European Observatory for Nanomaterials

The blood-brain barrier (BBB) is literally the brain’s gatekeeper. It is a biological boundary that protects the brain from being exposed to things it shouldn’t. Sitting between the blood stream and the brain, the BBB serves the twin role of providing the brain with the things it needs, nutrients and oxygen, whilst also forming a barrier to things it doesn’t, such as pathogens and toxins. The BBB has evolved to “recognise” all forms of chemicals and particles, including nanoparticles (particles in the size range between 1 and 100nm), since these have been present on Earth before the emergence of life. 

However, the technological developments of recent years have produced a different kind of nanoparticles, those intentionally made by us for specific applications, and whilst these particles may look like their natural counterparts to the BBB, they may act differently, thus exposing the brain to unanticipated activity. This could be both good and bad. On the positive side, medical interventions in the brain, for example to treat neurodegenerative disease, can be made possible if the nanoparticles and their medical cargo can cross the BBB. However, an undesirable effect is that nanoparticulate pollution can also find its way into our brain. Indeed, there is evidence that nanoparticles made of iron oxide and linked to urban pollution have been found in human brains1. But why and how? Recent work in my lab, published in PNAS (2), has used state of the art methods to understand better when the BBB may allow nanoparticles reach our brains.  

Firstly, we need to have an idea of what the BBB is made of. We can consider it to be similar to any other biological membrane; these are versatile structures that act as biological linings or barriers, and they can be leaky or tight. The BBB is of the latter kind. When nanoparticles we inhale, ingest, or come to contact through our skin work their way to our blood stream, they acquire the potential to reach and then cross the BBB. To understand how this might happen, we set out to systematically explore how different nanoparticle properties, such as composition, size, shape and propensity to dissolve, play a role in their potential to be transported across such a tight barrier. To be able to test our hypotheses, we first had to develop an artificial BBB that would behave like the real thing. This model BBB was constructed inside a special permeable well, on which human cells representative of the BBB were cultured and tested to ensure their function precisely replicated that of the real barrier. 

We then began investigating what factors affect the ability of a number of model nanoparticles, specifically cerium oxide, iron oxide, zinc oxide and silver in different particle sizes and shapes, to cross the model BBB.  Working in such a complex system and looking to assess the behaviour of such tiny particles is not much different from the proverbial needles in a haystack. For that reason, a number of advanced analytical techniques had to be used both in our lab in Birmingham, but also at the UK Synchrotron facility in Diamond. In the lab, we used Inductively Coupled Plasma Mass Spectrometry in single particle mode, a technique that allows simultaneous measurement of dissolved and particulate concentration of an element in media, thus enabling us to monitor nanoparticle dissolution, a key parameter controlling whether the nanoparticles cross the BBB as dissolved ions or in their pristine particulate form. In Diamond, we used X-ray Absorption Fine Structure methods to decipher the nanomaterials’ chemical environment within the actual cells, thus capturing their transport as it happens in extraordinary detail. We also collected complementary Scanning Transmission X-ray Microscopy data, a micro-mapping technique showing the spatial distribution and chemical state of the nanoparticles. These techniques, combined, helped us decipher which nanoparticles crossed the BBB, in what form and where they ended up.

With the help of these advanced techniques, we discovered that silver and zinc oxide nanoparticles, which are often used in consumer goods, including healthcare products, have the potential to cross the BBB and enter the brain in the form of both particles and dissolved ions, depending on the size, shape and exposure concentration. They can also affect cellular function and integrity of the BBB. Each nanoparticle tested showed a range of behaviours, influenced by their properties and quantities but in general, smaller particles cross the BBB more easily, but their shape was also found to be important. For example, wire-shaped particles were less successful in crossing the BBB, compared with their spherical counterparts. 

This study has revealed how nanoparticles may gain access to the brain and how they might bypass the brain’s guardian BBB. The knowledge acquired can help make the use of nanoparticles safer, by ensuring, for example, that properties that facilitate crossing of the BBB are designed out of products that could come to direct contact with our bodies. In contrast, if nanoparticles are used as vehicles for drug delivery, for example in order to fight diseases such as Parkinson’s and Alzheimer’s, then we should design in the properties that give them easy passage through the BBB.
 

A schematic of the blood-brain barrier. The red tube on the left represents a blood vessel with a  couple of red blood cells inside. The blue dots represent nanoparticles. The beige mass on the right is the brain, with the brown part at the bottom representing a part of the brain called cerebellum. The figure is an artist’s impression and various components are not to scale and do not comprehensively represent all parts of the BBB.

Artwork credit: Chantal Jackson, School of Geography, Earth & Environmental Sciences, University of Birmingham

• References: 

1. Maher B et al. Magnetite pollution nanoparticles in the human brain. Proceedings of the National Academy of Sciences 113.39 (2016): 10797-10801. DOI: 10.1073/pnas.1605941113.

2. Guo Z et al. Biotransformation modulates the penetration of metallic nanomaterials across an artificial blood-brain barrier model. Proceedings of the National Academy of Sciences 118.28 (2021). DOI: 10.1073/pnas.2105245118.
 

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