Project summary


MagNaStand - Towards an ISO standard for magnetic nanoparticles

 

 

Overview

Magnetic nanoparticles (MNP) find wide biomedical and technical applications. However, there are currently no existing standards for characterising this material class available. This project will expand and summarise the metrological knowledge on the measurement and characterisation of MNP and bring it into the current development of Opens external link in new windowISO 19807-1 “Nanotechnologies -- Magnetic nanomaterials -- Part 1: Specification of characteristics and measurements for magnetic nanosuspensions” by ISO/TC229 WG4. This will involve a close collaboration with national and international standardisation organisations, interaction with the involved European industry, and the uptake of results of about 90 previous EU research projects including “Opens external link in new windowNanoMag” and “Opens external link in new windowRADIOMAG”. In addition to the finalisation of ISO 19807-1, a roadmap for further measurement standards for magnetic nanoparticles will be developed.

 

 

Need

Magnetic nanoparticles (MNPs) have many applications in biomedicine and other technical areas, e.g. as diagnostic tracers and therapeutic agents in cancer therapy; as carriers in cell separation from biological liquids; in magnetic seals, in the damping of audio speakers or in environmental remediation.

So far, international standards for the definition and measurement of the magnetic properties of MNPs do not exist. This reduces the trust of MNP consumers with regards to the safety, reliability and functionality of MNP products and it increasingly hampers the market chances of European MNP producers, mostly SMEs that cannot solve this problem with their own resources.

In 2015, the International Organization for Standardization (ISO) began the development of a material specification for MNPs (ISO 19807) and a New Work Item Proposal for a standard on “Superparamagnetic beads for DNA extraction” (PG14) is since 2016 in preparation. Since then, ISO has decided to create a series of standards on magnetic nanomaterials, with the beforementioned drafts to be the first members as ISO 19807-1 and ISO 19807-2. In these documents, new magnetic parameters need to be defined and existing standards need to be applied to MNPs or products based on MNPs. This project will define, implement and test the measurement of magnetic parameters of MNPs and related products.

To finalise the development of ISO 19807-1, parameters need to be formulated and measurement methods and techniques need to be developed along with the transmission of the pre-normative scientific knowledge into a suitable form for an industrial standard. This can only be achieved through an effective communication with European stakeholders in MNP applications to represent their interests in the international standard and with the means to communicate with ISO/TC229 WG4 in an appropriate way, i.e. participation in committee meetings, in interim web meetings, and in the preparation of draft standards and ballots.

The European Union has already funded more than 90 research projects concerned with MNPs since 2010. Some of them, like the FP7 project NanoMag or the TD COST Action RADIOMAG, were explicitly focused on pre-normative metrological research. The uptake of these results into the development of ISO 19807-1 is needed to greatly enhance the scientific quality of the new standard.

 

Objectives

The objective of the project is to collect the available knowledge on standardised measurement of MNPs, to create it where it is not readily available, to make this knowledge available for the standardisation of MNPs at ISO and to involve stakeholders from industry and academia in the design and application of standardised measurements and labelling of magnetic nanoparticles.

1.      To develop measurement methods and techniques to ensure highly qualified scientific input into the preparation of ISO 19807-1.

Specifically, this shall include:

·       collection and preparation of existing pre-normative knowledge on identification and definition of relevant physical parameters of MNPs such as i) saturation magnetisation, ii) crystallite size distribution iii) hydrodynamic size distribution and iv) magnetic interaction between MNPs;

·       definition and description of appropriate measurement methods for MNPs magnetic parameters; specifically, static and dynamic magnetisation measurements and specific loss power; and

·       coherent application of existing standards for X-ray diffraction techniques (for example SAXS) for determination of crystallite structure and application of transmission electron microscopy (TEM) and dynamic light scattering (DLS) for MNP size characterisation.

2.      To summarise metrological knowledge on MNPs gained in this project according to the “Metrological Checklist” ISO/TC 229 N 673, so that further normative documents covering measurement techniques for MNPs (e.g. static magnetic susceptibility, dynamic magnetic susceptibility and specific loss power) can be prepared.

3.      To ensure the take up of results from finalised and ongoing FP7 and Horizon 2020 EU research projects on MNPs e.g. “NanoMag” and “RADIOMAG” into the international standardisation process. This will include the definition of terms for magnetic quantities and the compartments of magnetic nanoparticles, actual versions of standard operating procedures (SOPs) for magnetic measurements (static and dynamic magnetisation, determination of specific loss power) and surveys of industrial requirements on standardisation of magnetic nanoparticles.

4.      To ensure coordinated participation of European NMIs and stakeholders in ISO’s standardisation process on MNPs to provide the highest impact and the fastest development of the standard. To facilitate the take up of methods and technology developed in the project by technical committees e.g. ISO/TC 229 and end-users e.g. biomedicine, mechanical engineering and environmental remediation sectors.

 

Progress beyond the state of the art

Defining measurement procedures for the long-term stability of magnetic nanoparticle suspensions and specific loss power in magnetic hyperthermia

The project works on the definition of long-term stability of MNPs and of specific loss power in magnetic hyperthermia in a metrologically sound and traceable way. The requirements of industrial stakeholders are collected on topics such as characterisation, sampling, storage and labelling of MNPs and MNP based products. The project therefore establishes a framework to measure, monitor and guarantee MNP product quality for industrial use.

Bringing European expertise in MNPs to standard developing organisations

This project brings for the first time together experts in application and metrology of magnetic nanoparticles with those from standardisation and industrial specifications. The project consortium participates actively in the technical committees ISO/TC229 WG4 and WG5 in the preparation of new standards and coordinates with the European committee CEN/TC352.

Bringing the results of the previous projects “NanoMag” and “RADIOMAG” to standard developing organisations

The EU-FP7 project NanoMag (2013-2017) aimed to define relevant physical parameters and measurement methods for MNPs. The EU TD 1402 COST Action RADIOMAG (2014-2018) is a scientific network aimed at the application and standardisation of magnetic hyperthermia in cancer treatment. This project for the first time summarises and validates these previous results from a standardisation point of view, ensuring the knowledge is transferred to ISO and CEN standardisation bodies and standardisation at a national level.

 

Making the results of other previous EU projects available for standardisation

In addition to the prominent projects NanoMag and RADIOMAG, the EU has already funded more than 90 projects related to MNPs (source: CORDIS database). This project has gone beyond the state of the art by reviewing the huge amount of knowledge gained in these projects from a metrological and standardisation point of view and re-use the results for international standardisation.

 

 

Results

Development of measurement methods for structural and magnetic parameters of MNPs

We have collected and summarized the pre-normative knowledge on identification and definition of relevant physical parameters of MNPs like saturation magnetization, crystallite size distribution, hydrodynamic size distribution and magnetic interaction between MNPs.

Within the project, documents on the standardised measurement of magnetic properties of MNPs have been prepared, specifically for saturation magnetisation, AC- and DC-susceptibility and specific loss power. A large number of different single- and multicore MNP preparations have been synthesized and analysed using different magnetic measurement methods. With the help of these standardised measurement protocols, we were able to establish a procedure for assessment of the long-term stability of MNP samples. The development of a procedure for the standardised description of interactions between magnetic crystallites and particles is underway. The application of existing standards in the measurement of physical properties of MNPs will be summarised in the next reporting period.

Preparation of “Metrological Checklists” for measurement of magnetic properties of MNPs

The “Metrological Checklist” is a tool of the ISO/TC229 “Nanotechnologies” committee to document the maturity of a new nanomaterial measurement method for international standardisation. In the project metrological checklists including full background documentation have been prepared for measurements of the magnetic parameters of MNPs, e.g. for static and dynamic magnetisation and for specific loss power in magnetic hyperthermia.

Uptake of previous results from FP7 and Horizon 2020 EU research projects on MNPs for ISO standardisation

A report on previous MNP research funded by the EU in FP7 and H2020 has been prepared highlighting important results for international standardisation. The report contains an overview of over 108 previous EU projects together with statistical analysis whose combined project budgets have been estimated to amount to roughly € 267million. The report also includes details of an online survey where representatives were asked about their opinion on standardised measurement of magnetic parameters of MNP, based on a detailed assessment of magnetic measurement methods that had been employed in their projects. Special sections of the report are dedicated to results of the FP7 project “NanoMag” and of the TD COST Action “RADIOMAG”, both dedicated to metrological aspects of MNP manufacturing, characterisation and application. Our report summarized the definition of terms for magnetic quantities and the compartments of magnetic nanoparticles, the standard operating procedures (SOPs) for magnetic measurements (static and dynamic magnetisation, determination of specific loss power) and surveys of industrial requirements on standardisation of magnetic nanoparticles that were developed during these recent large-scale EU projects. For further uptake of the vast existing expertise, the MagNaStand project has coordinated three common workshops with members of “NanoMag” and “RADIOMAG”. During these exchanges with European experts, exact definitions of physical quantities for MNP characterization were discussed, that entered directly into the newly developed ISO standards.

 

Impact

The work on the development of measurement methods for the definition of physical and magnetic parameters of MNPs has been presented in 3 open access peer reviewed publications and 3 conference proceedings, as well as presented at 9 international conferences and workshops such as International Conference on the Scientific and Clinical Applications of Magnetic Carriers and BioNanoMed 2018.

In July 2017, the project held the first industrial stakeholder workshop in Berlin with the aim to inform about the consequences of standardisation of magnetic nanomaterials and to invite external stakeholders to share their interests with project representatives who are able to bring these views into the standardisation process. A second stakeholder workshop was held in November 2018, we had a good opportunity to discuss the details and implications of the new ISO standards with industrial representatives from several industrial user groups.

The project has reached a wider audience with interest in nanotechnology by placing 2 articles on MNP standardization in the Bionanonet newsletter.

Impact on industrial and other user communities

This project summarises European expertise and the interests of European stakeholders in contributing to the finalisation of Opens external link in new windowISO 19807-1 “Magnetic nanomaterials -- Part 1: Specification of characteristics and measurements for magnetic nanosuspensions” and Opens external link in new windowISO 19807-2 “Magnetic nanomaterials -- Part 2: superparamagnetic beads for DNA extraction”. Within this project, reports are prepared on the physical description of the main characteristics of MNPs, standard operating procedures for the preparation and measurement of samples, metrological aspects of the measurements (e.g. uncertainty budgets for specific methods), and a survey of the specific needs of European industry and other stakeholders. There are several industrial areas where the new ISO standards on MNPs will create impact:

·         Manufacturers of MNPs

Working according to an ISO standard for MNPs, the manufacturer can monitor MNP quality and market their products according to the definitions in the ISO standard. This improves consumer trust with regards to the reliability, functionality and safety of the MNP products and thus enhance market chances. The project partner micromod Partikeltechnologie GmbH have updated their application brochures to reflect the standardised description of MNP products in their user communication.

·         Manufacturers of products containing MNPs

A considerable part of the European MNP industry relies on superparamagnetic beads containing MNPs for in-vitro diagnostic applications. Although MNPs are in these cases only compartments of complicated high-technology products, their final performance depends also on the magnetic characteristics. The project contributions to the new standard ISO 19807-2 “Specification of characteristics and measurements for nanostructured superparamagnetic beads for nucleic acid extraction” is be of special importance for this industrial group. The project partners are in intensive discussions with a number of European manufacturers to explain the consequences of standardization and to learn about the interests of the manufacturers that should be reflected in the content of the new ISO standard.

·         Other commercial MNP users

These are companies that purchase the MNPs from other sources and apply them for biomedical or technical purposes. They have an interest in the proper specification of the magnetic and other MNP properties and in a clear understanding of what a parameter in a product statement means and how it is measured. A reliable specification of magnetic MNP parameters opens new application fields for MNPs. In addition, the exact definition of MNP parameters is crucial for all regulatory aspects of products or technologies involving these nanomaterials.

This project contributes to a framework enabling marketing of MNPs with an internationally accepted statement on defined and guaranteed magnetic properties.

Impact on the metrology and scientific communities

A significant activity within this project is the input of knowledge and production of content for ISO 19807-1 “Magnetic nanomaterials -- Part 1: Specification of characteristics and measurements for magnetic nanosuspensions’” that will define the important parameters of MNPs and the measurement methods to obtain them. The results of this project enhance the comparability and reliability of scientific reports on MNP properties. The availability of an ISO standard on MNP will support the acceptance of definitions, the consequent usage of SI units, and the implementation of standard operating procedures and a reliable uncertainty analysis, for the most common characterisation methods for MNPs. Noticeably, a recent publication refered to the importance of the new ISO standard in the context of determination of iron concentration (R. Costo, 2018, Opens external link in new windowDOI:10.1007/s00216-018-1463-2). Working in a standardised environment ensures the efficient use of research resources. By providing SOPs for reliable measurement methods, e.g. for the specific loss parameter in magnetic hyperthermia, the project immediately supports the development of new MNP-based therapeutic approaches for fighting cancer. Currently, magnetic hyperthermia using MNPs is being intensively researched as a new tumour therapy. The temperature rise in the tumour tissue during magnetic hyperthermia depends crucially on the specific loss parameter, which is now defined in the draft version of ISO 19807-1. A comparable and precise quantitative determination of this parameter is important for safety and efficacy of the new therapy.

 

Impact on relevant standards

The project has made an immediate impact by helping to initiate a series of standards on magnetic nanomaterials at ISO/TC229. Although ISO is an international organization with members from many countries over the world, it relies on active participation of the experts. MagNaStand members participated since the beginning of the project in three ISO/TC229 meetings and a number of web meetings of the experts on magnetic nanomaterials. They prepared numerous comments of the national standardisation organisations in UK, Sweden, Austria and Germany in order to improve the draft ISO standards on magnetic nanomaterials. This will be the first series on any nanomaterial and this is a direct output of the project. The main impact of this project on the actual standards is the contribution to the finalisation of the draft standards ISO 19807-1 “Magnetic nanomaterials -- Part 1: Specification of characteristics and measurements for magnetic nanosuspensions” and ISO 19807-2 “Magnetic nanomaterials -- Part 2: Specification of characteristics and measurements for nanostructured superparamagnetic beads for nucleic acid extraction”. MagNaStand collaborated closely with the project leader from NPL India in the preparation of ISO 19807-1. For the preparation of ISO 19807-2 PTB has taken over co-leadership at ISO/TC229 WG4, together with an expert from SAC China. Beside of the actual participating countries, the consortium exchanges via email information on the standardisation efforts with the respective NMIs and SDOs in France, Spain and in the Danubian countries (Bulgaria, Croatia, Czech Republic, Hungary, Romania, Slovakia, Slovenia and Serbia).

 

Longer-term economic, social and environmental impacts

An internationally accepted standard on the characteristics of MNPs that reflects both the available scientific knowledge and the needs of industry and society will greatly enhance the application of magnetic nanoparticles. After finalization of the material specification ISO 19807, further standards on specific MNP material and measurement methods, such as the standard on superparamagnetic beads are likely to follow. These further ISO standards will benefit from the scientific research results provided by this project.

Wider economic impact

MNPs already have a wide range of application possibilities, e.g.:

·         to promote the separation of cells, proteins or DNA from biological fluids;

·         to act as therapeutic agents or drug carriers in a number of new cancer therapies;

·         to be used as tracers or labels in biomedical imaging;

·         to support the cleaning of water, waste-water or contaminated soil;

·         to provide magnetic damping in loudspeakers; and

·         to provide vacuum seals as magnetic fluid O-rings for rotary shafts.

A standard document for magnetic nanoparticles will enhance and increase industrial applications by providing safety and reliability in the interaction between the particle manufacturer and the consumer. This safety of operation will open new application areas for MNPs.

Wider social impact

Especially in the biomedical area, patients suffering from cancer or other diseases will benefit from the new therapy approaches based on MNPs like magnetic hyperthermia, magnetic drug targeting or trans-membrane magnetofection of DNA. MNPs are currently being investigated as labels or tracers in several diagnostic modalities like MRI, MPI and others. It is already proven that MNPs can help in the early detection of cancer and inflammatory diseases of the heart, the vessels and other organs. An international standard on MNP characterization and measurement will speed up the development of these procedures while also ensuring the reliability, reproducibility and safety of the MNPs involved. Ultimately this will lead to a better treatment of patients, to the prolonging of life and to maintaining the quality of life of patients.

Wider environmental impact

The trust of consumers in the safety and reliability of new nanomaterial classes is decisive for the wider acceptance of this emerging new nanotechnology. Standardized measurement procedures help to control the safety aspects during synthesis and particle shipment as well as the degradation of the MNPs after their intended use. Standardized characteristics and measurement techniques are needed to monitor the complete life cycle of MNPs.

 

List of publications

Within the first 18 months:

 

1

Coïsson, M., Barrera, G., Appino, C., Celegato, F., Martino, L., Safronov, A. P., Kurlyandskaya, G.V., & Tiberto, P.

Specific loss power measurements by calorimetric and thermal methods on γ-Fe2O3 nanoparticles for magnetic hyperthermia. Journal of Magnetism and Magnetic Materials 473 (2019), 403-409
https://dx.doi.org/10.1016/j.jmmm.2018.10.107

2

Wells, J., Löwa, N., Paysen, H., Steinhoff, U., & Wiekhorst, F.

Probing particle-matrix interactions during magnetic particle spectroscopy. Journal of Magnetism and Magnetic Materials 475 (2019), 421-428

https://dx.doi.org/10.1016/j.jmmm.2018.11.109

3

Paysen, H., Wells, J., Kosch, O, Steinhoff, U, Franke, J, Trahms, L, Schaeffter, T, & Wiekhorst, F.

Improved sensitivity and limit-of-detection using a receive-only coil in magnetic particle imaging. Physics in Medicine & Biology 63 (2018) , 13NT02

https://dx.doi.org/10.1088/1361-6560/aacb87

4

Marks, G., Steinhoff, U., & Wiekhorst, F.

A model for uncertainty influences on static magnetisation measurements on magnetic nanoparticles. Journal of Physics: Conference Series 1065 (2018), 072030

https://dx.doi.org/10.1088/1742-6596/1065/7/072030

5

Spassov, S., Egli, R., Marks, G., and Steinhoff, U.,

Uncertainty Analyses of Static Measurements of Induced Magnetisation. Publications of the Institute of Geophysics, Polish Academy of Sciences; Geophysical Data Bases, Processing and Instrumentation 423 (2018), 145-146

https://dx.doi.org/10.25171/InstGeoph_PAS_Publs-2018-074

6

Wiekhorst, F, Marks, G, Wells, J, and Steinhoff, U.

Metrology and Standardisation of Magnetic Nanoparticles for Biomedical Applications. Biomedical Engineering / Biomedizinische Technik 63 (2018), S261

https://dx.doi.org/10.1515/bmt-2018-6048