bims-orenst 2021-07-18 papers

Issue of 2021–07–18
five papers selected by
Joram Mooiweer, University of Groningen

Acta Biomater. 2021 Jul 12. pii: S1742-7061(21)00444-X. [Epub ahead of print]

Modeling Nonalcoholic Fatty Liver Disease on a Liver Lobule Chip with Dual Blood Supply.

Kun Du, Shibo Li, Chengpan Li, Ping Li, Chunguang Miao, Tianzhi Luo, Bensheng Qiu, Weiping Ding.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a public health concern. To date, the mechanism of NAFLD progression remains unclear, and pharmacological treatment options are scarce. Traditional animal NAFLD models are limited in helping address these problems due to interspecies differences. Liver chips are promising for modeling NAFLD. However, pre-existing liver chips cannot reproduce complex physicochemical microenvironments of the liver effectively; thus, NAFLD modeling based on these chips is incomplete. Herein, we develop a biomimetic liver lobule chip (LC) and then establish a more accurate on-chip NAFLD model. The self-developed LC achieves dual blood supply through the designed hepatic portal vein and hepatic artery and the microtissue cultured on the LC forms multiple structures similar to in vivo liver. Based on the LC, NAFLD is modeled. Steatosis is successfully induced and more importantly, changing lipid zonation in a liver lobule with the progression of NAFLD is demonstrated for the first time on a microfluidic chip. In addition, the application of the induced NAFLD model has been preliminarily demonstrated in the prevention and reversibility of promising drugs. This study provides a promising platform to understand NAFLD progression and identify drugs for treating NAFLD. STATEMENT OF SIGNIFICANCE: Liver chips are promising for modeling nonalcoholic fatty liver disease (NAFLD). However, on-chip replicating liver physicochemical microenvironments is still a challenge. Herein, we developed a liver lobule chip with dual blood supply, achieving self-organized liver microtissue that is similar to in vivo tissue. Based on the chip, we successfully modeled NAFLD under physiologically differentiated nutrient supplies. For the first time, the changing lipid zonation in a single liver lobule with the early-stage progression of NAFLD was demonstrated on a liver chip. This study provides a promising platform for modeling liver-related diseases.

Keywords: Dual blood supply; Lipid zonation; Liver lobule chip; Microfluidics; Nonalcoholic fatty liver disease

DOI: https://doi.org/10.1016/j.actbio.2021.07.013

Sci Rep. 2021 Jul 13. 11(1): 14379

Studying dynamic stress effects on the behaviour of THP-1 cells by microfluidic channels.

Semra Zuhal Birol, Rana Fucucuoglu, Sertac Cadirci, Ayca Sayi-Yazgan, Levent Trabzon.

Atherosclerosis is a long-term disease process of the vascular system that is characterized by the formation of atherosclerotic plaques, which are inflammatory regions on medium and large-sized arteries. There are many factors contributing to plaque formation, such as changes in shear stress levels, rupture of endothelial cells, accumulation of lipids, and recruitment of leukocytes. Shear stress is one of the main factors that regulates the homeostasis of the circulatory system; therefore, sudden and chronic changes in shear stress may cause severe pathological conditions. In this study, microfluidic channels with cavitations were designed to mimic the shape of the atherosclerotic blood vessel, where the shear stress and pressure difference depend on design of the microchannels. Changes in the inflammatory-related molecules ICAM-1 and IL-8 were investigated in THP-1 cells in response to applied shear stresses in an continuous cycling system through microfluidic channels with periodic cavitations. ICAM-1 mRNA expression and IL-8 release were analyzed by qRT-PCR and ELISA, respectively. Additionally, the adhesion behavior of sheared THP-1 cells to endothelial cells was examined by fluorescence microscopy. The results showed that 15 Pa shear stress significantly increases expression of ICAM-1 gene and IL-8 release in THP-1 cells, whereas it decreases the adhesion between THP-1 cells and endothelial cells.

DOI: https://doi.org/10.1038/s41598-021-93935-w

Adv Mater. 2021 Jul 16. e2100701

A Noninvasive Gut-to-Brain Oral Drug Delivery System for Treating Brain Tumors.

Yang-Bao Miao, Kuan-Hung Chen, Chiung-Tong Chen, Fwu-Long Mi, Yu-Jung Lin, Yen Chang, Chi-Shiun Chiang, Jui-To Wang, Kun-Ju Lin, Hsing-Wen Sung.

Most orally administered drugs fail to reach the intracerebral regions because of the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), which are located between the gut and the brain. Herein, an oral prodrug delivery system that can overcome both the IEB and the BBB noninvasively is developed for treating gliomas. The prodrug is prepared by conjugating an anticancer drug on β-glucans using a disulfide-containing linker. Following oral administration in glioma-bearing mice, the as-prepared prodrug can specifically target intestinal M cells, transpass the IEB, and be phagocytosed/hitchhiked by local macrophages (Mϕ). The Mϕ-hitchhiked prodrug is transported to the circulatory system via the lymphatic system, crossing the BBB. The tumor-overexpressed glutathione then cleaves the disulfide bond within the prodrug, releasing the active drug, improving its therapeutic efficacy. These findings reveal that the developed prodrug may serve as a gut-to-brain oral drug delivery platform for the well-targeted treatment of gliomas.

Keywords: blood-brain barrier; glioma; intestinal epithelial barrier; macrophage hitchhiking; prodrugs

DOI: https://doi.org/10.1002/adma.202100701

J Biomech Eng. 2021 Jul 13.

In Vitro Flow Chamber Design for the Study of Endothelial Cell (patho)physiology.

Meghan E Fallon, Rick Mathews, Monica T Hinds.

In the native vasculature, flowing blood produces a frictional force on vessel walls that directly effects endothelial cell phenotype and function. In the arterial system, the vasculature's local geometry directly influences variations in flow profiles and shear stress magnitudes. Straight arterial sections with pulsatile shear stress have been shown to promote an athero-protective endothelial phenotype. Conversely, areas with a more complex geometry, such as arterial bifurcations and branch points with disturbed flow patterns and a lower, oscillatory shear stress, typically lead to endothelial dysfunction and the pathogenesis of cardiovascular diseases. Many studies have investigated the regulation of endothelial responses to various shear stress environments. Importantly, the accurate in vitro simulation of in vivo hemodynamics is critical to the deeper understanding of mechano-transduction through the proper use and design of flow chamber devices. In this review, we describe several flow chamber apparatuses and their fluid mechanics design parameters, including parallel plate flow chambers, cone-and plate devices, and microfluidic devices. In addition, chamber-specific design criteria and relevant equations are defined in detail for the accurate simulation of shear stress environments to study endothelial cell responses.

DOI: https://doi.org/10.1115/1.4051765

Adv Mater. 2021 Jul 15. e2008161

Mechanosensation Mediates Long-Range Spatial Decision-Making in an Aneural Organism.

Nirosha J Murugan, Daniel H Kaltman, Paul H Jin, Melanie Chien, Ramses Martinez, Cuong Q Nguyen, Anna Kane, Richard Novak, Donald E Ingber, Michael Levin.

The unicellular protist Physarum polycephalum is an important emerging model for understanding how aneural organisms process information toward adaptive behavior. Here, it is revealed that Physarum can use mechanosensation to reliably make decisions about distant objects in its environment, preferentially growing in the direction of heavier, substrate-deforming, but chemically inert masses. This long-range sensing is abolished by gentle rhythmic mechanical disruption, changing substrate stiffness, or the addition of an inhibitor of mechanosensitive transient receptor potential channels. Additionally, it is demonstrated that Physarum does not respond to the absolute magnitude of strain. Computational modeling reveales that Physarum may perform this calculation by sensing the fraction of its perimeter that is distorted above a threshold substrate strain-a fundamentally novel method of mechanosensation. Using its body as both a distributed sensor array and computational substrate, this aneural organism leverages its unique morphology to make long-range decisions. Together, these data identify a surprising behavioral preference relying on biomechanical features and quantitatively characterize how the Physarum exploits physics to adaptively regulate its growth and shape.

Keywords: Physarum polycephalum; TRP channel; basal cognition; decision-making; information processing; mechanosensing; stiffness

DOI: https://doi.org/10.1002/adma.202008161