Dynamic 3D On-Chip BBB Model Design, Development, and Applications in Neurological Diseases

Chen, Xingchi; Liu, Chang; Muok, Laureana; Zeng, Changchun; Li, Yan

doi:10.3390/cells10113183

Cited by 28 publications

(13 citation statements)

References 132 publications

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“…3-D microfluidics based BBB models have been reported in a few studies (Supplementary Figures S3-S5) (Linville et al, 2019;Vatine et al, 2019;Ahn et al, 2020;Chung et al, 2020;Chen X et al, 2021). These models can create a 3D tubular geometry (e.g., using collagen hydrogel) and introduce fluid flow in the tubular structure (e.g., using microfluidics), better mimicking the brain microvasculature.…”

Section: Discussionmentioning

confidence: 99%

“…Other methods include aggregates in hydrogels or in microfluidic channels (Gastfriend et al, 2018). The three-dimensional (3D) tissue-engineered models of BBB in different biomaterials and scaffolds are summarized in our recent review (Chen X et al, 2021) and reported by others (Faley et al, 2019;Grifno et al, 2019). The advantage of the transwell model is that it allows for the high TEER values of up to 5,000 ohms × cm 2 and the increased expression of tight junction proteins.…”

Section: Introductionmentioning

confidence: 99%

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Studying the Inflammatory Responses to Amyloid Beta Oligomers in Brain-Specific Pericyte and Endothelial Co-Culture From Human Stem Cells

et al. 2022

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Background: Recently, the in vitro blood–brain barrier (BBB) models derived from human pluripotent stem cells have been given extensive attention in therapeutics due to the implications they have with the health of the central nervous system. It is essential to create an accurate BBB model in vitro in order to better understand the properties of the BBB, and how it can respond to inflammatory stimulation and be passed by targeted or non-targeted cell therapeutics, more specifically extracellular vesicles.Methods: Brain-specific pericytes (iPCs) were differentiated from iPSK3 cells using dual SMAD signaling inhibitors and Wnt activation plus fibroblast growth factor 2 (FGF-2). The derived cells were characterized by immunostaining, flow cytometry, and RT-PCR. In parallel, blood vessels organoids were derived using Wnt activation, BMP4, FGF2, VEGF, and SB431542. The organoids were replated and treated with retinoic acid to enhance the blood–brain barrier (BBB) features in the differentiated brain endothelial cells (iECs). Co-culture was performed for iPCs and iECs in the transwell system and 3D microfluidics channels.Results: The derived iPCs expressed common markers PDGFRb and NG2, and brain-specific genes FOXF2, ABCC9, KCNJ8, and ZIC1. The derived iECs expressed common endothelial cell markers CD31, VE-cadherin, and BBB-associated genes BRCP, GLUT-1, PGP, ABCC1, OCLN, and SLC2A1. The co-culture of the two cell types responded to the stimulation of amyloid β42 oligomers by the upregulation of the expression of TNFa, IL6, NFKB, Casp3, SOD2, and TP53. The co-culture also showed the property of trans-endothelial electrical resistance. The proof of concept vascularization strategy was demonstrated in a 3D microfluidics-based device.Conclusion: The derived iPCs and iECs have brain-specific properties, and the co-culture of iPCs and iECs provides an in vitro BBB model that show inflammatory response. This study has significance in establishing micro-physiological systems for neurological disease modeling and drug screening.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Studying the Inflammatory Responses to Amyloid Beta Oligomers in Brain-Specific Pericyte and Endothelial Co-Culture From Human Stem Cells

et al. 2022

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“…In order to imitate the anatomical and physiological aspects of the BBB, an ideal in vitro BBB model should able to address some key attributes of in vivo BBBs which include: intercellular interactions, the vessel-like structural architecture of ECs resembling 3D vessels, flow dynamics provoked by shear stress on ECs, and the selective permeable basal membrane (BM) [ 91 ]. Further, the recapitulation of intact BBBs on microfluidic chips is influenced by many factors including different designs, the source of ECs, and the chip fabricating materials.…”

Section: Microfluidic-based Bbb Platformmentioning

confidence: 99%

Advances in Hydrogel-Based Microfluidic Blood–Brain-Barrier Models in Oncology Research

et al. 2022

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The intrinsic architecture and complexity of the brain restricts the capacity of therapeutic molecules to reach their potential targets, thereby limiting therapeutic possibilities concerning neurological ailments and brain malignancy. As conventional models fail to recapitulate the complexity of the brain, progress in the field of microfluidics has facilitated the development of advanced in vitro platforms that could imitate the in vivo microenvironments and pathological features of the blood–brain barrier (BBB). It is highly desirous that developed in vitro BBB-on-chip models serve as a platform to investigate cancer metastasis of the brain along with the possibility of efficiently screening chemotherapeutic agents against brain malignancies. In order to improve the proficiency of BBB-on-chip models, hydrogels have been widely explored due to their unique physical and chemical properties, which mimic the three-dimensional (3D) micro architecture of tissues. Hydrogel-based BBB-on-chip models serves as a stage which is conducive for cell growth and allows the exchange of gases and nutrients and the removal of metabolic wastes between cells and the cell/extra cellular matrix (ECM) interface. Here, we present recent advancements in BBB-on-chip models targeting brain malignancies and examine the utility of hydrogel-based BBB models that could further strengthen the future application of microfluidic devices in oncology research.

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“…The digital technology allows a reduced operating time and minimal errors, even for complex shapes [ 112 ]. Material choice is an essential factor for the final product quality, as the wide range of possibilities (from thermoplastic to biocompatible polymers and resins) provides the chance to individualize BBB-on-a-chip devices according to research needs [ 113 ]. In this context, different printing techniques are available.…”

Section: In Vitro Models Of the Human Blood–brain Barriermentioning

confidence: 99%

In Vitro Modeling of the Blood–Brain Barrier for the Study of Physiological Conditions and Alzheimer’s Disease

et al. 2022

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The blood–brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer’s disease. Thus, a deeper understanding of the BBB’s structure and function is mandatory for a better knowledge of neurodegenerative disorders and the development of effective therapies. Because studying the BBB in vivo imposes overwhelming difficulties, the in vitro approach remains the main possible way of research. With many in vitro BBB models having been developed over the last years, the main aim of this review is to systematically present the most relevant designs used in neurological research. In the first part of the article, the physiological and structural–functional parameters of the human BBB are detailed. Subsequently, available BBB models are presented in a comparative approach, highlighting their advantages and limitations. Finally, the new perspectives related to the study of Alzheimer’s disease with the help of novel devices that mimic the in vivo human BBB milieu gives the paper significant originality.

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Dynamic 3D On-Chip BBB Model Design, Development, and Applications in Neurological Diseases

Cited by 28 publications

References 132 publications

Studying the Inflammatory Responses to Amyloid Beta Oligomers in Brain-Specific Pericyte and Endothelial Co-Culture From Human Stem Cells

Studying the Inflammatory Responses to Amyloid Beta Oligomers in Brain-Specific Pericyte and Endothelial Co-Culture From Human Stem Cells

Advances in Hydrogel-Based Microfluidic Blood–Brain-Barrier Models in Oncology Research

In Vitro Modeling of the Blood–Brain Barrier for the Study of Physiological Conditions and Alzheimer’s Disease

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