Influence of Substrate Stiffness on Barrier Function in an iPSC-Derived In Vitro Blood-Brain Barrier Model

Bosworth, Allison M.; Kim, Hyosung; O’Grady, Kristin P.; Richter, Isabella; Lee, Lynn; O’Grady, Brian J.; Lippmann, Ethan S.

doi:10.1007/s12195-021-00706-8

Cited by 11 publications

(9 citation statements)

References 40 publications

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“…3C), showing increasing TEER as the cells are cultured for longer. These results are in contrast to other BBB models using iPSC-derived BMEC where TEER values over 1000 Ω.cm 2 are typically reported, but they tend to peak at about day 1 or 2 before gradually decreasing 7,31,53,56,57 . A possible reason for this difference is the substrate on which the cells are seeded.…”

Section: Resultscontrasting

confidence: 99%

Modular Tissue-in-a-CUBE Platform to Model Blood-brain-Barrier (BBB) and Brain Interaction

Koh

Hagiwara

2023

Preprint

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With the advent of increasingly sophisticated organoids, there is growing demand for technology to replicate the interactions between multiple tissues or organs. This is challenging to achieve, however, due to the varying culture conditions of the different cell types that make up each tissue. Current methods often require complicated microfluidic setups, but fragile tissue samples tend not to fare well with rough handling. Furthermore, the more complicated the human system to be replicated, the more difficult the model becomes to operate. Here, we present the development of a multi-tissue chip platform that takes advantage of the modularity and convenient handling ability of the CUBE device. We first developed a blood-brain barrier (BBB)-in-a-CUBE by layering astrocytes, pericytes, and brain microvascular endothelial cells in the CUBE, and confirmed the expression and function of important tight junction and transporter proteins in the BBB model. Then, we demonstrated the application of integrating Tissue-in-a-CUBE with a chip in simulating the testing of the permeability of a drug through the blood-brain barrier (BBB) to the brain and its effect on treating brain cancer. We anticipate that this platform can be adapted for use with organoids to build complex human systems in vitro by the combination of multiple simple CUBE units.

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Section: Resultscontrasting

confidence: 99%

Modular Tissue-in-a-CUBE Platform to Model Blood-brain-Barrier (BBB) and Brain Interaction

Koh

Hagiwara

2023

Preprint

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“…Similarly, non-porous membranes deflected by gas pressure have been employed to compress or stretch cells in cartilage 32 , heart 33 , and bone-on-chip 34 models. It is known that cells react to environmental cues, thus all the physical properties of the membrane such as roughness [35][36][37][38][39][40] , surface microstructure [41][42][43][44][45][46][47] , mechanical strength [48][49][50][51][52][53][54][55][56][57][58] , hydrophilicity 35,36,52,[59][60][61][62] , and porosity 55,[63][64][65] have a significant effect on cellular adhesion and membrane biocompatibility. Despite their importance, these aspects are often neglected in OOC in which membranes are typically obtained from commercial Transwell inserts [66][67][68][69][70][71][72][73][74]…”

Section: Membrane-based Organs-on-chipmentioning

confidence: 99%

“…Many orders of magnitude separate the softest tissue -the brain, with an elastic modulus of tenths of kPa-to the hardest -calcified bones with a modulus of the hundreds of MPa -and each specific cell type is tuned to the mechanical environment in which it resides. In particular, the stiffness of the cell microenvironment has a crucial role in many physiological and pathological processes of blood vessels 54,56,[91][92][93] as well as in the differentiation fate of stem cells 48,50,57,58 . Bosworth et al 54 demonstrated that substrate stiffness influences the barrier function of the Blood-Brain barrier model.…”

Section: Mechanical Stiffnessmentioning

confidence: 99%

Membrane-based microfluidic systems for medical and biological applications

Calzuola,

Newman,

Feaugas

et al. 2024

Preprint

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Microfluidic devices with integrated membranes that enable control of mass transport in constrained environments have shown considerable growth over the last decade. Membranes are a key component in several industrial processes such as chemical, pharmaceutical, biotechnological, food, and metallurgy separation processes as well as waste management applications, allowing for modular and compact systems. Moreover, the miniaturization of a process through microfluidic devices leads to process intensification together with reagents, waste and cost reduction, and energy and space savings. The combination of membrane technology and microfluidic devices allows therefore magnification of their respective advantages, providing more valuable solutions not only for industrial processes but also for reproducing biological processes. This review focuses on membrane-based microfluidic devices for biomedical science with an emphasis on microfluidic artificial organs and organs-on-chip. We provide the basic concepts of membrane technology and the laws governing mass transport. The role of the membrane in biomedical microfluidic devices, along with the required properties, available materials, and current challenges are summarized. We believe that the present review may be a starting point and a resource for researchers who aim to replicate a biological phenomenon on-chip by applying membrane technology, for moving forward the biomedical applications.

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“…Studies on brain endothelial cells are mostly focused on the BBB permeability, drug delivery, and the development of in vitro BBB models [160]. Shear stress in the brain increases the expression of tight junction proteins as well as their tightness [118,161], but only a few have characterized the impact that stiffness may have in such models [162]. There is likely little success in them forming monolayers on soft matrices, as evidenced by the improvement in monolayer coverage after stiffening collagen I gels with genipin crosslinkage [135].…”

Section: Organ-specific Responses To Tissue Stiffness Shear Stress An...mentioning

confidence: 99%

Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity

Gifre-Renom

Daems

Luttun

et al. 2022

IJMS

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Endothelial cells throughout the body are heterogeneous, and this is tightly linked to the specific functions of organs and tissues. Heterogeneity is already determined from development onwards and ranges from arterial/venous specification to microvascular fate determination in organ-specific differentiation. Acknowledging the different phenotypes of endothelial cells and the implications of this diversity is key for the development of more specialized tissue engineering and vascular repair approaches. However, although novel technologies in transcriptomics and proteomics are facilitating the unraveling of vascular bed-specific endothelial cell signatures, still much research is based on the use of insufficiently specialized endothelial cells. Endothelial cells are not only heterogeneous, but their specialized phenotypes are also dynamic and adapt to changes in their microenvironment. During the last decades, strong collaborations between molecular biology, mechanobiology, and computational disciplines have led to a better understanding of how endothelial cells are modulated by their mechanical and biochemical contexts. Yet, because of the use of insufficiently specialized endothelial cells, there is still a huge lack of knowledge in how tissue-specific biomechanical factors determine organ-specific phenotypes. With this review, we want to put the focus on how organ-specific endothelial cell signatures are determined from development onwards and conditioned by their microenvironments during adulthood. We discuss the latest research performed on endothelial cells, pointing out the important implications of mimicking tissue-specific biomechanical cues in culture.

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Influence of Substrate Stiffness on Barrier Function in an iPSC-Derived In Vitro Blood-Brain Barrier Model

Cited by 11 publications

References 40 publications

Modular Tissue-in-a-CUBE Platform to Model Blood-brain-Barrier (BBB) and Brain Interaction

Modular Tissue-in-a-CUBE Platform to Model Blood-brain-Barrier (BBB) and Brain Interaction

Membrane-based microfluidic systems for medical and biological applications

Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity

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