Developing the metrological basis to use extracellular vesicles as biomarkers

Microscope with lab glassware, science laboratory research and development concept
Microscope with lab glassware, science laboratory research and development concept

An EMPIR project played a pivotal role in developing standards to facilitate using extracellular vesicles as biomarkers for medical diagnosis

Extracellular vesicles as biomarkers

Finding new biomarkers is of great interest within the scientific community. Suitable biomarkers allow for early detection of disease and simplify screening methods, making it possible to screen larger parts of the population. Extracellular vesicles are potential disease biomarkers, however there was a lack of reference materials and calibration infrastructure to ensure traceable and comparable measurements.

Detection of biomarkers in biological samples is often performed with high throughput flow cytometry as the required machines are already present in most clinical laboratories.



METVES II project outcomes  

Two collaborative research projects within EURAMET’s European Metrology Research Programmes (EMRP and EMPIR) helped tackling this challenge. The EMRP project Metrological characterisation of micro-vesicles from body fluids as non-invasive diagnostic biomarkers (HLT02, METVES) started to develop the metrological basis needed to use extracellularvesicles as biomarkers, and the EMPIR project Standardisation of concentration measurements of extracellular vesicles for medical diagnoses (18HLT01, METVES II) continued the work. The project also cooperated with two companies, Exometry B.V. and Becton Dickinson, to help commercialise their new findings.

The project outcomes include:

  • Development of three different reference materials that form the metrological basis to allow traceable measurements of different properties of flow cytometers.
  • Hollow silica particles for traceable size
  • Liposomes for traceable measurements of fluorescence
  • Solid particles with a low refractive index to mimic the refractive index of extracellular vesicles
  • Development of a plasma-derived biological test sample containing extracellular vesicles that mimic the biological complexity of ‘real’ samples. Similar samples have also been derived from urine. These biological test samples can be used to validate reference materials and procedures in inter-laboratory comparisons and as quality control samples.
  • Production of a precision goniometer that helps to determine the lower and upper diameter range of extracellular vesicles in the scattering plot. This ensures accurate calibration of flow cytometry machines and a low expanded uncertainty of 1.4E-6.
  • Establishment of a metrological flow cytometer that has back scatter and a uniquely slow flow rate in the range of nl/min. The slower flow rate allows for a more detailed analysis of the extracellular vesicles properties. The development of the metrological fluorescence-activated cell sorting measurements machine was funded by VSL and AMC.
  • Application for a patent by BD for producing liposome reference material with the plan to commercialise this product in the future.
  • Development of a software to aid the analysis of fluorescence-activated cell sorting measurements. (Exometry)
  • Commercialisation of a new reference product consisting of beads that can be used as a reference material for extracellular vesicles in fluorescence-activated cell sorting measurements. (Exometry)
  • Organisation of a global interlaboratory comparison in which 24 labs from 12 different countries participated. The outcome from this comparison will be analysed soon and will help to reduce measurement variation.
  • Provide input for the content of the new standards ISO 19430 and ISO/TS 19590.
  • Successful dissemination of the project outcomes to the scientific community with 41 conference presentations and posters. Additionally, 13 peer reviewed publications were shared in open-access journals.

The project coordinator Rienk Nieuwland (VSL, AMC) comments on the extraordinary success of the project:

The collaboration between metrology institutes, industry and hospitals has been indispensable to develop a firm infrastructure to standardise measurements of extracellular vesicles in biofluids. As a next step, this infrastructure will be explored to investigate the clinical relevance of extracellular vesicles in health and disease.’

Further information about the project can be obtained on the project webpage.

This EMPIR project is co-funded by the European Union's Horizon 2020 research and innovation programme and the EMPIR Participating States.


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