The Influence of Silver Nanoparticles on the Blood-Brain and the Blood-Cerebrospinal Fluid Barrier in vitro

Cramer, Sandra; Tacke, Sebastian; Bornhorst, Julia; Klingauf, Jürgen; Schwerdtle, Tanja; Galla, Hans‐Joachim

doi:10.4172/2157-7439.1000225

Cited by 20 publications

(14 citation statements)

References 50 publications

(71 reference statements)

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“…The overall low and size‐dependent permeability to FITC‐dextrans further confirmed the barrier integrity of the BBB constructs in our model. Remarkably, we achieved extremely low permeabilities to FITC‐dextrans that were comparable to previously reported in vivo values (Shi et al, ; Yuan et al, ) and the in vitro data from transwell models with high TEER values (Cramer, ; Matthes et al, ). Our results were around two to three orders of magnitude lower than those reported from existing microfluidic BBB models (Booth and Kim, ).…”

Section: Resultssupporting

confidence: 89%

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Wang

Abaci

Shuler

2016

Biotech & Bioengineering

447

405

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Efficient delivery of therapeutics across the neuroprotective blood-brain barrier (BBB) remains a formidable challenge for central nervous system drug development. Highfidelity in vitro models of the BBB could facilitate effective early screening of drug candidates targeting the brain. In this study, we developed a microfluidic BBB model that is capable of mimicking in vivo BBB characteristics for a prolonged period and allows for reliable in vitro drug permeability studies under recirculating perfusion. We derived brain microvascular endothelial cells (BMECs) from human induced pluripotent stem cells (hiPSCs) and cocultured them with rat primary astrocytes on the two sides of a porous membrane on a pumpless microfluidic platform for up to 10 days. The microfluidic system was designed based on the blood residence time in human brain tissues, allowing for medium recirculation at physiologically relevant perfusion rates with no pumps or external tubing, meanwhile minimizing wall shear stress to test whether shear stress is required for in vivo-like barrier properties in a microfluidic BBB model. This BBB-on-a-chip model achieved significant barrier integrity as evident by continuous tight junction formation and in vivo-like values of trans-endothelial electrical resistance (TEER). The TEER levels peaked above 4000 V Á cm 2 on day 3 on chip and were sustained above 2000 V Á cm 2 up to 10 days, which are the highest sustained TEER values reported in a microfluidic model. We evaluated the capacity of our microfluidic BBB model to be used for drug permeability studies using large molecules (FITC-dextrans) and model drugs (caffeine, cimetidine, and doxorubicin). Our analyses demonstrated that the permeability coefficients measured using our model were comparable to in vivo values. Our BBB-on-a-chip model closely mimics physiological BBB barrier functions and will be a valuable tool for screening of drug candidates. The residence time-based design of a microfluidic platform will enable integration with other organ modules to simulate multi-organ interactions on drug response.

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Section: Resultssupporting

confidence: 89%

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Wang

Abaci

Shuler

2016

Biotech & Bioengineering

447

405

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“…An earlier study by Trickler et al reported that AgNPs increased the BBB permeability in primary rat brain endothelial cells, and induced a size-dependent pro-inflammatory response by secreting PGE2, TNF-α and Il-1β [58]. Cramer et al studied the effect of AgNPs’ surface coatings (citrate and ethylene oxide (EO) on neurotoxicity of primary porcine brain capillary endothelial cells (PBCECs) [219]. Neutral red uptake assay revealed that cell viability decreased markedly from 100% to 58% and 71%, respectively, upon exposure to EO-AgNPs and CT-AgNPs at 50 μg/mL.…”

Section: In Vitro Cell Cultivationmentioning

confidence: 99%

“…From in vitro cell cultivation, AgNPs increased the permeability of tight junctions of brain endothelial cells [219]. The ICP-MS measurements of in vivo animal model showed the presence of a small amount of AgNPs in the mice brain [229,232,234].…”

Section: In Vivo Animal Modelmentioning

confidence: 99%

Bactericidal and Cytotoxic Properties of Silver Nanoparticles

Liao

Tjong

2019

IJMS

747

436

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Silver nanoparticles (AgNPs) can be synthesized from a variety of techniques including physical, chemical and biological routes. They have been widely used as nanomaterials for manufacturing cosmetic and healthcare products, antimicrobial textiles, wound dressings, antitumor drug carriers, etc. due to their excellent antimicrobial properties. Accordingly, AgNPs have gained access into our daily life, and the inevitable human exposure to these nanoparticles has raised concerns about their potential hazards to the environment, health, and safety in recent years. From in vitro cell cultivation tests, AgNPs have been reported to be toxic to several human cell lines including human bronchial epithelial cells, human umbilical vein endothelial cells, red blood cells, human peripheral blood mononuclear cells, immortal human keratinocytes, liver cells, etc. AgNPs induce a dose-, size- and time-dependent cytotoxicity, particularly for those with sizes ≤10 nm. Furthermore, AgNPs can cross the brain blood barrier of mice through the circulation system on the basis of in vivo animal tests. AgNPs tend to accumulate in mice organs such as liver, spleen, kidney and brain following intravenous, intraperitoneal, and intratracheal routes of administration. In this respect, AgNPs are considered a double-edged sword that can eliminate microorganisms but induce cytotoxicity in mammalian cells. This article provides a state-of-the-art review on the synthesis of AgNPs, and their applications in antimicrobial textile fabrics, food packaging films, and wound dressings. Particular attention is paid to the bactericidal activity and cytotoxic effect in mammalian cells.

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“…24 Several studies have demonstrated that Ag-NPs can enter the CNS 25 and induce brain edema and neurotoxicity. 10,11,[26][27][28][29] Our previous studies showed that Ag-NPS and/or released Ag ions crossed the BBB and subsequently caused damage to astrocytes and neurons. 23 Cadherin and claudin expression were slightly changed in the Ag-NPS-exposure group, and astrocyte swelling was the most significant change after a 2-week gastrointestinal exposure to 1 mg/kg or 10 mg/kg of Ag-NPS in rats.…”

Section: Discussionmentioning

confidence: 99%

Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood–brain barrier primary triple coculture model

Shao

et al. 2015

IJN

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Background Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood–brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood. Method To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray. Results A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm 2 . After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1 . Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes. Conclusion These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes.

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The Influence of Silver Nanoparticles on the Blood-Brain and the Blood-Cerebrospinal Fluid Barrier in vitro

Cited by 20 publications

References 50 publications

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Bactericidal and Cytotoxic Properties of Silver Nanoparticles

Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood–brain barrier primary triple coculture model

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The Influence of Silver Nanoparticles on the Blood-Brain and the Blood-Cerebrospinal Fluid Barrier in vitro

Cited by 20 publications

References 50 publications

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Bactericidal and Cytotoxic Properties of Silver Nanoparticles

Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood&ndash;brain barrier primary triple coculture model

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Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood–brain barrier primary triple coculture model