stejskalova, Alican Ozkan, Queeny Dasgupta, Amir Bein, Abidemi Junaid, Aakanksha Gulati, Gautam Mahajan, Seongmin Kim, Nina T LoGrande, Arash Naziripour, Donald E Ingber.
      The surfaces of human internal organs are lined by a mucus layer that ensures symbiotic relationships with commensal microbiome while protecting against potentially injurious environmental chemicals, toxins, and pathogens, and disruption of this layer can contribute to disease development. Studying mucus biology has been challenging due to the lack of physiologically relevant human in vitro models. Here we review recent progress that has been made in the development of human organ-on-a-chip microfluidic culture models that reconstitute epithelial tissue barriers and physiologically relevant mucus layers with a focus on lung, colon, small intestine, cervix and vagina. These organ-on-a-chip models that incorporate dynamic fluid flow, air-liquid interfaces, and physiologically relevant mechanical cues can be used to study mucus composition, mechanics, and structure, as well as investigate its contributions to human health and disease with a level of biomimicry not possible in the past.
    Keywords:  Cervix; Colon; Intestine; Lung; Mucus; Organ Chip; Organoids; Static models; Vagina
    DOI:  https://doi.org/10.1016/j.addr.2022.114542
  3. Lab Chip. 2022 Sep 29.
    Recapitulation of dynamic nanoparticle transport around tumors using a triangular multi-chamber tumor-on-a-chip.
    You Chen, Yifan Xue, Langtao Xu, Weilin Li, Yiling Chen, Shunan Zheng, Rui Dai, Jie Liu.
      3D tumor models are emerging as valuable tools for drug screening and nanoparticle based personalized cancer treatments. The main challenges in building microfluidic chip-based 3D tumor models currently include the development of bioinks with high bioactivity and the reproduction of the key tumor extracellular matrix (ECM) with heterogeneous tumor microenvironments. In this study, we designed a triangular multi-chamber tumor-on-a-chip (TM-CTC) platform, which consisted of three circular chambers at the vertices of a triangle connected by three rectangular chambers; it significantly improved the culture efficiency of 3D tumor tissues. MCF-7 tumor cells were cultured in a 3D ECM and then dynamically perfused for 7 days of culture to obtain abundant tumor spheroids with uniform size (100 ± 4.1 μm). The biological features of the 3D tumor tissue including epithelial transformation (EMT), hypoxia and proliferation activities were reproduced in the triangular multi-chamber tumor-on-a-chip (TM-CTC) platform. The permeability results of NPs confirmed that the ECM exhibited a significant barrier effect on the transportation of NPs when compared with free drugs, indicating that the ECM barrier should be considered as one of the key factors of drug delivery carrier development. In addition, this TM-CTC model provided a suitable platform for constructing a complex heterogeneous tumor microenvironment with multiple cells (MCF-7, HUVEC and MRC-5) involved, which was beneficial for exploring the dynamic interaction between tumor cells and other cells in the tumor microenvironment. The above results suggest that this TM-CTC model can simulate the dynamic transportation of NPs around 3D tumor tissues, and thus provide a reliable platform for NP evaluation.
    DOI:  https://doi.org/10.1039/d2lc00631f
  4. Lab Chip. 2022 Sep 27.
    LY6E protein facilitates adeno-associated virus crossing in a biomimetic chip model of the human blood-brain barrier.
    Dan Liu, Mingyang Zhu, Yi Lin, Mengmeng Li, Ruolan Huang, Liu Yang, Yanling Song, Yong Diao, Chaoyong Yang.
      The blood-brain barrier (BBB) controls chemical access to the brain and maintains fluid homeostasis, but in vitro models accurately simulating the physiological characteristics of the BBB are lacking. Here, we describe a simple and reproducible biomimetic chip-based model of the human BBB. In this bilayer co-culture, astrocytes and brain microvascular endothelial cells (BMECs) are respectively seeded in upper and lower chambers separated by a semi-permeable membrane, with fluid shear force provided by a precision tilt shaker. Evaluation of barrier crossing by fluorescein sodium, 40 kDa or 70 kDa FITC-dextran, or adeno-associated virus (AAV) particles demonstrates that this bilayer model provides similar or greater barrier function than Transwell assays. Comparison of AAV serotypes indicated that AAV-PHP.eB can cross the human BBB in vitro, and at higher efficiency than AAV9. Additionally, RNAi knockdown and virus capsid protein binding assays show that AAV-PHP.eB delivery is facilitated by receptor protein lymphocyte antigen-6E (LY6E) in humans. This in vitro model system uses a miniaturized chip to enable high-throughput investigations of AAV crossing efficiency in the BBB, and provides strong initial evidence that human LY6E mediates AAV-PHP.eB crossing the BBB.
    DOI:  https://doi.org/10.1039/d2lc00698g
  5. Front Bioeng Biotechnol. 2022 ;10 965200
    Quantifying the transport of biologics across intestinal barrier models in real-time by fluorescent imaging.
    Arjen Weller, Morten B Hansen, Rodolphe Marie, Adam C Hundahl, Casper Hempel, Paul J Kempen, Henrik L Frandsen, Ladan Parhamifar, Jannik B Larsen, Thomas L Andresen.
      Unsuccessful clinical translation of orally delivered biological drugs remains a challenge in pharmaceutical development and has been linked to insufficient mechanistic understanding of intestinal drug transport. Live cell imaging could provide such mechanistic insights by directly tracking drug transport across intestinal barriers at subcellular resolution, however traditional intestinal in vitro models are not compatible with the necessary live cell imaging modalities. Here, we employed a novel microfluidic platform to develop an in vitro intestinal epithelial barrier compatible with advanced widefield- and confocal microscopy. We established a quantitative, multiplexed and high-temporal resolution imaging assay for investigating the cellular uptake and cross-barrier transport of biologics while simultaneously monitoring barrier integrity. As a proof-of-principle, we use the generic model to monitor the transport of co-administrated cell penetrating peptide (TAT) and insulin. We show that while TAT displayed a concentration dependent difference in its transport mechanism and efficiency, insulin displayed cellular internalization, but was restricted from transport across the barrier. This illustrates how such a sophisticated imaging based barrier model can facilitate mechanistic studies of drug transport across intestinal barriers and aid in vivo and clinical translation in drug development.
    Keywords:  drug development; drug transport; fluorescence live cell imaging; high through put screening platform; organ-on-a-chip
    DOI:  https://doi.org/10.3389/fbioe.2022.965200
  6. Adv Healthc Mater. 2022 Sep 27. e2201346
    High Throughput Omnidirectional Printing of Tubular Microstructures from Elastomeric Polymers.
    Chuan Liu, Scott B Campbell, Jianzhao Li, Dawn Bannerman, Simon Pascual-Gil, Jennifer Kieda, Qinghua Wu, Peter R Herman, Milica Radisic.
      Bioelastomers have been extensively used in biomedical applications due to their desirable mechanical strength, tunable properties, and chemical versatility; however, 3D printing bioelastomers into microscale structures has proven elusive. Herein, a high throughput omnidirectional printing approach via coaxial extrusion is described that fabricated perfusable elastomeric microtubes of unprecedently small inner diameter (350-550 μm) and wall thickness (40-60 μm). The versatility of this approach was shown through the printing of two different polymeric elastomers, followed by photocrosslinking and removal of the fugitive inner phase. Designed experiments were used to tune the dimensions and stiffness of the microtubes to match that of native ex vivo rat vasculature. This approach afforded the fabrication of multiple biomimetic shapes resembling cochlea and kidney glomerulus and afforded facile, high-throughput generation of perfusable structures that can be seeded with endothelial cells for biomedical applications. Post-printing laser micromachining was performed to generate numerous micro-sized holes (5-20 μm) in the tube wall to tune microstructure permeability. Importantly, for organ-on-a-chip applications, the described approach took only 3.6 minutes to print microtubes (without microholes) over an entire 96-well plate device, in contrast to comparable hole-free structures that take between 1.5 to 6.5 days to fabricate using a manual 3D stamping approach. This article is protected by copyright. All rights reserved.
    Keywords:  biomimicking; bioprinting; elastomer; organ-on-a-chip; photocrosslinking; polyester; vascular models
    DOI:  https://doi.org/10.1002/adhm.202201346
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