Pulmonary-arterial-hypertension (PAH)-on-a-chip: fabrication, validation and application

Al-Hilal, Taslim A.; Keshavarz, Ali; Kadry, Hossam; Lahooti, Behnaz; Alobaida, Ahmed; Ding, Zhongren; Li, Wěi; Kamm, Roger D.; McMurtry, Ivan F.; Lahm, Tim; Nozik‐Grayck, Eva; Stenmark, Kurt R.; Ahsan, Fakhrul

doi:10.1039/d0lc00605j

Cited by 26 publications

(42 citation statements)

References 41 publications

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“…Economic use of cells, short experimental time, device scalability, low production and operation cost make it an attractive model for drug testing and a viable alternative to animal experimentation. The only other existing PAH-on-a-chip model 71 included intimal, medial and adventitial cells from PAH pulmonary arteries grown on polylysine-coated glass in straight channels arranged side-by-side, with cell-to-cell contact restricted to the gaps between silicone posts situated between the channels. This model can provide valuable information regarding paracrine regulation of cell migration (de ned as remodelling sic) but cannot evaluate endothelial barrier function and is limited by poor accessibility of patient lung material, which precludes its wider application in research and drug testing.…”

Section: Discussionmentioning

confidence: 99%

A Microfluidic Chip for Pulmonary Arterial Hypertension

Wójciak-Stothard

Ainscough

Smith

et al. 2021

Preprint

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Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of a disease model representative of the human condition is a key obstacle to the development of new treatments. Here we present a model of PAH, based on a biomimetic pulmonary artery (PA)-on-a-chip, that permits the study of the molecular and functional changes in human pulmonary vascular endothelial and smooth muscle cells in response to triggers of the disease and their response to drugs. We combine natural or induced BMPR2 dysfunction with hypoxia in vascular endothelial cells to trigger smooth muscle activation and proliferation and relate accompanying transcriptomic changes in affected cells to functional effects. Changes in gene expression consistent with observations made in genomic and biochemical studies of the human disease enable insights into underlying disease pathways and mechanisms of drug response. The model offers a novel, promising and more easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH.

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Section: Discussionmentioning

confidence: 99%

A Microfluidic Chip for Pulmonary Arterial Hypertension

Wójciak-Stothard

Ainscough

Smith

et al. 2021

Preprint

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“…Microchip systems with micron-sized channels that permit cells to grow and interact with each other in a three-dimensional structure imitating the biological environment of tissues in the body have been used to bridge the gap between in vivo and in vitro systems [ 62 ]. In a recent publication, Al-Hilal et al from the Ahsan group used a microfluidic chip model simulating a PAH-insulted artery to study the sex discrepancy in PAH pathophysiology [ 63 ]. Chips composed of cells from male patients demonstrated decreased intimal (endothelial cells) but greater medial (smooth muscle cells) thickening compared to chips composed of cells from female patients [ 63 ].…”

Section: Sex Disparity In Pah and Microfluidic Chip Model Mimicking Pah-insulted Artery To Study Sex Discrepancy In Pah Pathophysiologymentioning

confidence: 99%

“…In a recent publication, Al-Hilal et al from the Ahsan group used a microfluidic chip model simulating a PAH-insulted artery to study the sex discrepancy in PAH pathophysiology [ 63 ]. Chips composed of cells from male patients demonstrated decreased intimal (endothelial cells) but greater medial (smooth muscle cells) thickening compared to chips composed of cells from female patients [ 63 ]. It is implicated that male patients develop a more severe disease compared to female patients illustrated by chips with male cells, exhibiting a higher number of PASMCs with a FSP-1 + CD31 − signature in the intimal and luminal layers [ 63 ].…”

Section: Sex Disparity In Pah and Microfluidic Chip Model Mimicking Pah-insulted Artery To Study Sex Discrepancy In Pah Pathophysiologymentioning

confidence: 99%

Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension

Hossen

Nguyen

et al. 2022

Biomedicines

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Pulmonary arterial hypertension (PAH) is a disease that progress over time and is defined as an increase in pulmonary arterial pressure and pulmonary vascular resistance that frequently leads to right-ventricular (RV) failure and death. Epigenetic modifications comprising DNA methylation, histone remodeling, and noncoding RNAs (ncRNAs) have been established to govern chromatin structure and transcriptional responses in various cell types during disease development. However, dysregulation of these epigenetic mechanisms has not yet been explored in detail in the pathology of pulmonary arterial hypertension and its progression with vascular remodeling and right-heart failure (RHF). Targeting epigenetic regulators including histone methylation, acetylation, or miRNAs offers many possible candidates for drug discovery and will no doubt be a tempting area to explore for PAH therapies. This review focuses on studies in epigenetic mechanisms including the writers, the readers, and the erasers of epigenetic marks and targeting epigenetic regulators or modifiers for treatment of PAH and its complications described as RHF. Data analyses from experimental cell models and animal induced PAH models have demonstrated that significant changes in the expression levels of multiple epigenetics modifiers such as HDMs, HDACs, sirtuins (Sirt1 and Sirt3), and BRD4 correlate strongly with proliferation, apoptosis, inflammation, and fibrosis linked to the pathological vascular remodeling during PAH development. The reversible characteristics of protein methylation and acetylation can be applied for exploring small-molecule modulators such as valproic acid (HDAC inhibitor) or resveratrol (Sirt1 activator) in different preclinical models for treatment of diseases including PAH and RHF. This review also presents to the readers the application of microfluidic devices to study sex differences in PAH pathophysiology, as well as for epigenetic analysis.

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“…Similar concepts have been applied to other organ systems. Al-Hilal et al (2020) reported a pulmonary-arterialhypertension (PAH) model on a chip to elicit arterial remodeling under PAH. The authors fabricated a microfluidic device to emulate the luminal, intimal, medial, adventitial, and perivascular layers of a pulmonary artery.…”

Section: Disease Modelingmentioning

confidence: 99%

Rebuilding the Vascular Network: In vivo and in vitro Approaches

Meng

Xing

et al. 2021

Front. Cell Dev. Biol.

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As the material transportation system of the human body, the vascular network carries the transportation of materials and nutrients. Currently, the construction of functional microvascular networks is an urgent requirement for the development of regenerative medicine and in vitro drug screening systems. How to construct organs with functional blood vessels is the focus and challenge of tissue engineering research. Here in this review article, we first introduced the basic characteristics of blood vessels in the body and the mechanism of angiogenesis in vivo, summarized the current methods of constructing tissue blood vessels in vitro and in vivo, and focused on comparing the functions, applications and advantages of constructing different types of vascular chips to generate blood vessels. Finally, the challenges and opportunities faced by the development of this field were discussed.

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Pulmonary-arterial-hypertension (PAH)-on-a-chip: fabrication, validation and application

Abstract: Currently used animal and cellular models for pulmonary arterial hypertension (PAH) only partially recapitulate its pathophysiology in humans and are thus inadequate in reproducing the hallmarks of the disease, inconsistent...

Cited by 26 publications

References 41 publications

A Microfluidic Chip for Pulmonary Arterial Hypertension

A Microfluidic Chip for Pulmonary Arterial Hypertension

Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension

Rebuilding the Vascular Network: In vivo and in vitro Approaches

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