bims-orenst 2021-12-19 papers

Issue of 2021–12–19
five papers selected by
Joram Mooiweer, University of Groningen

Fluids Barriers CNS. 2021 Dec 14. 18(1): 59

Modeling ischemic stroke in a triculture neurovascular unit on-a-chip.

Nienke R Wevers, Arya Lekshmi Nair, Tania M Fowke, Maria Pontier, Dhanesh G Kasi, Xandor M Spijkers, Charlie Hallard, Gwenaëlle Rabussier, Remko van Vught, Paul Vulto, Helga E de Vries, Henriëtte L Lanz.

BACKGROUND: In ischemic stroke, the function of the cerebral vasculature is impaired. This vascular structure is formed by the so-called neurovascular unit (NVU). A better understanding of the mechanisms involved in NVU dysfunction and recovery may lead to new insights for the development of highly sought therapeutic approaches. To date, there remains an unmet need for complex human in vitro models of the NVU to study ischemic events seen in the human brain.
METHODS: We here describe the development of a human NVU on-a-chip model using a platform that allows culture of 40 chips in parallel. The model comprises a perfused vessel of primary human brain endothelial cells in co-culture with induced pluripotent stem cell derived astrocytes and neurons. Ischemic stroke was mimicked using a threefold approach that combines chemical hypoxia, hypoglycemia, and halted perfusion.
RESULTS: Immunofluorescent staining confirmed expression of endothelial adherens and tight junction proteins, as well as astrocytic and neuronal markers. In addition, the model expresses relevant brain endothelial transporters and shows spontaneous neuronal firing. The NVU on-a-chip model demonstrates tight barrier function, evidenced by retention of small molecule sodium fluorescein in its lumen. Exposure to the toxic compound staurosporine disrupted the endothelial barrier, causing reduced transepithelial electrical resistance and increased permeability to sodium fluorescein. Under stroke mimicking conditions, brain endothelial cells showed strongly reduced barrier function (35-fold higher apparent permeability) and 7.3-fold decreased mitochondrial potential. Furthermore, levels of adenosine triphosphate were significantly reduced on both the blood- and the brain side of the model (4.8-fold and 11.7-fold reduction, respectively).
CONCLUSIONS: The NVU on-a-chip model presented here can be used for fundamental studies of NVU function in stroke and other neurological diseases and for investigation of potential restorative therapies to fight neurological disorders. Due to the platform's relatively high throughput and compatibility with automation, the model holds potential for drug compound screening.

Keywords: BBB-on-a-chip; Blood–brain barrier; Microfluidics; Neurovascular unit; Stroke

DOI: https://doi.org/10.1186/s12987-021-00294-9

Lab Chip. 2021 Dec 14.

Hybrid skin chips for toxicological evaluation of chemical drugs and cosmetic compounds.

Jong Seung Lee, Jin Kim, Baofang Cui, Su Kyeom Kim, Sun-A Cho, Susun An, Seung-Woo Cho.

Development of drugs and cosmetics for topical application require safety tests in skin models. However, current skin models, such as skin cell sheets and artificial tissue-engineered skin, do not allow sophisticated toxicological evaluations (e.g., sensory irritation, hepatotoxicity). Animal models are prohibited worldwide for testing cosmetics. Therefore, reliable human skin models that recapitulate physiological events in skin tissue need to be established under in vitro settings. In this study, hybrid human skin models that enable delicate toxicological evaluations of drugs and cosmetic compounds are demonstrated. To recapitulate skin cornification, keratinocytes in the top layer of a vertical microfluidic chip were cultured at the air-liquid interface. For the skin-nerve hybrid model, differentiated neural stem cells in 3D collagen were positioned adjacent to and right below the skin layer. This model enables real-time quantitative skin sensitization analysis following chemical treatments by detecting alterations in neuronal activity in combination with a calcium imaging technique. For the skin-liver model, hepatic cells derived from pluripotent stem cells were cultured in 3D collagen distant from the skin layer. Potential hepatotoxicity of cutaneously applied chemicals in this model can be evaluated by quantification of glutathione and reactive oxygen species. Our study suggests that 3D hybrid skin chips would provide useful human skin models in pharmaceutical and cosmetic industries.

DOI: https://doi.org/10.1039/d1lc00550b

Adv Mater. 2021 Dec 16. e2107876

Advanced Materials and Sensors for Microphysiological Systems: Focus on Electronic and Electro-optical Interfaces.

Hanie Kavand, Rohollah Nasiri, Anna Herland.

Advanced in vitro cell culture systems or microphysiological systems (MPSs), including microfluidic organ-on-a-chip (OoC), are breakthrough technologies in biomedicine. These systems recapitulate features of human tissues outside of the body. They are increasingly being used to study the functionality of different organs for applications such as drug evolutions, disease modeling, and precision medicine. Currently, developers and endpoint users of these in vitro models promote how they can replace animal models or even be a better ethically neutral and humanized alternative to study pathology, physiology, and pharmacology. Although reported models show a remarkable physiological structure and function compared to the conventional two-dimensional cell culture, they are almost exclusively based on standard passive polymers or glass with none or minimal real-time stimuli and readout capacity. The next technology leap in reproducing in vivo-like functionality and real-time monitoring of tissue function could be realized with advanced functional materials and devices. This review describes the currently reported electronic and optical advanced materials for sensing and stimulation of MPS models. In addition, we give an overview of multi-sensing for Body-on-Chip platforms. Finally, we give our perspective on how advanced functional materials could be integrated into in vitro systems to precisely mimic human physiology. This article is protected by copyright. All rights reserved.

Keywords: biosensors; electro-optical materials; microphysiological system; organ-on-a-chip

DOI: https://doi.org/10.1002/adma.202107876

Front Immunol. 2021 ;12 777932

Human Neutrophils Respond to Complement Activation and Inhibition in Microfluidic Devices.

Sinan Muldur, Douangsone D Vadysirisack, Sharan Ragunathan, Yalan Tang, Alonso Ricardo, Camil Elie Sayegh, Daniel Irimia.

Complement activation is key to anti-microbial defenses by directly acting on microbes and indirectly by triggering cellular immune responses. Complement activation may also contribute to the pathogenesis of numerous inflammatory and immunological diseases. Consequently, intense research focuses on developing therapeutics that block pathology-causing complement activation while preserving anti-microbial complement activities. However, the pace of research is slowed down significantly by the limitations of current tools for evaluating complement-targeting therapeutics. Moreover, the effects of potential therapeutic agents on innate immune cells, like neutrophils, are not fully understood. Here, we employ microfluidic assays and measure chemotaxis, phagocytosis, and swarming changes in human neutrophils ex vivo in response to various complement-targeting agents. We show that whereas complement factor 5 (C5) cleavage inhibitor eculizumab blocks all neutrophil anti-microbial functions, newer compounds like the C5 cleavage inhibitor RA101295 and C5a receptor antagonist avacopan inhibit chemotaxis and swarming while preserving neutrophil phagocytosis. These results highlight the utility of microfluidic neutrophil assays in evaluating potential complement-targeting therapeutics.

Keywords: RA101295; avacopan; complement; eculizumab; infection; microfluidic “lab-on-a-chip; neutrophil; phagocytosis

DOI: https://doi.org/10.3389/fimmu.2021.777932

Biomaterials. 2021 Nov 30. pii: S0142-9612(21)00658-X. [Epub ahead of print]280 121302

Imiquimod-gemcitabine nanoparticles harness immune cells to suppress breast cancer.

Bijay Singh, Sushila Maharjan, Daniel C Pan, Zongmin Zhao, Yongsheng Gao, Yu Shrike Zhang, Samir Mitragotri.

Monotherapy with a single chemotherapeutic regimen has met with significant hurdles in terms of clinical efficacy. The complexity of cancer accentuates the need for an alternative approach with a combination of two or more therapeutic regimens to win the battle. However, it is still a challenge to develop a successful combination of drugs with high efficiency and low toxicity to control cancer growth. While gemcitabine monotherapy remains a choice of standard treatment for advanced breast cancer, the approach has not prolonged the median survival time of metastatic breast cancer patients. Here, we report a hyaluronic acid (HA)-based drug combination of gemcitabine (GEM) with imiquimod (IMQ) to stimulate immune cells for anticancer activity. Treatment of the drug combination (IMQ-HA-GEM) showed enhanced anticancer activity against 4T1 breast tumor cells in vitro. Our study with a microfluidics-based 3D, compartmentalized cancer model showed that infiltration of THP-1 monocytes occurred particularly at the site of cancer cells treated with IMQ-HA-GEM. Moreover, IMQ-HA-GEM significantly suppressed the volume of 4T1 breast tumor of mice in vivo. Flow cytometry study displayed a significantly higher activation of CD11b+ immune cells in the blood of mice treated with IMQ-HA-GEM, whereas immunohistochemistry study revealed greater prevalence of CD68+ tumor-associated macrophages in the tumor. Histological examination of isolated tumors of mice treated with IMQ-HA-GEM further confirmed the efficacy of drug combination on cancer cells. This study supports the conclusion that imiquimod potentiates the effect of gemcitabine by activating immune cells to suppress tumors in the form of combination nanoparticles.

Keywords: Anticancer drugs; Breast cancer; Chemotherapy; Immunotherapy; Microfluidic organ-on-a chip; Nanoparticle drug delivery

DOI: https://doi.org/10.1016/j.biomaterials.2021.121302