bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2022–03–06
six papers selected by
Joram Mooiweer, University of Groningen
  1. Shear and endothelial induced late-stage calcific aortic valve disease-on-a-chip develops calcium phosphate mineralizations.
  2. A metastasis-on-a-chip approach to explore the sympathetic modulation of breast cancer bone metastasis.
  3. Invasive aspergillosis-on-chip: A quantitative treatment study of human Aspergillus fumigatus infection.
  4. Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics.
  5. Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system.
  6. Biomimetic Alveolus-on-a-Chip for SARS-CoV-2 Infection Recapitulation.
  1. Lab Chip. 2022 Mar 02.
    Shear and endothelial induced late-stage calcific aortic valve disease-on-a-chip develops calcium phosphate mineralizations.
    Melissa Mendoza, Mei-Hsiu Chen, Peter Huang, Gretchen J Mahler.
      Calcific aortic valve disease (CAVD) is an active pathobiological process leading to severe aortic stenosis, where the only treatment is valve replacement. Late-stage CAVD is characterized by calcification, disorganization of collagen, and deposition of glycosaminoglycans, such as chondroitin sulfate (CS), in the fibrosa. We developed a three-dimensional microfluidic device of the aortic valve fibrosa to study the effects of shear stress (1 or 20 dyne per cm2), CS (1 or 20 mg mL-1), and endothelial cell presence on calcification. CAVD chips consisted of a collagen I hydrogel, where porcine aortic valve interstitial cells were embedded within and porcine aortic valve endothelial cells were seeded on top of the matrix for up to 21 days. Here, we show that this CAVD-on-a-chip is the first to develop human-like calcified nodules varying in calcium phosphate mineralization maturity resulting from high shear and endothelial cells, specifically di- and octa-calcium phosphates. Long-term co-culture microfluidic studies confirmed cell viability and calcium phosphate formations throughout 21 days. Given that CAVD has no targeted therapies, the creation of a physiologically relevant test-bed of the aortic valve could lead to advances in preclinical studies.
    DOI:  https://doi.org/10.1039/d1lc00931a
  2. Mater Today Bio. 2022 Jan;13 100219
    A metastasis-on-a-chip approach to explore the sympathetic modulation of breast cancer bone metastasis.
    Francisco Conceição, Daniela M Sousa, Joshua Loessberg-Zahl, Anke R Vollertsen, Estrela Neto, Kent Søe, Joana Paredes, Anne Leferink, Meriem Lamghari.
      Organ-on-a-chip models have emerged as a powerful tool to model cancer metastasis and to decipher specific crosstalk between cancer cells and relevant regulators of this particular niche. Recently, the sympathetic nervous system (SNS) was proposed as an important modulator of breast cancer bone metastasis. However, epidemiological studies concerning the benefits of the SNS targeting drugs on breast cancer survival and recurrence remain controversial. Thus, the role of SNS signaling over bone metastatic cancer cellular processes still requires further clarification. Herein, we present a novel humanized organ-on-a-chip model recapitulating neuro-breast cancer crosstalk in a bone metastatic context. We developed and validated an innovative three-dimensional printing based multi-compartment microfluidic platform, allowing both selective and dynamic multicellular paracrine signaling between sympathetic neurons, bone tropic breast cancer cells and osteoclasts. The selective multicellular crosstalk in combination with biochemical, microscopic and proteomic profiling show that synergistic paracrine signaling from sympathetic neurons and osteoclasts increase breast cancer aggressiveness demonstrated by augmented levels of pro-inflammatory cytokines (e.g. interleukin-6 and macrophage inflammatory protein 1α). Overall, this work introduced a novel and versatile platform that could potentially be used to unravel new mechanisms involved in intracellular communication at the bone metastatic niche.
    Keywords:  Bone metastasis; Breast cancer; IL, interleukin; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; MIP-1α, macrophage inflammatory protein 1α; Metastasis-on-a-chip; NE, norepinephrine; PDMS, poly-dimethylsiloxane; Paracrine; SNS, Sympathetic Nervous System; Sympathetic nervous system; TH, tyrosine hydroxylase
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100219
  3. Biomaterials. 2022 Feb 24. pii: S0142-9612(22)00059-X. [Epub ahead of print]283 121420
    Invasive aspergillosis-on-chip: A quantitative treatment study of human Aspergillus fumigatus infection.
    T N M Hoang, Z Cseresnyés, S Hartung, M Blickensdorf, C Saffer, K Rennert, A S Mosig, M von Lilienfeld-Toal, M T Figge.
      Invasive pulmonary aspergillosis is associated with a high mortality rate and poses a direct threat to immunocompromised patients. Here, we present the invasive aspergillosis-on-chip (IAC) model to investigate Aspergillus fumigatus infection in vitro. The model allows the study of the lateral growth and the invasive behaviour of fungal hyphae from the endothelium into the epithelial cell layer in an alveolus-on-chip model. We established an algorithm-based analysis pipeline for three-dimensional confocal microscopy images to visualize and quantify fungal morphology, including hyphal growth and branching. Human macrophages in the IAC model partially inhibited the growth of the fungus, contributed to the release of proinflammatory cytokines (IL-1, IL-6, TNF) and chemokines (IL-8 and MCP-1) associated with an increased number of invasive hyphae. Similar to in vivo, the application of the fungistatic drug caspofungin limited the fungal growth and resulted in morphological changes of the hyphal tree previously described in other studies. The IAC infection model allows the identification and characterization of cellular infection targets and in vitro testing of antifungal drugs in clinically relevant concentrations. It thus represents a promising tool to broaden the understanding of pathogenicity and pathophysiology of invasive aspergillosis.
    Keywords:  Alveolus-on-chip; Aspergillus fumigatus; Caspofungin; Image analysis; Invasive aspergillosis; Microphysiological system
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121420
  4. Open Biol. 2022 Mar;12(3): 210333
    Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics.
    Tanvi Shroff, Kehinde Aina, Christian Maass, Madalena Cipriano, Joeri Lambrecht, Frank Tacke, Alexander Mosig, Peter Loskill.
      Non-clinical models to study metabolism including animal models and cell assays are often limited in terms of species translatability and predictability of human biology. This field urgently requires a push towards more physiologically accurate recapitulations of drug interactions and disease progression in the body. Organ-on-chip systems, specifically multi-organ chips (MOCs), are an emerging technology that is well suited to providing a species-specific platform to study the various types of metabolism (glucose, lipid, protein and drug) by recreating organ-level function. This review provides a resource for scientists aiming to study human metabolism by providing an overview of MOCs recapitulating aspects of metabolism, by addressing the technical aspects of MOC development and by providing guidelines for correlation with in silico models. The current state and challenges are presented for two application areas: (i) disease modelling and (ii) pharmacokinetics/pharmacodynamics. Additionally, the guidelines to integrate the MOC data into in silico models could strengthen the predictive power of the technology. Finally, the translational aspects of metabolizing MOCs are addressed, including adoption for personalized medicine and prospects for the clinic. Predictive MOCs could enable a significantly reduced dependence on animal models and open doors towards economical non-clinical testing and understanding of disease mechanisms.
    Keywords:  PK/PD; disease modelling; in silico modelling; in vitro to in vivo translation; metabolism; multi-organchip
    DOI:  https://doi.org/10.1098/rsob.210333
  5. Open Biol. 2022 Mar;12(3): 210320
    Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system.
    Vaishaali Natarajan, Camille R Simoneau, Ann L Erickson, Nathan L Meyers, Jody L Baron, Stewart Cooper, Todd C McDevitt, Melanie Ott.
      Hepatitis C virus (HCV) remains a global public health challenge with an estimated 71 million people chronically infected, with surges in new cases and no effective vaccine. New methods are needed to study the human immune response to HCV since in vivo animal models are limited and in vitro cancer cell models often show dysregulated immune and proliferative responses. Here, we developed a CD8+ T cell and adult stem cell liver organoid system using a microfluidic chip to coculture 3D human liver organoids embedded in extracellular matrix with HLA-matched primary human T cells in suspension. We then employed automated phase contrast and immunofluorescence imaging to monitor T cell invasion and morphological changes in the liver organoids. This microfluidic coculture system supports targeted killing of liver organoids when pulsed with a peptide specific for HCV non-structural protein 3 (NS3) (KLVALGINAV) in the presence of patient-derived CD8+ T cells specific for KLVALGINAV. This demonstrates the novel potential of the coculture system to molecularly study adaptive immune responses to HCV in an in vitro setting using primary human cells.
    Keywords:  CD8+ T cells; hepatitis C; liver organoid; microfluidics
    DOI:  https://doi.org/10.1098/rsob.210320
  6. Research (Wash D C). 2022 ;2022 9819154
    Biomimetic Alveolus-on-a-Chip for SARS-CoV-2 Infection Recapitulation.
    Ting Cao, Changmin Shao, Xiaoyu Yu, Ruipei Xie, Chen Yang, Yulong Sun, Shaohua Yang, Wangjian He, Ye Xu, Qihui Fan, Fangfu Ye.
      SARS-CoV-2 has caused a severe pneumonia pandemic worldwide with high morbidity and mortality. How to develop a preclinical model for recapitulating SARS-CoV-2 pathogenesis is still urgent and essential for the control of the pandemic. Here, we have established a 3D biomimetic alveolus-on-a-chip with mechanical strain and extracellular matrix taken into consideration. We have validated that the alveolus-on-a-chip is capable of recapitulating key physiological characteristics of human alveolar units, which lays a fundamental basis for viral infection studies at the organ level. Using virus-analogous chemicals and pseudovirus, we have explored virus pathogenesis and blocking ability of antibodies during viral infection. This work provides a favorable platform for SARS-CoV-2-related researches and has a great potential for physiology and pathophysiology studies of the human lung at the organ level in vitro.
    DOI:  https://doi.org/10.34133/2022/9819154
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