bims-orenst 2021-09-12 papers

Issue of 2021–09–12
five papers selected by
Joram Mooiweer, University of Groningen

Biomicrofluidics. 2021 Jul;15(4): 044103

Spheroid-on-chip microfluidic technology for the evaluation of the impact of continuous flow on metastatic potential in cancer models in vitro.

Thomas Collins, Emily Pyne, Martin Christensen, Alexander Iles, Nicole Pamme, Isabel M Pires.

The majority of cancer deaths are linked to tumor spread, or metastasis, but 3D in vitro metastasis models relevant to the tumor microenvironment (including interstitial fluid flow) remain an area of unmet need. Microfluidics allows us to introduce controlled flow to an in vitro cancer model to better understand the relationship between flow and metastasis. Here, we report new hybrid spheroid-on-chip in vitro models for the impact of interstitial fluid flow on cancer spread. We designed a series of reusable glass microfluidic devices to contain one spheroid in a microwell under continuous perfusion culture. Spheroids derived from established cancer cell lines were perfused with complete media at a flow rate relevant to tumor interstitial fluid flow. Spheroid viability and migratory/invasive capabilities were maintained on-chip when compared to off-chip static conditions. Importantly, using flow conditions modeled in vitro, we are the first to report flow-induced secretion of pro-metastatic factors, in this case cytokines vascular endothelial growth factor and interleukin 6. In summary, we have developed a new, streamlined spheroid-on-chip in vitro model that represents a feasible in vitro alternative to conventional murine in vivo metastasis assays, including complex tumor environmental factors, such as interstitial fluid flow, extracellular matrices, and using 3D models to model nutrient and oxygen gradients. Our device, therefore, constitutes a robust alternative to in vivo early-metastasis models for determination of novel metastasis biomarkers as well as evaluation of therapeutically relevant molecular targets not possible in in vivo murine models.

DOI: https://doi.org/10.1063/5.0061373

Lab Chip. 2021 Sep 06.

Compartmentalized microfluidic chambers enable long-term maintenance and communication between human pluripotent stem cell-derived forebrain and midbrain neurons.

Ziqiu Tong, Eunbi Kwak, Alita Aguiar, Bo Peng, Colin W Pouton, Nicolas H Voelcker, John M Haynes.

Compartmentalized microfluidic devices are becoming increasingly popular and have proven to be valuable tools to probe neurobiological functions that are inherently difficult to study using traditional approaches. The ability of microfluidic devices to compartmentalize neurons offers considerable promise for disease modeling and drug discovery. Rodent cortical neurons/neural progenitors are commonly used in such studies but, while these cells mature rapidly, they do not possess the same receptors, ion channels and transport proteins found in human cortical neurons. Human pluripotent stem cell derived neurons offer a human phenotype, but their slow maturation offsets this phenotypic advantage, particularly over long-term culture where overgrowth and subsequent death of neurons may be a problem. In this work, we integrate the use of Matrigel as a 3D cell culture scaffold that enables high cell seeding density over a small fraction of the culture surface. This approach, in an open chamber microfluidic system, enables culture over a five-month period without the use of growth inhibitors. Matrigel was also uniquely utilized to hinder agonist diffusion across microchannels. We demonstrate the development of neuron-to-neuron communication networks by showing that electrical stimulation or the unilateral addition of agonists to one chamber resulted in activation of neurons in the adjacent chamber. Lastly, using a delayed neuron seeding strategy, we show that we can foster essentially one-way communication between separate populations of human forebrain and midbrain dopaminergic neuron containing cultures.

DOI: https://doi.org/10.1039/d1lc00505g

ACS Biomater Sci Eng. 2021 Sep 10.

Facile Fabrication of Hollow Hydrogel Microfiber via 3D Printing-Assisted Microfluidics and Its Application as a Biomimetic Blood Capillary.

Dongxu Lan, Yulian Shang, Hongxian Su, Minhua Liang, Yang Liu, Haofei Li, Qi Feng, Xiaodong Cao, Hua Dong.

Simulating the structure and function of blood capillaries is very important for an in-depth insight into their role in the human body and treatment of capillary-related diseases. Due to the similar composition and structure, hollow hydrogel microfibers are well-recognized as potential biomimetic blood capillaries. In this paper, we report a novel, facile, and reproducible method to fabricate coaxial microfluidic chips via 3D printing-assisted soft lithography and then hollow hydrogel microfibers using the as-prepared coaxial microfluidic chips. Instead of traditional photoresist-based lithography, 3D printing of gelatin hydrogel under various extrusion pressures is used to construct sacrificial templates of coaxial microfluidic chips. Various solid and hollow hydrogel microfibers with complicated and hierarchical structures can be obtained via multitype coaxial microfluidic chips or a combination of coaxial microfluidic fabrication and post-treatment. The as-formed hollow hydrogel microfibers are evaluated in detail as biomimetic blood capillaries, including physicochemical and cytological properties. Our results prove that the hollow hydrogel microfibers exhibit excellent mass transport capacity, hemocompatibility, semipermeability, and mechanical strength, and their barrier function can be further enhanced in the presence of endothelial cells. Overall, our 3D printing-assisted fabrication strategy provides a new technique to construct microfluidic chips with complicated 3D microchannels, and the resulting hollow hydrogel microfibers are promising candidates for blood capillaries.

Keywords: 3D printing; barrier function; biomimetic blood capillary; coaxial microfluidic chip; hollow hydrogel microfiber

DOI: https://doi.org/10.1021/acsbiomaterials.1c00980

Lab Chip. 2021 Sep 10.

Establishment of a human three-dimensional chip-based chondro-synovial coculture joint model for reciprocal cross talk studies in arthritis research.

Mario Rothbauer, Ruth A Byrne, Silvia Schobesberger, Isabel Olmos Calvo, Anita Fischer, Eva I Reihs, Sarah Spitz, Barbara Bachmann, Florian Sevelda, Johannes Holinka, Wolfgang Holnthoner, Heinz Redl, Stefan Toegel, Reinhard Windhager, Hans P Kiener, Peter Ertl.

Rheumatoid arthritis is characterised by a progressive, intermittent inflammation at the synovial membrane, which ultimately leads to the destruction of the synovial joint. The synovial membrane as the joint capsule's inner layer is lined with fibroblast-like synoviocytes that are the key player supporting persistent arthritis leading to bone erosion and cartilage destruction. While microfluidic models that model molecular aspects of bone erosion between bone-derived cells and synoviocytes have been established, RA's synovial-chondral axis has not yet been realised using a microfluidic 3D model based on human patient in vitro cultures. Consequently, we established a chip-based three-dimensional tissue coculture model that simulates the reciprocal cross talk between individual synovial and chondral organoids. When co-cultivated with synovial organoids, we could demonstrate that chondral organoids induce a higher degree of cartilage physiology and architecture and show differential cytokine response compared to their respective monocultures highlighting the importance of reciprocal tissue-level cross talk in the modelling of arthritic diseases.

DOI: https://doi.org/10.1039/d1lc00130b

Elife. 2021 Sep 06. pii: e69310. [Epub ahead of print]10

Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease.

Abudupataer Mieradilijiang, Shichao Zhu, Shiqiang Yan, Kehua Xu, Jingjing Zhang, Shaman Luo, Wenrui Ma, Md Fazle Alam, Yuyi Tang, Hui Huang, Nan Chen, Li Wang, Guoquan Yan, Jun Li, Hao Lai, Chunsheng Wang, Kai Zhu, Weijia Zhang.

Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.
Methods: A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs).
Results: Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients.
Conclusions: The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.
Funding: National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

Keywords: human; medicine

DOI: https://doi.org/10.7554/eLife.69310