Overview

Project Highlights:

  • novel brain-on-a-chip array
  • testing nanoparticle link to Alzheimer’s
  • work within national facility FENAC

Engineered and incidental nanoparticles (NPs) are increasingly discovered in the environment, leading to concerns that they may be harmful to humans and biota. A key issues, regarding human health, is whether EINPs can enter the brain through the olfactory nerve. A recent study identified abundant nanoscale magnetite, resembling that formed by combustion, in human brains from polluted environments. Nanoscale magnetite has been linked to toxicity, via the production of reactive oxygen species (ROS), which has been associated with neurodegenerative diseases such as Alzheimer’s. This link to date is hypothetical, and challenging to demonstrate. The development of a model brain, may therefore allow further investigation of the processes occurring in the brain environment, associated with the presence of NPs and potentially leading to neurodegenerative diseases.

Developing of on-a-chip brain, based on microfluidic devices, may provide a solution to this challenge, by mimicking aspects of the brain, e.g. internal structure, cellular composition and fluid chemistry and enabling testing of interactions with NPs. Such microfluidic devices have the additional advantage of enabling automated, miniaturised, multichannel experimentation, thus enabling multiple spatially and temporally separated measurements, with a minimum consumption of materials and reagents. Increasingly such devises can have complex designs, integrating operations, such as cellular structure and composition, fluid chemistry and the effect of different array designs and materials, in reproducing biological functions.

The proposed project aims to innovate by assessing interactions between a variety of engineered and incidental NPs and a simulated brain environment, thus assessing the potential of in situ ROS generation and its effects on the brain cellular structure and cerebrospinal fluid composition and potential changes in protein properties.

A microfluidic array can be designed to model the interaction of nanoparticles with a model brain.

Methodology

For the development of a brain-on-a-chip, a microfluidic platform design developed around the key components of structure (cellular and chemical), composition and interactions with NPs. This first step will involve the design and fabrication of the chip, followed by optimisation of the fabrication parameters in order to improve performance and ensure reliable operation. This will be followed by experimental characterisation of alternative designs and finalising a prototype.

The optimum design will then be tested with a range of NP types, sizes and compositions. Multiple parameters will be studies, e.g. effects on the physicochemical properties of the NPs, chemical and structural compositions of the simulated brain components. Measurements will be carried out in a variety of set-ups to ensure method reproducibility and samples will be characterised by analytical techniques for the assessment of organic (e.g proteins) and inorganic (.e.g NP component) composition. A sub-set of assays will be studied in depth, including a full characterisation of individual components of spent chips to ensure a thorough system understanding.

Training and Skills

CENTA students are required to complete 45 days training throughout their PhD including a 10 day placement. In the first year, students will be trained as a single cohort on environmental science, research methods and core skills. Throughout the PhD, training will progress from core skills sets to master classes specific to the student's projects and themes. 

The student will gain unique access and skills in chip fabrication, as well as in analytical methods and NM reactivity assessment, followed by learning to develop on-a-chip arrays.  The project further involves the use of sophisticated microscopic and spectroscopic techniques. The student will attain analytical skills and expertise working with gel electrophoresis, GC-MS, UV-Vis, DLS, NTA, TEM, AFM. spICP-MS and their data interpretation. The project as a whole provides large support group for training and the successful applicant will work alongside a set of chemists, environmental, biological and materials scientists with a range of expertise in their area. Full training will be provided by the supervisory team.

Timeline

Year 1: Induction, literature search and laboratory based training on analytical methods and chip development.

Year 2: Development of brain cell lines and brain fluid proxies. On-a-chip array development to simulate the brain environment.

Year 3: Testing of nanoparticle brain-on-a-chip interactions. Array optimisation. Data analysis, attendance and presentation in conferences, publications and thesis preparation.

Partners and collaboration (including CASE)

The project will be supervised by the host team at the University of Birmingham, with the active participation of project partner Biolin. The supervisors have an established collaboration within EU funded project ACEnano and, although the student will be based at Birmingham, they will have the opportunity to be hosted by Biolin in Sweden.

Further Details

For further project details, please contact Professor Eva Valsami-Jones (e.valsamijones@bham.ac.uk).